Vaccination with DNA Plasmids Expressing Gn Coupled to C3d or Alphavirus Replicons Expressing Gn Protects Mice against Rift Valley Fever Virus

Abstract

Background

Rift Valley fever (RVF) is an arthropod-borne viral zoonosis. Rift Valley fever virus (RVFV) is an important biological threat with the potential to spread to new susceptible areas. In addition, it is a potential biowarfare agent.

Methodology/Principal Findings

We developed two potential vaccines, 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 naïve 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.

Conclusion/Significance

These results show that both DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn administered alone or in a DNA prime/replicon boost strategy are effective RVFV vaccines. These vaccine strategies provide safer alternatives to using live-attenuated RVFV vaccines for human use.

Author Summary

Rift Valley fever virus (RVFV) is an arthropod-borne phlebovirus associated with abortion storms, neonatal mortality in livestock and hemorrhagic fever or fatal encephalitis in a proportion of infected humans. Requirement of multiple booster immunizations to maintain the level of protective immunity with the inactivated vaccines and the ability of live-attenuated vaccines to cause detrimental side-effects are major limitations preventing the widespread use of current vaccines. In this paper, we describe the use of DNA and alphavirus replicon based vaccination approaches to elicit a protective immune response against RVFV. While both vaccines elicited high titer antibodies, DNA vaccination elicited high titer neutralizing antibodies, whereas the replicon vaccine elicited cellular immune responses. Both strategies alone or in combination elicited immune response that completely protected against not only mortality, but also illness. Even though the delivery vectors elicited some protection on their own, they did not prevent severe morbidity. These promising vaccines provide an alternative RVFV vaccine for livestock and humans.