Etiology Model for Clinical Studies’ Intramuscular Injection of Saline Solution Control Driving Innate Immune Response Associated Adverse Events in Volunteers

Abstract Clinical studies include placebo controls to enable differentiation between treatment efficacy and adverse events from placebo effects. Intramuscular injection of saline solution was used in COVID-19 vaccine clinical trials as the placebo control. The underlying hypothesis is that intramuscular injection of saline solution does not cause adverse events. Herein, an alternative hypothesis is advanced that intramuscular injection of saline solution can stimulate innate immune responses in volunteers and that these adverse events are not placebo effects. This implies that clinical studies including intramuscular injection of saline solution controls are comparing vaccine associated adverse events with saline solution innate immune response adverse events. This article proposes that innate immune responses to intramuscular injection of saline solution triggers a temporary surge in histamine levels. Further, this temporary surge of histamine levels is causative for the local and systemic adverse events experienced by the control volunteers.