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

Objective: A placebo is by definition a harmless substance with no therapeutic effect. Clinical studies often include placebo controls to enable differentiation between treatment efficacy and adverse events from placebo effects. Intramuscular injection of saline solution was used in coronavirus disease 2019 (COVID-19) vaccine clinical trials as the placebo control. The underlying hypothesis for using intramuscular injection of saline solution is that it should not cause adverse events. Multiple of these clinical trials reported systemic adverse event levels more consistent with an intervention than a placebo control. Methods: PubMed literature was searched for COVID-19 clinical trials including intramuscular injection of saline as a placebo control. Clinical trial placebo results for Pfizer COMIRNATY, Moderna SPIKEVAX, Janssen AD26.COV2.S, Medicago Covifenz (CoVLP) + AS03 (adjuvant system 03), Medigen MVC-COV1901, Novavax NVX-CoV2373, and Sinopharm WIBP-CorV were reviewed. Results: Two studies reported from China are consistent with intramuscular injection of saline associated systemic adverse events consistent with the definition of a placebo control. All other studies reported discordant results with more than 100,000 volunteers receiving intramuscular injection of saline solutions exhibited high levels of systemic adverse events; these frequencies of systemic adverse events are inconsistent with the definition of a placebo control. 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. Conclusion: This article proposes the hypothesis that innate immune responses to intramuscular injection of saline solution causes systemic adverse events in a subset of volunteers. Intramuscular injection of saline solution is proposed to trigger an innate immune response in some volunteers with released inflammatory molecules including a temporary surge in histamine levels. Further, this temporary surge of histamine levels may be causative for most of the systemic adverse events experienced by the control volunteers.