The tick-borne flavivirus (TBFV) group includes a number of important human pathogens that result in serious encephalitic or hemorrhagic diseases that are either Category B or C priority pathogens. The TBFV are considered to be emerging or re-emerging pathogens due to increases in the number of human cases, the expansion of geographic distribution, and emergence of new viruses. This application is directed at the development of a multivalent TBFV vaccine that provides broad cross-protection against at least five viruses in this group: Central European subtype of tick-borne encephalitis [TBE] (TBEV-Eu), Far Eastern subtype (TBE-FE), Alkhurma hemorrhagic fever virus (AHFV), Kyasanur Forest disease virus (KFDV) and Omsk hemorrhagic fever virus (OHFV). Inactivated vaccines exist for TBEV-Eu, TBE-FE and KFD in some endemic countries, but there are no vaccines for AHFV and OHFV. The development of monotypic vaccines against individual pathogens provides a strategy to mitigate the threat posed on a regional basis; however, the number of different viruses in the TBFV group poses a challenge in providing protection against all of the viruses in the group. Furthermore, there is no registered TBFV vaccine in the U.S. The lack of a vaccine in the U.S. has been deemed an unmet need by NIAID. An approach to provide broad protection against the TBFV group is the development of a multivalent vaccine that provides cross- protection against most, if not all, of the TBFVs. This vaccine will be developed by evaluating various combinations of soluble recombinant subunits proteins representing the envelope (E) protein from these five TBFVs. Preliminary data with recombinant TBEV-Eu has established a proof-of-principle for the potential of this approach. The monovalent rTBEV-EU vaccine has been demonstrated to provide monotypic and partial cross-protection and will serve as the core on which the multivalent vaccine will be established.
The Specific Aims of this project are: 1) development and evaluation of the immunogenicity and cross-reactive potential (cross-virus neutralizing ability) of additional E subunit proteins for inclusio in the multivalent vaccine; 2) assess the cross-protective potential of selected combinations of recombinant TBFV E proteins in a mouse challenge model; and 3) assess the potency of the selected multivalent vaccine to support further development of the vaccine. To accomplish these goals an established stable insect expression system with demonstrated FDA regulatory experience will be utilized to produce the recombinant E proteins. This includes the use of a modern adjuvant that has potential for advancement to human clinical trials. The selection of the multivalent candidate vaccine will focus on a vaccine composition with the least number of components (E proteins) that provides the greatest level of cross-protection. To accomplish the objectives of the proposed research, a strong multidisciplinary team of scientists has been assembled that provides the means to develop and evaluate a successful multivalent TBFV cross-protective vaccine. The development of multivalent TBFV vaccine would be of great value and in line with the priorities of NIH/NIAID to develop multivalent and cross-protective vaccine technologies.

Public Health Relevance

The proposed research is focused on developing a candidate vaccine that protects against a family of related viruses in the tick-borne flavivirus (TBFV) group which causes disease in humans. The vaccine candidate would be a single multivalent vaccine that would provide protection against many viruses in the TBFV group. The approach is based on a technology to produce vaccine components comprised of recombinant subunit envelope proteins. Although TBFVs are normally found outside the U.S. they are identified as priority pathogens, so a multivalent vaccine would help meet the mission of providing protection for U.S. citizens against several priority pathogens (biothreat agents) with a single vaccine. Such a multivalent TBFV vaccine can be utilized to protect military and state department personnel, first responders, and U.S. TBFV virus researchers who are currently forced to go abroad for vaccination, in addition to travelers or people at risk in endemic areas.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1-IMM-R (12))
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Repik, Patricia M
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Hawaii Biotech, Inc.
United States
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