Report 91: FDA Based Moderna’s mRNA COVID Vaccine Approval on Test of a Completely Different Non-COVID Vaccine. Only Males Included in Test.

Linnea Wahl, MS - Team 5

Moderna researchers did not test their COVID-19 mRNA drug, called SPIKEVAX, to find out where it would go in our bodies (biodistribution). Instead, their biodistribution study was for a completely different vaccine. Despite this substitution of one drug study for another, the U.S. Food and Drug Administration (FDA) approved SPIKEVAX for both emergency and routine use by Americans.

Introduction

The FDA declared in its own words that Moderna researchers did not test their COVID-19 mRNA drug SPIKEVAX to determine its distribution throughout the body. In the FDA reviewers' own words: “A biodistribution study was not performed with mRNA-1273 vaccine [SPIKEVAX]. Results from the biodistribution study of a different vaccine . . . were submitted in support of SPIKEVAX” (FDA 2022a, p. 14). (Italics added.) Incredibly, instead of testing their COVID vaccine for biodistribution, Moderna researchers substituted tests from a different mRNA drug. The researchers tested this completely different drug in the blood of rats  and examined its distribution in 13 different body tissues (Moderna Therapeutics n.d.). In spite of this substitution, on December 18, 2020, the FDA authorized emergency use of Moderna’s COVID-19 mRNA drug (FDA 2020), and on January 31, 2022, the FDA fully approved Moderna to manufacture and distribute SPIKEVAX (FDA 2022b). It does not appear that the FDA challenged the substitution of a completely different drug biodistribution study for the Moderna COVID-19 injection, SPIKEVAX.

What is a biodistribution study?

Why is it so important that one drug was substituted for another in Moderna's biodistribution study? A biodistribution is an important hurdle in the drug approval process. Before the FDA approves a new drug for use in humans, drug manufacturers need to show where the drug goes in the body, how long it stays there, and how it is removed. Test animals, such as mice, rats, monkeys, are used for this. Typically, a group of test animals receives the same drug at the same dosage that is proposed for use in humans. Then at regular intervals, researchers sacrifice a subset of the animals and examine their tissues to see how much of the drug has reached each tissue. A drug that biodistributes to inappropriate organs — such as to the heart, in the case of a drug designed to move through the lymph system — may not be safe for human use.

The FDA certainly recommends biodistribution studies for proposed drugs that involve gene therapy; drugs which include genetic materials such as RNA and messenger RNA (mRNA) (FDA 2023). As a result, Moderna officials would have fully expected that the FDA would regulate their mRNA drugs as gene therapy drugs (SEC 2019). This is why Moderna researchers had performed a biodistribution study in 2017 on their experimental mRNA drug against cytomegalovirus (CMV) (Moderna Therapeutics n.d.).

So, bizarrely, the FDA recommends biodistribution studies for mRNA gene therapies in general, but the agency excludes "vaccines" from this guidance even if they include gene therapy mRNA (Vervaeke et al. 2022).

No biodistribution study on SPIKEVAX

So, even though Moderna's mRNA-1273 drug for COVID-19 is a gene therapy, this wordplay loophole allowed Moderna to avoid a biodistribution study. Consequently, the researchers submitted the results of a study on a different mRNA drug (mRNA-1647) and asked FDA reviewers to accept it instead (ModernaTX n.d.).

Moderna researchers told FDA reviewers that SPIKEVAX would distribute throughout our bodies in the same way as Moderna's mRNA drug for CMV (a common virus that usually is not a problem for adults but can result in hearing loss in infants). Because Moderna claims that the two drugs use the same lipid nanoparticle (LNP) formulation to encapsulate mRNA, Moderna researchers argued that they would spread to tissues and organs in the body in the same way.

Substitute biodistribution study

But the substituted biodistribution study itself did not show anything like safety. The materials injected into the rats went everywhere.

The substitute biodistribution study was conducted from August 23, 2017, through September 7, 2017 (Moderna Therapeutics n.d.). Moderna researchers injected 35 male rats with an experimental mRNA drug that they hoped would cause the rats to produce antibodies to CMV. At seven timed intervals (0, 2, 8, 24, 48, 72, and 120 hours), researchers sacrificed five rats and analyzed their blood and tissues for the injected mRNA.

Researchers analyzed tissues from 13 organs after each group of rats was euthanized: lung, liver, heart, kidney, lymph nodes, spleen, brain, stomach, testes, eye, bone marrow, intestine, and injection site muscle. Blood samples were also collected.

Moderna’s rat study showed that the CMV mRNA drug quickly distributed to 12 of 13 organs and blood. Researchers measured maximum concentrations of the injected mRNA within 2 to 8 hours after injection, and they found mRNA in blood and all tissues except the rats’ kidneys. In the spleen and the eye tissues, researchers found mRNA at greater levels than in the blood, suggesting that the drug concentrated in those two organs. Despite the wide distribution of this drug throughout rats’ bodies, the FDA reviewers accepted this study as proof that Moderna’s SPIKEVAX was safe for human use (FDA 2020; FDA 2022b).

Faulty comparison

Are the two drugs similar enough to support Moderna’s claim that they distribute throughout the body in the same way? No. There are important differences between the two mRNA drugs. Table 1 summarizes the components of Moderna’s two mRNA drugs, as well as those of Pfizer’s COVID-19 mRNA drug, BNT162b2.

Table 1. Comparison of CMV and COVID-19 mRNA Drug Components

a ModernaTX n.d.

b Wilson and Geetha 2022

c Moderna Therapeutics n.d.

In SPIKEVAX, the LNP capsule has four lipid components (a lipid is a fatty compound): 1) an ionizable lipid called SM-102, 2) a helper lipid called DSPC, 3) a polyethylene glycol (PEG) lipid called PEG2000-DMG, and 4) a cholesterol molecule, which is essentially the same in all mRNA drugs that use LNP capsules (Barbier et al. 2022). Much less is known about the LNP capsule of Moderna’s CMV mRNA drug. Moderna admits only that the CMV mRNA drug is encased in an LNP shell that contains their “standard proprietary” SM-102-ionizable lipid (ModernaTX n.d.).

No information is available to prove that the other three lipids in Moderna's CMV drug are the same as lipids in SPIKEVAX. Yet LNP identicalness is the basis for Moderna’s claim that the two drugs spread throughout the body in the same way, and that Moderna researchers did not need a separate study of the biodistribution of SPIKEVAX.

More information is known about the mRNA that is inside Moderna’s LNP capsule—the genetic payload. In SPIKEVAX, the contents of the LNP shell are the genetic sequence that codes for the SARS-CoV-2 spike protein. By contrast, Moderna’s CMV mRNA drug consists of six different genetic sequences, all of which code for CMV proteins. While Moderna researchers argued that the contents of the LNP shells would not affect where the drug goes in the human body, no data are available to show this.

Are the LNP shells of the two drugs the same size, given that their contents are radically different mRNA molecules? Researchers have shown that the size of drug particles affects tissue distribution and clearance; for example, liver uptake and accumulation and kidney excretion depend significantly on LNP size (Danaei et al. 2018). Do the LNP particles of Moderna’s CMV and COVID-19 mRNA drugs biodistribute similarly? The FDA reviewers did not ask.

Where are the females?

Because the study included only male rats, no female rats were injected, and no female organs were analyzed. Nor did the FDA reviewers ask whether SPIKEVAX, for its sake, would concentrate in ovaries. The CMV mRNA drug biodistribution study, which excluded females, was not designed either to ask or answer questions about the drug's impact on female organs. How can the FDA thus conclude that SPIKEVAX will be safe for females?

Conclusion

The FDA approved Moderna's COVID-19 mRNA drug SPIKEVAX for both emergency use and routine use by Americans without adequate testing for biodistribution: Moderna replaced apples with oranges. As researchers have noted: “The wide and persistent biodistribution of mRNAs and their protein products, incompletely studied due to their classification as vaccines, raises safety issues” (Banoun 2023, p. 1)

Biodistribution studies must be done in animals of both sexes -- using the correct formula -- before FDA approval and not in humans after FDA approval.

References

Banoun 2023. Banoun H. mRNA: Vaccine or gene therapy? The safety regulatory issues. International Journal of Molecular Sciences, 24, 10514. doi: 10.3390/ijms241310514

Barbier et al. 2022. Barbier AJ, Jiang AY, Zhang P, Wooster R, Anderson DG. The clinical progress of mRNA vaccines and immunotherapies. Nature Biotechnology 40: 840—854. doi: 10.1038/s41587-022-01294-2

Danaei et al. 2018. Danaei M, Dahghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A, Khorasani S, Mozafari MR. Impact of particle size and polydispersity index on the clinical applications of lipid nanocarrier systems. Pharmaceutics10(2): 57. doi: 10.3390/pharmaceutics10020057

FDA 2020. U.S. Food and Drug Administration. FDA takes additional action in fight against COVID-19 by issuing emergency use authorization for second COVID-19 vaccine. https://www.fda.gov/news-events/press-announcements/fda-takes-additional-action-fight-against-covid-19-issuing-emergency-use-authorization-second-covid

FDA 2022a. U.S. Food and Drug Administration. Summary basis for regulatory action: SPIKEVAX. https://www.fda.gov/media/155931/download

FDA 2022b. U.S. Food and Drug Administration. BLA approval: SPIKEVAX. https://www.fda.gov/media/155815/download?attachment

FDA 2023. U.S. Food and Drug Administration. S12 nonclinical biodistribution considerations for gene therapy products: guidance for industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/s12-nonclinical-biodistribution-considerations-gene-therapy-products

ModernaTX no date. 2.4 Nonclinical overview FDA-CBER-2021-4379-0001131. Obtained by FOIA by Judicial Watch, Inc. https://www.judicialwatch.org/wp-content/uploads/2022/12/JW-v-HHS-Biodistribution-Prod-4-02418-pgs-671-701.pdf

Moderna Therapeutics, Inc. no date. A single dose intramuscular injection tissue distribution study of mRNA-1647 in male Sprague-Dawley rats. https://phmpt.org/wp-content/uploads/2023/08/125752_S1_M4_report-body-5002121-amend-1.pdf

NIH 2021. U.S. National Institutes of Health, Division of Microbiology and Infection Disease. Phase I, open-label, dose-ranging study of the safety and immunogenicity of 2019-nCoV vaccine (mRNA-1273) in healthy adults. DMID Protocol 20-0003, version 7.0.

SEC 2019. U.S. Securities Exchange Commission. Moderna, Inc: Annual report pursuant to section 13 or 15(d) of the Securities Exchange Act of 1934. https://www.sec.gov/Archives/edgar/data/1682852/000168285220000006/moderna10-k12312019.htm

Vervaeke et al. 2022. Vervaeke P., Borgos SE, Sanders NN, Combes F. Regulatory guidelines and preclinical tools to study the biodistribution of RNA therapeutics. Advanced Drug Delivery Reviews, 184, 114236. doi: 10.1016/j.addr.2022.114236

Wilson and Geetha. 2022. Wilson B, Geetha KM. Lipid nanoparticles in the development of mRNA vaccines for COVID-19. Journal of Drug Delivery Science and Technology 74: 103553. doi: 10.1016/j.jddst.2022.103553