Clinical Trials of Biodefense Vaccines (Dengue)

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

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 has been completed in Brazil. Phase I/II studies are underway in India and are separately sponsored by Panacea Biotec and Serum Institute of India. Through an Interagency Agreement initiated with the Walter Reed Army Institute of Research, a three-year Phase II study was recently completed and evaluated the tetravalent vaccine in subjects of decreasing age in Bangkok, Thailand. Through our intramural clinical contract with the JHU Center for Immunization Research, numerous clinical evaluations have been successfully completed and have demonstrated that the NIAID vaccine is fully immunogenic after a single dose, elicits a well-balanced immune response across all four serotypes in DENV-nave recipients, is capable of eliciting catch-up responses for missing serotypes in DENV sero-positive recipients, is safe and immunogenic in infants and children, and elicits a strong cross-reactive CD8+ T-cell response. We have recently completed several studies and they are undergoing final analysis and preparation for publication: Safety and immunogenicity of TV005 in older adults (age 50 70 years); TV005 vaccination followed by challenge with DENV-3; TV005 vaccination followed by DENV-2 challenge after one month to investigate the use of the vaccine in travelers to DENV endemic areas; and a study in which 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 collaboration with NIAID DMID and Janssen Pharmaceutica, we are planning to use our DENV-3 controlled human infection model to evaluate the effectiveness of a novel antiviral drug and an IND has been prepared and successfully completed its scientific review at the NIH. The development strategy for an effective live attenuated Zika virus vaccine consists of the clinical evaluation of attenuated 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 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, low infectivity was observed with limited immunogenicity. We currently have repeated the clinical trial using a higher dose in an attempt to increase infectivity. Additional ZIKV vaccine candidates containing microRNA targets to restrict virus replication in placental, reproductive, and neurological tissues have been produced under cGMP conditions and IND applications for their clinical evaluation are pending. After a protracted review period and clinical holds imposed by the FDA, the controlled human infection model for ZIKV has finally been approved for safety evaluation in human subjects and recruitment for this study will begin soon. This model will allow us to evaluate the protective capacity of a variety of ZIKV vaccines and interventions.