Prior spike protein exposures shape protection against SARS-CoV-2 Omicron variant


In a recent study published in Science, researchers found that immune-boosting by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is contingent on prior coronavirus disease 2019 (COVID-19) history.

Study: Immune boosting by B.1.1.529 (Omicron) depends on previous SARS-CoV-2 exposure. Image Credit: CROCOTHERY/Shutterstock

The SARS-CoV-2 Omicron variant, which emerged in late 2021, exhibited high transmissibility and quickly replaced previously dominant variants. It shows the highest divergence from the ancestral Wuhan strain and carries 36 coding mutations in the spike protein, more than any previous variants of concern (VOCs). Various studies have observed that double or triple vaccination is protective against severe disease and hospitalization due to Omicron infection.

Evidence suggests that neutralizing titers against the Omicron variant in vaccinated people are generally 20-to-40-fold lower, making it the most antibody-evasive variant. Moreover, protection against severe symptoms among vaccinated individuals could be attributed to the partial activity of residual neutralizing antibodies (nAbs) and primed B and T cell memory.

About the study

In the current study, researchers investigated the degree to which infection with SARS-CoV-2 Omicron boosts cross-reactive B and T cell immunity against itself and other VOCs. The authors recruited a cohort of healthcare workers (HCWs) longitudinally followed from March 2020 to January 2022, who were individuals with different combinations of vaccination and infection histories.

HCWs were identified from successive COVID-19 waves, viz., Alpha, Delta, and Omicron, and after partial (first dose), full (double dose), and booster (third dose) vaccination with the BNT162b2 vaccine. The nucleocapsid (N) and spike 1 (S1) receptor-binding domain (RBD) serology were longitudinally evaluated. The authors observed that the third exposure to the spike boosted S1 RBD titers in most HCW after two or three weeks of the most recent vaccination.

Moreover, antibody responses were plateaued by the third vaccination. Triple-vaccinated HCWs infected with SARS-CoV-2 Wuhan Hu-1 had significantly reduced anti-RBD titers against Beta, Delta, and Omicron variants compared to SARS-CoV-2-naïve HCWs. Also, the cross-reactive anti-RBD immunoglobulin G (IgG) and nAb against Omicron VOC were significantly diminished compared to other variants regardless of infection history.

The frequency of memory B cells (MBCs) against the S protein of Wuhan Hu-1, Delta, and Omicron variants was boosted two to three weeks post-third vaccination compared to 20-21 weeks after the second dose. While the MBC frequency against S protein of Wuhan Hu-1 and Delta variant was similar irrespective of prior infection, it significantly declined against Omicron S1 two to three weeks after the booster dose and 20-21 weeks after the second dose.

RBD or whole S antibody and live virus nAb half-maximal inhibitory concentration (IC­­50) correlated for Alpha and Delta variants but not for Beta, Gamma, and Omicron, implying that antibody binding was a poor marker of nAb IC­50. Next, T cell responses were compared after two to three weeks of booster administration among HCWs who were SARS-CoV-2-naïve or had been infected with Wuhan Hu-1, Delta, or Omicron variants.

T cell immunity was compared against a mapped epitope pool (MEP) of Wuhan Hu-1 spike peptides with S1 from Wuhan Hu-1 or S1 proteins with Delta or Omicron mutations. The magnitude of response for S1 of Omicron was significantly low. Of note, more than half the tested HCWs (54%) had no T cell responses against Omicron S1 irrespective of prior infection history.

They designed a peptide pool encompassing all S1 and S2 mutations of Omicron and a matched pool of equivalent sequences of Wuhan Hu-1. T cell responses against the Omicron peptide pool were diminished compared to the Hu-1 pool. About 42% of HCWs did not have T cell responses against the Omicron variant mutant pool.

The boosted HCWs were studied for B cell responses who experienced a breakthrough infection during the Omicron wave 14 weeks post-third vaccination. Boosted HCWs with previous Wuhan Hu-1 infection who were also infected during the Omicron wave had the highest N antibody binding. Infection-naïve boosted HCWs generated significantly elevated cross-reactive antibody binding responses against all VOCs, including Omicron. Nonetheless, RBD binding and nAb IC50 were depleted against Omicron compared to Wuhan Hu-1.

Notably, SARS-CoV-2-naïve HCWs who did not contract Omicron infection did not induce nAb IC50 response indicating the rapid loss of protection following booster. Fourteen weeks after the third dose, 90% of infection-naïve HCWs showed no cross-reactive T cell responses against Omicron S1. T cell response after Omicron infection in previously naïve HCWs was significantly decreased against Omicron S1 compared to S1 of Wuhan Hu-1 or Delta VOC.

Further, no HCW with infection history during the Wuhan Hu-1 wave responded to Omicron S1, indicating that Omicron infection could not boost T cell immunity against itself. This meant that people infected with Wuhan Hu-1 in the early pandemic and reinfected with Omicron do not exhibit increased T cell immunity.

Lastly, the team showed that 16-18 weeks after infection with Wuhan Hu-1 or Alpha VOC, non-vaccinated HCWs had no detectable cross-reacting RBD antibodies against the Omicron variant. The combination of the previous infection and single vaccination significantly increased S1 RBD binding antibodies against Omicron relative to the responses of naïve HCWs. However, Omicron RBD antibody waning was evident among HCWs infected during the Alpha wave after 20-21 weeks of the second vaccination.

Fourteen weeks after booster administration, increased Omicron RBD binding responses were observed among previously naïve HCWs during the Omicron wave. In contrast, those previously infected with Wuhan Hu-1 did not show this increase. This meant that prior infection with Hu-1 strain immune-imprinted does not boost antibody binding responses against Omicron despite infection with the variant itself.


To summarize, the authors demonstrated that B and T cell immunity against previous VOCs increased in boosted HCWs but was reduced against SARS-CoV-2 Omicron. They showed that the high global prevalence of SARS-CoV-2 Omicron infections and reinfections likely reflects the substantial subversion of recognition at B cell, T cell, nAb, and antibody binding levels. Moreover, certain imprinting combinations, like the infection during Wuhan Hu-1 and Omicron waves, might result in impaired responses.