Adenovirus Vaccines Reinstated After Long Absence

Adenovirus 3, 4, 7 vaccine, 1958. The College of Physicians of Philadelphia.Eighteen years after the sole manufacturer of adenovirus vaccine announced its discontinuation, adenovirus type 7 and type 4 vaccines are once again available for U.S. military trainees. The adenovirus vaccination program resumed in October 2011, with enlisted soldiers receiving the vaccine during basic training. The re-licensure of the vaccine required significant investment by the U.S. government and long years of testing and regulatory review, during which rates of adenovirus illness in the military rose. The history of the vaccine’s disappearance illustrates the precarious position of some of our lesser-used vaccines.

Research into the adenoviruses began in earnest in the 1950s. Maurice Hilleman, a microbiologist who would eventually be involved in the development of more than 40 vaccines, was working at the U.S. Army Medical Center’s Department of Respiratory Diseases (predecessor to the Walter Reed Army Institute of Research) in 1953, when he flew to Fort Leonard Wood, Missouri, to investigate a suspected influenza outbreak among Army troops.

When Hilleman and his group isolated viruses from the infected troops, they found that they had isolated not influenza virus, but multiple strains of a recently discovered type of virus—the group that would soon be named adenoviruses. (Researchers at the National Institutes of Health had identified the virus from adenoid tissue earlier in 1953. The name adenovirus was proposed in 1956.)

It came to be recognized that the majority of acute respiratory disease cases among U.S. military trainees were the result of adenovirus infections. Respiratory adenovirus infections can vary in symptoms from those similar to a common cold to pneumonia or bronchitis; at least 52 different types of adenoviruses can infect humans. In severe cases, deaths occurred from respiratory distress induced by the adenovirus infection. Military trainees may be especially vulnerable to contracting adenovirus illness because close crowding seems to promote easier spread of the virus. Additionally, the physical and psychological stress of training seems to increase susceptibility to adenovirus.

Just three years after the identification of adenoviruses, an adenovirus vaccine was developed at the Walter Reed Army Institute of Research in 1956. It was an inactivated, injectable vaccine that protected against two forms of adenovirus infection, types 4 and 7, which accounted for the majority of acute respiratory diseases among trainees. (A separate vaccine developed at the National Institutes of Health protected against type 3 in addition to types 4 and 7.)

Manufacturing problems led to the adenovirus vaccine license being revoked in 1963, but two live-virus vaccines were developed just a few years later. This development team included Philip K. Russell, Franklin Top, Jr., Robert M. Chanock,  Edward L. Buescher, and Robert Couch. These vaccines were unique in being produced as oral tablets with a coating that resisted stomach acid. After extensive military studies, both vaccines were given to new military trainees “within hours after their arrival” at basic training beginning in 1971. These tables were developed by Wyeth Laboratories' Benjamin A. Rubin, who also developed the bifucated needle to administer smallpox vaccine. Rates of adenovirus infection plummeted after introduction of the vaccines, with the vaccines also seeming to protect against some non-vaccine serotypes of adenovirus.

In 1994, Wyeth Laboratories, the adenovirus vaccine’s sole manufacturer, announced plans to end production of the vaccine unless the U.S. government could fund a new production facility to meet modern production standards. All stocks were depleted or expired in 1999. Outbreaks of acute respiratory disease caused by adenoviruses rose among military trainees following discontinuation of the vaccination program. At least 8 service member deaths were attributed to adenovirus infection in the years that the vaccine was not available.

The following account of the discontinuation of the adenovirus vaccine program is taken from a fact sheet from the U.S. Military Vaccine Agency:

“In November 1984, Wyeth Laboratories, then the only producer of adenovirus vaccine, advised the department that they needed a new facility to continue production of the vaccine. They would continue to manufacture vaccine as long as their equipment functioned. The department opened discussions with other manufacturers, but none were interested. In 1994, Wyeth informed the department that they would fill orders from inventory, that they would no longer manufacture the vaccine unless their facilities were upgraded….In December 1995, Wyeth informed the department that they would require two years for construction and one year for approval of the production line and product by FDA for continued manufacture of the vaccine; the estimated costs ranged from $3M to $5M. In July 1996, Wyeth indicated it preferred to transfer the technology rather than continuing to make the vaccine. Discussions within the department ultimately led to a decision to not fund the Wyeth request, or to take other procurement actions. The existing supply of vaccine was depleted or expired in 1999.”

In 2001, the Army provided funds to re-establish the adenovirus vaccines, and the government contracted with a manufacturer (Barr Pharmaceuticals) to restore a production line for adenovirus type 4 and type 7 vaccine tablets. After clinical trials and regulatory requirements were fulfilled, the vaccine was licensed in March 2011. The U.S. military began using it in training facilities beginning in October 2011. The Department of Defense invested about $100 million over about 10 years to re-establish vaccine production.

Surveillance of adenovirus illness suggests that the vaccine may already be having a measurable effect. A recent Naval Health Research Center report states, “FRI [febrile respiratory illness] rates and the proportion of FRI cases positive for adenovirus have decreased markedly since vaccine was reintroduced” (Febrile Respiratory Illness (FRI) Surveillance Update. Week 14). The chart on page 2 shows the rate of febrile respiratory illness (black line) and the proportion of FRI cases positive for adenovirus – note that the vaccine was restarted in weeks 42-46.

Earlier we referred to the precarious position of some lesser-used vaccines. Joel Gaydos, MD, MPH, science advisor for the Armed Forces Health Surveillance Center and co-author of “Adenovirus-associated deaths in US military during postvaccination period, 1999–2010” in Emerging Infectious Diseases, stressed that point when he told us, "The big concern many of us have is that interest in the vaccine will diminish after a while and the vaccine supply will again be in trouble. For this reason I think it is important to document the unfortunate loss of the adenovirus vaccine, the morbidity and mortality that were associated with the loss of the vaccine, and the long time it took to re-establish the two component vaccine. We should never take for granted the importance of maintaining the adenovirus vaccine supply." His concern is, of course, that support for the vaccination program may wane as incidence of adenovirus illness in the military drops and the threat of illness seems to disappear.

You can hear Gaydos and Robert Potter, MD, discuss the history of adenovirus in the military, surveillance of adenovirus illness, and the new vaccine at this 10-minute-long podcast from the CDC.

Sources

Friedman JE. Naval Medical Center Portsmouth Public Affairs. Vaccination program appears to reduce respiratory infections among recruits. http://www.navy.mil/search/display.asp?story_id=65070

Naval Health Research Center. Febrile respiratory illness (FRI) surveillance update. Week 14 (through 7 April 2012). http://www.med.navy.mil/sites/nhrc/geis/Documents/FRIUpdate.pdf

Hilleman MR. Efficacy and indications for use of adenovirus vaccine. Am J Public Health Nations Health. 1958 February; 48(2): 153–158. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1551483/?page=1

Potter RN, Cantrell JA, Mallak CT, Gaydos JC. Adenovirus-associated deaths in US military during postvaccination period, 1999–2010. Emerg Infect Dis [serial on the Internet]. 2012 Mar. http://dx.doi.org/10.3201/eid1803.111238

U.S. Military Vaccine Agency. Adenovirus fact sheet, 10/5/2004. http://www.vaccines.mil/documents/608AdenoFactSheet.pdf

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They omitted saying that the adenovirus vaccine given to our military in the early 1960's was contaminated with Simian Virus 40 which is associated with several kinds of cancer.

You're right, adenovirus vaccine given in the 1950s/early 1960s was found to have SV40. CDC has background here: http://www.cdc.gov/vaccinesafety/updates/archive/polio_and_cancer.htm There they list a number of studies that have shown no significant difference in rates of cancer in people presumed to have taken SV40 contaminated vaccine and those not presumed to have done so. ("...the majority of studies in the U.S. and Europe that compare persons known or strongly presumed to have received SV40-contaminated polio vaccine with those known or strongly presumed not to have received SV40-contaminated polio vaccine have not shown a causal relationship between receipt of SV40-contaminated polio vaccine and cancer.")

HIV formerly LAV might be a small adenovirus. Have you any evidence of connection?

Hey I thought this was a really interesting post. I think that clinical research on vaccines is crucial. I think that vaccines are very useful, but we need to continue researching and refining them. With new discoveries, medical researchers are understanding more and developing more effective vaccinations.

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