CONTRIBUTOR: Jeffrey P. Baker, MD, PhDDepartment of Pediatrics, Duke University School of Medicine, Durham, NorthCarolina

Address correspondence to Jeffrey P. Baker, MD, PhD, Trent Center forBioethics, Humanities, and History of Medicine, Box 3040 DUMC, Durham, NC27710. E-mail: baker009@mc.duke.edu

Accepted for publication Jun 21, 2011

ABBREVIATIONMMR—measles, mumps, rubella

doi:10.1542/peds.2011-1430

The First Measles VaccineLike in the more familiar story of poliovaccine, the development of the first suc-cessful live attenuated vaccine againstmeasles began in the laboratory of JohnEnders. One of the greatest virologists ofthe 20th century, Enders pioneered thetechnique of viral tissue culture, whichmakes it possible to growviruses in vitroin cells nourished in laboratory media.1

In 1949, he and his pediatric infectiousdisease fellows ThomasWeller and Fred-erick Robbins showed that polioviruscould be cultivated in tissue of nonneu-ronal origins, a discovery that set thestage for the first successful vaccinesagainst the disease and led to a NobelPrize in 1954.2 Enders himself was aremarkable character. He never triedto patent his work or share resultswith the media before peer review. Hewas consistently generous in sharinghis knowledge with potential competi-tors, and despite his personal wealthhe was equally known for his frugality;fellows learned to wash their ownglassware, and every year the “chief”returned unspent grant money to theNational Institutes of Health. Above all,Enders took seriously the role of men-tor, rounding each day beside thebenches of his select group of fellowswith his bow tie, vest, and jacket ask-ing, “Well, what’s new?” A positive re-

sponse was often rewarded by anhour-long conversation.3

In 1954, while the national field trials ofJonas Salk’s polio vaccine captivatedmediaattention, EndersandpediatricianThomas Peebles successfully cultivatedmeasles virus in human kidney cell cul-ture for the first time.4 Ever-ingenious infinding sources for his tissue cultures,Enders obtained kidneys from a neuro-surgeon colleague who treated hydro-cephalus by performing a unilateral ne-phrectomy and connecting a shunt tocarry cerebrospinal fluid to the ureter.Peebles traveled the Boston, Massachu-setts, area with a throat swab in searchof measles outbreaks in private board-ing schools. His first, and most famous,success involved an 11-year-old boynamed David Edmonston, whose namebecame attached to the strain thatwould become the source for the firstmeasles vaccine.3

Enders decided to play a much more“hands-on” role with measles vaccinethan he had with polio. He was un-happy with how the polio vaccine sagahad unfolded after he had left its devel-opment to others. Less than a monthafter the Salk vaccine’s approval andlicensure in April 1955, it became ap-parent that some of the vaccine lotswere contaminatedwithwild polio. The

ensuing disaster, in which some 260children developed paralytic poliofrom the vaccine, was widely blamedat the time on Cutter pharmaceuti-cals.5,6 Enders, however, believedSalk’s own inactivation process hadbeen at fault. He wanted to stay per-sonally involved to be sure that themeasles vaccine’s development wouldproceed more smoothly.3

An immediate problem was to find anew human tissue culture system; End-ers’ neurosurgery colleague was nolonger removing kidneys to placeshunts. Two new members now joinedthe Enders team: the Yugoslav virolo-gist Milan V. Milovanovic (who wouldlater be put in charge of polio vaccineproduction in Yugoslavia) and a pedi-atric infectious disease fellow, Sam-uel L. Katz. Enders set his eyes on theplacentas being discarded across thestreet by the Boston Lying-in Hospital:“There are those nice amnions that liein the placenta,” he observed to his col-leagues; “Let’s do something withthem.”3 Milovanovic and Katz set forthand returned with fresh placentas,from which they could peel off the am-niotic membranes and trypsinize theircells to make beautiful cell cultures.

Because humanswere the sole naturalhost of measles, Enders reasoned that

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the virus could be attenuated by beingadapted to a nonhuman species. Ear-lier investigators had grown influenza,mumps, and yellow fever viruses inembryonated chick eggs; indeed, in the1930s Max Theiler and Hugh Smithused this system to develop the atten-uated yellow fever vaccine still used to-day.7 After some early false starts,Milovanovic and Katz succeeded in es-tablishing measles vaccine in this sys-tem.8 The next step was to repeat thissuccess in tissue cultures obtained bytrypsinizing chick embryos. Althoughat first it was not clear whether any-thing was growing at all, characteris-tic cytopathic changes appeared in thefifth passage.3

After 3 years of work (involving 24passages through human kidney tis-sue culture, 28 through human amni-otic cell culture, 6 in fertilized hens’eggs, and 13 in chick embryo cell cul-tures), the investigators finally feltready to test the modified Edmonstonstrain in monkeys. The injected mon-keys developed a strong antibody re-sponse but no fever, viremia, or rash,which is consistent with successfulattenuation.9

After more safety trials in monkeys, itwas time to test the vaccine in humans.As the only physician on the team, Katzplayed an increasingly central role atthat point. Following the time-honoredtradition of autoexperimentation, thelead investigators first tested thestrain on each other. Their antibody ti-ters rose, and no adverse effects fol-lowed. Next, Enders and Katz ap-proached the Walter E. Fernald StateSchool near Waltham, Massachusetts.This was an institution typical of manyothers of the time that provided long-term custodial and medical care forseverely handicapped children withconditions such as microcephaly, tri-somy 21, and cerebral palsy. “Theylived in dormitories,” Katz recollected,“and they had really severe outbreaksof measles every few years—not justwith morbidity, but with mortality.”3

Conducting a clinical trial among insti-tutionalized children raised significantethical questions. Indeed, just 10 yearsearlier, the Fernald School had permit-ted nontherapeutic nutritional studieswithout informing families that theirchildren were being given radioiso-topes.10 Given that research ethics in

the 1950s remained largely unregu-lated, some historians have arguedthat the Nuremberg code’s powerfularticulation of informed consent in1946 had little impact on American re-search until the 1960s.11 In this light, itis notable that Katz explained the trialin person to every parent, and the en-suing article clearly stated that nochild was given the vaccine withoutwritten parental consent.3,12

Every morning and afternoon Katz andtechnician Ann Holloway went to theschool, examined the children, tookthroat swabs, and drew blood speci-mens. Returning to the laboratory,they attempted to detect measles virusfrom their samples but never did. Anumber of the children developed fe-vers and an evanescent rash but“seemed perfectly fine—in fact, it wasa little bit like roseola,” Katz recounted.The children had nonetheless devel-oped antibodies, and when the nextmeasles outbreak struck the FernaldSchool, all of them were totallyprotected.3

Enders and Katz then recruited a num-ber of colleagues from around thecountry to test the vaccine in childrenin other settings, both institutionalizedand home-dwelling. The resulting arti-cles appeared together in the New Eng-land Journal of Medicine on July 28,1960. Written by figures who were ontheir way to becoming pediatric lead-ers in their own right, such as SaulKrugman, C. Henry Kempe, and RobertHaggerty, they joined those of Enders,Milovanovic, and Katz to provide an im-pressive justification of the first livemeasles vaccine.13

The subsequent story can only betraced briefly here. The Edmonstonstrain became the basis for the firstmeasles vaccine licensed in the UnitedStates in 1963 and for the still-moreattenuated products developed in thenext several years by Anton Schwarz atPitman Moore-Dow and Maurice Hille-

FIGUREJohn Enders and Samuel L. Katz in the laboratory where live measles vaccine was developed.

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man at Merck.14 By the end of the de-cade, the annual number of measlescases in the United States had de-creased from several million to sev-eral thousand.15

Although the domestic eradication ofmeasles proved to be more difficultthan optimists in the late 1960s pre-dicted, the remarkable safety recordof measles vaccine (incorporatedinto Merck’s MMR combinationagainst measles, mumps, and ru-bella in 1971) is worth noting. In con-trast to whole-cell pertussis and livepolio vaccines, which were at thecenter of highly visible vaccine-safety controversies in the 1970s and80s, measles vaccine enjoyed widepublic acceptance. It figured promi-nently in the rise of school mandatesas a strategy for promoting vaccina-tion.16 Families who declined it did sonot so much for reasons of safetythan questioning the clinical severityof measles (as was the case, ironi-cally, with David Edmonston’s deci-sion not to vaccinate his own son).17

This long period of relatively littlesafety controversy ended abruptlywith the rise of the MMR/autism con-troversy in 1997. Perhaps becauseBritain did not begin to routinely vacci-nate infants with the MMR vaccine un-til the late 1980s, the vaccine began tobe used on a widespread basis in thatcountry at the same time that the num-ber of autism cases were rising. TheMMR vaccine/autism hypothesis hasbeen discredited on many fronts.18,19

For parents, one of the most intuitively

persuasive objections may simply bethe fact that the United States hadused the MMR vaccine widely since theearly 1970s and yet experienced nocorresponding rise in autism cases.

From a global perspective, measlesvaccine has been one of the greatestpublic health breakthroughs of the20th century. It is fitting to think of itsorigins 50 years ago in the no-frills lab-oratory of a Connecticut Yankee scien-tist John F. Enders.

REFERENCES

1. Weller TH, Robbins FC. John Franklin End-ers. In: Biographical Memoirs, NationalAcademy of Science. Vol 60. Washington, DC:National Academy Press; 1991:47–61

2. Enders JF, Weller TH, Robbins FC. Cultivationof the Lansing strain of poliomyelitis virusin cultures of various human embryonic tis-sues. Science. 1949;109(2822):85–87

3. Baker JP. Oral History Interview, Samuel L.Katz, March 7, 2002 [transcript at PediatricHistory Center]. American Academy ofPediatrics: Elk Grove Village, IL; 2002

4. Enders JF, Peebles TC. Propagation in tissuecultures of cytopathogenic agents from pa-tients with measles. Proc Soc Exp Biol Med.1954;86(2):277–286

5. Nathanson N, Langmuir AD. The Cutter inci-dent: poliomyelitis following formaldehyde-inactivated poliovirus vaccination in theUnited States during the spring of 1955. Am JHyg. 1963;78:16–81

6. Offit PA. The Cutter Incident: How America’sFirst Polio Vaccine Led to the Growing Vac-cine Crisis. New Haven, CT: Yale UniversityPress; 2005

7. Theiler M. Smith HH. Use of yellow fever vi-rus modified by in vitro cultivation for hu-man immunization. J Exp Med. 1937;65(6):787–800

8. Milovanovic MB, Enders JF, Mitus A. Cultiva-tion ofmeasles virus in human amnion cellsand in developing chick embryo. Proc SocExp Biol Med. 1957;95(1):120–127

9. Enders JF, Katz SL, Milovanovic MV, Hollo-way A. Studies on an attenuated measles-virus vaccine. I. Development and prepara-tion of the vaccine: technics for assay ofeffects of vaccination. N Engl J Med. 1960;263:153–159

10. Advisory Committee on Human RadiationExperiments. The Human Radiation Experi-ments: Final Report of the President’s Advi-sory Committee. Oxford, United Kingdom:Oxford University Press; 1996:210–212

11. Rothman D. Strangers at the Bedside: A His-tory of How Law and Bioethics TransformedMedical Decision Making. New York, NY: Al-dine de Gruyter; 2003

12. Katz SL, Enders JF, Holloway A. Studies on anattenuated measles-virus vaccine: clinical,virological, and immunological effects ofvaccine in institutionalized children. N EnglJ Med. 1960;263:159–161

13. Katz SL, Kempe HC, Black FL, et al. Studies onan attenuatedmeasles vaccine: VIII. Generalsummary and evaluation of results of vacci-nation. N Engl J Med. 1960;263:180–184

14. Galambos L, Sewell JE. Networks of Innova-tion: Vaccine Development at Merck, Sharp,and Dohme, and Mulford, 1895–1995. Cam-bridge, United Kingdom: Cambridge Univer-sity Press; 1995

15. Katz SL. The history of measles vaccine ofattempts to control measles. In: KoprowskiH, Oldstone MBA, eds. Microbe Hunters:Then and Now. Bloomington, IL: Medi-EdPress; 1996:69–76

16. Colgrove J. State of Immunity: The Politics ofVaccination in Twentieth-Century America.Berkeley, CA: University of California Press;2006

17. Allen A. Vaccine: The Controversial Story ofMedicine’s Greatest Lifesaver. New York,NY: WW Norton; 2007:247

18. Wakefield AJ, Murch SH, Anthony A, et al.Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmen-tal disorder in children. Lancet. 1998;351(9103):637–641

19. Fitzpatrick M. MMR and Autism. London,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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