A schematic illustrating the role of extant circulating and possibly mucosal antibodies in vaccine induced protection.
infection, nAbs
INFECTION, DISEASE, EMERGENCY
Four identical exposure scenarios are depicted. At a higher neutralization titer e.g., 1000 IU50/ml, extant antibody alone results in protection with no need for engagement of B cells, T cells, or other vaccine induced elements. At a lower titer e.g., <100 IU50/ml, mAb antibody alone is not enough for high protection. Thus, vaccine induced protection for lower titers requires engagement of some combination of anamnestic B cell responses (e.g., nAbs antibodies that mediate FcR effector functions), CD8 + T cells, and other vaccine induced immune responses.Vaccine induced nAbs are highly correlated with the prevention of COVID-19 in multiple vaccine trialsThe European Medicines Agency recently recommended authorizing Sanofi’s monovalent B.1.351 protein vaccine as a booster based on clinical immunobridging with a BNT162b2 mRNA comparator vaccine using nAb titer as an endpoint.In contrast, authorization of mAbs appears to require clinical endpoint studies, even though the case for nAb titer as a surrogate of protection is mechanistically stronger as the mAb is the single component of the intervention. Furthermore, recent meta-analyses show similar relationship between nAb titer and protection for vaccines and the monoclonal antibody adintrevimabThe current approach to Food and Drug Administration (FDA) and Emergency Use Authorization (EUA) regulation of mAbs is challenging. While nAb titer alone is currently insufficient as a surrogate of protection to support EUA, nAb titers are monitored against VOCs and inform recommendations to discontinue the use of previously authorized mAbs if there is evidence of substantial reduction in nAb titers to emergent variants. For example, the combinations balmlanivimab + estesvimab, casirivimab + imdevimab and sotrovimab are no longer authorized for treatment of COVID-19 based on low neutralization activity against the Omicron-lineage VOC. EvusheldOur study has the following limitations: mRNA-1273 induced nAbs declined relatively little during follow-up and the correlate of protection curve was not estimated for low titers, therefore not allowing for a side-by-side comparison of mRNA-1273 and casirivimab + imdevimab induced nAbs at low titers. Our studies were conducted in the pre-Omicron era limiting the generalizability of our results to additional variants. Ongoing work is assessing the impact of neutralization titer on Omicron disease and will be important to contrast with our results. While the COVE follow-up ended before the emergence of Delta, COV-2069 did extend into the Delta era. In deconstructing the role of extant antibody in vaccine induced protection, we used casirivimab and imdevimab which are both IgG1 antibodies and are an imperfect proxy for mRNA-1273 induced antibodies which are polyclonal and include other IgG isotypes, IgM and IgA, which may differ in their potential to penetrate the mucosa and in non-neutralizing functions. Our analyses are for a specific mAb combination and vaccine, similar analyses for other mAbs and vaccines would be informative. In the COV-2069 trial, testing for asymptomatic infection was participant driven after the first month resulting in relatively few asymptomatic cases later in the trial. We used predicted neutralization titer for each individual throughout follow-up; using actual titers from frequent sampling might sharpen our results but is not logistically feasible. Baseline characteristics of the participants in the two trials differ somewhat, ideally a randomized 3 arm trial of placebo, mAb, and vaccine would be analyzed. In the COV-2069 trial some vaccination occurred which might weaken our results. Finally, while the confidence of protective efficacy of casirivimab + imdevimab at titers >1000 IU50/ml is high, there is large uncertainty about the extent of protective efficacy at lower titers.Using clinical and drug concentration data from a randomized, controlled prevention trial with casirivimab and imdevimab (completed prior to the emergence of Omicron and Omicron lineage VOCs), alongside ex vivo data from a standardized neutralization assay using reference strain D614G, we identified a strong correlation between mAb neutralization titer and protective efficacy. This result coupled with evidence from other mAb trials, acceptance of neutralization titer against variants for established mAbs, and the extensive evidence from vaccine studies strongly supports the consideration of neutralization titer as a surrogate of clinical efficacy for the development of next generation mAbs for emerging SARS-CoV-2 variants. As SARS-CoV-2 evolution compromises the benefits of available mAbs, this issue has great urgency for millions of immunocompromised hosts who respond poorly to vaccines.