Omicron COVID-19 Immune Correlates Analysis of a Third Dose of mRNA-1273 in the COVE Trial

Abstract

In the coronavirus efficacy (COVE) phase 3 efficacy trial of the mRNA-1273 vaccine, IgG binding antibody (bAb) concentration against Spike (BA.1 strain) and neutralizing antibody (nAb) titer against Spike (BA.1 strain) pseudovirus were assessed as correlates of risk of Omicron COVID-19 and as correlates of relative boost efficacy in per-protocol recipients of a third (booster) dose. Markers were measured on the day of the boost (BD1) and 28 days later (BD29). For SARS-CoV-2 naive individuals, BD29 Spike IgG-BA.1 strain bAbs and BD29 BA.1-strain nAbs inversely correlated with Omicron COVID-19: hazard ratio (HR) per 10-fold marker increase [95% confidence interval (CI)] = 0.16 (0.03, 0.79); P=0.024 and 0.31 (0.10, 0.96); P = 0.042, respectively. These markers also inversely correlated with Omicron COVID-19 in non-naive individuals: HR = 0.15 (0.04, 0.63); P = 0.009 and 0.28 (0.07, 1.08); P = 0.06, trend. Fold-rise in markers from BD1 to BD29 had similarly strong inverse correlations. For SARS-CoV-2 naive individuals, overall booster relative (three-dose vs two-dose) efficacy was 46% (95% CI: 20%, 64%) and correlated with BA.1 strain nAb titer at exposure. At 56, 251, and 891 arbitrary units (AU)/ml (10th, 50th, and 90th percentile), the booster relative efficacies were -8% (95% CI: -126%, 48%), 50% (25%, 67%), and 74% (49%, 87%), respectively. Similar relationships were observed for Spike IgG-BA.1 strain bAbs and for the markers measured at BD29. The performance of bAb and nAb markers as correlates of protection against Omicron COVID-19 supports their continued use as surrogate endpoints for mRNA vaccination against Omicron COVID-19.

SARS-CoV-2 correlates of protection from infection against variants of concern

“…This indicated that antibodies capable of neutralizing D614G but not Omicron BA.1 in vitro translates to a diminished protection against Omicron BA.1/2 infection among PHIRST-C participants. The identification of variant-neutralizing antibodies derived from infection-induced immunity as CoPs against infections for both Delta and Omicron variants aligns with findings from studies on variant-specific correlates for vaccine-induced or hybrid immunity [21][22][23][24] . Considering that antibody-mediated protection against acquisition of infection likely operates at the mucosal site rather than in serum, it is interesting that serum antibodies levels can anticipate protection 26 .…”

“…further demonstrated that boosting of nAb titers against Omicron by a third dose of mRNA-1273 vaccine, afforded additional protection against Omicron compared to individuals who only received 2 doses of the mRNA-1273 vaccine. 22 Collectively, these empirical data lend support for using nAbs against circulating variant as immuno-bridging markers for periodic vaccine updates.…”

“…Given this complex evolutionary landscape, it remains important to identify CoPs induced by natural infections and/or vaccinations against SARS-CoV-2 variants to monitor population susceptibility, anticipate future waves, optimize rollout of existing vaccines, and facilitate design and approval of next generation vaccines 14 . There has been significant progress in defining serum neutralizing or binding antibodies to the spike protein as CoPs for COVID-19 vaccines, although most of the data are derived from early randomized controlled trials focused on peak immune response shortly after vaccination and measured against symptomatic disease caused by the ancestral strain, with updated data on variants [15][16][17][18][19][20][21][22][23][24] . In comparison, little is known about serum CoPs for infection-induced immunity and protection against acquisition of subclinical infections.CoPs may differ for immunity induced by infection vs. vaccination: SARS-CoV-2 infections tend to induce more robust mucosal immunity despite lower serum antibody responses than intramuscularly delivered mRNA vaccines, as shown in on a mouse model 25 , and mucosal immunity may play a more important role in reducing risk of infection and transmission than systemic immunity 26,27 .…”