U.S. Military and Vaccine History
Military research programs throughout history have made significant contributions to medicine and, in particular, to vaccine development. These efforts have been driven primarily by the effects of infectious disease on military conflicts: smallpox devastated the Continental Army in 1776, as well as troops on both sides of the United States Civil War; typhoid fever was common among soldiers in the Spanish American War. More person-days were lost among U.S. soldiers in malaria-endemic regions to malaria than to bullets throughout the entire 20th century; indeed, malaria continues to sap military strength into the current century.
To respond to these diseases and the many others that threaten both soldiers and the public, military forces have devoted significant time and effort toward public health methods and medical research.
Smallpox was a scourge of the American Colonies, decimating Native American populations and then playing a part in the Revolutionary War. British soldiers had better immunity to the disease than the colonial troops, and may have even used it as a weapon. In 1776, half of the 10,000 Continental Army soldiers around Quebec fell ill with smallpox; of the outbreak, John Adams wrote, “The smallpox is ten times more terrible than the British, Canadians and Indians together. This was the cause of our precipitate retreat from Quebec.”
The following year, George Washington, as commander-in-chief of the Continental Army, ordered mandatory inoculation against smallpox for any soldier who had not gained prior immunity against the disease through infection. The procedure in that era was known as variolation, intentionally exposing someone to a mild form of the smallpox virus (Jenner would not develop the smallpox vaccine until 1796). [See related timeline entry.] For the British Army in the North American colonies, inoculation was voluntary.
As a result of Washington’s orders, the Continental Army was the first in the world with an organized program to prevent smallpox. Some historians have suggested that if smallpox inoculation had been performed earlier, the smallpox outbreak among Continental soldiers in Quebec could have been avoided—speeding up the conclusion of the Revolutionary War and potentially allowing for the addition of some or all of the British colony of Canada to the United States.
Yellow fever was a serious problem for U.S. troops during the Spanish-American War of 1898. In response, the Army created a Yellow Fever Commission, headed by physician Walter Reed. The Commission members traveled to Cuba and, after extensive experiments and observation, validated a theory presented by Cuban physician Carlos Finlay two decades earlier: mosquitoes were responsible for the spread of the disease. Later investigators showed that a virus was its actual underlying cause, transmitted from one person to another using mosquitoes as vectors.
Later, the Commission’s work would lead to yellow fever control programs for both military camps and Cuban cities and towns. American physician William Crawford Gorgas organized these programs for both Cuba and the Panama Canal region. The control efforts by Gorgas’s group allowed for the completion of the Panama Canal by the Americans after French efforts were abandoned due to the difficulties of both yellow fever and malaria. After serving as Surgeon General of the U.S. Army, Gorgas would eventually join the Rockefeller Foundation’s Yellow Fever Commission as director of its work on yellow fever eradication. Years later, Harvard instructor Max Theiler would also join the commission and develop the 17D vaccine against yellow fever. Theiler, a virologist, would eventually win the Nobel Prize for his efforts, and the 17D vaccine is still used today.
After World War II, the majority of acute respiratory disease cases among U.S. military trainees were the result of adenovirus infections. 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, trainees could die of respiratory distress induced by the adenovirus infection.
Maurice Hilleman, a microbiologist who would eventually be involved in the development of more than 40 vaccines, joined the U.S. Army Medical Center’s Department of Respiratory Diseases after leaving E.R. Squibb & Sons in 1948. That research center would soon be renamed the Walter Reed Army Institute of Research (WRAIR), and Hilleman was still working there in 1953, when he flew to Fort Leonard Wood, Missouri, to investigate a suspected influenza outbreak among Army troops.
Instead, when Hilleman and his group isolated viruses from the infected troops, they discovered that they had isolated not influenza virus, but multiple strains of a newly discovered type of virus—the group that would eventually be named adenoviruses.
Just three years later, in 1956, an adenovirus vaccine was created at WRAIR. It was an inactivated 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 license for the vaccine being revoked in 1963, but two live-virus vaccines were developed just a few years later. 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. In 1994, however, the vaccine’s manufacturer ended production of it, and all stocks were depleted in 1999. Outbreaks of acute respiratory disease caused by adenoviruses rose among military trainees following discontinuation of the vaccination program. In 2001, the Army provided funds to re-establish an adenovirus vaccine, and the government contracted with a manufacturer to restore a production line for adenovirus type 4 and type 7 vaccine tablets. The vaccine was licensed in March 2011, and the U.S. military deployed it to training facilities beginning in October 2011. Early surveillance of adenovirus illness shows a marked decrease in incidence of all serotypes of adenovirus after re-introduction of the vaccine.
HIV and Malaria Vaccine Research
Today, military researchers are heavily involved in efforts to develop treatments and vaccines for malaria and HIV infection. The U.S. military HIV Research Program (MHRP) at the Walter Reed Army Institute of Research studies not only care and treatment but HIV prevention as well. MHRP scientists, collaborating with the U.S. National Institutes of Allergy and Infectious Diseases (NIAID), developed a viral vector HIV vaccine candidate that has reached human clinical testing in combination with another vaccine product. Separately, U.S. military researchers are also contributing to the testing of the leading vaccine candidate for malaria. Developed in cooperation with GlaxoSmithKline, the RTS,S malaria vaccine candidate is being tested in Phase 3 clinical trials in seven African countries, with the completion of the trial expected in mid-2012.
Artenstein AW, Opal JM, Opal SM, Tramont EC, Peter G, Russell PK. History of U.S. Military Contributions to the Study of Vaccines against Infectious Diseases. Military Medicine. 170, 4:3, 2005.
Centers for Disease Control and Prevention. Adenoviruses. May 19, 2010. Available at http://www.cdc.gov/ncidod/dvrd/revb/respiratory/eadfeat.htm. Accessed October 2, 2013.
Fact Sheet: RTS,S Malaria Vaccine Candidate. PATH Malaria Vaccine Initiative. Available at http://malariavaccine.org/files/UpdatedRTSS_FactSheet_21April2010.pdf. Accessed October 2, 2013.
Glynn I, Glynn J. The Life and Death of Smallpox. New York: Cambridge University Press, 2004.
Grabenstein JD, Pittman PR, Greenwood JT, Engler RJM. Immunization to Protect the U.S. Armed Forces: Heritage, Current Practice, Prospects. Epidemiological Reviews 2006;28:3-26.
Hilleman M. Efficacy of and Indications for Use of Adenovirus Vaccine. Am J Public Health Nations Health. 1958 February; 48(2): 153–158.
Military Vaccine Agency (MILVAX). Available at: http://www.vaccines.mil. Accessed October 2, 2013.
Naval Health Research Center. FRI Surveillance Update. http://www.med.navy.mil/sites/nhrc/geis/Documents/FRIUpdate.pdf Accessed October 2, 2013.
U.S. Military HIV Research Program (MHRP). Available at: http://hivresearch.org/. Accessed October 2, 2013.
Timeline Entry: 1900 U.S. Army Researchers Discover the Cause of Yellow Fever
Spurred by the massive yellow fever-related casualties in the Spanish-American War, members of the U.S. Army Yellow Fever Commission, headed by Walter Reed, traveled to Cuba to study the disease. Commission member Jesse Lazear (1866-1900) met Henry Rose Carter, a surgeon who had studied the incubation period of yellow fever. Carter gave Lazear a draft of a paper he’d authored defining the incubation period for the disease as a range of 10 to 17 days. Lazear reportedly stated that Carter’s dates, should they prove to be correct, suggested a living host for yellow fever. Determined to uncover the source of the illness, the Commission members visited Carlos Finlay and decided to test his theory of mosquito transmission.
Jesse Lazear hatched Finlay’s mosquito eggs and let the mosquitoes feed on patients infected with yellow fever at a Havana hospital. The mosquitoes were then allowed to feed on study volunteers over a period of two weeks—yet no infections resulted. Two days later, however, Lazear once again allowed the mosquitoes to feed. This time, both of the men who were bitten fell ill. These experiments validated the theory Finlay had presented two decades earlier: mosquitoes (specifically, the Aedes aegypti variety) were the transmission vector of yellow fever. The researchers went on to rule out a bacterium as the disease agent. They determined that an infectious particle too small to be filtered with a standard bacterial filter was the source of the disease: the first human virus ever discovered. (German scientists had identified the virus that caused foot-and-mouth disease in animals in 1898.)
The two men Lazear exposed to yellow fever via the experiment’s mosquitoes recovered. Lazear himself, however, was not so lucky. It is likely that he allowed himself to be bitten as part of the experiment. Lazear contracted yellow fever and died in September 1900, at age 34.
The Army experiments, however, continued, with Reed naming newly designed facilities “Camp Lazear.” The group proceeded to determine that the mosquitoes could transmit the disease only after a certain period of time had passed since they had fed on another human infected with it (in the range of 12-20 days) and that a victim bitten by an infected mosquito would typically fall ill within six days.
William Crawford Gorgas (1854-1920), a Colonel in the U.S. Army Medical Corps, later described the details of the discovery:
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They… found out that [a man], before he had been bitten by the yellow-fever mosquito, could sleep in the bed in which a patient had died of yellow fever, could be covered with a black vomit from a yellow-fever patient, or be exposed to the emanations from yellow fever in any other way, and as long as he was kept safe from the bite of the mosquito he would not have yellow fever; but this same man, after all this exposure, if afterwards bitten by an infected mosquito, would very certainly catch the disease.
…They had a little frame building built in this camp furnished with jars and the necessary simple material for breeding mosquitoes… Eggs of this particular species of mosquito were obtained and hatched in one of the jars. A female mosquito was taken from the booth thus hatched. The male mosquito will not bite… The female mosquito selected was put into a small glass tube, stoppered with a little cotton, so that she could get air but not escape, taken to Habana, placed on the hand of a patient in the first three days of an attack of yellow fever, and allowed to fill herself with blood. She was then brought back to her former home, placed in a large glass jar, and allowed to digest the blood she had obtained.
…So confident were the men in charge of the mosquitoes that I have known them to put their hands in the jars and let the mosquitoes feed upon them, up to the fifth or sixth day after the mosquito had bitten a yellow-fever patient. The mosquito, you recollect, can not convey the disease till from 12 to 20 days have passed from the time of her biting the yellow-fever case from which she becomes infected.
On the other hand, I once saw a party of 12 or 15 doctors in the mosquito room one day, when the mosquito-bar covering of the jar accidentally came off and the insects escaped into the room. These doctors had come from other countries to investigate the subject, and were not then convinced that the mosquito carried yellow fever. Still, they did not care to put the matter to a practical test in their own persons, and got out of the room so rapidly that the wire-screen door was broken down during their exit. It happened that the mosquitoes in this jar had never bitten a yellow-fever patient and were not infected.
-- Colonel William C. Gorgas, Medical Corps, United States Army, A few general directions with regard to destroying mosquitoes, particularly the yellow-fever mosquito