Adverse Events Following Immunization- The Known Unknowns and Black Box: Based on 10th Dr. I. C. Verma Excellence Award for Young Pediatricians Delivered as Oration on 9th Oct. 2022

Although vaccines are one of the most rigorously tested biological products, the safety concerns persist globally. The vaccine safety concerns linked to measles, pentavalent and human papillomavirus (HPV) vaccines have affected the vaccine coverage significantly in past. While surveillance of adverse events following immunization (AEFI) is part of the national immunization program mandate, it suffers from challenges and biases related to reporting, completeness, and quality. Some conditions of concern, termed as adverse events of special interest (AESI) following vaccination, mandated specialised studies to prove/disprove the association. The AEFIs/AESIs are usually caused by one of the four pathophysiologic mechanisms, but for several AEFIs/AESIs, the exact pathophysiology remains elusive. For the causality assessment of AEFIs, a systematic process with checklists and algorithm are followed to classify into one of the four causal association categories. While the causal association primarily banks on epidemiological observations for several AEFIs, the emerging evidences indicate roles of underlying genetic, gender, age and other pro-inflammatory risk factors for AEFIs and AESIs. The emerging evidences suggest role of antigenic mimicry, autoantibody(ies) and underlying genetic susceptibility for the AEFIs/AESIs. The uncertainty about the frequency, profile, interval, and severity of AEFIs/AESIs and variations across the population, ambiguity about the exact pathophysiology mechanism, absence of definite markers, suggest a possible black box effect of the vaccines. Unless these unanswered questions concerning the AEFIs/AESIs are addressed appropriately and communicated to the stakeholders (professionals, care providers, beneficiaries, general public and media), the anti-vaccine movement shall keep challenging the vaccine and vaccination program.