Examining protective effects of SARS-CoV-2 neutralizing antibodies after vaccination or monoclonal antibody administration

Abstract

While new vaccines for SARS-CoV-2 are authorized based on neutralizing antibody (nAb) titer against emerging variants of concern, an analogous pathway does not exist for preventative monoclonal antibodies. In this work, nAb titers were assessed as correlates of protection against COVID-19 in the casirivimab + imdevimab monoclonal antibody (mAb) prevention trial (ClinicalTrials.gov #NCT4452318) and in the mRNA-1273 vaccine trial (ClinicalTrials.gov #NCT04470427). In the mAb trial, protective efficacy of 92% (95% confidence interval (CI): 84%, 98%) is associated with a nAb titer of 1000 IU50/ml, with lower efficacy at lower nAb titers. In the vaccine trial, protective efficacies of 93% [95% CI: 91%, 95%] and 97% (95% CI: 95%, 98%) are associated with nAb titers of 100 and 1000 IU50/ml, respectively. These data quantitate a nAb titer correlate of protection for mAbs benchmarked alongside vaccine induced nAb titers and support nAb titer as a surrogate endpoint for authorizing new mAbs.

Trial registration: ClinicalTrials.gov NCT04452318 NCT04470427.

Fig. 1. Predicted pseudo-virus neutralization titer by days since full immunization (day 1 for mAbs, day 57 for vaccine) for ten randomly selected participants from the COVE immunogenicity subcohort (gold) and COV-2969 (green) trials.

The COVE lines use the measured Day 57 neutralization titer (red circle) with subsequent decay determined by a common slope estimated from independent data. Casirivimab + imdevimab mAb lines use concentration curves based on sex and weight and subsequently converted to neutralization titer. The curves start at day 8 days post full immunization (vaccine) or injection (mAb) and stop at the time of event or the end of follow-up.

Fig. 2. Protective efficacy (PE) of casirivimab + imdevimab mAbs (solid green curve) and vaccine efficacy (VE) of mRNA-1273 (dashed orange curve) against COVID-19 as a function of predicted pseudo-virus neutralization titer at the time of exposure.

Shaded area provides 95% pointwise confidence intervals with lighter green emphasizing greater uncertainty for lower titers. PE and VE curves cover the distribution of titers achieved during follow-up with no extrapolation.

Fig. 3. Binding antibody concentration and neutralization titers at 28 days post second dose, the onset of COVID-19 symptoms, and 28 days later in vaccinated participants who acquired COVID-19 during the blinded phase of COVE.

Day 0 is the onset of symptoms.

Fig. 4. A schematic illustrating the role of extant circulating and possibly mucosal antibodies in vaccine induced protection.

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.

Fig. 5. Schematic of the COV-2069 mAb prevention trial and mRNA-1273 vaccine trial (COVE) as analyzed in this report.

Both trials were conducted before the emergence of the Omicron VOC in trial participants, had similar populations, enrolled SARS-CoV-2 naïve individuals, and had similar definitions of symptomatic COVID-19 illness.

Fig. 6. Derivation of the pseudo-virus neutralization titer decay curves for casirivimab + imdevimab mAb combination.

A Ten randomly selected population PK predicted casirivimab + imdevimab mAb combined antibody serum concentration vs time curves as a function of days since injection. B 18 paired measurements, sampled throughout the course of follow-up (black dots) were used to estimate a linear relationship (black line). A day 150 population PK predicted mAb concentration (turquoise dot) thus results in a predicted ID50 (turquoise triangle). The predicted ID50s were used to generate neutralization titer decay curves (Panel C).