Safety and immunogenicity of a variant-adapted SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant as a booster in adults primed with authorized vaccines

BackgroundBooster vaccines providing protection against emergent SARS-CoV-2 variants are needed. In an international phase 3 study, we evaluated booster vaccines containing prototype (D614) and/or Beta (B.1.351) variant recombinant spike proteins and AS03 adjuvant (CoV2 preS dTM-AS03). MethodsAdults, primed 4-10 months earlier with mRNA (BNT162b2, mRNA-1273]), adenovirus-vectored (Ad26.CoV2.S, ChAdOx1nCoV-19) or adjuvanted protein (CoV2 preS dTM-AS03 [D614]) vaccines and stratified by age (18-55 and [≥]56 years), were boosted with monovalent (MV) D614 (5g, n=1285), MV (B.1351) (5g, n=707) or bivalent (BiV) (2.5g D614 plus 2.5g B.1.351, n=625) CoV2 preS dTM-AS03. SARS-CoV-2-naive adults (controls, n=479) received a primary series (two injections, 21 days apart) of CoV2 preS dTM-AS03 containing 10g D614. Antibodies to D614G, B.1.351 and Omicron BA.2 and BA.1 variants were evaluated using validated pseudovirus (lentivirus) neutralization (PsVN) assay. D614G or B.1.351 PsVN titers 14 days (D15) post-booster were compared with pre-booster (D1) titers in BNT162b2-primed participants (18-55 years old) and controls (D36), for each booster formulation (co-primary objectives). Safety was evaluated throughout the trial. Results of a planned interim analysis are presented. ResultsAmong BNT162b2-primed adults (18-55 years old), PsVN titers against D614G or B.1.351 were significantly higher post-booster than anti-D614G titers post-primary vaccination in controls, for all booster formulations, with an anti-D614G GMT ratio (98.3% CI) of 2.16 (1.69; 2.75) for MV(D614), an anti-B.1.351 ratio of 1.96 (1.54; 2.50) for MV (B.1.351) and anti-D614G and anti-B.1.351 ratios of 2.34 (1.84; 2.96) and 1.39 (1.09; 1.77), respectively, for BiV. All booster formulations elicited cross-neutralizing antibodies against Omicron BA.2 across vaccine priming subgroups and against Omicron BA.1 (evaluated in BNT162b2-primed participants). Similar patterns in antibody responses were observed for participants aged [≥]56 years. No safety concerns were identified. ConclusionCoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine. ClinicalTrials.govNCT04762680 FundingSanofi and federal funds from the Biomedical Advanced Research and Development Authority (BARDA), part of the office of the Administration for Strategic Preparedness and Response at the U.S. Department of Health and Human Services under Contract # HHSO100201600005I, and in collaboration with the U.S. Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense under Contract # W15QKN-16-9-1002.

Ultrastructural insight into SARS-CoV-2 attachment, entry and budding in human airway epithelium

Ultrastructural studies of SARS-CoV-2 infected cells are crucial to better understand the mechanisms of viral entry and budding within host cells. Many studies are limited by the lack of access to appropriate cellular models. As the airway epithelium is the primary site of infection it is essential to study SARS-CoV-2 infection of these cells. Here, we examined human airway epithelium, grown as highly differentiated air-liquid interface cultures and infected with three different isolates of SARS-CoV-2 including the B.1.1.7 variant (Variant of Concern 202012/01) by transmission electron microscopy and tomography. For all isolates, the virus infected ciliated but not goblet epithelial cells. Two key SARS-CoV-2 entry molecules, ACE2 and TMPRSS2, were found to be localised to the plasma membrane including microvilli but excluded from cilia. Consistent with these observations, extracellular virions were frequently seen associated with microvilli and the apical plasma membrane but rarely with ciliary membranes. Profiles indicative of viral fusion at the apical plasma membrane demonstrate that the plasma membrane is one site of entry where direct fusion releasing the nucleoprotein-encapsidated genome occurs. Intact intracellular virions were found within ciliated cells in compartments with a single membrane bearing S glycoprotein. Profiles strongly suggesting viral budding from the membrane was observed in these compartments and this may explain how virions gain their S glycoprotein containing envelope.

First-in-Human Trial of a SARS CoV 2 Recombinant Spike Protein Nanoparticle Vaccine

BackgroundNVX-CoV2373 is a recombinant nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins. We present the Day 35 primary analysis of our trial of NVX-CoV2373 with or without the saponin-based Matrix-M1 adjuvant in healthy adults. MethodsThis is a randomized, observer-blinded, placebo-controlled, phase 1 trial in 131 healthy adults. Trial vaccination comprised two intramuscular injections, 21 days apart. Primary outcomes were reactogenicity, safety labs, and immunoglobulin G (IgG) anti-spike protein response. Secondary outcomes included adverse events, wild-type virus neutralizing antibody, and T-cell responses. ResultsParticipants received NVX-CoV2373 with or without Matrix-M1 (n=106) or placebo (n=25). There were no serious adverse events. Reactogenicity was mainly mild in severity and of short duration (mean [≤]2 days), with second vaccinations inducing greater local and systemic reactogenicity. The adjuvant significantly enhanced immune responses and was antigen dose-sparing, and the two-dose 5g NVX-CoV2373/Matrix-M1 vaccine induced mean anti-spike IgG and neutralizing antibody responses that exceeded the mean responses in convalescent sera from COVID-19 patients with clinically significant illnesses. The vaccine also induced antigen-specific T cells with a largely T helper 1 (Th1) phenotype. ConclusionsNVX-CoV2373/Matrix-M1 was well tolerated and elicited robust immune responses (IgG and neutralization) four-fold higher than the mean observed in COVID-19 convalescent serum from participants with clinical symptoms requiring medical care and induced CD4+ T-cell responses biased toward a Th1 phenotype. These findings suggest that the vaccine may confer protection and support transition to efficacy evaluations to test this hypothesis. (Funded by the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number, NCT04368988).

Early Stage Prediction of US County Vulnerability to the COVID-19 Pandemic

ImportanceThe rapid spread of COVID-19 means that government and health services providers have little time to plan and design effective response policies. It is therefore important to rapidly provide accurate predictions of how vulnerable geographic regions such as counties are to the spread. ObjectiveDeveloping county level prediction around near future disease movement for COVID-19 occurrences using publicly available data. DesignOriginal Investigation; Decision Analytical Model Study for County Level COVID-19 occurrences using data from March 14-31, 2020. SettingDisease spread prediction for US counties. ParticipantsAll US county level granularity based on data fused from multiple publicly available sources inclusive of health statistics, demographics, and geographical features. Exposure(s) (for observational studies)Daily county level reported COVID-19 occurrences from March 14-31, 2020. Main Outcome(s) and Measure(s)We developed a 3-stage model to quantify, firstly the probability of COVID-19 occurrence for unaffected counties using XGBoost classifier and secondly, the number of potential occurrences of a county via XGBoost regression. Thirdly, these results are combined to compute the county level risk. This risk is then used as an estimated after-five-day-vulnerability of the county. ResultsUsing data from March 14-31, 2020, the model shows a sensitivity over 71.5% and specificity over 94%. Conclusions and RelevanceWe found that population, population density, percentage of people aged 70 or greater and prevalence of comorbidities play an important role in predicting COVID-19 occurrences. We found a positive association between affected and urban counties as well as less vulnerable and rural counties. The developed model can be used for identification of vulnerable counties and potential data discrepancies. Limited testing facilities and delayed results introduces significant variation in reported cases and produces a bias in the model. Trial RegistrationNot Applicable Key PointsO_ST_ABSQuestionC_ST_ABSWhat are key factors that define the vulnerability of counties in the US to cases of the COVID-19 virus? FindingsIn this epidemiological study based on publicly available data, we develop a model that predicts vulnerability to COVID-19 for each US county in terms of likelihood of going from no documented cases to at least one case within five days and in terms of number of occurrences of the virus. MeaningPredicting county vulnerability to COVID-19 can assist health organizations to better plan for resource and workforce needs.