The objective of the pre-clinical experiments proposed in this application is to select a vaccine modality that hopefully will address significant deficiencies in the slate of candidate DEN vaccines currently in development. Live attenuated vaccines likely will fail to induce endogenous responses to all four DEN serotypes in infants born to monotypically immune mothers and immunized prior to the decay of maternal antibody. If this problem is avoided by delaying vaccination until maternal antibody decays sufficiently to allow use of live attenuated vaccines, then these infants will be left unprotected from severe DEN disease during this period. DNA vaccines for DEN are likely to circumvent the maternal antibody problem, but DNA vaccines generally have been disappointing in human trials, especially in terms of inducing humoral responses which are the most important responses for protection against DEN. We have proposed a sequence of experiments that will first determine the configuration of the E protein most effective in inducing responses in mice and macaques, testing a promising new configuration of E in soluble form that showed a significantly improved neutralizing response. Second, we will determine in mice and infant macaques whether a VRP vaccine cocktail induces a balanced response to all four serotypes and does so safely and in the presence of passively transferred neutralizing antibodies, as would be predicted from our previous experiments with DEN2-VRP in mice. Third, we will test a newly developed DNA launched form of the VEE vectors for their utility a) in mice and macaques, b) in the face of anti-DEN neutralizing antibodies, and c) in the presence of neutralizing antibodies to VEE. Finally, we will test mixed modality prime-boost regimens that may well represent the optimal vaccination strategy for VEE based vaccine vectors. We feel that at the conclusion of these studies, we will have established a solid justification for advancement of a VEE based vaccine candidate for DEN into phase I human trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI078060-05
Application #
8262713
Study Section
Special Emphasis Panel (ZAI1-TP-M (J2))
Program Officer
Cassetti, Cristina
Project Start
2008-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$1,070,488
Indirect Cost
$248,950
Name
Global Vaccines, Inc.
Department
Type
DUNS #
607832719
City
Research Triangle Park
State
NC
Country
United States
Zip Code
27709
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Khalil, Syed Muaz; Tonkin, Daniel R; Mattocks, Melissa D et al. (2014) A tetravalent alphavirus-vector based dengue vaccine provides effective immunity in an early life mouse model. Vaccine 32:4068-74
Zellweger, Raphael M; Miller, Robyn; Eddy, William E et al. (2013) Role of humoral versus cellular responses induced by a protective dengue vaccine candidate. PLoS Pathog 9:e1003723
White, Laura J; Sariol, Carlos A; Mattocks, Melissa D et al. (2013) An alphavirus vector-based tetravalent dengue vaccine induces a rapid and protective immune response in macaques that differs qualitatively from immunity induced by live virus infection. J Virol 87:3409-24