Comparative effectiveness of different primary vaccination courses on mRNA-based booster vaccines against SARs-COV-2 infections: a time-varying cohort analysis using trial emulation in the Virus Watch community cohort.

BACKGROUND: The Omicron B.1.1.529 variant increased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in doubly vaccinated individuals, particularly in the Oxford-AstraZeneca COVID-19 vaccine (ChAdOx1) recipients. To tackle infections, the UK's booster vaccination programmes used messenger ribonucleic acid (mRNA) vaccines irrespective of an individual's primary course vaccine type, and prioritized the clinically vulnerable. These mRNA vaccines included the Pfizer-BioNTech COVID-19 vaccine (BNT162b2) the Moderna COVID-19 vaccine (mRNA-1273). There is limited understanding of the effectiveness of different primary vaccination courses on mRNA booster vaccines against SARs-COV-2 infections and how time-varying confounders affect these evaluations. METHODS: Trial emulation was applied to a prospective community observational cohort in England and Wales to reduce time-varying confounding-by-indication driven by prioritizing vaccination based upon age, vulnerability and exposure. Trial emulation was conducted by meta-analysing eight adult cohort results whose booster vaccinations were staggered between 16 September 2021 and 05 January 2022 and followed until 23 January 2022. Time from booster vaccination until SARS-CoV-2 infection, loss of follow-up or end of study was modelled using Cox proportional hazard models and adjusted for age, sex, minority ethnic status, clinically vulnerability and deprivation. RESULTS: A total of 19 159 participants were analysed, with 11 709 ChAdOx1 primary courses and 7450 BNT162b2 primary courses. Median age, clinical vulnerability status and infection rates fluctuate through time. In mRNA-boosted adults, 7.4% (n = 863) of boosted adults with a ChAdOx1 primary course experienced a SARS-CoV-2 infection compared with 7.7% (n = 571) of those who had BNT162b2 as a primary course. The pooled adjusted hazard ratio (aHR) was 1.01 with a 95% confidence interval (CI) of: 0.90 to 1.13. CONCLUSION: After an mRNA booster dose, we found no difference in protection comparing those with a primary course of BNT162b2 with those with a ChAdOx1 primary course. This contrasts with pre-booster findings where previous research shows greater effectiveness of BNT162b2 than ChAdOx1 in preventing infection.

Evasion of neutralizing antibody responses by the SARS-CoV-2 BA.2.75 variant.

The newly emerged BA.2.75 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant contains 9 additional mutations in its spike (S) protein compared to the ancestral BA.2 variant. Here, we examine the neutralizing antibody escape of BA.2.75 in mRNA-vaccinated and BA.1-infected individuals, as well as the molecular basis underlying functional changes in S. Notably, BA.2.75 exhibits enhanced neutralization resistance over BA.2 but less than the BA.4/5 variant. The G446S and N460K mutations of BA.2.75 are primarily responsible for its enhanced resistance to neutralizing antibodies. The R493Q mutation, a reversion to the prototype sequence, reduces BA.2.75 neutralization resistance. The impact of these mutations is consistent with their locations in common neutralizing antibody epitopes. Further, BA.2.75 shows enhanced cell-cell fusion over BA.2, driven largely by the N460K mutation, which enhances S processing. Structural modeling reveals enhanced receptor contacts introduced by N460K, suggesting a mechanism of potentiated receptor utilization and syncytia formation.

The neutralizing response to SARS-CoV-2 Omicron variants BA.1 and BA.2 in COVID-19 patients and homologous and heterologous vaccinees.

The rapid replacement of Omicron BA.1 by BA.2 sublineage is very alarming, raising the question of whether BA.2 can escape the immunity acquired after BA.1 infection. We compared the neutralizing activity toward the Omicron BA.1 and BA.2 sub-lineages in five groups: COVID-19 patients; subjects who had received two doses of mRNA vaccine; subjects naturally infected with SARS-CoV-2 who had received two doses of mRNA; and subjects who had received three doses of homologous or heterologous vaccine. The results obtained highlight the importance of vaccine boosters in eliciting neutralizing antibody responses against Omicron sub-lineages, and suggest that the adenovirus vectored vaccine elicits a lower response against BA.1 than against BA.2 sub-lineage.

Incidence and Risk Factors of COVID-19 Vaccine Breakthrough Infections: A Prospective Cohort Study in Belgium.

The objective of this study was to investigate the incidence and risk factors associated with COVID-19 vaccine breakthrough infections. We included all persons ≥18 years that had been fully vaccinated against COVID-19 for ≥14 days, between 1 February 2021 and 5 December 2021, in Belgium. The incidence of breakthrough infections (laboratory confirmed SARS-CoV-2-infections) was determined. Factors associated with breakthrough infections were analyzed using COX proportional hazard models. Among 8,062,600 fully vaccinated adults, we identified 373,070 breakthrough infections with an incidence of 11.2 (95%CI 11.2-11.3)/100 person years. Vaccination with Ad26.COV2.S (HR1.54, 95%CI 1.52-1.56) or ChAdOx1 (HR1.68, 95%CI 1.66-1.69) was associated with a higher risk of a breakthrough infection compared to BNT162b2, while mRNA-1273 was associated with a lower risk (HR0.68, 95%CI 0.67-0.69). A prior COVID-19-infection was protective against a breakthrough infection (HR0.23, 95%CI 0.23-0.24), as was an mRNA booster (HR0.44, 95%CI 0.43-0.45). During a breakthrough infection, those who had a prior COVID-19 infection were less likely to have COVID-19 symptoms of almost all types than naïve persons. We identified risk factors associated with breakthrough infections, such as vaccination with adenoviral-vector vaccines, which could help inform future decisions on booster vaccination strategies. A prior COVID-19 infection lowered the risk of breakthrough infections and of having symptoms, highlighting the protective effect of hybrid immunity.