Substantial Differences in SARS-CoV-2 Antibody Responses Elicited by Natural Infection and mRNA Vaccination

Abstract We analyzed data from two ongoing serologic surveys, a longitudinal cohort of health care workers (HCW) from the University of California Irvine Medical Center (Orange County, CA, USA), collected from May and December 2020 through March 2021, and a cross sectional county-wide study in July 2020 (actOC; Orange County, CA) and a more focused community study in the city of Santa Ana (Santa Ana Cares; Orange County, CA, USA), collected in December 2020 - in order to compare the antibody responses to SARS-CoV-2 natural infection and vaccination. In addition, we serially tested 9 volunteers at multiple time points to analyze the time course of vaccine-induced antibody response in more detail. In May 2020, 1060 HCW were enrolled and had finger stick samples collected. Finger stick samples were again collected in December 2020, before vaccination, as well as January, February and March 2021 during vaccination campaign. A total of 8,729 finger stick blood specimens were probed and analyzed for IgG and IgM antibodies using a coronavirus antigen microarray (COVAM).The microarray contained 10 SARS-CoV-2 antigens including nucleocapid protein (NP) and several varying fragments of the spike protein, as well as 4 SARS, 3 MERS, 12 Common CoV, and 8 Influenza antigens.Based on a random forest based prediction algorithm, between May and December, prior to vaccine rollout, we observed that seropositivity in the HCW cohort increased from 4.5% to 13%. An intensive vaccination campaign with mRNA vaccines was initiated on December 16, 2020 and 6,724 healthcare workers were vaccinated within 3 weeks. The observed seropositivity of the HCW specimens taken in the last week of January 2021 jumped to 78%, and by the last week in February it reached 93%, and peaked at 98% seropositive in March. The antibody profile induced by natural exposure differed from the profile induced after mRNA vaccination. Messenger RNA vaccines induced elevated antibody (Ab) reactivity levels against the Receptor Binding Domain (RBD) domain of SARS-CoV-2 spike, and cross-reactive responses against SARS and MERS RBD domains. Nucleocapsid protein (NP), which is an immunodominant antigen induced after natural exposure, is not present in the vaccine and can be used as a biomarker of past exposure. The results show that naturally-exposed individuals mount a stronger anti-spike response upon vaccination than individuals that were not previously exposed. Longitudinal specimens taken at approximately weekly intervals from 9 individuals show variation in the response to the mRNA vaccine, with some showing a vigorous response to the first dose (prime) and others requiring a subsequent dose (boost) to reach high anti-SARS-CoV-2 levels. Antibody titers determined by serial dilution of the specimens were used to accurately compare antibody levels in these samples. mRNA vaccinees after the boost have higher Ab titers (up to 10 times higher) than convalescent plasmas from donors who recovered from natural infection. The results of this study exemplify the time course and outcomes expected from similar mRNA mass vaccination campaigns conducted in other institutions.