Vesicular Stomatitis Virus-Based Vaccines Provide Cross-Protection against Andes and Sin Nombre Viruses

Abstract

Andes virus (ANDV) and Sin Nombre virus (SNV) are the main causative agents responsible for hantavirus cardiopulmonary syndrome (HCPS) in the Americas. HCPS is a severe respiratory disease with a high fatality rate for which there are no approved therapeutics or vaccines available. Some vaccine approaches for HCPS have been tested in preclinical models, but none have been tested in infectious models in regard to their ability to protect against multiple species of HCPS-causing viruses. Here, we utilize recombinant vesicular stomatitis virus-based (VSV) vaccines for Andes virus (ANDV) and Sin Nombre virus (SNV) and assess their ability to provide cross-protection in infectious challenge models. We show that, while both rVSVΔG/ANDVGPC and rVSVΔG/SNVGPC display attenuated growth as compared to wild type VSV, each vaccine is able to induce a cross-reactive antibody response. Both vaccines protected against both homologous and heterologous challenge with ANDV and SNV and prevented HCPS in a lethal ANDV challenge model. This study provides evidence that the development of a single vaccine against HCPS-causing hantaviruses could provide protection against multiple agents.

Keywords: Andes virus; Hantavirus; Sin Nombre virus; hantavirus cardiopulmonary syndrome; prophylactic immunization; vaccination; vaccine.

Figure 1

Growth kinetics of different recombinant vesicular stomatitis viruses (VSVs). Each virus was used to infect VeroE6 cells at MOI 10⁻⁴ for 96 h. The TCID50/mL of each virus is indicated for each time point. Data shown are mean + SD.

Figure 2

Humoral immune responses of vaccinated hamsters. Hamsters were vaccinated with either rVSVΔG/LASVGPC (n = 12), rVSVΔG/ANDVGPC (n = 15), or rVSVΔG/SNVGPC (n = 15) and IgG titers against either (A) ANDV or (B) SNV were assessed. NT80 against either (C) ANDV or (D) SNV was determined via microneutralization assay using recombinant VSV expressing either ANDV or SNV glycoprotein and GFP. Data medians are shown. Statistical significance was determined by one way ANOVA. *, p = <0.05; ***, p = <0.0001. Empty diamond represents a hamster that succumbed to ANDV infection. Black diamonds are rVSVΔG/LASVGPC vaccinated, red diamonds are or rVSVΔG/SNVGPC vaccinated, and blue diamonds are rVSVΔG/ANDVGPC vaccinated.

Figure 3

Blocking of ANDV GPC:PCDH1 interaction by hamster sera. (A) Neutralization activity of sera from vaccinated hamsters was assessed using primary human endothelial cells infected with rVSVΔG/ANDVGPC. Average ± SD (n = 6) from 3 independent experiments. (B) Ability of vaccinated hamster sera to block binding of ANDV GPC to soluble PCDH1 was assessed by competition ELISA. Mean ± SD (n = 9) from 3 independent experiments.

Figure 4

Protective efficacy of rVSVΔG/ANDVGPC and rVSVΔG/SNVGPC against ANDV challenge (A) Survival of hamsters vaccinated with either rVSVΔG/ANDVGPC (n = 6), rVSVΔG/SNVGPC (n = 6), or control vaccine rVSVΔG/LASVGPC (n = 6) following challenge with ANDV. (B) Presence, following ANDV challenge, of ANDV RNA in the serum and tissues in groups of vaccinated hamsters at 8 days post-infection (dpi) (n = 3). Data means + SEM are shown. Statistical significance was determined via log-rank test (A). **, p = <0.01.

Figure 5

Protective efficacy of rVSVΔG/ANDVGPC and rVSVΔG/SNVGPC against HA-SNV challenge. Presence of SNV RNA in the serum and tissues of vaccinated hamsters at (A) 4 dpi and (B) 7 dpi (n = 3/group) following HA-SNV challenge. Data means + SEM are shown.

Figure 6

Histopathology of organs in vaccinated hamsters. Hematoxylin and eosin staining was performed on the lungs, livers, and spleens of hamsters on day 7 post-ANDV infection, following vaccination with either VSVΔG/LASVGPC, VSVΔG/ANDVGPC, or VSVΔG/SNVGPC. Scale bar = 200 µm.