The development strategy for an effective tetravalent dengue vaccine has consisted of the clinical evaluation of monovalent vaccine candidates for each of the four serotypes with the goal of selecting suitable candidates for inclusion in a tetravalent formulation. Optimal admixtures (TV003 and TV005: DEN1del30, DEN2/4del30, DEN3del30/31, DEN4del30) have been selected and induce an unprecedented level of infectivity and neutralizing antibody in sero-nave subjects after a single dose. Tbhis vaccine response is well balanced among the serotypes and sufficient to provide protection against safety-tested challenge strains of DENV-2 and DENV-3. This indicates a significant advantage of the NIAID vaccine compared to other live attenuated DENV vaccines which require two or three doses to achieve a similar result and which require the prior exposure to DENV to ensure safety and full efficacy. The selection of an optimal tetravalent admixture has enabled the further development of the vaccine by several manufacturers located in Brazil, India, Vietnam, Taiwan and the United States. Through ongoing technological and scientific support, these licensees are making significant progress in the development of the vaccine and a Phase III is underway in Brazil. Through an Interagency Agreement initiated with the Walter Reed Army Institute of Research, a Phase II study has been designed to evaluate the tetravalent vaccine in subjects of decreasing age in Bangkok, Thailand. In addition, an NIAID-sponsored Phase II trial is underway in subjects of decreasing age in Dhaka, Bangladesh. Through our intramural clinical contract with the JHU Center for Immunization Research, several clinical evaluations have recently been successfully completed and are undergoing final analysis: Safety and immunogenicity of TV005 in older adults (age 50 70 years); safety and immunogenicity of a prime-boost vaccination regimen consisting of a TV005 prime vaccination followed by a dengue subunit boost (Merck); and TV005 vaccination followed by challenge with DENV-3. Ongoing studies include TV005 vaccination followed by DENV-2 challenge after one month to investigate the use of the vaccine in travelers to DENV endemic areas. We have also completed enrollment of two clinical studies to investigate the immune response to DENV. In the first study, subjects received a trivalent preparation of vaccine viruses (lacking DENV-2) and were then challenged with DENV-2 to evaluate cross-protection from DENV-1, -3, and -4. In the second study, we sought to model natural sequential infections by administering a DENV-1 vaccine followed 9 months later by challenge with DENV-2. From this study, we are evaluating the repertoire of both cross-reactive and enhancing antibodies. The development of effective vaccination strategies against dengue virus infection and clinically significant disease remains a task of high global public health value and significance, while also being a challenge of considerable complexity. A recent efficacy trial of the most advanced dengue vaccine candidate, demonstrated only partial protection against all four DENV serotypes and enhancement of subsequent dengue disease in young children, despite three subsequent immunizations and detection of neutralizing antibodies to each serotype in most subjects. These results have challenged the hypothesis that seroconversion is the only reliable correlate of protection. We have shown that CD4(+) and CD8(+) T cell responses in vaccinees were readily detectable and comparable to natural dengue virus infection. Detailed knowledge of the T cell response may further contribute to the identification of robust correlates of protection in natural immunity and vaccination against DENV. The development strategy for an effective live attenuated Zika virus vaccine consists of the clinical evaluation of a chimeric ZIKV/DENV vaccine candidates as monovalent presentations prior to their eventual combination with TV003 or TV005 tetravalent DENV vaccines to generate a pentavalent vaccine for both DENV and ZIKV. We have recently begun enrollment of a clinical study to evaluate the safety and immunogenicity of chimeric vaccine candidate rZIKV/D4del30.

Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
Zip Code
Gallichotte, Emily N; Baric, Thomas J; Yount Jr, Boyd L et al. (2018) Human dengue virus serotype 2 neutralizing antibodies target two distinct quaternary epitopes. PLoS Pathog 14:e1006934
Nguyen, Thi Hanh Tien; Clapham, Hannah E; Phung, Khanh Lam et al. (2018) Methods to discriminate primary from secondary dengue during acute symptomatic infection. BMC Infect Dis 18:375
Popper, Stephen J; Strouts, Fiona R; Lindow, Janet C et al. (2018) Early transcriptional responses after dengue vaccination mirror the response to natural infection and predict neutralizing antibody titers. J Infect Dis :
Ricciardi, Michael J; Magnani, Diogo M; Grifoni, Alba et al. (2017) Ontogeny of the B- and T-cell response in a primary Zika virus infection of a dengue-naïve individual during the 2016 outbreak in Miami, FL. PLoS Negl Trop Dis 11:e0006000
Grifoni, Alba; Angelo, Michael; Sidney, John et al. (2017) Patterns of Cellular Immunity Associated with Experimental Infection with rDEN2?30 (Tonga/74) Support Its Suitability as a Human Dengue Virus Challenge Strain. J Virol 91:
Angelo, Michael A; Grifoni, Alba; O'Rourke, Patrick H et al. (2017) Human CD4+ T Cell Responses to an Attenuated Tetravalent Dengue Vaccine Parallel Those Induced by Natural Infection in Magnitude, HLA Restriction, and Antigen Specificity. J Virol 91:
Whitehead, Stephen S; Durbin, Anna P; Pierce, Kristen K et al. (2017) In a randomized trial, the live attenuated tetravalent dengue vaccine TV003 is well-tolerated and highly immunogenic in subjects with flavivirus exposure prior to vaccination. PLoS Negl Trop Dis 11:e0005584
Whitehead, Stephen S; Subbarao, Kanta (2017) Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Enhanced Disease after Vaccination? The Risks of Incomplete Immunity to Dengue Virus Revealed by Vaccination. Cold Spring Harb Perspect Biol :
Durbin, Anna P; Whitehead, Stephen S (2017) Zika Vaccines: Role for Controlled Human Infection. J Infect Dis 216:S971-S975
Pierce, Kristen K; Whitehead, Stephen S; Kirkpatrick, Beth D et al. (2017) A Live Attenuated Chimeric West Nile Virus Vaccine, rWN/DEN4?30, Is Well Tolerated and Immunogenic in Flavivirus-Naive Older Adult Volunteers. J Infect Dis 215:52-55

Showing the most recent 10 out of 24 publications