Vaccines for Rift Valley Fever, Yellow Fever, Omsk HF, and Kyasanur Forest Disease

Mary Beth Nierengarten, Larry I. Lutwick, MD

Disclosures

August 02, 2002

In This Article

Rift Valley Fever

Found primarily in Africa, RVF is an acute viral disease affecting domesticated animals and humans. Natural transmission is by mosquitoes infected with the virus. Outbreaks in livestock such as sheep, cattle, buffalo, and goats incur high death rates, as highlighted by reports of more than 100,000 sheep dying during an outbreak in Kenya in the early 1950s.

Humans can contract the disease through mosquito bites or by exposure to blood or bodily fluids from infected animals. Persons involved in livestock slaughtering and food preparation in endemic areas are at particular risk of contracting the disease. Transmission through the air is also possible. Natural occurrences of RVF were first documented in Egypt in 1978, which killed more than 600 people and sickened over 200,000,[4] and in another, more recent outbreak in 1993.[5] An outbreak in Senegal in 1987 caused hundreds of deaths.[6] A recent outbreak in Yemen in 2000 was the first documented occurrence outside of Africa.[7]

Vaccine development is focusing on protecting both animals and humans. Several vaccine candidates are at various stages of development ( Table 1 ), with 2 currently available in limited supply with investigational new drug (IND) status in the United States.

One of the most promising is the live attenuated vaccine candidate MP-12. This vaccine was developed by researchers at the US Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland, in the mid-1980s and produced at the army's contract facility, the Salk Institute-Government Service Division (TSI-GSD). The vaccine has proven effective and safe in sheep and cattle.[8] Unlike the first attenuated RVF vaccine, which carried unacceptable side effects in animals such as birth defects and spontaneous abortions, MP-12 is reported to lack these negative effects.[9,10] In addition, the vaccine is easy to administer (requires only 1 inoculation) and induces rapid immunity. Human trials of this vaccine in more than 60 people have shown good preliminary results, says Dr. Clarence Peters, University of Texas Medical Branch, Galveston, but he added that testing on hundreds of people is necessary to more accurately know the safety and efficacy of the vaccine. Further testing of this vaccine on humans is stalled, according to Dr. Peters, who plans on responding to a current call by the National Institute of Allergy and Infectious Diseases (NIAID) to pursue further development of the vaccine.

A naturally derived variant of MP-12, called Clone 13 (C-13), has been developed by researchers at the Institut Pasteur, Paris, France. According to Dr. Michele Bouloy, the lead researcher working on C-13, the new virus carries attenuation markers in 1 of the 3 segments that constitute the genome for the virus (segment S). "One of the properties is a deletion in a gene, a nonstructural phosphoprotein (NSs), that is important for virulence," explains Dr. Bouloy. "This attenuates the virus, since it allows an interferon response which otherwise is blocked by the virulent viruses." Testing of this virus is in progress; data from a trial in Senegal involving sheep showed immunity as well as no adverse effects on prenatal development or inducing abortions. It is also being developed as a vaccine for animals in South Africa. Currently, Dr. Bouloy and her colleagues are developing a new virus, R566, which combines the properties of both C-13 and MP-12.[11] The new vaccine has been tested in animals, but a vaccine for humans is not yet in development

The other vaccine candidate with IND status is a formalin-inactivated vaccine called TSI-GSD-200, which has been shown to be safe and immunogenic in early human studies. Testing of this vaccine in 598 at-risk laboratory personnel at USAMRIID from 1986-1997 showed only minor side effects and good long-term immunity at 12-year follow-up.[12](Immunity was measured by a plaque-reduction neutralization antibody titer ≥ 1:40.) To confer optimal protection, 3 doses appear best, along with a booster if immunity begins to drop, said Dr. Peters, senior author of the 12-year follow-up study. According to Dr. Peters, this vaccine continues to be used to immunize laboratory workers studying RVF.

Other vaccine strategies under investigation include naked DNA vaccination and alphavirus replicons. According to Dr. Jon Smith, former researcher at USAMRIID and currently Vice President of AlphaVax, Inc. (Research Triangle Park, North Carolina), a vaccine candidate for RVF using alphavirus replicons was developed years ago at USAMRIID and showed promise in mice. Although AlphaVax is pursuing this vaccine strategy for other viruses, such as HIV and malaria, it is not currently doing any work on RVF vaccines.

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