SARS-CoV-2 infection enhances vaccine-induced immunological memory against spike protein

By Pooja Toshniwal PahariaReviewed by Benedette Cuffari, M.Sc.Mar 22 2023

In a recent study published in the journal Science Translational Medicine, researchers in France perform a longitudinal follow-up assessment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) glycoprotein-specific immunological memory among unvaccinated and vaccinated coronavirus disease 2019 (COVID-19) convalescents, as well as COVID-19-naïve vaccinees.

Study: Prior SARS-CoV-2 infection enhances and reshapes spike protein–specific memory induced by vaccination. Image Credit: Andrus Ciprian / Shutterstock.com

Hybrid immunity against COVID-19

Hybrid immune protection against SARS-CoV-2 results from COVID-19 vaccine- and prior SARS-CoV-2 infection-induced antibodies. This hybrid immunity is associated with more robust memory B- and T- lymphocyte responses, stronger neutralizing antibodies, and a lower risk of reinfections and associated outcomes.

Evaluating immune responses induced by prior COVID-19 and subsequent vaccinations could improve the understanding of how this hybrid immunity contributes to immunological memory. Furthermore, this information could aid in identifying high-risk individuals to be prioritized for booster vaccinations against COVID-19.

About the study

In the present study, researchers compare cellular (memory lymphocytes) and serological (antibodies) immunological memory among vaccinated or unvaccinated individuals with a history of COVID-19 and SARS-CoV-2 infection-naïve vaccinated individuals.

The study comprised 613 COVID-19 patients, from the Covid-Ser and Immunonosocor cohorts. These individuals were categorized as mild or severe COVID-19 convalescents, mild COVID-19 convalescents who received single or double Pfizer’s BNT162b2 messenger ribonucleic acid (mRNA) vaccination or a single adenovirus vector-based ChAdOx1 vaccination, and SARS-CoV-2 infection-naïve individuals who received two homologous BNT162b2 doses, or heterologous ChAdOx1/BNT162b2 vaccination.

The occurrence of breakthrough infections was monitored based on the rebound of SARS-CoV-2 S receptor-binding domain (RBD) immunoglobulin G (IgG) titers using SARS-CoV-2 IgG assays. The researchers also examined serological memory B lymphocyte parameters such as avidity, neutralization potential, and titers of antibodies against the S protein subunit 1 (S1) and S RBD proteins.

The capability of serological samples to protect Vero E6 cells from infection with SARS-CoV-2 19A, Delta, or Omicron strains was assessed using 50% plaque reduction neutralization test (PRNT₅₀) assays. In addition, human airway epithelium (HAE) cells with anti-RBD IgG titers were tested for their ability to neutralize 19A. Anti-RBD antibody avidity was determined using biolayer interferometry.

Anti-RBD memory T lymphocyte responses were assessed using interferon-gamma (IFN-γ) release assays. Comparative phenotypical analyses were performed using the cluster of differentiation (CD-137) and OX-40 as surface activation-induced markers (AIMs).

Flow cytometry was performed to analyze the anti-RBD memory B lymphocyte compartment. Anti-RBD memory B lymphocyte trafficking and expression patterns were assessed based on α4β1, α4β7, β1/β7 integrins, cutaneous lymphocyte antigen (CLA), C-C chemokine receptor (CCR)-4,7, 9, and CD62L. Matrix analysis was performed to determine the correlation between cellular and serological anti-S memory B lymphocyte markers.

Results

Vaccinated convalescents with hybrid immune protection had the highest anti-S titers at six months following vaccination. In comparison to SARS-CoV-2 infection-naïve vaccinees, vaccinated convalescents also exhibited greater frequencies of atypical (IgD⁻ CD27⁻) mucosa-targeted subset of DN2 (double-negative type 2) CD21⁻CD11c⁺ memory B lymphocytes, with an exclusive mucosal homing potential. These individuals also exhibited elevated helper T 1 (T_H1) lymphocyte polarization of the anti-SARS-CoV-2 S follicular helper T lymphocyte (T_FH) pool.

Cellular anti-S B lymphocyte memory was less subject to quantitative variations than its serological counterpart but more susceptible to qualitative changes instructed by prior COVID-19 history. These findings indicate that vaccinating individuals who have previously been infected with SARS-CoV-2 reinforced the serological component of memory B lymphocytes and reshaped memory B lymphocyte compartment’s composition and tracking patterns. No reinfections were reported during the six months between SARS-CoV-2 infection/vaccination and the collection of blood samples.

Median antibody titers, which are expressed as binding antibody unit (BAU)/mL, among vaccinated COVID-19 convalescents for single BNT162b2 vaccination, double BNT162b2 vaccination, and single ChAdOx vaccination were 1,214, 1,193, and 851 BAU/mL, respectively.

Unvaccinated convalescents exhibited the least anti-RBD IgG titers, particularly for mildly symptomatic COVID-19, with median values of 206 and 81 and for severe and mild SARS-CoV-2 infections, respectively. The median anti-RBD IgG titers among COVID-19 vaccinees without a history of infection were 180 and 249 for double homologous BNT162b2 and ChAdOx/BNT162b2 heterologous vaccinations, respectively.

Similar trends were observed for anti-S IgA titers. Serological samples from convalescent vaccinees displayed five- to 10-fold greater serum-neutralizing antibody titers against SARS-CoV-2 19A and Delta strains as compared to those from the convalescent or naïve vaccinated individuals. Concerning Omicron, neutralizing antibody titers were four- to 19-fold lower than those for 19A.

Similar findings were observed in the HAE model, irrespective of anti-RBD IgG titers. Anti-RBD antibodies had higher avidity among vaccinees than among unvaccinated COVID-19 convalescents, irrespective of prior COVID-19 history.

IFN-γ secretion was two- to four-fold greater in response to RBD peptides among convalescent vaccinees than unvaccinated COVID-19 convalescents or naïve homologous double BNT162b2 vaccinees. ChAdOx/ BNT162b2 vaccinees expressed IFN-γ at levels similar to that among individuals with hybrid immunity.

Significantly greater T_FH1 and lower T_FH2 lymphocyte frequencies were observed among convalescent COVID-19 vaccinees than among naïve vaccinees. Cellular and serological markers of anti-S memory B lymphocytes correlated with each other.

Conclusions

The study findings showed that a history of COVID-19 increased anti-S titers induced by subsequent COVID-19 vaccinations. Furthermore, hybrid immunity was characterized by anti-S memory B lymphocyte pool remodeling that is compatible with improved functional protection at mucosal sites.

Prior SARS-CoV-2 infection and vaccination conferred greater immune protection than either of them alone in terms of serological anti-S titers and neutralizing antibodies.