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The SARS-CoV-2 Omicron variant escapes neutralizing antibodies elicited by vaccines or infection. However, whether Omicron triggers cross-reactive humoral responses to other variants of concern (VOCs) remains unknown. We use plasma from 20 unvaccinated and seven vaccinated individuals infected by Omicron BA.1 to test binding, Fc effector function and neutralization against VOCs. In unvaccinated individuals, Fc effector function and binding antibodies target Omicron and other VOCs at comparable levels. However, Omicron BA.1-triggered neutralization is not extensively cross-reactive for VOCs (14 to 31-fold titer reduction) and we observe 4-fold decreased titers against Omicron BA.2. In contrast, vaccination followed by breakthrough Omicron infection was associated with improved cross-neutralization of VOCs, with titers exceeding 1:2,100. This has important implications for vulnerability of unvaccinated Omicron-infected individuals to reinfection by circulating and emerging VOCs. While Omicron-based immunogens may be adequate boosters, they are unlikely to be superior to existing vaccines for priming in SARS-CoV-2 naive individuals.

Antibody Fc effector functions contribute to HIV control and have been implicated in the partial efficacy seen in the RV144 vaccine trial. Fc-mediated trogocytosis has been previously described for anti-cancer antibodies and results in the removal of membrane fragments from target cells. Here we developed a flow cytometry-based assay which measures the transfer of membrane fragments from a gp120-coated CD4+ lymphocytic cell line (CEM.NKR-CCR5 cells stained with a membrane dye PKH26) to monocytic cells (THP-1 cells stained with CFSE). We showed that this transfer occurred rapidly, within 1 h, and was mediated through engagement of the FcγRIIa/b receptors on the THP-1 cells. HIV-specific IgG as well as gp120 and CD4 could be detected on the surface of THP-1 cells in a process that we demonstrated was distinct from phagocytosis. Furthermore, while the THP-1 effector cells remained intact following the receipt of new membrane proteins, the viability of the target CEM.NKR-CCR5 cells decreased over time. Analysis of HIV-specific plasma revealed that antibodies with trogocytic activity were common in acute and chronic HIV infection but were higher in individuals with broadly neutralizing antibody responses We also examined trogocytosis mediated by broadly neutralizing antibodies (bNAbs) targeting multiple epitopes on the BG505.SOSIP.664 trimer and show that levels of binding correlated with the trogocytosis score. Overall, our data describe a new antiviral Fc effector function mediated by HIV-specific antibodies that could be harnessed for vaccination and cure strategies.

B cell receptor (BCR) sequencing is a powerful tool for interrogating immune responses to infection and vaccination, but it provides limited information about the antigen specificity of the sequenced BCRs. Here, we present LIBRA-seq (linking B cell receptor to antigen specificity through sequencing), a technology for high-throughput mapping of paired heavy- and light-chain BCR sequences to their cognate antigen specificities. B cells are mixed with a panel of DNA-barcoded antigens so that both the antigen barcode(s) and BCR sequence are recovered via single-cell next-generation sequencing. Using LIBRA-seq, we mapped the antigen specificity of thousands of B cells from two HIV-infected subjects. The predicted specificities were confirmed for a number of HIV- and influenza-specific antibodies, including known and novel broadly neutralizing antibodies. LIBRA-seq will be an integral tool for antibody discovery and vaccine development efforts against a wide range of antigen targets.