Posted on: Friday, April 19th 2024 at 3:00 am
A disturbing connection between the modified genetic code in mRNA vaccines and the promotion of cancer growth has emerged, raising urgent questions about the long-term safety of these widely-administered shots.
Two recent studies suggest that the chemical modifications used in mRNA COVID-19 vaccines to evade immune detection may inadvertently be promoting cancer growth and metastasis. Modified mRNA vaccines were found to impair key anti-tumor immune pathways, in contrast to non-modified mRNA which exhibited robust anti-cancer effects in an animal model. The findings underscore the need for further research into the oncogenic potential of these vaccine modifications.
In the frantic race to develop vaccines against the novel coronavirus, mRNA technology emerged as a frontrunner, promising rapid development and deployment.1 The Pfizer-BioNTech and Moderna mRNA vaccines, first rolled out in late 2020, relied on a key modification called N1-methyl-pseudouridine (m1Ψ) to overcome the fragility and immunogenicity of conventional mRNA.2 By swapping out the standard RNA building block uridine with the engineered analog m1Ψ, the vaccines could evade immune detection long enough to generate a robust antibody response against the encoded SARS-CoV-2 spike protein.3
While this immune-evading strategy proved highly effective in generating neutralizing antibodies and preventing severe COVID-19, troubling new research suggests it may come at a steep price.4 Two recent studies raise the specter that the very same m1Ψ modification that enables the vaccines' success may also be unwittingly promoting the growth and spread of cancer.5,6
In a preprint posted on April 15, Brown University researchers Shengliang Zhang and Wafik El-Deiry reported that the SARS-CoV-2 spike protein inhibits p53, a critical tumor suppressor known as the "guardian of the genome."5 Alarmingly, this effect was observed not only with the spike protein from the virus itself but also from the mRNA vaccines encoding it. "Our results have implications for the biological effects of spike S2 subunit in human cells whether spike is present due to primary COVID-19 infection or due to mRNA vaccines where its expression is used to promote anti-viral immunity," the authors wrote.5
Impairment of p53 and its associated DNA damage repair pathways, they warned, "provides a potential molecular mechanism by which SARS-CoV-2 infection may impact tumorigenesis, tumor progression and chemotherapy sensitivity."5 In other words, both contracting COVID-19 and receiving the mRNA vaccines may make individuals more vulnerable to developing cancer, having existing tumors grow and spread, and responding poorly to cancer treatments.
While Zhang and El-Deiry's findings are preliminary and not yet peer-reviewed, they align with earlier research linking SARS-CoV-2's spike protein to weakened DNA repair mechanisms.7 A peer-reviewed study published in Viruses in October 2021 by Hui Jiang and Ya-Fang Mei similarly found that the spike inhibited recruitment of key DNA repair proteins BRCA1 and 53BP1.8 "Our findings reveal a potential molecular mechanism by which the spike protein might impede adaptive immunity and underscore the potential side effects of full-length spike-based vaccines," Jiang and Mei concluded, before their paper was abruptly retracted under murky circumstances suggestive of political motivations.9
Now, a new review paper by biologist Alberto Rubio-Casillas and colleagues published in the International Journal of Biological Macromolecules on April 5 lends further weight to the spike-cancer connection.6 Examining a melanoma model, the review found that 100% m1Ψ-modified mRNA vaccines stimulated tumor growth and metastasis, whereas non-modified mRNA vaccines had the opposite effect, reducing cancer progression.6
"Evidence is provided that adding 100% of N1-methyl-pseudouridine (m1Ψ) to the mRNA vaccine in a melanoma model stimulated cancer growth and metastasis, while non-modified mRNA vaccines induced opposite results, thus suggesting that COVID-19 mRNA vaccines could aid cancer development," Rubio-Casillas et al. wrote. "Based on this compelling evidence, we suggest that future clinical trials for cancers or infectious diseases should not use mRNA vaccines with a 100% m1Ψ modification, but rather ones with the lower percentage of m1Ψ modification to avoid immune suppression."6
The findings highlighted by Rubio-Casillas and colleagues come from a seminal study by Sittplangkoon et al., originally published in Frontiers in Immunology in November 2022.[10] Using a B16 murine melanoma model, the researchers tested the effects of varying percentages of m1Ψ incorporated into mRNA encoding the ovalbumin antigen (OVA), delivered via a lipid nanoparticle platform (OVA-LNP).
Non-modified OVA-LNP elicited robust production of type I interferons (a key mediator of anti-tumor immunity) and activation of dendritic cells, effects that were "negatively correlated with rising percentages of m1Ψ modification."10 Strikingly, while non-modified OVA-LNP dramatically reduced tumor growth and prolonged survival in the melanoma-bearing mice, 100% m1Ψ-modified OVA-LNP had the reverse impact, increasing tumor progression and mortality.10 All the animals receiving the non-modified vaccine survived until the end of the 31-day experiment, compared to only half of those given the maximally modified mRNA.10
Further experiments shed light on the mechanisms behind these divergent outcomes. Non-modified mRNA strongly activated toll-like receptors TLR7/8, inducing an M1 macrophage phenotype associated with anti-tumor effects, while m1Ψ modification blocked this pathway.10 The unmodified vaccine also prevented lung metastasis, an effect completely ablated by 100% m1Ψ-modified mRNA.10
Though Sittplangkoon et al.'s study utilized a cancer vaccine model rather than the COVID-19 shots specifically, the differences they observed were entirely attributable to the presence or absence of m1Ψ, which the coronavirus vaccines contain. As Rubio-Casillas et al. noted, "m1Ψ constitutes a positive outcome for COVID-19 vaccine success by dampening the anti-RNA immune response. However, avoiding immune detection of the mRNA by adding m1Ψ favors a greater spike protein synthesis but, in contrast, it might induce immune suppression that could favor the reactivation of quiescent bacterial, viral, or fungal infections, as well as perhaps enabling the unrestrained multiplication of cancer cells."6
While the potential oncogenic impact of mRNA vaccine modifications requires further study and validation, the preclinical evidence that has emerged thus far is troubling. COVID-19 vaccine trials and post-authorization monitoring have focused almost exclusively on short-term efficacy and safety endpoints like antibody titers and adverse events in the weeks following immunization.11 Long-term effects on complex processes like cancer development remain unknown in the absence of extended follow-up and adequate control groups.
Cancer often progresses silently for years or decades before becoming clinically apparent.12 To determine whether the billions of people who have received m1Ψ-modified mRNA vaccines face elevated cancer risks, large-scale epidemiological studies with rigorous designs and lengthy durations will be necessary. In the meantime, a precautionary approach is warranted.
As Rubio-Casillas and colleagues urged, "we suggest that until it is demonstrated that mRNA vaccines do not promote the development of cancer, clinical trials using 100% modified mRNA vaccines with m1Ψ should not be carried out."6 While the global pandemic created intense pressure to develop vaccines with unprecedented speed, short-cutting safety evaluations can have grave unintended consequences.
The discovery that a modest chemical tweak to mRNA can profoundly alter its interactions with the immune system, at times tipping the scales from anti-cancer to pro-cancer effects, should give us serious pause. A technology hailed as a panacea may yet prove to be a Pandora's box. Only time and rigorous scientific inquiry can disentangle the full web of effects unleashed by these powerful but incompletely understood genetic interventions. Lives hang in the balance.
References
1. Jackson, N.A., Kester, K.E., Casimiro, D., Gurunathan, S. and DeRosa, F. "The promise of mRNA vaccines: a biotech and industrial perspective." npj Vaccines 5 (2020): 1-6. https://doi.org/10.1038/
2. Karikó, K., Buckstein, M., Ni, H. and Weissman, D. "Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA." Immunity 23 (2005): 165-175. https://doi.org/10.1016/j.
3. Karikó, K., Muramatsu, H., Welsh, F.A., Ludwig, J., Kato, H., Akira, S. and Weissman, D. "Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability." Molecular Therapy 16 (2008): 1833-1840. https://doi.org/10.1038/mt.
4. Seneff, S., Nigh, G., Kyriakopoulos, A.M., McCullough, P.A. "Innate immune suppression by SARS-CoV-2 mRNA vaccinations: The role of G-quadruplexes, exosomes, and MicroRNAs." Food and Chemical Toxicology 164 (2022): 113008. https://doi.org/10.1016/j.fct.
5. Zhang, S., El-Deiry, W. "SARS-CoV-2 spike S2 subunit inhibits p53 activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2 proteins in cancer cells." Preprint (2023). bioRxiv. https://doi.org/10.1101/2023.
6. Rubio-Casillas, A., Cowley, D., Raszek, M., Uversky, V.N., Redwan, E.M. "Review: N1-methyl-pseudouridine (m1Ψ): Friend or foe of cancer?" International Journal of Biological Macromolecules 267 (2024): 131427. https://doi.org/10.1016/j.
7. Jiang, H., Mei, Y.F. "SARS-CoV-2 Spike Impairs DNA Damage Repair and Inhibits V(D)J Recombination In Vitro." Viruses 13 (2021): 2056. https://doi.org/10.3390/
8. Jiang, H., Mei, Y.F. "SARS-CoV-2 Spike Impairs DNA Damage Repair and Inhibits V(D)J Recombination In Vitro." Viruses 13 (2021): 2056. https://doi.org/10.3390/
9. Ji, S. "Welcome to Gilead: A Primer on the Retraction of 'SARS-CoV-2 Spike Impairs DNA Damage Repair and Inhibits V(D)J Recombination In Vitro'." Arkmedic. (2022). https://arkmedic.substack.com/
10. Sittplangkoon, C., Alameh, M.G., Weissman, D., Sardesai, N. "mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model." Frontiers in Immunology 13 (2022): 983000. https://doi.org/10.3389/fimmu.
11. Polack, F.P., Thomas, S.J., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., Perez, J.L., Pérez Marc, G., Moreira, E.D., Zerbini, C. and Bailey, R. "Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine." New England Journal of Medicine 383 (2020): 2603-2615. https://doi.org/10.1056/
12. Nadler, D.L., Zurbenko, I.G. "Estimating cancer latency times using a Weibull model." Advances in Epidemiology (2014). https://doi.org/10.1155/2014/
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