Vaccine Development & Licensing Events

Max Theiler and his colleagues developed a live attenuated vaccine for yellow fever using tissue cultures prepared from embryonated chicken eggs. Among the many subcultures of the yellow fever virus in the laboratory, the one designated “17D” was used, giving the vaccine its name. He published results of U.S. vaccine trials in humans in 1937. The vaccine was easily adapted for mass production and became the universal standard.

Maurice Hilleman, working at E. R. Squibb and Sons, helped develop a Japanese encephalitis vaccine to protect American troops in the World War II Pacific theater of operations.

Hilleman’s vaccine was never widely tested. It was given to thousands of U.S. soldiers in wartime and likely prevented disease in many of them. Later, other vaccines replaced it.

In a press conference at the University of Michigan, Thomas Francis Jr., MD (a scientist with extensive experience with influenza vaccines), and colleagues announced the results of the Salk poliovirus vaccine trial. The vaccine, they said, was 80-90% effective against paralytic polio.

The U.S. government licensed Salk’s vaccine later this same day. The press conference and licensure paved the way for widespread distribution and use of the vaccine.

Albert Sabin’s live poliovirus vaccine was recommended by the U.S. Surgeon General to be licensed. This vaccine provided protection against Type 1 poliovirus. Soon, vaccines for Types 2 and 3 would be licensed. A 1963 vaccine would combine all three types.

Hilleman and colleagues received a new influenza A virus, Type A2, Hong Kong strain, that had caused widespread illness in Hong Kong. They rushed to manufacture a vaccine from the new flu strain. In four months, Merck had manufactured more than nine million doses of vaccine.

Meruvax, Hilleman’s HPV-77 rubella vaccine, was licensed. Later, it would be replaced by vaccines derived from Stanley Plotkin’s RA 27/3 strain of rubella virus.

Rubella is typically a mild illness. Its symptoms are low fever, rash, and swollen glands. If, however, a pregnant woman contracts rubella, especially early in her pregnancy, the effects can be devastating. Babies exposed to rubella in utero may suffer deafness, blindness, mental retardation and other deformities. A devastating rubella pandemic developed during 1962-1965. In the United States, more than 20,000 babies were born with congenital rubella syndrome. Tens of thousands of women suffered miscarriages or elected to have abortions due to rubella infection. The pandemic focused medical researchers’ attention on the need for an effective vaccine.

The U.S. government licensed Merck’s combined trivalent measles, mumps, and rubella vaccine (MMR).

Combination vaccines have several advantages over single vaccines. They reduce the need for several separate injections, and they reduce costs of stocking and shipping multiple containers. Combination vaccines can help improve overall vaccination rates by simplifying the vaccination process.

Hilleman ushered a series of meningococcal polysaccharide vaccines to licensure (group A, group C, combined groups A+C, and then a quadrivalent vaccine against groups A, C, Y, and W-135) beginning in 1974 with a vaccine that was effective against meningococcal group A, one of five major types of meningococcal bacteria.

The vaccines represented a new approach in vaccine science: using not live or attenuated pathogens, but rather the polysaccharide (complex sugar) outer coating of these bacteria. Much of the work on isolating the polysaccharides for both group A and group C was done at Walter Reed Army Institute of Research by Army researchers at Hilleman's earlier professional base.

Maurice Hilleman and other scientists met with U.S. President Gerald Ford to discuss a vaccine response to an outbreak of swine influenza at Fort Dix, New Jersey. Congress committed funds to a nationwide vaccination program.

Merck intended to produce 50 million swine flu vaccine doses by January 1977 and delivered about 11 million doses in late September 1976. The nationwide vaccination program, however, ended after vaccination was associated with an increased risk of a condition called Guillain-Barré syndrome (GBS). GBS has several causes, the most common of which is infection with bacteria called Campylobacter. But GBS occurred in recipients of the 1976 swine-flu vaccine at a rate higher than usual: beyond the normal "expected" rate for the general population, about one additional case occurred for every 100,000 vaccine recipients. And, despite what first promised to be a widespread outbreak, few cases of swine flu actually developed among the American people.

The FDA licensed Hilleman’s human-blood-derived hepatitis B vaccine, Heptavax-B. It was the first subunit viral vaccine developed in the United States.

Hilleman transformed the hepatitis B surface protein, discovered by Baruch Blumberg and known as the Australia antigen, into an effective vaccine. Hilleman harvested serum from several IV drug users and homosexual men, in whom the disease was sometimes present, to obtain the antigen. He used three methods to purify the blood so that the infectious particles were assuredly killed, but the antigen remained.

The vaccine proved effective at preventing hepatitis B. But, because of concerns about HIV infection, it was superseded in 1986 by a product that did not use human serum. This new effort produced the first vaccine based on recombinant technology--in this case, changing yeast cells so that they produced the protein that is the active ingredient in the current hepatitis B vaccine.

The FDA licensed Merck’s Recombivax HB. This hepatitis B vaccine was the first human vaccine produced by recombinant DNA methods.

A challenge in creating the vaccine involved avoiding the use of human blood products, as did Maurice Hilleman’s first hepatitis B vaccine. Therefore, Merck used an enzyme to remove the virus’s surface protein (HBsAg, the Australia antigen). Researchers inserted the code for the antigen into yeast cells, which produced more of the surface protein. The yeast-derived surface protein produced immunity to the hepatitis B virus.

Work by American scientists John Robbins, MD, and Rachel Schneerson, MD, led to the first conjugate vaccine against Haemophilus influenzae (Hib) disease being licensed in the United States. Conjugate vaccines are better able to induce an immune response than polysaccharide vaccines in infants and young children, the age group most at risk from Hib. This vaccine replaced a previous polysaccharide Hib disease vaccine.

Today there are three conjugate Hib disease vaccines available in the United States, as well as two combination vaccines that provide protection against multiple diseases, including Hib disease. For optimal protection, children need 3-4 doses of the vaccine starting around 2 months of age.

The FDA licensed Maurice Hilleman’s hepatitis A vaccine.

Hilleman had been working on hepatitis A for decades. He was one of the first scientists to detect the hepatitis A virus and its antibodies. Tests in 1992 showed that the vaccine was 100% effective in preventing the disease. Hepatitis A vaccine would later be added to the recommended vaccination schedule for children, and its incidence subsequently decreased by about 75%.

The FDA licensed Varivax, the first chickenpox vaccine. Hilleman had adapted a Japanese chickenpox virus for use in the United States.

Before the chickenpox vaccine, each year in the United States chickenpox infected 4 million people, leading to about 10,000 hospitalizations and about 100 deaths. In the post-vaccine era, hospitalization and death rates from chickenpox have decreased dramatically.

The U.S. Advisory Committee on Immunization Practices recommended routine infant immunization with three doses of the recently licensed Rotavirus Vaccine, Live, Oral, Pentavalent (tradename RotaTeq), developed by H. Fred Clark, PhD, Stanley A. Plotkin, MD, and Paul A. Offit, MD. The recommended schedule for immunization with this vaccine is at ages 2 months, 4 months, and 6 months.

According to the CDC, “Before introduction of a vaccine in 2006, rotavirus caused an estimated 20 to 60 deaths, 55,000 to 70,000 hospitalizations, and 205,000 to 272,000 emergency department visits in the United States each year.”

The Food and Drug Administration licensed another rotavirus vaccine, Rotarix, for use in the United States. The recommended schedule for Rotarix involves two doses of the vaccine, given at ages 2 months and 4 months.

CDC has carefully monitored incidence of rotavirus disease in the United States since 2000. Their studies show that that the number of positive test results for rotavirus was substantially lower than the median observed during 2000-2006. Additionally, it appears that hospitalization rates for acute gastroenteritis dropped by 16% in 2007 and by 45% in 2008 compared with the earlier period. Researchers have estimated that rotavirus vaccination prevented about 55,000 hospitalizations in 2008.

Worldwide, rotavirus continues to take a toll. More than 500,000 children under age 5 die each year from rotavirus illness.

The FDA announced the approval of a vaccine for group B meningococcal disease. The vaccine (generic name meningococcal group B vaccine, trade name Trumenba, manufactured by Pfizer) was advanced on an accelerated approval regulatory pathway. Outbreaks of meningococcal group B disease on several college campuses in 2013-2014 spurred the quicker pathway. The vaccine is approved for use in individuals ages 10-25 years and is given in three-dose series.

During 2015, the Advisory Committee on Immunization Practices will consider making a recommendation for the vaccine. This may include recommending it for high-risk groups, for researchers working with the bacteria, for individuals during outbreaks, and/or for the adolescent population at large.

During the 2013-14 outbreaks, the FDA approved a different group B meningococcal vaccine (generic name meningococcal group B vaccine [rDNA, component, adsorbed], trade name Bexsero, manufactured by Novartis) for use only in the affected populations at Princeton University and University of California, Santa Barbara. The FDA is considering the approval of that vaccine for more widespread use.