Pre-clinical development of a hydrogen peroxide-inactivated West Nile virus vaccine

Abstract

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-001 WNV. 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-001 WNV is a promising vaccine candidate.

Comparative Pathology of West Nile Virus in Humans and Non-Human Animals

“…The most severe lesions were seen in the hippocampus. In contemporary work, the use of rats is primarily related to toxicology studies which assess for the safety of WNV vaccines [188][189][190].…”

An observer blinded, randomized, placebo-controlled, phase I dose escalation trial to evaluate the safety and immunogenicity of an inactivated West Nile virus Vaccine, HydroVax-001, in healthy adults

“…The HydroVax-001 vaccine is a West Nile virus-Kunjin strain, Vero cell tissue culture-derived, purified whole virion vaccine inactivated with 3% hydrogen peroxide. HydroVax-001 drug product contains 4 mcg purified whole virion WNV formulated in a volume of 0.5 mL/dose with 0.1% aluminum hydroxide and 2% sorbitol in phosphate-buffered saline [27]. Sodium Chloride Injection USP 0.9% as a sterile, nonpyrogenic, isotonic solution was used as the vaccine diluent and the placebo.…”

“…As an alternative to traditional formaldehyde-based vaccines, a novel hydrogen peroxide (H 2 O 2 ) inactivation approach has been developed to produce a first-generation whole-virus vaccine against WNV that was tested at concentrations ranging from 1 to 40 mcg/dose [25–27]. Preliminary studies explored the use of H 2 O 2 -based inactivation of wild-type NY99 WNV for vaccine development, with vaccine antigen able to elicit robust neutralizing antibody responses in amice and protect against lethal challenge [27]. Further studies using WNV-Kunjin virus (WNV-KV), a naturally attenuated Lineage 1 WNV strain, expanded on these preliminary results [26].…”

“…Both young and aged mice immunized with H 2 O 2 -inactivated WNV-KV, formulated with aluminum hydroxide, demonstrated robust antiviral B and T cell immunity and protection in a stringent intracranial challenge model using a heterologous North American WNV strain [26]. A scaled manufacturing approach for production was established and clinical-grade vaccine, termed HydroVax-001 WNV, was produced and found to be stable, safe and immunogenic in three animal species [27]. In light of these promising results, HydroVax-001 WNV, a 3% hydrogen peroxide-inactivated, whole virion (WNV-Kunjin strain) vaccine, was administered as a two-dose intramuscular (IM) vaccine scheduled at a 28-day interval to assess safety and immunogenicity in humans.…”

Vaccines for epidemic infections and the role of CEPI

“…Another relatively easy target is West Nile Virus. 53 This infection started in Africa, spread to North Africa, Europe and eventually the United States, where it migrated from New York City to virtually the entire country through mosquito-borne infection of birds, from which vector mosquitoes could transmit the virus to humans. 54 Although the incidence of West Nile Virus has decreased recently, presumably because the reservoir has diminished due to death of many infected birds and postinfection immunity in others, there were still over 2,000 cases in the US in 2015.…”