Longitudinal dynamics of SARS-CoV-2-specific cellular and humoral immunity after natural infection or BNT162b2 vaccination

PLoS Pathog. 2021 Dec 28;17(12):e1010211. doi: 10.1371/journal.ppat.1010211. eCollection 2021 Dec.


The timing of the development of specific adaptive immunity after natural SARS-CoV-2 infection, and its relevance in clinical outcome, has not been characterized in depth. Description of the long-term maintenance of both cellular and humoral responses elicited by real-world anti-SARS-CoV-2 vaccination is still scarce. Here we aimed to understand the development of optimal protective responses after SARS-CoV-2 infection and vaccination. We performed an early, longitudinal study of S1-, M- and N-specific IFN-γ and IL-2 T cell immunity and anti-S total and neutralizing antibodies in 88 mild, moderate or severe acute COVID-19 patients. Moreover, SARS-CoV-2-specific adaptive immunity was also analysed in 234 COVID-19 recovered subjects, 28 uninfected BNT162b2-vaccinees and 30 uninfected healthy controls. Upon natural infection, cellular and humoral responses were early and coordinated in mild patients, while weak and inconsistent in severe patients. The S1-specific cellular response measured at hospital arrival was an independent predictive factor against severity. In COVID-19 recovered patients, four to seven months post-infection, cellular immunity was maintained but antibodies and neutralization capacity declined. Finally, a robust Th1-driven immune response was developed in uninfected BNT162b2-vaccinees. Three months post-vaccination, the cellular response was comparable, while the humoral response was consistently stronger, to that measured in COVID-19 recovered patients. Thus, measurement of both humoral and cellular responses provides information on prognosis and protection from infection, which may add value for individual and public health recommendations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antibodies, Neutralizing / blood
  • Antibodies, Viral / blood*
  • BNT162 Vaccine / immunology*
  • COVID-19 / immunology*
  • Female
  • Humans
  • Immunoglobulin G / blood
  • Longitudinal Studies
  • Male
  • Middle Aged
  • SARS-CoV-2 / immunology*
  • Spike Glycoprotein, Coronavirus / immunology
  • T-Lymphocytes / immunology*
  • Vaccination*


  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Immunoglobulin G
  • Spike Glycoprotein, Coronavirus
  • BNT162 Vaccine

Grants and funding

This study was supported by the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (COVID-19 research call COV20/00181) — co‐financed by the European Development Regional Fund “A way to achieve Europe”, Operative Program Intelligent Growth 2014‐2020, by Consejeria de Sanidad de la Comunidad de Madrid (CIVICO study 2020/0082) and by a private donation (code 2021/55). RLG holds a research contract “Rio Hortega” (CM19/00120) from the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation. MCL holds a predoctoral fellowship (FPU19/06393) from the Spanish Ministry of Science and Innovation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.