Highly Thermotolerant SARS-CoV-2 Vaccine Elicits Neutralising Antibodies Against Delta and Omicron in Mice

As existing vaccines fail to completely prevent COVID-19 infections or community transmission, there is an unmet need for vaccines that can better combat SARS-CoV-2 variants of concern (VOC). We have previously developed highly thermo-tolerant monomeric and trimeric receptor binding domain derivatives that can withstand 100{degrees}C for 90 minutes and 37{degrees}C for four weeks, and help eliminate cold chain requirements. We show that mice immunised with these vaccine formulations elicit high titres of antibodies that neutralise SARS-CoV-2 variants VIC31 (with Spike: D614G mutation), Delta and Omicron (BA.1.1) VOC. Compared to VIC31, there was an average 14.4-fold reduction in neutralisation against BA.1.1 for the three monomeric antigen-adjuvant combinations, and 16.5-fold reduction for the three trimeric antigen-adjuvant combinations; the corresponding values against Delta were 2.5 and 3.0. Our findings suggest that monomeric formulations are suitable for the upcoming Phase I human clinical trials, and that there is potential for increasing efficacy with vaccine matching to improve responses against emerging variants. These findings are consistent with in silico modelling and AlphaFold predictions which show that while oligomeric presentation can be generally beneficial, it can make important epitopes inaccessible, and also carries the risk of eliciting unwanted antibodies against the oligomerisation domain.

At least three doses of leading vaccines essential for neutralization of SARS-CoV-2 Omicron variant

Plasma samples taken at different time points from donors who received either AstraZeneca (Vaxzevria) or Pfizer (Comirnaty) or Moderna (Spikevax) coronavirus disease-19 (COVID-19) vaccine were assessed in virus neutralization assays against Delta and Omicron variants of concern and a reference isolate (VIC31). With the Pfizer vaccine there was 6-8-fold reduction in 50% neutralizing antibody titres (NT50) against Delta and VIC31 at 6 months compared to 2 weeks after the second dose; followed by 25-fold increase at 2 weeks after the third dose. Neutralisation of Omicron was only consistently observed 2 weeks after the third dose, with most samples having titres below the limit of detection at earlier timepoints. Moderna results were similar to Pfizer at 2 weeks after the second dose, while the titres for AstraZeneca samples derived from older donors were 7-fold lower against VIC31 and below the limit of detection against Delta and Omicron. Age and gender were not found to significantly impact our results. These findings indicate that vaccine matching may be needed, and that at least a third dose of these vaccines is necessary to generate sufficient neutralising antibodies against emerging variants of concern, especially Omicron, amidst the challenges of ensuring vaccine equity worldwide.

Cooccurrence of N501Y, P681R and other key mutations in SARS-CoV-2 Spike

Analysis of circa 4.2 million severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome sequences on Global Initiative on Sharing All Influenza Data (GISAID) shows the spike mutations N501Y (common to Alpha, Beta, Gamma, Omicron variants) and P681R (central to Delta variants spread) have cooccurred 3,678 times between 17 October 2020 and 1 November 2021. In contrast, the N501Y+P681H combination is present in Alpha and Omicron variants and circa 1.1 million entries. Two-thirds of the 3,678 cooccurrences were in France, Turkey or US (East Coast), and the rest across 62 other countries. 55.5% and 4.6% of the cooccurrences were Alphas Q.4 and Gammas P.1.8 sub-lineages acquiring P681R; 10.7% and 3.8% were Deltas B.1.617.2 lineage and AY.33 sub-lineage acquiring N501Y; remaining 10.2% were in other variants. Despite the selective advantages individually conferred by N501Y and P681R, the N501Y+P681R combination counterintuitively didnt outcompete other variants in every instance. Although a relief to worldwide public health efforts, in vitro and in vivo studies are urgently required in the absence of a strong in silico explanation for this phenomenon. This study demonstrates a pipeline to analyse combinations of key mutations from public domain information in a systematic manner and provide early warnings of spread.