For rapidly mutating viruses such as influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), immune memory recalled by antigenically drifted variants primarily comprises antibodies that cross-react to the priming strain rather than de novo elicited responses, a phenomenon termed original antigenic sin or immune imprinting. The composition and functionality of de novo responses elicited by variant exposures remain unclear. Here we isolated and characterized hundreds of recall and de novo neutralizing monoclonal antibodies after sequential exposures to SARS-CoV-2 variants in ancestral-imprinted humans. De novo variant type-specific antibodies used different V(D)J genes that were closer to germline sequence, potently neutralized future variants and targeted distinct receptor binding domain epitopes compared to ancestral cross-reactive (recall) antibodies. Nevertheless, neutralizing responses to the updated 2024–2025 booster were predominantly ancestral cross-reactive. These results reveal the distinct contributions of recall and de novo antibodies to a balanced immune response and underscore the benefit of updated booster vaccines, which augment both subsets. Updated SARS-CoV-2 boosters broaden humoral immunity by recalling cross-reactive antibodies and eliciting new less cross-reactive Omicron type-specific antibodies that target distinct RBD epitopes and more potently neutralize recent variants.
T. Johnston, S. Li, M. Painter et al.· Nature Immunology· 2 citations
Assembly of flaviviruses such as Zika virus (ZIKV), dengue virus, and West Nile virus in the host cell endoplasmic reticulum is driven by the structural envelope (E) and premembrane (prM) proteins. The formation of an infectious virion requires cleavage of prM by the host furin protease during a maturation step that is dependent on a conformational change in virion structure. Here, we demonstrate that the biogenesis of flavivirus particles does not require an intact prM protein or proteolytic activation. The expression of E protein preceded by a truncated version of prM (M-E) was sufficient for the formation of noninfectious ZIKV subviral particles and pseudo-infectious reporter virions. Subviral particles encoded by a ZIKV M-E DNA vaccine elicited a neutralizing antibody response in macaques that was insensitive to the virion maturation state, a feature of flavivirus humoral immunity shown to correlate with protection. M-E vaccines that uniformly present structural features shared with mature virions offer a higher-quality and more broadly applicable approach for vaccination against flaviviruses.
Kimberly A. Dowd, Michelle Schroeder, Egan Sanchez et al.· Science Translational Medici...· 0 citations
Virus exposure history, particularly first exposure, is believed to shape vaccine efficacy and infection susceptibility; however, evidence for mechanistic links between immune responses in individuals and epidemiological outcome in populations is scarce. Recent co-circulation of SARS-CoV-2 variants XFG and BA.3.2 has revealed a striking enrichment in BA.3.2 cases among children. By combining epidemiological modeling, serology and monoclonal antibody analysis in children and adults, we show the dependence of effective variant-specific antibodies on vaccination history which may explain birth-year influence on differential susceptibility to these co-circulating variants. Ancestral cross-reactive site I antibodies frequently neutralize BA.3.2, but not XFG. By contrast, Omicron type-specific site I/III and III antibodies frequently neutralize XFG but not BA.3.2, revealing a tradeoff in the ability to neutralize these two co-circulating strains. These findings mechanistically link immune history, variant neutralization, antibody repertoire and variant infection risk, and suggest that vaccination regimens in children should prioritize neutralization breadth.
T. Johnston, Rahul Subramanian, Wakinyan Benhamou et al.· bioRxiv· 0 citations
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