SARS-CoV-2 Vaccination Elicits Unconventional IgM Specific Responses in Naïve and Previously COVID19-Infected Individuals

Abstract

Background: IgG antibodies specific for the SARS-CoV-2 Spike protein are under intensive investigation for the urgent need to identify a correlate of protective immunity in individuals vaccinated with licensed and candidate COVID-19 vaccines. Limited data are available on vaccine-elicited IgM antibodies and their potential implication in immunity to SARS-CoV-2. Methods: We performed a longitudinal study to quantify IgG and IgM antibodies specific for the SARS-CoV-2 spike protein (IgG-S and IgM-S) in 1873 health care worker (HCW) recipients of the BNT162b2 (Comirnaty) vaccine. Samples were collected before administration (T0), at the second dose (T1) and three weeks after the second dose (T2). The cohort included 1584 immunologically naïve to SARS-CoV-2 (IN) and 289 had a history of previous infection (PI). Findings: In IN we identified three patterns of responses: (a) IgG positive/IgM negative (36.1%), (b) coordinated IgM-S/IgG-S responses appearing three weeks after the first dose (37.4%) and (c) delayed IgM appearing after IgG (26.3%). Coordinated IgM-S/IgG-S responses were associated with higher IgG titers. Of the 289 PI vaccinees, 64.5% were IgM-S positive before vaccination, whereas 32% and 3.5% developed IgM-S after the first and second vaccine dose respectively. IgM-S positive sera had higher pseudovirus neutralization titers compared to the IgM-S negative. Similar results were observed in individuals who received either Moderna or Astrazeneca. Interpretation: Coordinated expression of IgG-S and IgM-S after vaccination was associated with a significantly more efficient response in both antibody titers and virus-neutralizing activity, representing a potential correlate of protection. Instead, the unconventional IgG-S positive/IgM-S negative responses may be suggestive of a recruitment of cross coronaviruses immunity by vaccination, warranting further investigation.Funding Information: This work was supported by the Italian Ministry of Health under “Fondi Ricerca Corrente”- L1P5 and “Progetto Ricerca Finalizzata COVID-2020-12371675” to IRCCS Sacro Cuore Don Calabria Hospital, by FUR 2020 Department of Excellence 2018-2022, MIUR, Italy and by The Brain Research Foundation Verona. Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: University of Verona biobank (Ethics Committee approval prot. N. 1538). Tropica Biobank of the IRCCS Sacro Cuore Don Calabria Hospital (Ethics Committee approval prot. N. 17985). All participants signed informed consent.