Dr. Maurice Hilleman

& the Story of M-M-R® & M-M-R®II (d38th(and 38 other vaccines i) )

BbBarbara Kuter, PhD PhDMPH, MPH Merck Vaccines 3 A pr 2011

ESCMID, Prague 1 Maurice Ralph Hilleman, PhD, DSc

„ Developed & licensed >40 vaccines „ >500 publications „ 23 patents „ And a true legend . . .

2 http://www.harpercollins.com/books/9780061459016/vaccinated/index.aspx 3 Some Background . . .

4 Birthplace on a Farm in Miles City, Montana, 1919 5 Hilleman, age 6, 1925 6 Abbreviated Curriculum Vitae

„ Custer High School 1933-1937 „ Manager Training Program, JC Penney 1937 „ Montana State University 1937-1941 „ University of Chicago 1941-1944 „ ER Squibb & Sons , New Jersey 1944 -1948 „ Walter Reed Army Institute of Research 1948-1957 „ Merck (Virus & Cell Biology Dept) 1957-2005

Hilleman, Immunological Review, 1999; Offit, 2007; MRH CV (65 pages) 7 Montana State University, 1941 8 University of Chicago , 1941 -1944

„ Won fellowship „ PhD in Bacteriology & Parasitology (Virology) „ Prize winning PhD dissertation on Chlamydia „ Developed antibody system to distinguish different subtypes „ Infected chickens with a type of Chlamydia found in parrots

„ Assisted in teachingggy first formal course in virology in US with Prof Francis Gordon

Hilleman, Immunological Review, 1999; Offit, 2007; Hilleman CV 9 ER Squibb – 1944-1948

„ Interest in pursuing the practical & contributing to war effort „ Though t th at sc ient ists ha d a respons ibility to prov ide a return on knowledge gained in the laboratory „ “I wanted to make things” „ Head of new department „ Learned to mass produce influenza vaccine „ His 1st vaccine was J a panese B ence pha litis „ Urgently needed by troops in Pacific Offensive

Hilleman Immunological Reviews 1999 10 Walter Reed Army Institute, 1948-1957

Head of Pandemic Influenza Team „ Iden tified concept of “d“diftrift & shift” „ Helped prevent pandemic of Hong Kong flu in 1957 „ ElEarly detect ion o f H2 AiAsian stra in & vacci ne devel opment

„ >40 million vaccine doses distributed 11 Merck, Sharp, and Dohme, 1957-2005 12 The Story of ® ® M-M-Rmonovalent& M-M-Rvaccines II. . . Started with with the the

13 Measles

„ >8 million deat hs in wor ld due to meas les in 1960s „ ~500,000 cases in US; 300-400 cases of encephalitis „ 1954 Nobel Prize in Medicine „ Enders, Weller and Robbins „ Discovery of ability of polio virus to grow in cultures of various types of tissue „ 1954 measles outbreak at private boys school outside Boston „ Virus obtained from 13 yr old, David Edmonston

Offit Vaccinated 2007 14 The New England Journal of Medicine ______Volume 263 JULY 28, 1960 Number 4 ______STUDIES ON AN ATTENUATED MEASLES-VIRUS VACCINE* JOHN F. ENDERS, PH.D., SAMUEL L. KATZ, M.D. MILAN V. MILOVVNVANOVIC , M.D. , AN D ANN HOLLOW AY •Edmonston strain evaluated in children starting in 1958 •Effect ive, but too reactogen ic ↑ fever, rash, malaise

15 Merck’s Development of Measles Vaccine

„ Hilleman obtained virus from Boston group „ Issues in vaccine development & licensure: „ Correct dose (decrease measles virulence) „ RlfilkiiRemoval of avian leukemia virus „ Assess safety & efficacy „ Determine age for administration (impact of maternal antibody) „ Establish product stability

Hilleman, Immunological Review, 1999; Offit, 2007 16 Beyer & Hilleman looking at tissue culture of measles virus, Virus Inoculation Room, Merck, 1961 17 Clinical Research Team

Joe Sto kes, Hilleman, an d Bo b We ibe l, mid 1960s 18 The American Journal of the Diseases of Children 1962: 103: 366-379

ENDERS’ LIVE MEASLES-VIRUS VACCINE WITH HUMAN IMMUNE GLOBULIN I. Clinical Reactions II. Evaluation of Efficacy

Maurice R. Hilleman, Joseph Stokes, Robert E. Weibel, Robert Halenda, Harry Goldner

PROBLEM 1: •Reactoggyenicity decreased by simultaneous administration of immune globulin

19 PROBLEM 2 Avian Leukosis & Leukemia Virus „ Derivedfd from ch ick emb ryo cell s used to propagate th e virus „ Affected ~20% of all chickens in the US „ Division of Biological Standards not particularly concerned (in YF vaccine for years) „ Kimb er F arms ( chi ck & egg comp any i n CA) developed leukosis-free flocks „ Merck took over flock & became largest egg producer in world

20 “Coming from a farm, “I always had a good friend called the chicken.”

Maurice Hilleman

21 Measles Vaccine „ Rubeovax® licensed in 1963 with leukosis-free measles virus „ Use d in t he US from 1963-1968 „ 95% decrease in measles & enceppyhalitis by 1968-69

22 The Taming of a Virus”

Charles Collingwood and Hilleman, 1963, during CBS interview about measles vaccine23 Journal of the American Medical Association, October 14, 1968; Vol 206, pp 587-590 Development and Evaluation of the Moraten Measles Virus Vaccine Maurice R. Hilleman, PhD. DSc, Eugene B. Buynak, PhD: Robert E. Weibel, MD; Joseph Stokes, Jr; James E. Whitman, Jr., PhD; and M Bernice Leagus, PhD

• Desire to eliminate administration with IG • Further attenuated Edmonston strain • 40 more passages through chick embryos at lower temperature • Less reactions but still adequate immunogenicity • Attenuvax® licensed in 1968; Moraten strain still

used today 24 Mumps

25 The Jeryl Lynn strain

„ Isolated from 5-year old daughter, Jeryl Lynn, in 1963 „ Awakened her father complaining of fever & swollen glands „ Late night trip to lab to retrieve equipment (cotton swabs & beef broth) to culture her virus „ Grew & attenuated mumps virus in cells of chicken embryos „ World’ s first live virus vaccine against mumps

26 Buynak & Hilleman work on development of mumps vaccine, 1966

27 LIVE ATTENUATED MUMPS VIRUS VACCINE. II. EARLY CLINICAL STUDIES Joseph Stokes, Jr. , M.D., Robert E. Weibel, M.D., Eugene B. Buynok, Ph.D ., and Maurice R . Hilleman , Ph. D.

PEDIATRICS, Vol. 39,,, No. 3, March 1967

„ 3 studies in ~120 institutionalized PA children (()1965) „ Evaluated level A & B Jeryl Lynn strain (12th &17& 17th passage) „ Clinical, virologic & serologic assessment „ Level A not sufficiently attenuated „ Parotitis „ Transient virus excretion 28 Clin ica l Trial of Jeryl Lynn Mumps Vaccine, 1966

Jeryl Lynn & Kirsten Hilleman & Dr. Robert Weibel 29 The New England JlfdiiJournal of Medicine ______Volume 276 Feb 14, 1967 Number 5 ______LIVE ATTENUATED MUMPS VIRUS VACCINE* Protective efficacy measured in field evaluation MAURICE R. HILLEMAN, EUGENE B. BUYNAK, ROBERT E. WEIBEL, JOSEPH STOKES, JR

• Safety and efficacy demonstrated • Muupsvmpsvax® licensed in 1967

30 Efficacy of Mumps Vaccine

Mumps Cases Protective Group No/Total Rate Efficacy Vaccinated 5/174 3% 95% Control 133/224 59%

Hilleman et al NEJM 1967: 276: 252-258. 31 Rubella

32 Rubella

„ Weller & Parkman identified rubella virus in 1962 „ Major outbreak of rubella in US in 1964 „ ~20,000 f etal d eath s & ~20 ,000 congeni tal d ef ects „ Use of gamma globulin had little effect „ Rubella outbreak expected in 1970-71 (every 6-9 yrs) „ Chick embryo cells did not support growth of rubella virus „ Buynak et al (Merck) identified duck embryo cells as vehicle for virus group & viral attenuation

Stokes et al Pediatrics, 1969 33 Hilleman injects rubella virus into duck held by Gene Buynak, late 1960s 34 Rubella Vaccine

„ Clinical trials conducted with HPV-77 strain „ Meruvax® licensed in 1971 „ ACIP & AAP issued prelicensure statement on the vaccine „ l19 million doses administered 1st year after licensure

Krugman J Peds 1971 35 Combination Vaccines (M-M-R®, M-M-R®II)

„ Substantial public health value in increasing compliance, d ecreas ing in ject ions & pro ducts to store „ Reqqjuired adjustment of viral dosag e of each of the 3 component „ Achieve acceptable immune response without interference

36 Journal of the American Medical Association, March 24, 1969 Vol 207 No. 12 CbidLiMlMCombined Live Measles, Mumps, and Rubella Virus Vaccines Euggy,ene B. Buynak, PhD: Robert ,JE. Weibel, MD: James E. Whitman, Jr., PhD; Joseph Stokes. Jr., MD. DSc: and c Maurice R. Hilleman, PhD. DS • M-M-R® licensed in 1971

37 Rubella Vaccine – One More More Time Time

„ Stanley Plotkin experienced rubella first hand during ppgediatric training in UK in 1961 & 1964 ep idemic in US „ Wistar Institute „ Isolated virus from aborted fetus (RA 27/3 strain) „ Grew well at lower temperatures, poorly at body temperature „ Tested in thousands & found to work better than HPV/77

RA = rubella aborticus 27th sample, 3rd attempt Krugman J Peds 1971 38 PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE 165: 44-49,(1980 )

Clinical and Laboratory Studies of Live Attenuated RA 27/3 and HPV 77- DE Rubella Virus Vaccines (40931) ROBERT E. WEIBEL, *VICTOR M. VILLAREJOS, ELENA B. KLEIN, EUGENE B. BUYNAK, ARLENE A. McLEAN, AND MAURICE HILLEMAN

RA 27/3 demonstrated: • Higher antibody levels • More persistent antibody • More resistance to reinfection M®IIdMMeruvax®II and M-M-R®II li cense d in 197 8 Plotkin et al Vaccines 2008 39 Hilleman & his team in Virus & Cell Biology, late 1970s 40 What Was the Impact of These Vaccines ?

41 Measles, Mumps900 & Rubella - United States 800 700 600 Rubeovax® licensed (1963) 300 Attenuvax® licensed (1968)

es Reported es 500 sands) Measles ss 400 200 Trivalent M-M-R® licensed (1971)

(Thou Trivalent M-M-R licensed(1978) 100 II

Measles Ca Measles 0 160 1950 1960 1970 1980 1990 2000

Mumpsvax® licensed (1967) 140100 Trivalent M-M-R® licensed (1971)

rted 120

oo 80 Mumps 60 Trivalent M-M-R licensed (1978) 4020 II s Cases Rep s Cases (Thousands) pp 0 Mum 60 1970 1975 1980 1985 1990 1995 2000 2005 90 Meruvax® licensed (1969)

80

dd 70 100 50 ® Rbll&Rubella & Trivalent M-M-R licensed (1971) 70 Congenital Rubella Syndrome Trivalent M-M-RII licensed(1978) (CRS) 40 60 20 30 Rubella CRS 50 usands) es Reported es ases Reporte oo 30 ss CC 20 40

(Th 10 10 CRS Ca Rubella 0 0 42 1966 1970 1975 1980 1985 1990 1995 2000 2005 And just in case that wasn’t enough . . .

43 Lifetime Dedicated to Vaccines 40 Licensed Products Vaccine Date Vaccine Date Japanese B 1945 Rubella 1969 Pandemic A influenza 1957 Purified influenza 1969, 70 Adenovirus 1958 Mumps-rubella 1970 Purified Polio 1960 Measles-rubella 1971 Measles Edmonston B 1963 Measles-mumps-rubella 1971 + GGlbliGamma Globulin Mumps 1967 Marek’s Disease 1971, 75 (cancer of chickens) Measles-smallpox 1967,70 Purified influenza 1969, 70 Measles Moraten 1968 Adjuvanted influenza 1973 44 Lifetime Dedicated to Vaccines 40 License d Pro ducts (cont ) Vaccine Date Vaccine Date Measles-mumps 1973 Hepatitis B – plasma 1981 MiMeningococcus A 1974 MiMening A-C-Y-W135 1982 Meningococcus C 1975 Pneumococcus - 23 1983 Mening A-C 1975 Hepatitis B - recombinant 1986 Pneumococcus - 14 1977 HinfluenzaeH. influenzae 1989 Hepatitis B IG 1978 Hepatitis A 1996 Hepatitis A IG 1979 Varicella 1995

Im prove d vacc ines (ru be lla, MR, MMRII, H in f – liqu id) ar e not i ncl ud ed

45 Lifetime Dedicated to Vaccines A few that never got licensed ….

„ RSV „ HSV 1 „ HSV 2 „ CMV „ Common cold „ Live attenuated hepatitis A „ Killed rubella

46 And a little bit about the man . . .

47 “My Hobby is Working” Maurice Hilleman, 2005

„ Strong proponent of a 7-day work week for scientists „ Cited his upbringing on a farm in Montana for both his : „ WkhiWork ethic „ Coarse language „ Retired at 65, but still went into office every day

Offit Vaccinated 2007 48 “You make it, you take it ”

Weibel inoculates Hilleman with Hep B vaccine49 Management Style

“I ran into conflict with just about everybody . . . I was told I had a very unusual management style. In spite of all this, I survived at Merck.”

Maurice Hilleman 2005

Nature Medicine Supplement, 2005: 11(4): 52. 50 A highly dedicated Merck team - Interferon Team, 1960s 51 Some well deserved recognitions . . .

52 Lasker Award, 1983 53 National Academy of Sciences, 1985 54 National Medal of Science, 1988 55 US National Millennium Time Capsule Merck’s 20th Cent ur y V accine Le gacy c December 31, 1999 Vaccines • Measles, Mumps, Rubella • Varicella • Hepatitis A • Pneumococcus • Hepatitis B (Recombinant) • H. influenza B

(1919-2005)

400 Presidential & Congressional Medal Winners Invited by Pres & Mrs. Clinton

56 How to summarize such greatness , such accomplishments?

57 Saved Millions of Lives Each Year

“Few youngsters mi gh t recogni ze M aur ice Hilleman as the man behind their childhood immunizations. But with more than 40 vaccines to his credit, it’s no exaggeration to say Hilleman saves millions of lives each year.”

Alan Dove, reporter Philadelphia

Nature Medicine Supplement, 2005: 11(4): 52. 58 True Giants of Science

“Dr Hilleman is one of the true giants of science, medicine,,p and public health in the 20th century. One can say without hyperbole that Maurice has changed the world .”

TFiTony Fauci Director National Institute for Allergy & Infectious Diseases (US) 2005

59 Most Successful Vaccinologist in History

“If I had to name a person who has done more for the benefit of human health, with less recognition than anyone else, it would be Maurice Hilleman. Maurice should be recognized as the most successful vaccinologist in history.”

Bob Gallo Director, University of Maryland Institute of Human Virology Cofounder of the AIDS virus 1999

Inquirer Magazine August 29, 1999 60 Outstanding Gift to the World

“Maurice was an incredible boss & one I shall never fHforget. He gave an outstandi diifhldng gift to the world – the saving of lives through vaccines. May we all remember him with sincere gratitude. His picture in my office reminds me everyyy day of why I do what I do.”

Barbara Kuter 2011

61 Maurice Hilleman, 1919-2005 62 63