Antibody levels predict vaccine efficacy Symptomatic COVID-19 infection can be prevented by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. A “correlate of protection” is a molecular biomarker to measure how much immunity is needed to fight infection and is key for successful global immunization programs. Gilbert et al . determined that antibodies are the correlate of protection in vaccinated individuals enrolled in the Moderna COVE phase 3 clinical trial (see the Perspective by Openshaw). By measuring binding and neutralizing antibodies against the viral spike protein, the authors found that the levels of both antibodies correlated with the degree of vaccine efficacy. The higher the antibody level, the greater the protection afforded by the messenger RNA (mRNA) vaccine. Antibody levels that predict mRNA vaccine efficacy can therefore be used to guide vaccine regimen modifications and support regulatory approvals for a broader spectrum of the population. —PNK

The TZM-bl assay measures antibody-mediated neutralization of HIV-1 as a function of reductions in HIV-1 Tat-regulated firefly luciferase (Luc) reporter gene expression after a single round of infection with Env-pseudotyped viruses. This assay has become the main endpoint neutralization assay used for the assessment of preclinical and clinical trial samples by a growing number of laboratories worldwide. Here we present the results of the formal optimization and validation of the TZM-bl assay, performed in compliance with Good Clinical Laboratory Practice (GCLP) guidelines. The assay was evaluated for specificity, accuracy, precision, limits of detection and quantitation, linearity, range and robustness. The validated manual TZM-bl assay was also adapted, optimized and qualified to an automated 384-well format.

IMPORTANCEAn effective HIV-1 vaccine will need to overcome the extraordinary genetic variability of the virus, where most variation occurs in the viral envelope glycoproteins that are the sole targets for neutralizing antibodies. Efforts to elicit broadly cross-reactive neutralizing antibodies that will protect against infection by most circulating strains of the virus are guided in part by in vitro assays that determine the ability of vaccine-elicited antibodies to neutralize genetically diverse HIV-1 variants. Until now, little information was available on how many and which strains of the virus are best suited for this purpose. We applied robust statistical methods to evaluate a large neutralization data set and identified a small panel of viruses that are a good representation of the global epidemic. The neutralization properties of this new panel of reference strains should facilitate the development of an effective HIV-1 vaccine.

Background: In the Coronavirus Efficacy (COVE) trial, estimated mRNA-1273 vaccine efficacy against coronavirus disease-19 (COVID-19) was 94%. SARS-CoV-2 antibody measurements were assessed as correlates of COVID-19 risk and as correlates of protection. Methods: Through case-cohort sampling, participants were selected for measurement of four serum antibody markers at Day 1 (first dose), Day 29 (second dose), and Day 57: IgG binding antibodies (bAbs) to Spike, bAbs to Spike receptor-binding domain (RBD), and 50% and 80% inhibitory dilution pseudovirus neutralizing antibody titers calibrated to the WHO International Standard (cID50 and cID80). Participants with no evidence of previous SARS-CoV-2 infection were included. Cox regression assessed in vaccine recipients the association of each Day 29 or 57 serologic marker with COVID-19 through 126 or 100 days of follow-up, respectively, adjusting for risk factors. Results: Day 57 Spike IgG, RBD IgG, cID50, and cID80 neutralization levels were each inversely correlated with risk of COVID-19: hazard ratios 0.66 (95% CI 0.50, 0.88; p=0.005); 0.57 (0.40, 0.82; p=0.002); 0.41 (0.26, 0.65; p<0.001); 0.35 (0.20, 0.60; p<0.001) per 10-fold increase in marker level, respectively, multiplicity adjusted P-values 0.003-0.010. Results were similar for Day 29 markers (multiplicity adjusted P-values <0.001-0.003). For vaccine recipients with Day 57 reciprocal cID50 neutralization titers that were undetectable (<2.42), 100, or 1000, respectively, cumulative incidence of COVID-19 through 100 days post Day 57 was 0.030 (0.010, 0.093), 0.0056 (0.0039, 0.0080), and 0.0023 (0.0013, 0.0036). For vaccine recipients at these titer levels, respectively, vaccine efficacy was 50.8% (-51.2, 83.0%), 90.7% (86.7, 93.6%), and 96.1% (94.0, 97.8%). Causal mediation analysis estimated that the proportion of vaccine efficacy mediated through Day 29 cID50 titer was 68.5% (58.5, 78.4%). Conclusions: Binding and neutralizing antibodies correlated with COVID-19 risk and vaccine efficacy and likely have utility in predicting mRNA-1273 vaccine efficacy against COVID-19. Trial registration number: COVE ClinicalTrials.gov number, NCT04470427