New Opportunities Projects
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Preclinical Testing of YF17D/LAS, a Bivalent Vaccine for Lassa and Yellow Fevers
Collaborating Institutions: Southwest
Foundation for Biomedical Research (SFBR), San Antonio, TX (WRCE) Co-Investigators: Ricardo Carrion Jr., PhD – SFBR, San Antonio, TX (WRCE) Igor
Lukashevich, MD, PhD – UMBI, Baltimore, MD (MARCE) Expected Product: Demonstrate the safety, immunogenicity, and efficacy of a bivalent vaccine against Lassa virus and yellow fever virus.
Description: 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 agents of biological warfare contribute to 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 toll-like receptors 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- glycoprotein precursor (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.
In a previous RCE-funded project, we used marmosets as a model of LF to perform advanced proof-of concept 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 BSL3) 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.
In this project, we will extend our pre-clinical studies in primates and we 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, and (2) efficacy–test the hypothesis that YF17D/LAS-vaccinated will be protected against LAS challenge. We are confident that this approach will result in a promising bivalent vaccine candidate for LF and YF. |
