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Maurice Ralph Hilleman (August 30, 1919 – April 11, 2005) was a leading American microbiologist who specialized in vaccinology and developed over 40 vaccines, an unparalleled record of productivity. It is estimated that his vaccines save nearly 8 million lives each year. Many have described him as one of the most influential vaccinologists of all time.

Of the 14 vaccines routinely recommended in current American vaccine schedules, he developed eight: those for measles, mumps, hepatitis A, hepatitis B, chickenpox, Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae bacteria. He also played a role in the discovery of antigenic shift and drift, the cold-producing adenoviruses, the hepatitis viruses, and the potentially cancer-causing virus SV40.

Early life and education
Maurice Ralph Hillemann was born on his family's farm—near the Tongue and Yellow Rivers, outside of Miles City, Montana—on August 30, 1919 during the Spanish flu pandemic. His parents were Anna (Uelsmann) and Gustav Hillemann, and he was their eighth child. His twin sister was stillborn and his mother died two days after the birth, from eclampsia. Upon his mother's request, he was raised in the nearby household of his uncle and aunt, Robert and Edith Hilleman, and worked in his youth on the family farm, selling the food they grew and working in Miles City as landscapers. Hilleman later recalled of his childhood: "Nobody was looking out for you." When he was eight, Hilleman was severely sick with diphtheria. He later credited much of his success to his work with chickens as a boy; since the 1930s, fertile chicken eggs had often been used to grow viruses for vaccines.

His family belonged to the Lutheran Church–Missouri Synod. When he was in the eighth grade, he discovered Charles Darwin, and was caught reading On the Origin of Species in church. Later in life, he rejected religion. As a child he admired Howard Taylor Ricketts. While attending Custer County High School, Hilleman was hired by J. C. Penney as an assistant manager during the Great Depression and intended to continue working with the company, instead of attending college. His eldest brother encouraged him to go to college instead, and Hilleman graduated first in his class in 1941 from Montana State University on a full scholarship. He had a Bachelor of Science in Bacteriology and Chemistry from the college.

He applied to ten medical schools and won a fellowship to the University of Chicago, where he received his doctoral degree in microbiology and chemistry in 1944, finishing a program that normally took five years in three while working part-time. His doctoral thesis was on chlamydia infections, which were then thought to be caused by a virus. Hilleman showed that these infections were, in fact, caused by a species of bacterium, Chlamydia trachomatis, that grows only inside of cells. For showing how to distinguish immunologically between chlamydiae he received the college's Howard Taylor Ricketts Prize. While at Chicago, Hilleman discovered that it was possible to grow Japanese encephalitis in mice and kill it with formaldehyde.

Career
Upon graduation, Hilleman took a job with E.R. Squibb & Sons (now Bristol-Myers Squibb) as a research associate. He co-developed an influenza vaccine that was centrifuged and purified, and continued research on chlamydiae. Hilleman was directed to create a vaccine against Japanese B encephalitis, a disease that threatened American troops in the Pacific Ocean theater of World War II. The company had bid that it could have production started within 30 days, and Hilleman was convinced that he could produce hundreds of thousands of vaccines for the army. He developed a vaccine by infecting mice with the disease, using ether to kill them, scooping out the brains, and blending them. The mice brains were then blended together in a Waring blender. A group of thirty women blended around thirty thousand brains a day to make large quantities of the vaccine. In 1947 Hilleman was made chief of the company's division that made smallpox and rabies vaccines. But he was unsatisfied and soon decided to head to Walter Reed.

In 1947 Hilleman proved that hemagglutinin of the virus changes when the influenza virus mutates, known as "antigenic shift" and "antigenic drift", which he theorized would mean that a yearly influenza vaccination would be required.

Army Institute of Research
Hilleman arrived at the Walter Reed Army Institute of Research in spring 1948, where he was mentored by Joseph Smadel. He entered the Army Medical Service Graduate School, graduating in 1955. Walter Reed was one of two major institutes that monitored strains of influenza around the world, the other being the World Health Organization (WHO). At Walter Reed, he was assigned “to study respiratory illnesses of military significance and to devise a science and a strategy for averting the ‘next influenza pandemic.‘"

In 1956, Hilleman became head of the Department of Respiratory Diseases. One of the division's main focuses was adenoviruses. When an influenza-like epidemic of acute respiratory disease of recruits (ARD) cases occurred at Fort Leonard Wood, Missouri, in the winter of 1952–1953, Hilleman and J. H. Warner traveled to the camp, where they collected throat washings from sick soldiers. There they worked to isolate the first adenovirus associated with acute respiratory disease of recruits. ARD is a condition caused by several adenovirus types and was a "major cause of morbidity in all military training camps" during and in the years after World War II. Hilleman and Warner were were the first to culture adenovirus type 4, which turned out to be the "major cause" of ARD. Hilleman then created tests for several diseases caused by adenoviruses and developed a killed virus vaccine. In Fort Dix in 1956, Hilleman demonstrated the effectiveness of such a vaccine against ARD.

By 1957, Hilleman was also director of the Laboratory of Viral Surveillance.

1957–1958 influenza pandemic
The 1957–1958 influenza pandemic began in Asia when a new strain of the influenza emerged, which very few people had immunity to. On April 17, 1957, The New York Times published a four-paragraph article titled "Hong Kong Battling Influenza Epidemic" about the pandemic in Hong Kong, with a photo showing patients at hospitals in the city. After seeing the report, Hilleman reported that he said “My God. This is the pandemic. It’s here!” and sent a telegram to American military bases in Asia, requesting that they obtain a specimen of the disease.

He received samples from a US Navy serviceman via a lab in Japan on 17 May 1957. After testing them for five days and nights, first using sera from hundreds of military personnel and then hundreds of civilians, for a total of perhaps thousands of samples, he found no evidence the subjects had encountered the strain before. His research found that the new strain was “distinctly different from type A strains previously isolated from this country and Europe." Hilleman promptly sent the samples to the World Health Organization, the United States Public Health Service, and US Army laboratories. Subsequent studies by these groups determined that very few people around the world had antibody resistance to the strain (only survivors of the 1889–1890 pandemic had resistance)

He went on to predict in a press release on 22 May that the strain was the next influenza pandemic and it would not reach the US until the first week of September 1957, "on the second or third day of the opening of school". Hilleman then reached out to six major vaccine manufactures, telling them to keep their roosters alive, as fertilized hen's eggs are used in developing influenza vaccines. In order to prepare for the arrival of the disease, Hilleman also sent samples of the strain to the vaccine manufactures on 22 May and directly requested that they work on a vaccine—instead of going through the Division of Biologic Standards of the United States Department of Health and Human Services.

Six days later, on 28 May, Hilleman co-authored a report and letter with Harry M. Meyer warning that the virus would become a “health problem in the U.S. A. and probably much of the world.” The strain reached the US around June and cases peaked in autumn. By then, 40 million vaccine doses had been produced and distributed. It has since been estimated that one million more Americans could have been killed by the disease if the vaccine was not distributed. For his work, Hilleman received the Distinguished Service Medal from the US Army. He left Walter Reed shortly after the pandemic to head development of vaccines at Merck & Co, being appointed in 1957 to direct the Merck Institute for Therapeutic Research starting on February 1, 1958.

Merck
By 1957 Merck & Co. searching for a scientist who could revitalize their laboratory in West Point, Pennsylvania. Max Tishler and John T. Connor, leaders of the company, decided that Hilleman was a good fit for the position, and offered him a job. Hilleman was initially reluctant to leave his position at Walter Reed, where he had developed a strong reputation. He feared that moving to Merck would force him to abandon scientific research. However, he accepted the offer after being promised the ability to continue research and offered a sufficiently high salary. Hilleman joined Merck in 1957 as head of Virus and Cell Biology Research at the Merck Institute for Therapeutic Research.

It was while with Merck that Hilleman developed most of the forty experimental and licensed animal and human vaccines with which he is credited, working both at the laboratory bench as well as providing scientific leadership.

He was also involved in the early isolation of rhinovirus.

Interferon
In the early 1960s Hilleman's attention was drawn to interferon, as he thought it had potential to develop into an antiviral drug. His team began work on purifying interferon. in chicks He hoped, incorrectly, that once it was purified in chicks, the substance would become active in human cells. After those efforts were unsuccessful, he developed a negative attitude towards the potential of the substance. The researcher Kari Cantell wrote that he "probably convinced most of those who read his many articles published on the subject that there was no practical future for interferon as a drug."

In 1967, Hilleman's lab discovered that some double stranded nucleic acids were very effective in inducing production of interferon, one of which was Poly I:C. He began to advertise inducement as the future of using interferon through lectures and articles. Cantell guesses that "almost every laboratory in the world with interest in interferon started at least some work with poly I:C." However, Poly I:C had several problems. Hilleman became the first to purify and mass produce interferon. The substance is now used to treat several chronic infections and cancers.

Marek's
In [UNCLEAR WHAT DATE, need to specify], Hilleman began working to develop a vaccine for Marek's disease, a a highly contagious viral disease found chickens. Ben Burmester, a veterinary researcher in Michigan, had isolated a herpesvirus found in turkey and quail that was similar to Marek's disease. Burmester found that the virus served as an effective vaccine in chickens against Marek's disease, and contacted Hilleman, who developed it into a product that was soon released. As a result of the vaccine, Merck purchased Hubbard Farms, a major chicken farm, in 1974. The farm made Merck the world's largest producer of both chicken and eggs. The vaccine made Hilleman the first to develop a vaccine that prevented cancer.

Mumps vaccine
In 1963, after his daughter Jeryl Lynn complained of feeling ill, and Hilleman finding a sensitive lump in her jaw, diagnosed her with the mumps. Aware that mumps, while usually mild, could cause severe symptoms, he decided he wanted to prevent others from being infected. Using material from Merck, and a sample from Jeryl, he cultivated the disease. By passing it through flasks of chick cells, the mumps disease improved at destroying the cells. Hilleman's reasoning was by doing this, it was losing its efficacy at destroying human cells, and would therefore be capable of triggering an immune response without triggering the disease.

Like many other vaccines and medications of that time period, the vaccine was initially tested in kids with intellectual disabilities who lived in group homes—this was because, given the poor hygiene and cramped quarters of their accommodations, they were at much higher risk of infectious disease, but also included his other daughter, Kirsten, in these very early mumps vaccine trials. Hilleman would remain a staunch advocate of these decisions later in life "my vaccine gave all of these children the chance to avoid the harm of that disease. Why should retarded children be denied that chance?"

Naming it for his daughter, the Jeryl Lynn strain remains used today, in the mumps component of the trivalent MMR vaccine that he also developed. Since creation of the original vaccination, the worldwide incidence has fallen by 99%, despite occasional resurgences in the 21st century.

Measles vaccine
Measles, a ubiquitous virus at the time, killed twice as many children as polio, in the late 1950s and early 1960s. Thomas C. Peebles and John Franklin Enders created an initial vaccine that was effective at reducing the full symptomatic rate, but had major side-effect issues. When Hilleman received material to produce vaccines and trialled it in healthy children, roughly 50% had a rash and a majority received significant fever, some over 103 degrees Fahrenheit - enough to cause seizures in a few. Hilleman described it as "toxic as hell". There was also concern that the original vaccine may cause cancer, even though the Measles virus did not. Though unknown at the time, the sample given to Hilleman was contaminated with a retrovirus causing leukemia in chickens, due to contamination from the eggs used to make it.

Hilleman worked with Joseph Stokes to mitigate side effects. Stokes was an expert in gamma globulin, the component of blood that contains antibodies. In the past, Stokes had shown that its use, taken from survivors of a disease, could help protect from both Polio and Hepatitis. He now proposed its addition to the Measles vaccine. This change, coupled with further attenuation of the disease were put into small scale trials at the nursery of Clinton Farms prison for women in the early 1960s, with vastly reduced side effect frequency. The testing was then rolled out to hundreds of children and after its use became standard from 1968, frequency of a rash as a side effect fell from 50% to 1% and a fever from 85% to 5%.

Hepatitis B vaccine
He and his group invented a vaccine for hepatitis B by treating blood serum with pepsin, urea and formaldehyde. This was licensed in 1981, but withdrawn in 1986 in the United States when it was replaced by a vaccine that was produced in yeast. This vaccine is still in use today. By 2003, 150 countries were using it and the incidence of the disease in the United States in young people had decreased by 95%. Hilleman considered his work on this vaccine to be his single greatest achievement. Liver transplant pioneer Thomas Starzl said "...controlling the hepatitis B virus scourge ranks as one of the most outstanding contributions to human health of the twentieth century...Maurice removed one of the most important obstacles to the field of organ transplantation".

Hilleman was one of the early vaccine pioneers to warn about the possibility that simian viruses might contaminate vaccines. The best-known of these viruses became SV40, a viral contaminant of the polio vaccine, whose discovery led to the recall of Salk's vaccine in 1961 and its replacement with Albert Sabin's oral vaccine. The contamination actually occurred in both vaccines at very low levels, but because the oral vaccine was ingested rather than injected, it did not result in infections or any harm.

Hilleman served on numerous national and international advisory boards and committees, academic, governmental and private, including the National Institutes of Health's Office of AIDS Research Program Evaluation and the Advisory Committee on Immunization Practices of the National Immunization Program. In his later life, Hilleman was an adviser to the World Health Organization. He retired as senior vice president of the Merck Research Labs in 1984 at the mandatory retirement age of 65. He then directed the newly created Merck Institute for Vaccinology where he worked for the next twenty years.

At the time of his death in Philadelphia on April 11, 2005, at the age of 85, Hilleman was Adjunct Professor of Pediatrics at the University of Pennsylvania in Philadelphia.

Method and personality
Hilleman was a forceful man who was at the same time modest in his claims. None of his vaccines or discoveries are named after him. He ran his laboratory like a military unit, and he was the one in command. For a time, he kept a row of "shrunken heads" (actually fakes made by one of his children) in his office as trophies that represented each of his fired employees. He used profanity and tirades freely to drive his arguments home, and once, famously, refused to attend a mandatory "charm school" course intended to make Merck middle managers more civil. His employees were fiercely loyal to him.

Awards and honors
Hilleman was an elected member of the National Academy of Science, the Institute of Medicine, the American Academy of Arts and Sciences, and the American Philosophical Society. In 1988, President Ronald Reagan presented him with the National Medal of Science, the nation's highest scientific honor. He received the Prince Mahidol Award from the King of Thailand for the advancement of public health, as well as a special Lifetime Achievement Award (1996) from the World Health Organization, the Mary Woodard Lasker Award for Public Service and the Sabin Gold Medal and Lifetime Achievement Awards. In 1975, Hilleman received the Golden Plate Award of the American Academy of Achievement.

Legacy
Hilleman made over 450 publications in his lifetime. In March 2005, the University of Pennsylvania School of Medicine's Department of Pediatrics and The Children's Hospital of Philadelphia, in collaboration with The Merck Company Foundation, announced the creation of The Maurice R. Hilleman Chair in Vaccinology.

In April 2005, Robert Gallo, co-discoverer of HIV, the virus that causes AIDS, once said "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."

In April 2005, After Hilleman's death Ralph Nader wrote, "Yet almost no one knew about him, saw him on television, or read about him in newspapers or magazines. His anonymity, in comparison with Madonna, Michael Jackson, Jose Canseco, or an assortment of grade B actors, tells something about our society's and media's concepts of celebrity; much less of the heroic."

In 2005, Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases, said that Hilleman's contributions were “the best kept secret among the lay public. If you look at the whole field of vaccinology, nobody was more influential.” In addition, Fauci said that "Hilleman is one of the true giants of science, medicine and public health in the 20th century. One can say without hyperbole that Maurice has changed the world."

In 2007, Paul Offit published a biography of Hilleman, entitled Vaccinated: One Man's Quest to Defeat the World's Deadliest Diseases.

In 2007, Anthony S. Fauci wrote in a biographical memoir of Hilleman: "Maurice was perhaps the single most influential public health figure of the twentieth century, if one considers the millions of lives saved and the countless people who were spared suffering because of his work. Over the course of his career, Maurice and his colleagues developed more than forty vaccines. Of the fourteen vaccines currently recommended in the United States, Maurice developed eight."In 2008, Merck named its Maurice R. Hilleman Center for Vaccine Manufacturing, in Durham, North Carolina, in memory of Hilleman.

In 2016, a documentary film titled Hilleman: A Perilous Quest to Save the World's Children, chronicling Hilleman's life and career, was released by Medical History Pictures, Inc.

In 2016, Montana State University dedicated a series of scholarships in memory of its alumnus Hilleman, called the Hilleman Scholars Program, for incoming students who "commit to work at their education beyond ordinary expectations and help future scholars that come after them."

Personal life
Maurice first married in 1943, to Thelma Mason, on New Year's eve, and would have a daughter, Jeryl. . Diagnosed with breast cancer she died in 1962, 4 months before Jeryl was diagnosed with Measles.

Hilleman's attempts to recommence dating were not initially successful, stating "I had a couple of dates. Christ. Finding women is sort of like by Brownian action. You don't know whether they're drunkards, or they'll spend all your money, or whether they have venereal diseases". He instead decided to seek a potential wife amongst Merck's application pool, asking his administrative aid to send him one woman to meet a week. He married his second wife, Lorraine, in 1963, with whom he had a second daughter, Kirsten.