The provisional approval granted to Moderna for its anti-Covid mRNA in January 2021 reveals that regulators knew much more than they published about the product’s defects. In particular, Moderna did not provide sufficient evidence of the compliance of its mRNA product, excipients and lipid nanoparticle (LNP) components.
Source Swiss Medic, content provided by Dr. Hélène Banoun
Residual DNA contaminants are not properly assessed, mRNA compliance is not proven, LNPs size is not specified, nor are lipid impurities. Data are lacking on new excipients and PEG. The in-vitro transcription process used to obtain mRNA from DNA is unsatisfactory.
The results of tests for the presence of bacterial endotoxin (from the production process) are not provided. The method for sequencing the mRNA obtained is not correctly described.
Moderna has shown in its marketing authorization application that the spike produced in the vaccinee spreads to the lymph nodes, spleen and bloodstream, liver and lungs, but research into other tissues is lacking.
As of January 2021, Swissmedic is concerned about the risk of reverse transcriptase of vaccine mRNA into DNA and the resulting integration into the genome. Swissmedic recommends that Moderna address the risk of reverse transcriptases (LINE-1, HIV) converting N1-methyl-pseudouridine-modified mRNA into DNA.
Following the biodistribution of the vaccine spike throughout the body, SwissMedic warns against post-vaccination autoimmune diseases, pointing out that these disorders may appear after a long pre-symptomatic phase. Moderna is asked to investigate various types of autoantibodies in both vaccinated and non-vaccinated subjects.
Approval decision SwissMedic points out that the documentation submitted up to 12 January 2021 is “insufficient for the granting of an ordinary marketing authorization.
SwissMedic document provided by Viviane Cuendet https://drive.google.com/file/d/1WDXt55l9fAjRjNfhxZK5gEe6JHtQ9iID/view Provisional authorization of Covid Moderna mRNA vaccine by SwissMedic on January 12, 2021 Bern, 12.01. 2021
MA number: 68267 – COVID-19 Vaccine Moderna dispersion for injection
Application number: 102643108 Your application dated 09.11.2020
Here are some useful comments from SwissMedic
The definition of “drug substance” is not consistent: only the mRNA is considered as DS by Moderna; for a definitive MA Moderna will have to provide documentation also for the excipients, the drug product.
SwissMedic requests re-evaluations of:
Residual DNA Template
– %5′ Capped
– % PolyA Tailed RNA
– Polydispersity
– LNP size
– Content of the four lipids
– Lipid impurities
Post-Main Peak impurities by RP-HPLC
There is a discrepancy between the In-Vitro Transcription Non-critical Process Parameters range defined in the protocol PV-VL-RPT-0001 and those defined in 3.2.S.2 .2 “Description of the Manufacturing Process and Process Controls {CX-024414)” (e.g. DNAse reaction duration range is larger in the PPQ report, Oligo dT chromatography flow rates are not listed). Please ensure that the parameters used in all the PPQ runs are compliant with the predefined parameters and their NORs and if necessary, they should be corrected is the next eCTD sequence.
The verification report of the Endotoxin test methods is not attached
Request
Provide an overview of the plasmid manufacturing process and release testing
Product characterization
The Sanger sequencing method described for Lonza does not correspond to the one used by ~ (contract labor for Lonza). Please update the method description accordingly in the next eCTD Sequence.
Analytical Procedure UPLC-CAD: Detection and quantitation limit for other lipids and individual impurities have to be evaluated by 30 SEP-2021.
Data are missing on the new excipient SM-102 and on PEG2000-DMG
Biodistribution
Moderna performed a characterisation of the antigen expression in cells at the injection site, in the draining lymph nodes, spleen and in systemic circulation (liver, lung, any other tissues?).
Reverse transcription risk
Swissmedic agrees that the risk of reverse transcription of modified mRNA by LINE-1 encoded RT and subsequent integration into the genome is very small. However, the public interest in the paper published by the Jaenish lab is not to underestimate.
Zhang L, Bisht P, Flamier A, Barrasa MI, Friesen M, Richards A, Hughes SH, Jaenisch R. LINE1-Mediated Reverse Transcription and Genomic Integration of SARS-CoV-2 mRNA Detected in Virus-Infected but Not in Viral mRNA-Transfected Cells. Viruses. 2023 Feb 25;15(3):629. doi: 10.3390/v15030629. PMID: 36992338; PMCID: PMC10057545. https://pubmed.ncbi.nlm.nih.gov/36992338/
Swissmedic recommends that Moderna addresses the risk whether reverse transcriptases (LINE-1, HIV) can convert N1-methyl-pseudouridine-modified mRNA into DNA.
Auto-immunity
The widespread distribution of SARS CoV-2 spike protein encoding mRNA may also occur in humans and may pave the way to various organ-specific autoimmune disorders.
Such disorders usually have a long pre-symptomatic phase in which only organ-specific autoantibodies are found. It would be informative if the sponsor would provide data on auto-antibodies in a significant number of vaccinated and unvaccinated subjects (ANA, anti-dsDNA, liver, neural tissues, muscle, neuromuscular junction, thyroid, pancreas, joints, blood vessels, red blood cells etc.).
