Letter to the editor
Second reply to the second letter to the editor by Alessandria, Berrino, Malatesta and Donzelli (doi: 10.17179/excli2026-9442)
Lamberto Manzoli1,2, Cecilia Acuti Martellucci1, Maria Elena Flacco2
1Department of Medical and Surgical Sciences, University of Bologna, 40100 Bologna, Italy
2Department of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, Italy
EXCLI J 2026;25:Doc479
We appreciate the effort to establish a constructive scientific debate by Alessandria, Berrino, Malatesta and Donzelli (Alessandria et al., 2026[3]).
We had extensively acknowledged the biases inherent to our studies in the primary text (Acuti Martellucci et al., 2025[1]; Flacco et al., 2023[5]), and these authors tried to quantify further bias using the following methods: (1) unadjusted estimation of death rates (Berrino et al., 2023[4]), and (2) calculation of death hazard ratios without adjusting for age, in a sample where the vaccinated individuals were 8 years older, on average, than the unvaccinated (Alessandria et al., 2024[2]). We clarified our study design in the previous reply (Manzoli et al., 2025[6]), however we fear that the dialogue may not develop further if Alessandria et al. defend the major methodological faults described above on the basis of one report which did use multivariable models adjusted for age (Weberpals et al., 2018[8]), and another one which conducted Monte-Carlo simulations adjusted for randomly generated baseline covariates (Mi et al., 2016[7]).
Given the above, we believe that the only possible conclusion is that, whatever the bias was in our study, it was smaller than the biases of the studies that were supposed to disprove our findings.
Declaration
All authors declare no conflict of interest.
No artificial intelligence was used.
References
1.
Acuti Martellucci C, Capodici A, Soldato G, Fiore M, Zauli E, Carota R, et al. COVID-19 vaccination, all-cause mortality, and hospitalization for cancer: 30-month cohort study in an Italian province. EXCLI Journal. 2025;24:690-7072.
Alessandria M, Malatesta GM, Berrino F, Donzelli A. A Critical Analysis of All-Cause Deaths during COVID-19 Vaccination in an Italian Province. Microorganisms. 2024;12:13433.
Alessandria M, Malatesta GM, Berrino F, Donzelli A. Reply to the letter to the editor by Manzoli, Acuti Martelucci and Flacco. EXCLI Journal. 2026;25:476-4784.
Berrino F, Donzelli A, Bellavite P, Malatesta G. COVID-19 vaccination and all-cause and non-COVID-19 mortality. A revaluation of a study carried out in an Italian Province. Epidemiol Prev. 2023;47:374-85.
Flacco ME, Acuti Martellucci C, Soldato G, Di Martino G, Carota R, De Benedictis M, et al. COVID-19 Vaccination Did Not Increase the Risk of Potentially Related Serious Adverse Events: 18-Month Cohort Study in an Italian Province. Vaccines. 2023;11:31-446.
Manzoli L, Acuti Martellucci C, Flacco ME. Reply to the Letter to the editor by Malatesta, Alessandria, Berrino and Donzelli. EXCLI Journal. 2025;24:1800-17.
Mi X, Hammill BG, Curtis LH, Lai EC, Setoguchi S. Use of the landmark method to address immortal person-time bias in comparative effectiveness research: a simulation study. Stat Med. 2016;20;35:4824-368.
Weberpals J, Jansen L, Silversmit G, Verbeeck J, van der Geest LG, Vissers PA, et al. Comparative performance of a modified landmark approach when no time of treatment data are available within oncological databases: exemplary cohort study among resected pancreatic cancer patients. Clin Epidemiol. 2018;10:1109-25