Pre-exposure to mRNA-LNP inhibits adaptive immune responses and alters innate immune fitness in an inheritable fashion

Abstract

Abstract During the ongoing SARS-CoV-2 pandemic, hundreds of millions of people have been exposed to the experimental mRNA-LNP-based COVID vaccines, of which long-term immune effects are unknown. We previously showed that this vaccine platform is highly inflammatory. Its synthetic ionizable lipid component, which has a long in vivohalf-life, is responsible for the induction of inflammation and adaptive immune responses. The inflammatory component’s long in vivohalf-life could be a reminiscence of a chronic infection, which is known to lead to immune exhaustion and non-responsiveness. Therefore, here, we sought to determine the effects of pre-exposure to the mRNA-LNP on adaptive immune responses and innate immune fitness. We found that pre-exposure to mRNA-LNPs or LNP alone led to long-term inhibition of the adaptive immune response, which could be overcome using standard adjuvants. On the other hand, we report that after pre-exposure to mRNA-LNPs, the resistance of mice to heterologous infections with influenza virus increased while resistance to Candida albicansdecreased. The diminished resistance to Candida albicanscorrelated with a general decrease in blood neutrophil percentages. Interestingly, mice pre-exposed to the mRNA-LNP platform can pass down the acquired immune traits to their offspring, providing better protection against influenza. In summary, the mRNA-LNP vaccine platform induces long-term unexpected immunological changes affecting both adaptive immune responses and heterologous protection against infections. Thus, our studies highlight the need for more research to determine this platform’s true impact on human health. National Institute of Allergy and Infectious Diseases (https://www.niaid.nih.gov) R01AI146420 and R01AI146101