This study aims to assess the safety profile of COVID-19 vaccines (mRNA and viral vector vaccines) in teenagers and young adults, as compared to Influenza and HPV vaccines, and to early data from Monkeypox vaccination in United States.MethodsWe downloaded data from the Vaccine Adverse Event Reporting System (VAERS) and collected the following Serious Adverse Events (SAEs) reported for COVID-19, Influenza, HPV and Monkeypox vaccines: deaths, life-threatening illnesses, disabilities, hospitalizations. We restricted our analysis to the age groups 12–17 and 18–49, and to the periods December 2020 to July 2022 for COVID-19 vaccines, 2010–2019 for Influenza vaccines, 2006–2019 for HPV vaccines, June 1, 2022 to November 15, 2022 for Monkeypox vaccine. Rates were calculated in each age and sex group, based on an estimation of the number of administered doses.ResultsAmong adolescents the total number of reported SAEs per million doses for, respectively, COVID-19, Influenza and HPV vaccines were 60.73, 2.96, 14.62. Among young adults the reported SAEs rates for, respectively, COVID-19, Influenza, Monkeypox vaccines were 101.91, 5.35, 11.14. Overall, the rates of reported SAEs were significantly higher for COVID-19, resulting in a rate 19.60-fold higher than Influenza vaccines (95% C.I. 18.80–20.44), 4.15-fold higher than HPV vaccines (95% C.I. 3.91–4.41) and 7.89-fold higher than Monkeypox vaccine (95% C.I. 3.95–15.78). Similar trends were observed in teenagers and young adults with higher Relative Risks for male adolescents.ConclusionThe study identified a risk of SAEs following COVID-19 vaccination which was markedly higher compared to Influenza vaccination and substantially higher compared to HPV vaccination, both for teenagers and young adults, with an increased risk for the male adolescents group. Initial, early data for Monkeypox vaccination point to significantly lower rates of reported SAEs compared to those for COVID-19 vaccines. In conclusion these results stress the need of further studies to explore the bases for the above differences and the importance of accurate harm-benefit analyses, especially for adolescent males, to inform the COVID-19 vaccination campaign.