Heat Shock Protein 70 Enhances Mucosal Immunity against Human Norovirus When Coexpressed from a Vesicular Stomatitis Virus Vector

Abstract

IMPORTANCEHuman norovirus (NoV) is responsible for more than 95% of acute nonbacterial gastroenteritis worldwide. Currently, there is no vaccine for this virus. Development of a live attenuated vaccine for human NoV has not been possible because it is uncultivable. Thus, a live vector-based vaccine may provide an alternative vaccine strategy. In this study, we developed a vesicular stomatitis virus (VSV)-based human NoV vaccine candidate. We constructed rVSV-HSP70-VP1, coexpressing heat shock protein (HSP70) and capsid (VP1) genes of human NoV, and rVSV-Luc-VP1, coexpressing firefly luciferase (Luc) and VP1 genes. We found that VSVs with a double gene insertion were significantly more attenuated than VSV with a single VP1 insertion (rVSV-VP1). Furthermore, we found that coexpression or coadministration of HSP70 from VSV vector significantly enhanced human NoV-specific mucosal immunity. Collectively, we developed an improved live vectored vaccine candidate for human NoV which will be useful for future clinical studies.

Norovirus vaccines: Correlates of protection, challenges and limitations

“…A recent recombinant vesicular stomatitis virus (rVSV) expressing human NoV capsid protein (rVSV-VP1) was administered intranasally and orally to BalB/c mice; this model induced in BalB/c mice NoV-specific mucosal and T cell immune responses. 106 High NoV-specific serum IgG response was detected; this response was described to be stronger than the one induced by VLP-based candidate vaccines. Specifically, fecal and vaginal IgA was detected following inoculation of mice with this vaccine candidate.…”

Norovirus Vaccines and Potential Antinorovirus Drugs: Recent Advances and Future Perspectives

“…An alternative strategy to produce VLPs utilizes viral vectors, such as vesicular stomatitis virus (VSV) [99,100], avian paramyxoviruses (Newcastle disease virus, NDV) [102], adenovirus [111] and Venezuelan equine encephalitis virus (VEEV) [103]. Recombinant viral vectors are appealing as they likely require only a single dose and inoculate the host with higher amounts of VLPs than conventional VLP preparations.…”

“…VLPs expressed from VSV have been examined in mice [99,100]. Insertion of HuNoV VP1 in VSV attenuated viral growth in vitro and in vivo [100].…”

“…VSV-VP1 (combined IN and oral) inoculated mice experienced severe weight loss, suggesting this vaccine vector system requires further attenuation [100]. Coexpression of HSP70 further attenuated VSV in mice, but did not prevent spread of VSV to the CNS [99]. HSP70 likely induced this attenuation by simultaneously stimulating antiviral interferons and suppressing transcription of downstream VSV genes [99].…”

“…Coexpression of HSP70 further attenuated VSV in mice, but did not prevent spread of VSV to the CNS [99]. HSP70 likely induced this attenuation by simultaneously stimulating antiviral interferons and suppressing transcription of downstream VSV genes [99]. Both VSV preparations induced serum, cellular and humoral responses, though VSV-HSP70-VP1 required increased doses for cellular and humoral responses [99,100].…”