Ongoing COVID-19 vaccination in Italy. Online survey of gender- and age-related side effects

Background: Evidences suggest that gender may influence the response to various vaccines in terms of immune response and side effects. Whether similar differences also occur with COVID-19 vaccine, is still uncertain. Materials and Methods: In March 2021, we advertised a short anonymous questionnaire (Google forms) to medical doctors, nurses, postgraduates, students and general public, consisting of 30 questions exploring 16 possible side effects (local pain or hardness, swelling, redness, allergic reaction, tiredness, headache, sleep disorders, myalgia, fever, enlarged lymph nodes, irritability, diarrhea, urticaria, vomiting, anaphylaxis). We recorded side effects after 1st dose, and within one week after 2nd dose. Data were analyzed according to gender and seven age groups. Results: We received 1,034 questionnaires from all over Italy (369 males, 665 females, age range 20-83 years). Injected vaccines were Pfizer-BioNTech (96.9%), Astra-Zeneca (2.4%), Moderna (0.7%). Major adverse events were absent. Minor adverse events occurred with both 1st dose (76.0%) and 2nd dose (78.0%) and were invariably higher in females than in males (1st dose: 79.4% vs 69.9% p = 0.0006;2nd dose: 81.8% vs 70.7%, p = 0.00004). The significant cluster of adverse events were local pain, redness, hardness at the injection site, fever, sleep disturbances, headache, lymph nodes enlargement following both doses (0.00001 < p < 0.02). Effects disappeared within 48hrs in 80% of cases (range 1-7 days). The gender difference was confirmed in the age class 30-39 after 1st dose (85.8% vs 70%, in females and males, respectively p = 0.03), and in the age classes 30-39 (84.6% vs 75.5%, in females and males, respectively p = 0.03) and 40-49 (74.8% vs 57.9%, in females and males, respectively p = 0.02) after 2nd dose. Fever tended to be more frequent in females after the 1st dose (6.5% vs 3.8%) and became significantly higher after the 2nd dose (32.9% vs 17.3%, p = 0.00001). After 50 years of age, the rate of all the recorded adverse events was similar between genders. Conclusions: COVID-19 vaccines generate frequent, although mild side effects with a gender (female) prevalence, especially in the age range 30-49 years. The gender difference disappears after 50 years of age, thus pointing to possible involvement of sex hormones and attenuated immune response.