The COVID-19 pandemic, caused by SARS-CoV-2, necessitates the rapid development of efficient and cost-effective vaccines for mass immunization. SARS-CoV-2, a single-stranded RNA virus, utilizes its spike (S) protein to bind the host cell receptor ACE2, initiating infection. The S protein is a prime target for neutralizing antibodies. Vesicular stomatitis virus (VSV), a non-segmented negative-sense RNA virus, has been successfully used as a vaccine platform due to its easy propagation, strong immune response elicitation, and low reactogenicity when its glycoprotein (G) is removed. This study aimed to develop a recombinant VSV (rVSV)-based vaccine, rVSV-ΔG-spike, where the VSV-G gene is replaced by the SARS-CoV-2 S gene, to effectively combat COVID-19. The urgency of the situation underscores the need for rapid vaccine development, prompting the exploration of this promising platform.

Several vaccine technologies are being explored to combat SARS-CoV-2, including RNA and DNA vaccines, viral vectored vaccines, recombinant proteins, and live attenuated or inactivated vaccines. The rVSV platform offers several advantages, such as high titer production, strong cellular and humoral immunity induction, and attenuation through G protein removal. Previous studies have demonstrated the efficacy of rVSV-based vaccines for other viral pathogens. The choice of the rVSV platform for SARS-CoV-2 vaccine development aligns with the need for a safe, efficient, and rapidly deployable vaccine, capitalizing on the established advantages of this system.

The rVSV-ΔG-spike vaccine was generated by replacing the VSV-G open reading frame (ORF) with the full-length human codon-optimized SARS-CoV-2 S gene in a VSV full-length expression vector. The virus was recovered in BHK-21 cells using MVA-T7 and accessory plasmids, followed by passaging in Vero E6 cells to remove residual VSV-G. The vaccine was characterized using quantitative real-time RT-PCR, plaque assay, immunofluorescence analysis, and transmission electron microscopy (TEM) to confirm S protein expression and structural integrity. Antigenic similarity to SARS-CoV-2 was assessed using neutralization assays with COVID-19 convalescent sera. The efficacy of the vaccine was evaluated in a golden Syrian hamster model of COVID-19. Hamsters were vaccinated with various doses of rVSV-ΔG-spike and challenged with SARS-CoV-2. Body weight changes, viral loads in lungs and nasal turbinates, and histopathological analysis of lung tissue were used to assess the protective effects of the vaccine. Antibody isotype profiling was performed in mice to determine the Th1/Th2 balance of the immune response.

The rVSV-ΔG-spike vaccine efficiently replicated in cultured cells, with robust S protein expression on the viral surface and infected cells. The vaccine induced neutralizing antibodies that effectively bound and neutralized SARS-CoV-2, as demonstrated by a strong correlation between neutralization of rVSV-ΔG-spike and SARS-CoV-2 by convalescent sera. In the hamster model, a single dose of rVSV-ΔG-spike was safe and elicited a dose-dependent neutralizing antibody response. Vaccination significantly protected hamsters against SARS-CoV-2 challenge, resulting in reduced weight loss, reduced viral loads in lungs and nasal turbinates (up to a 3-log reduction), and attenuated lung pathology. Histopathological analysis revealed significantly less lung damage in vaccinated hamsters compared to unvaccinated controls. Antibody isotype analysis in mice showed a Th1-biased immune response, characterized by high levels of IgG2c and low levels of IgG1.

The findings demonstrate the potential of rVSV-ΔG-spike as a safe and effective vaccine candidate against SARS-CoV-2. The vaccine's ability to induce neutralizing antibodies, reduce viral load, and mitigate lung pathology in the hamster model strongly supports its protective efficacy. The observation of a Th1-biased response further enhances its safety profile, minimizing the risk of vaccine-associated enhanced respiratory disease. The relatively high viral titers achieved in cell culture indicate potential for large-scale production, making this vaccine a strong candidate for further development and clinical evaluation.

This study successfully developed a replication-competent rVSV-ΔG-spike vaccine that showed promising results in preclinical studies. A single dose conferred significant protection in hamsters, with reduced viral load, minimal lung damage, and a Th1-biased immune response. The ease of production and the observed safety profile highlight the potential of this vaccine candidate for clinical trials and further development as a potential tool in combating the COVID-19 pandemic. Future research should focus on clinical trials to assess its safety and efficacy in humans, and to optimize vaccine dosage and delivery strategies.

The study was conducted using a hamster model, which may not fully recapitulate the complexities of human immune responses to SARS-CoV-2. Further studies in non-human primates or human clinical trials are necessary to validate these findings. The observed mutations in the spike protein during vaccine generation warrant further investigation to understand their impact on vaccine efficacy and safety in humans. The isotype analysis was performed in mice, which may not precisely reflect the human response.