The investigation was led by Reem M. Aljowaie, Ibrahim M. Aziz, Mohamed A. Farrag, Noorah A. Alkubaisi, Asma N. Alsaleh and Fahad N. Almajhdi of the Department of Botany and Microbiology at King Saud University. Between 2014 and 2020, the team collected 311 respiratory specimens from patients presenting with influenza-like illness in Riyadh. Each sample was screened by reverse transcription polymerase chain reaction, a molecular technique capable of detecting viral RNA with high sensitivity. Of the 311 specimens, 88, or 28.3 percent, tested positive for influenza A, while only six samples, representing 1.9 percent, were positive for influenza B virus. Although the number of influenza B detections was modest, the researchers sequenced the complete hemagglutinin and neuraminidase genes of these viruses, providing the full-length genetic data needed for rigorous evolutionary analysis.

Hemagglutinin and neuraminidase are the two surface proteins that define the antigenic identity of influenza viruses. Hemagglutinin mediates entry into host cells and is the principal target of neutralizing antibodies, while neuraminidase facilitates the release of newly formed viral particles. Mutations accumulating in these proteins can alter antigenic properties and, by extension, the degree of protection conferred by vaccination. The Riyadh team recorded mutations at both the nucleotide and amino acid levels, mapped N-linked glycosylation sites, and compared their sequences against WHO vaccine reference strains. They also generated six influenza B isolates from the 2014 to 2020 specimens and incorporated 31 previously published Riyadh sequences covering 2010 through 2025, allowing the analysis to extend across a decade and a half of local viral evolution.

The phylogenetic results revealed a clear lineage replacement event. Viruses belonging to the B/Yamagata lineage were detected in Riyadh in 2015, whereas samples from 2020 belonged exclusively to the B/Victoria lineage. Influenza B viruses are divided into these two genetically and antigenically distinct lineages, which co-circulated globally for decades before the B/Yamagata lineage dramatically declined after the COVID-19 pandemic. The Riyadh dataset mirrors this global pattern: among the sequenced isolates available for the full 2010 to 2025 period, no B/Yamagata-lineage viruses were detected in recent years, and sustained B/Victoria predominance was observed throughout the later portion of the surveillance window.

Within the B/Victoria lineage, the analysis showed that recent isolates from 2023 to 2025 carried the characteristic deletion of amino acids at positions 164 and 165 in the hemagglutinin protein. This deletion, located in or near antigenic regions of the protein, first emerged in globally circulating Victoria-lineage viruses and has become a defining feature of newer subclades. The Riyadh sequences from 2021 to 2025 all belonged to the V1A.3a.2 subclade, which has become the globally dominant form of B/Victoria. Earlier viruses in the dataset fell within subclades V1A.3 and related groups, illustrating the stepwise genetic drift that has characterized the lineage over the surveillance period.

Despite this ongoing evolution, the study found that the hemagglutinin and neuraminidase proteins of the circulating viruses were highly conserved relative to the WHO vaccine strains. Substitutions were identified in the major antigenic regions of hemagglutinin, including the 120-loop, the 150-loop, the 160-loop and the 190-helix, structural elements that antibodies recognize when they neutralize the virus. However, these changes were limited in number and did not translate into substantial genetic distance from the vaccine components. The B/Yamagata viruses from earlier years displayed lineage-specific glycosylation patterns, while the Victoria-lineage viruses maintained largely conserved N-linked glycosylation profiles, with one notable exception: some isolates showed a gain or loss of a glycosylation site at hemagglutinin position 197, a change that could potentially influence antigenicity and deserves continued monitoring.

Perhaps the most reassuring finding from a public health standpoint concerns vaccine compatibility. The researchers compared recent Riyadh isolates with the WHO-recommended vaccine strains B/Austria/1,359,417/2021 and B/Tokyo/EIS13-175/2025 and found that the local viruses remained genetically close to both, exhibiting only limited amino acid substitutions. This suggests that the influenza B component of seasonal vaccines has continued to match the viruses circulating in Riyadh, supporting the effectiveness of current vaccination strategies in the region. Because influenza B vaccine mismatch has historically contributed to reduced vaccine effectiveness in some seasons, this genetic concordance is a meaningful indicator for Saudi immunization planning.

The study also underscores the practical challenges of influenza B surveillance. With only 1.9 percent of the collected specimens testing positive for influenza B, the virus circulates at low levels in Riyadh compared with influenza A, and the number of sequences available for any given season is small. The authors are careful to frame their lineage replacement conclusion as reflecting the available surveillance dataset rather than an absolute claim of global or even national disappearance of B/Yamagata. Nevertheless, the finding aligns with international observations that B/Yamagata has not been robustly detected since around 2020, raising questions about whether the lineage may have gone extinct and whether quadrivalent vaccines, which include both B lineages, will continue to be necessary or whether trivalent formulations lacking B/Yamagata will become standard.

The research was approved by the Research Ethics Committee at King Saud University under Institutional Review Board number 14/4463/IRB 03/IRB, approved on December 3, 2014, and conducted in accordance with the Declaration of Helsinki, with informed consent obtained from all participants. The work was funded by the Ongoing Research Funding Program of King Saud University under grant ORF-2026-198. The authors declare no competing interests, and the article is published open access under a Creative Commons license.

For Saudi Arabia and the wider Middle East region, where long-term influenza B sequence data have historically been sparse, this fifteen-year record fills an important gap in the global map of influenza B evolution. The authors conclude that the predominance of B/Victoria and the non-detection of B/Yamagata within the available dataset underscore the need for continuous molecular surveillance to monitor viral evolution, assess vaccine strain compatibility, and support influenza prevention efforts in the kingdom. As influenza B continues its slow but steady genetic drift, sustained sequencing efforts in underrepresented regions such as Saudi Arabia will remain essential for ensuring that vaccine recommendations rest on a genuinely global picture of viral diversity.

Subject of Research: Long-term molecular epidemiology and genetic evolution of influenza B virus in Riyadh, Saudi Arabia, from 2010 to 2025

Article Title: Long-term molecular surveillance of influenza B virus in Riyadh, Saudi Arabia (2010–2025): lineage replacement, genetic evolution, and vaccine strain compatibility

Article References: Aljowaie, R. M., Aziz, I. M., Farrag, M. A., Alkubaisi, N. A., Alsaleh, A. N., & Almajhdi, F. N. (2026). Long-term molecular surveillance of influenza B virus in Riyadh, Saudi Arabia (2010–2025): lineage replacement, genetic evolution, and vaccine strain compatibility. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14442-9

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14442-9

Keywords: influenza B virus, B/Victoria lineage, B/Yamagata lineage, hemagglutinin, vaccine effectiveness, phylogenetic analysis, molecular epidemiology, lineage replacement, glycosylation, Saudi Arabia, viral evolution, surveillance

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