Nature 585, 268C272 (2020). mRNA-1273-induced IgG to na?ve hamsters was sufficient to mediate protection. Thus, mRNA-1273 vaccine-induced humoral immune responses are a mechanistic correlate of protection against SARS-CoV-2 in NHPs. One-Sentence Summary: mRNA-1273 vaccine-induced antibody responses are a mechanistic correlate of protection against SARS-CoV-2 contamination in NHP. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has resulted in more than 180 million infections and 4 million deaths worldwide as of July 13, 2021 (1). Mass vaccination offers the most efficient public health intervention to control the pandemic. Two mRNA-based vaccinesModernas mRNA-1273 and Pfizer/BioNTechs BNT162b2both produce a stabilized version of the spike glycoprotein (2, 3), show 94% efficacy against symptomatic COVID-19 in interim Phase 3 analyses (4, 5), and are currently being administered globally. Several other vaccines have shown 60 to 80% efficacy against COVID-19 in Phase 3 trials (6, 7) and a number of candidate vaccines are in earlier stages of clinical development (8). A critical issue for optimizing the use of COVID-19 vaccines is usually defining an immune correlate of protection. This predictor of vaccine efficacy 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 durability of protection, necessity for booster vaccination and immune mechanisms of protection (9). The nonhuman primate (NHP) model has been used to demonstrate immunogenicity and protective efficacy against SARS-CoV-2 with several vaccine candidates (10C13). The high level of protection achieved with mRNA vaccines in NHPs using clinically relevant dose regimens parallels results from human trials. This model exhibits upper and lower airway contamination and pathology much like clinical presentations of moderate COVID-19 in humans (14). Although immune responses associated with protection after primary contamination have been assessed in NHPs (15), you will find no studies to date that have specifically defined immune correlates of protection in upper and lower airways after vaccination with any COVID-19 vaccine approved for use in humans. We used immunogenicity and protection assessments from our previous NHP mRNA-1273 vaccine study (13) to test the hypothesis that serum antibody serves as an immune correlate of protection. Here, in a dose de-escalation study, we evaluated how multiple measurements of humoral and cellular Capsaicin immunity correlate with the reduction of viral replication in the upper and lower airway following challenge. Antibody analyses were also performed on bronchoalveolar lavages (BAL) and nasal washes after vaccination to assess correlates relevant for clinical disease and transmission, respectively. Finally, we exhibited the ability of passively transferred IgG from mRNA-immunized NHP to protect against SARS-CoV-2 contamination of animals. Thus, this work delineates spike (S)-specific antibodies as a correlate of protection, highlights the ability of localized mucosal antibodies to control upper and lower airway viral replication, and confirms that mRNA-1273-induced Capsaicin IgG is sufficient for protection against SARS-CoV-2 contamination in preclinical models. Results mRNA-1273 vaccination elicits antibody responses in a dose-dependent manner We previously exhibited dose-dependency of serum antibody responses in NHP following vaccination with 10 or 100 g of mRNA-1273, with high-level protection against SARS-CoV-2 challenge in both dose groups (fig. S1A) (13). These and other immunogenicity outcomes from an additional NHP study in Capsaicin which animals were vaccinated with 30 g of mRNA-1273 (fig. S1B) were used to design a study to evaluate immune correlates of protection following mRNA-1273 vaccination in the current study (fig. S1C). Doses of mRNA-1273 ranging from 0.3 to 30 g were administered in the standard clinical Capsaicin regimen at weeks 0 and 4 to generate a range of immune responses and protective outcomes. We first assessed temporal serum S-specific antibody binding, avidity, and neutralization responses post-prime and -boost. Consistent with our previous statement (13), S-specific binding antibody (2, 3) was increased over baseline after each immunization, reaching 7900 and 64,000 median reciprocal endpoint titers by 4 weeks post-prime and -boost, respectively, following immunization with 30 g of mRNA-1273 (fig. S2A). There was an 8C10-fold increase in S-specific binding antibodies after the boost in all dose groups, except for the 0.3-g dose for which boosting elicited 300-fold more S-specific IL22R antibodies. The boost improved not only antibody quantity, but also binding strength as shown by S-specific antibody avidity that increased twofold after the boost in all vaccine groups except for the 0.3-g dose, with no differences between the vaccine groups (fig. S2B)..