| Institution: | 1. Najít Technologies, Inc., Beaverton, OR, USA;2. Division of Neuroscience, Oregon National Primate Research Center, Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Beaverton, OR, USA;1. Department of Biochemistry, Escola Paulista de Medicina, Universidade de Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil;2. Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul (UFRGS), RS, Brazil;3. Faculdade de Veterinária, Universidade Federal do Rio Grande do Sul (UFRGS), RS, Brazil;4. Instituto Nacional de Ciência e Tecnologia em Entomologia Molecular (INCT-em), RJ, Brazil;5. Instituto de Patobiologia Veterinaria, Centro de Investigaciones en Ciencias Veterinarias y Agronómicas (CICVyA), INTA-Castelar, Los Reseros y Nicolas Repetto s/n, Hurlingham 1686, Argentina;6. National Council of Scientific and Technological Research (CONICET), Ciudad Autónoma de Buenos Aires C1033AAj, Argentina;1. Friedrich-Loeffler-Institute, Institute of Molecular Virology and Cell Biology, Department of Experimental Animal Facilities and Biorisk Management, Institute of Immunology, Greifswald-Insel Riems, Germany;2. IDT Biologika Riems, Greifswald-Insel Riems, Germany;1. Department of animal pathology and public health. Hassan II Agronomy & Veterinary Medicine Institute, Rabat, Morocco;2. CIRAD, UMR ASTRE, F-34398 Montpellier, France;3. ASTRE, CIRAD, INRA, Univ Montpellier, Montpellier, France;4. Veterinary Division, FAR Military Health Service, Meknes, Morocco;5. Département de Production, Protection et Biotechnologies Végétales, Unité de Zoologie, Hassan II Agronomy and Veterinary Medicine Institute, Rabat, Morocco;1. Center for Immunization Research, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA;2. Department of Pediatrics, Vanderbilt University, Nashville, Tennessee, USA;3. Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA |
| Abstract: | West Nile virus (WNV) is the most frequent mosquito-borne disease reported in the continental United States and although an effective veterinary vaccine exists for horses, there is still no commercial vaccine approved for human use. We have previously tested a 3% hydrogen peroxide (H2O2)-based WNV inactivation approach termed, HydroVax, in Phase I clinical trials and the vaccine was found to be safe and modestly immunogenic. Here, we describe an advanced, next-generation oxidation approach (HydroVax-II) for the development of inactivated vaccines that utilizes reduced concentrations of H2O2 in combination with copper (cupric ions, Cu2+) complexed with the antiviral compound, methisazone (MZ). Further enhancement of this oxidative approach included the addition of a low percentage of formaldehyde, a cross-linking reagent with a different mechanism of action that, together with H2O2/Cu/MZ, provides a robust two-pronged approach to virus inactivation. Together, this new approach results in rapid virus inactivation while greatly improving the maintenance of WNV-specific neutralizing epitopes mapped across the three structural domains of the WNV envelope protein. In combination with more refined manufacturing techniques, this inactivation technology resulted in vaccine-mediated WNV-specific neutralizing antibody responses that were 130-fold higher than that observed using the first generation, H2O2-only vaccine approach and provided 100% protection against lethal WNV infection. This new approach to vaccine development represents an important area for future investigation with the potential not only for improving vaccines against WNV, but other clinically relevant viruses as well. |
