Recent research demonstrates that differences in antibody responses among individuals significantly influence which influenza strains become dominant within a population.
This investigation, released today as a Reviewed Preprint in eLife, employs a cutting-edge high-throughput sequencing technique to assess antibody responses to prevalent H3N2 influenza strains in both pediatric and adult populations. The editors highlight it as a significant contribution that deepens our knowledge of immunity at the population scale, noting the robustness of the evidence presented. Such findings hold substantial value for experts in immunology, virology, vaccine formulation, and those developing mathematical models for infectious disease dynamics.
Influenza viruses undergo continuous mutations that enable them to dodge antibodies produced by the body’s defenses following previous infections or immunizations. Consequently, individuals may experience multiple flu infections over their lifetime, necessitating frequent updates to vaccines to sustain their protective efficacy. The immune system’s reaction to influenza is molded by numerous elements, particularly the specific viral strains an person has been exposed to in the past.
“Variations in prior infections and vaccination experiences among people lead to substantial diversity in population-level immunity toward particular flu variants,” explains co-lead author Caroline Kikawa, an MD/PhD candidate in the Department of Genome Sciences at the University of Washington in Seattle, USA, and affiliated with the Division of Basic Sciences and Computational Biology Program at Fred Hutch Cancer Center in Seattle, USA. “Elucidating how this diversity in antibody profiles across a community impacts the evolutionary triumph of emerging flu strains has proven difficult, largely due to the limitations of traditional assays for measuring antibody concentrations, which are labor-intensive and restricted to processing only a limited number of specimens simultaneously.” Kikawa collaborated as lead author with Andrea Loes, who serves as Staff Scientist and Lab Manager in the laboratory of senior author Jesse Bloom at the Division of Basic Sciences and Computational Biology Program, Fred Hutch Cancer Center.
In tackling this issue, Kikawa, Loes, and their collaborators devised an advanced high-throughput neutralization assay designed to evaluate the capacity of individual serum samples—the blood fraction rich in antibodies—to inhibit infection by an array of diverse influenza viruses. The term “high-throughput” underscores the method’s proficiency in handling vast quantities of data in parallel.
The research group generated viruses that express 78 unique hemagglutinin (HA) proteins derived from flu viruses circulating in 2023 as well as those featured in recent vaccines, each distinguished by a specific genetic barcode. Hemagglutinin proteins represent critical viral components targeted by antibodies, prone to swift alterations that circumvent immune detection. By combining these barcoded viruses with serum samples and applying Illumina sequencing technology, the team precisely determined the neutralization efficiency of each virus variant.
Through this innovative methodology, the scientists quantified neutralization titers—indicating the serum volume required to neutralize the virus—across the 78 flu variants utilizing 150 serum specimens from children and adults gathered in the United States during 2023. This effort yielded more than 11,000 distinct titer readings, offering a comprehensive view of population immunity as the 2023–2024 flu season commenced.
The outcomes revealed substantial heterogeneity in neutralization capacities among participants. For instance, certain pediatric serum samples exhibited robust neutralization against virtually all examined strains, whereas others demonstrated markedly diminished activity. Adult samples tended to display more uniform immunity profiles, yet notable individual discrepancies persisted. Collectively, the strongest neutralization was observed in a particular group of children, aligning with the notion that antibody responses peak against strains encountered early in life. Additionally, children’s higher susceptibility to flu might result in more frequent recent immune stimulation. These observations underscore the profoundly individualized nature of flu immunity.
To explore the implications of such variability for viral evolution, the investigators correlated neutralization titers with the proliferation rates of individual strains throughout the 2023 flu season. Employing a statistical tool known as multinomial logistic regression, they examined shifts in strain frequencies within the human population over time, juxtaposing these against the proportion of serum samples exhibiting suboptimal neutralization titers for each strain.
Their analysis indicated that strains achieving the greatest prevalence were precisely those capable of evading neutralization in a broader segment of the tested sera. In particular, viral strains proliferated more rapidly when a substantial percentage of individuals possessed titers falling below critical thresholds, signifying inadequate protective immunity. These results affirm that expansive sequencing-driven neutralization assessments can illuminate the mechanisms driving flu virus evolution.
Notably, this correlation was evident only when assessing individual serum samples, not when sera were combined into pools. Certain virus monitoring protocols rely on pooled sera to gauge collective immunity; however, this study suggests that such aggregated data may overlook the spectrum of individual immune variabilities.
“Our results emphasize that heterogeneity in immune responses at the individual level, rather than mere population averages, critically shapes the dominance of specific flu strains,” states Loes.
Although the research encompassed an extensive array of titer evaluations, the authors acknowledge constraints related to the geographic and demographic scope of sample collection. Pediatric specimens were predominantly sourced from a Seattle hospital, while adult samples originated from vaccinated groups in Philadelphia and Australia. Thus, the dataset might not comprehensively mirror worldwide immunity landscapes.
“Even so, this represents one of the most substantial datasets connecting human antibody responses to the population-level success of influenza strains,” remarks senior author and HHMI Investigator Jesse Bloom, Professor in the Basic Sciences Division and Herbold Computational Biology Program at Fred Hutch Cancer Center, as well as Affiliate Professor of Genome Sciences at the University of Washington. “It establishes a foundational framework for comprehending how varied immune backgrounds influence viral adaptation. These techniques have the potential to enhance current surveillance infrastructures and guide vaccine formulation strategies by delivering nuanced perspectives on community immunity profiles.”
