SARS-CoV-2 naïve and recovered individuals show qualitatively different antibody responses following mRNA vaccination

mRNA-based vaccines effectively induce protective neutralizing antibody responses against SARS-CoV-2, the etiological agent of COVID-19. The specific compositional patterns of these responses remain largely unknown. We found that SARS-CoV-2-naïve individuals receiving the first dose of an mRNA vaccine developed a SARS-CoV-2-specific antibody response with a subclass profile comparable to that induced by the natural infection, except IgA2, which did not increase. SARS-CoV-2-naïve subjects also mounted a robust virus-specific recall response after receiving the second dose. This response increased all IgG subclasses, but boosted neither IgM nor IgA1 and IgA2 subclasses. In contrast, individuals recovered from COVID-19 mounted peak virus-specific antibody responses upon primary immunization and did not further augment such responses following secondary immunization. Remarkably, compared to SARS-CoV-2-naïve subjects, individuals with pre-existing immunity showed increased levels of all virus-specific antibodies but IgG3 following primary vaccination. By dissecting the heterogeneity of mRNA vaccine-induced humoral responses to SARS-CoV-2, our findings indicate that the induction of optimal immune protection may require the development of personalized vaccination programs. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement We would like to thank all the subjects who participated in our studies. This study was supported by the COVID-19 call grant from Generalitat de Catalunya, Department of Health (to G.M and L.D.C.M), grant Miguel Servet research program (to G.M) and by National Health Institute Carlos III (ISCIII) through the project COV20_00508 grant (Co-funded by European Regional Development Fund/European Social Fund) (to R.G.). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All procedures followed were approved by the Ethical Committee for Clinical Investigation of the Institut Hospital del Mar d Investigacions Mèdiques (Number 2020/9621/I). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Requests for resources and reagents should be directed to and will be fulfilled by the corresponding author, Giuliana Magri (gmagri{at}imim.es).