Vaccine

A child with measles, a vaccine-preventable disease[16]

There is overwhelming scientific consensus that vaccines are a very safe and effective way to fight and eradicate infectious diseases.[17][18][19][20] The immune system recognizes vaccine agents as foreign, destroys them, and "remembers" them. When the virulent version of an agent is encountered, the body recognizes the protein coat on the virus, and thus is prepared to respond, by first neutralizing the target agent before it can enter cells, and secondly by recognizing and destroying infected cells before that agent can multiply to vast numbers.[21][22]

Limitations to their effectiveness, nevertheless, exist.[23] Sometimes, protection fails for vaccine-related reasons such as failures in vaccine attenuation, vaccination regimens or administration.[24]

Failure may also occur for host-related reasons if the host's immune system does not respond adequately or at all. Host-related lack of response occurs in an estimated 2-10% of individuals, due to factors including genetics, immune status, age, health and nutritional status.[24] One type of primary immunodeficiency disorder resulting in genetic failure is X-linked agammaglobulinemia, in which the absence of an enzyme essential for B cell development prevents the host's immune system from generating antibodies to a pathogen.[25][26]

Host–pathogen interactions and responses to infection are dynamic processes involving multiple pathways in the immune system.[27][28] A host does not develop antibodies instantaneously: while the body's innate immunity may be activated in as little as twelve hours, adaptive immunity can take 1–2 weeks to fully develop. During that time, the host can still become infected.[29]

Once antibodies are produced, they may promote immunity in any of several ways, depending on the class of antibodies involved. Their success in clearing or inactivating a pathogen will depend on the amount of antibodies produced and on the extent to which those antibodies are effective at countering the strain of the pathogen involved, since different strains may be differently susceptible to a given immune reaction.[28] In some cases vaccines may result in partial immune protection (in which immunity is less than 100% effective but still reduces risk of infection) or in temporary immune protection (in which immunity wanes over time) rather than full or permanent immunity. They can still raise the reinfection threshold for the population as a whole and make a substantial impact.[30] They can also mitigate the severity of infection, resulting in a lower mortality rate, lower morbidity, faster recovery from illness, and a wide range of other effects.[31][32]

Those who are older often display less of a response than those who are younger, a pattern known as Immunosenescence.[33] Adjuvants commonly are used to boost immune response, particularly for older people whose immune response to a simple vaccine may have weakened.[34]

The efficacy or performance of the vaccine is dependent on several factors:

• the disease itself (for some diseases vaccination performs better than for others)
• the strain of vaccine (some vaccines are specific to, or at least most effective against, particular strains of the disease)[35]
• whether the vaccination schedule has been properly observed.
• idiosyncratic response to vaccination; some individuals are "non-responders" to certain vaccines, meaning that they do not generate antibodies even after being vaccinated correctly.
• assorted factors such as ethnicity, age, or genetic predisposition.

If a vaccinated individual does develop the disease vaccinated against (breakthrough infection), the disease is likely to be less virulent than in unvaccinated cases.[36]

Important considerations in an effective vaccination program:[37]

1. careful modeling to anticipate the effect that an immunization campaign will have on the epidemiology of the disease in the medium to long term
2. ongoing surveillance for the relevant disease following introduction of a new vaccine
3. maintenance of high immunization rates, even when a disease has become rare

In 1958, there were 763,094 cases of measles in the United States; 552 deaths resulted.[38][39] After the introduction of new vaccines, the number of cases dropped to fewer than 150 per year (median of 56).[39] In early 2008, there were 64 suspected cases of measles. Fifty-four of those infections were associated with importation from another country, although only thirteen percent were actually acquired outside the United States; 63 of the 64 individuals either had never been vaccinated against measles or were uncertain whether they had been vaccinated.[39]

Vaccines led to the eradication of smallpox, one of the most contagious and deadly diseases in humans.[40] Other diseases such as rubella, polio, measles, mumps, chickenpox, and typhoid are nowhere near as common as they were a hundred years ago thanks to widespread vaccination programs. As long as the vast majority of people are vaccinated, it is much more difficult for an outbreak of disease to occur, let alone spread. This effect is called herd immunity. Polio, which is transmitted only among humans, is targeted by an extensive eradication campaign that has seen endemic polio restricted to only parts of three countries (Afghanistan, Nigeria, and Pakistan).[41] However, the difficulty of reaching all children, cultural misunderstandings, and disinformation have caused the anticipated eradication date to be missed several times.[42][43][44][45]

Vaccines also help prevent the development of antibiotic resistance. For example, by greatly reducing the incidence of pneumonia caused by Streptococcus pneumoniae, vaccine programs have greatly reduced the prevalence of infections resistant to penicillin or other first-line antibiotics.[46]

The measles vaccine is estimated to prevent a million deaths every year.[47]

Vaccines typically contain attenuated, inactivated or dead organisms or purified products derived from them. There are several types of vaccines in use.[53] These represent different strategies used to try to reduce the risk of illness while retaining the ability to induce a beneficial immune response.

Inactivated

Main article: Inactivated vaccine

Some vaccines contain inactivated, but previously virulent, micro-organisms that have been destroyed with chemicals, heat, or radiation[55] – "ghosts", with intact but empty bacterial cell envelopes. They are considered an intermediate phase between the inactivated and attenuated vaccines.[56] Examples include IPV (polio vaccine), hepatitis A vaccine, rabies vaccine and most influenza vaccines.[57]

Avian flu vaccine development by reverse genetics techniques

Experimental

Electroporation system for experimental "DNA vaccine" delivery

Many innovative vaccines are also in development and use.

• Dendritic cell vaccines combine dendritic cells with antigens to present the antigens to the body's white blood cells, thus stimulating an immune reaction. These vaccines have shown some positive preliminary results for treating brain tumors[73] and are also tested in malignant melanoma.[74]
• Recombinant vector – by combining the physiology of one micro-organism and the DNA of another, immunity can be created against diseases that have complex infection processes. An example is the RVSV-ZEBOV vaccine licensed to Merck that is being used in 2018 to combat ebola in Congo.[75]
• T-cell receptor peptide vaccines are under development for several diseases using models of Valley Fever, stomatitis, and atopic dermatitis. These peptides have been shown to modulate cytokine production and improve cell-mediated immunity.
• Targeting of identified bacterial proteins that are involved in complement inhibition would neutralize the key bacterial virulence mechanism.[76]
• The use of plasmids has been validated in preclinical studies as a protective vaccine strategy for cancer and infectious diseases. However, in human studies, this approach has failed to provide clinically relevant benefit. The overall efficacy of plasmid DNA immunization depends on increasing the plasmid's immunogenicity while also correcting for factors involved in the specific activation of immune effector cells.[77]
• Bacterial vector – Similar in principle to viral vector vaccines, but using bacteria instead.[64]
• Antigen-presenting cell[64]

While most vaccines are created using inactivated or attenuated compounds from micro-organisms, synthetic vaccines are composed mainly or wholly of synthetic peptides, carbohydrates, or antigens.

Vaccines may be monovalent (also called univalent) or multivalent (also called polyvalent). A monovalent vaccine is designed to immunize against a single antigen or single microorganism.[78] A multivalent or polyvalent vaccine is designed to immunize against two or more strains of the same microorganism, or against two or more microorganisms.[79] The valency of a multivalent vaccine may be denoted with a Greek or Latin prefix (e.g., bivalent, trivalent, or tetravalent/quadrivalent). In certain cases, a monovalent vaccine may be preferable for rapidly developing a strong immune response.[80]

When two or more vaccines are mixed in the same formulation, the two vaccines can interfere. This most frequently occurs with live attenuated vaccines, where one of the vaccine components is more robust than the others and suppresses the growth and immune response to the other components. This phenomenon was first noted in the trivalent Sabin polio vaccine, where the amount of serotype 2 virus in the vaccine had to be reduced to stop it from interfering with the "take" of the serotype 1 and 3 viruses in the vaccine.[81] This phenomenon has also been found to be a problem with the dengue vaccines currently being researched, where the DEN-3 serotype was found to predominate and suppress the response to DEN-1, -2 and -4 serotypes.[82]

Various fairly standardized abbreviations for vaccine names have developed, although the standardization is by no means centralized or global. For example, the vaccine names used in the United States have well-established abbreviations that are also widely known and used elsewhere. An extensive list of them provided in a sortable table and freely accessible is available at a US Centers for Disease Control and Prevention web page.[95] The page explains that "The abbreviations [in] this table (Column 3) were standardized jointly by staff of the Centers for Disease Control and Prevention, ACIP Work Groups, the editor of the Morbidity and Mortality Weekly Report (MMWR), the editor of Epidemiology and Prevention of Vaccine-Preventable Diseases (the Pink Book), ACIP members, and liaison organizations to the ACIP."[95]

Some examples are "DTaP" for diphtheria and tetanus toxoids and acellular pertussis vaccine, "DT" for diphtheria and tetanus toxoids, and "Td" for tetanus and diphtheria toxoids. At its page on tetanus vaccination,[96] the CDC further explains that "Upper-case letters in these abbreviations denote full-strength doses of diphtheria (D) and tetanus (T) toxoids and pertussis (P) vaccine. Lower-case "d" and "p" denote reduced doses of diphtheria and pertussis used in the adolescent/adult-formulations. The 'a' in DTaP and Tdap stands for 'acellular', meaning that the pertussis component contains only a part of the pertussis organism."[96]

Another list of established vaccine abbreviations is at the CDC's page called "Vaccine Acronyms and Abbreviations", with abbreviations used on U.S. immunization records.[97] The United States Adopted Name system has some conventions for the word order of vaccine names, placing head nouns first and adjectives postpositively. This is why the USAN for "OPV" is "poliovirus vaccine live oral" rather than "oral poliovirus vaccine".

A vaccine licensure occurs after the successful conclusion of the development cycle and further the clinical trials and other programs involved through Phases I–III demonstrating safety, immunoactivity, immunogenetic safety at a given specific dose, proven effectiveness in preventing infection for target populations, and enduring preventive effect (time endurance or need for revaccination must be estimated).[98] Because preventive vaccines are predominantly evaluated in healthy population cohorts and distributed among the general population, a high standard of safety is required.[99] As part of a multinational licensing of a vaccine, the World Health Organization Expert Committee on Biological Standardization developed guidelines of international standards for manufacturing and quality control of vaccines, a process intended as a platform for national regulatory agencies to apply for their own licensing process.[98] Vaccine manufacturers do not receive licensing until a complete clinical cycle of development and trials proves the vaccine is safe and has long-term effectiveness, following scientific review by a multinational or national regulatory organization, such as the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA).[100][101]

Upon developing countries adopting WHO guidelines for vaccine development and licensure, each country has its own responsibility to issue a national licensure, and to manage, deploy, and monitor the vaccine throughout its use in each nation.[98] Building trust and acceptance of a licensed vaccine among the public is a task of communication by governments and healthcare personnel to ensure a vaccination campaign proceeds smoothly, saves lives, and enables economic recovery.[102][103] When a vaccine is licensed, it will initially be in limited supply due to variable manufacturing, distribution, and logistical factors, requiring an allocation plan for the limited supply and which population segments should be prioritized to first receive the vaccine.[102]

In order to provide the best protection, children are recommended to receive vaccinations as soon as their immune systems are sufficiently developed to respond to particular vaccines, with additional "booster" shots often required to achieve "full immunity". This has led to the development of complex vaccination schedules. Global recommendations of vaccination schedule are issued by Strategic Advisory Group of Experts and will be further translated by advisory committee at the country level with considering of local factors such as disease epidemiology, acceptability of vaccination, equity in local populations, and programmatic and financial constraint.[106] In the United States, the Advisory Committee on Immunization Practices, which recommends schedule additions for the Centers for Disease Control and Prevention, recommends routine vaccination of children against[107] hepatitis A, hepatitis B, polio, mumps, measles, rubella, diphtheria, pertussis, tetanus, HiB, chickenpox, rotavirus, influenza, meningococcal disease and pneumonia.[108]

The large number of vaccines and boosters recommended (up to 24 injections by age two) has led to problems with achieving full compliance. To combat declining compliance rates, various notification systems have been instituted and many combination injections are now marketed (e.g., Pentavalent vaccine and MMRV vaccine), which protect against multiple diseases.

Besides recommendations for infant vaccinations and boosters, many specific vaccines are recommended for other ages or for repeated injections throughout life – most commonly for measles, tetanus, influenza, and pneumonia. Pregnant women are often screened for continued resistance to rubella. The human papillomavirus vaccine is recommended in the U.S. (as of 2011)[109] and UK (as of 2009).[110] Vaccine recommendations for the elderly concentrate on pneumonia and influenza, which are more deadly to that group. In 2006, a vaccine was introduced against shingles, a disease caused by the chickenpox virus, which usually affects the elderly.[111]

Scheduling and dosing of a vaccination may be tailored to the level of immunocompetence of an individual[112] and to optimize population-wide deployment of a vaccine when it supply is limited,[113] e.g. in the setting of a pandemic.

One challenge in vaccine development is economic: Many of the diseases most demanding a vaccine, including HIV, malaria and tuberculosis, exist principally in poor countries. Pharmaceutical firms and biotechnology companies have little incentive to develop vaccines for these diseases because there is little revenue potential. Even in more affluent countries, financial returns are usually minimal and the financial and other risks are great.[114]

Most vaccine development to date has relied on "push" funding by government, universities and non-profit organizations.[115] Many vaccines have been highly cost effective and beneficial for public health.[116] The number of vaccines actually administered has risen dramatically in recent decades.[117] This increase, particularly in the number of different vaccines administered to children before entry into schools may be due to government mandates and support, rather than economic incentive.[118]

Vaccine production is fundamentally different from other kinds of manufacturing – including regular pharmaceutical manufacturing – in that vaccines are intended to be administered to millions of people of whom the vast majority are perfectly healthy.[121] This fact drives an extraordinarily rigorous production process with strict compliance requirements that go far beyond what is required of other products.[121]

Depending upon the antigen, it can cost anywhere from US$50 to $500 million to build a vaccine production facility, which requires highly specialized equipment, clean rooms, and containment rooms.[122] There is a global scarcity of personnel with the right combination of skills, expertise, knowledge, competence and personality to staff vaccine production lines.[122] With the notable exceptions of Brazil, China, and India, many developing countries' educational systems are unable to provide enough qualified candidates, and vaccine makers based in such countries must hire expatriate personnel to keep production going.[122]

Vaccine production has several stages. First, the antigen itself is generated. Viruses are grown either on primary cells such as chicken eggs (e.g., for influenza) or on continuous cell lines such as cultured human cells (e.g., for hepatitis A).[123] Bacteria are grown in bioreactors (e.g., Haemophilus influenzae type b). Likewise, a recombinant protein derived from the viruses or bacteria can be generated in yeast, bacteria, or cell cultures.[124][125]

After the antigen is generated, it is isolated from the cells used to generate it. A virus may need to be inactivated, possibly with no further purification required. Recombinant proteins need many operations involving ultrafiltration and column chromatography. Finally, the vaccine is formulated by adding adjuvant, stabilizers, and preservatives as needed. The adjuvant enhances the immune response to the antigen, stabilizers increase the storage life, and preservatives allow the use of multidose vials.[124][125] Combination vaccines are harder to develop and produce, because of potential incompatibilities and interactions among the antigens and other ingredients involved.[126]

The final stage in vaccine manufacture before distribution is fill and finish, which is the process of filling vials with vaccines and packaging them for distribution. Although this is a conceptually simple part of the vaccine manufacture process, it is often a bottleneck in the process of distributing and administering vaccines.[127][128][129]

Vaccine production techniques are evolving. Cultured mammalian cells are expected to become increasingly important, compared to conventional options such as chicken eggs, due to greater productivity and low incidence of problems with contamination. Recombination technology that produces genetically detoxified vaccines is expected to grow in popularity for the production of bacterial vaccines that use toxoids. Combination vaccines are expected to reduce the quantities of antigens they contain, and thereby decrease undesirable interactions, by using pathogen-associated molecular patterns.[126]

A woman receiving a vaccine by injection

One of the most common methods of delivering vaccines into the human body is injection.

The development of new delivery systems raises the hope of vaccines that are safer and more efficient to deliver and administer. Lines of research include liposomes and ISCOM (immune stimulating complex).[131]

Notable developments in vaccine delivery technologies have included oral vaccines. Early attempts to apply oral vaccines showed varying degrees of promise, beginning early in the 20th century, at a time when the very possibility of an effective oral antibacterial vaccine was controversial.[132] By the 1930s there was increasing interest in the prophylactic value of an oral typhoid fever vaccine for example.[133]

An oral polio vaccine turned out to be effective when vaccinations were administered by volunteer staff without formal training; the results also demonstrated increased ease and efficiency of administering the vaccines. Effective oral vaccines have many advantages; for example, there is no risk of blood contamination. Vaccines intended for oral administration need not be liquid, and as solids, they commonly are more stable and less prone to damage or spoilage by freezing in transport and storage.[134] Such stability reduces the need for a "cold chain": the resources required to keep vaccines within a restricted temperature range from the manufacturing stage to the point of administration, which, in turn, may decrease costs of vaccines.

A microneedle approach, which is still in stages of development, uses "pointed projections fabricated into arrays that can create vaccine delivery pathways through the skin".[135]

An experimental needle-free[136] vaccine delivery system is undergoing animal testing.[137][138] A stamp-size patch similar to an adhesive bandage contains about 20,000 microscopic projections per square cm.[139] This dermal administration potentially increases the effectiveness of vaccination, while requiring less vaccine than injection.[140]

Goat vaccination against sheep pox and pleural pneumonia

Vaccinations of animals are used both to prevent their contracting diseases and to prevent transmission of disease to humans.[141] Both animals kept as pets and animals raised as livestock are routinely vaccinated. In some instances, wild populations may be vaccinated. This is sometimes accomplished with vaccine-laced food spread in a disease-prone area and has been used to attempt to control rabies in raccoons.

Where rabies occurs, rabies vaccination of dogs may be required by law. Other canine vaccines include canine distemper, canine parvovirus, infectious canine hepatitis, adenovirus-2, leptospirosis, Bordetella, canine parainfluenza virus, and Lyme disease, among others.

Cases of veterinary vaccines used in humans have been documented, whether intentional or accidental, with some cases of resultant illness, most notably with brucellosis.[142] However, the reporting of such cases is rare and very little has been studied about the safety and results of such practices. With the advent of aerosol vaccination in veterinary clinics, human exposure to pathogens not naturally carried in humans, such as Bordetella bronchiseptica, has likely increased in recent years.[142] In some cases, most notably rabies, the parallel veterinary vaccine against a pathogen may be as much as orders of magnitude more economical than the human one.

Comparison of smallpox (left) and cowpox inoculations sixteen days after administration (1802)

Prior to the introduction of vaccination with material from cases of cowpox (heterotypic immunisation), smallpox could be prevented by deliberate variolation with smallpox virus. The earliest hints of the practice of variolation for smallpox in China come during the tenth century.[151] The Chinese also practiced the oldest documented use of variolation, dating back to the fifteenth century. They implemented a method of "nasal insufflation" administered by blowing powdered smallpox material, usually scabs, up the nostrils. Various insufflation techniques have been recorded throughout the sixteenth and seventeenth centuries within China.[152]^: 60 Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers.[153]

An early 19th-century satire of antivaxxers by Isaac Cruikshank

Mary Wortley Montagu, who had witnessed variolation in Turkey, had her four-year-old daughter variolated in the presence of physicians of the Royal Court in 1721 upon her return to England.[152] Later on that year, Charles Maitland conducted an experimental variolation of six prisoners in Newgate Prison in London.[154] The experiment was a success, and soon variolation was drawing attention from the royal family, who helped promote the procedure. However, in 1783, several days after Prince Octavius of Great Britain was inoculated, he died.[155] In 1796, the physician Edward Jenner took pus from the hand of a milkmaid with cowpox, scratched it into the arm of an 8-year-old boy, James Phipps, and six weeks later variolated the boy with smallpox, afterwards observing that he did not catch smallpox.[156][157] Jenner extended his studies and, in 1798, reported that his vaccine was safe in children and adults, and could be transferred from arm-to-arm, which reduced reliance on uncertain supplies from infected cows.[155] In 1804, the Spanish Balmis smallpox vaccination expedition to Spain's colonies Mexico and Philippines used the arm-to-arm transport method to get around the fact the vaccine survived for only 12 days in vitro. They used cowpox.[158] Since vaccination with cowpox was much safer than smallpox inoculation,[159] the latter, though still widely practiced in England, was banned in 1840.[160]

French print in 1896 marking the centenary of Jenner's vaccine

Following on from Jenner's work, the second generation of vaccines was introduced in the 1880s by Louis Pasteur who developed vaccines for chicken cholera and anthrax,[15] and from the late nineteenth century vaccines were considered a matter of national prestige. National vaccination policies were adopted and compulsory vaccination laws were passed.[156] In 1931 Alice Miles Woodruff and Ernest Goodpasture documented that the fowlpox virus could be grown in embryonated chicken egg. Soon scientists began cultivating other viruses in eggs. Eggs were used for virus propagation in the development of a yellow fever vaccine in 1935 and an influenza vaccine in 1945. In 1959 growth media and cell culture replaced eggs as the standard method of virus propagation for vaccines.[161]

Vaccinology flourished in the twentieth century, which saw the introduction of several successful vaccines, including those against diphtheria, measles, mumps, and rubella. Major achievements included the development of the polio vaccine in the 1950s and the eradication of smallpox during the 1960s and 1970s. Maurice Hilleman was the most prolific of the developers of the vaccines in the twentieth century. As vaccines became more common, many people began taking them for granted. However, vaccines remain elusive for many important diseases, including herpes simplex, malaria, gonorrhea, and HIV.[156][162]

Generations of vaccines

First generation vaccines are whole-organism vaccines – either live and weakened, or killed forms.[163] Live, attenuated vaccines, such as smallpox and polio vaccines, are able to induce killer T-cell (T_C or CTL) responses, helper T-cell (T_H) responses and antibody immunity. However, attenuated forms of a pathogen can convert to a dangerous form and may cause disease in immunocompromised vaccine recipients (such as those with AIDS). While killed vaccines do not have this risk, they cannot generate specific killer T cell responses and may not work at all for some diseases.[163]

Second generation vaccines were developed to reduce the risks from live vaccines. These are subunit vaccines, consisting of specific protein antigens (such as tetanus or diphtheria toxoid) or recombinant protein components (such as the hepatitis B surface antigen). They can generate T_H and antibody responses, but not killer T cell responses.

RNA vaccines and DNA vaccines are examples of third generation vaccines.[163][164][165] In 2016 a DNA vaccine for the Zika virus began testing at the National Institutes of Health. Separately, Inovio Pharmaceuticals and GeneOne Life Science began tests of a different DNA vaccine against Zika in Miami. Manufacturing the vaccines in volume was unsolved as of 2016.[166] Clinical trials for DNA vaccines to prevent HIV are underway.[167] mRNA vaccines such as BNT162b2 were developed in the year 2020 with the help of Operation Warp Speed and massively deployed to combat the COVID-19 pandemic. In 2021, Katalin Karikó and Drew Weissman received Columbia University's Horwitz Prize for their pioneering research in mRNA vaccine technology.[168]

Since at least 2013, scientists have been trying to develop synthetic third-generation vaccines by reconstructing the outside structure of a virus; it was hoped that this will help prevent vaccine resistance.[169]

Principles that govern the immune response can now be used in tailor-made vaccines against many noninfectious human diseases, such as cancers and autoimmune disorders.[170] For example, the experimental vaccine CYT006-AngQb has been investigated as a possible treatment for high blood pressure.[171] Factors that affect the trends of vaccine development include progress in translatory medicine, demographics, regulatory science, political, cultural, and social responses.[172]

Vaccine hesitancy is a delay in acceptance, or refusal of vaccines despite the availability of vaccine services. The term covers outright refusals to vaccinate, delaying vaccines, accepting vaccines but remaining uncertain about their use, or using certain vaccines but not others.[175][176][177][178] There is an overwhelming scientific consensus that vaccines are generally safe and effective.[179][180][181][182] Vaccine hesitancy often results in disease outbreaks and deaths from vaccine-preventable diseases.[183][184][185][186][187][188] The World Health Organization therefore characterizes vaccine hesitancy as one of the top ten global health threats.[189][190]

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External video
Modern Vaccine and Adjuvant Production and Characterization, Genetic Engineering & Biotechnology News

• Vaccines and Antisera at Curlie
• WHO Vaccine preventable diseases and immunization
• World Health Organization position papers on vaccines
• The History of Vaccines, from the College of Physicians of Philadelphia

  This website was highlighted by Genetic Engineering & Biotechnology News in its "Best of the Web" section in January 2015. See: "The History of Vaccines". Best of the Web. Genetic Engineering & Biotechnology News. Vol. 35, no. 2. 15 January 2015. p. 38.