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Review 1: "Universal Protection against SARS-CoV-2 Viruses by Multivalent mRNA Vaccine in Mice"

The reviewer found the study potentially informative, examining the antibody responses to a multi-valent mRNA vaccine for SARS-CoV-2. While the methods were deemed appropriate and the results interesting, the reviewer highlighted several limitations.

Published onJul 01, 2024
Review 1: "Universal Protection against SARS-CoV-2 Viruses by Multivalent mRNA Vaccine in Mice"
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key-enterThis Pub is a Review of
Universal protection against SARS-CoV-2 viruses by multivalent mRNA vaccine in mice
Universal protection against SARS-CoV-2 viruses by multivalent mRNA vaccine in mice
Description

Abstract The continual emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants challenges available SARS-CoV-2 vaccines for adequate control of outbreaks. Currently, universal vaccines capable of obviating the need for exact strain matching between mRNA vaccines and circulating viruses are absent. In this study, we designed, manufactured, and evaluated a nucleoside-modified lipid nanoparticle mRNA vaccine, aimed for offering broad-spectrum protection against recent SARS-CoV-2 variants. Additionally, the protection efficiency of monovalent, bivalent, quadrivalent, and XBB.1.5 mRNA vaccines was compared with the proposed universal vaccine. The neutralizing antibody activity against wuhan-1, BA.4/5, XBB.1.5, B.1.1.529, BQ.1.1, EG.5.1 and JN.1 was assessed using enzyme-linked immunosorbent assay, rapid fiber-optic biolayer interferometry-based biosensor, and pseudovirus neutralization test. Our results reveal that the proposed multivalent vaccine affords comprehensive protection against previously circulating, current and previously unidentified SARS-CoV-2 strains.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.

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Review: Lei et al. test the antibody responses to a multi-valent mRNA vaccine for SARS-CoV-2 to determine whether a multivalent vaccination strategy can elicit antibodies that recognize divergent strains. They generate lipid nanoparticles using the same strategy as the Moderna vaccine. They use several different methods to evaluate the production of antibodies against SARS-CoV-2 Spike in immunized mice. Their results show that monovalent and quadrivalent vaccine elicit antibodies mostly against cognate strains, but that their multivalent approach results in antibodies that also recognize other strains that are not present in the vaccine. Their conclusion is that exposing the immune system to multiple variants may generate a more polyfunctional response.

The methods seems appropriate and robust and the results are interesting. However, it is unclear how widely generalizable this will be and also whether they are truly looking at a polyvalent response. The authors do not provide information about the differences between the two strains that are not in the vaccine but are sensitive to antibodies from mice vaccinated with their multivalent vaccine (BQ.1.1 and EG.5.1) and the strains that are included. Moreover, the monovalent XBB.1.5 vaccine also elicits antibodies that work against BQ.1.1 and EG.5.1. Therefore, the reason that the multivalent vaccine works could be because of the inclusion of XBB.1.5 in the vaccine, rather than the generation of a polyvalent response. Assays with different combinations of viruses in the vaccine or with more divergent emerging strains will be necessary to resolve this question.

There were also many points where the authors skipped over details or were not clear about details of their set-up, which made the paper something hard to follow and/or evaluate in context, including:

  • unclear if the design of the mRNA construct (UTRs etc.) is the same as that of the current vaccines

  • unclear how they picked the strains to include in the vaccine - also a phylogenetic tree would help see how they are related to each other, and specifying which ones are in current vaccines for the reader would be informative

  • FO-BLI assay was not well explained, and their figures (Fig 1 and Fig 4A) do not seem to make sense without an explanation because there is an antibody depicted only in the condition that says “without Nabs”

  • unclear what assay they used in Fig. 4C

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