SARS-CoV-2 mRNA Vaccines Elicit Different Responses in Immunologically Naïve and Pre-Immune Humans

Front Immunol. 2021 Sep 27;12:728021. doi: 10.3389/fimmu.2021.728021. eCollection 2021.


As the COVID-19 pandemic continues, the authorization of vaccines for emergency use has been crucial in slowing down the rate of infection and transmission of the SARS-CoV-2 virus that causes COVID-19. In order to investigate the longitudinal serological responses to SARS-CoV-2 natural infection and vaccination, a large-scale, multi-year serosurveillance program entitled SPARTA (SARS SeroPrevalence and Respiratory Tract Assessment) was initiated at 4 locations in the U.S. The serological assay presented here measuring IgG binding to the SARS-CoV-2 receptor binding domain (RBD) detected antibodies elicited by SARS-CoV-2 infection or vaccination with a 95.5% sensitivity and a 95.9% specificity. We used this assay to screen more than 3100 participants and selected 20 previously infected pre-immune and 32 immunologically naïve participants to analyze their antibody binding to RBD and viral neutralization (VN) responses following vaccination with two doses of either the Pfizer-BioNTech BNT162b2 or the Moderna mRNA-1273 vaccine. Vaccination not only elicited a more robust immune reaction than natural infection, but the level of neutralizing and anti-RBD antibody binding after vaccination is also significantly higher in pre-immune participants compared to immunologically naïve participants (p<0.0033). Furthermore, the administration of the second vaccination did not further increase the neutralizing or binding antibody levels in pre-immune participants (p=0.69). However, ~46% of the immunologically naïve participants required both vaccinations to seroconvert.

Keywords: SARS-CoV-2; antibody response; coronavirus; immunization; neutralization; pre-immune; vaccination.

Publication types

  • Comparative Study
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2019-nCoV Vaccine mRNA-1273
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Neutralizing / blood*
  • Antibodies, Viral / blood*
  • BNT162 Vaccine
  • COVID-19 / diagnosis
  • COVID-19 / immunology
  • COVID-19 / prevention & control*
  • COVID-19 / virology
  • COVID-19 Serological Testing
  • COVID-19 Vaccines / administration & dosage*
  • COVID-19 Vaccines / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • Immunogenicity, Vaccine*
  • Male
  • Middle Aged
  • SARS-CoV-2 / immunology*
  • Spike Glycoprotein, Coronavirus / immunology*
  • Time Factors
  • United States
  • Vaccination*
  • Young Adult


  • Antibodies, Neutralizing
  • Antibodies, Viral
  • COVID-19 Vaccines
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • 2019-nCoV Vaccine mRNA-1273
  • BNT162 Vaccine