The WHO Algorithm for Causality Assessment of Adverse Effects Following Immunization with Genetic-Based Anti-COVID-19 Vaccines: Pitfalls and Suggestions for Improvement.

Clarifying and differentiating the causes of diseases is an essential step in any clinical activity, but it takes on particular relevance and complexity in the case that arise following vaccinations. The WHO has proposed a protocol that uses a list of specific questions about vaccine-related adverse events and an algorithm for making a judgement. Here, we analyze and discuss the important limitations of this protocol when applied to the new genetic-based anti-COVID-19 vaccines, particularly once dealing with rare and unexpected pathological events. The main controversial aspects concern: (a) the prevailing consideration of other possible causes; (b) the biological plausibility and the choice of an appropriate time window to consider adverse effects possibly caused by vaccines; (c) the reference to scientific literature, which may be very limited and often controversial in early stages of introducing new vaccines because of the short period of observation; (d) the final classification of the algorithm into only three classes, which leaves ample space for the "indeterminate" category. Failure to address these issues may lead to distorted pharmacovigilance reports with significant consequences on the benefit/harm assessment. In anticipation of possible future pandemics managed with new vaccines, the WHO algorithm needs to be revised with appropriate protocols for monitoring and evaluation of adverse effects that take into account the novel mechanism of action and real-world epidemiological data.