Immunogenicity and safety of high-dose VS. Standard-dose influenza vaccines administered over consecutive seasons to lung transplant recipients

The National Institute of Allergy and Infectious Diseases awarded Vanderbilt University Medical Center a cooperative agreement totaling $887,964 on April 13, 2026, to conduct a clinical trial comparing immunogenicity and safety of high-dose versus standard-dose inactivated influenza vaccines administered over consecutive seasons to lung transplant recipients.

The study extends an existing NIH-sponsored trial (DMID Protocol 22-0014) comparing two doses of high-dose vaccine to two doses of standard-dose vaccine within a single season to lung transplant recipients 1–35 months post-transplant. The proposed research addresses a gap in current knowledge by examining whether two doses of influenza vaccine are necessary in the subsequent season and what dose level (standard versus high) confers safe and sufficient protection in that later season. Lung transplant recipients experience more severe influenza disease than other solid organ transplant recipients, including respiratory failure, acute cellular rejection, antibody-mediated rejection, and chronic lung allograft dysfunction, but respond poorly to standard-dose inactivated influenza vaccines due to high-level maintenance immunosuppression required to prevent allograft rejection.

The award funds work performed in Nashville, Tennessee, with a period of performance through March 31, 2031. The funding derives from the Allergy and Infectious Diseases Research program (CFDA 93.855).

Northwestern University, Division of Sponsored Research, serves as a sub-grantee on the award, receiving a sub-award with obligation date August 12, 2026.

Abstract

Influenza virus is a significant pathogen in solid organ transplant (SOT) recipients, including lung transplant recipients. Compared to other solid organs, patients with lung transplants experience more severe influenza disease, including respiratory failure, acute cellular rejection, antibody-mediated rejection, and chronic lung allograft dysfunction. Inactivated influenza vaccines (iivs) are recommended for all immunocompromised individuals six months and older to mitigate severe influenza illness. However, lung transplant recipients respond poorly to standard dose (SD)-IIV due to the high levels of maintenance immunosuppression required to prevent allograft rejection. Recent studies have investigated two strategies to overcome attenuated immune responses to SD-IIV in SOT recipients: administration of one high-dose (HD)-IIV or two doses of SD-IIV in the same influenza season. However, these studies were conducted during the late post-transplant period (e.g., >1 year) and lacked crucial information from the early post-transplant phase when SOT patients are most vulnerable to influenza. Additionally, prior studies had limited representation of lung transplant recipients, a population at greater risk for influenza-related morbidity and mortality compared to other SOT recipients. We are conducting an NIH-sponsored clinical trial comparing two doses of HD-IIV to two doses of SD-IIV administered within the same season to lung transplant recipients 1-35 months post-transplant (dmid protocol number 22-0014). However, our current study does not address whether two doses of IIV are necessary for the subsequent influenza season and, relatedly, the required dose level (standard VS. High) to confer safe and sufficient protection in the subsequent season. The proposed research will compare the immunogenicity and safety of two doses of HD-IIV to two doses of SD-IIV in lung transplant recipients over two consecutive influenza seasons, elucidate cellular immune phenotypes and responses to vaccination, and define cellular immune predictors and correlates of influenza vaccine antibody responses in repeatedly vaccinated lung transplant recipients. The central immunogenicity hypothesis of our proposal is that within each vaccine group, the hemagglutination inhibition (HAI) geometric mean titer (GMT) following one vaccine dose in the repeater year will exceed the HAI GMT following two doses in the first year. To test this hypothesis and address critical knowledge gaps outlined above, lung transplant patients at vanderbilt university medical center enrolled in dmid protocol number 22-0014 during the 2024-2025 and 2025-2026 influenza seasons will be enrolled the following season (2025-2026 and 2026-2027, respectively) in the proposed study and receive either two doses of HD-IIV or two doses of SD-IIV by replicating their respective first-season dose assignments. Results of this study will provide comprehensive insights into humoral and cellular immune responses in adult lung transplant recipients and guide long-term vaccine recommendations. Moreover, our findings will inform optimal vaccine strategies in other SOT populations.