Unlike influenza A, influenza B virus lacks a broad animal reservoir and, with it, the pandemic potential that makes influenza A a constant global security concern. But the absence of pandemic risk has never equated to clinical irrelevance. Influenza B virus drives substantial morbidity in seasonal epidemics, and its two historically circulating lineages, B/Victoria and B/Yamagata, have followed strikingly different trajectories in recent years. Surveillance has documented no confirmed naturally circulating B/Yamagata-lineage viruses since March 2020, a development widely linked to the intense non-pharmaceutical interventions of the COVID-19 pandemic era. Current influenza B activity is now overwhelmingly attributable to B/Victoria-lineage viruses, a shift with real consequences for vaccine composition and the interpretation of vaccine effectiveness studies.

The central premise of the review is that the host genome may help explain a persistent puzzle: why individuals exposed to the same virus, and receiving the same vaccine, experience markedly different outcomes. Variation in genes governing antigen presentation, innate viral sensing, interferon signaling, and host dependency or restriction factors could plausibly generate heterogeneity in susceptibility, disease severity, cross-lineage immunity, and responsiveness to immunization. This framework draws on decades of immunogenetic research in influenza A and in broader antiviral biology, but the authors stress a crucial caveat: much of what has been proposed for influenza B rests on inference rather than on direct, influenza B virus-specific human data.

At the heart of the immunogenetic hypothesis lies the human leukocyte antigen system, the protein complex responsible for presenting viral peptide fragments to T cells. Differences in HLA alleles can alter which viral epitopes are displayed, how strongly T cells respond, and consequently how efficiently an infected or vaccinated individual clears virus or mounts protective memory. For influenza A, associations between specific HLA variants and outcomes such as infection risk, severity, and antibody titers after vaccination have been reported across multiple populations. Extending these findings to influenza B is not straightforward, however, because the two virus types differ in their evolutionary dynamics, transmission patterns, and the antigenic landscape they present to the immune system. Epitope repertoires are not interchangeable, and a genetic variant that enhances clearance of one influenza type may have little or no measurable effect on the other.

Beyond antigen presentation, the review considers the innate immune machinery that first detects invading influenza viruses. Pattern recognition receptors such as the toll-like receptors and RIG-I-like receptors sense viral RNA and trigger signaling cascades that culminate in interferon production. Genetic polymorphisms in these sensors and in the downstream interferon pathway can modulate the vigor of the early antiviral response, potentially determining whether an infection is contained quickly or gains a foothold. Similarly, host dependency factors that the virus requires for entry, replication, and assembly, along with restriction factors that actively inhibit viral replication, represent additional layers where inherited variation could shape susceptibility. Each of these domains offers a plausible mechanistic route by which host genotype could influence influenza B outcomes, yet the authors find that direct evidence in the influenza B context remains sparse and fragmentary.

When it comes to vaccine response, the review is similarly measured. The best-supported determinants of influenza vaccine performance, the authors conclude, are not genetic at all. Antigenic match between vaccine strains and circulating viruses, the continuous process of antigenic drift that erodes that match over time, the age of the vaccinee, prior exposure history, and baseline immunity stand out as the factors with the strongest evidentiary grounding. These non-genetic determinants have been repeatedly validated across seasons and populations, and they explain a considerable portion of the year-to-year variability in vaccine effectiveness. Genetic predictors specific to influenza B, by contrast, remain incompletely defined, and no validated host-genetic biomarker currently exists to guide vaccination decisions for this virus.

This asymmetry between well-established extrinsic factors and poorly characterized intrinsic ones is not merely an academic gap. Predictive models of influenza B immune control and vaccine performance are limited by the absence of genotype-linked outcome data. Without large, well-phenotyped cohorts in which host genotype, immune phenotyping, and lineage-resolved virologic outcomes are collected together, the field cannot distinguish genuine genetic effects from confounding by age, prior exposure, or antigenic distance. The authors argue that such integrated studies represent the most important priority for future research, and they outline a research agenda built around linking these data streams in a single analytical framework.

The disappearance of the B/Yamagata lineage adds an unusual wrinkle to this agenda. With no naturally circulating Yamagata viruses detected for years, vaccine components targeting that lineage have become biologically obsolete, and regulatory and advisory bodies have been reconsidering the composition of seasonal vaccines, including the transition from quadrivalent to trivalent formulations. For immunogenetic studies, the loss of a circulating lineage complicates the interpretation of historical cross-lineage immunity data and underscores the need for lineage-resolved outcome measures in future cohorts. Any genetic association study conducted today will, in practice, be measuring responses against B/Victoria viruses, and generalizing those findings to influenza B as a whole carries inherent uncertainty.

Population-specific variation presents another challenge. Immunogenetic associations identified in one ancestry or geographic setting frequently fail to replicate elsewhere, reflecting both genuine differences in allele frequencies and differences in study design, exposure patterns, and co-circulating pathogens. The international composition of the review team, spanning institutions in China, Pakistan, and Uzbekistan, reflects a growing recognition that influenza B research must extend beyond the settings where it has traditionally been studied. Building the evidence base for immunogenetic determinants will require multi-center collaborations with standardized genotyping platforms, harmonized immune phenotyping protocols, and consistent definitions of susceptibility, severity, and vaccine response.

The review, which received support from the Guangdong Basic and Applied Basic Research Foundation and the Dongguan Science and Technology of Social Development Program, ultimately delivers a message of disciplined optimism. The biological logic connecting host genetic variation to influenza B outcomes is sound, and the methodological tools needed to test it, from affordable genome sequencing to sophisticated immune profiling, are now widely available. What is missing is the concerted, influenza B-specific data collection that would convert plausible mechanisms into clinically actionable knowledge. Until that work is done, antigenic match, age, and exposure history will remain the most reliable predictors of how influenza B behaves in populations, while the genome’s contribution waits to be quantified.

Subject of Research: Immunogenetic determinants of influenza B virus susceptibility and vaccine response

Article Title: Immunogenetic determinants of influenza B virus susceptibility and vaccine response: current evidence, gaps, and future directions

Article References: Din, G. U., Khan, H., Tariq, Z., Zhao, J., Khan, A., Eshboev, F., Xu, G., Hu, Y., & Huang, K. (2026). Immunogenetic determinants of influenza B virus susceptibility and vaccine response: current evidence, gaps, and future directions. Virology Journal. https://doi.org/10.1186/s12985-026-03292-1

Image Credits: AI Generated

DOI: 10.1186/s12985-026-03292-1

Keywords: influenza B virus, immunogenetics, host susceptibility, vaccine response, immune heterogeneity, antigenic drift, HLA, interferon, B/Victoria lineage, B/Yamagata lineage, Immunogenetic, determinants

A new study from Korea University College of Medicine, published in Nature Immunology on June 15, 2026, offers a detailed molecular portrait of how an mRNA-based influenza vaccine may accomplish exactly that. Led by Associate Professor Jiwon Lee of the Department of Convergence Medicine and the Vaccine Innovation Center, and conducted in collaboration with Professor Ali Ellebedy and his group at Washington University in St. Louis, the investigation compared an investigational quadrivalent mRNA influenza vaccine, designated mRNA-1010, against the licensed conventional split-virion vaccine Fluarix in a head-to-head clinical evaluation. The central question was whether the mRNA platform could stimulate stronger and more persistent germinal-center responses than a conventional vaccine, and whether that persistence would translate into a measurably broader antibody repertoire in the blood.

The germinal center is the crucible where vaccine-induced immunity is forged. Within specialized microenvironments of draining lymph nodes, B cells that recognize vaccine antigen undergo rounds of proliferation, somatic hypermutation, and selection. Each cycle introduces random mutations into the genes encoding the B-cell receptor, and only those variants whose mutated receptors bind antigen with higher affinity are permitted to survive and expand. Over weeks, this Darwinian process generates plasma cells that secrete high-affinity antibodies and memory B cells that persist for years. The duration and intensity of germinal-center activity are therefore widely regarded as key determinants of both the breadth and the durability of antibody responses. A vaccine that keeps germinal centers active for longer gives B cells more opportunities to mutate, diversify, and explore antibody solutions that recognize conserved or varied features of the virus.

To test whether mRNA vaccination extends this critical phase, the researchers enrolled 75 healthy adults aged 20 to 50 years and followed them across two influenza seasons. Of these, 38 participants received mRNA-1010 and 37 received Fluarix. Blood samples were collected at multiple time points through 26 weeks after vaccination, allowing the team to track the evolution of circulating antibodies over nearly half a year. Crucially, a subset of participants also underwent ultrasound-guided fine-needle aspiration of draining axillary lymph nodes, an invasive but informative procedure that enabled direct sampling of germinal centers as they formed and matured. This combination of peripheral blood monitoring and lymph-node sampling is rare in human vaccine studies and gave the investigators an unusually complete view of the immune response as it unfolded in real time.

The laboratory analysis was correspondingly comprehensive. The team deployed flow cytometry to characterize immune cell populations, ELISpot assays to quantify antigen-specific antibody-secreting cells, single-cell RNA sequencing and B-cell receptor sequencing to resolve individual B-cell lineages, serum IgG proteomics to catalog circulating antibody clonotypes, and a battery of antibody binding and neutralization assays to test functional activity against antigenically diverse influenza strains. Together, these methods profiled the response at scales ranging from single cells to whole serum, providing a multidimensional dataset that conventional vaccine trials, which typically rely on bulk antibody titers alone, cannot match.

The findings were striking. The mRNA vaccine elicited a substantially more diverse and broader serum antibody repertoire than Fluarix, according to Dr. Lee. Most notably, influenza-specific germinal-center responses persisted for up to 26 weeks in 5 of 13 mRNA-1010 recipients whose draining lymph nodes were sampled, while persistent germinal centers were not detected among any of the Fluarix recipients sampled. Six months of sustained germinal-center activity after a single vaccination is an unusually long window of B-cell evolution, and it suggests that the mRNA platform provides antigen persistence and inflammatory signaling that keep the selection machinery running far longer than a conventional protein-based split-virion preparation.

That prolonged activity left a measurable imprint on the antibody repertoire. The mRNA vaccine increased the diversity of the serum IgG repertoire and promoted the diversification of pre-existing B-cell lineages through somatic hypermutation, meaning that antibodies the immune system had already learned to make against earlier influenza exposures were not merely recalled but actively refined and expanded. These molecular changes were associated with broader antibody binding across antigenically diverse influenza strains and with significantly greater increases in neutralization titers against 11 of 13 A/H1N1 viruses tested. In practical terms, the antibodies generated after mRNA vaccination recognized a wider range of viral variants and neutralized more of them, including strains that differed antigenically from those contained in the vaccine itself. Dr. Lee summarized the distinction succinctly: the mRNA platform does not simply produce more antibodies, it produces a more diversified antibody response, which leads to greater binding and neutralizing breadth.

A key methodological strength of the study was Ig-Seq, a mass-spectrometry-based technology that identifies individual antibody clonotypes circulating in the blood after vaccination. Conventional vaccine studies typically measure bulk binding or neutralization titers, aggregate numbers that reveal how much antibody activity is present but say little about its composition. Ig-Seq resolves the response down to individual antibody clonotypes, revealing which antibody lineages emerged, expanded, and diversified after vaccination. Combined with B-cell receptor sequencing, this molecular-level approach allowed the researchers to trace the genealogical trees of antibody families as they mutated and branched over the six-month observation period, directly linking sustained germinal-center activity in the lymph node to the diversification of antibodies measurable in the serum. The authors identify Ig-Seq as a defining strength of the work because it captures information that bulk serology fundamentally cannot.

The broader implications reach toward the long-sought goal of a more universal influenza vaccine. If mRNA vaccination can sustain germinal-center activity for months rather than weeks, it creates a temporal window in which B cells can accumulate mutations that broaden their recognition of the virus’s antigenic landscape. This mechanism could in principle support protection that carries over between seasons, reducing the need for annual reformulation and re-vaccination. However, the authors are careful to note that further studies are needed to determine whether these broadened responses translate into multi-season protection or permit longer vaccination intervals. The study population consisted of healthy adults aged 20 to 50, and future research must investigate whether the same benefits are maintained in older adults and immunocompromised populations, whose germinal-center function, B-cell repertoire diversity, and overall immune responsiveness differ substantially from those of healthy younger recipients.

What the study establishes, with unusual molecular resolution, is a mechanistic bridge between a vaccine platform and the quality of the immunity it generates. Persistent germinal centers, diversified B-cell lineages, and a broader serum antibody repertoire form a coherent causal chain, and tools such as Ig-Seq now make each link observable in humans. As mRNA technology matures beyond its first applications, findings like these suggest that its most consequential contribution to vaccinology may lie not in speed of development but in the depth and breadth of the immune memory it leaves behind, offering a rational template for influenza vaccines designed to stay ahead of a virus that never stops changing.

Subject of Research: A clinical study comparing mRNA-1010 and Fluarix influenza vaccines in healthy adults, examining germinal-center persistence and antibody repertoire breadth

Article Title: Korea University study uncovers how mRNA vaccination may broaden flu antibody responses

Article References: Korea University study uncovers how mRNA vaccination may broaden flu antibody responses. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: mRNA vaccine, influenza, germinal center, antibody breadth, B cells, somatic hypermutation, Ig-Seq, neutralization, vaccinology, Nature Immunology, Korea University, immune repertoire

The study, published in EClinicalMedicine by Yan Xie, Taeyoung Choi, and Ziyad Al-Aly of the VA St. Louis Health Care System, drew on the electronic health records of the U.S. Department of Veterans Affairs, an integrated system spanning 172 health systems, 142 hospitals, and 1,241 outpatient sites. The researchers identified 1,401,492 participant-trials among veterans who attended an in-person primary care visit between September 15, 2025, and February 28, 2026, the period when the seasonal vaccine was widely available across the VA. Within this cohort, 526,350 participant-trials involved vaccination at the index visit and 875,142 involved no vaccination at that visit or during follow-up, and the cohort collectively contributed more than 635,000 person-years of observation, with a median follow-up of roughly six months.

What sets this analysis apart from the interim estimates issued by surveillance networks in England, Canada, and the United States is its design. Most seasonal vaccine effectiveness figures come from test-negative case-control studies, which compare vaccination rates between patients who test positive and those who test negative for influenza among people seeking care for acute respiratory illness. These designs efficiently control for care-seeking and testing behavior but estimate only relative protection among tested patients. The VA team instead emulated a target trial, a framework that asks what would happen if eligible people were, hypothetically, randomized to vaccination or no vaccination at a real clinical encounter. Because vaccination occurs throughout the season while influenza activity rises and falls, the investigators did not run a single trial spanning the entire season. They instead emulated 24 sequential 7-day trials, assigning vaccination status at the start of each window and following vaccinated and unvaccinated participants concurrently so that both groups faced the same circulating viruses at the same calendar time.

This structure was engineered to blunt two well-known distortions in observational vaccine research. Immortal time bias arises when follow-up time during which a person cannot experience the outcome is misattributed to one group, and healthy-vaccinee bias arises because people who choose to get vaccinated tend to be healthier and more engaged with care than those who do not. To reduce the latter, the team restricted eligibility to veterans with a primary care visit in the previous 18 months, guaranteeing comparable engagement with the health system, and excluded participant-visits involving acute illness, recent hospitalization, end-of-life care, advanced organ failure or cancer, recent surgery, and very high predicted short-term risks of hospitalization or death. The result was a comparison between people who plausibly could have been vaccinated and people who plausibly could have remained unvaccinated at the same visit.

Statistical refinement went further. The researchers applied marginal structural models with inverse-probability weighting, estimating propensity scores from a comprehensive covariate set that included demographics, comorbidities, frailty indices, laboratory values, healthcare utilization, vaccination histories across five prior influenza seasons, COVID-19 vaccination records, and algorithmically selected high-dimensional variables drawn from diagnoses, medications, laboratory results, and procedures. Veterans in the unvaccinated group who later received the vaccine were censored, with time-varying inverse probability of censoring weights correcting for the informative nature of that departure. Outcomes were strictly defined by laboratory confirmation: an influenza-associated emergency department or urgent care visit within one day of a positive test, or a hospitalization within 30 days of a positive test.

The headline numbers were sobering but far from discouraging. Vaccination was associated with a vaccine effectiveness of 22.25 percent against laboratory-confirmed influenza-associated emergency department visits, 31.84 percent against influenza-associated hospitalizations, and 21.95 percent against the composite of the two outcomes. In absolute terms, vaccination prevented approximately five emergency department visits and one hospitalization per 10,000 vaccinated persons over the follow-up period. Protection appeared consistent across time windows, with effectiveness against the composite outcome of roughly 21 to 24 percent during the intervals from 31 to 120 days after vaccination, and it held across prespecified subgroups defined by age, split at 65 years, and by immunocompromised status.

To gauge how much the subclade K mismatch mattered, the researchers ran the identical design on the 2024–2025 season. The contrast was clear: effectiveness in the prior season reached 31.03 percent against emergency department visits, 48.57 percent against hospitalizations, and 32.15 percent against the composite outcome. The ratio between seasons worked out to roughly 0.7, meaning relative effectiveness in 2025–2026 was about 30 percent lower than in the year before, a statistically significant decline consistent with the antigenic drift of subclade K. Yet the direction of benefit remained firmly positive, echoing interim estimates from the CDC VISION network, which reported about 30 percent protection against adult influenza-associated hospitalization, and from England and Canada, which found meaningful if reduced protection against medically attended H3N2 illness.

The authors deployed an unusually thorough robustness program. Thirteen sensitivity analyses varied the follow-up horizon, cohort exclusion criteria, outcome definitions, target populations, model specifications, weight truncation thresholds, grace periods, and landmark exposure definitions, and the estimates held steady throughout. Negative outcome control analyses provided an additional check for residual confounding: vaccination showed no association with all-cause hospitalization within 14 days of follow-up or all-cause death within the same window, exactly the null results expected if the design were not systematically biased. These controls cannot prove the absence of confounding, but they strengthen confidence that the observed protection reflects a genuine vaccine effect rather than an artifact of who chooses to be vaccinated.

Limitations remain. The VA population skews older, whiter, and more male than the general United States population, which may limit generalizability. Outcomes required laboratory confirmation within VA data, so infections tested or treated elsewhere were likely missed, meaning the absolute reductions probably represent a lower bound on the vaccine’s real-world impact. Vaccinations received outside the VA system may also have been incompletely captured, a form of misclassification that would tend to bias effectiveness estimates downward. The study did not evaluate influenza-associated death, because event counts were too small for adequate statistical power, nor did it estimate effectiveness against specific viral subtypes separately.

The public health message, however, comes through clearly. Even in a season when the predominant virus drifted away from the vaccine strain after strain selection, vaccination continued to reduce emergency department visits and hospitalizations attributable to laboratory-confirmed influenza. Given that seasonal influenza causes an estimated 9.4 million to 51 million illnesses, 120,000 to 710,000 hospitalizations, and 6,300 to 52,000 deaths annually in the United States, absolute reductions of even a few events per 10,000 people translate into substantial averted morbidity across the tens of millions of doses administered each year. The findings argue against letting an imperfect antigenic match undermine vaccination campaigns, and they make the case for timely, season-specific effectiveness monitoring using complementary designs. As the authors conclude, the 2025–2026 vaccine was less effective than its predecessor by roughly 30 percent in relative terms, but it still did its most important job: keeping veterans out of emergency departments and hospital beds during a challenging influenza season.

Subject of Research: Real-world effectiveness of the 2025–2026 seasonal influenza vaccine against influenza-associated emergency department visits and hospitalizations among U.S. veterans during an H3N2 subclade K-dominated season

Article Title: Effectiveness of the 2025–2026 seasonal influenza vaccine among U.S. veterans: an observational study

Article References: Xie, Y., Choi, T., & Al-Aly, Z. (2026). Effectiveness of the 2025–2026 seasonal influenza vaccine among U.S. veterans: an observational study. eClinicalMedicine, 100, Article 104183. https://doi.org/10.1016/j.eclinm.2026.104183

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104183

Keywords: influenza vaccine, vaccine effectiveness, H3N2 subclade K, target trial emulation, Veterans Affairs, antigenic drift, hospitalization, emergency department, observational study, marginal structural models, 2025–2026 season, public health