G germline revertant analysis of the COV2-3731 mAb provided additional insights into how this COV2-3731 and other IGHV3-53/3-66-encoded public antibodies evolve to gain breadth against antigenically distinct SARS-CoV-2 variants such as BA.2.3.2, BA.3.1, KP.2.2, and, to some extent, KP.3.3.2.
Analysis suggests mAbs generically defined as class 1/4 mAbs may be separated into two classes, like Class 1/4 mAbs, and class 4/1 mAbs that make extensive interactions with the class-4 epitope and limited contacts with the class-1 knob498-596.
M. Piepenbrink, Yao Ma, Simran Panjwani et al.· iScience· 0 citations
ABSTRACT Objective Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) continuously evolves to evade antibodies elicited by prior infection or vaccination. Most IGHV3‐53/3‐66 public antibodies potently neutralize the prototype strain, but show limited activity against recent variants. However, some acquire broad neutralizing activity through accumulation of somatic hypermutations. We assessed whether non‐broadly neutralizing IGHV3‐53/3‐66 antibodies could mature into broadly neutralizing antibodies. Methods A series of mutant antibodies was constructed based on the IGHV3‐53/3‐66 antibodies, 9‐105 and K4‐66. Neutralizing and binding activities were compared with the original antibodies. Results Introducing six mutations frequently observed in broadly neutralizing antibodies markedly improved the neutralization and binding of 9‐105 against Omicron variants. Introducing Y66F into K4‐66 enhanced neutralization of variants including BA.4/5 and JN.1. Conclusion These findings show that mutations within the IGHV3‐53/3‐66 gene can enhance antibody breadth and potency, suggesting the potential of vaccine strategies to promote the maturation of these widely prevalent public antibodies.
Takeo Kuwata, K. Okazaki, Hiroshi Morioka et al.· Immunity, Inflammation and D...· 0 citations
Data on immune responses to COVID-19 vaccination in West and Central Africa remain limited, particularly across SARS-CoV-2 variants and vaccine platforms. Using the InVITE cohort in the Democratic Republic of Congo, Guinea, Liberia, and Mali, we evaluated anti-spike (anti-S) antibody binding to nine SARS-CoV-2 variants in 96 participants equally selected from pre-vaccination assay defined seropositive and seronegative groups. Participants received mRNA, adenovirus-vectored, or inactivated virus vaccines. Anti-S binding was measured before vaccination and two months after completion of the primary series using a Meso Scale Discovery 10-plex assay. Before vaccination, antibody binding was significantly higher against pre-Omicron variants (Ancestral, Alpha, Beta, and Delta) than Omicron variants in both seronegative (fold change [FC] 3.85, 99% CI 3.45–4.17) and seropositive (FC 3.57, 99% CI 3.33–3.84) participants. Seropositive individuals showed greater binding than seronegative individuals across all variants. Two months post-vaccination, mRNA vaccines elicited higher antibody binding than adenovirus-vectored or inactivated vaccines, whereas no significant differences were observed between adenovirus-vectored and inactivated vaccines. Antibody binding remained higher against pre-Omicron than Omicron variants across all vaccine platforms and serostatus groups. These findings provide rare data on variant-specific vaccine-elicited antibody binding responses in West and Central African populations with distinct demographic, epidemiologic, and immunologic background.
Trial registration: Registration ClinicalTrials.gov: NCT05096091, Registration date: 10-26-2021, Clinical trial registry:
https://clinicaltrials.gov/study/NCT05096091?term=NCT05096091rank=1#study-overview
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E. Lusamaki, Ana M. Ortega-Villa, Daouda Camara et al.· Scientific Reports· 0 citations
R1-32-like public antibodies, characterized by shared IGHV1-69/IGLV1-40 usage, are elicited in more than 50% of individuals with COVID-19 and have been implicated in driving recurrent mutations at L452SARS2 and F490SARS2 within their convergent epitope in the SARS-CoV-2 spike receptor-binding domain. These mutations effectively mediate escape from non-affinity-matured R1-32-like antibodies with germline-like sequences. Here, we characterize four affinity-matured human R1-32-like antibodies, C092, C807, BD56-104, and BD56-597, that tolerate L452SARS2 and F490SARS2 mutations. We show that this tolerance arises from residues introduced by somatic hypermutation at convergent positions across multiple CDR loops and surrounding regions, thereby creating additional contacts that reinforce epitope binding. An unusual N354SARS2 glycosylation site, which emerged in BA.2.86 and became fixed in its descendants, is linked to escape from affinity-matured R1-32-like antibodies, implying ongoing selection by this public antibody class. Using an AI model trained on extensive neutralization data, we further identified ZL525, an ultrapotent human R1-32-like antibody with pan-SARS-CoV-2 variant activity, including against the highly evasive KP.3 variant carrying the N354SARS2 glycosylation, and broad sarbecovirus cross-reactivity extending to SARS-CoV-1. Together, these findings show how affinity maturation enables public antibodies to adapt to viral antigenic drift, reveal their role in shaping SARS-CoV-2 antigenic evolution, and demonstrate the potential of AI-empowered strategies for discovering broadly neutralizing antibodies.
Chuan-Ying Niu, Xiao-Han Huang, Qi-Hong Yan et al.· PLoS Biology· 0 citations
It is shown that a Wuhan-lineage-based multi-antigen VLP vaccine can provide cross-protection against an antigenically divergent SARS-CoV-2 variant that is not fully explained by detectable serum neutralizing activity alone, suggesting the importance of integrated immune responses involving humoral, cellular, and local immune mechanisms.
Seung-Ji Kim, Howon Kim, Seung-Eun Son et al.· Vaccine· 0 citations
Two human-derived monoclonal antibodies are characterized that recognize conserved epitopes on the SARS-CoV-2 RBD and retain activity across antigenically distinct variants, and conserved, mutationally constrained epitopes may serve as targets for vaccines designed to elicit antibody responses resilient to ongoing SARS-CoV-2 evolution and future sarbecovirus emergence.
M. Abernathy, William B. Foreman, Jasmyn A. Lopez et al.· bioRxiv· 0 citations
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