SARS-CoV-2 mRNA vaccines confer robust protection against COVID-19, but the emergence of variants has generated concerns regarding the protective efficacy of the currently approved vaccines, which lose neutralizing potency against some variants. Emerging data suggest that antibody functions beyond neutralization may contribute to protection from the disease, but little is known about SARS-CoV-2 antibody effector functions. Here, we profiled the binding and functional capacity of convalescent antibodies and Moderna mRNA-1273 COVID-19 vaccine-induced antibodies across SARS-CoV-2 variants of concern (VOCs). Although the neutralizing responses to VOCs decreased in both groups, the Fc-mediated responses were distinct. In convalescent individuals, although antibodies exhibited robust binding to VOCs, they showed compromised interactions with Fc-receptors. Conversely, vaccine-induced antibodies also bound robustly to VOCs but continued to interact with Fc-receptors and mediate antibody effector functions. These data point to a resilience in the mRNA-vaccine-induced humoral immune response that may continue to offer protection from SARS-CoV-2 VOCs independent of neutralization.

The introduction of vaccines has inspired new hope in the battle against SARS-CoV-2. However, the emergence of viral variants, in the absence of potent antivirals, has left the world struggling with the uncertain nature of this disease. Antibodies currently represent the strongest correlate of immunity against COVID-19, thus we profiled the earliest humoral signatures in a large cohort of severe and asymptomatic COVID-19 individuals. While a SARS-CoV-2-specific immune response evolved rapidly in survivors of COVID-19, non-survivors exhibited blunted and delayed humoral immune evolution, particularly with respect to S2-specific antibody evolution. Given the conservation of S2 across β-coronaviruses, we found the early development of SARS-CoV-2-specific immunity occurred in tandem with pre-existing common β-coronavirus OC43 humoral immunity in survivors, which was selectively also expanded in individuals that develop paucisymptomatic infection. These data point to the importance of cross-coronavirus immunity as a correlate of protection against COVID-19.

The robust protection conferred by SARS-CoV-2 mRNA vaccines represents a critical milestone in the COVID-19 vaccine development. However, the emergence of variants has inspired renewed concern related to the protective efficacy of currently approved vaccines, which lose neutralizing potency against some variants. However, emerging data suggest that antibody functions, beyond neutralization, may contribute to protection from disease. Thus, here we profiled the binding and functional capacity of convalescent antibodies and Moderna mRNA-1273 COVID-19 vaccine-induced antibodies across SARS-CoV-2 variants of concern (VOC). While neutralizing antibody responses are affected by VOCs, antibodies generated after infection exhibited robust binding to VOCs but compromised interactions with Fc-receptors. Conversely, vaccine-induced antibodies bound robustly to VOCs and continued interacting with Fc-receptors and mediated antibody effector functions. These data point to a previously unappreciated resilience in the mRNA vaccine-induced humoral immune response that may continue to provide protection from SARS-CoV-2 VOCs independent of neutralization. Trial Registration: This work used samples from the phase 1, dose-escalation, open-label clinical trial designed to determine the safety, reactogenicity, and immunogenicity of mRNA-1273 (mRNA-1273 ClinicalTrials.gov number, NCT04283461 mRNA-1273 study; DOI: 10.1056/NEJMoa2022483). Funding: We acknowledge support from the Ragon Institute of MGH, MIT, and Harvard, the Massachusetts Consortium on Pathogen Readiness (MassCPR), the NIH (3R37AI080289-11S1, R01AI146785, U19AI42790-01, U19AI135995-02, U19AI42790-01, 1U01CA260476 – 01, CIVIC75N93019C00052), the Gates Foundation Global Health Vaccine Accelerator Platform funding (OPP1146996 and INV-001650), Translational Research Institute for Space Health through NASA Cooperative Agreement (NNX16AO69A), and the Musk Foundation. This work used samples from the phase 1 mRNA-1273 study (NCT04283461; DOI: 10.1056/NEJMoa2022483). The mRNA-1273 phase 1 study was sponsored and primarily funded by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD. This trial has been funded in part with federal funds from the NIAID under grant awards UM1AI148373, to Kaiser Washington; UM1AI148576, UM1AI148684, and NIH P51 OD011132, to Emory University; NIH AID AI149644, and contract award HHSN272201500002C, to Emmes. Funding for the manufacture of mRNA-1273 phase 1 material was provided by the Coalition for Epidemic Preparedness Innovation. Declaration of Interest: G.A. is a founder of Seromyx Systems Inc. A.C. is employee of Moderna Inc. D.D., P.M., A.S.M, and E.R.M. are employees of Space Exploration Technologies Corp. All other authors have declared that no conflict of interest exists. Ethical Approval: The MGH IRB reviewed the ethics protocol for secondary use under record 2020P004042 and the project was deemed Not Human Research.