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The Janssen (JohnsonJohnson) Ad26.COV2.S non-replicating viral vector vaccine has been widely deployed for COVID-19 vaccination programs in resource-limited settings. Here we confirm that neutralizing and binding antibody responses to Ad26.COV2.S vaccination are stable for 6 months post-vaccination, when tested against multiple SARS-CoV-2 variants. Secondly, using longitudinal samples from individuals who experienced clinically mild breakthrough infections 4 to 5 months after vaccination, we show dramatically boosted binding antibodies, Fc effector function, and neutralization. These high titer responses are of similar magnitude to humoral immune responses measured in convalescent donors who had been hospitalized with severe illness, and are cross-reactive against diverse SARS-CoV-2 variants, including the neutralization-resistant Omicron (B.1.1.529) variant that currently dominates global infections, as well as SARS-CoV-1. These data have implications for population immunity in areas where the Ad26.COV2.S vaccine has been widely deployed, but where ongoing infections continue to occur at high levels.

The Janssen (Johnson & Johnson) Ad26.COV2.S non-replicating viral vector vaccine has been widely deployed for COVID-19 vaccination programs in resource-limited settings. Here we confirm that neutralizing and binding responses to Ad26.COV2.S vaccination are stable for 6 months post-vaccination, when tested against multiple SARS-CoV-2 variants. Secondly, using longitudinal samples from individuals who experienced clinically mild breakthrough infections 4 to 5 months after vaccination, we show dramatically boosted binding antibodies, Fc effector function and neutralization. These high titer responses are of similar magnitude to humoral immune responses measured in severely ill, hospitalized donors, and are cross-reactive against diverse SARS-CoV-2 variants, including the extremely neutralization resistant Omicron (B.1.1.529) variant that currently dominates global infections, as well as SARS-CoV-1. These data have implications for population immunity in areas where the Ad26.COV2.S vaccine has been widely deployed, but where ongoing infections continue to occur at high levels.

Neutralization escape by SARS-CoV-2 variants, as has been observed in the 501Y.V2 (B.1.351) variant, has impacted the efficacy of first generation COVID-19 vaccines. Here, the antibody response to the 501Y.V2 variant was examined in a cohort of patients hospitalized with COVID-19 in early 2021 - when over 90% of infections in South Africa were attributed to 501Y.V2. Robust binding and neutralizing antibody titers to the 501Y.V2 variant were detected and these binding antibodies showed high levels of cross-reactivity for the original variant, from the first wave. In contrast to an earlier study where sera from individuals infected with the original variant showed dramatically reduced potency against 501Y.V2, sera from 501Y.V2-infected patients maintained good cross-reactivity against viruses from the first wave. Furthermore, sera from 501Y.V2-infected patients also neutralized the 501Y.V3 (P.1) variant first described in Brazil, and now circulating globally. Collectively these data suggest that the antibody response in patients infected with 501Y.V2 has a broad specificity and that vaccines designed with the 501Y.V2 sequence may elicit more cross-reactive responses.

Neutralization escape by SARS-CoV-2 variants, as has been observed in the 501Y.V2 (B.1.351) variant, has impacted the efficacy of first generation COVID-19 vaccines. Here, the antibody response to the 501Y.V2 variant was examined in a cohort of patients hospitalized with COVID-19 in early 2021 - when over 90% of infections in South Africa were attributed to 501Y.V2. Robust binding and neutralizing antibody titers to the 501Y.V2 variant were detected and these binding antibodies showed high levels of cross-reactivity for the original variant, from the first wave. In contrast to an earlier study where sera from individuals infected with the original variant showed dramatically reduced potency against 501Y.V2, sera from 501Y.V2-infected patients maintained good cross-reactivity against viruses from the first wave. Furthermore, sera from 501Y.V2-infected patients also neutralized the 501Y.V3 (P.1) variant first described in Brazil, and now circulating globally. Collectively these data suggest that the antibody response in patients infected with 501Y.V2 has a broad specificity and that vaccines designed with the 501Y.V2 sequence may elicit more cross-reactive responses.

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.

SARS-CoV-2 501Y.V2 (B.1.351), a novel lineage of coronavirus causing COVID-19, contains substitutions in two immunodominant domains of the spike protein. Here, we show that pseudovirus expressing 501Y.V2 spike protein completely escapes three classes of therapeutically relevant antibodies. This pseudovirus also exhibits substantial to complete escape from neutralization, but not binding, by convalescent plasma. These data highlight the prospect of reinfection with antigenically distinct variants and foreshadows reduced efficacy of spike-based vaccines. Substitutions in SARS-CoV-2 spike protein present in the B.1.351 variant first detected in South Africa, when expressed in pseudoviruses, mediate escape from neutralization by monoclonal antibodies under clinical development and by plasma from individuals previously infected with SARS-CoV-2, but do not prevent binding of convalescent plasma to recombinant spike protein containing B.1.351 lineage substitutions.

Broadly neutralizing antibodies (bNAbs) are essential for a preventative HIV-1 vaccine but have not been elicited through vaccination. bNAbs develop in 20–30 per cent of HIV-1 infections and often target the V3-glycan epitope of the HIV envelope protein (Env). In these individuals, virus-antibody co-evolution is thought to drive the maturation of antibody lineages to neutralization breadth. We used deep sequencing of env genes and antibody transcripts from fourteen time points spanning the first 3 years of infection to characterize the virus-antibody co-evolution in donor CAP255 who developed V3-glycan-specific bNAbs. Sequencing and cloning of env genes, followed by neutralization assays, were used to identify Env mutations associated with neutralization escape from two bNAbs (CAP255.G3 and CAP255.C5) isolated at 149 weeks post-infection (wpi). Sequencing data indicated that CAP255 was co-infected by three related viral variants, all of which had an intact N332 glycan, which persisted in > 90 per cent of later viruses. A recombinant V3-region became fixed from 8 wpi, conferring slight neutralization resistance to CAP255.G3/C5 and other V3-glycan bNAbs. Later, T415R/K substitutions in V4 emerged by 51 wpi and were associated with complete viral escape from CAP255.G3/C5, though not from the polyclonal plasma response. All 93-week and later Envs were resistant to CAP255.G3/C5 and V3-glycan bNAb PGT135. Viral escape by 51 wpi suggested that the CAP255 bNAbs arose earlier, driving escape, but persisted to 149 weeks. This was supported by preliminary deep sequencing of the antibody repertoire that indicated bNAb lineage members were already present in the plasma at 39 wpi. Escape from V3-glycan bNAbs via T415R/K mutations have not previously been shown, suggesting a novel mode of recognition within the V3-glycan supersite. Further work will focus on identifying the bNAb-initiating Env and intermediate bNAb lineage members that were capable of engaging contemporaneous Env neutralization escape mutants. Characterization of Envs that engaged bNAb precursors, as well as those that selected for broader members of the bNAb lineage, will inform the design of immunogens capable of eliciting V3-glycan bNAbs in a novel HIV-1 vaccine regimen.

The human retinoblastoma binding protein 6 (RBBP6) is implicated in esophageal, lung, hepatocellular and colon cancers. Furthermore, RBBP6 was identified as a strong marker for colon cancer prognosis and as a predisposing factor in familial myeloproliferative neoplasms. Functionally, the mammalian protein interacts with p53 and enhances the activity of Mdm2, the prototypical negative regulator of p53. However, since RBBP6 (known as PACT in mice) exists in multiple isoforms and pact−/− mice exhibit a more severe phenotype than mdm2−/− mutants, it must possess some Mdm2-independent functions. The function of the invertebrate homologue is poorly understood. This is complicated by the absence of the Mdm2 gene in both Drosophila and Caenorhabditis elegans. We have experimentally identified the promoter region of Snama, the Drosophila homologue, analyzed potential transcription factor binding sites and confirmed the existence of an additional isoform. Using band shift and co-immunoprecipitation assays combined with mass spectrometry, we found evidence that this gene may be regulated by, amongst others, DREF, which regulates hundreds of genes related to cell proliferation. The potential transcription factors for Snama fall into distinct functional groups, including anteroposterior embryonic patterning and nucleic acid metabolism. Significantly, previous work in mice shows that pact−/− induces an anteroposterior phenotype in embryos when rescued by simultaneous deletion of p53. Taken together, these observations indicate the significance of RBBP6 proteins in carcinogenesis and in developmental defects.