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Review 4: "A self-amplifying RNA vaccine against COVID-19 with long-term room-temperature stability"

This preprint provides a proof-of-concept demonstration for a new COVID-19 vaccine that can be stored at room temperature. Reviewers noted that though the evidence generally justifies the main claim, more work is needed to use this as an alternative to existing licensed vaccines.

Published onApr 16, 2022
Review 4: "A self-amplifying RNA vaccine against COVID-19 with long-term room-temperature stability"
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A self-amplifying RNA vaccine against COVID-19 with long-term room-temperature stability
Description

ABSTRACTmRNA vaccines were the first to be authorized for use against SARS-CoV-2 and have since demonstrated high efficacy against serious illness and death. However, limitations in these vaccines have been recognized due to their requirement for cold storage, short durability of protection, and lack of access in low-resource regions. We have developed an easily-manufactured, potent self-amplifying RNA (saRNA) vaccine against SARS-CoV-2 that is stable at room temperature. This saRNA vaccine is formulated with a nanostructured lipid carrier (NLC), providing enhanced stability, improved manufacturability, and protection against degradation. In preclinical studies, this saRNA/NLC vaccine induced strong humoral immunity, as demonstrated by high pseudovirus neutralization titers to the Alpha, Beta, and Delta variants of concern and induction of long-lived bone marrow-resident antibody secreting cells. Robust Th1-biased T-cell responses were also observed after prime or homologous prime-boost in mice. Notably, the saRNA/NLC platform demonstrated thermostability at room temperature for at least 6 months when lyophilized. Taken together, this saRNA delivered by NLC represents a potential improvement in RNA technology that could allow wider access to RNA vaccines for the current COVID-19 and future pandemics.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review:

In this manuscript, Voigt et al. described the development of a self-amplifying RNA (saRNA) vaccine against COVID-19 that can be administered coupled to lipid nanoparticles providing high stability at room temperature. The vaccine was effective at inducing neutralizing antibodies against different SARS-CoV-2 variants including the beta and delta variants. The most interesting finding in this study is the possibility to store the saRNA lipid-formulated vaccine at room temperature for up to six months, without a significant decrease in activity, at least for antibody induction.

The authors demonstrated very clearly that the vaccine was able to induce both humoral and cellular immune responses against SARS-CoV-2. Although other saRNA vaccines for COVID-19 have been already published, this is the first one that can be stored at room temperature. Although this is an important aspect of this vaccine, a comparison with more conventional mRNA vaccines using the same formulation would be desired in the future. The strength of the evidence provided is strong, and the study’s main claims should be considered quite conclusive. However, one point that would make the results more relevant would be to test the neutralizing antibodies elicited with the vaccine stored at room temperature using a SARS-CoV-2 infectivity assay, instead of using an assay based on a pseudotyped lentivirus vector.

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