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I ain't no biologist, but I came across a paper recently and tried to understand it:

SARS–CoV–2 Spike Impairs DNA Damage Repair and Inhibits V(D)J Recombination In Vitro

My question: Is it a correct takeaway that vaccines that are based on the full-length spike-protein such as the one from BioNTech may possibly be undermining our DNA repair system, rendering our immune system more vulnerable in general than it was before?

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The authors explicitly suggest the first part of your question in their discussion section:

indicating that full–length spike–based vaccines may inhibit the recombination of V(D)J in B cells,

However, for this to have a meaningful effect on the immune system as a whole requires that a significant portion of B cells uptake the vaccine and express spike protein, which isn't demonstrated. The paper also, frustratingly, doesn't indicate if their results showing an effect of spike protein on DNA-repair occur in the presence of the non-structural proteins Nsp1, 5, etc., which as they mentioned are known to transport themselves to the nucleus. If spike protein can't get to the nucleus without these other viral proteins which are not included in the vaccine, then there's no reason to suspect the vaccine-produced spikes would have this effect.

With regards to the second part, "rendering our immune system more vulnerable in general than it was before", the spike-based vaccines have been demonstrated to generate a robust B-cell response, so we can rule that out. The immune functions full-length spike protein is suggested to impair are measurably functioning well in vaccinated individuals. In the cytoplasm of cells, mRNA of vaccines and the spike protein they produce can be expected to be recycled after a day or two, so long term effects of this nature are very unlikely.

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While the linked paper presents interesting results, the conclusions must be interpreted in context of their in vitro methods and cannot be readily extrapolated to understand the in vivo effect of SARS-CoV-2 mRNA-LNP vaccines. Here is their important caveat:

Although no evidence has been published that SARS–CoV–2 can infect thymocytes or bone marrow lymphoid cells, our in vitro V(D)J reporter assay shows that the spike protein intensely impeded V(D)J recombination.

They show that spike protein expressed in human embryonic kidney cells (HEK293) can localize to the nucleus and inhibit non-homologous end-joining (NHEJ), which is a vital process in the generation of diversity in the antigen-binding regions of antibodies. However, the way the human adaptive immune system works is such that the cells responsible for generating antibody diversity never internalize the antigenic protein. Once injected, the mRNA-containing lipid nanoparticles are endocytosed by dendritic cells. The mRNA is then translated and the spike protein is presented to T- and B-cells in lymphoid tissues to elicit an immune response. These T- and B-cells are the cells that carry out V(D)J recombination, but they are not the cells that are engulfing the nanoparticle load.

Two good reviews that cover this process in-depth:

  1. Teijaro JR, Farber DL. COVID-19 vaccines: modes of immune activation and future challenges. Nat Rev Immunol. 2021 Apr;21(4):195-197.
  2. Angeli F, Spanevello A, Reboldi G, Visca D, Verdecchia P. SARS-CoV-2 vaccines: Lights and shadows. Eur J Intern Med. 2021 Jun;88:1-8.
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