The Effectiveness of Four Quadrivalent, Inactivated Influenza Vaccines Administered Alone or in Combination with Pneumococcal and/or SARS-CoV-2 Vaccines: A Population-Wide Cohort Study

<b>Background</b>: Several influenza vaccine formulations are available, including adjuvanted, high-dose, trivalent, and quadrivalent vaccines, and direct, comparative evidence on the relative effectiveness is limited. Real-life data on the potential impact of the co-administration of pneumococcal and/or SARS-CoV-2 vaccinations are also very scarce. During the 2023-2024 influenza season, we carried out a retrospective cohort study on the entire elderly population of the Pescara province, Italy, in order to evaluate the effectiveness of the quadrivalent influenza vaccine, offered alone or in combination with other recommended vaccinations. <b>Methods</b>: All the immunization, demographic, co-payment, and hospitalization data were extracted from the official National Healthcare System, and the follow-up lasted from October 2023 to September 2024. The outcomes were all-cause mortality and hospital admissions for influenza and/or pneumonia. All the Cox models were adjusted (or stratified) for gender, age, hypertension, diabetes, COPD, CVD, renal disorders, cancer, and previous SARS-CoV-2 infection. <b>Results</b>: Overall, 43.9% of the population aged ≥60 years received an influenza vaccine (n = 46,355/105,527). A total of 3188 (3.0%) and 1047 (1.0%) individuals died of any cause or were hospitalized for influenza and/or pneumonia, respectively. During the follow-up, compared with the unvaccinated, those who received an influenza vaccine showed almost half the likelihood of death (adjusted HR: 0.52; 95%CI: 0.49-0.56) and hospitalization (aHR: 0.55; 95%CI: 0.48-0.62), regardless of the gender and age group. As compared with sole influenza immunization, the co-administration of a pneumococcal or COVID-19 vaccine was associated with a significantly lower risk of both outcomes. No substantial differences were observed by influenza vaccine formulation (MF59 adjuvanted; non-adjuvanted, standard dose; non-adjuvanted, high dose), with the exception of a greater mortality reduction for the MF59-adjuvanted vaccine as compared with the high-dose formulation. <b>Conclusions</b>: During the influenza season 2023-2024, all the influenza vaccines were largely effective among the elderly, with no substantial differences by formulation, age, or gender. However, the co-administration of a pneumococcal and/or SARS-CoV-2 vaccine further reduced the risk of both death and hospitalization. Specific, head-to-head randomized trials are required to confirm both findings.