Jul 2026· Open Forum Infectious Diseases· Vol 13 8, pp.
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· 0 citations
Medicine
TL;DR
The observed waning of cross-neutralizing antibodies against emerging variants underscores the challenge of maintaining durable protection and supports the need for continued monitoring of antibody responses to guide evidence-based updates to COVID-19 vaccines.
Abstract
Background
Widespread immunity from vaccination and infection has reduced COVID-19 morbidity and mortality, but this immunity varies across the population. Understanding how repeated antigenic exposures influence antibody responses helps to inform future vaccination strategies.
Methods
We characterized neutralizing antibody (nAb) responses in serum samples collected 1- and 6-months after XBB.1.5 vaccination from 25 healthcare workers with varying, complex histories of vaccination and reported infections. Neutralizing activity was assessed against a range of variants, from pre-Omicron to recent Omicron JN.1 sublineage, and divergent BA.3.2 variants using lentiviral pseudoviruses. Participants were stratified into 5 exposure groups based on their documented vaccination and reported infection history.
Results
XBB.1.5 vaccination elicited broad neutralizing responses, with strong boosting against previously encountered antigens relative to vaccine-matched XBB.1.5 and newer variants. Geometric mean neutralization titers were generally comparable across exposure groups, though small subgroup sizes and considerable intragroup heterogeneity precluded definitive conclusions about the influence of prior exposure history. At 6 months, titers declined by 36-62% across all variants. Titers remained highest against pre-Omicron variants and were lowest against JN.1 sublineage variants, with some falling to very low levels.
Conclusions
In this cohort with extensive prior antigenic exposures, broad nAb profiles were observed following XBB.1.5 vaccination, though these responses waned substantially after 6 months. The observed waning of cross-neutralizing antibodies against emerging variants underscores the challenge of maintaining durable protection and supports the need for continued monitoring of antibody responses to guide evidence-based updates to COVID-19 vaccines.
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
.
E. Lusamaki, Ana M. Ortega-Villa, Daouda Camara et al.· Scientific Reports· 0 citations
SARS-CoV-2 vaccination and infection generate diverse immune histories, but antibody waning beyond 1 year remains insufficiently characterized. We estimated 2-year antibody trajectories and antibody-associated protection across different combinations of vaccination and infection history. We conducted a repeated cross-sectional study using four nationwide seroepidemiological surveys of 25,800 adults in Japan between December 2021 and March 2023. We measured total antibodies against the ancestral spike receptor-binding domain and neutralizing antibody titers against Omicron BA.5. Bayesian hierarchical models estimated antibody waning according to vaccine dose number, infection history, Omicron-adapted bivalent vaccination, age, sex, and vaccine product. Antibody trajectories were linked to an antibody-risk model to estimate protection against symptomatic infection. Here we show that, among uninfected individuals, three to five vaccine doses produce higher anti-spike antibody titers than two doses, while antibody kinetics after the third or later doses are broadly similar. Relative to titers 30 days after the third dose, titers in the three-, four-, or five-dose groups decline to 0.18-fold (95% credible interval [CredI], 0.16–0.19), 0.19-fold (95% CredI, 0.13–0.26), or 0.21-fold (95% CredI, 0.13–0.33) at 1 year and 0.10-fold (95% CredI, 0.07–0.14), 0.14-fold (95% CredI, 0.06–0.24), or 0.14-fold (95% CredI, 0.05–0.29) at 2 years. Omicron breakthrough infection is associated with higher and more durable anti-spike and BA.5 neutralizing antibody titers than vaccination alone. Based on anti-spike antibody trajectories, estimated 90% protection against symptomatic BA.5 infection lasts 99 days (95% CredI, 89–108) after three doses and 116 days (95% CredI, 111–121) after four or five doses in uninfected individuals, but 276 days (95% CredI, 245–319) to 450 days (95% CredI, 343 to >730) in Omicron-infected individuals. Hypothetical neutralization-escape scenarios substantially shorten estimated protection. These findings provide a quantitative framework for evaluating long-term antibody waning and booster timing across populations with diverse immune histories, and may inform the development of next-generation vaccination strategies that induce broader, more durable antibody responses against circulating SARS-CoV-2 variants.
K. Numakura, Sho Miyamoto, A. Sataka et al.· Communications Health· 0 citations
Despite widespread COVID‐19 vaccination, emerging SARS‐CoV‐2 variants continue to evade neutralizing responses. To determine how exposure history influences neutralizing breadth against SARS‐CoV‐2, plasma collected from 46 participants in the Clinical, Virological and Immunological COVID‐19 study cohort (CVIC) was analyzed. Participants were categorized into six groups reflecting distinct SARS‐CoV‐2 exposure profiles: individuals infected with either Wuhan‐Hu‐1 or Delta variants, infection‐naïve individuals who received two or four doses of mRNA vaccine (including a bivalent BA.4/5 booster), previously infected individuals subsequently vaccinated, and individuals with four vaccine doses plus breakthrough Omicron infection. Neutralizing breadth was assessed using a pseudoparticle panel representing major variants of interest/concern (Alpha, Beta, Gamma, Delta, Lambda, and Kappa) and a panel of representative Omicron subvariants (BA.1, BA.2, BA.5, BA.2.75, BA.2.86, BQ.1, XBB.1.5, EG.5, HV.1, and JN.1). Primary exposure through infection elicited potent homologous but variable heterologous neutralization, whereas vaccination alone induced lower yet more consistent responses across variants. Additional antigenic exposures, through either repeated vaccination or breakthrough infection, markedly enhanced cross‐variant neutralization, with the greatest potency and breadth of neutralizing responses observed in individuals with the highest number of SARS‐CoV‐2 exposures. Nonetheless, neutralizing activity against more recently emerged Omicron subvariants, including EG.5, HV.1, and JN.1, remained low. Taken together, these findings demonstrate that both the nature and number of antigenic exposures can shape the potency and breadth of SARS‐CoV‐2 neutralizing responses. While cumulative exposures improve cross‐variant immunity, ongoing viral evolution continues to erode neutralization capacity, emphasizing the need for continued variant monitoring and periodic vaccine reformulation to maintain population‐level protection.
Greta Vizgirda, Alexander P. Underwood, Ulrik Fahnøe et al.· Journal of Medical Virology· 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
The policy question for COVID-19 vaccination has shifted from whether vaccines induce protection to how long clinically meaningful protection persists and how immune information should guide preparedness. This question is especially relevant to Saudi Arabia, where Hajj and Umrah create predictable periods of dense population mixing among pilgrims with diverse vaccination histories, prior infection exposures, ages, and comorbidity profiles. This structured narrative review synthesizes evidence on durability of COVID-19 vaccine-induced immunity, Saudi epidemiological and serological data, heterologous booster strategies, hybrid immunity, and operational implications for mass-gathering preparedness. A structured search of biomedical databases and public-health sources was undertaken for evidence published from January 2020 to May 2026. The review highlights those circulating antibodies and neutralizing activity decline after vaccination, particularly against antigenically divergent variants, whereas memory B-cell responses and CD4+ and CD8+ T-cell immunity generally provide more durable protection against severe disease. Saudi evidence remains limited but informative: national seroprevalence studies, vaccine-rollout data, clinical-effectiveness analyses, and recent serological work indicate substantial prior exposure, strong post-vaccination antibody responses, and meaningful protection against hospitalization and intensive-care admission, particularly after booster dosing. Heterologous schedules and hybrid immunity appear to broaden immune protection, but their policy relevance lies in flexible risk-based planning rather than in promoting infection as a strategy. For Hajj and Umrah, the main implication is a shift from simple dose counting toward immune durability, risk stratification, booster timing, vaccination documentation, genomic surveillance, and integrated respiratory-virus monitoring.
Leena E. Azhar, A. Alsaieedi, Mariam Aleissa et al.· Frontiers in Public Health· 0 citations
Despite extensive research on SARS-CoV-2 immunity, longitudinal studies integrating functional neutralization, antigenic relationships, and host genetic variability remain limited, particularly in Southeast Asian populations with distinct HLA backgrounds. Here, we performed a longitudinal analysis of a Vietnamese COVID-19 cohort before and after vaccination to characterize determinants of cross-variant antibody responses. Our findings indicate that while HLA polymorphisms contribute to inter-individual variability following natural infection, vaccination substantially enhanced cross-variant neutralization and reduced the apparent contribution of HLA-associated variability of neutralizing responses across genetically diverse individuals.
We analyzed 189 Vietnamese COVID-19 convalescent individuals at approximately 7 months post-infection (unvaccinated) and 72 individuals at approximately 15 months (predominantly vaccinated). Anti-S1 and anti-RBD IgG were quantified by ELISA, and neutralizing antibody titers (PRNT
50
) were measured against Wuhan and major variants of concern. High-resolution HLA genotyping was performed using next-generation sequencing, and associations with antibody responses were evaluated using linear regression models with correction for multiple comparisons.
Vaccination markedly increased antibody levels and neutralizing titers across all variants, with fold-increases ranging from approximately 10-fold (Omicron) to 132-fold (Wuhan). Neutralization breadth expanded substantially after vaccination, although reduced activity against Omicron persisted. Strong correlations between binding and neutralizing antibodies were observed, particularly post-vaccination. While several HLA alleles were associated with variation in neutralizing antibody magnitude at earlier time points, multivariable analyses demonstrated that vaccination was the strongest factor associated with neutralization breadth at 15 months.
Vaccination robustly enhances both the magnitude and breadth of humoral immunity in previously infected individuals, consistent with hybrid immunity. Although HLA polymorphisms contribute to inter-individual variability, their contribution appeared smaller than the effect associated with vaccination. These findings highlight how vaccination reshapes immune variability across genetically diverse populations and provide population-specific insight into long-term SARS-CoV-2 immunity.
Thi Thanh Ngan Nguyen, K. Huynh, Hien Anh Thi Nguyen et al.· Frontiers in Immunology· 0 citations
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