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. The selection of an optimal tetravalent admixture has enabled the further development of the vaccine by several manufacturers located in Brazil, India, Bangladesh, 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 III studies are underway by Panacea Biotec (India) and Merck (Latin America and Southeast Asia). A Phase III study is under development by Serum Institute of India. Through our intramural clinical contract with the JHU Center for Immunization Research, numerous clinical evaluations have been successfully completed and data from these studies has supported the Phase III trial dossiers. All vaccine lot materials continue to be monitored and stored for distribution in support of new investigative studies and for use by our manufacture licensees. The development strategy for an effective live attenuated Zika virus vaccine has been very challenging due to a primary restriction: compatibility with the live tetravalent DENV vaccine. Our original goal was to develop a ZIKV vaccine candidate that could be co-formulated with the tetravalent DENV vaccine, thus generating 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 was safe for use in humans, low infectivity was observed with limited immunogenicity, even following the use of a high dose. Additional ZIKV vaccine candidates containing microRNA targets to restrict virus replication in placental, reproductive, and neurological tissues were prepared by our collaborator Alexander Pletnev, but these vaccine candidates do not appear to be of greater infectivity in animal models than the failed rZIKV/D4del30 Candidate. We are currently collaborating with Butantan Institute to generate a whole virus inactivated vaccine candidate. Although this preparation cannot be co-formulated with the DENV vaccine, the possibility of co-administration remains a viable option. As an addition to our vaccine development efforts, we have also developed controlled human infection models for DENV (DENV-2 and DENV-3) and ZIKV (SJRP/2016 and Nicaragua/2016). The challenge viruses have been shown to be safe and reproducibly infectious in a number of early clinical trials and are now being used for several investigations: 1) a clinical evaluation of the protection against ZIKV infection conferred by the DENV vaccine is nearing completion at JHU; 2) through a CRADA with Janssen Pharmaceutica, we are using our DENV-3 controlled human infection model to demonstrate the effectiveness of a novel antiviral drug (publication under review); 3) Abviro is using the DENV-3 model to demonstrate the effectiveness of a novel monoclonal antibody against DENV; 4). Mahidol University is using the DENV-2 strain to develop a safe controlled human infection model for DENV in Thailand, a country endemic for DENV; 5) UP Oncolytics, Nemours Children's Health (FL), and NCI are investigating the use of the ZIKV model strains as oncolytic agents for the treatment of specific cancers.