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SPECIAL FEATURE: PERSPECTIVE PERSPECTIVE SPECIAL FEATURE: History of vaccination Stanley Plotkin1 Department of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104 Edited by Rino Rappuoli, Novartis Vaccines, Siena, Italy, and approved February 5, 2014 (received for review January 13, 2014) Vaccines have a history that started late in the 18th century. From the late 19th century, vaccines could be developed in the laboratory. However, in the 20th century, it became possible to develop vaccines based on immunologic markers. In the 21st century, molecular biology permits vaccine development that was not possible before. killed vaccines | proteins | live vaccine | genetic engineering One of the brightest chapters in the history of in humans (7). This idea played a role in the varicella vaccines were all made possible science is the impact of vaccines on human development of bacillus Calmette–Guérin through selection of clones by cell-culture longevity and health. Over 300 y have elapsed but is even more obvious in the selection of passage in vitro (17–21). In essence, passage since the first vaccine was discovered. In rhesus and bovine rotavirus strains to aid in cell culture leads to adaptation to growth a short article, it is not possible to do justice the creation of human rotavirus vaccines as in that medium, and the mutants best capa- to a subject that encompasses immunology, mentioned below under Reassortment. bleofgrowthhaveoftenlostormodifiedthe molecular biology, and public health, but sev- It was Pasteur and his colleagues who most genes that allow them to infect and spread eral more extensive sources are available clearly formulated the idea of attenuation and within a human host. The oral polio vaccine to the interested reader (1–5). Rather than demonstrated its utility, first with Pasteurella is a good example, in that the mutants that attempting a chronological narrative, I will multocida, the cause of a diarrheal disease in occur in cell-culture passage that confer in- consider vaccine development from the view- chickens (8), then anthrax in sheep and most ability to cause paralysis were isolated by point of the technologies used to create vac- sensationally rabies virus in animals and selection of clones with low neurovirulence in cines. However, Table 1 provides a general humans (9). Their first approaches involved monkeys. These mutations are at least partly idea of the chronology. exposure to oxygen or heat, both of which lost after replication of attenuated strains in In current articles that describe novel played a role in the development of the rabies the human intestine, leading to rare cases of technologies, it is often said that they will vaccine and in the famous anthrax challenge paralysis after vaccination (22). Adaptation of “ ” enable rational development of vaccines. experiment at Pouilly-le-Fort (10). However, viruses to growth at temperatures below 37 °C, The opposite of rational is irrational, but pre- themorepowerfultechniqueofserialculti- the normal temperature of humans, also is sumably the writers mean to contrast rational vation of a pathogen in vitro or in inhabitual attenuating, as was the case for rubella vaccine “ ” with empiric. However, in fact, vaccine de- hosts originated with Calmette and Guérin, (20). Another live vaccine, thus far used only velopment has been based on rational choices who passaged bovine tuberculosis bacteria in the military to prevent epidemic pneumo- ever since the mid-20th century, when im- 230 times in artificial media to obtain an nia, consists of adeno 4 and 7 viruses grown in munology advanced to the point of distin- attenuated strain to protect against human human diploid cell strains and administered guishing protection mediated by antibody tuberculosis (11). Later in the 20th century, orally to replicate in the intestine (23). Other and that mediated by lymphocytes, and when Sellards and Laigret (12) and, more success- live vaccines attenuated in cell-culture passage passage in cell culture permitted the selection fully, Theiler and Smith (13) attenuated yel- are the monovalent rotavirus vaccine attenu- of attenuated mutants. After that point, suc- low fever virus by serial passage in mice and ated by passage in Vero cells (24) and the cessful vaccines have been “rationally” devel- in chicken embryo tissues, respectively. Japanese encephalitis strain SA14-14-2 (25). oped by protection studies in animals; by Cell Culture inference from immune responses shown to Reassortment By the 1940s, virologists understood that at- protect against repeated natural infection (the Certain RNA viruses have segmented ge- tenuation could be achieved by passage in so-called mechanistic correlates of protection) nomes that can be manipulated in a way abnormal hosts. Notably, Hilary Koprowski (6); and from the use of passive administra- similar to the chromosomes of eukaryotes. and coworkers developed rabies and oral tion of antibodies against specific antigens to Cocultivation of two viruses in cell culture polio vaccines by passage in chicken embryo show that those antigens should be included with clone selection by plaque formation or mice (14, 15). However, this method was in vaccines. allows isolation of viruses with RNA seg- inefficient, and mice were not a sterile me- Attenuation dium. A revolution happened with the dis- ments from both viruses. Reassortment has The idea of attenuation of virulent infections covery that cells could be cultured in vitro developed slowly over the course of centuries. and used as substrates for viral growth. Author contributions: S.P. wrote the paper. Variolation was analogous to the use of small Enders, Weller, and Robbins (16) showed The author declares no conflict of interest. amounts of poison to render one immune to that many viruses could be grown in cell This article is a PNAS Direct Submission. ’ toxic effects. Jenner s use of an animal pox- culture, including polio and measles, and this This article is part of the special series of PNAS 100th Anniversary virus (probably horsepox) to prevent small- method was vigorously taken up by vaccine articles to commemorate exceptional research published in PNAS pox was essentially based on the idea that an developers. The oral polio vaccine of Albert over the last century. agent virulent for animals might be attenuated Sabin and the measles, rubella, mumps, and 1Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1400472111 PNAS | August 26, 2014 | vol. 111 | no. 34 | 12283–12287 Downloaded by guest on September 29, 2021 Table 1. Outline of the development of human vaccines Live attenuated Killed whole organisms Purified proteins or polysaccharides Genetically engineered 18th Century Smallpox (1798) 19th Century Rabies (1885) Typhoid (1896) Cholera (1896) Plague (1897) Early 20th Century, first half Tuberculosis (bacille Pertussis (1926) Diphtheria toxoid (1923) Calmette–Guérin) (1927) Yellow fever (1935) Influenza (1936) Tetanus toxoid (1926) Rickettsia (1938) 20th Century, second half Polio (oral) (1963) Polio (injected) (1955) Anthrax secreted proteins (1970) Hepatitis B surface antigen recombinant (1986) Measles (1963) Rabies (cell culture) (1980) Meningococcus polysaccharide (1974) Lyme OspA (1998) Mumps (1967) Japanese encephalitis (mouse brain) Pneumococcus polysaccharide (1977) Cholera (recombinant toxin B) (1992) (1993) Rubella (1969) Tick-borne encephalitis (1981) Haemophilus influenzae type B polysaccharide (1985) Adenovirus (1980) Hepatitis A (1996) H.influenzae type b conjugate (1987) Typhoid (Salmonella TY21a) (1989) Cholera (WC-rBS) (1991) Typhoid (Vi) polysaccharide (1994) Varicella (1995) Meningococcal conjugate Acellular pertussis (1996) (group C) (1999) Rotavirus reassortants (1999) Hepatitis B (plasma derived) (1981) Cholera (attenuated) (1994) Cold-adapted influenza (1999) 21st Century Rotavirus (attenuated and new Japanese encephalitis (2009) Pneumococcal conjugates* Human papillomavirus reassortants) (2006) (Vero cell) (heptavalent) (2000) recombinant (quadrivalent) (2006) Zoster (2006) Cholera (WC only) (2009) Meningococcal conjugates* Human papillomavirus (quadrivalent) (2005) recombinant (bivalent) (2009) Pneumococcal conjugates* Meningococcal group B proteins (13-valent) (2010) (2013) *Capsular polysaccharide conjugated to carrier proteins. enabled the creation of three major vaccines: rotavirus and one coding for the VP7 surface ween French, German, and English workers live and inactivated influenza (26, 27), as well protein of human rotaviruses (30). Because of to develop antibacterial vaccines. Inactivated as one of the two rotavirus vaccines (28). In safety issues, that vaccine was superseded by vaccines against typhoid were first applied by the case of inactivated influenza, the objective a pentavalent vaccine combining RNA seg- Wright and Semple in England and Pfeiffer is to select the segments coding for hemag- ments from a bovine rotavirus with one seg- and Kolle in Germany (34, 35). Humans were glutinin and neuraminidase and to combine ment from human rotaviruses coding for vaccinated against plague by Haffkine, using them with segments coding for the internal either surface V44 or VP7 proteins, (31) as inactivated plague bacilli (36). Live vaccines genes of viruses that grow well. Thus, well as the monovalent vaccine previously against cholera were developed by Ferran in one obtains a vaccine virus that is safe to mentioned under Cell Culture. Spain and Haffkine in France (37), but it was handle but still generates
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