Hybrid immunity improves B cells

The emergence of SARS-CoV-2 variants compromises the efficacy of current vaccines and limits the application of monoclonal antibody therapy for COVID-19 (refs. 1,2). Here, we analyzed memory B cells from five naïve and five convalescent individuals vaccinated with the BNT162b2 mRNA vaccine to investigate the nature of the B cell and antibody response at the single cell level. Nearly 6,000 cells were sorted, more than 3,000 cells produced monoclonal antibodies against the spike protein, and more than 400 cells neutralized the original SARS-CoV-2 virus first identified in Wuhan, China. China.

The B.1.351 (Beta) and B.1.1.248 (Gamma) variants escaped nearly 70% of these antibodies, while a much smaller portion was impacted by B.1.1.7 (Alpha) and B.1.617.2 (Delta) variants. Overall loss of neutralization was always significantly higher in antibodies from naïve people. This was partly due to the germline IGHV2-5;IGHJ4-1, which was only found in recovering individuals and generated potent and largely neutralizing antibodies. Our data suggest that people who are HIV-positive following infection or primary vaccination will produce antibodies of increased potency and magnitude and be able to better control emerging SARS-CoV-2 variants. .

Twenty months into the COVID-19 pandemic, with 252 million people infected, 5 million deaths and 7.2 billion doses of vaccine administered, the world is still struggling to control the virus. In most developed countries, vaccines have dramatically reduced serious illnesses, hospitalizations and deaths, but they have not been able to control infections fueled by newer, more infectious variants.

A large number of studies to date have shown that protection against infection is linked to the production of neutralizing antibodies against the spike (S) protein of the virus3,4,5,6. It is a trimeric class 1 metastable fusion glycoprotein, composed of S1 and S2 subunits, and mediates virus entry from a prefusion to postfusion conformation after binding to the enzyme receptor conversion of human angiotensin 2 (ACE2) and heparan sulfates on host cells7.

Potent neutralizing antibodies recognize the S1 subunit of each monomer, which includes the immunodominant receptor binding domain (RBD) and N-terminal domain (NTD)8 sites. The vast majority of neutralizing antibodies bind to the receptor binding motif, within the RBD, and a smaller fraction targets the NTD5,9. Neutralizing antibodies directed against the S2 subunit have been described; however, their potency is very low5,10. Neutralizing antibodies generated after infection are largely from germline IGHV3-53 and closely related IGHV3-66 with very few somatic mutations11,12.

Beginning in June 2020, the virus began to generate mutations that allowed the virus to evade neutralizing antibodies, become more infectious, or both. Some of the mutant viruses completely replaced the original SARS-CoV-2 first detected in Wuhan, China. The most successful variant viruses are B.1.1.7 (Alpha), B.1.351 (Beta), B.1.1.248 (Gamma) and B.1.617.2 (Delta), which have been named variants of concern (VoC) 13. The Delta variant is currently spreading throughout the world and is causing great concern also in fully vaccinated populations.

It is therefore imperative to understand the molecular mechanisms of the immune response to vaccination to design better vaccines and vaccination policies. Several researchers have shown that vaccinating recovering people can produce neutralizing antibodies that can be up to a thousand times higher than those induced by infection or vaccination, suggesting that one way to control the pandemic could be the induction of a hybrid immunity-like response using a third booster dose14,15,16,17,18. At the single-cell level, here we compared the nature of the neutralizing antibody response against the original virus first detected in Wuhan and VoCs in naïve and convalescent participants who were immunized with the BNT162b2 mRNA vaccine.

We recruited ten donors who were vaccinated with the BNT162b2 mRNA vaccine: five of them were healthy people who had not been infected with SARS-CoV-2 at the time of vaccination (seronegative) and the other five had recovered from SARS-CoV-2 infection before vaccination (seropositive). Participant details are summarized in