how vaccines changed the world essay

REVIEW article

Vaccines through centuries: major cornerstones of global health.

• 1 Department of Biomedical Sciences, Oakland University William Beaumont School of Medicine, Rochester, MI, USA
• 2 Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
• 3 Lebanese Health Society, Beirut, Lebanon
• 4 Department of Experimental and Clinical Neurosciences, University of Palermo, Palermo, Italy

Multiple cornerstones have shaped the history of vaccines, which may contain live-attenuated viruses, inactivated organisms/viruses, inactivated toxins, or merely segments of the pathogen that could elicit an immune response. The story began with Hippocrates 400 B.C. with his description of mumps and diphtheria. No further discoveries were recorded until 1100 A.D. when the smallpox vaccine was described. During the eighteenth century, vaccines for cholera and yellow fever were reported and Edward Jenner, the father of vaccination and immunology, published his work on smallpox. The nineteenth century was a major landmark, with the “Germ Theory of disease” of Louis Pasteur, the discovery of the germ tubercle bacillus for tuberculosis by Robert Koch, and the isolation of pneumococcus organism by George Miller Sternberg. Another landmark was the discovery of diphtheria toxin by Emile Roux and its serological treatment by Emil Von Behring and Paul Ehrlih. In addition, Pasteur was able to generate the first live-attenuated viral vaccine against rabies. Typhoid vaccines were then developed, followed by the plague vaccine of Yersin. At the beginning of World War I, the tetanus toxoid was introduced, followed in 1915 by the pertussis vaccine. In 1974, The Expanded Program of Immunization was established within the WHO for bacille Calmette–Guerin, Polio, DTP, measles, yellow fever, and hepatitis B. The year 1996 witnessed the launching of the International AIDS Vaccine Initiative. In 1988, the WHO passed a resolution to eradicate polio by the year 2000 and in 2006; the first vaccine to prevent cervical cancer was developed. In 2010, “The Decade of vaccines” was launched, and on April 1st 2012, the United Nations launched the “shot@Life” campaign. In brief, the armamentarium of vaccines continues to grow with more emphasis on safety, availability, and accessibility. This mini review highlights the major historical events and pioneers in the course of development of vaccines, which have eradicated so many life-threatening diseases, despite the vaccination attitudes and waves appearing through history.

Introduction

Vaccines constitute one of the greatest success stories within the health sector. They form part of a multifaceted public health response to the emergence of pandemics. This review is general in nature. It highlights the major historical cornerstones in the development and progress of various types of vaccines since the beginning and through the ages until today.

It recognizes the major pioneers whose work has made a difference in the advancement of this vital health field, despite all the anti-vaccination movements that appeared through the ages. Multiple reviews were encountered during our literature search; however, each of those reviews dealt with a specific aspect of vaccination like effectiveness of a particular vaccine, or side effects of another or even attitudes toward vaccines. Consequently, this work tried to put together the major achievements through history stressing the importance, continuous vital role, and the need for immunization for health prevention and protection as well as its impact on human experience.

The physiological mechanisms behind vaccination are well established. Vaccination activates the immune system and induces both innate and adaptive immune responses thus leading to the production of antibodies, in the case of a humoral response, or to the generation of memory cells that will recognize the same antigen, if there is a later exposure. Periodic repeat injections can improve the efficacy and effectiveness of inoculations ( 1 ).

The approval of a vaccine abides by a set of well-established international rules and regulations. Prior to their approval by the respective health authorities, scientists test vaccines extensively in order to ensure their efficacy, safety, and effectiveness. Next to antibiotics, vaccines are the best defense that we have to date against infectious diseases; however, no vaccine is actually 100% safe or effective for everyone. This is attributed to the fact that each body reacts to vaccines differently ( 2 – 4 ). Significant progress has been made over the years to monitor side effects and conduct research relevant to vaccine safety. In addition, vaccine licensing is a lengthy process that may take 10 years or longer. The Food and Drug Administration (FDA) and the National Institute of Health (NIH) require that vaccines undergo the required phases of clinical trials on human subjects prior to any use in the general public. This process is becoming more complex as more caution and care is being allocated to the quality of the market product.

Furthermore, vaccines can be divided into different categories depending on the way that they are prepared including live-attenuated vaccines, inactivated vaccines, subunit vaccines, conjugate vaccines, and toxoids.

Live-Attenuated Vaccines

Live-attenuated vaccines are used more frequently for viruses rather than bacteria, since the former contain a lesser amount of genes and can be controlled more easily ( 5 ). The most common method in formulating live-attenuated vaccines involves passing the virus through successions of cell cultures to weaken it. This will produce a form of the virus that is no longer able to replicate in human cells. However, it will still be recognized by the human immune system, hence protecting the body from future invasions. Examples of such vaccines are measles, rubella, mumps, varicella (more commonly known as chickenpox), and influenza. The disadvantage of using this technique is that the virus may transform into a more virulent form due to a certain mutation and cause illness once injected into the body. Although this rarely occurs, it must always be taken into consideration ( 6 ).

Inactivated Vaccines

By using heat, radiation, or certain chemicals, one can inactivate a microbe. The microbe will no longer cause illness but can still be recognized by the immune system. Poliovirus and Hepatitis A are common examples of inactivated vaccines. This type of vaccine has the disadvantage of being effective for a shorter period of time than live-attenuated vaccines. Multiple boosters of the vaccine are sometimes required to improve effectiveness and sustainability ( 6 ).

Subunit Vaccines

A subunit vaccine contains only portions of the microbe that can be presented as antigens to the human immune system instead of the microbe as a whole. The antigens or the microbe portions that best activate the immune response are usually selected. An influenza vaccine in the form of shots is an example. In addition, a recombinant subunit vaccine has been made for the hepatitis B virus. Hepatitis B genes are injected into maker cells in culture. Once these cells reproduce, the desired antigens of the virus are produced as well, and these can be purified for use in vaccines ( 6 ).

Conjugate Vaccines

Conjugate vaccines are designed from parts of the bacterial coat. However, these parts may not produce an effective immune response when presented alone. Hence, they are combined with a carrier protein. These carrier proteins are chemically linked to the bacterial coat derivatives. Together, they generate a more potent response and can protect the body against future infections. Vaccines against pneumococcal bacteria used in children are an example of conjugate vaccines ( 6 ).

Some bacteria release harmful toxins that cause illness in infected individuals. Vaccinations against such types of bacteria are prepared by inactivating or weakening the toxin using heat or certain chemicals. This will help prepare the immune system against future invasion. The vaccine against tetanus caused by the neurotoxin of Clostridium tetani is a good example of a toxoid ( 6 ).

Vaccination: Its Determinants and Modulation with Age

The generation of vaccine-mediated protection is a complex challenge. Effective early protection is conferred primarily by the induction of antigen-specific antibodies. The quality of such antibody responses has been identified as a determining factor of efficacy. Efficacy requires long-term protection, namely, the persistence of vaccine antibodies and/or the generation of immune memory cells capable of rapid and effective reactivation upon subsequent microbial exposure ( 7 ).

The exponential development of new vaccines raises many questions about their impact on the immune system. Such questions related to immunological safety of vaccines as well as triggering conditions such as allergy, autoimmunity, or even premature death ( 7 ). Such issues were always looked for and monitored and some vaccines were even stopped because of these issues.

Recent vaccine models rely on both a cell-mediated response and a humoral immune response with highly specific antibodies and have shown an adequate amount of success. This, however, has not been the case for a few diseases such as tuberculosis where the humoral immunity mounted by the bacille Calmette–Guerin (BCG), the only currently used human vaccine, is inefficient in conferring proper immunization ( 8 ). However, T cells do take part indirectly in the production of antibodies and of secreted biological molecules (e.g., Interferon) for protection. It seems that a proper mounted immunity is better achieved by vaccine-induced antibodies, whereas a T cell immune response is needed for disease attenuation. Hence, a robust understanding of B and T cell function is needed for proper immunization ( 9 ).

Multiple determinants modulate the primary vaccine antibody response in healthy individuals; they include the vaccine type, live versus inactivated, protein versus polysaccharide, and use of adjuvants ( 10 ). They also include the nature of the antigen and its intrinsic immunogenicity ( 11 ), the dose of the antigen, the route of administration, the vaccine schedule, and the age at administration ( 12 ). In addition, genes play a direct role in the body’s response to vaccination even in healthy individuals ( 13 , 14 ). For each of the above determinants, there might be a particular mechanism involved and is further influenced by other factors including extremes of life, acute or chronic diseases, immunosuppression, and nutrition status ( 12 ).

Early life immune responses are limited by (1) limited magnitude of antibody responses to polysaccharides and proteins, (2) short persistence of antibody responses to protein, (3) influence of maternal antibodies, and (4) limited CD8+ T cell and interferon-gamma responses. Such factors are difficult to study in human infants due to neonatal immune immaturity and the inhibitory influence of maternal antibodies, which increase with gestational age and wane a few months post-natal ( 7 ).

On the other hand, in elderly persons, the immune system undergoes characteristic changes, termed immunosenescence, which leads to increased incidence and severity of infectious diseases and to insufficient protection following vaccination ( 15 ). Vaccines induce both innate (non-specific) and adaptive (specific) immune responses, which decline substantially with age thus leading to the decreased efficacy of vaccines in elderly persons. In the elderly, the innate immune response will witness a reduced phagocytic capacity of neutrophils and macrophages, a decrease in their oxidative burst, and impairment in the up-regulation of MHC class II expression among other parameters ( 16 ). In addition, persistent inflammatory processes occur with increasing age and may reduce the capacity to recognize stimuli induced by pathogens or vaccines. For the elderly, improved special antigen delivery systems are needed to overcome these limitations ( 12 ).

Furthermore, the adaptive immune response is functionally defective in the elderly. The involution of the thymus with aging leads to a decrease in content and in output of mature naïve T cells into the periphery, which hampers the induction of adaptive immune responses to neoantigens. In the context of primary vaccination, this causes reduced response rate ( 7 – 12 ). B cells also undergo age-related changes that aggravate the functionality of B cells colonies. As effector B cells accumulate, naïve B cells decrease in number and this leads to a reduction in the diversity of antibody responses. In brief, vaccines tailored to the needs of the elderly will have to be developed, taking into consideration these limitations in order to improve protection in this population.

Vaccine Efficacy and Effectiveness in the Context of the Translational Research Map

In 2010, Weinberg and Szilagyl eloquently approached the issues of efficacy and effectiveness clarifying the road to correctly answer the relevant but complex question: “How well does the candidate vaccine prevent the disease for which it was developed?” They highlighted clearly the distinction between efficacy (individual level) and effectiveness (population level), which are often confused terms that fit well into the new paradigm of translational research ( 15 ). At about the same time, Curns et al. elaborated on the distinction between the epidemiologic concepts of vaccine efficacy and effectiveness within the context of translational research ( 17 ). Such concepts were also addressed earlier, but slightly differently, by Clemens and co-workers in two separate publications in 1984 and 1996, and also by Orenstein et al. in 1989 ( 18 – 20 ).

Accordingly, vaccine efficacy is measured as the proportionate reduction in disease attack rate when comparing vaccinated and unvaccinated populations. Vaccine efficacy studies always have rigorous control for biases through randomized prospective studies and vigilant monitoring for attack rates ( 15 ). In addition to proportionate reduction in attack rates, these studies can furthermore assess outcomes through hospitalization rates, medical visits, and costs. Despite the complexity and expenses that arise from the initial trials, they are needed to establish vaccine efficacy ( 15 ).

On the other hand, the related but distinct concept of vaccine effectiveness has always been compared to a “real world” view of how a vaccine reduces disease in a population. As such, it can evaluate risks versus benefits behind a vaccination program under more natural field conditions rather than in a controlled clinical trial. Vaccination program efficiency is proportional to vaccine potency or efficacy in addition to the degree and success of immunization of the target groups in the population. In brief, it is influenced by other non-vaccine-related factors that could influence the outcome. The “real world” picture provided by vaccine effectiveness data is desirable in planning public health initiatives, an advantage that makes these studies attractive. Translating research data into real public health application are a process that has been reengineered by the NIH as part of a road map for future research. Consequently, a new expanded definition of translational research, consisting of four steps was proposed, which fits nicely within the continuum of vaccine research ( 21 ). In this new process of phase I to phase IV clinical trials, safety, immunogenicity, efficacy, and post-licensure effectiveness of a particular vaccine are assessed ending up in phase IV with the burden of the disease ( 15 ).

Vaccines stood the test of time and many techniques have been introduced into the world of vaccination. Practitioners used to write articles about their vaccinating instruments and techniques. According to John Kirkup, vaccinators and physicians used various instruments and techniques to inject the vaccinating material into the human body. More than 45 different vaccinating instruments have been recorded in British, American, German, and French catalogs between the years 1866 and 1920; most of them are out of use nowadays ( 22 ).

Beginning of Vaccines

There are multiple major landmarks in the history of vaccines. It was reported that the origin goes as far back as Hippocrates, the father of modern medicine, 400 B.C. He described mumps, diphtheria, and epidemic jaundice among other conditions ( 23 ). The earliest methods of immunization and protection against smallpox date back to about 1000 A.D., and are attributed to the Chinese. It has been said that the son of a Chinese statesman was inoculated against smallpox by blowing powdered smallpox sores into his nostrils ( 24 ). Another method used for inoculation was the removal of fluid from the pustules of an infected individual and subsequently rubbing it into a skin scratch of a healthy individual. This procedure was later introduced into Turkey around 1672, long before reaching Europe ( 25 ). It took six centuries for variolation to be introduced to Great Britain, in 1721 ( 26 ).

Through the Eighteenth Century

The eighteenth century was marked by several major events that started with the spread of variolation from Turkey and China to England and America, followed, in the late eighteenth century, by Edward Jenner’s breakthrough of vaccination.

Variolation from Turkey to England

Variolation, derived from the Latin word varus , meaning “mark on the skin,” or inoculation, derived from the Latin word inoculare , meaning “to graft,” are two words that were used interchangeably in describing the aforementioned immunization process. By 1715, variolation was introduced to England after the pursuit of an English aristocrat, Lady Mary Wortley Montague, who had been personally inflicted with an episode of smallpox. After being informed of the method of variolation, she made the embassy surgeon, Charles Maitland, perform the procedure on her 5-year-old son in 1718 in Turkey. In 1721, Dr. Charles Maitland performed the first English variolation on Lady Montague’s 4-year-old daughter after their return to London ( 27 ).

Lady Montague became a great proponent of the procedure and worked thoroughly on advocating this process for its ability to protect against the spread of smallpox.

Data from the U.S. National Library of Medicine and the NIH showed that 1–2% of those variolated died as compared to 30% of those who contracted the disease naturally. Correspondingly, Rev. Cotton Mather and Dr. Zabdiel Boylston introduced variolation in America and were also great advocates of this procedure especially since, in the same year, there was a smallpox epidemic in Boston that killed hundreds ( 28 ). However, Lady Montague, Rev. Mather, and Dr. Boylston faced great opposition regarding their promotion of variolation even with the presentation of the comparative analysis of fatality rates, which reached 2% for those variolated compared to 14% for the naturally occurring disease ( 27 ).

Spreading the Word

Despite some variolation-related deaths, the word of inoculation kept spreading along with data suggesting that variolation was still the safeguard against the spread of smallpox. In addition, Benjamin Franklin, who lost his son in 1736, wrote: “I long regretted that I had not given it to him by inoculation, which I mention for the sake of parents who omit that operation on the supposition that they should never forgive themselves if a child died under it; my example showing that the regret may be the same either way, and that therefore the safer should be chosen” ( 24 ). In 1759, Dr. William Heberden, at his own expense and with the support of Benjamin Franklin, wrote a pamphlet entitled “Some Account of the Success of Inoculation for the Small-Pox in England and America: together with plain instructions by which any person may be enabled to perform the operation and conduct the patient through the distemper” ( 29 ).

Edward Jenner’s Breakthrough

Toward the late eighteenth century came Jenner’s breakthrough in finding a safer immunizing technique than variolation, which is vaccination.

The method of variolation had low yet significant death rates; therefore, physicians were on the quest of finding a new and more secure method of immunization with minimal or no death rates. On this basis, an English physician named Edward Jenner (1748–1823) searched for a cure for smallpox, a debilitating disease that rendered the world helpless. Jenner became interested in certain individuals who were immune to smallpox because they had contracted cowpox in the past. He personally witnessed this when he learned of a dairymaid that was immune to smallpox due to her previous infection with the cowpox virus, usually transmitted from infected cattle. During that time, an English farmer named Benjamin Jesty personally took charge of inoculating his wife and children with fresh matter from a cowpox lesion in one of his cows out of fear of having his wife and children become victims of the smallpox epidemic. He applied this method after having contracted cowpox himself and believing he was immune to smallpox. He never published his results even though his wife and children did not show symptoms after being exposed to smallpox ( 27 ). During these years, there were still outbreaks of smallpox. George Washington, after surviving smallpox, ordered mandatory inoculation for his troops in 1777 ( 27 ).

After many speculations on the role of cowpox and its immunizing effect against smallpox, Jenner, in 1796, inoculated an 8-year-old boy named James Phipps using matter from a fresh cowpox lesion on the hands of a dairymaid named Sarah Nelms who caught them from her infected cattle. After several days, Jenner inoculated the boy again but this time with fresh matter from a smallpox lesion and noted that the boy did not acquire the disease proving that he was completely protected ( 27 ). A few years later, word of his success circulated among the public, and Jenner wrote “ An Inquiry into the Causes and Effects of the Variolae Vaccinae, a Disease Discovered in some of the Western Counties of England, particularly Gloucestershire and Known by the Name of CowPox ,” after adding several cases to his initial achievement with the boy Phipps. At first, his publication and achievement did not stir any interest in his community, but with time, word of Jenner’s breakthrough began spreading ( 27 ).

The late eighteenth century was characterized by the implementation of the new process of immunization, vaccination, which required the inoculation of fresh matter from cowpox lesions into the skin of healthy individuals.

Through the Nineteenth Century

The nineteenth century was a major landmark in the history of vaccines since it witnessed discoveries made by Louis Pasteur, the father of microbiology, and Robert Koch, the scientist who discovered the germ responsible for tuberculosis ( 26 ).

Vaccination Versus Variolation

In the beginning of the nineteenth century, the term “Vaccination” was introduced by Richard Dunning from the Latin word for cow “Vacca.” After becoming aware of the fact that vaccination was more secure than variolation, several physicians initiated movements against the use of variolation and advocated for its eradication. Dr. Jean de Carro, for example, aided in the elimination of variolation and its substitution with vaccination. Some of the major efforts implemented in America were initiated by Dr. Benjamin Waterhouse, who received the vaccine from Edward Jenner and vaccinated his own family. He later proved that they acquired immunity when they remained asymptomatic after he infected them with smallpox. Waterhouse worked effectively on making vaccination universal in the U.S. Unfortunately, like any other medical breakthrough, problems arose both because Waterhouse aimed at making profit and the public was not ready to implement these procedures. However, after breaking his initial monopoly, Waterhouse accepted to share his vaccines and made the supplies available to other physicians ( 24 ). Despite all these efforts, smallpox epidemics continued to occur and Jenner stated in a pamphlet that he wrote, “The annihilation of the small pox, the most dreadful scourge of the human species, must be the final result of this practice.” Eradication was finally achieved 176 years later. The time it took could be attributed to the fact that Jenner did not think of the necessity of revaccination nor of the instability of vaccines, which made them unable to handle different environmental conditions, including countries other than England ( 30 ).

The late nineteenth century was distinguished by Pasteur’s achievements that made him the father of vaccines after creating the first laboratory vaccine. Louis Pasteur (1822–1895), a French chemist and microbiologist, was the first to propose the “Germ Theory” of disease in addition to discovering the foundations of vaccination ( 26 ). He studied chicken cholera and received strains of bacteria causing anthrax and septic Vibrio . Pasteur started his experiments by intentionally infecting chickens by feeding them cholera-polluted meals and then recording the fatal progression of the illness. At first, Pasteur was using fresh cultures of the bacteria to inoculate the chickens, most of which did not survive. During that time, Pasteur had to go on a holiday, so he placed his assistant in charge of injecting the chickens with fresh cultures. However, his assistant accidentally forgot to perform the injections, and the bacterial cultures were left in a medium that was exposed to room air for about a month. Later, the attendant injected the chickens with the now “attenuated” strain of bacteria resulting in mild, non-fatal symptoms. Pasteur later re-injected these chickens, but this time with fresh bacteria. To his surprise, they did not get ill. Ultimately, Pasteur reasoned that what made the bacteria less deadly was exposure to air, mainly oxygen. Pasteur used the French verb “vacciner” during the years 1879 and 1880 to describe how he was able to provide total body immunity through vaccination by inoculation of an attenuated virulence which was the first vaccine made by a human in the laboratory ( 31 ).

Pasteur also developed the anthrax vaccine in his laboratory, not long after performing his studies on chicken cholera. In 1881, Pasteur used his own anthrax vaccine, which contained attenuated live bacterial cultures in addition to carbolic acid, and demonstrated that all vaccinated animals survived while the control group died ( 32 ). During the same year, Louis Pasteur in France and George Miller Sternberg in the U.S. almost simultaneously and independently isolated and grew the pneumococcus organism. Later in 1884, Pasteur successfully fought rabies that was endangering the European livestock by using his attenuated rabies vaccine obtained from desiccated brain tissue inactivated with formaldehyde, which provided immunity to dogs against rabies in his experiments ( 26 ). He reported his success to the Academy of Sciences in France, and a year later, he applied his original vaccine 60 h after a 9-year-old boy was bitten several times by a rabid dog. The boy survived after being first inoculated with the most attenuated organisms, then subsequently with less attenuated organisms each day for 10 days ( 33 ). In 1888, the Pasteur Institute was established as a rabies treatment center as well as an infectious diseases research and training institute.

From Live Vaccines to Killed Vaccines

After Pasteur’s successful live vaccines, a new type of vaccine was introduced in the last few years of the nineteenth century. These were killed vaccines, which were directed against three chief bacterial causes of human morbidity: cholera, typhoid, and the plague. The first cholera vaccine used to immunize humans was actually a live vaccine developed by Jaime Ferran (1852–1929), which provided a high level of protection during the 1884 epidemic in Spain. However, the first killed vaccine for cholera was developed in 1896 by Wilhelm Kolle (1868–1935) and was used in Japan in 1902 with over 80% efficiency. The credit for developing the killed typhoid vaccine during the 1890s goes to both Richard Pfeiffer and Almroth Wright who made great contributions. Wright was later credited for carrying out the “first large-scale vaccination using a killed typhoid vaccine” ( 34 ). Finally, the killed vaccine for plague was first developed in 1896 by Haffkine, who was one of Pasteur’s followers, when an epidemic struck Bombay.

Late Nineteenth and Twentieth Century

During this period, vaccine production was taken over by factory-type laboratories, which formed the precursors of the biological products supply houses. Many types were produced.

Paul Ehrlich (1854–1915), a German physician and scientist who worked under a contractual collaboration with Behring, noted the existence of toxoids in the late 1890s. He also promoted enrichment and standardization protocols. These protocols enabled the exact determination of quality of the diphtheria antitoxins. In 1907, it was demonstrated that toxoids could be used to durably immunize guinea pigs. It is crucial to briefly address the historical background of the bacterial infections that led to some of the earliest and most successful use of toxoids, inactivated forms of bacterial toxins, for the purpose of immunization. Until the twentieth century, diphtheria, tetanus, and pertussis proved to be significant causes of illness and death with no effective treatments or prevention in sight. Fortunately, advances in 1890 improved the prognosis of numerous future patients ( 35 ). At the end of the nineteenth century, especially in 1896 and 1897, the cholera and typhoid vaccines were developed, followed by the introduction of the plague vaccine. The latter was preceded by the preparation of anti plague horse serum at the Pasteur Institute by Alexandre Yersin.

Yersin demonstrated disease protection in animals. Later, he went to China to try his vaccine on humans during a plague epidemic ( 26 ).

Diphtheria is a potentially fatal disease that primarily involves tissues of the upper respiratory tract and kills its victims slowly by suffocation. In 1884, a German physician, Edwin Klebs (1834–1913), was able to successfully isolate the bacteria that proved to be the etiological agent of the disease. It was later proved that toxin production is initiated only after the bacteria are themselves infected by a specific virus or a bacteriophage carrying the toxin’s genetic instructions ( 35 ).

In France, during the year 1888, Emile Roux discovered the diphtheria toxin. His discovery led to the development of passive serum therapies through the scientific contributions of many, including Emil Von Behring and Paul Ehrlich ( 26 ). Similarly, the etiological agent of Pertussis, commonly known as the “whooping cough,” was found to be a bacterium isolated from infected patient tissues in 1906 ( 36 ). Tetanus was similarly a significant cause of mortality usually resulting from dysfunction of the autonomic nervous system or the respiratory muscles ( 37 ). In 1884, another German scientist, Arthur Nicolaier (1862–1942), correlated tetanus with an anaerobic soil bacterium found in wounds. A few years later, the Japanese investigator Shibasaburo Kitasato (1853–1931) was able to isolate this bacterium ( 35 ). At the beginning of World War I in 1914, the tetanus toxoid was introduced following the development of an effective therapeutic serum against tetanus by Emil Von Behring and Shibasaburo Kitasato. The rabies and typhoid vaccines were then licensed in the U.S. as the etiology of these destructive diseases was slowly being uncovered, by Shibasaburo Kitasato along with Emil von Behring ( 26 ). They discovered that the serum of animals that had been exposed to sub-lethal doses of the bacteria involved in tetanus and diphtheria was protective against the lethal effects associated with these pathogens by having an antitoxin effect when injected into another animal. Additionally, this discovery, which earned Behring the inaugural Nobel Prize for Physiology and Medicine in 1901, was the concept of passive transfer in addition to serum therapy. He proved that serum could be acquired from immune animals and transferred to others as protection ( 38 ). Once this concept made its way to clinical practice in 1891, technical problems were faced while developing the right antitoxin concentration and potency. As a result, in the early twentieth century, the U.S. Congress enacted the Biologics Control Act legislation “to regulate the sale of viruses, serums, toxins, and similar products” to ensure medication quality control. Nevertheless, with the increasing use and popularity of antitoxins derived from animal serum, scientists began to observe a syndrome now called serum sickness, or a reaction to immune-complexes formed from combining high concentrations of antigens with antibodies. This eventually led to the use of human rather than animal serum in order to decrease the frequency of adverse events; still, serum therapy was not perfect in preventing disease due to the frequency of adverse events and its brief duration of action. Later on, combining diphtheria toxin and antitoxin in the same syringe proved much more effective in decreasing mortality rate. This combination became commercially available in 1897. This was the first step in the shift from passive to active immunization ( 35 ). In 1923, Gaston Ramon (1886–1963), a French veterinarian working at the Pasteur Institute, used a diphtheria toxoid produced by formalin and heat inactivation without the use of antitoxin to safely induce active immunity in humans. This product, termed anatoxine, was the basis for the novel and clinically effective toxoid vaccine against diphtheria. Experiments followed to improve the durability of the protective response of the vaccine, and in 1926, the importance of aluminum salts as an adjuvant added to the vaccine to augment the immune response to the antigen, became apparent ( 38 ). This was discovered by Alexander Thomas Glenny (1882–1965) who proved that toxoid alone produced a lower level of antibody and immunity than desired, whereas better immunity was achieved when an inflammatory reaction was triggered. With these significant improvements, tetanus and diphtheria toxoids became routinely used across America and Europe in the 1930s and 1940s ( 35 ).

Since then, refinements have been made to these vaccines to yield higher purity and reduce the number of booster doses. Nowadays, widespread childhood vaccination is reducing the burden of these diseases. While this is a huge advantage, vaccines may potentially produce adverse effects that can discourage their acceptance by some populations. This has led to numerous safety movements which culminated in the congressionally legislated National Childhood Vaccine Injury Act in the 1980s created to compensate families for selected adverse events potentially related to mandatory childhood vaccinations ( 37 ). Nevertheless, global recommendations continue to call for routine immunization of children against diphtheria, tetanus, and pertussis with the combined DTP vaccine to sustain immunity in childhood and adolescence. DTP has, therefore, become one of the most widely used vaccines to achieve widespread immunity across age groups ( 35 ).

Tuberculosis and BCG

Tuberculosis, otherwise known as the “Great White Plague,” is another disease that started spreading as an epidemic once industrialization began. This disease caused approximately 15% of deaths in the eighteenth and nineteenth centuries across all socioeconomic groups ( 39 ).

A French physician named Jean Antoine Villemin (1827–1892) demonstrated that the mode of transmission of disease is through the respiratory system. Robert Koch (1843–1910), known as the founder of modern bacteriology, revealed in 1882 that the causative agent of the disease is Mycobacterium tuberculosis , which later became known as Koch’s bacillus ( 40 ). Following this discovery, Koch created what later came to be known as Koch’s postulates, which listed the criteria necessary for proof of bacterial causality: “the organism must be present in diseased tissues; it must be isolated and grown in pure culture; and the cultured organisms must induce the disease when inoculated into healthy experimental animals” ( 39 ).

In 1908, two bacteriologists working in the Pasteur Institute in Lille, Albert Calmette (1863–1933) and Camile Guerin (1872–1961), announced their discovery of Mycobacterium bovis , which is a strain of tubercle bacilli that could be used to create a vaccine against tuberculosis. This occurred after it became evident that different forms of the bacterium were required to prevent or treat tuberculosis, including non-pathogenic, attenuated, or killed tubercle bacilli from different sources, including human, bovine, and equine. This strain had an attenuated virulence while maintaining its antigenicity and became known as BCG ( 40 ).

Bacille Calmette–Guerin vaccinations proved to be successful in animal studies in 1921 and were soon used as an oral vaccine to immunize humans against tuberculosis. In 1927, the BCG vaccine, constituted by the live-attenuated M. bovis , was first used in newborns. It has become the most widely administered of all vaccines in the WHO Expanded Program for Immunization, but has been estimated to prevent only 5% of all potentially vaccine-preventable deaths due to tuberculosis ( 26 ). Despite its imperfections, BCG remains the only effective vaccination for protection against human tuberculosis ( 39 ).

Yellow Fever

Yellow fever is a highly fatal infection caused by a small, enveloped, single-stranded RNA virus and results in renal, hepatic, and myocardial injury, along with hemorrhage and shock ( 41 ). Unlike previously mentioned diseases, the history of yellow fever is highly uncertain and filled with misconceptions. Early work on immunization against the disease began with Carlos Finlay (1833–1915) in the 1870s and 1880s when Koch’s postulates were becoming increasingly accepted. Finlay proposed that mosquitos carried the yellow fever “germ.” He attempted to prove it by feeding mosquitos that had fed on yellow fever patients. However, it was later revealed that his process failed due to the lack of an incubation period within the mosquito, which is a transmission requirement that Finlay was unaware of ( 42 ).

Since 1900, significant advances have been made in creating a vaccine by the Yellow Fever Commission, which was originally led by Walter Reed (1851–1902) along with Jesse Lazear, Aristedes Agramonte, and James Carroll. Reed’s experiments took Finlay’s discovery one step further by adding an incubation period of approximately 2 weeks and achieved the same positive results. When mosquitos bite non-immune individuals after feeding on individuals who had yellow fever, none of the non-immune subjects died and very few suffered disease. This led the Commission of investigators to a major discovery, namely, the identification of the Asibi strain, which is the parent strain of the present 17D vaccine, obtained via continuous indirect passage through the Aegypti mosquitos and direct passage through monkeys. In addition to identifying the etiological agent of the disease, the Commission also identified rhesus monkeys as susceptible hosts, hence providing a means for testing future vaccine attempts. This paved the way for Max Theiler and other Rockefeller Foundation scientists to develop a successful live-attenuated vaccine for yellow fever in 1937. “The most important experimental passage series – designated 17D – used a virus that had been subcultured eighteen times in whole mouse embryos, followed by 58 passages in whole-minced chick embryo cultures, after which the virus was passed in minced chick embryo depleted of nervous tissue.” Theiler himself was actually one of the first individuals to be successfully vaccinated. The vaccine was quickly implemented, and alternative vaccines shown to be more dangerous were discontinued ( 42 ).

Influenza has proved to be very difficult to trace back in history due to its non-specific symptoms and features. It was not until the early twentieth century that influenza outbreaks began to be systematically studied due to well-documented clinical descriptions and epidemiological data. In 1918, the “Spanish flu” influenza pandemic was responsible for 25–50 million deaths worldwide and more than one-half million in the U.S. This virus was unusual because it spread so quickly, was so deadly ( 26 ). Richard E. Shope (1901–1966), a physician who conducted his research in the Department of Animal Pathology at The Rockefeller Institute in Princeton, was the first to isolate influenza virus; a member of the orthomyxovirus family, from a mammalian host in 1931 ( 43 ). He was able to induce the syndrome of swine influenza in pigs by applying respiratory secretions intranasally. He also isolated a bacterium from the respiratory tract of infected pigs called Haemophilus influenzae suis . When this bacterium was combined with a filterable agent and inoculated, the pigs developed the clinical manifestations of swine influenza. These two agents seemed to act synergistically with the virus to damage the respiratory tract hence creating the suitable environment needed for the virus to exercise its pathological effects. In 1933, scientists from the British National Institute for Medical Research including Christopher Andrews, Wilson Smith, and Patrick Laidlaw successfully isolated and transmitted the influenza virus from humans. Throughout this year, “Burnet has successfully cultivated the organism in chick embryos; other influenza types had been recognized; neutralizing antibodies had been identified and quantitated; and viral surface glycoproteins, H and N had been described” ( 43 ).

These discoveries led scientists to introduce the inactivated vaccine in the mid-1940s that is still used to this day ( 44 ). The influenza A/B vaccine was initially presented to the Armed Forces Epidemiological Board in 1942. It was licensed following the war and used for civilians in 1945 in the U.S. Starting 1985, a series of vaccines were licensed for Haemophilus influenza type b (Hib) polysaccharide vaccines. These vaccines are recommended routinely for children at 15 and 24 months of age. The vaccine was, however, not consistently immunogenic in children <18 months of age. In 1987, the protein-conjugated Hib vaccine was licensed and in the next 2 years, it became available. During 1996, a combined vaccine Hib conjugate and Hepatitis B was licensed. Later on, in 2003, the first nasally administered influenza vaccine was licensed. This live influenza A and B virus vaccine was indicated for healthy, non-pregnant persons ages 5–49 years. The contracts to develop vaccine against the H5N1 avian influenza virus were awarded to Aventis Pasteur and to Chiron in 2004. During the following year, an inactivated, injectable influenza vaccine was licensed. It was indicated for adults 18 years of age and older.

During the same year, the FDA approved Afluria, a new inactivated influenza vaccine, for use in people aged 18 years and older. Two years later in 2009, the Department of Health and Human Services, supported the building of a facility to manufacture cell-based influenza vaccine. It also directed toward development of a vaccine for novel influenza A (H1N1). During the same year, the FDA approved four vaccines against the H1N1 influenza virus high-dose inactivated influenza vaccine (Fluzone High-Dose) for people aged 65 years and older. In 2012, the FDA approved several vaccines: HibMenCY a new combination of meningococcal and Hib vaccine for infants; Flucelvax, which is the first seasonal influenza vaccine, manufactured using cell culture technology and a quadrivalent formulation of Fluarix ( 26 ).

Unfortunately, one of the difficulties in dealing with influenza is the continuous mutability of the viral genome necessitating annual reassessments and reformulations of the vaccine. This has led to a suboptimal effectiveness of influenza vaccines, which are only successful against strains included in the vaccine formulation or strains of homogenous subtype. Several pandemics were caused by the influenza virus: during the years 1957–1958, The “Asian” influenza pandemic caused by H2N2 influenza virus resulted in an estimated 70,000 deaths in the U.S. alone and in the years 1968–1969, the “Hong Kong” influenza pandemic caused by an H3N2 influenza virus induced roughly 34,000 deaths in the U.S. ( 26 ). Future studies should focus on producing vaccines protective against variant strains and creating surveillance systems to detect novel strains in time to formulate the proper vaccines.

Poliomyelitis

Poliomyelitis, or Polio, is an intestinal infection spread between humans through the fecal–oral route. It is a disease of the developed nations striking younger individuals most frequently in warmer weather. One of the most famous polio victims, President Franklin D. Roosevelt, founded the National Foundation for Infantile Paralysis in 1938, later known as the March of Dimes ( 26 ). It is well established that better hygiene decreases childhood exposure to the disease, when infection would usually be milder since protective maternal antibodies are present ( 45 ). In 1954, the Nobel Prize in Medicine was awarded to John Enders, Thomas Weller, and Fredrick Robbins for their discovery of the ability of poliomyelitis viruses to grow in tissue cultures ( 26 ). Two major lifelong competitors were involved in the race for the Polio vaccine, Jonas Salk (1914–1995) and Albert Sabin (1906–1993). Salk took a more traditional route using a killed-virus approach, which did not involve natural infection in acquiring immunity. Instead, his approach involved a fully inactivated virus that still had the ability to induce protective antibodies. Sabin, on the other hand, set out to create a live-virus vaccine based on the belief that this would trigger natural immunity and provide a lasting protection. Salk had speed, simplicity, and safety on his side since a killed-virus did not have the ability to revert to virulence, whereas the live-virus vaccine could be given orally, establish longer lasting immunity, and offer passive vaccination through the excreted weakened virus potentially immunizing a large portion of non-vaccinated communities ( 46 ).

Not surprisingly, Salk’s vaccine was the first to make it to the population. Following successful clinical trials in 1954, six companies began mass production of the vaccine. Unfortunately, Salk’s vaccines were soon suspended and recalled when contaminated samples were found in the market due to poor monitoring and control in some laboratories leading to serious health consequences and national panic. The first Cutter polio vaccine incident was reported on April 25, 1955 with 5 more cases reported just a day later with the number eventually rising to 94 of those vaccinated and in 166 of their close contacts. On April 27, the Laboratory of Biologics Control requested that Cutter Laboratories recall all vaccines and the company did so immediately. On May 7, the Surgeon General recommended that all polio vaccinations be suspended pending inspection of each manufacturing facility and thorough review of the procedures for testing vaccine safety. The investigation found that live polio virus had survived in two batches of vaccines produced by Cutter Laboratories. Large-scale polio vaccinations resumed in the fall of 1955 ( 26 ). At the same time, Sabin had been making great advances with his live-virus vaccine since 1951. After successful clinical trials conducted in the Soviet Union that left polio virtually wiped out with no safety issues, it soon became the vaccine of choice in the West. The Polio Vaccination Assistance Act was enacted by Congress and was the first federal involvement in immunization activities. It allowed Congress to appropriate funds to the Communicable Diseases Center [later the Centers for Disease Control and Prevention (CDC)] to help states and local communities acquire and administer vaccines. At the beginning of the 1960s, the oral polio vaccine types 1, 2, and 3 as well as the trivalent product were licensed in the U.S. The first 2 were developed by Sabin and grown in monkey kidney cell culture, while the trivalent oral polio was developed to improve upon the killed Salk vaccine ( 26 ). As a result, in the late 1990s, the CDC recommended switching back to Salk’s killed-virus polio vaccine, while the WHO also advocated the switch for polio-free nations and the continued use of the favored live-virus vaccine for routine immunization ( 45 ).

The last two cases of wild type polio were reported in an unvaccinated Amish in 1979 and in a 5-year-old boy from Peru in 1991 ( 26 ). In 1990, the enhanced-potency inactivated poliovirus vaccine was licensed.

Measles, Mumps, and Rubella

Following successful developments in the polio vaccine, attention soon shifted to three other common viral diseases of childhood: measles, mumps, and rubella.

The measles virus is an RNA virus from the genus Morbillivirus belonging to the Paramyxooviridae family. It causes an acute illness that includes fever, cough, malaise, coryza, and conjunctivitis, in addition to a maculopapular rash. In general, measles is a mild disease but, like many others, has the potential to cause serious complications. In addition, measles is known to be one of the most contagious human diseases causing major outbreaks to occur very often. Until the year 2000, measles was still the leading cause of vaccine-preventable childhood deaths worldwide ( 47 ).

John Enders (1897–1985), known as the “Father of Modern Vaccines” had a particular interest in revealing the virus responsible for measles. He isolated the Edmonston strain of the virus in 1954, which was named after the child from whom it was isolated. A formalin-inactivated measles virus vaccine derived from this strain was subsequently licensed in the U.S. in 1963. However, following the discontinuation of this vaccine in 1967 due to short-lived and incomplete immunity, over 20 further attenuated vaccines were developed and used throughout the world, most of which were also derived from the Edmonston strain ( 48 ). The first live-virus measles vaccine, Rubeovax, was licensed in 1963. Other live-attenuated virus measles vaccines were eventually licensed in the U.S. in 1965. The recommended age for routine administration was changed from 9 to 12 months of age.

The first national measles vaccine campaign was launched in 1966. The world recorded a 90% decreased incidence compared to the pre-vaccination years. In 1968, a second live, further attenuated measles virus vaccine was also licensed. In 1989, both the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP) issued recommendations for a routine second dose of the measles vaccine. During the mid-to-late 1980s, a high proportion of reported measles cases were in school-aged children (5–19 years) who had been appropriately vaccinated. These vaccine failures led to new national recommendations of a second dose of measles-containing vaccine ( 26 ).

Mumps is another acute viral illness. It is the only virus known to cause epidemic parotiditis in humans accompanied by fever, anorexia, headache, and malaise. K. Habel and John Enders isolated the virus in 1945 ( 26 ), and trials of formalin-inactivated mumps vaccine in humans began the same year by Joseph Stokes and colleagues and by Enders. This approach was abandoned in the 1950s due to short-lived immunity, and work began to develop live-attenuated mumps vaccines in 1959 by the vaccinologist Maurice Hilleman (1919–2005) and colleagues ( 48 ). Hilleman isolated the wild type virus from his daughter, Jeryl Lynn, who contracted the virus at the age of 5 and was recovering from it. It became known as the Jeryl Lynn strain of mumps virus. The mumps live-virus vaccine was licensed in December 28, 1967 ( 26 ). Trials with this attenuated virus resulted in 100% protective efficacy and the vaccine was licensed in the U.S. in 1967. This strain is still used to produce mumps vaccines until this day. It is given as part of the measles, mumps, and rubella (MMR) vaccine ( 49 ).

Rubella is a rash disease in children and adolescents caused by a filterable virus. It poses a severe threat to pregnant women and their children by potentially causing congenital deafness and cataracts. In 1964, a rubella epidemic swept the U.S. resulting in 12.5 million cases of rubella infection, with an estimated 20,000 newborns having congenital rubella syndrome (CRS), along with fetal and neonatal deaths in the thousands ( 26 ). The rubella virus was detected and isolated by two groups of scientists, Thomas Weller and Franklin Neva at Harvard Medical School, in addition to Paul Parkman and colleagues at the Walter Reed Army Institute of Research (WRAIR). Similar to measles and mumps, inactivated whole virus vaccines proved ineffective, so efforts turned to discovering a live-attenuated vaccine ( 26 ).

In 1963, Paul Parkman left WRAIR and joined Harry Meyer Jr. at the NIH Division of Biological Standards, and the pair developed the first live-attenuated rubella vaccine in 1966, HPV-77, which was subsequently included in the initial MMR vaccine used in the U.S. in the 1970s ( 26 ). Maurice Hilleman discovered the superior RA 27/3 vaccine that became the only vaccine used outside of Japan starting in the late 1970s. This vaccine maintained its preference due to many factors including increased durability and harmlessness to fetuses of inadvertently vaccinated pregnant women ( 47 ). In 1969, three rubella virus strains were licensed in the U.S.: HPV-77 strain grown in dog-kidney culture, HPV-77 grown in duck-embryo culture, and Cendehill strain grown in rabbit-kidney culture. A decade later, in 1979, the RA 27/3 (human diploid fibroblast) strain of rubella vaccine (Meruvax II) by Merck was licensed. All other strains were discontinued. Merck’s combined trivalent MMR as well as the combined measles and rubella vaccine (M-RVax) developed by Maurice Hilleman and colleagues, was licensed by the U.S. government in 1971 ( 26 ), and is still in use today. Moreover, the age for routine vaccination with MMR vaccine was changed from 12 to 15 months in the year of 1976. The next vaccine that combined measles, mumps, rubella, and varicella antigens (Proquad) was licensed in 2005. It was indicated for use in children 12 months to 12 years. In response to the association of this vaccine with autism, in 2004, the eighth and final report of the Immunization Safety Review Committee was issued by the Institute of Medicine concluded that the body of epidemiological evidence favors rejection of a causal relationship between the MMR vaccine and autism ( 26 ). Combination vaccines hold many advantages including reduced need for several injections, therefore, reducing the incidence of vaccination site reaction ( 48 ).

The etiological agent of clinical hepatitis, identified by its distinguishing yellow jaundice, was found to be infectious in the early 1900s. The different hepatitis strains, A and B, were first differentiated in 1942 ( 26 ). In the mid-1960s, Blumberg and co-workers and Prince discovered hepatitis B surface antigen in the circulating blood of carriers of the infection. Deinhardt et al. soon followed this discovery with that of the hepatitis A virus ( 49 ). Provost et al. successfully prepared a killed hepatitis A vaccine in 1986, which proved to be safe and highly effective in extensive clinical trials. The first inactivated hepatitis A vaccine (Havrix) was licensed in 1995. The following year, a second inactivated vaccine (Vaqta) also became available ( 50 ).

Hepatitis B, on the other hand, rarely causes any severe risk as a primary infection. However, those who develop a chronic persistent infection may continue to have severe disease for the rest of their lives. This may even lead to cirrhotic destruction of the liver due to host immune response to the virus. The discovery of the surface antigen particles of the hepatitis B virus by Blumberg and colleagues in the plasma of human carriers was followed by attempts to create a vaccine. In 1968, a killed hepatitis B vaccine was developed and clinical trials began in 1975 proving the safety and efficacy of the vaccine. Merck and Pasteur Institute subsequently independently licensed the plasma-derived vaccine in 1981 ( 50 ). On July 23rd 1986, the recombinant hepatitis B vaccine (Recombivax HB) was licensed. Using recombinant DNA technology, Merck scientists developed a hepatitis B surface antigen subunit vaccine. Three years later, on August 28th 1989, the recombinant hepatitis B vaccine (Engerix-B) was licensed. A decade later in 1999, the FDA approved a two-dose schedule of hepatitis B vaccination for adolescents 11–15 years of age using Recombivax HB (by Merck) with the 10-μg (adult) dose at 0 and 4–6 months later. At the beginning of the new millennium, in 2001, a combined hepatitis A inactivated and hepatitis B (recombinant) vaccine, Twinrix was licensed. The following year, a vaccine combining diphtheria, tetanus, acellular pertussis, inactivated polio, and hepatitis B antigens (Pediarix) was licensed ( 26 ). In conclusion, fortunately, both hepatitis A and B are now preventable due to the discovery of these highly effective vaccines that proved to maintain long-term immunity in vaccinated individuals ( 50 ).

MID Twentieth and Twenty-First Century

In 1966, the World Health Assembly called for global smallpox eradication, which was launched the following year. During the first year of the program 217,218 cases of polio were reported in 31 countries that were endemic to smallpox. Four years later, the CDC recommended discontinuation of routine vaccination for smallpox in the U.S. following a greatly reduced risk of disease ( 26 ).

During the 70s, especially in 1974, the Expanded Program on Immunization was created within WHO, in response to poor immunization levels in developing countries (<5% of children in 1974). The following vaccines were used by the Expanded Program on Immunization: BCG, Polio, DTP, measles (often MMR vaccine), yellow fever (in endemic countries), and hepatitis B. Three years later, in October 1977, the last case of naturally acquired smallpox occurred in the Merca District of Somalia. In the same year, the first pneumococcal vaccine was licensed, containing 14 serotypes (of the 83 known serological groups) that composed 80% of all bacteremic pneumococcal infections in the U.S. ( 26 ).

On May 8 1980, the World Health Assembly declared the world free of naturally occurring smallpox. On the other hand, in July 1983, two enhanced pneumococcal polysaccharide vaccines (Pneumovax 23 and Pnu-imune 23) were certified. These vaccines included 23 purified capsular polysaccharide antigens of Streptococcus pneumoniae and replaced the 14-valent polysaccharide vaccine licensed in 1977. A few years later, in 1988, the World Health Assembly passed a resolution to eradicate polio by the year 2000 ( 26 ). Later on, in 1992, the Japanese encephalitis (JE) inactivated virus vaccine (JE-Vax) was licensed.

During the year 1994, The Expanded Program for Vaccine Development and the Vaccine Supply and Quality Program were merged creating the Global Program for Vaccines and Immunization. During the same year, the Western Hemisphere was finally labeled as “polio-free” by the International Commission for the Certification of Polio-Eradication.

The 1996 was another monumental year with the launching of the International AIDS Vaccine Initiative (IAVI) that called for the speedy development of a human immunodeficiency virus (HIV) vaccine for use worldwide. This in turn led to the introduction of the Scientific Blueprint for AIDS Vaccine Development. IAVI was funded by several NGOs and foundations. It is a Collaborating Center of the Joint United Nations Program on HIV/AIDS (UNAIDS) whose efforts led finally lead to the first possible vaccine against HIV (Aidsvax) which reached Phase III trials, the largest recorded human HIV vaccine trial at that time. The trial involved 5400 volunteers from the U.S., Canada, and the Netherlands, the majority of whom were men who have sex with men ( 26 ). Preliminary results from the trial of AIDS VAX (VaxGen) vaccine were reported in early 2003. While the vaccine was shown to be protective amongst non-Caucasian populations, especially African-Americans, the same effect was not reproducible in Caucasians ( 26 ).

During the same year, the Children’s Vaccine Program was established at WHO’s Program for Appropriate Technology in Health (PATH). The program’s goal was to provide vaccines to children in the developing world and to accelerate research and development of new vaccines. The first vaccines purchased were Hib, Hepatitis B, Rotavirus, and Pneumococcal, which were not commonly used in the developing world ( 26 ).

At the beginning of the new millennium, the Western Pacific Region of the world was certified as polio-free. During the next 2 years, the European Region also became certified as polio-free. In 2006, the FDA licensed the first vaccine developed to prevent cervical cancer (Gardesil), precancerous genital lesions and genital warts due to human papillomavirus (HPV) types 6, 11, 16, and 18. The first smallpox vaccine for certain immune-compromised populations was delivered under Project BioShield on July 10th 2010. The following year 2010, the WHO declared the “Decade of Vaccines” and in 2012, the United Nations Foundation launched Shot@Life campaign ( 26 ).

Varicella Zoster: Herpes Virus

Varicella (“chickenpox”) is caused by the varicella zoster virus (VZV). Michiaki Takahashi, Professor of Virology at the Research Institute for Microbial Diseases at Osaka University, successfully produced the Oka vaccine strain of live, attenuated varicella vaccine in the 1970s. Takahashi was able to make this remarkable advance at a time when very few viruses had been attenuated to produce efficacious live-virus vaccines including yellow fever, polio, measles, mumps, and rubella as previously mentioned. The VZV vaccine is the first and only licensed live, attenuated herpesvirus vaccine in the world. Numerous trials in the early 1970s continued to prove the safety and efficacy of the vaccine in both healthy and immunocompromised, high-risk individuals. As a result of these successful trials, the live varicella virus vaccine (Varivax) was licensed in 1995 for the active immunization of persons 12 months of age and older ( 51 ). About 10 years later, in 2006, VariZIG, a new immune globulin product for post-exposure prophylaxis of varicella, became available under an Investigational New Drug Application Expanded Access Protocol ( 26 ).

As a herpesvirus, VZV possesses the unique ability to establish latent infection subsequent to primary infection. Zoster results from reactivation of latent VZV that spreads through nerves to the skin. Therefore, one fear associated with this vaccination was the possibility that it could increase the incidence and/or severity of zoster when compared to natural disease. Conversely, it was actually shown that following vaccination, zoster is less common than after natural infection ( 51 ). In 2006, the FDA licensed a new vaccine to reduce the risk of shingles in the elderly. The vaccine, Zostavax was approved for use in people aged 60 years of age and older ( 26 ).

Rotavirus is the leading cause of severe diarrhea and vomiting (severe acute gastroenteritis) among young infants and children worldwide. No significant difference was found in the incidence of rotavirus in industrialized and developing countries, suggesting that vaccination may be the only way to control the impact of this severe disease. Dr. Ruth Bishop and colleagues were the first to describe rotavirus in humans in 1973. It was clear, early on, that a naturally acquired first infection, whether symptomatic or asymptomatic, was the most effective defense against severe reinfection, and subsequent infections progressively created greater protection. Therefore, the goal was to create a vaccination that mimicked the effectiveness of naturally acquired immunity following infection. The development of live, attenuated, oral, safe, and effective rotavirus vaccines was then attempted starting in the mid-1970s. Dr. Albert Kapikian and colleagues, at the NIH, developed the RRV strain that was subsequently used to develop the RRV-TV, or the RotaShield, live oral, and tetravalent vaccine licensed in 1998 to be used in infants at 2, 4, and 6 months of age ( 26 ). However, due to several reported cases of vaccine-associated intestinal intussusception, RotaShield was pulled off the market in the U.S. 14 months after its introduction on the 16th of October, 1999. In 2004, the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH, awarded a new license agreement for RotaShield to BIOVIRx, Inc. of Minneapolis, MN, USA, which planned its global commercialization. In 2011, history of intussusception was added as a contraindication for rotavirus vaccination ( 26 ). Clark, Offit, and Plotkin then produced the RotaTeq vaccine by Merck based on their bovine strain WC3 in 1992, which was licensed in 2006 by the U.S. FDA. This vaccine, live oral and pentavalent, is destined for use in infants ages 6–32 weeks ( 26 ). Another vaccine, Rotarix, was also licensed in 2008. It is a liquid given in a two-dose series to infants from 6 to 24 weeks of age. Before being licensed, both vaccines were shown to be safe and effective in rigorous clinical trials ( 52 ).

Response to Emerging Diseases in the Twenty-First Century

During the past two decades, improvements in environmental health have contributed tremendously to disease vector control. However, substantial challenges remain in dealing with the newly emerging diseases such as severe acute respiratory syndrome (SARS), H1N1, H7N9, and H5N1 influenza, middle east respiratory syndrome (MERS-CoV), rotavirus, Ebola virus, and a variety of other viral, bacterial, and protozoal diseases ( 53 ).

The role of vaccines in the control and protection from the above mentioned emerging diseases cannot be overemphasized. Actually, the importance of inducing protective immunity through vaccination came out to be the most powerful tool and effective strategy to prevent the spread of emerging viruses among populations, in particular, among people that are immunologically naïve and susceptible hosts. Such emerging diseases represent a major public health concern; they affect livestock and humans thus threatening the world’s economy and public health. Vaccine strategies for emerging pathologies are limited by sudden appearance of the pathogen and the delayed time consuming traditional vaccine development process. Novel methods to rapidly develop vaccine are being experimented, whereby investigators are working to achieve a better understanding of the nature of the interactions between the immune system and a panel of novel harmful microbes. On this basis several novel strategies have been developed and applied. Such strategies included the use of (1) recombinant proteins, or nanoparticles like in SARS-CoV and MERS-CoV, (2) synthetic peptides like the case of influenza virus, (3) virus-like particles, (4) multimeric presentation of viral antigens like the case of Hepatitis, (5) replication of competent viral vectors like in the Rift Valley Fever virus or the EBOLA viruses, (6) recombinant bacteria for Listeria and Salmonella among others, and (7) nucleic acid vaccines for EBOLA or Dengue or Rift Valley Fever viruses ( 54 ).

In managing or even in preventing the emergence of new infectious diseases, a plan should be developed to strengthen surveillance and promote a multi-partners response within local, national, and global programs.

With the high burden of emerging infectious diseases (EID) it becomes an essential part to find an effective method of either preventing or controlling their spread, that is where the role of vaccines prevails. It is significant to mention that the average case fatality rate for Ebola is around 50% and outbreaks are affecting both developed and developing countries. Another emerging disease, MERS-CoV, has caused the death of around 36% of people reported to have contracted the disease. Another disease with high health and economic burden would be rotavirus which was estimated to have annual direct and indirect costs of around $1 billion with “more than 400,000 physician visits, more than 200,000 emergency department (ED) visits, 55,000 to 70,000 hospitalizations, and 20 to 60 deaths each year in children younger than 5 years” (CDC, 2015). These are few of the facts regarding the affliction of EID most of which have no approved vaccine yet. On the other hand, the influenza virus which was estimated to cause an average of 23,607 deaths annually with a $12 billion cost of an epidemic, showed that with the introduction of its vaccine, studies proved it to be 80% effective in preventing death ( 55 ). These figures have managed to influence many governmental and non-profit organizations to intervene either through governmental funding of vaccines where the congress provides yearly international EID funding to several U.S. governmental agencies or through international non-profit organizations which are the leaders in global health innovation ( 56 ).

Disease Burden: Different Influential Aspects

Vaccines remain among the most reliable and effective medical interventions in providing the means to fight debilitating and preventable diseases thus ensuring the continuity of mankind and saving lives. Through reviewing the factsheets provided by the World Health Organization, which provide statistical data on the mortality and morbidity percentages before and after the introduction of the vaccines, one can comprehend the vital role vaccines have played up till this day. Some of the figures that depict the impact of vaccines in decreasing mortality and morbidity include more than 99% decrease in Polio cases since 1988, with cases reaching 350,000 from over 125 endemic countries down to 359 cases as reported in 2014 with only 2 endemic countries, measles vaccine has prevented the death of around 15.6 million children during 2000–2013, in general vaccines prevent around 6 million deaths annually worldwide ( 57 ). This success in providing better public health does not negate the economic burden of vaccination. Vaccination programs require excessive funding to ensure proper handling and maintenance of vaccines, adequate staffing and ongoing provision over efficacy and safety of vaccines and the development of newer vaccines ( 58 ). Nevertheless, the economic and social burden related to the expenses in hospitalizing affected unvaccinated people still outweighs the aforementioned burden. Moreover, better health in the society would promote economic growth and productivity. Consequently, public awareness and public efforts agree on the importance of vaccination and the implementation of policies regarding mandatory vaccinations as a way to decrease outbreaks of preventable diseases and improve global health and prosperity.

Turning Point: Vaccine Controversies

As early as the introduction of vaccines, campaigns against vaccination were raging. As with any new medical intervention there are safety concerns that arise which might be deleterious to the public health. Concerns regarding vaccines often follow a path that starts with the hypothesis of a potential adverse event that is impulsively announced to the public without having reproducible studies to confirm this hypothesis, and thus it would take the public several years to regain trust in the vaccine. A notable example in the recent history would be of the paper published by Andrew Wakefield in the British medical journal the Lancet in 1998, linking the MMR vaccine to autism. However, his research was discredited and the paper was retracted from the journal after it was proven that actually there is no link between MMR vaccine and autism as per the systemic review by the Cochrane library ( 59 ). The battle against vaccines did not reach a halt, and there are still ongoing campaigns that come from religious, political, community-based, and even individual-based grounds raising even ethical issues regarding the mandatory vaccinations proposed by the government. According to the CDC, this year 95% of the children were vaccinated in the U.S., leaving 5% unvaccinated due to religious and philosophical exemptions or even parental refusal due to the fear of vaccine’s side effects and concerns regarding autism from vaccines ( 60 ); this is still a critical number since the unvaccinated would pose risk of outbreaks even among the immunized, which necessitates the need for additional awareness campaigns regarding the importance of vaccination since vaccines remain the only plausible measure of protection against preventable diseases. Actually, a trend was reported in the health news lately, in the U.S., that pediatricians refuse to offer medical care for children whose parents declined their vaccination.

Vaccination has been of great importance throughout centuries (Tables 1 and 2 ). People started with inoculation techniques dating back to 1000 A.D. with the Chinese, Turks, and Asians. With every century and with every curious physician, inoculation techniques improved gradually giving rise to newer vaccination techniques with Edward Jenner and later on, Louis Pasteur and others. However, there is still plenty of room for improvement with the presence of ongoing epidemics and the spread of newly emerging diseases. One important goal is to strengthen the science base for vaccine development and for public health action and disease prevention. Despite the common belief that infectious diseases were virtually eliminated by the middle of the twentieth century, new and reemerging infections are appearing along with drug resistant infections in the past two decades in the various parts of the world and whose incidence threatens to increase in the near future, due to changes in human demographics and behavior, immigration, and speed of international travel among other things ( 61 – 63 ). The importance of vaccine safety continued to grow throughout the twenty-first century, with the development and licensure of new vaccines added to the already robust immunization armamentarium. Scientists also perfected new ways of administering immunizations including edible vaccines and needleless injections. However, formulated or delivered, vaccines will remain the most effective tool we possess for preventing disease and improving public health in the future. Despite the anti-vaccination campaign and the association of vaccines with some side effects, vaccines continue to remain a cornerstone in global health.

Table 1. Development, introduction, infectious agent, schedule, and efficacy of vaccines .

Table 2. Development, introduction, infectious agent, schedule, and efficacy of potential new vaccines .

The distinctions between national and international health problems are losing ground and could be misleading, the “world is a village.” Clinicians and public health workers need to interact on regular basis with veterinarians and veterinary public health. Actually, good examples of the necessity of such collaboration is the emergence of SARS-CoV and MERS-CoV, it shows clearly how coronaviruses can spillover from animals into humans at any time, causing lethal diseases. Foodborne diseases could lead to regional and international outbreaks which might constitute a threat to national and global security.

Author Contributions

IH is the first author. She provided the idea and followed along with AJ the execution of the work and final editing. NC and SC did the literature search for the eighteenth and nineteenth century and the respective preliminary writing about this period. SS and RB did the literature search for the twenty-first century, and about general aspects of vaccination and the respective preliminary writing about this period. MR did the literature search regarding vaccine efficacy and effectiveness in the context of the transnational research map and regarding vaccination instruments and inoculating techniques. AG did the literature search and the preliminary writing for the early history of vaccination and wrote a draft of a manuscript about this period. AL edited thoroughly and commented on the final manuscript. AJ supervised the whole process from inception to the final submission and edited the whole manuscript.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

1. Centers for Disease Control and Prevention. Vaccines and Immunizations: The Basics . Washington, DC: Government Printing Office (2012).

Google Scholar

2. CDC.gov . Pinkbook. Epidemiology of VPDs, Vaccine Safety . (2015). Available from: http://www.cdc.gov/vaccines/pubs/pinkbook/safety.html

3. Ellenberg S, Chen RT. The complicated task of monitoring vaccine safety. Public Health Rep (1997) 112 (1):10–20.

PubMed Abstract | Google Scholar

4. Chen RT, Hibbs B. Vaccine safety: current and future challenges. Pediatr Ann (1998) 27 (7):445–55. doi:10.3928/0090-4481-19980701-11

CrossRef Full Text | Google Scholar

5. NIAID. Topics: Vaccines (2012). Available from: http://www.niaid.nih.gov/topics/vaccines/documents/undvacc.pdf

6. The College of Physicians of Philadelphia. Articles – Different Types of Vaccines (2014). Available from: http://www.historyofvaccines.org/content/articles/different-types-vaccines

7. Siegrist CA. General aspects of vaccination. 6th ed. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines . Philadelphia, PA: Elseiver Inc (2008). p. 17–36.

8. Hanekom WA. The immune response to BCG vaccination of newborns. Ann N Y Acad Sci (2005) 1062 :69–78. doi:10.1196/annals.1358.010

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Casadevall A. The methodology for determining the efficacy of antibody-mediated immunity. J Immunol Methods (2004) 291 :1–10. doi:10.1016/j.jim.2004.04.027

10. Rimaniol AC, Gras G, Verdier F, Capel F, Grigoriev VB, Porcheray F, et al. Aluminum hydroxide adjuvant induces macrophage differentiation towards a specialized antigen presenting cell type. Vaccine (2004) 22 :3127–35. doi:10.1016/j.vaccine.2004.01.061

11. Tan PL, Jacobson RM, Poland GA, Jacobsen SJ, Pankratz VS. Twin studies of immunogenicity–determining the genetic contribution to vaccine failure. Vaccine (2001) 19 :2434–9. doi:10.1016/S0264-410X(00)00468-0

12. Weinberger B, Herndler-Brandstetter D, Schwanninger A, Weiskopf D, Grubeck-Loebenstein B. Biology of immune responses to vaccines in elderly persons. Clin Infect Dis (2008) 46 (7):1078–84. doi:10.1086/529197

13. Konradsen HB, Henrichsen J, Wachmann H, Holm N. The influence of genetic factors on the immune response as judged by pneumococcal vaccination of mono- and dizygotic Caucasian twins. Clin Exp Immunol (1993) 92 :532–6. doi:10.1111/j.1365-2249.1993.tb03433.x

14. Newport MJ, Goetghebuer T, Weiss HA, Whittle H, Siegrist CA, Marchant A, et al. Genetic regulation of immune responses to vaccines in early life. Genes Immun (2004) 5 :122–9. doi:10.1038/sj.gene.6364051

15. Weinberg GA, Szilagyi PG. Vaccine epidemiology: efficacy, effectiveness, and the translational research roadmap. J Infect Dis (2010) 201 (11):1607–10. doi:10.1086/652404

16. Gomez CR, Boehmer ED, Kovacs EJ. The aging innate immune system. Curr Opin Immunol (2005) 17 :457–62. doi:10.1016/j.coi.2005.07.013

17. Curns AT, Steiner CA, Barrett M, Hunter K, Wilson E, Parashar UD. Reduction in acute gastroenteritis hospitalizations among us children after introduction of rotavirus vaccine: analysis of hospital discharge data from 18 US states. J Infect Dis (2010) 201 (10):1617–24. doi:10.1086/652403

18. Clemens JD, Shapiro E. Resolving the pneumococcal vaccine controversy: are there alternatives to randomized clinical trials? Rev Infect Dis (1984) 6 :589–600. doi:10.1093/clinids/6.5.589

19. Clemens J, Brenner R, Rao M, Tafari N, Lowe C. Evaluating new vaccines for developing countries. Efficacy or effectiveness? JAMA (1996) 275 :390–7. doi:10.1001/jama.275.5.390

20. Orenstein WA, Bernier RH, Hinman AR. Assessing vaccine efficacy in the field. Further observations. Epidemiol Rev (1988) 10 :212–41.

21. Szilagyi PG. Translational research and pediatrics. Acad Pediatr (2009) 9 :71–80. doi:10.1016/j.acap.2008.11.002

22. Kirkup J. The Evolution of Surgical Instruments . Novato, CA: Historyofscience.com (2006).

23. Stanford S. The history of pediatric infectious diseases. Pediatr Res (2004) 55 :163–76. doi:10.1203/01.PDR.0000101756.93542.09

24. The College of Physicians of Philadelphia. History of Vaccines Timelines . The College of Physicians of Philadelphia (1885). Available from: http://www.historyofvaccines.org/content/timelines/all

25. Marble A. Surgeons, Smallpox, and the Poor: A History of Medicine and Social Conditions in Nova Scotia, 1749-1799 . Montreal, QC: McGill-Queen’s University Press (1993).

26. The Immunization Action Coalition. Vaccine Timeline . The Immunization Action Coalition (2013). Available from: http://www.immunize.org/timeline/

27. Riedel S. Edward Jenner and the history of smallpox and vaccination. Proc (Bayl Univ Med Cent) (2005) 18 (1):21–5.

28. Henry EH. Experience in Massachusetts and a few other places with smallpox and vaccination. Boston Med Surg J (1921) 185 :221–8. doi:10.1056/NEJM192108251850802

29. Pepper W. The Medical Side of Benjamin Franklin . Philadelphia, PA: W.J. Campbell (1911).

30. Fenner F. History of Vaccine Development (Smallpox Eradication: The Vindication of Jenner’s Prophesy Chapter) . New York, NY: Springer Science & Business Media (2011). p. 27–32.

31. Bazin H. History of Vaccine Development. (Pasteur and the Birth of Vaccines Made in the Laboratory Chapter) . New York, NY: Springer Science & Business Media (2011). p. 33–45.

32. Sternbach G. The history of anthrax. J Emerg Med (2003) 24 (4):463–7. doi:10.1016/S0736-4679(03)00079-9

33. Bourhy H, Perrot A, Cavaillon J. Vaccines: A Biography (Rabies) . New York, NY: Springer Science & Business Media (2010). p. 73–85.

34. Carpenter C, Hornick R. Vaccines: A Biography (Killed Vaccines: Cholera, Typhoid, and Plague) . New York, NY: Springer Science & Business Media (2010). p. 87–103.

35. Grabenstein JD. Vaccines: A Biography (Toxoid Vaccines) . New York, NY: Springer Science & Business Media (2010). p. 105–24.

36. Cherry JD. Historical review of pertussis and the classical vaccine. J Infect Dis (1996) 174 :59–63. doi:10.1093/infdis/174.Supplement_3.S259

37. CDC.gov . Preventing tetanus, diphtheria, and pertussis among adolescents: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines recommendations of the advisory committee on immunization practices (ACIP). (2015). Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5503a1.htm

38. Lombard M, Pastoret PP, Moulin AM. A brief history of vaccines and vaccination. Rev Sci Tech (2007) 26 (1):29–48.

39. Gheorghiu M, Lagranderie M, Balazuc AM. Vaccines: A Biography (Tuberculosis and BCG Chapter) . New York, NY: Springer Science & Business Media (2010). p. 125–40.

40. Daniel TM. The history of tuberculosis. Respir Med (2006) 100 (11):1862–70. doi:10.1016/j.rmed.2006.08.006

41. Barrett ADT, Higgs S. Yellow fever: a disease that has yet to be conquered. Annu Rev Entomol (2007) 52 :209–29. doi:10.1146/annurev.ento.52.110405.091454

42. Monath TP. Vaccines: A Biography (Yellow Fever Chapter) . New York, NY: Springer Science & Business Media (2010). p. 159–89.

43. Potter CW. A history of influenza. J Appl Microbiol (2001) 91 :572–9. doi:10.1046/j.1365-2672.2001.01492.x

44. Artenstein AW. Vaccines: A Biography (Influenza Chapter) . New York, NY: Springer Science & Business Media (2010). p. 191–205.

45. Oshinsky D. Vaccines: A Biography (Polio Chapter) . New York, NY: Springer Science & Business Media (2010). p. 207–21.

46. Blume S, Geesink I. A brief history of polio vaccines. Science (2000) 288 (5471):1593–4. doi:10.1126/science.288.5471.1593

47. Gallagher KM, Plotkin SA, Katz SL, Orenstein WA. Vaccines: A Biography (Measles, Mumps, and Rubella Chapter) . New York, NY: Springer Science & Business Media (2010). p. 223–47.

48. Stern AM, Markel H. The history of vaccines and immunization: familiar patterns, new challenges. Health Aff (2005) 24 (3):611–21. doi:10.1377/hlthaff.24.3.611

49. Hilleman MR. Vaccines in historic evolution and perspective: a narrative of vaccine discoveries. Vaccine (2000) 18 :1436–47. doi:10.1016/S0264-410X(99)00434-X

50. Hilleman MR. History of Vaccine Development (Three Decades of Hepatitis Vaccinology in Historic Perspective. A Paradigm of Successful Pursuits Chapter) . New York, NY: Springer Science & Business Media (2011). p. 233–46.

51. Gershon AA. Vaccines: A Biography (Varicella and Zoster Chapter) . New York, NY: Springer Science & Business Media (2010). p. 265–77.

52. Dennehy PH. Vaccines: A Biography (Rotavirus Chapter) . New York, NY: Springer Science & Business Media (2010). p. 347–60.

53. Fineberg HV. Pandemic preparedness and response – lessons from the H1N1 influenza of 2009. N Engl J Med (2014) 370 :1335–42. doi:10.1056/NEJMra1208802

54. Hughes JM. Emerging infectious diseases: a CDC perspective. Emerg Infect Dis (2001) 7 (3):494–6. doi:10.3201/eid0707.017702

55. World Health Organization. Fact Sheets . World Health Organization (2015). Available from: http://www.who.int/mediacentre/factsheets/en/

56. KFF.org . The U.S. Government & Global Emerging Infectious Disease Preparedness and Response (2015). Available from: http://kff.org/global-health-policy/fact-sheet/the-u-s-government-global-emerging-infectious-disease-preparedness-and-response/

57. Andre F, Booy R, Bock H, Clemens J, Datta S, John T, et al. Vaccination greatly reduces disease, disability, death and inequity worldwide. Bull World Health Organ (2008) 86 (2):140–6. doi:10.2471/BLT.07.040089

58. Roush S. Historical comparisons of morbidity and mortality for vaccine-preventable diseases in the United States. JAMA (2007) 298 (18):2155. doi:10.1001/jama.298.18.2155

59. Demicheli V, Rivetti A, Debalini M, Di Pietrantonj C. Vaccines for measles, mumps and rubella in children. Cochrane Database Syst Rev (2012) 19 (4):CD004407. doi:10.1002/14651858.CD004407.pub3

60. CDC.gov . Vaccination Coverage Among Children in Kindergarten – United States, 2013–14 School Year (2015). Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6341a1.htm

61. Immunize.org . Historic Dates and Events Related to Vaccines and Immunization (2015). Available from: http://www.immunize.org/timeline/

62. CDC.gov . Morbidity and Mortality Weekly Report (MMWR) | MMWR (2015). Available from: http://www.cdc.gov/mmwr/index.html

63. Clinicaltrials.gov . Home – ClinicalTrials.gov (2015). Available from: https://clinicaltrials.gov/ct2/home

Keywords: vaccines, immunization, history of vaccines, global health

Citation: Hajj Hussein I, Chams N, Chams S, El Sayegh S, Badran R, Raad M, Gerges-Geagea A, Leone A and Jurjus A (2015) Vaccines Through Centuries: Major Cornerstones of Global Health. Front. Public Health 3:269. doi: 10.3389/fpubh.2015.00269

Received: 07 September 2015; Accepted: 11 November 2015; Published: 26 November 2015

Reviewed by:

Copyright: © 2015 Hajj Hussein, Chams, Chams, El Sayegh, Badran, Raad, Gerges-Geagea, Leone and Jurjus. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Inaya Hajj Hussein, hajjhuss@oakland.edu

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Counting the impact of vaccines

For a safer, healthier world.

The COVID-19 pandemic has ushered in a new era for vaccines and immunization, reminding the world of the power of vaccines to bring us closer to a safe and healthy future. To maximize the lifesaving impact of immunization over the next decade, WHO and its partners are launching the Immunization Agenda 2030 (IA2030), an ambitious global strategy that envisions a world where everyone, everywhere, at every age fully benefits from vaccines for good health and well-being.

Immunization is a vital component of primary health care, reaching more people than any other health or social service. Here are three ways immunization benefits our world.

1. Immunization saves lives and protects peoples’ health

Immunization keeps people healthy and has reduced the number of deaths from infectious diseases dramatically. Between 2010 and 2017, the mortality rate of children under 5 years of age declined by nearly a quarter. 1 Measles vaccines alone prevented 25.5 million deaths since 2000, and enormous progress towards the eradication of polio – which can cause lifelong paralysis and sometimes death – have brought cases down by over 99% since 1988. 2,3

Vaccines benefit not only infants and children but also older people. They can prevent infection-related cancers caused by viruses like hepatitis and HPV, and protect the health of the working population, the elderly and the vulnerable, allowing people to live longer, healthier lives. In addition, fewer infections mean less risk of transmitting disease to relatives and other members of the community.

2. Immunization improves countries’ productivity and resilience

Immunization is the foundation of a healthy, productive population. Every dollar invested in immunization programmes in 94 low- and middle-income countries over the next decade will return more than US$ 52 by lowering treatment costs, boosting productivity, and reducing long-term disability. 4

Vaccines also protect countries from the overwhelming economic impact of disease outbreaks. As we have seen with the COVID-19 pandemic, disease outbreaks are disruptive and costly. They can overwhelm and profoundly disrupt public health programmes, clinical services, and health systems, and keep children out of school. They may also have adverse effects on travel, tourism, trade and overall development.

For seasonal diseases like influenza, the costs of treatment and lost productivity are borne repeatedly. Immunized communities are resistant to infectious disease outbreaks, and strong health systems and immunization programmes can rapidly detect and limit the impact of infectious diseases.

At the individual level, preventing infections through immunization helps reduce families’ healthcare costs and provides financial protection against out-of-pocket payments that could have a catastrophic impact on household finances.  

3. Immunization helps ensure a safer, healthier world

Vaccines are key to global health security. Outbreaks of highly infectious diseases, such as measles and COVID-19, have shown us how quickly disease can spread between countries in an increasingly interconnected world. In 2019, measles cases increased in countries where it had been previously eliminated, partially due to low vaccination rates among travelers. 5

Immunization can help us prevent and respond to future infectious disease threats. Immunization and disease surveillance are core capacities required by the International Health Regulations (2005). They contribute to resilient, sustainable health systems that can respond to outbreaks, public health risks and emergencies . 6 A recent study found that a 10% increase in these core capacities (e.g., surveillance and risk communication) is associated with a 20% decrease in the incidence of cross-border infectious disease threats. 6

Immunization is critical to the prevention and control of communicable diseases; strengthening country productivity, which contributes to economies; and helping to ensure a safer, healthier world. Vaccines provide a profound return on investment and are a key component of improving health and well-being for everyone, everywhere.

• Global burden of disease. Seattle (WA): Institute for Health Metrics and Evaluation; 2017.
• Patel MK, Goodson JL, Alexander JP Jr., et al. Progress Toward Regional Measles Elimination — Worldwide, 2000–2019. MMWR Morb Mortal Wkly Rep 2020;69:1700–1705.
• Poliomyelitis. World Health Organization; 2019
• Sim SY, Watts E, Constenla D, et al. Return On Investment From Immunization Against 10 Pathogens In 94 Low- And Middle-Income Countries, 2011–30. Health Affairs. 39(8):1343-1353.
• Patel M, Lee AD, Redd SB, et al. Increase in Measles Cases — United States, January 1–April 26, 2019. MMWR Morb Mortal Wkly Rep 2019;68:402–404.
• Semenza JC, Sewe MO, Lindgren E, Brusin S, Aaslay KK, Mollet T, et al. Systemic resilience to cross‐border infectious disease threat events in Europe. Transbound Emerg Dis. 2019;66(5):1855–63.

Vaccination explained in 60 seconds: ideas that changed the world

How a medical breakthrough has saved countless millions of lives

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In this series , The Week looks at the ideas and innovations that permanently changed the way we see the world.

Vaccination in 60 seconds

Vaccination trains the immune system to recognise and protect the body against pathogens from viruses or bacteria. Molecules from or similar to the pathogens are introduced into the body, usually through an injection.

Feminism explained in 60 seconds: ideas that changed the world The printing press explained in 60 seconds: ideas that changed the world Colonialism explained in 60 seconds: ideas that changed the world

The process may sound counter-intuitive, but vaccination can “confer active immunity against a specific harmful agent by stimulating the immune system to attack the agent”, explained Encyclopaedia Britannica . Once stimulated, “the antibody-producing cells, called B lymphocytes, remain sensitised and ready to respond to the agent should it ever gain entry to the body”, the reference website continued.

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You cannot catch a disease through vaccination, added the NHS website. That’s because the pathogens inside vaccines have been “weakened or destroyed in a laboratory first”.

If the vaccinated individual then comes into contact with the targeted disease, their immune system should be able to quickly recognise and fight it.

How did vaccination come about?

The first vaccine was developed by English surgeon Edward Jenner in 1796, to inoculate against smallpox, a leading cause of death in the 18th century that left many survivors permanently disfigured.

Prior to Jenner’s breakthrough, some doctors tried to protect their patients from smallpox by deliberately exposing them to smallpox scabs, a process originating in China called variolation, but this system often proved ineffective and made the recipient temporarily infectious to others.

Jenner observed that people who had previously caught cowpox, a relatively harmless virus passed on from close contact with cows, appeared to be immune to smallpox.

To test his theory, he obtained permission from his gardener to inoculate his eight-year-old son, applying lesions from a dairymaid with cowpox to a scratch on the boy’s skin. The child was mildly ill for a few days, but soon recovered – and when later subjected to variolation, he did not experience any symptoms of smallpox.

Initially, “Jenner’s newly proven technique for protecting people from smallpox did not catch on as he anticipated”, meeting with resistance from the medical establishment and sceptical patients, said Oxford-based research organisation The Jenner Institute .

But his technique was quickly adopted across Europe and in the US and Russia. By the time of Jenner’s death, in 1823, the significance of his work was recognised in countries worldwide and he was feted as a hero. Exactly 30 years later, it became mandatory in Britain to vaccinate children against smallpox, with parents who failed to do so fined or imprisoned.

Further major vaccines were developed in the following decades. In 1881, French biologist Louis Pasteur refined techniques to immunise sheep against anthrax, with his vaccine for rabies following four years later.

And an early typhoid vaccine developed by British bacteriologist Almroth Edward Wright was used successfully by the British military during the Boer War in South Africa between 1899 and 1902.

The following century would bring vaccines for diseases including mumps, measles, cholera, plague, tuberculosis, tetanus, influenza, yellow fever and some types of hepatitis.

The world watched in real time, the rapid development and deployment of new life-saving vaccines in 2020 when the Covid-19 virus was infecting millions and sparked a global pandemic. By 2022, nearly two-thirds of the global population had received at least one dose of a Covid vaccine, and the Imperial College London estimated the vaccines had prevented about 20 million deaths worldwide.

How did it change the world?

Vaccination has led to the eradication of the smallpox virus and some types of polio. Other diseases have been dramatically brought under control, including mumps, diphtheria, rubella and hepatitis.

The Measles, Mumps, Rubella (MMR) vaccine has been particularly successful in curbing the spread of measles, the most infectious disease on the planet and still a leading cause of childhood mortality in the developing world.

Public Health England estimated that in the UK alone, “20 million measles cases and 4,500 deaths have been averted” since the introduction of the measles vaccine in 1968. The disease was considered to be eliminated in the UK, but in 2018 cases began to rise, and about 50 cases were confirmed in England in the early part of 2023, The Guardian reported. Experts believe the recent decline in MMR uptake in children is due in part to a rise in vaccine hesitancy among parents, said The Lancet .

The Covid pandemic ushered in a new era for vaccination. The messenger ribonucleic acid (mRNA) technology used in some of the most popular vaccines, including those made by Pfizer-BioNTech and Moderna, paved the way “for a whole new class of mRNA vaccines with the potential to eradicate countless other diseases, even cancer”, said Penn Medicine .

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Here’s Why Vaccines Are so Crucial

If children in poor countries got the shots that rich countries take for granted, hundreds of thousands of young lives could be saved.

Biology, Health

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Go see the child, Samir Saha said. Just sit with her. Probably the siblings will be there too, the brother and sister whose lives are also altered permanently.

‘This is why the vaccine is so important,’ Saha said.

‘We want to reduce this number to a minimum if not zero. So no other children will be like this.’

It was a little after dawn in Dhaka, the capital of Bangladesh, and Saha was in the back seat of his car, brooding. A uniformed driver threaded the Toyota through a cacophonous mess of jitneys, motorcycles, rickshaws , trucks, and battered buses with passengers hanging out the doors. “We could save the life, but we could not …” He left the sentence unfinished. “You’ll be seeing the scenario,” he said. “You’ll understand.”

Saha is a microbiologist, internationally renowned for his research on a bacterium called pneumococcus. The laboratory he founded is wedged into one corner of Dhaka Shishu, the biggest children’s hospital in Bangladesh. Just down the hall, rows of beds fill the open wards; during family hours, each bed seems to hold both a sick child and many attentive relatives. Inside the lab, white-jacketed men and women spend their days in intimate study of pneumococcal cells : hunting for them in vials of blood and other bodily fluids, smearing them into petri dishes, peering at them through microscopes .

Pneumococcal bacteria are ubiquitous in the modern world; easily spreadable through sneezing or casual contact, they can live without ill effect in the nasal passages of people with healthy immune systems . But when our defenses fail us, pneumococcus can migrate, multiply, and set off life-threatening infectious disease. Young children are especially vulnerable. Young children in places without ready access to antibiotics and good medical care are the most vulnerable of all. At the start of the 21st century, as the world’s first effective children’s vaccine became available in the United States and Canada, pneumococcal disease was killing more than 800,000 children worldwide every year—more than three-quarters of a million infants and kids under five, that is, dying not from some headline epidemic like Ebola or Zika but from a common organism that blew up into pneumonia (infected lungs) or meningitis (infected brain lining) or a mortal assault on the bloodstream . The vast majority of those deaths were occurring in impoverished countries such as Bangladesh.

In 2015 pneumococcal conjugate vaccine, as the children’s formulation is called, reached the Bangladeshis, and Saha’s research team is intently tracking its progress. If PCVs prove as effective around the world as vaccine experts hope, they promise both a greatly lowered mortality rate—that’s many thousands of small children staying alive instead of dying before they’re old enough to start school—and much less nonmortal sickness. Less of the rapid pneumonia breathing; less of the fever, the sucking chest, the rattling cough, the blue lips, the bedside watch by parents pulled away from the paid work that supports their other children. Less …  suffering,  I kept hearing Saha and his Bangladeshi colleagues say, as though sensing that an outsider might need help appreciating the stakes.

Because from the vantage of a country like the United States, it can be easy to imagine that the most pressing vaccine challenge of 2017 lies in convincing certain communities of skeptical parents that they really ought to inoculate their kids. Those efforts are important, to be sure. But even more urgent—more ambitious , more complex, involving many governments and billions of philanthropic dollars—is the international collaboration to get new vaccines to children in the developing world, where to this day the suffering caused by vaccine -preventable disease is as vivid and nontheoretical as the frantic families Saha sees every day in the halls of Dhaka Shishu.

This is why he was sending me to Sanjida Sahajahan, 11 years old, the middle child of a rickshaw repairman and his wife. Go now, Saha said, as we pulled up to the hospital’s main gate; when you come back, we shall discuss what you observed. Jamal and Tasmim will accompany you. That van in the parking lot is waiting.

The hospital van bumped through crowded Dhaka streets that kept narrowing until we were inching past market displays: piles of sweet potatoes and used clothes and car parts. The road ran out of vehicle room. We got out to walk. Jamal Uddin is a physician, Tasmim Sultana Lipi a community health worker, and the two of them knew the right muddy passageways to follow. Along metal-roofed buildings to either side, barred windows offered glimpses of family after family inhabiting separate single rooms.

Lipi nodded toward one of the doorways and ducked in. Observing neighborhood protocol, we all removed our shoes.

Sanjida, who had been carried into Dhaka Shishu at the age of three with what turned out to be pneumococcal meningitis, was propped up in a small plastic armchair beside the family bed. Meningitis is an inflammation , sometimes irreversibly destructive, of the membranes that surround the brain and spinal cord. Sanjida has no control over her head, her grimaces, or the sounds she makes—mewling cries, mostly, as she is unable to form words. Her mother, Nazma, had been outside with the baby when we arrived; in these rooms nine families share two toilets and a single tap, and now Nazma hurried in, holding the baby in one arm, wiping dry her face. She lowered herself onto a stool. She took Sanjida’s hand.

In Bangla, she told us the story: their bright, talkative three-year-old’s unexplained fever; the neighbors urging acetaminophen, for sale in a shop nearby; the fever receding after the pills; the fever rising again. A few days later came the first convulsion and the terrified journey to the hospital—by bus and motorcycle taxi, as a rickshaw repairman doesn’t have the means to summon an ambulance. By the time doctors saw Sanjida, she was losing consciousness. Her last understandable words, Nazma said, were “Hug me. I feel very bad.”

Sanjida’s father, Mohammad, stood quietly while Nazma spoke. Their 14-year-old son came in and picked up the baby and stood too; there was nowhere else to sit. A disassembled wheelchair had been shoved beneath the bed—a charity gift, Nazma said, very nice idea, but their living quarters were too small. A wall cabinet held toys and dishware, and now Mohammad pulled from a drawer a creased yellow card: Sanjida’s national health record. Here was her birth date, in September 2005.

And here, the first markings dated six weeks later, were the notations for Sanjida’s vaccinations. Like her older brother, Sanjida received every inoculation then in Bangladesh’s national immunization plan, on schedule and for free: whooping cough, measles, diphtheria , tuberculosis , tetanus, hepatitis B, polio . No smallpox ; worldwide vaccination had already erased that disfiguring contagion from the planet by 1980, two centuries after the English physician Edward Jenner published his famous treatise on deliberately infecting children with cowpox, a mild virus that turned out to stimulate immunity against the far more serious smallpox .

An extraordinary global health history had been abbreviated, in a way, on Sanjida’s little yellow card. No one can tally accurately the total number of lives saved by widespread vaccination, but it remains one of the greatest achievements of modern medicine . Measles, for example, was killing more than two million children a year worldwide in the 1980s; by 2015, according to the World Health Organization, vaccination had dropped the death toll to 134,200. Mass vaccination has ended polio in all but three countries; Bangladesh and its giant neighbor India were pronounced polio free in March 2014. And when I asked Nazma how she first learned about vaccines —what gave her the idea that taking healthy babies for injections was a good idea?—she looked startled. Then she responded with a passionate outpouring that Uddin and Lipi distilled into English:  But every Bangladeshi knows this.

On television—the Sahajahans’ is crammed in atop that wall cabinet—popular singers and athletes in public service ads praise the lifesaving gift of inoculation. Encouragements to vaccinate trumpet from thousands of minarets , like calls to prayer; Bangladesh is predominantly Muslim , and while pushing for polio inoculation in the late 1980s, health officials and Islamic leaders together came up with a plan for “ mosque miking.” Once, in a village outside Dhaka, the local imam proudly pushed up a sleeve to show me the trace of his last tuberculosis vaccination. Protecting one’s health is part of a religiously observant life, he explained, and faithful parents are obliged to do the same for their children.

Delivering vaccines in Bangladesh isn’t easy. The terrain is crisscrossed by flooding rivers and barely passable roads, and the vaccines must be kept at just the right cold temperature to preserve their potency. Maintaining this “cold chain” is an urgent priority for immunization programs in all countries with hot climates and shaky power grids ; a single faulty chiller or a rural power outage can wreck a whole batch of vaccine . But Bangladesh has worked hard to preserve the cold chain, equipping local health centers with solar panels, pressing bicycles and riverboats into service to ferry vaccines to the most remote clinics.

The Bangladeshi inoculation program is widely respected for its remarkable reach, in fact, and on the way back to Dhaka Shishu, the three of us silent and sad in the hospital van, I understood what Samir Saha most wanted me to see. By 2005, when the infant Sanjida got all her shots, the new vaccine against pneumococcal infection was routinely being injected into children all over the United States and was spreading fast across the developed world. The problem was in places like Bangladesh, which needed the vaccine far more desperately but couldn’t pay what the manufacturer had decided to charge.

Vaccines , with very few exceptions, are made by private companies, in business to return a profit. Until recently, their manufacture worldwide has been dominated by a few U.S. and European pharmaceutical giants. As officials of these companies point out when advocacy organizations like Doctors Without Borders press them to lower their prices (or else open their books to prove why they can’t), developing a new vaccine is especially expensive. After all, it typically involves injecting a disabled germ or fragment of a germ into healthy trial participants—followed by a drawn-out process of watching and waiting to make certain the vaccine isn’t harmful, that it stimulates an immune response against the infectious germ , and that the people who receive it contract the disease less often than those who don’t. All that takes years.

For a pneumococcal vaccine that worked right in children, it took decades. Good adult vaccines were on the market by the early 1980s, but they never set off the hoped-for immune response in small kids. It wasn’t until the late 1990s that researchers finally found a way to biologically amend, or “conjugate,” the contents of those adult vaccines so they would be recognized by immature immune systems.

Pneumococcus presents another vexing challenge: Saha and other scientists have identified nearly a hundred versions, or serotypes, of pneumococcal cells. Serotypes can be geographically distinct, and for reasons not yet fully understood, only a small number are dangerous. (Serotype 1, for example, causes comparatively little disease in the United States but is a prime source of pneumococcal illness and death in Africa and South Asia.) So a finished vaccine that works for children and targets exactly the right serotypes is really multiple vaccines, individually amended and tested and then mixed into one vial.

All these complications helped make the first children’s pneumococcal vaccine one of the most expensive in history. Called Prevnar, it was launched in early 2000 by the American pharmaceutical company Wyeth (which was later taken over by Pfizer). It was formulated to work against the seven serotypes responsible for most of the disease—in the United States, that is, which could absorb a children’s vaccine priced at $232 per four-dose course. Among the dangerous kinds of pneumococcus that vaccine was  not   formulated to fight off was serotype 1. Yet the poorest regions of Africa and South Asia are precisely where any pneumococcal infection is likeliest to kill a child or leave her crippled for life—not just because parents can’t reach a doctor in time but also because the bacteria do extra damage inside small bodies already weakened by malnutrition , other lingering diseases, and too much exposure to cook-fire smoke.

“When I started work on this, what kept me up at night was the inequity,” says Orin Levine, vaccine delivery director at the Bill and Melinda Gates Foundation. Years ago a colleague of his watched a woman in a Mali hospital lose a daughter to pneumococcal pneumonia; she’d lost another daughter the same way. Levine still remembers the mother’s name. His own daughters were about the same age.

“The chances of a kid dying of pneumococcal disease in the rich world were a hundredfold less,” he says. “Why was it that my kids could get the vaccine when Tiemany Diarra’s kids, Mali’s kids, needed it more and didn’t get it?”

He knew the answer, of course: The surest economic return to vaccine manufacturers doesn’t come from meeting the most critical need.

Imagine Levine's frustration echoed by a world of vaccine experts, and you understand the impetus behind the Global Alliance for Vaccines and Immunisation, or Gavi. This multibillion-dollar public-private collaboration got under way in 2000, just as PCVs reached the U.S. market. Kicked off in part by a $750 million pledge from the Gates Foundation, Gavi channels wealthy nations’ resources—private philanthropy plus government aid from such countries as the United States, the United Kingdom, and Norway—into vaccine support for poorer countries that apply for the aid. Gavi helps negotiate with vaccine companies to slash prices specifically for those large-volume sales; subsidies from the donor fund then reduce the cost to developing countries even further, so that they pay a small fraction of the usual market price.

“It’s been absolutely transformational—the financial muscle and the dedication that global actors and manufacturers and countries have agreed to,” says Katherine O’Brien, a pediatrician and pneumococcus expert who directs the International Vaccine Access Center at Johns Hopkins University. Gavi wasn’t assembled just to help with pneumococcal vaccine, O’Brien points out; the alliance concentrated at first on making established childhood inoculations like tetanus and hepatitis B more accessible.

PCVs joined the vaccine list only in 2010, after years of continued testing and negotiation. But the demand from developing countries was so high that soon Gavi was devoting a half billion donor dollars a year to PCV support—the alliance’s single biggest financial commitment. A special arrangement with Pfizer and GSK, the only companies currently making PCVs, is supposed to ensure there will be enough supply; both have promised to produce as much vaccine, at the Gavi-arranged discount, as each of the receiving countries agrees to buy.

With those deals in place, the manufacturers have also developed new formulations that extend the effectiveness of PCVs to include children a long way from the U.S. and Europe. In 2010 Pfizer released a new blend called Prevnar 13, designed to work against serotype 1 and five others not targeted in the original mix. The GSK product, introduced in 2009, also is configured to fight serotypes prevalent in Africa and Asia. And since March 2015, when Bangladeshi health officials received their inaugural delivery of Gavi-discounted PCV, vaccine shipments have arrived by air freight every three months from a GSK distribution center in Belgium.

“Small chiller boxes,” Saha told me. “Like when you are going camping. But these are a little more sophisticated, with monitoring systems for the temperature.”

The vaccines, health officials say, are reaching families all over the country. Bangladesh, at least so far, has experienced no surge of “vaccine hesitancy,” as global health experts prefer to call the problem of parents declining to vaccinate their children. Elsewhere in South Asia, suspicion and hostility have troubled recent inoculation campaigns; in Pakistan, for example, polio vaccinators a few years ago were turned away or attacked amid rumors both false and true. (False: that the vaccines were part of a Western plot against Islam. True: that the CIA used house-to-house vaccinators to hunt for Osama bin Laden.) And in parts of India, a measles-rubella vaccination campaign foundered earlier this year, after anonymous posts on social media claimed the vaccines were dangerous or even meant to sterilize the children of religious minorities.

Even in vaccine-receptive Bangladesh, Saha told me, he’s heard people wonder about the merits of adding PCVs to the already ambitious national inoculation effort. “I was on a talk show on the TV,” he said. “A banker’s wife, a powerful person, said, ‘Why are you talking about vaccines so much?’ ” Pneumonia and other pneumococcal infections are treatable with penicillin, the banker’s wife objected; Saha had just said so himself. “And my answer was: ‘Oh, madam. You want to wait until pneumonia develops, and  then  you should treat it?’ ”

Had she walked the Dhaka Shishu wards with Saha, this woman would have seen listless children lying under oxygen masks, the families gathered at their bedside or crowded somberly in the hallways, waiting for antibiotics to take hold. And those are the families who have made it to the hospital. “For the remotest places,” Saha said, “this”—the preemptive strike of a working vaccine—“is the only tool we have.” In the villages and poorest city slums, pneumococcus-sickened children still die by the thousands at home.

Sanjida Sahajahan made it to Dhaka Shishu, but doctors could do little for her. Saha carries special frustration about her case. His lab identified the pneumococcus that infected her brain: serotype 1, one of the varieties not targeted in the inaugural version of Prevnar. So even if Bangladesh had been able to afford the vaccine in 2005, it would not have protected Sanjida—because the manufacturer had launched a lifesaving product not meant for her part of the world.

“And it’s not only that child who is nonfunctional,” Saha said. “The mother is nonfunctional. She cannot go anywhere. Each and every member of that family is really half dead.”

He was quiet. “We gave them a wheelchair,” he said. “Was she using it?”

It was in pieces, I said, under the bed. Saha winced. But the two-month-old baby, Jannat—the parents showed us her health card too, I told him, and its new column with the check mark in place: pneumococcal conjugate vaccine. If the inoculation does its job, Jannat will be protected from the pathogen that devastated her sister, and when Saha thought about all this, the grief and hope all shoved together inside that very small home, he sighed. “We should still look at how many children we lost, and how many were disabled like this, in those 10 years while we were waiting for the vaccine,” he said. “But thank God we have got the vaccine now.”

The sprawling GSK campus in the Belgian city of Wavre is the biggest vaccine production facility in the world. The day I met Luc Debruyne, the company’s global vaccines president, I’d already been obliged twice to change clothes. Each vaccine’s biological and mixing work is hermetically contained inside its own separate building, and stepping into one of these dedicated structures requires a complete switch to clean-room suit, cleansed white shoes, and protective goggles and cap over eyeglasses and hair.

Those buildings, along with other parts of the company’s vaccine operation, represent an investment of more than five billion dollars over the past decade, Debruyne said. “It  is  a profitable business,” he added. “It needs to be profitable to be sustainable, to be able to offer massive volume and affordable pricing to the developing world.”

The children’s pneumococcal vaccine GSK delivers to Dhaka is a global production: Mixing starts at the company’s plant in Singapore, vaccine batches are sent to Belgium and then France for processing, and the vials are finally returned to Belgium for shipping. As I peered through those goggles at the great silvery machines and vats at Wavre, though, the product under preparation was another GSK offering—a vaccine against a pathogen called rotavirus, the leading cause of children’s diarrhea, which sickens millions every year. In the poorest countries of sub-Saharan Africa and South Asia, it kills by the hundreds of thousands. Many children in Dhaka Shishu are struggling to recover from it.

Bangladesh has Gavi approval to start receiving GSK’s rotavirus vaccine , probably sometime next year. After the negotiated discount and additional financial support, the government will pay about 50 cents for each two-dose course of a vaccine that currently costs an American physician $220. For an impoverished health system, that’s irresistible, but there’s a colossal catch. Gavi aid is supposed to be temporary—a means for poor countries to help more children grow up healthy, and in doing so help improve the countries’ own economies to the point where they can finance important vaccines on their own.

Once a recipient country rises above the world’s lowest per capita income levels, the Gavi subsidy is supposed to be phased out. “It’s called ‘transitioning,’ ” says Doctors Without Borders vaccine policy adviser Kate Elder. “But I’ve heard ministers of health call this being expelled.” Even though leaders of GSK and other major U.S. and European vaccine manufacturers have promised to maintain impoverished -country discounts, losing the subsidy still means a comparatively huge cost increase. In Bangladesh, for example, it could push the GSK pneumococcal vaccine cost from 60 cents to $9.15 per child.

That still looks like a bargain to an American doctor paying more than 50 times that much. But Doctors Without Borders and other critics argue that the prices big American and European drug companies charge for children’s vaccines are unacceptably high, even at a discount. A third of the world’s countries have not yet brought PCVs into their immunization programs; a key reason is long-term cost. From the drug companies, Elder says, “we get this a lot of the time: ‘Why aren’t you just celebrating the kids who do have access now?’ And we say, ‘Yes, but we want more.’ ”

One remedy may lie in emerging competition from outside the U.S. and Europe—from pharmaceutical companies in India, Brazil, Vietnam, Cuba, South Korea, and even Bangladesh, where a Dhaka enterprise now sells nearly a dozen kinds of vaccine, using ingredients shipped in from other countries. An enormous Indian manufacturer called the Serum Institute produces from scratch more than a billion doses a year of relatively inexpensive vaccines, shipping them throughout India as well as abroad. Disease experts at the Gates Foundation and PATH, a global health nonprofit also based in Seattle, are helping Serum develop its own children’s pneumococcal vaccine. Trials are underway in India and Africa, and that vaccine could be on the market by 2020.

Samir Saha is 62 now, with no imminent plans for retirement. It’s too soon to assess definitively the success of PCVs in Bangladesh, but the last time we walked through Dhaka Shishu together, he was upbeat. Only three pneumococcus patients were in the general ward that day, none appeared in grave danger, and one of Saha’s researchers was at a computer working on a bar graph that showed a tantalizing case drop for autumn 2016—one short bar, dwarfed by much taller ones from the six preceding autumns.

Saha pulled up a chair and looked closely at the graph. Let’s wait and see next year, he said. But he was smiling. “Good for the patients,” he said. “Less pneumonia in the hospital. Less death.” He waved his arm toward all the researchers bent over microscopes. “Jobless!” Saha joked, and his smile broadened. “All of them will be jobless!”

Originally published by National Geographic Magazine and natgeo.com in November 2017.

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Helen Branswell, STAT Helen Branswell, STAT

• Copy URL https://www.pbs.org/newshour/health/12-lessons-covid-19-taught-us-about-developing-vaccines-during-a-pandemic

12 lessons COVID-19 taught us about developing vaccines during a pandemic

The extraordinary drive to develop COVID-19 vaccines was like a moonshot — and like that fabled acceleration of space exploration science, it delivered. Just a little over six months after the first COVID-19 vaccines were authorized for use, nearly 3 billion vaccine doses have been administered around the globe.

The world got very lucky; so much went right in the quest for vaccines to end this pandemic. But there have been setbacks (see: Sanofi) and failures (see: Merck) along the way, and the progress toward supplying vaccine to less affluent parts of the world has been scandalously slow.

As life begins to return to normal — at least in countries with access to vaccines — STAT wanted to take stock of some of the things that worked in the fast-tracked development of vaccines and some of the things that didn’t. Interviews with a number of experts in immunology, drug development, and government research revealed a dozen lessons we should learn from the COVID-19 vaccine project for next time. Sadly, there will be a next time.

Basic science investments can pay huge dividends

On Jan. 11, 2020, the genetic sequence of the new coronavirus, later named SARS-CoV-2, was published in Genbank, an international repository available to scientists around the world. Almost 11 months to the day later, the United Kingdom started immunizing people with the first vaccine authorized in the West, the one made by Pfizer and BioNTech. Clinical trials had shown it was 95 percent protective against COVID-19. Vaccines made by Moderna, AstraZeneca, and Johnson & Johnson quickly followed Pfizer into use.

This is a historic feat.

“Nobody expected to get a vaccine available within 2020 — I mean, it was just ridiculous to think that. So, to get multiple vaccines out there within a year, a full year, has been a pretty amazing accomplishment overall,” said John Moore, an immunologist at Weill Cornell Medical College.

But it wasn’t a miracle or a fluke, stressed John Mascola, who heads the National Institute of Allergy and Infectious Diseases Vaccine Research Center. The 2002-2003 SARS outbreak alerted scientists to the epidemic risk coronaviruses pose; that lesson was re-emphasized when a camel coronavirus, MERS, started causing sporadic outbreaks on the Arabian Peninsula in 2012. Scientists worked for years figuring out how to target coronaviruses with vaccines.

READ MORE: Johnson & Johnson says its Covid vaccine protects against Delta variant

When China revealed a coronavirus was the cause of its fast-moving outbreak in Wuhan, scientists who design vaccines built on that early work, focusing on the main protein on the exterior of the virus, the spike protein, as a vaccine target. The rest is history.

The other part of this is the money governments — particularly the U.S. government — invested so the vaccines could be fast-tracked, said Anna Durbin, a vaccine researcher at the Johns Hopkins Bloomberg School of Public Health.

“Without the support from the federal government for the clinical trials and advanced purchase vaccines, we never would have been able to move to Phase 3 clinical trial so quickly and have the manufacturers commit to large-scale production,” Durbin said.

Redundancy is critical in a vaccine quest

Vaccine development is a fraught area of research. Historically, more projects fail than succeed. Knowing that, the leadership of Operation Warp Speed, the U.S. effort to fast-track vaccines, diagnostics, and drugs decided to spread the government assistance around.

Warp Speed funded different types of vaccines, and where possible, chose to support a couple of each type it funded or committed to purchase. “Several bets in each lane. … I think that was important,” said Bruce Gellin, chief of global public health strategy at the Rockefeller Foundation.

Warp Speed wasn’t interested in the old-school inactivated virus vaccines some Chinese developers were making; experience has shown those vaccines often don’t trigger a strong enough immune response. It chose two messenger RNA vaccines, two made using viral vectors, and two protein-based vaccines. Astonishingly, five of the six projects have led to vaccines that are already in use or will soon be, here or abroad.

“Having multiple shots on goal with different platforms, this was the best way to do this and, you know, let the chips fall,” said Larry Corey, co-leader of the National Institutes of Health’s Covid-19 Prevention Network and a virologist at the Fred Hutchinson Cancer Research Center.

mRNA was ready for prime time

Scientists had been working for years to harness the promise of messenger RNA as a vaccination platform. Like the preparatory work on designing vaccines to target coronaviruses, this paid off in spades.

It had long been recognized that vaccines based on messenger RNA would be faster to make. It wasn’t clear they would be as potent as other vaccine platforms. But potent they were. The Pfizer-BioNTech and Moderna vaccines were both shown to be more than 90% protective.

“Had it been five years ago, mRNA would not have been in the state of maturity, I don’t think, to have been rapidly used in the way it was here,” Mascola said.

READ MORE: Could editing the genomes of bats prevent future coronavirus pandemics? Two scientists think it’s worth a try

This is one of the major scientific achievements of the pandemic. “Five or 10 years from now and when we look back and try to find a ‘positive side’ for the Covid pandemic, I think it will be that it gave the opportunity for RNA to show its full potential as a vaccine platform,” said Ali Ellebedy, an associate professor of pathology and immunology at Washington University School of Medicine in St. Louis who has been studying how the vaccines work.

Ellebedy calls these vaccines “remarkable in basically all aspects.”

mRNA vaccines aren’t the sole solution

CureVac is an important cautionary tale that mRNA is not a fail-proof vaccine platform. On Wednesday the German company revealed that the final results of its Phase 3 clinical trial were a disappointment. The vaccine was only 48 percent protective , which likely isn’t good enough to win regulatory approval. It’s not yet clear why it didn’t succeed, though crucial differences in its design versus those of the Pfizer and Moderna vaccines are thought to be responsible.

FILE PHOTO: A healthcare worker prepares a dose of the Johnson & Johnson vaccine for the coronavirus disease (COVID-19) during the opening of the MTA’s public vaccination program at Grand Central Terminal train station in Manhattan in New York City, New York, U.S., May 12, 2021. REUTERS/Carlo Allegri/File Photo

“So there’s still potential for failure. It’s not that every RNA works,” Corey said.

And despite the spectacular efficacy of the Pfizer-BioNTech and Moderna vaccines, some people are uncomfortable with the new technology, preferring techniques with longer track records, he noted.

“The world does need diversity,” Corey added. “The pathogens and the infectious agents are diverse, the diseases are diverse, and the solutions will always be diverse. There’s never going to be a single solution to every problem.”

When one vaccine crosses the finish line, challenges arise for other clinical trials

The questions started to emerge almost as soon as the Pfizer-BioNTech vaccine was granted an emergency use authorization in early December and began to become available. How do you keep people in blinded clinical trials — where they might have been given a placebo — to continue testing other vaccines once they have the option to quit and get the authorized product?

“All of a sudden there were questions that were … I don’t know if they were novel, but we hadn’t faced them in a while,” admitted Christine Grady, chief of the department of bioethics at the National Institutes of Health Clinical Center. “We probably should have anticipated it.’’

In the very early days, supply of the Pfizer vaccine was so scarce most people in clinical trials had no chance of getting doses. But the Moderna vaccine became available and supplies increased. So did the incentive for people to drop out of the trials that were still underway.

The Food and Drug Administration worried about the loss of long-term data and urged manufacturers to consider working a “crossover” into their trial designs to retain participants. Everyone who had received placebo would later receive vaccine; those who’d received vaccine would get placebo shots. Most of companies dismissed the idea as too complex and too expensive.

The sole exception among U.S. trialed vaccines was Novavax, which was several months behind the first vaccines. “They didn’t have a choice,” said Moore. “By the time they got their trial started, many people had access to the mRNA vaccines.”

Moore was enrolled in that study; within a month of its start he could have gotten vaccinated at work. He stayed in the trial, but Novavax had 5,000 dropouts, the company revealed earlier this month when it reported its vaccine was 90 percent protective.

Experience is important, but it’s not everything

When a research group from the University of Oxford teamed up with drug maker AstraZeneca to develop their COVID vaccine, the union raised some eyebrows. The Oxford researchers had a laudable goal; they wanted to make an inexpensive and easy to use vaccine that could be produced in multiple parts of the globe. The world’s vaccine, it was dubbed. But AstraZeneca was a minor player in vaccine production.

Conducting pivotal Phase 3 trials is complex stuff; these trials have to generate data that convince regulatory agencies of a vaccine’s safety and efficacy. Some unfortunate choices by the Oxford group left regulatory agencies in a quandary about how to use this vaccine. The Oxford team enrolled few people over age 65, the demographic that most needs COVID vaccines, and ran several studies that generated data that were hard to compare. The European Medicines Agency even noted in its ruling that the data generation might have benefited from more involvement of the manufacturer.

“AstraZeneca — that should be a Harvard Business School case study,” remarked one expert who didn’t want to be named.

But three of the world’s most experienced manufacturers have not managed to produce a COVID vaccine. Merck tried two approaches; both failed. Sanofi likewise entered two horses in the race, but a costly error with its most advanced vaccine forced it to redo its Phase 2 study. Unique among the major vaccine manufacturers, GSK didn’t even try to develop its own vaccine. It partnered with Sanofi — providing a boosting compound called an adjuvant — on one vaccine and is now working with CureVac on a second-generation mRNA vaccine.

Vaccines aren’t vaccinations

The Trump administration generously funded Operation Warp Speed, but seemed to ignore the challenges of the so-called last mile — what happens when vaccine doses arrive at the point of delivery. Initially that lack of planning and funding led to chaos.

“The big lesson is that as soon as you start coming up with a vaccine, you should start thinking about the vaccination end of it,” said Gellin, of the Rockefeller Foundation. “It’s worked out over time. But the ‘Hunger Games,’ to try to get a reservation to get a vaccine — that was not thought through.”

Claire Hannan agrees the early efforts were rocky.

“To me that was the hardest thing. To watch people not be able to find the vaccine. … To understand that, ‘OK, I need to wait my turn,’ but to not know when their turn was, and to have their turn be different in every state and to have that anxiety about their parents getting the vaccine or their loved ones getting the vaccine,” said Hannan, executive director of the Association of Immunization Managers.

“We’ve got to learn from that.”

Complex priority schedules are hard to execute

It was always apparent that demand for vaccine would far outstrip supply in the early days. A lot of effort went into trying to determine who should be first in line.

The National Academies of Sciences, Engineering, and Medicine appointed a panel of experts to come up with a plan for equitable allocation of vaccines. The Advisory Committee on Immunization Practices, which advises the Centers for Disease Control and Prevention on vaccine use, came up with its own plan. The documents weren’t identical, but both stressed the need to include essential workers near the front of the line.

But with the exception of health workers, who would be vaccinated at work, figuring out who qualifies as an essential worker is no small task. And asking vaccination clinics to check for people’s bona fides wasn’t going to happen; everyone knew it would function — if it functioned — on an honor system.

Many states ignored the plans.

“It’s very difficult to implement [an] essential workers [category],” Hannan said. “We don’t have a way of enforcing that. I think some states discovered ‘We know who’s 80. … We can do it a lot easier that way.’”

Packaging matters

The first vaccine to be put into use was both a miracle and a nightmare. The Pfizer vaccine was 95 percent protective, a virtual home run. But it required ultra-cold storage, a capacity neither doctors’ offices nor pharmacies had.

To make matters worse, the company decided to set its minimum order at more than 1,000 doses, which benefited Pfizer but restricted where the vaccine could be used. The company shipped the vaccine in special freezer packs that could only be opened twice a day. There was nothing easy about putting this vaccine into the field, and Pfizer’s packaging made it harder.

“It very much limited the providers that could be used. And it placed an enormous amount of stress on the planners because it was an enormous challenge. And it took time away from all of the other little things because it was just such a huge undertaking,” Hannan said.

There’s power in numbers

With several new vaccines being rolled out at once, regulatory agencies have been keeping a keen eye out for any hints of adverse events. The authorized vaccines appeared safe in the clinical trials, but rare side effects will only show up when millions of people are vaccinated.

READ MORE: Something to celebrate: delivering vaccines to essential workers

A number of regulatory agencies set up a “red phone” system — they call it that, but in truth, it’s a WhatsApp group — to share information about potential adverse events. If any member agency spots something that looks like a problem, it pings the other members. When needed, conference calls are rapidly convened.

FILE PHOTO: Mary Cordelli of Hedgesville, West Virginia, receives her boost dose at a coronavirus disease (COVID-19) community vaccination event, as the vaccination rate in West Virginia ranks among highest in world, in Martinsburg, U.S. February 25, 2021. Photo by Kevin Lamarque/Reuters.

The system has worked well, officials from the EMA and Health Canada revealed during an online conference last week hosted by MaRS, a Toronto-based innovation hub. The FDA, and regulatory agencies from Britain, Switzerland, South Korea, and Singapore, among others, are also members.

“The larger the group of people exposed, you have a better idea, you have more confidence in your findings,” Agnes Saint-Raymond, who heads the EMA’s division of international affairs, said during the panel.

Pregnant and lactating people were left in the lurch yet again

When new vaccines are being developed, manufacturers routinely test them in healthy adults first, later moving to more vulnerable demographic groups. Pregnant and lactating people and children are typically last on the list.

It’s born of a desire to protect, but it often ends up creating a conundrum. If pregnant people weren’t included in clinical trials, how would they know if it was safe to be vaccinated?

Johns Hopkins researcher Ruth Karron and colleagues argued from the earliest days of the pandemic that pregnant and lactating people should be included in the clinical trials. They were not. And though vaccine manufacturers promised to do the critical animal studies — known as developmental and reproductive toxicology, or DART, studies — needed before vaccines can be tested in pregnant people, they were slow to do them.

With the U.S. government helping to fund development of the vaccines, there was no excuse for not doing this work early, said Karron.

“When resources were limitless, nobody could claim, ‘Oh, we can’t do DART studies early because gee, the resources just don’t exist, and those are really expensive studies.’”

The lack of data left pregnant people and their doctors to decide on their own whether they wanted to be vaccinated. A recent study from the CDC showed that as of early May, only 16% of pregnant people in the U.S. had opted to be vaccinated.

“By all means, we should have learned this lesson,” Karron said.

Grady suggested it may require action from government to change this persistent problem, such as linking government assistance to a requirement to do early testing in pregnant people.

Vaccine inequity is well and truly entrenched

The United States has more vaccine than people willing to be vaccinated at this point. Nearly 78 percent of people over 65 are fully vaccinated; 54 percent of Americans over the age of 12 are fully vaccinated.

Canada, Britain, and a number of other rich countries have high and growing rates of vaccine coverage. Meanwhile, many less affluent countries haven’t yet vaccinated 1 percent of their populations.

There’s been a lot of talk about what to do, but it’s not translating into swift action. The lesson many countries are surely learning is that when it comes to pandemics, national interests trump global solidarity.

The director-general of the World Health Organization, Tedros Adhanom Ghebreyesus, regularly pleads with countries that have vaccine to share more of it, calling the situation a “catastrophic moral failure.”

Durbin, the Johns Hopkins researcher, said over the longer term, the answer has to be greater capacity to make vaccines — capacity that’s distributed across the globe, and not solely in rich countries.

“We need more vaccine manufacturing infrastructure (not only buildings but experience in producing vaccines and evaluating the safety and efficacy of vaccines) globally, particularly in [lower- and middle-income countries],” she wrote in an email.

“If they had the ability to produce them, they could meet the needs of their own countries. We need to continue to invest in the vaccine sciences and in vaccine manufacturing.”

This article has been updated to include the final results of CureVac’s Phase 3 vaccine trial.

Editor’s note: Johnson & Johnson is a funder for the PBS NewsHour.

This article is reproduced with permission from STAT. It was first published on June 30, 2021. Find the original story here.

Helen Branswell is STAT’s infectious diseases and public health reporter.

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Dr. Fauci on delta variant, booster shots and masks for the vaccinated

Health Jun 29

The Anti-Vax Movement Isn’t Going Away. We Must Adapt to It

A merica’s immunization policies are facing a bleak future. Political polarization about vaccine policies is likely to cause outbreaks of previously controlled infectious diseases. If we cannot prevent these disasters, we should pivot our focus towards managing them.

Resistance to vaccination is not a new problem , but the COVID-19 pandemic exacerbated it. It should be clear by now that neither persuasion nor coercion is sufficient to change the minds or the behavior of people who are determined to refuse vaccines. Education and research cannot defeat coordinated misinformation. And government efforts—at federal, state, and local levels—are stymied by a combination of inadequate power, insufficient political will, and a lack of perceived legitimacy by vaccine refusers. One of America’s core lessons from the COVID-19 pandemic is that a heavy-handed response to vaccine refusal can make things worse.

Many U.S. states have ended their COVID-19 vaccine mandates. But America’s childhood vaccine mandates for school entry are also vulnerable. As researchers of vaccination social science, ethics, and policy, we have sometimes encountered an optimistic view that immunization in America will soon snap back to a pre-pandemic “normal.” But this hope ignores the cracks that were already present in America’s immunization social order before the pandemic, cracks that COVID-19 only widened. State-based conflicts over school enrollment vaccine mandates became increasingly political and contentious during the 2010s. Continued political polarization about vaccine mandates is likely to reduce immunization rates and precipitate the return of previously controlled diseases. That’s why it’s time to adapt to vaccine refusal and prepare to manage these outbreaks, rather than hope they can be prevented.

More From TIME

All American states require vaccines for school enrollment, but most permit parents to opt out of vaccinating by obtaining a nonmedical exemption. Nonmedical exemptions may be available based upon religious or personal beliefs, depending on the state. Attempts to change these exemption policies have emerged as polarizing flashpoints for Democrats and Republicans. In 2015, California took the unprecedented first step of eliminating nonmedical exemptions to its vaccine requirements to reduce rates of vaccine refusal. Since 2015, Democrats, major physician organizations like the American Medical Association, and pro-vaccine parent activists have tried to remove nonmedical exemptions in many other states.

Democratic lawmakers have now eliminated nonmedical exemptions in California, New York , Washington State (for measles vaccine), Maine, and Connecticut. New national organizations, like the Safe Families Coalition, are pushing for similar changes in many other states. Where Democrats organized to abolish vaccine opt-outs, Republicans fought to protect or expand them. The fight continues, as Republicans look for ways to further weaken childhood vaccine mandates. A case in point: on 17 April this year a Republican judge in Mississippi reinstated a religious exemption to that state’s vaccine mandates that courts had overturned in 1979. 

Attempts to scrap nonmedical exemptions inject new kinds of coercion into a fracturing immunization social order. This intensifies the politicization of school vaccine mandates and erodes public support for these critical policies. Conflicts about COVID-19 pandemic control measures were not outliers, but instead signs of a crumbling immunization consensus. The bitter truth is that nonpartisan vaccine policy was dead before the world had heard of COVID-19.  

Removing nonmedical vaccine exemptions will not overcome vaccine refusal or prevent outbreaks. Only in states where Democrats control all levers of state power can such bills pass, given unified Republican opposition. These policies can deliver local increases in immunization rates. However, even in Democrat-led states, enforcement is likely to be uneven at best, and to be worse in communities where immunization rates are already low. For example, the leadership of private schools is unlikely to enforce strict vaccine mandates that they believe are inconsistent with their values, or that will cause them to lose substantial tuition revenue.

Local successes in Democrat-led states are likely to be overshadowed by immunization policy failures in Republican-led states. In the current political climate, Democrats own the issue of eliminating nonmedical exemptions. In contrast, Republicans have emerged as champions of preserving and expanding them, or even of eliminating mandates altogether. Republicans will weaken existing mandates in the states that they control, and this will lead to lower immunization rates in those places, and perhaps beyond, as vaccination policy embeds more deeply in America’s culture wars.

Read More : How the Anti-Vax Movement Is Taking Over the Right

The implications are significant. The near future likely portends escalating disputes about immunization policy, lower vaccination rates, and a resurgence of diseases once tamed by vaccines. Our response should be to adapt to widespread vaccine refusal rather than to nurture naïve hopes of overcoming it. If we can’t prevent outbreaks, we will need to learn to live with them.

Public health institutions have a crucial role in this shift towards adaptation. They must enhance their capacities, extending COVID-19 surveillance techniques like sewage sampling to encompass other diseases. This method helped New York State Department of Health detect polio virus in wastewater samples in 2022. There is also an urgent need to train medical professionals in diagnosing and treating vaccine-preventable diseases that were once thought to be controlled or eliminated. And governments should prepare to rapidly deploy mobile clinics and response teams to areas hit by outbreaks.

Community-level planning is essential for adapting to more frequent outbreaks in schools and other institutions. Strategies should include the ability to move between in-person and online schooling and the provision of daycare services for essential workers’ children, especially to safeguard the capacities of health care institutions.

Private institutions, from businesses to cultural organizations, must plan their own disease control measures. These may include private vaccine mandates, although state legislatures may outlaw such policies, as some did for COVID-19. However, businesses will be able to keep the assembly lines going and the service counters staffed only if they can reduce the impact of disease on their workforce.

Given the prospect of uneven state and institutional support for vaccination, individuals and families must also brace themselves for more frequent disease outbreaks. Some new parents already prevent unvaccinated relatives from visiting their babies. Families will need to consider extending these forms of private immunization governance when states can no longer protect them.

We are not talking about “giving up.” Governments should continue to promote vaccine acceptance and enforce vaccine mandates. The right kinds of outreach can sway some people who are on the fence about vaccinating. But these efforts alone are unlikely to be sufficient to prevent future outbreaks. Adapting to the times we live in is the only way forward.     

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OMNIA Q&A: Shots Fired: The Controversy Surrounding Vaccinations, Then and Now

Robert Aronowitz, Walter H. and Leonore C. Annenberg Professor in the Social Sciences, reflects on vaccine hesitancy today compared to the past, and the politicization of public health.

The story of the COVID-19 vaccines is a winding one. Never in the world’s history has a vaccine been developed and deemed safe and effective so quickly—in less than 12 months. For many, it felt like a miracle. For others, it brought trepidation. In the United States—where vaccines are widely available—about 23 percent of eligible individuals have chosen to not get a jab. The ongoing controversy around vaccination uptake has left many Americans on opposite sides of a fiery debate which has significant implications for public health.

Robert A. Aronowitz, Walter H. and Leonore C. Annenberg Professor in the Social Sciences

Robert Aronowitz, Walter H. and Leonore C. Annenberg Professor in the Social Sciences, has extensively researched vaccines related to HPV and Lyme disease and says, “Every vaccine has a unique history. How the public reacts to a vaccine is based on the target condition it’s treating, the concerns and fears that are raised, and the era in which it comes up. No vaccine story is the same.”

We asked Aronowitz, a professor in the Department of History and Socology of Science and co-editor of Three Shots at Prevention: The HPV Vaccine and the Politics of Medicine’s Simple Solutions, his thoughts on how vaccine hesitancy today compares to the past, the politicization of public health, and the power of vaccination mandates.

How does current vaccine hesitancy and controversy look either familiar or different compared to the past?

The resistance to COVID-19 vaccinations is by no means the first instance of vaccine hesitancy. There has been opposition to vaccinations throughout history. For example, the controversies around the MMR vaccine to protect against measles, mumps, and rubella and the erroneous belief that it causes autism is one example. My HPV research looked at, among other points of contention, how the overreach of pharmaceutical companies—in underhanded lobbying of state legislatures, high pricing, and aggressive marketing that created and exploited fear—undermined the trust necessary for many ordinary people to get jabbed.

I would say that the controversy around the COVID-19 vaccines has more of a left-right political quality to the opposition than existed with some of the other vaccines of the past. Certainly, some of the opposition to older vaccines did arise from a feeling that there was overreach of the local, state, and federal government, which is a political point of view. However, the left-right dimension to the COVID skepticism seems more extreme. As a historian, I would say this is about a moment in time and the politics of that moment. Perhaps if we had had better leadership and direction under the Trump administration, this would have played out differently.

There have been some COVID vaccine mandates for healthcare workers, within private corporations, and soon, within the federal government. Are mandates historically a useful tool to increase vaccine uptake?   

I’m on sabbatical in California right now and there is a mandate for healthcare workers here to be vaccinated, and compliance is really high. Mandates can work to get people who are on the fence or dragging their feet to get it done.

Based on the research of other experts, I’d mention the effectiveness of leverage points. A good example of this is the vaccinations that children are required to receive to begin schooling. The push for school mandates for childhood vaccinations came about because of the awareness that lots of people were not getting vaccinated because they had substandard access to healthcare, particularly the poor and minorities. There were social and racial inequalities in vaccine uptake, which was threatening herd immunity and the health of children not vaccinated. The basic idea was that by mandating vaccination for entry into school, you could create a powerful leverage point to influence people and put pressure on localities to find ways of providing and paying for vaccines.

Many people choose not to vaccinate because it’s inconvenient to do so, not necessarily because of ideological reasons. Everyone wants their kids in school—it’s a powerful incentive. Every state in the union eventually had school vaccine mandates and that went hand-in-hand with other programs like CHIP, the expansion of Medicaid’s service to children, and programs to subsidize what families pay for vaccinations. The approach was quite effective.

You’ve extensively studied vaccinations for HPV and Lyme Disease. How does your research dovetail with the current COVID landscape?   

My research emphasizes that we have to look closely at the particular circumstances in which vaccines are developed, what the target disease is, and the peculiarities of its preexisting controversies. For example, vaccine hesitancy around Lyme disease had little to do with the kind of concerns or politics that surrounded vaccines like the MMR or others of the time, and everything to do with the problematic nature of what Lyme disease is.

There was a preexisting and ongoing fight over whether Lyme disease is a relatively straightforward tick-borne disease that doesn’t usually cause long-term, serious problems even if left untreated, that is relatively easily treated when identified, doesn’t require multiple courses of antibiotics, and only very rarely leads to chronic symptoms. That’s the sort of mainstream expert medical view of the disease, but a lot of other people believe that Lyme disease is much more serious: That it’s not easily treated by oral antibiotics, that it requires multiple courses of intravenous antibiotics, and that it can cause all kinds of symptomatology, including chronic fatigue, weakness, and various other neurological manifestations. This group originally supported a Lyme disease vaccine, but they turned against it when the success of the vaccine seemed to undermine their alternative view of Lyme disease. The very definition of the disease used in the clinical trials was this narrow acute problem version.

Before introducing the vaccine, there was some issues with the immunological criteria to diagnose Lyme disease. Because clinicians use immunological tests to diagnose the disease, there was concern that there would be overlap between people who were vaccinated and people who looked like they had the disease. So, they changed their criteria and some people in the Lyme disease community got really angry about the narrowing of immunological criteria for diagnosis. Additionally, the more lay oppositional view posited a possible immunological mechanism for the chronic symptoms of Lyme disease, basically a kind of autoimmune reaction to the offending spirochete. If you believe that theory, then you worry that a vaccine could cause long-term problems because vaccines work by inducing immunity. As of today, there is no Lyme disease vaccine for humans currently available largely because of this particular context and other factors such as medical ambivalence about a vaccine against a treatable, non-deadly disease in comparison to, say, the often untreatable and potentially deadly consequences of HPV infection, which does have a vaccine. Ultimately, the context and the details surrounding vaccines matter when talking about the vaccine hesitancy that may arise in each case.

Katelyn Silva

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• CORONAVIRUS COVERAGE

How COVID-19 is changing our expectations for other vaccines

The shots developed during this pandemic have been stunningly successful—and experts worry that may spell trouble for future vaccine uptake.

As scientists raced to create new vaccines that would fight the novel coronavirus, Matthew Motta had a question: What did Americans expect from these vaccines?

Motta, a political scientist at Oklahoma State University who studies vaccine hesitancy, polled nearly 1,000 American adults on their expectations for the then-hypothetical shots. His peer-reviewed study , published this March in Social Science & Medicine , uncovered what he described as predictable results: Given the choice between various efficacy rates and single or multi-dose shots, the vaccine Americans would most prefer was a single dose that boasted at least 90 percent efficacy and almost zero chance of causing even minor side effects.

“It’s not too surprising that people would prefer safe and effective vaccines,” he says. But as Motta reviewed the poll’s results last year, he says he was worried because “these vaccines were never particularly likely to live up to the hype.”

And then they did.

The first two vaccines approved for emergency use authorization in the United States — shots created by Moderna and Pfizer-BioNTech using new-to-market mRNA technology — boasted 94 and 95 percent efficacy rates, respectively, shattering the U.S. Food and Drug Administration’s benchmark of 50 percent and causing the scientific community and the public alike to celebrate.

It was, Motta says, “amazing news.” But it also led him to another worrisome question: Would these spectacularly efficacious and safe shots — produced in record-breaking time — fundamentally change people’s vaccine expectations? In other words, would people come to expect that future vaccines be created as quickly and be as safe and potent as the COVID-19 vaccines?

Motta is seeking funding to find the answer. But he and other experts suspect that — at least in the short term — some people’s vaccine expectations have risen, with potentially serious consequences: Expecting quickly created, near-perfect vaccines could increase hesitancy in those already inclined to waver in their vaccine convictions if future vaccines fall short.

How people evaluate vaccines

Historically, “a vaccine for a disease was either available or not,” explains Rossi Hassad, an epidemiologist and professor of psychology at Mercy College. “Evaluating the efficacy and safety of vaccines has not been part of the public’s pre-COVID-19 psyche and vocabulary.”

For example, the yellow fever vaccine — a one-shot vaccine recommended for those traveling to at-risk areas in Africa and South America — carries a miniscule risk of severe reactions and even death. But “most people don’t know that,” says Paul Offit , director of the Vaccine Education Center at the Children’s Hospital of Philadelphia and a government adviser on vaccine policy. “I think most people don’t know the risks because we didn’t trumpet them like we trumpeted this.”

Amid the pandemic, however, almost all publications focused on covering the virus and potential ways to fight it, including the development of vaccines. The public could choose from dozens of articles each day relaying details of the vaccines’ development, including the potential risks they posed for those who would later decide to get inoculated.

In late 2020, Jennifer Trueblood , an associate professor of psychology at Vanderbilt University asked roughly 34,000 Americans about their willingness to take a COVID-19 vaccine. The subsequent study , published in March in Social Psychological and Personality Science , revealed that people who are risk averse were less likely to say that they would get a COVID-19 vaccine.

“What’s clear is that people are viewing [COVID-19] vaccines as a risky decision,” she says. And the public’s collective and all-consuming attention to “very specific information about the risks and rewards is shaping how people are thinking about vaccines more generally,” she adds.

A new standard?

To make decisions, many people need a reference point — information that helps them weigh the pros and cons of a particular choice. For example, if a college graduate is offered a starting salary of $50,000, she may not know whether that is a good deal. But if she learns the majority of her classmates have been offered only $30,000, then she is likely to believe that she is earning very good money.

In this way, the first COVID-19 vaccines to be authorized for emergency use in the U.S. may have set a reference point for people to evaluate future shots, says Gretchen Chapman , a psychologist and professor of social and decision sciences at Carnegie Mellon University.

Hassad adds: “The standard set by the mRNA vaccines — in terms of speed of development and the level of efficacy and effectiveness — will quite likely raise the bar in terms of public expectations: wanting more, better, and faster when it comes to … vaccines for other diseases.”

If a doctor recommends a particular vaccine, he explains, “I can hear people saying, ‘How good is that vaccine? How effective is it? Is it good for people like me? Are there any factors about my life that I need to consider?’ I think it’s just really upped the bar in terms of patient education in their personal health — which, of course, will contribute to their decision-making about health.”

The COVID-19 vaccines were also produced in less than a year. Decades of research and billions of dollars of government funding, combined with a single-minded focus from the scientific community, facilitated their swift production. But at the end of the day, what sticks for some is the headline: that a vaccine can be created and go to market in less than a year.

Offit rejects the notion that people’s vaccine expectations are shifting fundamentally, in part because he believes that people have always expected the very safest and efficacious vaccines.

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But he says the quick creation of COVID-19 vaccines “should have awakened people to the fact that when you put an enormous amount of money into something, we have the scientific ability and know-how to do something as remarkable as this.”

Motta’s study, conducted ahead of the release of the vaccines’ final clinical trial results, showed that participants only had a slight preference for shots that take longer to develop: they were almost equally likely to take a vaccine that took a little more than a year to create and one that took a little less than a year to produce. “At the time, that was good news, because it meant that people were willing to take a shot that, relatively speaking, was developed quickly,” Motta says.

But he also wonders if the speed at which they were created could cause a future problem: “If a vaccine takes longer to develop, will people be less likely to take it?” Motta asks.

The answer, he says, is unknowable now. However, a national survey conducted in March by the Pew Research Center revealed that “a sense that vaccines were developed and tested too quickly” was a top concern for 67 percent of the respondents who say that they do not plan to get a COVID-19 shot. A separate April poll found that about one in five Americans say they will not get a vaccine.

Expecting a choice

The COVID-19 vaccines may have also set another reference point: that the public should have its choice among vaccines targeting a specific disease. Though many people have struggled to get their first shots , others have had the luxury of choosing which COVID-19 vaccine to get.

And for some, that choice was between what they perceived to be a better and worse vaccine.

The third vaccine to be authorized for emergency use in the U.S. was Johnson & Johnson’s shot, which scientists hailed as a success: Unlike its predecessors, the vaccine didn’t require ultra-cold storage, which meant it could potentially better reach rural communities. And its one-dose regimen could make it easier for vulnerable communities — such as those without transportation or paid time off work — to get inoculated. But when publications shared the vaccine’s efficacy rate for preventing COVID-19 infection, 66 percent, some people perceived it to be subpar . (The Johnson & Johnson vaccine trials included some of the more easily transmissible variants of COVID-19, which could have lowered its efficacy rates, but most experts agree it is an excellent vaccine .)

“There’s such a sensitivity about the vaccines and what they represent in terms of effectiveness and safety, especially since Johnson & Johnson entered the scene,” Hassad says.

And a nationwide poll conducted in mid-April by ABC News and the Washington Post found that people’s confidence in the shot plummeted when the FDA temporarily paused its distribution after six women contracted life-threatening blood clots : a majority of unvaccinated Americans — about 73 percent — said that they were unwilling to get the J & J vaccine. The FDA later lifted its pause , and recommended its continued distribution.

While the evidence is currently based on polls and anecdotal accounts, “it looks like we might be developing perceptions of a hierarchy of good versus not-as-good vaccines,” says Kasisomayajula Viswanath , a professor of health communication in the Department of Social and Behavioral Sciences at the Harvard T. H. Chan School of Public Health, “and that worries me.”

In the short term, unreasonable expectations of vaccines can have devastating consequences: By pausing the distribution of the J & J vaccine, Offit says the FDA put a “scarlet letter” on the shot — and with that red flag in place, “there are people who would have gotten that vaccine who now won’t, and because they won’t get that vaccine, they don’t get a vaccine.”

In the long term, having a choice between COVID-19 vaccines could also potentially create an “analogous phenomenon” that applies to other vaccines, whether COVID-19 boosters or other vaccines entirely, says Chapman. “If people know that a choice is possible — and especially for some savvy consumer patients who are going to read up on all the comparison points between the vaccines — it’s possible that now they’re going to come in and demand a particular vaccine.”

But overall, in the pandemic or out, “if people delay for long periods, unvaccinated, to wait to get access to what they perceive as a better vaccine, they put themselves and their communities at risk,” says Walter Orenstein, a physician and associate director of the Emory Vaccine Center.

Learning to evaluate risk

Trueblood says that people’s overall expectations of vaccines are “likely to be determined by their experiences with recent vaccines,” and that the COVID-19 shots could serve as a reference point for coronavirus boosters and even novel vaccines produced in the next couple of years.

However, it’s “really hard to tell” if those expectations will persist, she says. “It’s my hunch that they would have less of an influence as time goes on,” Trueblood adds.

Events that are similar to one another can cause people to recall specific memories: If another pandemic-causing disease emerged in a decade, “that’s going to cause people to remember this experience more,” Trueblood says. But if a novel vaccine is created to fight a different disease, under different circumstances, “it’s hard for me to believe that people’s experiences with the COVID-19 vaccines will have much of an influence,” she says.

Some experts believe looking to the upcoming influenza season could provide clues to whether vaccine expectations now will have a lingering effect later. “What I’m seeing is a year from now — when COVID-19 becomes very manageable — at that point, we will get back to the issue of flu vaccines,” Viswanath says. “And I'm wondering if people will start paying attention to them.”

Fewer than half of American adults get flu shots each year, which range in effectiveness from 40 to 60 percent . “I’m wondering now, if even more adults will say that, compared to COVID-19, the flu is really not that severe and the efficacy rates are so much lower — so why should I bother kind of a thing?” Viswanath says. Other adult vaccines are much more effective: The shingles vaccine, for example, is 90 percent effective at preventing the infection and pain.

In the meantime, the right kind of health communication is essential to helping people set reasonable expectations of vaccines — and encourage vaccinations in spite of perceived risk.

When people are oversaturated with vaccine information, targeted messages that appeal to their perceptions and beliefs are crucial, says Hassad. Motta agrees. “You can sometimes move the needle on vaccine hesitancy, pun intended, with information,” he says. “But a far more effective way to convince people to vaccinate is to make an effort to understand why they don’t want to vaccinate and then present them with information in a way that [assuages] those concerns.”

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COVID-19 vaccines: rapid development, implications, challenges and future prospects

Shivaji kashte.

1 Department of Stem Cell and Regenerative Medicine, Center for Interdisciplinary Research, D.Y. Patil Education Society (Institution Deemed To Be University), Kolhapur, Maharashtra 416006 India

Arvind Gulbake

2 Dehradun Institute of Technology (DIT) University, Dehradun, Uttarakhand 248009 India

Saadiq F. El-Amin III

3 El-Amin Orthopaedic and Sports Medicine Institute, Lawrenceville, GA 30043 USA

4 BioIntegrate, Lawrenceville, GA 30043 USA

Ashim Gupta

5 South Texas Orthopaedic Research Institute, Laredo, TX 78045 USA

6 Veterans in Pain, Valencia, CA 91354 USA

7 Future Biologics, Lawrenceville, GA 30043 USA

COVID-19 has affected millions of people and put an unparalleled burden on healthcare systems as well as economies throughout the world. Currently, there is no decisive therapy for COVID-19 or related complications. The only hope to mitigate this pandemic is through vaccines. The COVID-19 vaccines are being developed rapidly, compared to traditional vaccines, and are being approved via Emergency Use Authorization (EUA) worldwide. So far, there are 232 vaccine candidates. One hundred and seventy-two are in preclinical development and 60 in clinical development, of which 9 are approved under EUA by different countries. This includes the United Kingdom (UK), United States of America (USA), Canada, Russia, China, and India. Distributing vaccination to all, with a safe and efficacious vaccine is the leading priority for all nations to combat this COVID-19 pandemic. However, the current accelerated process of COVID-19 vaccine development and EUA has many unanswered questions. In addition, the change in strain of SARS-CoV-2 in UK and South Africa, and its increasing spread across the world have raised more challenges, both for the vaccine developers as well as the governments across the world. In this review, we have discussed the different type of vaccines with examples of COVID-19 vaccines, their rapid development compared to the traditional vaccine, associated challenges, and future prospects.

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infections and the resulting diseases, coronavirus disease 2019 (COVID-19) have spread to millions of people worldwide. The World Health Organization (WHO) declared the COVID-19, a pandemic in March 2020 [ 1 ]. The SARS-CoV-2 has affected over 105 million people and has claimed over 2.29 million lives worldwide, as of February 5, 2021. The most affected countries have been the United States of America, with over 26.7 million cases and 456,000 deaths, and India, with over 10.8 million cases and 155,000 deaths as of February 5, 2021 [ 2 ]. COVID-19 has negatively impacted the health and lifestyle of people as well as the economy throughout the world [ 3 ]. An intensive search for an effective drug against the SARS-CoV-2 did not lead to any breakthrough candidates. The drugs like Hydroxychloroquine and Remdesivir were advocated as desperate measures based on contradictory and inconclusive studies and have significantly failed to combat the pandemic [ 4 ]. As the number of COVID-19 patients continues to increase, detecting, assessing, and interpreting the immune response to SARS-CoV-2 infection becomes essential. Multiple vaccine candidates are under development but safe and effective vaccines against COVID-19 are urgently needed to combat escalating cases and deaths worldwide. These vaccine candidates need to be manufactured as soon as possible and made available to all countries and populations affected by the pandemic at an affordable price. A vaccine has the ability to induce herd immunity in societies, which can decrease the occurrence of the disease, block transmission, and reduce the social and economic burden of the disease.

On December 2, 2020, United Kingdom (UK) became the first country to approve the COVID-19 vaccine, BNT162, developed by Pfizer and BioNTech via Emergency Use Authorization (EUA). WHO approved BNT162 for emergency use on December 31, 2020 to allow for easier global manufacturing and distribution. Similar EUA processes were adapted by several countries including, United States, Canada, Russia, China, and India to approve different COVID-19 vaccine candidates (CVCs) and the list is growing. There are a total of 232 vaccine candidates at various stages of development, of which 172 are in preclinical development, 60 are in clinical development, and 9 are approved under EUA by different countries (Tables ​ (Tables1 1 and ​ and2) 2 ) [ 5 ]. Despite the rollout of these vaccines under EUA, several questions need to be answered. How are these vaccines developed so rapidly? Are these vaccines safe and efficacious? How long the efficacy will last? What are potential threats? What are challenges? Are they effective against changing strains of virus? In this review, we will discuss and emphasize the vaccines approved via EUA and the ones that have entered Phase III clinical trials and have demonstrated the potential to be approved.

COVID-19 Vaccine candidates that are in clinical phase and approved under Emergency Use Authorization by different countries

Potential COVID-19 vaccine candidates that are in the clinical phase

What is a vaccine?

“Vaccines are biologics that provide active adaptive immunity against specific diseases” [ 5 ]. Vaccine development involves utilizing the microorganisms responsible for the disease either in the killed or attenuated form, or it involves the use of microorganisms’ toxins or surface proteins. The vaccines are introduced in the body via mouth, injection or by nasal route to incite the immune system against foreign bodies [ 6 ].

In the process of immunity development, the body produces antibodies against specific microorganisms, which generates the defense mechanism. When a person encounters the same microorganisms later, the antibodies produced by the body in response to the microorganisms’ antigens either prevents the person from the disease induced by the microorganism or lessens the severity of the disease [ 6 ]. Vaccines, in general, are considered the most economical healthcare interventions and its said that “A dollar spent on a childhood vaccination not only helps save a life but greatly reduce spending on future healthcare” [ 6 , 7 ].

What are different types of vaccines?

There are different types of vaccines including live attenuated, inactivated, protein-based, nucleic acid, and viral vector-based. Each type of vaccine has a subtle structure, advantages and disadvantages with respect to immunogenicity, safety, ease of use and effectiveness.

Live attenuated vaccines

“Live attenuated vaccines are viruses weakened by passing through animal or human cells, until genome mutates and is unable to cause disease” [ 7 ]. The attenuated virus replicates like a natural infection and causes strong T cell and B cell immune responses [ 7 ]. Live attenuated vaccines have the inherent ability to induce toll-like receptors (TLRs) such as TLR 3, TLR 7/8, and TLR 9 of the innate immune system that involves B cells, CD4 and CD8 T cells. They can be obtained from ‘cold adapted’ virus strains, reassortments, and reverse genetics; and can be low-cost and rapidly produced [ 7 ]. Herd immunity can be achieved through these vaccines in the community [ 7 ]. Broad adjunct testing is required to confirm their safety and efficacy. There is also a possibility of mutations during viral replication which may lead to recombinants post-vaccination [ 8 ]. In addition, cold chain distribution in the community is required. Some examples of live attenuated vaccines include BCG, Smallpox, and Polio (OPV) [ 7 ]. An example of such vaccine to mitigate COVID-19 is DelNS1-SARS-CoV2-RBD, by University of Hong Kong [ 7 ].

Inactivated vaccines

These are inactivated viruses developed using formaldehyde or heat. They do not have any live component of the viral particles [ 8 ]. These are noninfectious, stable, and safer compared to a live attenuated vaccine [ 8 ]. These vaccines can be freeze-dried and do not require cold chains for distribution [ 7 ]. Such vaccines do not replicate and have a suboptimum immune response. They can be used along with adjuvants to increase their immunogenicity. As large quantities of viruses need to be handled while maintaining their integrity [ 6 – 8 ], there are chances of Th2 cell skewed response (antibody-dependent enhancement, ADE). Some examples of inactivated vaccines include Hepatitis A and Rabies. An example of such a vaccine to mitigate COVID-19 is PiCoVacc, by Sinovac Biotech.

Protein-based vaccines

Protein sub-unit.

These are antigenic components [spike (S) protein] generated in vitro. They do not have any live components of the viral particle. They are considered safe and have less adverse effects. They exhibit low immune response, therefore, need multiple dosing and adjuvants. Even memory for future responses is doubtful [ 6 – 8 ]. The S protein of the SARS-CoV-2 is the most suitable antigen to induce the neutralizing antibodies against the pathogen [ 9 ]. One of the examples of such a vaccine to mitigate COVID-19 is NVX-CoV2373, by Novavax [ 7 ].

Virus-like particles

These are empty virus shells without genetic material. They are considered safe, induce a strong immune response, and are difficult to manufacture [ 7 , 8 ]. One example of such a vaccine to mitigate COVID-19 is Triple-Antigen Vaccine, by Premas Biotech [ 7 ].

Nucleic acid vaccines: new generation vaccines

Dna vaccines.

These vaccines are made by introducing DNA encoding the antigen from the pathogen into a plasmid (antigenic components of SARS-CoV-2 such as spike protein). These are considered safe, unable to cause disease. These types of vaccines are unproven in practice. They can cause adverse events (ADE) when used alone [ 6 – 8 ]. These vaccines are highly immunogenic; generate a high titer of neutralizing antibodies when given with inactivated vaccine. An electroporation device is needed to deliver these vaccines. One example of such a vaccine to mitigate COVID-19 is INO-4800, by INOVIO Pharma, Korean Institute of Health, and International Vaccine Institute [ 8 ].

RNA vaccines

RNA vaccines are lipid-coated mRNA of the SARS-CoV-2 expressing spike protein. These are considered safe and unable to cause disease, but are able to induce ADE and are unproven in practice [ 6 , 7 ]. Examples of such vaccines to mitigate COVID-19 are mRNA-1273, by Moderna; and BNT162 (a1, b1, b2, c2), by BioNTech/Fosun Pharma/Pfizer [ 8 ].

Viral vector vaccines

Recombinant DNA technology is used to create these vaccines. The DNA encoding an antigen from the pathogen is inserted into the bacteria or virus vectors. These bacteria or virus vectors then express the antigen in these cells. The antigens are harvested and then purified from the bacteria or virus vectors. Viral vector vaccines could be replicating or nonreplicating.

Replicating

An unrelated virus-like measles or adenovirus is genetically engineered to encode the gene of interest. These are considered safe and are able to induce strong T cell and B cell response. Some examples of such vaccines include Hepatitis B, HPV, and pertussis [ 6 – 8 ].

Nonreplicating

An unrelated virus, like measles or adenovirus (with the inactive gene), is genetically engineered to encode the gene of interest. These are considered safe and require booster doses to induce long-term immunity. These types of vaccines are not licensed yet [ 6 , 7 ]. Examples of such vaccines to mitigate COVID-19 are Ad5-nCoV by CanSino Biological Inc./Beijing Institute of Biotechnology; and ChAdOx-nCoV-19 by the University of Oxford [ 8 ].

How COVID-19 vaccines are developed rapidly as compared to traditional vaccines?

Vaccine development is a complex multidisciplinary activity, blending knowledge of host–pathogen interactions with clinical science, population-level epidemiology, and the biomechanical requirements of production. The core is an insight into immune processes that influence the disease and protection and their variation between individuals, risk groups, and populations [ 10 ]. Traditional vaccine development (Fig.  1 ) has been a complex and time-consuming process that typically takes around 10–15 years. Vaccine development usually begins with an exploratory stage focusing on basic research and computational modeling to find out potential natural or synthetic antigens as a vaccine candidate. After this, a pre-clinical study (18–30 months) starts with cell-culture followed by animal studies to analyze the safety and immunogenic potential of the vaccine candidate. After appropriate in vivo results on safety, immunogenicity, and efficacy, human clinical trials initiated for safety and immunogenicity in small groups, and later in the large groups over 3 phases (Phase 1 or I, 2 or II and 3 or III). The primary goal of Phase 1 trial (~ 30 months) is to assess the safety and immunogenicity of the vaccine candidate. In Phase 1 trial, the vaccine is administered to less than a hundred healthy participants. If promising results are obtained in Phase 1, Phase 2 trial (~ 32 months) is carried out in more than a hundred participants, divided into multiple groups by demographics. The goal of the phase 2 trial is to confirm the safety and immunogenicity of vaccine candidates. Also, the suitable dose required for Phase 3 is calculated. If encouraging results in Phase II trials are obtained, Phase 3 trial (~ 30 months) is then carried out in thousands of participants to evaluate the efficacy. “Incidence of disease at the time of phase 3 trials impacts the sample size” [ 11 ]. If there is a low incidence of disease in the community, large sample size will be required to satisfactorily decide the vaccine efficacy. After completion of these trials, safety and the clinical efficacy are calculated, then the vaccine is reviewed for approval by regulatory bodies, such as Food and Drug Administration (FDA) of the United States of America (USA), or the European Medicines Agency in European Union (EU). Later, manufacturing and post-marketing surveillance are done after the vaccine is marketed for public use and monitored for general effectiveness within the population. Even after the vaccine is adopted for widespread use, events of adverse effects are recorded. The developer advances the vaccine development only if the data is promising, the risk of failure is relatively low and there is a market for the vaccine [ 11 ].

Rapid development of COVID-19 vaccine as compared to traditional vaccine development.

Adapted from Calina et al. [ 76 ]

The mumps was the only fastest developed and approved vaccine for use, taking about 5 years. Even with this experience, it is clearly a big challenge to develop a vaccine against COVID-19 in a span of 12–24 months. COVID-19 vaccine development (Fig.  1 ) has targeted to significantly reduce this 10–15-year timeline to 12–24 months. The initial process started as soon as the genome sequence of SARS-CoV-2 was available. The significant amount of time was saved by using the data from the preclinical development of vaccine candidates for SARS-CoV and MERS-CoV and omitting the initial step of the exploratory phase. Some vaccine candidates used modified production processes from those of existing vaccine candidates while others used preclinical and toxicology data from related vaccines. Therefore, the first clinical trial of CVCs started in March 2020 (NCT04283461) [ 11 ]. Clinical trials were designed to reduce the time horizon by overlapping clinical trial phases. The initial phase I/II trials were followed by rapid advancement to phase III trials as soon as the interim analysis of the phase I/II data was completed. The US accelerated the development of five CVCs under the Operation Warp Speed to make them available by the end of 2020 for emergency use and have billions of doses ready by 2021 [ 11 ]. Manufacturers prepared themselves to rapidly produce billions of doses and few of them already started the commercial production of vaccines without any results from phase III trials. The review process is expedited via Emergency Use Authorization (EUA) by countries like UK, USA and subsequently followed by many more. The challenging task of developing CVCs is achieved in record time frame of 12–16 months as compared to traditional vaccine development taking 10–15 years (Fig.  1 ) [ 12 ].

COVID-19 vaccines approved through Emergency Use Authorization

Vaccines traditionally used are live attenuated viruses, inactivated viruses, protein or polysaccharide conjugated subunit vaccines and virus-like particles. Also, recently included vaccines are nucleic acids, DNA and RNA and viral vectors and recombinant proteins.

SARS-CoV-2 induces a strong adaptive immune response of both T and B cell. Additionally, antibodies IgG and IgM appear about 10 days post-infection. The majority of the patients are able to seroconvert in 3 weeks. The antibodies are created against internal nucleoprotein (N) and spike protein (S) of the virion and possess neutralizing activity. Antibodies which bind to the spike protein, particularly to its receptor-binding domain (RBD), inhibit its attachment to the host cell and counteract the virus [ 13 ]. Table ​ Table1 1 lists few vaccine candidates approved through EUA that reached up to or completed Phase 3 trials.

BNT162 vaccine by Pfizer and BioNTech

On December 2, 2020, UK became the first country to approve COVID-19 vaccine BNT162 developed by Pfizer and BioNTech via EUA. On December 11, 2020 US FDA issued first EUA for BNT162 having demonstrated 95% efficacy in preventing disease in phase III clinical trial results [ 14 ]. Later Canada and Mexico also approved BNT162 via respective EUA pathways. On December 31, 2020, WHO approved first vaccine candidate, BNT162, for emergency use thereby making it easier to manufacture and distribute this vaccine globally [ 15 ]. Initially, four candidates were developed of which two were nucleoside modified mRNA, modRNA; one was uridine containing mRNA, uRNA; and other was self-amplifying mRNA, saRNA. In the preclinical study, modRNA BNT162b2 showed protective antiviral effects in Rhesus macaques with concurrent elevated neutralizing antibody titers and a Th-1 biased cellular response in Rhesus macaques , as well as in mice. Therefore, BNT162b2 was selected for Phase 2/3 clinical trials [ 16 ].

In Phase 1/2 trial of two hundred participants aged 18–55 years with a vaccine dose range of 1–100 µg is currently recruiting (NCT04380701) as is a Phase 2/3 trial of about 32,000 participants (NCT04368728) and a Phase 1/2 trial of 160 participants between age 20–85 (NCT04588480) [ 16 ].On November 9, 2020, Pfizer and BioNTech declared interim results of 94 participants of Phase 3 trial claiming > 90% efficacy of BNT162b2 against SARS-Cov-2 infection at 7 days after the administration of second dose [ 16 ]. Phase 1 trial data showed similar immunogenicity between BNT162b1 and BNT162b2, while BNT162b2 was associated with a lower incidence and severity of systemic reactions than BNT162b1 [ 17 ].

Another study of Phase 1/2 data for BNT162b1 (NCT04368728) showed robust immunogenicity at all three doses of 10 µg, 30 µg and 100 µg among 45 participants, 18–55 years of age. Adverse reactions were high at the maximum dose and therefore, participants were not given a second dose. Participants who were given two doses between 1 and 50 µg of BNT162b1 had vigorous receptor-binding domain (RBD)-specific IgG antibody, T-cell and favorable cytokine responses [ 18 ].

Both BNT162b1 and BNT162b2 received the FDA Fast Track designation. But BNT162b2 was preferred over BNT162b1 for Phase 2/3 safety study, based on preclinical and clinical study results. The developers have asked the FDA to consider an expanded protocol for the Phase 3 trial to include up to 44,000 participants. Europeans Medicines Agency (EMA) has initiated a rolling review of BNT162b2 which helped to accelerate its approval [ 16 ]. One drawback with this vaccine is that it requires storage at − 80° to − 60 °C, a fact that could pose logistic problems [ 19 ].

mRNA-1273 vaccine by Moderna

Moderna’s mRNA-1273 becomes the second CVC to be approved by FDA under EUA. It is developed on the basis of available data of coronaviruses causing severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS). A Phase 3 trial of 30,000 participants at higher risk for COVID-19 is ongoing. Participants will be given 100 µg dose of mRNA-1273 or placebo and then be followed for up to 24 months (COVE trial; NCT04470427). After successful completion of Phase 1 trial (NCT04283461) of 105 participants, Phase 2 trial of 600 participants evaluating 25 µg, 100 µg and 250 µg dose levels of the vaccine was carried out (NCT04405076). Then, Phase 3 results of 95 participants after an interim analysis revealed 94.5% efficiency of the vaccine with no significant safety concerns [ 20 ].

The mRNA-1273 effectively produced neutralizing antibody titers in 8 participants of Phase 1 trial after receiving 25 µg or 100 µg doses. Neutralizing antibody titers of these participants were similar to the convalescent sera from COVID-19 recuperated patients [ 21 ]. Higher age adults subjects who received two doses of either 25 µg or 100 µg of the mRNA-1273 demonstrated safety and suffered mild or moderate effects including, fatigue, chills, headache, myalgia, and pain at the injection site [ 22 ]. In a preclinical study, mRNA-1273 prevented viral replication in the lungs and produced neutralized titers similar to subjects receiving 25 µg or 100 µg doses of the vaccine [ 23 ]. Another preclinical study consisting of nonhuman primates challenged with SARS-CoV-2 showed neutralizing activity and reduced inflammation and lung activity post administration of mRNA-1273 [ 24 ].

The mRNA-1273 also got the Fast Track designation from the US FDA. A Phase 3 trial of the vaccine is currently underway and is funded by the Operation Warp Speed [ 25 ]. One potential issue for this vaccine could be the storage temperature requirement of − 25° to − 15 °C is required [ 19 ].

AZD1222 by AstraZeneca and University of Oxford

On December 30, 2020, UK and on January 2, 2021, India approved AZD1222 COVID-19 vaccine developed by AstraZeneca and the Oxford Vaccine Group at the University of Oxford. It was previously called as ChAdOx1, a chimpanzee adenovirus vaccine [ 26 , 27 ]. This group has previously developed a MERS vaccine. In India, this vaccine is jointly developed by Serum Institute of India and AstraZeneca and is branded as Covishield. A preclinical study showed significantly reduced viral load and humoral and cellular immune response [ 28 ]. Another preclinical study demonstrated an immune response in both mice and pigs [ 29 ]. ChAdOx1, a replication-deficient simian adenoviral vector expressing the full-length SARS-CoV-2 spike (S) protein, was commenced in April 2020 following preclinical studies involving non-human primates using a single dose. When one vs two doses of ChAdOx1 in both mice and pigs were compared, a single dose induced antigen-specific antibody and T cells responses, and a second booster dose enhanced antibody responses, particularly in pigs, with a significant increase in the level of SARS-CoV-2 neutralizing titers [ 29 ].

A Phase 1/2 (NCT04324606) study involving 1077 healthy adult participants aged 18–55 years, assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine, expressing the spike protein of SARS-CoV-2. The results demonstrated an acceptable safety profile for ChAdOx1 nCoV19 and increased antibody response by homologous boosting [ 30 ]. A Phase 3 trial (NCT04516746) is ongoing and has enrolled more than 40,000 subjects. Preliminary results have demonstrated that the safety profile of the vaccine candidate is acceptable, with most patients demonstrating an antibody response after one dose and all patients showing a response after two doses [ 30 ]. A Phase 3 trial in Brazil reported one death, which was confirmed by the Brazilian National Health Surveillance Agency (ANVISA). AstraZeneca stated that the results from the Phase 3 trial demonstrate immunogenicity, but have not yet publicly released any data [ 31 ]. An inhaled version of the vaccine candidate is also being tested in a small trial involving 30 participants [ 31 ].

The trials by AstraZeneca are funded by BARDA and Operation Warp Speed. IQVIA also announced they are partnering with AstraZeneca to advance clinical trials for this vaccine. Phase 3 trials are being conducted in the United States and India but were put on hold following reporting of a serious adverse event. Trials have since restarted. Additionally, EMAs human medicines committee (CHMP) and Health Canada have initiated a rolling review of AZD1222 to reduce the decision-making time related to safety and efficacy. The Australian Therapeutic Good Administration (TGA) granted AZD1222 provisional determination, the first step in the approval process. In Britain, the Medicines and Healthcare products Regulatory Agency (MHRA) has also started an accelerated review of AZD1222 [ 31 ]. This vaccine requires refrigeration (2–8 °C), which can potentially be problematic for use in low-income countries [ 19 ].

CoronaVac by Sinovac

CoronaVac (formerly PiCoVacc) is approved by China through EUA. CoronaVac is a formalin-inactivated and alum adjuvanted vaccine candidate developed by Sinovac Biotech, China [ 32 ]. Results from preclinical studies showed partial or complete protection in non-human primates exposed to SARS-CoV-2 [ 33 ].

A Phase 1/2 trial of 743 healthy participants (18–59 years old) who received two different dosages of the vaccine or placebo is active but not recruiting (NCT04551547). A Phase 1 trial of 143 participants (NCT04352608) and Phase 2 trial of 600 participants (NCT04383574) are both active but not recruiting. Phase 3 trial is underway (NCT04456595) to have 9000 participants. Trials are also ongoing in Turkey (NCT04582344) and in Indonesia (NCT04508075). Phase 1/2 trials revealed that the vaccine has good safety and immunogenicity with seroconversion occurring in 92.4% of participants after the 3 µg dose given on a 0–14 day schedule and 97.4% of participants with the same dose on a 0–28 day interval [ 34 ].

Preliminary results from the Instituto Butantan trial, declared by the Sinovac, showed CoronaVac is safe with no reported serious adverse events. However, the trial in Brazil was briefly suspended due to patient death, though the trial has resumed later [ 35 ].

COVID-19 vaccine by Sinopharm and the Wuhan Institute of Virology, China

China approved this vaccine via EUA. Sinopharm and Wuhan Institute of Virology under the Chinese Academy of Sciences have developed an inactivated CVC [ 36 ]. A Phase 1/2 clinical trial (ChiCTR2000031809) involving healthy subjects is ongoing. According to a release from China National Biotec Group, this vaccine has demonstrated a strong neutralizing antibody response. Phase 1 and Phase 2 trials data also showed immunogenicity [ 37 ]. A Phase 3 trial is in progress in Peru, Morocco, and United Arab Emirates.

Sputnik V by the Gamaleya Research Institute, Russia

Russia has approved first CVC as Sputnik V (previously as Gam-COVID-Vac). The Gamaleya Research Institute in Russia and Health Ministry of the Russian Federation are assessing their non-replicating viral vector vaccine, Sputnik V, in a Phase 3 trial. However, there is no trial data available to date. This led to criticism as even there is a lack of data on safety and efficacy, the vaccine is approved.

Two Phase 1/2 trials with 38 subjects each were conducted (NCT04436471, NCT04437875). Sputnik V is additionally being evaluated in a small Phase 2 trial with 110 subjects older than 60 years (NCT04587219). A Phase 3 trial with about 40,000 participants is also in progress (NCT04530396). Aside from Russia, Sputnik V is also being evaluated in Belarus (NCT04564716) and the United Arab Emirates. The results from the Phase 1/2 trials demonstrated the safety and immunogenicity of the vaccine [ 38 ]. The Russian Direct Investment Fund also announced that Sputnik V is 92% effective based on the interim trial results from 20 participants. A preliminary pre-submission of the vaccine has also been proposed in Brazil [ 39 ].

BBIBP-CorV by Sinopharm and Beijing Institute of Biological Products, China

BBIBP-CorV is inactivated CVC developed by Sinopharm in association with Beijing Institute of Biological Products, China. Firstly China and later on United Arab Emirates (UAE) approved the vaccine through EUA [ 36 ].

BBIBP-CorV is currently being assessed in Phase 2 (CHiCTR2000032459) and Phase 3 trial in China (ChiCTR2000034780) as well as Phase 3 trial in Argentina (NCT04560881). BBIBP-CorV is shown to be highly effective in preventing disease against SARS-CoV-2 in Rhesus macaques [ 40 ]. Phase 1 results showed that BBIBP-CorV was safe and tolerated at all dose levels, with all participants showing a humoral response to the vaccine after 42 days. The UAE announced that the vaccine is 86% effective [ 41 ].

EpiVacCorona by Federal Budgetary Research Institution State Research Center of Virology and Biotechnology, Russia

Russia also granted regulatory approval to EpiVacCorona, a peptide vaccine candidate for COVID-19, developed by Federal Budgetary Research Institution State Research Center of Virology and Biotechnology [ 42 ].

A Phase 1/2 trial in Russia is assessing the effectiveness of the vaccine (NCT04527575). A Phase II clinical trial of the vaccine was completed recently. Head of the zoonotic diseases and flu department with the State Research Center of Virology and Biotechnology has said “participants have developed immunity a month after the first vaccination” [ 43 ], but there is no data available in the public domain.

Covaxin by Bharat Biotech and National Institute of Virology, India

On January 2, 2021, India approved an inactivated vaccine called Covaxin, developed by Bharat Biotech and India’s National Institute of Virology [ 27 ]. A Phase 1/2 trial of about 1100 healthy subjects is ongoing after obtaining permission from the Drug Controller General of India. The Indian Council of Medical Research (ICMR) reported that Covaxin has entered Phase 2 clinical trials. On October 27, 2020, the ICMR approved Covaxin for Phase 3 trial. Results of a two-dose regimen study administered to Rhesus macaques demonstrated an increase in SARS-CoV-2 specific IgG and neutralizing antibodies as well as diminished viral replication in the nasal cavity, throat, and lungs [ 44 ]. According to the trial principal investigator, initial results from the first fifty participants who received the vaccine seem to be promising. In addition, according to Bharat Biotech, the first two phases of the trial did not demonstrate any major adverse events [ 45 ]. The proposed distribution for this vaccine is February 2021, according to an ICMR scientist who spoke with Reuters.

COVID-19 vaccines under clinical trials

Some of the potential CVCs that are in Phase 3 clinical trials and might get EUA approval are described below. The other CVCs that are in clinical trials are listed in Table ​ Table2 2 .

JNJ-78436735 by Johnson & Johnson

Johnson & Johnson (J&J) is developing JNJ-78436735 (Previously as Ad26.COV2.S), using their AdVac and PERC6 systems, also used to develop the Ebola vaccine. In partnership with BARDA, J&J has promised to invest more than $1 billion in vaccine research and development. JNJ-78436735 is currently funded by Janssen, BARD, NAID and the Operation Warp Speed [ 46 ].

A randomized, double blind, placebo-controlled, Phase 1/2 study of recombinant JNJ-78436735 in 1045 healthy subjects, 18–55 years of age, and in adults 65 years or older is ongoing. Study sites are selected in the US and Belgium (NCT04436276). The Phase 3 ENSEMBLE trial will enroll up to 60,000 subjects in the US and other countries (NCT04505722). The study protocol for the Phase 3 ENSEMBLE trial was released by J&J on September 23, 2020. Results from the Phase 1/2 study showed that a single dose of the vaccine was safe and immunogenic [ 47 ]. The results of the preclinical study showed that a single injection of JNJ-78436735 produced a strong neutralizing antibody response and offered complete or near-complete protection in bronchoalveolar lavage and nasal swabs after SARS-CoV-2 administration in Rhesus macaques [ 48 ]. Another preclinical study in hamsters indicated that the vaccine protected against severe disease when tested [ 49 ].

On June 10, 2020, J&J announced it is fast-tracking the Phase 1/2 trials. The ENSEMBLE trial was on hold pending a review of an adverse event, but J&J has been cleared to resume the trial in the US and Brazil after clearance from the Independent Data Safety and Monitoring Board. J&J also plan to start testing its vaccine in adolescents as soon as possible [ 46 ]. This vaccine candidate requires storage at 2–8 °C [ 19 ].

Ad5-nCoV by CanSino Biologics

China’s CanSino Biologics has developed a recombinant novel coronavirus vaccine that incorporates the adenovirus type 5 vector (Ad5) called Ad5-nCoV. A Phase 1 clinical trial in China involving 108 participants, 18–60 years old, is active, but not recruiting. In this trial the participants will receive low, medium, and high doses of Ad5-nCoV (NCT04313127). A Phase 1 trial in China is also assessing intramuscular as well as mucosal vaccination of Ad5-nCoV across two doses (NCT04552366).

A Phase 1/2 trial involving 696 participants in Canada is registered and not yet recruiting (NCT04398147). A Phase 2 double-blind, placebo-controlled trial with 508 participants in China (NCT04341389) is active but not recruiting. A phase 2b trial in China is evaluating the safety and immunogenicity of Ad5-nCoV in participants who are 6 years of age and older (NCT04566770). A Phase 3 trial in Russia with 500 participants across multiple study centers is ongoing (NCT04540419). A Phase 3 trial involving 40,000 participants in countries including Pakistan, Saudi Arabia and Mexico is also ongoing (NCT04526990). A single dose of Ad5-nCoV vaccine protects against upper respiratory infection of SARSCoV-2 in ferrets. Results from the Phase 1 trial showed a humoral and immunogenic response to the vaccine. Adverse reactions such as pain (54%), fever (46%), fatigue (44%), headache (39%), and muscle pain (17%) were reported in 83% of the patients in the low and medium dose groups and in 75% of the patients in the high dose group. Results from the Phase 2 trial showed neutralizing antibodies and specific interferon γ enzyme-linked immunosorbent assay, at all dose levels for most of the participants. On June 25, 2020, China’s Central Military Commission announced that Ad5-nCoV can be used in the military for a period of 1 year.

NVX-CoV2373 by Novavax

In March 2020, Novavax announced that it has manufactured a stable, prefusion protein nanoparticle vaccine candidate for COVID-19. A Phase 1/2 trial evaluating NVX-CoV2373 commenced on May 25, 2020 [ 50 ].

A randomized, observer-blinded, placebo-controlled trial involving 130 healthy participants, 18–59 years of age, is ongoing at two sites in Australia. In this trial, patients will receive a two-dose regimen of 5 µg or 25 µg of NVX-CoV2373 with or without Novavax’s Matrix-M adjuvant (NCT04368988). A Phase 2b trial is also ongoing in South Africa, with two cohorts, group of 2,665 healthy adults and group of 240 HIV positive adults (NCT04533399). Phase 1 trial participants who received the vaccine developed an antibody response at multiple doses. NVX-CoV2373 was also reported to be safe [ 51 ].

Novavax received the Fast Track Designation from the FDA for NVX-CoV2373 [ 52 ]. On May 11, 2020, CEPI announced that they had provided Novavax with $384 million for the development and manufacturing of NVX-CoV2373. Novavax plans to produce 1 billion doses of NVX-CoV2373 by 2021 as part of their latest acquisition of Praha Vaccines. Novavax was also awarded a $60 million US Department of Defense contract towards manufacturing NVX-CoV2373, and another $1.6 billion from Operation Warp Speed, if the candidate will be proved effective in clinical trials [ 53 ]. A Phase 3 trial has also begun in the United Kingdom, which will evaluate the vaccine in 10,000 participants. Novavax provided an update on October 27, 2020, of its Phase 3 trial of NVX-CoV2373 in North America, stating that the trial would commence at the end of November, roughly one month later than expected [ 53 ].

COVID-19 vaccines: challenges and future prospects

The vaccine development effort over the globe for the COVID-19 pandemic is unprecedented, in terms of scale, speed, and supply chain. It is made possible to have a safe and effective vaccine available by the end of the year 2020, for the more vulnerable group of the population and hopefully in the first half of 2021 to all the others. Operation Warp Speed program was introduced in US to fast-track vaccine development. Moderna’s mRNA vaccine and AstraZeneca/University of Oxford’s AZD1222 vaccine are part of this program. Classical clinical efficacy trials of vaccines usually enroll thousands or tens of thousands of healthy participants. However, to accelerate the COVID-19 vaccine development, clinical trial phases were combined, and smaller population was enrolled. This is a noteworthy concern when the vaccine is supposed to be given to people throughout the world, there could be emergence of unknown side-effects in the larger population, which were previously not witnessed in smaller groups during short-term trials. It is important to consider whether there was an appropriate demographic consideration in the design of the clinical trials including, different races, varying age groups and those with comorbidities, as the exclusion of these may lead to unforeseen outcomes upon vaccinating these individuals when the vaccine is released for public use.

The production teams of the vaccine candidates have stated to be under pressure to develop a vaccine within few months as compared to the conventional process of 10–15 years. With a fast-track process, post-marketing surveillance turns out to be important. Post-marketing surveillance would ensure that the vaccines are observed for side effects when administered in diverse populations. The foremost ethical concern is to find a safe and effective vaccine but at the same time not exposing clinical trial participants to avoidable risks [ 54 ].

Fast-tracking of vaccines may turn unfavorable as it could result in ineffective vaccine and may only provide partial or no immunity to some vaccinated persons. Although it is assumed that there will be thorough inspection of the vaccine candidates for safety and efficacy from the scientific community before vaccine is released for administration into the public. It is important to consider the recent small trials of the Russian vaccine Sputnik V as well as the Chinese vaccine candidates. Both Russia and China have begun the mass rollout of state-sponsored vaccine candidates with limited data. In the perspective of a public health emergency of international concerns, such shortened regulatory pathways and fast-tracked implementations are still commonly regarded as experimental interventions and are unique. However, to preserve public trust in vaccines, it is vital that complete transparency in all facets of vaccine development is available.

Due to increased demand and limited supply of vaccines, several countries including the US, India, and Europe have decided that the vaccines will be provided first to their own citizens. However, questions are being raised concerning the ethics associated with fair allocation. Though AstraZeneca has announced a collaboration with Serum Institute of India to provide an adequate number of doses to low and middle-income countries, it will be interesting how the allocation will be done when the vaccine candidates are approved and becomes available. It is also crucial to prioritize certain groups of people for vaccine allotment including, health care workers, immunocompromised individuals, those with comorbidities, the elderly, and those with lower socioeconomic status to guarantee distributive justice. There are also worries that the political pressure to hasten the development and approval processes, may result in an ineffective vaccine being released to the public. Such a consequence may lead to the public being hesitant from receiving future vaccines [ 55 ].

To date, no trials for COVID-19 vaccine has focused on pregnant women, despite being deemed a vulnerable population by the US Centers for Disease Control and Prevention (CDC). Although there are unanswered questions regarding the safety and efficacy of COVID-19 vaccines in pregnant women, FDA-approved COVID-19 vaccines should not be refused to women solely based on their pregnancy or lactation status, when they otherwise meet the conditions for vaccination. Patient-provider discussions should also consider the patient’s individual risk–benefit profile concerning exposure at work or at home, risk to expose other members of their household, current health status and perceived risk of COVID-19 associated impediments [ 56 ]. Pregnant women should get COVID-19 vaccine without delay, as the consequences of COVID-19 infections in pregnancy are equivalent or worse than in non-pregnant populations. There is potential for damage to not one but two lives, and females of childbearing potential may have heightened workplace exposure to SARS-CoV-2. Additionally, the ongoing vaccine trials should include pregnant women to test vaccine candidates’ study safety and efficacy [ 57 ].

Vaccine efficacy

Vaccine effectiveness is described as the protection provided by immunization in a defined population. It includes both direct (vaccine-induced) and indirect (population-related) protection. The effectiveness of a vaccine is proportional to its efficacy but is also influenced by the vaccine coverage, access to healthcare centers, associated costs, and other factors not directly related to the vaccine [ 58 ]. The question is, how much efficacy is actually needed for a vaccine to be considered immunogenic? Though more research is required, preliminary research studies have revealed that efficacy of > 70% is desired to eradicate the infection. A preventative vaccine with an efficacy of < 70% will still have a major effect and may add to obliterating the virus, given proper social distancing measures. Vaccines with an efficacy below 70% may contribute to decreasing the length of infection. Another study with simulation experiments showed that to prevent a pandemic, the vaccine efficacy has to be at least 60% with 100% vaccination coverage. The vaccine efficacy threshold rises to 70% when coverage drops to 75% [ 59 ].

Phase III clinical trials are required for all vaccine candidates to demonstrate that they are effective and safe in a larger population. In addition, the majority of vaccine candidates currently in clinical trials are administered intramuscularly. Though this administration route induces a strong IgG response, which is believed to protect the lower respiratory tract, unlike natural infection, it does not initiate the secretory IgA responses required to protect the upper respiratory tract [ 11 ]. Thus, most vaccines will provide protection against infection of the lower respiratory tract and not induce sterilizing immunity in the upper respiratory tract. This could lead to protection from symptomatic diseases but might still allow virus spread by infected person. Thus, a vaccine that could induce sterilizing immunity in the upper respiratory tract would be preferable to stop virus spread. Live attenuated vaccines or viral vectors that can be administered intranasally, would probably also lead to a strong mucosal immune response as well as an IgG response. Alas, very few vaccines that are appropriate for intranasal administration are undergoing development and none have made it to the clinical trials yet [ 11 ].

The next ethical question is, what will be the effect of the vaccine on older individuals who are at higher risk from COVID-19? According to Sinovac’s inactivated vaccine and Pfizer’s mRNA vaccine, the effect of the vaccine in older individuals is less compared to younger adults. Thus, there is a need for different vaccine formulation or a booster dose to improve immune responses in older individuals [ 11 ]. The children usually show increased reactogenicity compared to adults. As many CVCs have fairly strong adverse effects, low-dose vaccines might be required for children, particularly for AdV and mRNA-based vaccines. Pfizer has considered this approach and accordingly reduced the reactogenicity of its mRNA vaccine in older adults, making it appropriate for children [ 11 ].

There is also risk of vaccine enhanced disease for inactivated vaccine candidates (VAERD) that need to be considered. The higher numbers of antibodies are unable to neutralize the virus in case of high viral load, resulting in VAERD. Furthermore, ADE has been observed with other coronaviruses including MERS-CoV and SARS-CoV and could be a risk for CVCs. ADE occurs when antibodies bind to the virus and the resulting antibody-virus complex facilitates viral entry by host macrophages instead of neutralizing the virus. However, when there is an urgent need for CVCs globally, being concerned and assessing such risks should not prevent the release of otherwise safe and effective vaccines to the public [ 60 ].

If there is an incidence of the adverse reaction, there should be programs in place to safeguard proper medical treatment and compensation is provided to affected individuals and records are kept for re-evaluating the safety of the vaccine(s). The accountable authorities should also ensure that an effective and fair policy is in place, for instances where vaccination is compulsory, so the public trust in the health care system is not risked. Pre-existing immunity to adenoviruses is a concern, specifically for those vaccine candidates utilizing human adenoviruses such as CanSino’Ad5 vaccine, as it may lead to a decreased immune response to the vaccine. AstraZeneca/Oxford’s AZD is another adenovirus-based vaccine candidate, but instead of utilizing adenovirus derived from humans, it utilizes a genetically modified chimpanzee-derived adenovirus. This effectively eliminates the concern about pre-existing immunity and thus, averts the negative impact on the immune response generated to the vaccine [ 60 ]. Although some vaccines are approved through EUA, long-term data on vaccine safety is also crucial. The well-known case of Dengue vaccine should not be overlooked, where dengue vaccine protected individuals against virologically confirmed dengue (VCD) and severe VCD for 5 years, who had exposure to dengue prior to vaccination. There was also a higher risk of VCD and severe VCD in vaccinated individuals who were not exposed to dengue earlier [ 61 ]. Thus, to avert such obstacles after vaccination, even after EUA approval, long-term safety and efficacy data is essential.

Furthermore, if a vaccine is approved for use but subsequently it is found to be not as effective as expected in the population, it could lead to a loss of trust in the vaccines. There are reports of few adverse effects with the Pfizer vaccine (Table ​ (Table3) 3 ) [ 62 – 64 ] and these recent adverse reactions were confirmed by the Finnish Medicines Agency Filmea, Finland [ 65 ]. Thus, when an effective vaccine is launched, fewer people may be inclined to accept it, which in turn can lead to further worsening of the pandemic and a decline in the confidence in already approved and effective vaccines against infections. Hence, it is vital to building trust in the public health system by being completely transparent and reporting accurate data in a timely fashion [ 61 ]. Thus, the ideal characteristics of CVCs described by WHO are important to consider while developing vaccines (Table ​ (Table3) 3 ) [ 66 , 67 ].

Few mild side effects of Pfizer/BioNTech COVID-19 vaccine that should not last more than a week [ 60 – 62 ] and Ideal COVID-19 vaccine characteristics according to WHO [ 64 , 65 ]

Manufacturing and distribution

Manufacturers have a valuable share in the vaccine supply chain as their credibility rest on the effectiveness of their vaccines. The risks of poorly performing supply chains are detrimental for the safety and effectiveness of the vaccines, with potential consequences for future supply in case of adverse events [ 68 ]. Manufacturers from developing countries are disparate in nature and are either privately or state-owned [ 68 ]. To ensure that the threat of COVID-19 is eliminated, it is critical that a coordinated and cooperative approach is taken. This includes collaboration between several international organizations to safeguard sufficient financing and fair distribution of the vaccine supply. The organizations such as Developing Countries Vaccine Manufacturers Network (DCVMN), The Global Alliance for Vaccines and Immunizations (GAVI), Global Vaccine Action Plan (GVAP), Coalition for Epidemic Preparedness Innovations (CEPI), COVID-19 Vaccine Global Access Facility (COVAX), Bill and Melinda Gates Foundation and WHO are working in tandem to overcome this epidemic. DCVMN is a public-health-driven alliance that represents vaccine manufacturers from developing countries engaged in research, development, manufacturing and vaccine supply for domestic and international use. They aim to protect all people against known and emerging infectious diseases [ 69 ]. The number of vaccines supplied collectively by DCVMN members in 2018–2019 was about 3.5billion doses. DCVMN is working in partnership with global health authorities, international organizations and vaccine developers to support the advancement of COVID-19 vaccines. This will allow to rapidly manufacture, fill-finish and supply needed COVID-19 vaccines. Nonetheless, details about the capability for quality control, supply chain and delivery abilities must to be closely assessed [ 69 ]. To progress the supply chain, an expert group of representatives of DCVMN prioritized three main areas as Traceability in the context of global digital health initiatives, amassing in the context of addressing vaccine shortages, stock-outs, outbreaks and epidemic prevention, and new packaging technologies. It is imperative that vaccine manufacturers are actively involved in worldwide stakeholders forums as equal partners in determining the best practices for improving the vaccine supply chain [ 68 ].

The GAVI is a global public–private partnership to ensure that individuals from emerging countries, mainly children, have access to immunizations. GAVI is also a part of the recent Global Vaccine summit, which allocated funding for COVID-19 vaccine development along with to healthcare systems of GAVI eligible countries to ensure sufficient supply for emerging countries [ 70 ]. GVAP unanimously supported by the World Health Assembly in 2012, outlined a bold strategy to improve immunization. It created a Monitoring and Evaluation/Accountability (M&E/A) to track and drive growth. Nevertheless, there is noteworthy improvement to upsurge the visibility for immunization and the benefits of the GVAP M&E/A framework. Only few limitations are needed to be circumvented such as the limited ownership by countries and other stakeholders leading to inadequate implementation of the strategy and poor culpability for achieving GVAP targets. It could hasten the immunization cover in pandemic situations like COVID-19 [ 71 ].

Bill and Melinda Gates Foundation have allocated $250 million towards vaccines development and for supporting the health care systems of Sub-Saharan Africa and other emerging countries. CEPI is a foundation involved in financing vaccine development and has launched COVAX in order to allow for equal accessibility of the COVID-19 vaccine for all countries. WHO is also involved in all aspects of thwarting the COVID-19 pandemic. WHO is also recording data from vaccine candidates in its Draft Landscape of COVID-19 vaccine and periodically updates it. Additionally, cooperation from individual countries is equally crucial in the fight against COVID-19 [ 55 ].

In the past, platforms based on nucleic acids such as DNA and RNA have not resulted in a successful vaccine for human diseases and so, it is yet to be seen how mRNA vaccines that are temperature-sensitive may pose difficulties for scaling up production. Moreover, for DNA vaccines, its dependence on electroporation or an injector delivery device for vaccine administration is a probable concern. Although, electroporation is considered to be a safe procedure and is vital to generate an enhanced immune response, it can complicate the vaccine delivery [ 60 ]. The global vaccine Summit has also called for an equal allocation of vaccines whenever a vaccine is released. There is still a concern that some countries will want to secure the vaccine supply for their citizens first. An example of this is the recent stockpiling of the drug, Remdesivir, in the US. This drug is used for the treatment of patients infected with COVID-19 [ 60 ]. Swift large-scale manufacturing of vaccines still remains a challenge with loads of ambiguity to meet the demand. It is likely that two doses of vaccine will be necessary. In this case, at least a 16 billion doses will be needed to meet the worldwide demand. Various vaccines described in this article are being developed by entities that have never manufactured a vaccine. Therefore, unanticipated problems with scaling could cause setbacks. It is also not yet clear whether bottlenecks will occur in the availability of supplies including, syringes or glass vials; how vaccines will be distributed worldwide; and how rollout will occur within different countries [ 11 ].

WHO has developed the Emergency Use Assessment and Listing Procedure (EUAL) to accelerate the accessibility of vaccines required in public health emergency situations. It will monitor UN procurement agencies and Member States on the suitability for use of a particular vaccine in the framework of public health emergency, based on minimum available quality, safety and efficacy data. It will speed up the acceptance and rollout of these vaccines in member countries, specifically in low and middle income countries [ 72 , 73 ]. Vaccine immunogenicity and efficacy is dependent upon how they are packaged, stored, prepared and administered. Vaccines must be kept in the proper cold chain; the cold chain must be appropriately examined; and vaccines must be used only within critical time points after removal from the cold chain or once a multi-dose vial is punctured [ 19 ].

Vaccine hesitancy

Vaccine hesitancy is defined as a delay in acceptance or denial of vaccination regardless of the accessibility of vaccination services. Vaccine hesitancy is complicated and context-specific, differing across time, place, and vaccine to vaccine. It is affected by factors such as complacency, convenience, and confidence [ 74 ] . If there is greater hesitancy, it can lead to reduced vaccine demand. However, low levels of hesitancy do not certainly mean a higher vaccine demand. The vaccine hesitancy determinants matrix illustrates the factors affecting the behavioral decision to accept, delay or reject some or all vaccines, beneath three categories namely contextual, individual and group, and vaccine/vaccination-specific influences [ 74 ].

Protective behaviors are critical to controlling epidemics, and vaccines could be the key for COVID-19. If a COVID-19 vaccine comes to be available, it will be a key public health strategy to reduce the overall COVID-19 burden [ 75 ]. However, the anti-vaxxers community always poses a threat and is already countering the statements by experts related to the vaccines. Misleading beliefs of anti-vaxxers and their effects overlaid the path for the nastiest measles eruption in the US in 2019. Now many peoples fear similar outcomes for COVID-19. One poll in US in May 2020, demonstrated that 14–23% of the Americans are not willing to be vaccinated, whereas another poll showed that only 49% of the Americans are willing to take the COVID-19 vaccine. Yet, another study from June 2020, showed nearly 70% of the adults in the US would be willing to take COVID-19 vaccine, if one becomes available. Other countries like Germany and Australia too have a fair share of anti-vaxxers. Hence, there should be a strategy to improve the vaccine acceptance rate in public and to counteract vaccine hesitancy [ 75 ]. Frontline healthcare workers play a decisive role in ensuring that all age groups get the recommended immunizations, and by educating people about the importance of immunization [ 58 ]. For example, the support for mandatory influenza vaccination in Denmark was significantly less [ 76 ]. The reasons for lack of vaccine uptake included considerations by employees that they do not get sick often, the vaccine was not regarded as essential, forgetfulness, and/or lack of time. Only 37.8% were in favor of mandatory influenza vaccination [ 76 ]. Thus, educational campaigns regarding benefits offered by vaccines can be helpful.

An online survey of 566 Individuals from Chile to assess an individual’s willingness-to-pay (WTP) for a hypothetical COVID-19 vaccine utilized a contingent valuation methodology. The factors that positively influenced the WTP included pre-existing chronic diseases, knowledge of COVID-19, sickness associated with COVID-19, perception of government performance, income and employment status. The factors that negatively influenced the WTP included belonging to a private health system, not adjusting to work from home with children due to quarantine, and recovery from COVID-19 associated infections. In addition, there would be costs associated with manufacturing and distribution, and the developing laboratories should be financially compensated. Thus, the WTP results from this study can serve as an incentive model for the vaccine developers [ 3 ].

The impact of immunization is measured by directly assessing the effects on the vaccinated individual, indirectly on the unvaccinated community—whether herd protection is achieved or not, the epidemiology of the pathogen like altering circulating serotypes or prevention of epidemic cycles, and the added benefits rising from the better health. Aside from the protection of the individual, the larger success of immunization is dependent on attaining a level of coverage enough to interrupt microbial (virus, bacteria, etc.) transmission. Diminished coverage is certainly linked to the resurgence in disease, with outbreaks possibly leading to substantial morbidity and loss of life. The sustained success of immunization programs is the responsibility of all involved parties including individuals, healthcare professionals, government and industry [ 58 ].

Future prospects

There are numerous unanswered questions associated with SARS-CoV-2 immunity, specifically the protective immunity. There is a necessity for different types of vaccines for differing populations such as infants and children, pregnant women, immunocompromised individuals, as a majority of the vaccines under development are targeting the healthy population i.e., 18–55 years old adults. A safe regulatory pathway must also be delineated for use of these vaccines in children, pregnant women, and immunocompromised individuals. Recent outbreaks of pertussis and measles in countries where these diseases were formerly controlled demonstrated that the success of immunization programs cannot be taken for granted. Changes that occur over decades, such as lessened compliance with immunization or modifying epidemiology of disease can overturn original assumptions about the impact of the vaccine [ 58 ]. Post-marketing surveillance should also be continued to record adverse events [ 65 ].

In order to develop a safe and effective vaccine, it is vital that pre-clinical trials are done with caution to avoid severe adverse events. Moreover, cooperation between international organizations such as the WHO, CEPI, GAVI and Bill and Melinda Gates Foundation is needed to ensure ample funding for vaccines. It is anticipated that vaccines will be available worldwide by mid-2021 to mitigate this pandemic. However, the efficacy of approved vaccines on the new mutant strains found in the United Kingdom and South Africa, are yet to be studied. The implementation of the first‐generation vaccines could be achieved by pushing the nucleic acid‐based priming vaccines followed by a booster dose of protein‐based vaccines to rein in the mortality among high‐risk communities. In parallel, more potent and efficient second‐generation vaccines can be developed and manufactured to combat mutations in the virus.

Abbreviations

Author contributions

Conceptualization SK, ArG and AG. Writing—original draft preparation SK and ArG. Writing—review and editing ArG, SE, and AG. Supervision AG. Project administration AG. All authors have read and agreed to the published version of the manuscript.

This research received no external funding.

Declarations

The authors declare that they no conflict of interest.

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