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World Rabies Day: Rabies Vaccines
Museum curator Anna Dhody recently alerted us to a box of vaccines and other medical supplies she found in a little-visited storage area in the museum basement. The box belonged to a collection of medical equipment donated by James G. Kitchen II, MD (d. 1998), who was a Pocono Lake, Pennsylvania, physician and fellow of The College of Physicians of Philadelphia. Dr. Kitchen stocked the vaccine in his office supplies to address what was probably a fairly uncommon need in his practice: post-exposure rabies prophylaxis in humans.
Pictured above is a Semple-type, phenol-killed human rabies vaccine. The packaging holds 14 5-mL doses (National Drug Company, expiration 5/14/1964). This vaccine was named for its developer, David Semple, MD (1856-1937), a British army officer in the Indian Medical Service. Semple, who was a protégé of British physician and typhoid vaccine developer Almroth Wright, MD, opened a Pasteur Institute in Kisauli, India, in the foothills of the Himalayas in 1900. His killed virus vaccine, developed in 1911, relied at first on the growth of rabies virus in the brains of rabbits. Later, Semple and others relied on the brains of infected sheep and goats. As with other nervous tissue vaccines, this vaccine, while generally effective, could cause significant neurological side effects. It remained the most commonly used rabies vaccine in the world until vaccines became available that were produced using duck embryos (late 1950s) and then cell culture techniques (1970s). Semple vaccine is currently used in only a few countries in Asia and Africa. The World Health Organization's position is that "the use of brain-tissue [rabies] vaccines should be discontinued."
A later rabies vaccine for use in humans is pictured below (Lilly, expiration 9/26/1970). This vaccine developed from virus propagated in duck embryos was an advance over nervous tissue rabies vaccines in that it caused fewer side effects. However, this vaccine still required 14 or 23 injections for post-exposure vaccination and produced a less robust immune response than desired.
An inactivated vaccine made from rabies virus propagated in the human diploid cell strain WI-38 was licensed in Europe in 1976 and in the United States in 1980. History of Vaccines advisors Hilary Koprowski, MD, and Stanley Plotkin, MD, along with the late Tadeusz Wiktor, VMD, developed this vaccine, known as HDCV, at the Wistar Institute in Philadelphia to avoid the problems that plagued vaccines that relied on nervous system tissue. Plotkin’s article in the Sources section below discusses how Koprowski’s team adapted the rabies virus to replicate in WI-38 cells. (This Wistar cell strain has been used in other licensed and experimental vaccines, such as polio, rubella, cytomegalovirus, and varicella). The postexposure vaccine schedule calls for vaccination with HDCV on days 0, 3, 7, 14, and 28. HDCV is the gold standard of rabies vaccines, but its high cost makes it too expensive to use in some developing countries.
The risk of rabies to U.S. residents is small because of mandatory rabies vaccination of household pets. In developing countries, however, people face a much higher risk of rabies infection. Indeed, in India, where dogs are not universally immunized for rabies, the disease kills about 20,000 people a year. In the World Health Organization’s South-East Asia Region alone, more than 1.4 billion people are at potential risk of rabies.
In the United States, Sanofi and Novartis produce rabies vaccine for both pre-exposure vaccination and post-exposure prophylaxis (Sanofi's HCDV and Novartis's purified chick embryo vaccine). India, a growing vaccine producer, manufactures more than 15 million doses of human rabies vaccine each year, including HDCV and vaccine made in Vero (green monkey kidney) cells and in chick and duck embryos.
The Wistar Institute’s Hildegund Ertl, MD, in a 2009 review, discusses the future of rabies vaccines. She notes that the only vaccines with the potential to be inexpensive and long-lasting enough to be used for the preventative vaccination of children are based on adenovirus vectors. Ertl also discusses the promise of DNA and viral recombinant vaccine, as well as new adjuvants, that could make rabies vaccine cheaper, more effective, and more immunogenic.
Chakrabarti P. “Living vs. dead:” the Pasteurian paradigm and imperial vaccine research. Bull Hist Med. 2010 Fall: 387-423. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2966399/
Ertl HCJ. Novel vaccines to human rabies. PLoS Negl Trop Dis 3(9): e515. doi:10.1371/journal.pntd.0000515. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2742899/
Plotkin SA. Rabies vaccine prepared in human cell cultures: progress and perspectives. Reviews of Infectious Diseases. May-June 1980:433-448. http://cid.oxfordjournals.org/content/2/3/433.full.pdf
World Health Organization, Regional Office for South-East Asia. Rabies in the South-East Asia Region. No date. http://www.searo.who.int/LinkFiles/CDS_rabies.pdf.pdf