Immunogenicity and efficacy of heterologous ChAdOx1-BNT162b2 vaccination

Nature. 2021 Dec;600(7890):701-706. doi: 10.1038/s41586-021-04120-y. Epub 2021 Oct 21.


Following severe adverse reactions to the AstraZeneca ChAdOx1-S-nCoV-19 vaccine1,2, European health authorities recommended that patients under the age of 55 years who received one dose of ChAdOx1-S-nCoV-19 receive a second dose of the Pfizer BNT162b2 vaccine as a booster. However, the effectiveness and the immunogenicity of this vaccination regimen have not been formally tested. Here we show that the heterologous ChAdOx1-S-nCoV-19 and BNT162b2 combination confers better protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection than the homologous BNT162b2 and BNT162b2 combination in a real-world observational study of healthcare workers (n = 13,121). To understand the underlying mechanism, we conducted a longitudinal survey of the anti-spike immunity conferred by each vaccine combination. Both combinations induced strong anti-spike antibody responses, but sera from heterologous vaccinated individuals displayed a stronger neutralizing activity regardless of the SARS-CoV-2 variant. This enhanced neutralizing potential correlated with increased frequencies of switched and activated memory B cells that recognize the SARS-CoV-2 receptor binding domain. The ChAdOx1-S-nCoV-19 vaccine induced a weaker IgG response but a stronger T cell response than the BNT162b2 vaccine after the priming dose, which could explain the complementarity of both vaccines when used in combination. The heterologous vaccination regimen could therefore be particularly suitable for immunocompromised individuals.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies, Neutralizing / blood
  • Antibodies, Neutralizing / immunology
  • BNT162 Vaccine / administration & dosage*
  • BNT162 Vaccine / immunology*
  • COVID-19 / immunology*
  • COVID-19 / prevention & control*
  • ChAdOx1 nCoV-19 / administration & dosage*
  • ChAdOx1 nCoV-19 / immunology*
  • Female
  • France / epidemiology
  • Hospitals, University
  • Humans
  • Immunologic Memory / immunology
  • Incidence
  • Male
  • Memory B Cells / immunology
  • Memory T Cells / immunology
  • Middle Aged
  • SARS-CoV-2 / immunology*
  • Spike Glycoprotein, Coronavirus / immunology
  • Vaccination / statistics & numerical data*


  • Antibodies, Neutralizing
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • ChAdOx1 nCoV-19
  • BNT162 Vaccine