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SARS-CoV-2 Delta (B.1.617.2) variant of concern (VOC) and other VOCs are spreading in Europe. Micro-neutralisation assays with sera obtained after Comirnaty (BNT162b2, BioNTech/Pfizer) vaccination in 36 healthcare workers (31 female) demonstrated significant fold change reduction in neutralising titres compared with the original virus: Gamma (P.1) 2.3, Beta (B.1.351) 10.4, Delta 2.1 and 2.6. The reduction of the Alpha (B.1.1.7) variant was not significant. Despite being lower, remaining neutralisation capacity conferred by Comirnaty against Delta and other VOCs is probably protective.

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BACKGROUNDFollowing the emergence of the Omicron variant of concern, we investigated immunogenicity, efficacy and safety of BNT162b2 or mRNA1273 fourth dose in an open-label, clinical intervention trial.METHODSPrimary end-points were safety and immunogenicity and secondary end-points were vaccine efficacy in preventing SARS-CoV-2 infections and COVID-19 symptomatic disease. The two intervention arms were compared to a matched control group. Eligible participants were healthcare-workers (HCW) vaccinated with three BNT162b2 doses, and whose IgG antibody levels were ≤700 BAU (40-percentile). IgG and neutralizing titers, direct neutralization of live VOCs, and T-cell activation were assessed. All participants were actively screened for SARS-CoV-2 infections on a weekly basis.RESULTSOf 1050 eligible HCW, 154 and 120 were enrolled to receive BNT162b2 and mRNA1273, respectively, and compared to 426 age-matched controls. Recipients of both vaccine types had a ∼9-10-fold increase in IgG and neutralizing titers within 2 weeks of vaccination and an 8-fold increase in live Omicron VOC neutralization, restoring titers to those measured after the third vaccine dose. Breakthrough infections were common, mostly very mild, yet, with high viral loads. Vaccine efficacy against infection was 30% (95%CI:-9% to 55%) and 11% (95%CI:-43% to +43%) for BNT162b2 and mRNA1273, respectively. Local and systemic adverse reactions were reported in 80% and 40%, respectively.CONCLUSIONSThe fourth COVID-19 mRNA dose restores antibody titers to peak post-third dose titers. Low efficacy in preventing mild or asymptomatic Omicron infections and the infectious potential of breakthrough cases raise the urgency of next generation vaccine development.Trial registration numberclicaltrials.gov: NCT05231005, NCT05230953

Background Despite high vaccine coverage, an increase in breakthrough COVID-19 infections, prompted administration of a third BNT162b2 dose to people>60 years in Israel since July 2021. Here, we report real-world immunogenicity following third dose. Methods Overall, 208 healthcare workers aged>60 were included. Paired pre- and post-second and/or -third dose IgG and neutralizing-antibody titers were compared. A subpopulation of low-responders to the second dose were also tested for T-cell activation. For 25 paired serum samples we tested neutralization of wild-type vs. neutralization of delta and lambda variants, pre- and post-third dose. Active surveillance of vaccine adverse-events was conducted through surveys. Results A pronounced immune response was observed following the third dose, including a 33-fold and 51-fold increase in IgG and neutralizing ab, respectively. The neutralizing antibody levels post-third-dose were 9.34 times higher than post-second-dose (GMT 2598 95%CI 2085-3237 vs. 207 95%CI 126-339). Nine previously low-responders, had a significant antibody increase post-third-dose, and 7/9 showed increase in T cell activation. Additionally, sera obtained post-third-dose, highly and comparably neutralized the wild-type, delta and lambda variants. Of 1056 responders to the adverse-event survey, none had serious events. Conclusions We demonstrate a rapid and broad immune response to the third BNT162b2 dose in individuals>60 years.

The global spread of SARS-CoV-2 led to major economic and health challenges worldwide. Revealing host genes essential for infection by multiple variants of SARS-CoV-2 can provide insights into the virus pathogenesis, and facilitate the development of novel therapeutics. Here, employing a genome-scale CRISPR screen, we provide a comprehensive data-set of cellular factors that are exploited by wild type SARS-CoV-2 as well as two additional recently emerged variants of concerns (VOCs), Alpha and Beta. We identified several host factors critical for SARS-CoV-2 infection, including various components belonging to the Clathrin-dependent transport pathway, ubiquitination, Heparan sulfate biogenesis and host phosphatidylglycerol biosynthesis. Comparative analysis of the different VOCs revealed the host factors KREMEN2 and SETDB1 as potential unique candidates required only to the Alpha variant. Furthermore, the analysis identified GATA6, a zinc finger transcription factor, as an essential proviral gene for all variants inspected. We show that GATA6 directly regulates ACE2 transcription and accordingly, is critical for SARS-CoV-2 cell entry. Analysis of clinical samples collected from SARS-CoV-2 infected individuals shows elevated levels of GATA6, suggesting a role in COVID-19 pathogenesis. Finally, pharmacological inhibition of GATA6 resulted in down-modulation of ACE2 and inhibition of viral infectivity. Overall, we show GATA6 may represent a target for the development of anti-SARS-CoV-2 therapeutic strategies and reaffirm the value of the CRISPR loss-of-function screens in providing a list of potential new targets for therapeutic interventions.

This work evaluated neutralising antibody titres against wild type (WT) SARS-CoV-2 and four Omicron variants (BA.1, BA.2, BA.4 and BA.5) in healthcare workers who had breakthrough BA.1 infection. Omicron breakthrough infection in individuals vaccinated three or four times before infection resulted in increased neutralising antibodies against the WT virus. The fourth vaccine dose did not further improve the neutralising efficiency over the third dose against all Omicron variants, especially BA.4 and BA.5. An Omicron-specific vaccine may be indicated.