P-717. Genetic Analysis of A(H3N2) Influenza Viruses and Associations with Host Characteristics among Kaiser Permanente Northern California Adults during the 2018-2019 Season
Authors: Jollivet Ombeline , Chaves Sandra S , Carré Christophe , Pan Chao-Yang , Guevara Hugo , Wadford Debra , Klein Nicola P , Hsiao Amber , Ng Kamela , Izikson Ruvim , Kabler Heidi , Harvey William T , Josset Laurence , El Guerche-Séblain Clotilde 
Published: January 2025

Abstract

Background
Influenza A(H3N2) viruses exhibit significant genetic diversity and mutations may escape acquired host immunity, potentially triggering infections among vaccinees. This study aims to explore associations between genetic changes in A(H3N2) viruses and vaccinal status of their adult hosts vaccinated with quadrivalent attenuated standard dose (SD-IIV4) vaccine, with recombinant (RIV4) vaccine, or not vaccinated, alongside exploration of associations with other host demographics.
Overview of virus and host populations characteristics.
On the left part is shown the phylogenetic tree based on HA nucleotide sequences. On the right is displayed the clinical characteristics of the associated host population: from left to right, the columns represent age, sex, any comorbidities (asthma, diabetes, COPD, CHD), vaccination status in 2018/2019 season and vaccination status in the season just before, 2017/2018 season.

Methods
We conducted whole genome sequencing of 192 A(H3N2) viruses collected during the 2018/2019 season from Kaiser Permanente Northern California members aged 18-64 years vaccinated with either SD-IIV4 (n=89) or RIV4 (n=62) or unvaccinated (n=41) who developed a mild influenza disease. Additional host variables included age, sex, underlying medical conditions and previous season (2017/2018) vaccination status.
Phylogenetic analyses were performed at nucleotide and amino acid level. Associations between specific mutations of hemagglutinin (HA) and neuraminidase (NA) and vaccine status were assessed by a) known antigenic drift mutations and b) agnostically, considering all mutations. Various clustering analyses were performed, including Multiple Component Analysis, Discriminant Analysis of Principal Components, and K-means.
Observed number of amino acid distinct patterns by the vaccination status.
Blue represents when all viruses sharing a similar amino acid pattern were identified in vaccinated hosts, and red color when not, i.e. both the unique patterns were found for viruses detected in vaccinated and unvaccinated hosts. A distinct pattern is defined here as a - unique - set of hemagglutinin and neuraminidase amino acids.

Results
Our sample set reflects the mismatch between circulating viruses and 2018/2019 vaccine composition (Figure 1). The observed viral genetic diversity among vaccinated individuals was higher than those who were unvaccinated (Figure 2): among 58 observed unique amino acid combinations, 64% were found solely in those vaccinated. The vaccine type administered was rarely associated with HA mutations known to trigger a drift: 1 in 44 (Figure 3).
Relative frequencies of non-synonymous HA mutations per vaccine status of their associated host, per known risk of antigenic drift – from 0, no knowledge to 3,high known risk-.
Risk of antigenic drift were the ones identified by FluSurver[3]. Red color of “T151K” tick highlights the fact this is the unique mutation where frequency in vaccinated and in unvaccinated sub-populations is statistically different (p-value=0.023).

Conclusion
Preliminary results revealed an increased frequency of mutations in the HA and NA genes of vaccinated cases relative to non-vaccinated cases. Holistic characterization of influenza viruses can help contextualize the effectiveness of influenza vaccines, especially in a season of substantial mismatch. Further analyses, including with robust sample size, could consolidate these findings, shedding light on the impact of viral mutations on host immune escape.

Disclosures
Ombeline Jollivet, MSc, Sanofi: Employee|Sanofi: Stocks/Bonds (Private Company) Sandra S. Chaves, MD, MSc, Sanofi: Employee|Sanofi: Employee|Sanofi: Stocks/Bonds (Private Company)|Sanofi: Stocks/Bonds (Private Company) Christophe Carré, PhD, Sanofi: Employee Nicola P. Klein, MD, PhD, CSL Seqirus: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Merck: Grant/Research Support|Pfizer: Grant/Research Support|Sanofi Pasteur: Grant/Research Support Kamela Ng, PhD, Sanofi: Employee|Sanofi: Stocks/Bonds (Private Company) Ruvim Izikson, MD, MPH, Sanofi: Employee|Sanofi: Stocks/Bonds (Private Company) Heidi Kabler, MD, Sanofi: Employee|Sanofi: Stocks/Bonds (Private Company) Clotilde El Guerche-Séblain, PhD, Sanofi: Employee|Sanofi: Stocks/Bonds (Private Company)