RESUMO
West Nile virus (WNV) is a mosquito-transmitted pathogen with a wide geographical range that can lead to long-term disability and death in some cases. Despite the public health risk posed by WNV, including an estimated 3 million infections in the United States alone, no vaccine is available for use in humans. Here, we present a scaled manufacturing approach for production of a hydrogen peroxide-inactivated whole virion WNV vaccine, termed HydroVax-001WNV. Vaccination resulted in robust virus-specific neutralizing antibody responses and protection against WNV-associated mortality in mice or viremia in rhesus macaques (RM). A GLP-compliant toxicology study performed in rats demonstrated an excellent safety profile with clinical findings limited to minor and transient irritation at the injection site. An in vitro relative potency (IVRP) assay was developed and shown to correlate with in vivo responses following forced degradation studies. Long-term in vivo potency comparisons between the intended storage condition (2-8°C) and a thermally stressed condition (40±2°C) demonstrated no loss in vaccine efficacy or protective immunity over a 6-month span of time. Together, the positive pre-clinical findings regarding immunogenicity, safety, and stability indicate that HydroVax-001WNV is a promising vaccine candidate.
Assuntos
Febre do Nilo Ocidental/prevenção & controle , Vacinas contra o Vírus do Nilo Ocidental/imunologia , Animais , Anti-Infecciosos Locais/metabolismo , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Temperatura Alta , Peróxido de Hidrogênio/metabolismo , Macaca mulatta , Masculino , Camundongos Endogâmicos BALB C , Ratos Sprague-Dawley , Análise de Sobrevida , Estados Unidos , Potência de Vacina , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/efeitos adversos , Vacinas de Produtos Inativados/imunologia , Vacinas de Produtos Inativados/isolamento & purificação , Viremia/prevenção & controle , Vacinas contra o Vírus do Nilo Ocidental/administração & dosagem , Vacinas contra o Vírus do Nilo Ocidental/efeitos adversos , Vacinas contra o Vírus do Nilo Ocidental/isolamento & purificaçãoRESUMO
West Nile virus (WNV), an emerging mosquito-borne and zoonotic flavivirus, continues to spread worldwide and represents a major problem for human and veterinary medicine. In recent years, severe outbreaks were observed in the USA and Europe with neighboring countries, and the virus is considered to be endemic in an increasing number of areas. Although most infections remain asymptomatic, WNV can cause severe, even fatal, neurological disease, which affects mostly the elderly and immunocompromised individuals. Several vaccines have been licensed in the veterinary sector, but no human vaccine is available today. This review summarizes recent strategies that are being followed to develop WNV vaccines with emphasis on technologies suitable for the use in humans.
Assuntos
Febre do Nilo Ocidental/prevenção & controle , Vacinas contra o Vírus do Nilo Ocidental/imunologia , Vacinas contra o Vírus do Nilo Ocidental/isolamento & purificação , Vírus do Nilo Ocidental/imunologia , Animais , Europa (Continente)/epidemiologia , Humanos , Estados Unidos/epidemiologia , Febre do Nilo Ocidental/veterináriaRESUMO
West Nile encephalitis emerged in 1999 in the United States, then rapidly spread through the North American continent causing severe disease in human and horses. Since then, outbreaks appeared in Europe, and in 2012, the United States experienced a new severe outbreak reporting a total of 5,387 cases of West Nile virus (WNV) disease in humans, including 243 deaths. So far, no human vaccine is available to control new WNV outbreaks and to avoid worldwide spreading. In this review, we discuss the state-of-the-art of West Nile vaccine development and the potential of a novel safe and effective approach based on recombinant live attenuated measles virus (MV) vaccine. MV vaccine is a live attenuated negative-stranded RNA virus proven as one of the safest, most stable and effective human vaccines. We previously described a vector derived from the Schwarz MV vaccine strain that stably expresses antigens from emerging arboviruses, such as dengue, West Nile or chikungunya viruses, and is strongly immunogenic in animal models, even in the presence of MV pre-existing immunity. A single administration of a recombinant MV vaccine expressing the secreted form of WNV envelope glycoprotein elicited protective immunity in mice and non-human primates as early as two weeks after immunization, indicating its potential as a human vaccine.