Rapid Response to: Will covid-19 vaccines save lives? Current trials aren’t designed to tell us

“Peter Doshi’s nuanced article has opened up a rigorous and valuable discussion about the ongoing COVID-19 mRNA vaccine clinical trials, and I would like to home in on what is perhaps the most salient source of concern about their efficacy and safety, and a key step in building public confidence: the need for extensive data on the vaccines' cellular tropism and MHC Class I vs. MHC Class II-mediated antigen presentation, with attendant questions about potential seeding of autoimmunity. The mRNA vaccines’ nucleic acid payload is ferried into human cells via complex lipid nanoparticles (LNPs) with a lipophilic formulation capable of traversing phospholipid bilayers, through endocytosis and other mechanisms. While some LNP vehicles have been engineered with specific tropisms for target tissues, others have less selective tropisms (or are even potentially omnitropic), capable of entering diverse cell types. From studies thus far, it remains unclear under which category the LNPs used in the COVID vaccine trials appear to fall, and this point is essential for gauging long-term safety and efficacy. If these LNPs have a broad cell tropism, then they would be capable of entering and expressing the SARS-CoV-2 viral spike protein within the parenchyma of vital organs and tissues, well beyond the tropism of wild-type coronavirus. The resulting non-self protein, presented to immune surveillance via MHC-I complexes, would trigger a cytotoxic (CD8-mediated) immune response to the expressing cells, which could with time engender clinically significant tissue damage…

At present, relatively little has been reported on the tissue localization of the LNPs used to encase the SARS-CoV-2 spike protein-encoding messenger RNA, and it is vital to have more specific information on precisely where the liposomal nanoparticles are going after injection, both in concurrent animal studies and in the two ongoing mRNA vaccine human trials. This process can be commenced in straightforward fashion through cell culture and animal-based investigations, by supplying mRNA expressing a fluorophoric reporter gene (such as green fluorescent protein) delivered via the same LNP formulations as used in the two vaccine trials, and tracking its ingress into varied cells and tissues. The mRNA vaccines represent a remarkable and promising technology, with potential to expedite the development of immunization protocols for future epidemics, but this promise will evaporate if unanticipated safety issues and side effects emerge to weaken public trust in the new modality. Cellular and tissue localization data on the vaccines’ tissue tropisms, obtained and confirmed across multiple independent laboratories, would constitute a valuable step to reinforce public confidence in this regard.”