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Authors: Jesse H. Erasmus et al.

Link to paper: https://www.biorxiv.org/content/10.1101/2020.05.28.121640v1

Journal/ Pre-Print: BioRxiv

Tags: Immunology/Immunity, Vaccines

Research Highlights 

1. The authors demonstrate the generation of S-specific neutralising antibodies in NHP and mice after a single dose of a virus-derived replicon RNA (repRNA) vaccine formulated with a Lipid InOrganic Nanoparticle (LION), referred to as LION/repRNA-CoV2S.

2. Dosage for mice (10 µg, 1 µg and 0.1 µg) differ from those of NHP (250 µg once or 50 µg twice). Single dose in NHP results in higher titers than the boost regimen using two doses of 50 µg. These differences might relate to antigen persistence and the higher dose of NHP vaccinated with 250 µg. Overall, the vaccine showed a good safety profile in pigtail macaques.

3. The formulation is apparently stable for a week at RT.

Summary 

This work briefly characterises a vaccine based on of a virus-derived replicon RNA (repRNA) expressing the full spike protein. This vaccine is complexed with a Lipid InOrganic Nanoparticle (LION) with apparently good stability at RT for a week. Using SARS-CoV-2 Wuhan-Hu-1 pseudotype the authors demonstrate that under different immunization regimens the vaccine induces neutralising antibody titers in both mice and NHP. Furthermore, based on the suggestive observation of a predominance of Th1-linked antibodies the authors suggest that the vaccine induced Th1 cellular immunity. However, evaluation of T cell responses required a boost in mice suggesting that the potency of the vaccine is less than expected. The lack of a challenge study limits the usefulness and translational potential of this work.

Impact for SARS-CoV2/COVID19 research efforts

Develop a vaccine for SARS-CoV2/COVID19

Study Type

· In vitro study

· In vivo study (mouse, NHP)

Strengths and limitations of the paper

Novelty: similar to https://www.biorxiv.org/content/10.1101/2020.04.22.055608v1

Similar to the LNP vaccine described by Paul F. McKay et al. The authors also suggest their easier scalability and implementation in the context of the global SARS-CoV-2 pandemic.

Standing in the field:

The use of self-replicating RNA for vaccination in general, but also specifically against SARS-CoV-2 is a promising approach. Used by others (e.g. developed by Moderna and the Vaccine Research Center at the National Institutes of Health, ClinicalTrials.gov: NCT04283461).

Appropriate statistics: No, lack of quantifications, independent experimentation and proper controls (see below).

Viral model used:

1. Virus-derived replicon RNA (repRNA) expressing the full spike protein of SARS-CoV-2 isolate Wuhan-Hu-1 (GenBank: MN908947.3)

2. SARS-CoV-2 Wuhan-Hu-1 pseudotype.

Translatability:

Limited as there was no challenge study to address the efficacy of the vaccine.

Main limitations:

· Figure 1B, lacks control of uninfected cells to appreciate the degree of specific staining.

· Fig 2B, E and F: To properly appreciate the stability of the formulation, at least three independent experiments should be performed, using different lots of the vaccine formulation.

· Fig. 3. And lines 36-39 in page 3: The authors claim that this vaccine prototype, as a virus-derived replicon RNA unlike other nucleic acid based technologies does not require multiple immunisations. However, to evaluate T cell responses this work draw on immunisation boosts at day 12 post-initial administration. Fig 3E and 3F should also show ELISpot data to appreciate the level of unspecific IFN-gamma secretion. Data in E and F are not comparable as the percentage of T cells will be vastly different between spleen and the lungs. This data should be corrected to the number of T cells in the assay. How do the authors explain the different number of mice in E and F?

· Fig. 4: The authors assess the single dose vaccine in older BALB/C mice, however observe significantly lower antibody titres in the older mice compared to younger mice. It would have been useful to see the effect of additional doses on the titres, to determine the usefulness of this vaccine in older mice.

· Fig 5: Lack of an appropriate negative controls in the pigtail macaque studies, and very small sample sizes (n=3, n=2), thus accurate statistical analysis cannot be carried out.

· The use of reciprocal IC50 titers is confusing as they show dilutions instead of concentrations, and actual dilutions instead of their reciprocals (1/X instead of X). There is no actual calculation of IC50 looking at the data. When talking about dilutions the higher the number the better, when talking about IC50 the lesser the number the better, as this indicates a greater potency of the serum to neutralise. As such, the term “reciprocal dilution” is not properly used, leading to potential confusions and poor interpretation of IC50 values.