CONTRIBUTOR: Jeffrey P. Baker, MD, PhD Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina Address correspondence to Jeffrey P. Baker, MD, PhD, Trent Center for Bioethics, Humanities, and History of Medicine, Box 3040 DUMC, Durham, NC 27710. E-mail: [email protected] Accepted for publication Jun 21, 2011 ABBREVIATION MMR—, , doi:10.1542/peds.2011-1430 The First Measles Like in the more familiar story of sponse was often rewarded by an ensuing disaster, in which some 260 vaccine, the development of the first suc- hour-long conversation.3 children developed paralytic polio cessful live against In 1954, while the national field trials of from the vaccine, was widely blamed measles began in the laboratory of John ’s captivated at the time on Cutter pharmaceuti- Enders. One of the greatest virologists of media attention, Enders and pediatrician cals.5,6 Enders, however, believed the 20th century, Enders pioneered the Thomas Peebles successfully cultivated Salk’s own inactivation process had technique of viral tissue culture, which measles virus in human kidney cell cul- been at fault. He wanted to stay per- makes it possible to grow viruses in vitro ture for the first time.4 Ever-ingenious in sonally involved to be sure that the in cells nourished in laboratory media.1 finding sources for his tissue cultures, measles vaccine’s development would In 1949, he and his pediatric infectious Enders obtained kidneys from a neuro- proceed more smoothly.3 disease fellows Thomas Weller and Fred- surgeon colleague who treated hydro- An immediate problem was to find a erick Robbins showed that poliovirus cephalus by performing a unilateral ne- new human tissue culture system; End- could be cultivated in tissue of nonneu- phrectomy and connecting a shunt to ers’ neurosurgery colleague was no ronal origins, a discovery that set the carry cerebrospinal fluid to the ureter. longer removing kidneys to place stage for the first successful Peebles traveled the Boston, Massachu- shunts. Two new members now joined against the disease and led to a Nobel setts, area with a throat swab in search the Enders team: the Yugoslav virolo- Prize in 1954.2 Enders himself was a of measles outbreaks in private board- gist Milan V. Milovanovic (who would remarkable character. He never tried ing schools. His first, and most famous, later be put in charge of polio vaccine to patent his work or share results success involved an 11-year-old boy production in Yugoslavia) and a pedi- with the media before peer review. He named David Edmonston, whose name atric infectious disease fellow, Sam- was consistently generous in sharing became attached to the strain that uel L. Katz. Enders set his eyes on the his knowledge with potential competi- would become the source for the first placentas being discarded across the tors, and despite his personal wealth measles vaccine.3 street by the Boston Lying-in Hospital: he was equally known for his frugality; Enders decided to play a much more “There are those nice amnions that lie fellows learned to wash their own “hands-on” role with measles vaccine in the placenta,” he observed to his col- glassware, and every year the “chief” than he had with polio. He was un- leagues; “Let’s do something with returned unspent grant money to the happy with how the polio vaccine saga them.”3 Milovanovic and Katz set forth National Institutes of Health. Above all, had unfolded after he had left its devel- and returned with fresh placentas, Enders took seriously the role of men- opment to others. Less than a month from which they could peel off the am- tor, rounding each day beside the after the Salk vaccine’s approval and niotic membranes and trypsinize their benches of his select group of fellows licensure in April 1955, it became ap- cells to make beautiful cell cultures. with his bow tie, vest, and jacket ask- parent that some of the vaccine lots Because humans were the sole natural ing, “Well, what’s new?” A positive re- were contaminated with wild polio. The host of measles, Enders reasoned that

PEDIATRICS Volume 128, Number 3, September 2011 435 Downloaded from www.aappublications.org/news by guest on September 29, 2021 the 1950s remained largely unregu- lated, some historians have argued that the Nuremberg code’s powerful articulation of informed consent in 1946 had little impact on American re- search until the 1960s.11 In this light, it is notable that Katz explained the trial in person to every parent, and the en- suing article clearly stated that no child was given the vaccine without written parental consent.3,12 Every morning and afternoon Katz and technician Ann Holloway went to the school, examined the children, took throat swabs, and drew blood speci- mens. Returning to the laboratory, they attempted to detect measles virus FIGURE John Enders and Samuel L. Katz in the laboratory where live measles vaccine was developed. from their samples but never did. A number of the children developed fe- vers and an evanescent rash but “seemed perfectly fine—in fact, it was the virus could be attenuated by being After more safety trials in monkeys, it adapted to a nonhuman species. Ear- was time to test the vaccine in humans. a little bit like roseola,” Katz recounted. lier investigators had grown influenza, As the only physician on the team, Katz The children had nonetheless devel- mumps, and yellow viruses in played an increasingly central role at oped antibodies, and when the next embryonated chick eggs; indeed, in the that point. Following the time-honored measles outbreak struck the Fernald 1930s Max Theiler and Hugh Smith tradition of autoexperimentation, the School, all of them were totally 3 used this system to develop the atten- lead investigators first tested the protected. uated still used to- strain on each other. Their antibody ti- Enders and Katz then recruited a num- day.7 After some early false starts, ters rose, and no adverse effects fol- ber of colleagues from around the Milovanovic and Katz succeeded in es- lowed. Next, Enders and Katz ap- country to test the vaccine in children tablishing measles vaccine in this sys- proached the Walter E. Fernald State in other settings, both institutionalized tem.8 The next step was to repeat this School near Waltham, Massachusetts. and home-dwelling. The resulting arti- success in tissue cultures obtained by This was an institution typical of many cles appeared together in the New Eng- trypsinizing chick embryos. Although others of the time that provided long- land Journal of Medicine on July 28, at first it was not clear whether any- term custodial and medical care for 1960. Written by figures who were on thing was growing at all, characteris- severely handicapped children with their way to becoming pediatric lead- tic cytopathic changes appeared in the conditions such as microcephaly, tri- ers in their own right, such as Saul fifth passage.3 somy 21, and cerebral palsy. “They Krugman, C. Henry Kempe, and Robert After 3 years of work (involving 24 lived in dormitories,” Katz recollected, Haggerty, they joined those of Enders, passages through human kidney tis- “and they had really severe outbreaks Milovanovic, and Katz to provide an im- sue culture, 28 through human amni- of measles every few years—not just pressive justification of the first live otic cell culture, 6 in fertilized hens’ with morbidity, but with mortality.”3 measles vaccine.13 eggs, and 13 in chick embryo cell cul- Conducting a among insti- The subsequent story can only be tures), the investigators finally felt tutionalized children raised significant traced briefly here. The Edmonston ready to test the modified Edmonston ethical questions. Indeed, just 10 years strain became the basis for the first strain in monkeys. The injected mon- earlier, the Fernald School had permit- measles vaccine licensed in the United keys developed a strong antibody re- ted nontherapeutic nutritional studies States in 1963 and for the still-more sponse but no fever, viremia, or rash, without informing families that their attenuated products developed in the which is consistent with successful children were being given radioiso- next several years by Anton Schwarz at attenuation.9 topes.10 Given that research ethics in Pitman Moore-Dow and Maurice Hille-

436 BAKER Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS PERSPECTIVES man at Merck.14 By the end of the de- persuasive objections may simply be 9. Enders JF, Katz SL, Milovanovic MV, Hollo- cade, the annual number of measles the fact that the United States had way A. Studies on an attenuated measles- virus vaccine. I. Development and prepara- cases in the United States had de- used the MMR vaccine widely since the tion of the vaccine: technics for assay of creased from several million to sev- early 1970s and yet experienced no effects of . N Engl J Med. 1960; eral thousand.15 corresponding rise in cases. 263:153–159 Although the domestic eradication of From a global perspective, measles 10. Advisory Committee on Human Radiation vaccine has been one of the greatest Experiments. The Human Radiation Experi- measles proved to be more difficult ments: Final Report of the President’s Advi- than optimists in the late 1960s pre- public health breakthroughs of the sory Committee. Oxford, United Kingdom: dicted, the remarkable safety record 20th century. It is fitting to think of its Oxford University Press; 1996:210–212 of measles vaccine (incorporated origins 50 years ago in the no-frills lab- 11. Rothman D. Strangers at the Bedside: A His- into Merck’s MMR combination oratory of a Connecticut Yankee scien- tory of How Law and Bioethics Transformed tist John F. Enders. Medical Decision Making. New York, NY: Al- against measles, mumps, and ru- dine de Gruyter; 2003 bella in 1971) is worth noting. In con- REFERENCES 12. Katz SL, Enders JF, Holloway A. Studies on an trast to whole-cell pertussis and live attenuated measles-virus vaccine: clinical, 1. Weller TH, Robbins FC. John Franklin End- virological, and immunological effects of polio vaccines, which were at the ers. In: Biographical Memoirs, National center of highly visible vaccine- Academy of Science. Vol 60. Washington, DC: vaccine in institutionalized children. N Engl J Med. 1960;263:159–161 safety controversies in the 1970s and National Academy Press; 1991:47–61 13. Katz SL, Kempe HC, Black FL, et al. Studies on 80s, measles vaccine enjoyed wide 2. Enders JF, Weller TH, Robbins FC. Cultivation of the Lansing strain of poliomyelitis virus an attenuated measles vaccine: VIII. General public acceptance. It figured promi- in cultures of various human embryonic tis- summary and evaluation of results of vacci- nently in the rise of school mandates sues. Science. 1949;109(2822):85–87 nation. N Engl J Med. 1960;263:180–184 as a strategy for promoting vaccina- 3. Baker JP. Oral History Interview, Samuel L. 14. Galambos L, Sewell JE. Networks of Innova- tion.16 Families who declined it did so Katz, March 7, 2002 [transcript at Pediatric tion: Vaccine Development at Merck, Sharp, History Center]. American Academy of and Dohme, and Mulford, 1895–1995. Cam- not so much for reasons of safety Pediatrics: Elk Grove Village, IL; 2002 bridge, United Kingdom: Cambridge Univer- than questioning the clinical severity 4. Enders JF, Peebles TC. Propagation in tissue sity Press; 1995 of measles (as was the case, ironi- cultures of cytopathogenic agents from pa- 15. Katz SL. The history of measles vaccine of cally, with David Edmonston’s deci- tients with measles. Proc Soc Exp Biol Med. attempts to control measles. In: Koprowski 1954;86(2):277–286 sion not to vaccinate his own son).17 H, Oldstone MBA, eds. Microbe Hunters: 5. Nathanson N, Langmuir AD. The Cutter inci- Then and Now. Bloomington, IL: Medi-Ed This long period of relatively little dent: poliomyelitis following formaldehyde- Press; 1996:69–76 safety controversy ended abruptly inactivated poliovirus vaccination in the 16. Colgrove J. State of : The Politics of United States during the spring of 1955. Am J Vaccination in Twentieth-Century America. with the rise of the MMR/autism con- Hyg. 1963;78:16–81 troversy in 1997. Perhaps because Berkeley, CA: University of California Press; 6. Offit PA. The Cutter Incident: How America’s 2006 Britain did not begin to routinely vacci- First Polio Vaccine Led to the Growing Vac- 17. Allen A. Vaccine: The Controversial Story of nate infants with the MMR vaccine un- cine Crisis. New Haven, CT: Yale University Press; 2005 Medicine’s Greatest Lifesaver. New York, til the late 1980s, the vaccine began to NY: WW Norton; 2007:247 7. Theiler M. Smith HH. Use of yellow fever vi- be used on a widespread basis in that rus modified by in vitro cultivation for hu- 18. Wakefield AJ, Murch SH, Anthony A, et al. country at the same time that the num- man . J Exp Med. 1937;65(6): Ileal-lymphoid-nodular hyperplasia, non- ber of autism cases were rising. The 787–800 specific colitis, and pervasive developmen- tal disorder in children. Lancet. 1998; MMR vaccine/autism hypothesis has 8. Milovanovic MB, Enders JF, Mitus A. Cultiva- tion of measles virus in human amnion cells 351(9103):637–641 18,19 been discredited on many fronts. and in developing chick embryo. Proc Soc 19. Fitzpatrick M. MMR and Autism. London, For parents, one of the most intuitively Exp Biol Med. 1957;95(1):120–127 United Kingdom: Routledge; 2004

FINANCIAL DISCLOSURE: The author has indicated he has no financial relationships relevant to this article to disclose.

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