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Marburg virus vaccines based upon alphavirus replicons protect guinea pigs and nonhuman primates
1United States Army Medical Research Institute for Infectious Diseases, Fort Detrick, Frederick, Maryland, 21702, USA.
Abstract:
Marburg virus (MBGV), for which no vaccines or treatments currently exist, causes an acute hemorrhagic fever with a high mortality rate in humans. We previously showed that immunization with either killed MBGV or a glycoprotein (GP) subunit prevented lethal infection in guinea pigs. In the studies reported here, an RNA replicon, based upon Venezuelan equine encephalitis (VEE) virus, was used as a vaccine vector; the VEE structural genes were replaced by genes for MBGV GP, nucleoprotein (NP), VP40, VP35, VP30, or VP24. Guinea pigs were vaccinated with recombinant VEE replicons (packaged into VEE-like particles), inoculated with MBGV, and evaluated for viremia and survival. Results indicated that either GP or NP were protective antigens while VP35 afforded incomplete protection. As a more definitive test of vaccine efficacy, nonhuman primates (cynomolgus macaques) were inoculated with VEE replicons expressing MBGV GP and/or NP. Three monkeys received packaged control replicons (influenza HA); these died 9 or 10 days after challenge, with typical MBGV disease. MBGV NP afforded incomplete protection, sufficient to prevent death but not disease in two of three macaques. Three monkeys vaccinated with replicons which expressed MBGV GP, and three others vaccinated with both replicons that expressed GP or NP, remained aviremic and were completely protected from disease.
Insights
New vaccines using Venezuelan equine encephalitis virus (VEEV) replicons show promise against Marburg virus (MBGV). Glycoprotein (GP) or nucleoprotein (NP) antigens protected nonhuman primates from lethal MBGV infection.
Area of Science:
- Virology
- Vaccinology
- Infectious Diseases
Background:
- Marburg virus (MBGV) causes severe hemorrhagic fever with high mortality.
- No current vaccines or treatments exist for MBGV.
- Previous studies showed killed MBGV or glycoprotein (GP) subunit immunization protected guinea pigs.
Purpose of the Study:
- To evaluate the efficacy of Venezuelan equine encephalitis virus (VEEV) RNA replicons as a vaccine vector for MBGV.
- To identify protective antigens against MBGV using a VEEV replicon system.
Main Methods:
- Recombinant VEEV replicons encoding MBGV antigens (GP, NP, VP40, VP35, VP30, VP24) were generated.
- Guinea pigs and cynomolgus macaques were vaccinated with packaged VEEV replicons.
- Animals were challenged with MBGV and monitored for viremia, survival, and disease.
Main Results:
- Vaccination with VEEV replicons expressing MBGV GP or NP provided protection in guinea pigs.
- In cynomolgus macaques, MBGV NP offered incomplete protection, preventing death but not disease.
- MBGV GP, alone or with NP, conferred complete protection, preventing viremia and disease in macaques.
Conclusions:
- VEEV replicons are effective vaccine vectors against MBGV.
- MBGV GP and NP are key protective antigens.
- Vaccines expressing MBGV GP show potential for preventing Marburg hemorrhagic fever.