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-naive subjects after a single dose. This 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 with a soon to be released interim analysis. Through an Interagency Agreement initiated with the Walter Reed Army Institute of Research, a Phase II study was 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. In collaboration with NIAID DMID and Janssen Pharmaceutica, we are planning to use our DENV controlled human infection model to evaluate the effectiveness of a novel antiviral drug. 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 recently completed our first clinical study to evaluate the safety and immunogenicity of a live-attenuated chimeric vaccine candidate rZIKV/D4del30. Although this candidate appears to be safe for use in humans, it was observed to be over-attenuated with low infectivity and subsequently limited immunogenicity. Additional candidates are currently undergoing preclinical development and evaluation. After a protracted review period, the controlled human infection model for ZIKV is moving forward and the IND has been submitted to the FDA for approval. We look forward to using this model to evaluate the protective capacity of a variety of ZIKV vaccines and interventions.
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