Mass vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) offers the most efficient public health intervention to control the COVID-19 pandemic. Two mRNA-based vaccines, Moderna’s mRNA-1273 and Pfizer/BioNTech’s BNT162b2, both of which encode the prefusion-stabilized spike glycoprotein S-2P, showed >94% efficacy against symptomatic COVID-19 in interim phase 3 analyses and are currently being administered globally. Several other vaccines have shown 60 to 80% efficacy against symptomatic COVID-19 in phase 3 trials, and a number of candidate vaccines are in earlier stages of clinical development. An immune correlate of protection can be used to inform potential dose reduction, advance approval of other vaccine candidates in lieu of phase 3 efficacy data, extend indications for use to other age groups, and provide insights into the immune mechanisms of protection.

In assessing immunogenicity and protection of vaccines against SARS-CoV-2, nonhuman primates (NHPs) have been a useful model for clinical translation. NHP innate immune responses and B and T cell repertoires show much greater similarity to humans than do those of rodents, allowing immune responses to be assessed using clinically applicable vaccine doses and regimens. After SARS-CoV-2 infection, NHPs have transient viral replication in the upper and lower airways and mild inflammation in the lung that recapitulates the features of mild infection in humans. Here, we used immunogenicity and protection assessments from a previous NHP mRNA-1273 vaccine study combined with new data from a dose de-escalation study. We evaluated how multiple measurements of humoral and cellular immunity correlate with the reduction of viral replication in the upper and lower airway after challenge. Antibodies in bronchoalveolar lavage (BAL) and nasal swabs (NS) after vaccination were analyzed to assess site-specific immune correlates. Finally, immunoglobulin G (IgG) from mRNA-immunized NHPs was passively transferred in a highly pathogenic Syrian hamster SARS-CoV-2 challenge model to determine whether these antibodies were sufficient for protection.

NHPs received either no vaccine or doses ranging from 0.3 to 100 μg of mRNA-1273, an mRNA vaccine encoding S-2P, at weeks 0 and 4. mRNA-1273 vaccination elicited circulating and mucosal antibody responses in a dose-dependent manner. Using the World Health Organization standard for measuring S-specific IgG, a 10-fold increase in S-binding titers was associated with ~10-fold reductions in viral replication in BAL and NS after challenge. No animal with S-specific IgG >336 IU/ml had BAL subgenomic RNA (sgRNA) >10,000 copies/ml, and no animal with S-specific IgG >645 IU/ml had NS sgRNA >100,000 copies/swab, so these were chosen as the thresholds for protection. These reductions in viral replication in BAL were associated with limited inflammation and viral antigen detection in lung tissue. Finally, passive transfer of vaccine-induced IgG from NHPs to naïve hamsters was sufficient to mediate protection.

mRNA-1273 vaccine–induced antibody responses are a mechanistic correlate of protection against SARS-CoV-2 infection in NHPs. Protection in the lower respiratory tract was achieved at lower serum antibody concentrations than in the upper respiratory tract. These data explain in part the consistent finding that vaccine efficacy against severe lower tract disease is greater than that against mild upper tract disease. These findings have potential implications for how additional boosting may sustain …