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Review 3: "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 3: "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:

  • 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:

In this paper, Voigt et al have described nano-structured lipid carriers as a potential delivery system for RNA-based vaccines, highlighting the possibility to manufacture thermostable vaccines that could reach developing countries. An proof-of-concept was presented in mice showing comparable potency of the self-amplifying mRNA (saRNA) complexed with NLCs, following storage at elevated temperatures. 

saRNAs are currently being promoted by several groups for their potential to reduce the RNA dose, and improve tolerability, without impacting potency. However, these potential advantages have not yet been shown in the clinic. Hence, to support the potential improvements offered by saRNA, a study with a broad dose range would have been valuable, as described previously saRNA[1]. In addition, evaluation of lower  ‘non saturating’ doses would have allowed for a better evaluation of the retained potency in vivo. We were surprised to not see any in vitro potency data being presented, which is more typical of product development. Obviously in vitro data can be generated much more quickly than an in vivo study, which is key to rapid product release, and in fact, is often much more sensitive to any performance changes in the vaccine. The NLCs have been shown in this paper to provide for complexation, however, any ‘free’ RNA is insufficiently characterized, not clear if the adsorption is complete. 

NLCs are described as easy to manufacture, with simpler access to raw materials and equipment in comparison to the firmly established lipid nanoparticles (LNPs). Nevertheless, the absence of a direct comparison with LNPs and NLCs for saRNA delivery is disappointing. Maybe NLC have potential, but how less potent than the ‘gold standard’ LNP are they, it is not possible to gauge here. Moreover, quaternary amine-based cationic lipids like DOTAP have been generally associated with poor tolerability [2], and the tertiary amines used in LNP are thought to be a step forward intolerability. In addition, formulating with any cationic lipid at an N:P ratio of 15 seems unattractive and would require a thorough investigation of reactogenicity in man. Nevertheless, the lyophilized vaccine potency being comparable to freshly formulated liquid vaccine is encouraging, although more studies with lower dose levels would significantly  benefit the data, along with thorough in vitro evaluations. A thermostable saRNA vaccine stable for at  least 6 months would be attractive, and this paper may provide potential insightsto researchers working  on improving the stability of RNA vaccines. This paper provides a positive outcome of a potential  alternative to LNPs to deliver mRNA, particularly during a pandemic situation, owing to easy access to raw  materials and prior experience in manufacturing; yet comparison with LNPs to evaluate potency in clinic  is pivotal to further development and optimization of this strategy. 

1. Maruggi, G., et al., A self-amplifying mRNA SARS-CoV-2 vaccine candidate induces safe and robust  protective immunity in preclinical models. Molecular Therapy, 2022. 

2. Lonez, C., M. Vandenbranden, and J.-M. Ruysschaert, Cationic lipids activate intracellular  signaling pathways. Advanced Drug Delivery Reviews, 2012. 64(15): p. 1749-1758.


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