Post-vaccination neutralization responses to Omicron sub-variants

BackgroundThe emergence of the Omicron variant (B.1.1.529) which correlated with dramatic losses in cross-neutralization capacity of post-vaccination sera raised concerns about the effectiveness of COVID-19 vaccines against infection and disease. Clinically relevant sub-variants (BA.1, BA.1.1, BA.2, BA.2.12.1, BA.3, and BA.4/5) subsequently emerged rapidly. MethodsWe evaluated published and pre-print studies reporting sub-variant specific reductions in cross-neutralization compared to the prototype strain of SARS-CoV-2 and between sub-variants. Median fold-reduction across studies was calculated by sub-variant and vaccine platform. ResultsAmong 153 studies with post-vaccination data, after primary vaccination the sub-variant specific fold-reduction in neutralization capacity compared to the prototype antigen varied widely, from median 4.2-fold for BA.3 to 21.9-fold for BA.4/5; in boosted participants fold-reduction was similar for all sub-variants (5.9-fold to 7.1-fold) except for BA.4/5 which was 12.7-fold. Relative to BA.1, the other Omicron sub-variants had similar neutralization capacity post-primary vaccination (range median 0.8-fold to 1.1-fold) and post-booster (0.9-fold to 1.2-fold) except for BA.4/5 which was higher (2.0-fold). Omicron sub-variant specific responder rates were low post-primary vaccination (range median 33.5% to 56.7%) compared to the prototype (median 96.0%), but improved post-booster (range median 85.4% to 92.6%). ConclusionFold-reductions in neutralization titers among Omicron sub-variants compared to the prototype strain varied widely post-primary vaccination but were comparable post-booster, except for BA.4/5 which had higher fold-reduction (2-fold relative to BA.1). Considering large fold-decreases in neutralization titers to the parental strain for all Omicron sub-variants, vaccine effectiveness is very likely to be reduced against all Omicron sub-variants, and probably more so against Omicron BA.4/5.

How Important Are Study Designs? A Simulation Assessment of Vaccine Effectiveness Estimation Bias with Time-Varying Vaccine Coverage, and Heterogeneous Testing and Baseline Attack Rates

ObjectiveWe studied how commonly used vaccine effectiveness (VE) study designs (variations of cohorts, and test-negative designs) perform under epidemiological nuances more prominent in the COVID-19 era, specifically time-varying vaccine coverage, and heterogeneous testing behaviour and baseline attack rates with selection on willingness to vaccinate. MethodologyWe simulated data from a multi-parameter conceptual model of the epidemiological environment using 888125 parameter sets. Four configurations of cohorts, and two test-negative designs, were conducted on the simulated data, from which estimation bias is computed. Finally, stratified and fixed effects linear regressions were estimated to quantify the sensitivity of estimation bias to model parameters. FindingsIrrespective of study designs, dynamic vaccine coverage, and heterogeneous testing behaviour and baseline attack rates are important determinants of bias. Study design choices have non-trivial effects on VE estimation bias even if these factors are absent. The importance of these sources of bias differ across study designs. ConclusionA re-benchmarking of methodology, especially for studying COVID-19 VE, and implementation of vaccine-preventable disease surveillance systems that minimise these sources of bias, are warranted. HighlightsO_LIThis paper simulated a theoretical model with frictions in vaccination, testing, baseline disease risks, and heterogeneous vaccine effectiveness to evaluate estimation bias across four cohort and two test-negative designs. C_LIO_LIIn theory, bias depends on behavioural asymmetries (in testing, and baseline risk) between the vax-willing and vax-unwilling, and the speed of vaccination rollout. C_LIO_LIThere is intrinsic estimation bias across all study designs, with the direction and magnitude contingent on specific conditions. C_LIO_LIIn scenarios that may be reflective of past SARS-CoV-2 waves, the degree of bias can be substantial, attributable to variation in assumed testing and baseline risk frictions. C_LIO_LIA regression-based decomposition indicates that study designs have visibly different primary sources of estimation bias, and degree of robustness in general. C_LIO_LIThis study warrants a re-benchmarking of methodology and reporting checklists for VE research, and informs the design of cost-effective surveillance by quantifying part of the bias-implementation cost trade-off. C_LI

Binding and Neutralizing Antibody Responses to SARS-CoV-2 in Infants and Young Children Exceed Those in Adults

SARS-CoV-2 infections are frequently milder in children than adults, suggesting that immune responses may vary with age. However, information is limited regarding SARS-CoV-2 immune responses in young children. We compared Receptor Binding Domain binding antibody (RBDAb) and SARS-CoV-2 neutralizing antibody (neutAb) in children aged 0-4 years, 5-17 years, and in adults aged 18-62 years in a SARS-CoV-2 household study. Among 55 participants seropositive at enrollment, children aged 0-4 years had >10-fold higher RBDAb titers than adults (373 vs.35, P<0.0001), and the highest RBDAb titers in 11/12 households with seropositive children and adults. Children aged 0-4 years had 2-fold higher neutAb than adults, resulting in higher binding to neutralizing (B/N)Ab ratios compared to adults (1.9 vs. 0.4 for ID50, P=0.0002). Findings suggest that young children mount robust antibody responses to SARS-CoV-2 following community infections. Additionally, these results support using neutAb to measure the immunogenicity of COVID-19 vaccines in children aged 0-4 years.

A systematic review of COVID-19 vaccine efficacy and effectiveness against SARS-CoV-2 infection and disease

Billions of doses of COVID-19 vaccines have been administered globally, dramatically reducing SARS-CoV-2 incidence and severity in some settings. Many studies suggest vaccines provide a high degree of protection against infection and disease, but precise estimates vary and studies differ in design, outcomes measured, dosing regime, location, and circulating virus strains. Here we conduct a systematic review of COVID-19 vaccines through February 2022. We included efficacy data from Phase 3 clinical trials for 15 vaccines undergoing WHO Emergency Use Listing evaluation and real-world effectiveness for 8 vaccines with observational studies meeting inclusion criteria. Vaccine metrics collected include protection against asymptomatic infection, any infection, symptomatic COVID-19, and severe outcomes including hospitalization and death, for partial or complete vaccination, and against variants of concern Alpha, Beta, Gamma, Delta, and Omicron. We additionally review the epidemiological principles behind the design and interpretation of vaccine efficacy and effectiveness studies, including important sources of heterogeneity.