LASSA FEVER BIVALENT VACCINE EFFICACY IN MARMOSETS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Yellow Fever (YF) and Lassa Fever (LF) are two viral hemorrhagic fevers (VHFs) endemic for West Africa. Among causative agents of VHFs, Lassa (LAS) and YF viruses affect the largest number of people. The sizeable disease burden and the possibility that these viruses can be used as an agent of biological warfare make a strong case for vaccine development. There is no vaccine available for LF. In contrast, a live attenuated YF17D vaccine has been available for human immunization since 1936. However, poor availability of YF17D vaccine has led to inadequate control of the disease representing a failure of public health policy. In the past 15 years, YF re-emerged in Africa and in South America. Therefore, there is an urgent need to increase YF17D vaccine production. The YF17D is one of the most effective and safest vaccines in the world and is regarded as one of the best candidates for viral expression vector. YF17D activates multiple TLRs on dendritic cells to elicit a mixed Th1/Th2 cytokine profile and antigen-specific CD8+ T cells. Importantly, YF17D-based recombinant constructs elicit strong and long-lasting humoral and cell-mediated immune responses against unrelated (non-flavivirus) epitopes cloned in the YF17D vector. We have used a full-length infectious cDNA clone of the vaccine strain YF17D as a vector to design recombinant (not chimeric) YF17D/LAS-GPC vaccine expressing LAS glycoproteins into infected cells. We demonstrated that recombinant YF17D/LAS-GPC virus is replication competent in vitro and in vivo, induces immune responses against both pathogens, and protects guinea pigs against fatal LF. We previously used marmosets as a model of LF to perform advanced-proof studies with reassortant vaccine ML29. This vaccine candidate serves as an excellent standard for efficacy, breadth, and immunogenicity. However, the current CDC vector biosafety status (ML29 is classified as BSL-3) has complicated further development of the ML29 vaccine. The design of bivalent YF17D/LAS recombinant vaccine is a very attractive alternative to control both infections in overlapping endemic areas. The current project will test the hypothesis that the YF17D/LAS recombinant will be highly immunogenic and induce protective immune responses in marmosets challenged with LAS virus. Our specific aims are: 1)immunogenicity; test the hypothesis that YF17D/LAS immunization will stimulate LAS-and YF-specific immune responses; 2) efficacy; test the hypothesis that YF17D/LAS-vaccinated will be protected against LAS challenge. Successful completion of this project will result in a promising bivalent vaccine candidate for LF and YF.