Review 1: "Oral Immunization with rVSV Bivalent Vaccine Elicits Protective Immune Responses, Including ADCC, Against Both SARS-CoV-2 and Influenza A Viruses"

RR:C19 Evidence Scale rating by reviewer:

• Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

***************************************

Review: 

In this study, Ouyang et al. investigated the immune response induced by oral immunization with an rVSV bivalent vaccine (v-EM2/SPΔC1Delta) in a mouse model. They demonstrated that this vaccine was capable of eliciting robust and protective immune responses. These responses included elevated levels of antibodies that could mediate neutralization and/or antibody-dependent cellular cytotoxicity (ADCC) against both SARS-CoV-2 and influenza M2 in the sera of mice.

The data presented appears to be internally consistent, and the overarching objective of eliciting a strong immune response against both H1N1 and SARS CoV-2 has been successfully accomplished. The references cited align well with the assertions made in the main text, and the methodologies employed are firmly established and well documented.

Moreover, the vaccine's structural design is notably compelling due to its incorporation of various antigenic determinants. Notably, it includes EBOV-GPΔM, a modification involving the removal of the mucin-like domain, which has been shown to significantly enhance the targeting of dendritic cells and macrophages, leading to more potent immune responses.

However, it is important to note that this study did not assess the vaccine's effectiveness against the Delta variant. Furthermore, the study did not investigate mucosal immune responses in terms of the activation of T and B cells, the release of IgA in the lung's lumen, or the neutralizing capacity in these mucosal areas. This leaves us with an incomplete understanding of local mucosal immunity induced by oral or nasal routes.

Additionally, the presence of immune memory cells in the spleen or other lymphoid organs was not examined in this study. The ADCC reporter assay used in this research could only detect ADCC activity induced by IgG, so the data presented in the study pertained solely to IgG-associated ADCC activity and did not include IgA-related ADCC.

Taken together, these limitations prevent us from making a definitive claim that this vaccine is effective in protecting against infection or preventing the spread of the infection among individuals.

Furthermore, the paper lacks any information regarding the safety of this vaccine. While we can make the assumption (due to the absence of data) that the survival rate following vaccination is 100%, it's important to note that the immune system of rodents, such as BALB mice, is generally more permissive compared to that of humans. Therefore, a thorough examination of both mucosal and systemic innate immune responses is necessary before characterizing this vaccine as "promising from a translational perspective."

Overall, this study falls within the realm of oral vaccines against SARS-CoV-2, without providing sufficient data to be considered better or worse than others currently available in the scientific literature.