Obesity Impacts Influenza Vaccine-induced Immunity and Protection in a Sex-specific MannerFemales with Obesity Exhibit Greater Influenza Vaccine-induced Immunity and Protection than Males in a Mouse Model

Brian Wolfe¹Saurav Pantha¹Saranya Vijayakumar¹Shristy Budha Magar¹Tawfik Aboellail²Santosh Dhakal^1*

• ¹Kansas State University Department of Diagnostic Medicine/Pathobiology, Manhattan, United States
• ²Kansas State Veterinary Diagnostic Laboratory, Manhattan, United States

Introduction: Obesity is increasing globally, and it negatively impacts influenza vaccine efficacy. Although sex-specific differences in influenza vaccine responses are studied in non-obese hosts, studies investigating sex differences the interaction of biological sex and obesity to impactin influenza vaccine-induced immunity and protection during obesity are limited. Materials and methods: Using the C57BL/6J mouse model of high-fat diet (HFD)-induced obesity or low-fat diet controls, we investigated sex differences in influenza vaccine-induced immunity and protection during obesity. Male and /female mice with or without obesity were vaccinated intramuscularly twice at a 3-week interval with an inactivated 2009 H1N1 influenza A virus (IAV) vaccine. At 35 days post-vaccination (dpv), antibody responses in plasma and Band T-cell responses in spleen and bone marrow were quantified. At 42 dpv, mice were intranasally challenged with a drift variant of the H1N1 IAV, and disease severity was assessed by monitoring the change in body mass up to 21 days post-challenge (dpc). Subsets of mice were euthanized at 3 dpc to determine pulmonary virus replication (TCID50 assay), histopathology (H&E staining), and cytokine/chemokine responses (multiplex ELISA). Results: Female mice, irrespective of diet and obesity status, developed higher antibody responses and were better protected compared to males. Vaccinated males with obesity mounted the poorest antibody responses, experienced a more severe disease, were unable to clear replicating virus from the lungs effectively, and demonstrated heightened pulmonary inflammation. Despite these differences, splenic Band T-cell frequencies were comparable, suggesting the inefficiency of B cells to produce antibodies in males but not in females with obesity. Discussion: Our findings suggesthow that sex differences is observed in obesity impacts influenza vaccine-induced immunity and protection in a sex-specific mannerduring obesity, where males are more severely affected. These findings highlight the importance of considering biological sex and obesity status in influenza vaccine design and testing.