Outcomes of laboratory-confirmed SARS-CoV-2 infection in the Omicron-driven fourth wave compared with previous waves in the Western Cape Province, South Africa

Objectives: We aimed to compare COVID-19 outcomes in the Omicron-driven fourth wave with prior waves in the Western Cape, the contribution of undiagnosed prior infection to differences in outcomes in a context of high seroprevalence due to prior infection, and whether protection against severe disease conferred by prior infection and/or vaccination was maintained. Methods: In this cohort study, we included public sector patients aged ≥20 years with a laboratory confirmed COVID-19 diagnosis between 14 November-11 December 2021 (wave four) and equivalent prior wave periods. We compared the risk between waves of the following outcomes using Cox regression: death, severe hospitalization or death and any hospitalization or death (all ≤14 days after diagnosis) adjusted for age, sex, comorbidities, geography, vaccination and prior infection. Results: We included 5,144 patients from wave four and 11,609 from prior waves. Risk of all outcomes was lower in wave four compared to the Delta-driven wave three (adjusted Hazard Ratio (aHR) [95% confidence interval (CI)] for death 0.27 [0.19; 0.38]. Risk reduction was lower when adjusting for vaccination and prior diagnosed infection (aHR:0.41, 95% CI: 0.29; 0.59) and reduced further when accounting for unascertained prior infections (aHR: 0.72). Vaccine protection was maintained in wave four (aHR for outcome of death: 0.24; 95% CI: 0.10; 0.58). Conclusions: In the Omicron-driven wave, severe COVID-19 outcomes were reduced mostly due to protection conferred by prior infection and/or vaccination, but intrinsically reduced virulence may account for an approximately 25% reduced risk of severe hospitalization or death compared to Delta.

Vaccine Protection of Mice With Primary Immunodeficiencies Against Disseminated Coccidioidomycosis

Disseminated coccidioidomycosis (DCM), often a severe and refractory disease leading to poor outcomes, is a risk for people with certain primary immunodeficiencies (PID). Several DCM-associated PID (STAT4, STAT3, IFNγ, and Dectin-1) are modeled in mice. To determine if vaccination could provide these mice protection, mice with mutations in Stat4, Stat3, Ifngr1, Clec7a (Dectin-1), and Rag-1 (T- and B-cell deficient) knockout (KO) mice were vaccinated with the live, avirulent, Δcps1 vaccine strain and subsequently challenged intranasally with pathogenic Coccidioides posadasii Silveira strain. Two weeks post-infection, vaccinated mice of all strains except Rag-1 KO had significantly reduced lung and spleen fungal burdens (p<0.05) compared to unvaccinated control mice. Splenic dissemination was prevented in most vaccinated immunodeficient mice while all unvaccinated B6 mice and the Rag-1 KO mice displayed disseminated disease. The mitigation of DCM by Δcps1 vaccination in these mice suggests that it could also benefit humans with immunogenetic risks of severe disease.

Structural basis of Omicron neutralization by affinity-matured public antibodies

The SARS-CoV-2 Omicron Variant of Concern (B.1.1.529) has spread rapidly in many countries. With a spike that is highly diverged from that of the pandemic founder, it escapes most available monoclonal antibody therapeutics and erodes vaccine protection. A public class of IGHV3-53-using SARS-CoV-2 neutralizing antibodies typically fails to neutralize variants carrying mutations in the receptor-binding motif, including Omicron. As antibodies from this class are likely elicited in most people following SARS-CoV-2 infection or vaccination, their subsequent affinity maturation is of particular interest. Here, we isolated IGHV3-53-using antibodies from an individual seven months after infection and identified several antibodies capable of broad and potent SARS-CoV-2 neutralization, extending to Omicron without loss of potency. By introducing select somatic hypermutations into a germline-reverted form of one such antibody, CAB-A17, we demonstrate the potential for commonly elicited antibodies to develop broad cross-neutralization through affinity maturation. Further, we resolved the structure of CAB-A17 Fab in complex with Omicron spike at an overall resolution of 2.6 angstroms by cryo-electron microscopy and defined the structural basis for this breadth. Thus, public SARS-CoV-2 neutralizing antibodies can, without modified spike vaccines, mature to cross-neutralize exceptionally antigenically diverged SARS-CoV-2 variants.

COVID-19 vaccine effectiveness among immunocompromised populations: a targeted literature review of real-world studies

IntroductionFrom July through October of 2021, several countries issued recommendations for increased COVID-19 vaccine protection for individuals with one or more immunocompromised (IC) conditions. It is critically important to understand the vaccine effectiveness (VE) of COVID-19 vaccines among IC populations as recommendations are updated over time in response to the evolving COVID-19 pandemic.Areas coveredA targeted literature review was conducted to identify real-world studies that assessed COVID-19 VE in IC populations between December 2020 and September 2021. A total of 10 studies from four countries were identified and summarized in this review.Expert opinion/commentaryVE of the widely available COVID-19 vaccines, including BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), Ad26.COV2.S (Janssen), and ChAdOx1 nCoV-19 (Oxford/AstraZeneca), ranged from 64%-90% against SARS-CoV-2 infection, 73%-84% against symptomatic illness, 70%-100% against severe illness, and 63%-100% against COVID-19-related hospitalization among the fully vaccinated IC populations included in the studies. COVID-19 VE for most outcomes in the IC populations included in these studies was lower than in the general populations. These findings provide preliminary evidence that the IC population requires greater protective measures to prevent COVID-19 infection and associated illness, hence should be prioritized while implementing recommendations of additional COVID-19 vaccine doses.

Increased resistance of SARS-CoV-2 Omicron Variant to Neutralization by Vaccine-Elicited and Therapeutic Antibodies

Currently authorized vaccines for SARS-CoV-2 have been highly successful in preventing infection and lessening disease severity. The vaccines maintain effectiveness against SARS-CoV-2 Variants of Concern but the heavily mutated, highly transmissible Omicron variant poses an obstacle both to vaccine protection and monoclonal antibody therapies. Analysis of the neutralization of Omicron spike protein-pseudotyped lentiviruses showed a 26-fold relative resistance (compared to D614G) to neutralization by convalescent sera and 26-34-fold resistance to Pfizer BNT162b2 and Moderna vaccine-elicited antibodies following two immunizations. A booster immunization increased neutralizing titers against Omicron by 6-8-fold. Previous SARS-CoV-2 infection followed by vaccination resulted in the highest neutralizing titers against Omicron. Regeneron REGN10933 and REGN10987, and Lilly LY-CoV555 and LY-CoV016 monoclonal antibodies were ineffective against Omicron, while Sotrovimab was partially effective. The results highlight the benefit of a booster immunization in providing protection against Omicron but demonstrate the challenge to monoclonal antibody therapies.

Reliably Assessing Duration of Protection for COVID-19 Vaccines

Decision-making about booster dosing for COVID-19 vaccine recipients hinges on reliable methods for evaluating the longevity of vaccine protection. We show that modeling of protection as a piecewise linear function of time since vaccination for the log hazard ratio of the vaccine effect provides more reliable estimates of vaccine effectiveness at the end of an observation period and also more reliably detects plateaus in protective effectiveness as compared with the traditional method of estimating a constant vaccine effect over each time period. This approach will be useful for analyzing data pertaining to COVID-19 vaccines and other vaccines where rapid and reliable understanding of vaccine effectiveness over time is desired.

Estimates of reduced vaccine effectiveness against hospitalization, infection, transmission and symptomatic disease of a new SARS-CoV-2 variant, Omicron (B.1.1.529), using neutralizing antibody titers

The emergence of the Omicron variant (B.1.1.529) of SARS-CoV-2 has raised concerns about how mutations in the spike protein might influence immune escape and vaccine protection against infection and disease, COVID-19. Initial estimates of immune escape measure neutralizing antibody titers, which have been shown to be a correlate of protection for COVID-19, but vary among studies. However, no studies have examined variation in vaccine effectiveness (VE) using estimated reductions in neutralizing antibody titers across virus variants. We quantified consistency in relative neutralizing antibody titers across studies. We then examined relationships between variant-specific reductions in neutralizing antibodies and protection against documented infection, symptomatic disease, and hospitalizations across variants and vaccines. We found considerable variation in variant-specific neutralizing antibody titers between studies, but within-study comparisons across variants were far more robust. There was insufficient data to estimate VE for a single vaccine across variants, especially for higher levels of immune evasion (>7-fold reductions in neutralizing antibody titers) observed with the Omicron variant (40-fold). Instead, we leveraged variation among both vaccines and virus variants to estimate VE - neutralizing antibody titer relationships across a 30 to 100-fold range of neutralizing antibody titers reduction. Omicron increased the risk of hospitalization four to five-fold and increased the risk of symptomatic disease seven to ten-fold for mRNA vaccinees, with similar relative effects for recently vaccinated, or individuals with waned antibody titers. Third doses restored titers and protection to levels similar to waned immunity against Delta. Overall, these analyses indicate that vaccine effectiveness against severe disease is significantly diminished for waned individuals, and protection against infection, symptomatic disease and transmission is nearly eliminated. However, third doses significantly ameliorate these reductions but only restore protection to levels equivalent to waned protection against the Delta variant. The invasion of Omicron is likely to result in widespread infection, and substantial hospitalizations unless widespread boosting of immunity occurs.

Clinical and genomic signatures of rising SARS-CoV-2 Delta breakthrough infections in New York

In 2021, Delta has become the predominant SARS-CoV-2 variant worldwide. While vaccines effectively prevent COVID-19 hospitalization and death, vaccine breakthrough infections increasingly occur. The precise role of clinical and genomic determinants in Delta infections is not known, and whether they contribute to increased rates of breakthrough infections compared to unvaccinated controls. Here, we show a steep and near complete replacement of circulating variants with Delta between May and August 2021 in metropolitan New York. We observed an increase of the Delta sublineage AY.25, its spike mutation S112L, and nsp12 mutation F192V in breakthroughs. Delta infections were associated with younger age and lower hospitalization rates than Alpha. Delta breakthroughs increased significantly with time since vaccination, and, after adjusting for confounders, they rose at similar rates as in unvaccinated individuals. Our data indicate a limited impact of vaccine escape in favor of Delta’s increased epidemic growth in times of waning vaccine protection.