Tuesday, June 22, 2010

Another Ph.D. Friend, Another Major Paper.

A report published in the Public Library of Science (PLoS) journal Neglected Tropical Diseases shows two new approaches could form the basis for the first human vaccine for Rift Valley Fever (RVF), a dangerous zoonotic disease. Researchers at the University of Pittsburgh Center for Vaccine Research have shown that experimental vaccines developed using these approaches produced strong immune responses in mice, and is potentially safe for human use.

RVF is a viral zoonosis which primarily affects domestic livestock, but can also be passed to humans and is potentially fatal. Viral spread is achieved by infected mosquitoes, typically the Aedes or Culex genera. Disease is caused by the RVF virus, a member of the Bunyaviridae family. Other notable Bunyaviridae family members include Crimean-Congo Hemorhagic Fever Virus and Hantavirus Hemorrhagic fever.

The disease, first reported in livestock in Kenya around 1915, wasn't isolated until 1931. RVF outbreaks occur across sub-Saharan Africa, with outbreaks occurring elsewhere infrequently (but sometimes severely - in Egypt in 1977-78, several million people were infected and thousands died during a violent epidemic. In Kenya in 1998, the virus claimed the lives of over 400 Kenyans. In September 2000 an outbreak was confirmed in Saudi Arabia and Yemen).

In humans the virus can cause several different syndromes. Typically, sufferers show no symptoms or only a mild illness with fever, headache, myalgia and liver abnormalities. However, in roughly 2% of people infected, the illness can progress to hemorrhagic fever syndrome, meningoencephalitis, or eye complications. Patients who become ill usually experience fever, generalized weakness, back pain, dizziness, and weight loss at the onset of the illness. Typically, patients recover within 2–7 days after onset.

RVF mainly affects farm animals however, the virus has spread to human populations causing serious illness and death in several regions in Africa and the Middle East. Additionally, it has been classified as a select agent by the U.S. federal government because of its potential use in biowarfare, prompting vaccine development research.

"RVF is a veterinary and public health threat that continues to spread," said Ted M. Ross, Ph.D., lead author of the study and associate professor, University of Pittsburgh Center for Vaccine Research. "At the same time, vaccine development has been challenging because of adverse side effects from live virus vaccines and uncertainty about whether the virus could revert to a more dangerous form during vaccine manufacturing."

Using DNA plasmids and alphavirus replicons expressing the Gn glycoprotein of RVFV alone or fused to three copies of complement protein, C3d, each vaccine was administered to mice in an all DNA, all replicon, or a DNA prime/replicon boost strategy and both the humoral and cellular responses were assessed. DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn elicited high titer neutralizing antibodies that were similar to titers elicited by the live-attenuated MP12 virus. Mice vaccinated with an inactivated form of MP12 did elicit high titer antibodies, but these antibodies were unable to neutralize RVFV infection. However, only vaccine strategies incorporating alphavirus replicons elicited cellular responses to Gn. Both vaccines strategies completely prevented weight loss and morbidity and protected against lethal RVFV challenge. Passive transfer of antisera from vaccinated mice into na─▒ve mice showed that both DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn elicited antibodies that protected mice as well as sera from mice immunized with MP12.

"These vaccine strategies may be advantageous to controlling RVF because they provide a safer alternative and appear to work as well as live virus vaccines," said Dr. Ross.

The graduate student responsible for the vast majority of the work is a friend/classmate of mine from Pitt, Nitin Bhardwaj DVM, MS.

I was at one time considering the Ross lab, however the wind took me elsewhere. Great job guys, nice paper.

Lance D. Presser has a PhD in Microbiology & Immunology, and is a Public Health Laboratorian.

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