mRNA vaccines and hybrid immunity use different B cell germlines against Omicron BA.4 and BA.5

Abstract

Severe acute respiratory syndrome 2 Omicron BA.4 and BA.5 are characterized by high transmissibility and ability to escape natural and vaccine induced immunity. Here we test the neutralizing activity of 482 human monoclonal antibodies isolated from people who received two or three mRNA vaccine doses or from people vaccinated after infection. The BA.4 and BA.5 variants are neutralized only by approximately 15% of antibodies. Remarkably, the antibodies isolated after three vaccine doses target mainly the receptor binding domain Class 1/2, while antibodies isolated after infection recognize mostly the receptor binding domain Class 3 epitope region and the N-terminal domain. Different B cell germlines are used by the analyzed cohorts. The observation that mRNA vaccination and hybrid immunity elicit a different immunity against the same antigen is intriguing and its understanding may help to design the next generation of therapeutics and vaccines against coronavirus disease 2019.

B-cell and antibody responses to SARS-CoV-2: infection, vaccination, and hybrid immunity

“…Several more mechanisms are discussed below as explanations for the beneficial features of hybrid immunity. First, vaccine- and infection-primed B-cell responses use different variable region genes, i.e., select different B-cell clones, which might broadly favor nAbs in convalescent patients [ 236 , 237 ]. Second, SARS-CoV-2 infection induces more MBCs and more pronounced T H 1 responses than vaccination [ 238 ].…”

High-resolution map of the Fc functions mediated by COVID-19-neutralizing antibodies

“…This information was used to understand the S protein RBD regions that mainly drive the antibody Fc-mediated response. Class 1/2, class 3, and class 4 nAbs were, respectively, n = 17, 24, and 0 for SN2, n = 98, 30, and 3 for SN3, and n = 114, 48, and 7 for SP2 ( 17 ). Our results showed that almost all nAbs in the three cohorts induce ADCP against the SARS-CoV-2 Wuhan virus ( Fig.…”

“…These nAbs were isolated from class-switched memory B cells (CD19 + CD27 + IgD − IgM − ). Therefore, our total nAb panel is composed of 482 antibodies neutralizing the Wuhan virus of which 74 to 98% had lost the ability to neutralize Omicron BA.1 and BA.2 variants ( 17 ). To specifically assess and identify the S protein domains and epitopes involved in Fc functions, all nAbs were expressed as IgG1.…”

“…In our previous work, we identified the S protein domain recognized by our nAb panel. To better understand the impact of S protein domains, we analyzed the ADCP activity of the 369 RBD-binding antibodies (SN2 = 37, SN3 = 154, and SP2 = 178), the 89 NTD-targeting nAbs (SN2 = 9, SN3 = 43, and SP2 = 37) and the 24 antibodies that bind to the S protein trimer (SN2 = 6, SN3 = 9, and SP2 = 9) ( 17 ). Compared to RBD and NTD-targeting nAbs, the low numbers of S protein trimer–targeting nAbs are a limit of the analysis for this group of antibodies.…”

“…Given the relevance of the Fc-mediated functions, it becomes of utmost importance to understand which are the epitopes and B cell germlines involved in this response and if they overlap with those inducing neutralizing antibodies. To answer this question, we took advantage of our unique panel of 482 Wuhan neutralizing human monoclonal antibodies (nAbs), most of which lost their neutralization activity against Omicron variants ( 17 ). These antibodies derived from naive donors who were immunized with two mRNA vaccine doses (Seronegative, SN2) and subsequently re-enrolled after receiving the third vaccine dose (Seronegative, SN3), and convalescent donors who had been infected before vaccination (Seropositive, SP2) ( 18 , 19 ).…”