How many vaccinations do you need to become immune to Covid19?
Depending on the variant in circulation and the variant your last booster is formulated to you can develop immune tolerance to SARS-COV-2 from any number of repeated modRNA booster doses and it must be modRNA LNP transfections as other platforms such as the inactive or attenuated antigen, adenoviral vector and recombinant spike protein shots do not appear to have this effect based on current available evidence.
Repeated modRNA doses have been found to promulgate an antibody subclass shift from more inflammatory IgG1, IgGE and IgG3 antibodies that stimulate complement immune responses such as phagocytosis of infected cells to a higher prevalence of non-neutralizing IgG4 antibodies that not only don’t stimulate complement immune processes but may actually block other subclasses of antibodies from doing so, resulting in disease enhancement, because the body typically creates them after repeated exposure to non-pathogenic antigen to induce immune tolerance (Trampert et al., 2018). Between the primary series and the boosters, non-neutralizing immunoglobulin G4 titers rise from normal levels to a disproportionate G4 response after boosting, rising from 0.04% of antibodies after the primary series to 19.3% after the first booster dose. (Valk et al.,) found that IgG4 levels rose as high as 21.2% after the first booster dose. Nature Microbiology identifies non-neutralizing and sub-neutralizing antibodies (e.g. IgG2 & IgG4) binding to viral antigens as one of two mechanisms that creates antibody dependent enhancement (of disease), specifically by binding to viral surfaces and incorporating them into white blood cells that effectively become hosts for replication. Non-neutralizing antibodies have been found to enhance viral infections of alveolar and peritoneal white blood cells in particular.
Immunoglobulin G subclass switch to G4 that is associated with immune tolerance to foreign antigens could also allow cancer development. The immunoglobulin G4 subclass switch of SARS-Cov-2 specific antibodies has been found to occur several months after the second dose of the primary series with the booster enhancing the risk of breakthrough infection after a few months by increasing the proportion of G4 immunoglobulin G. We know that the subclass switch is not protective because, as Uversky and colleagues note, patients who die with critical COVID disease have a greater proportion of immunoglobulin G4 than patients who recover. The COVID mortality noticeably increased when IgG4 serum concentrations exceeded a ratio of 0.05 (5%) to IgG1 antibody levels. The G4 subclass switch of IgG antibodies is also why VE wanes after a few months except it isn’t the modRNA effectiveness that is waning but your immune system’s effectiveness in stopping infection.
In their review, they also point out that boosters substantially increase the development of immune tolerance. A serological study found that about half of modRNA recipients had detectable anti-SP IgG4 antibodies 5-6 months after the second dose while only 1 out of 51 adenoviral vector recipients had detectable concentrations. All modRNA recipients experienced a substantial increase in IgG4 antibody proliferation after the first booster. The subclass shift takes at least a few months to occur which may explain why we observe initially high VE against infection and symptoms in the first two months that rapidly declines between months 2-3 post administration, becomes negligible between months 4-6 and results in negative VE against infection after 6 months (well before the next annual booster rollout). However, this precipitous rise in IgG4 levels was only seen if the recipient was vaccinated prior to infection (Buhre et al. 2022), since, as explained by (Mulligan et al., 2020) prior infection provides much more comprehensive immune response that is not restricted to lymphocyte production against the spike protein your cells are instructed to synthesize but other viral proteins as well and it is also mediated through interferons released during viral infection.
A recent blood sample study conducted by Kalkeri et al., which analyzed and compared antibodies from blood samples taken 6 months after patients had received their last Pfizer or Moderna boosters followed by a single dose of Novavax recombinant spike shot (n = 20) with patients who had received only 4 Novavax doses (n = 18) found that recipients of 4 Novavax recombinant spike had >10x higher anti-spike IgG3 (inflammatory) antibodies, which are responsible for 80% of neutralizing activity, compared to recipients of ModRNA boosters while said recipients had >75x anti-spike IgG4 (non-inflammatory) antibodies that are linked to immune tolerance and suppression.
Another study published in Vaccines, (Sheehan et al.,) collected blood samples from (n = 16) SARS-COV-2 naive booster recipients at 6 times points over 420 days, including prior to vaccination, and found that receptor binding domain and spike-specific IgG4 antibody levels were significantly elevated in boosted but not primary series immune blood samples. IgG1 and IgG3 neutralizing antibody levels peaked at 3 weeks after the second dose and declined after four months. While IgG2 and IgG4 levels were initially negligible during the primary series the booster dose induced changes in the subclass distribution. While receptor binding domain and s-protein reactive IgG2 and IgG3 were not detected 6 months after the booster antigen specific IgG1 and IgG4 antibodies persisted after this duration. Neutralizing titers declined to pre-immune levels 6 months after the booster.
While boosters enhanced serum IgG Ab reactivity and nAb responses against variant strains, all variants tested showed resistance to two- and three-dose immune sera. Our data reflect the poor durability of vaccine-induced nAb responses which are a strong predictor of protection from symptomatic SARS-CoV-2 infection. The induction of IgG4-switched humoral responses may permit extended viral persistence via the downregulation of Fc-mediated effector functions.
I posted more serological and observational evidence of immune tolerance last year in response to a similar question:
What Makes the ModRNA Vaccine So Effective
Observations of modRNA shots creating immune tolerance to specific antigens and possible enhancement of disease are not new and have previously been observed in clinical trials for HIV [113] and Malaria vaccines [115] which directly linked increased risk of infection with IgG4 selection.
In an HIV vaccine trial statistically significant protection was associated with G1 and G3 immunoglobulin production while negligible VE was associated with G4 immunoglobulin production. The HIV vaccine that offered negligible protection involved a higher number of shots that impaired the Fc effort function of antibodies.
Similarly, in a malaria vaccine trial, doubling the production of G1 and G3 immunoglobulin G in the second year after immunization reduced the relative risk of contracting malaria by 50% and 60% respectively. However, doubling the amount of G4 immunoglobulin G increased the risk of contracting Malaria 3x. Overall, G1 and G3 resulted in a 51% and 56% lower relative risk of infection for vaccinees at 2 years of age while G4 proliferation resulted in an increased risk of infection at that age. A separate Malaria vaccine trial found the same results.
The downside of developing immune tolerance to a pathogen, even a less virulent one, isn’t constrained to more frequent reinfections or even antibody dependent enhancement of disease for the immune compromised because elevated Immunoglobulin G4 concentrations in tissue with cancer cells can hinder other antibody mediated immune responses to the cancer aiding cancer progression. Three separate rodent experiments demonstrated that Immunoglobulin G4 administration sped up cancer growth. IgG4 proliferation can also create autoimmune disorders by impeding regulatory T cells.
Repeated antigen stimulation of the immune system (via boosters) has also been found to cause memory T cell exhaustion and immune suppression through repeated receptor binding domain immunization. T cells can become highly specialized through a process known as "terminal differentiation" after high concentration inoculations and lose their ability to divide and proliferate leading to immune exhaustion.
Interferons are critical immune modulating proteins that modRNA shots temporarily impair. As the name implies they interfere with viral proliferation by binding to different cell receptors. Some interferon types, like type I alpha interferons, are released by the immune system's white blood cells and memory cells upon encountering viral particles and can induce cell differentiation, cell death and the activation of other white blood cells like cytotoxic (killer) T cells against infected cells.
mRNA and inactivated vaccines temporally impair interferon signaling [142,143], possibly causing immune suppression and leaving the individual in a vulnerable situation against any other pathogen. In addition, this immune suppression could allow the re-activation of latent viral, bacterial, or fungal infections and might also allow the uncontrolled growth of cancer cells [144].
modRNA LNPs may not cause cancer but a combination of long term immune tolerance and T cell exhaustion and temporary interferon impairment after each booster could allow cancer cell growth. Type 1 Interferons initiate immune responses to tumors. modRNA also impairs Toll-like receptors that signal tumor progression to the rest of the immune system.
As Rubio-Casillas and colleagues note in their Review: N1-methyl-pseudouridine friend or foe of cancer? two prior rodent studies 100% modified N1-Methyl-psuedouridine LNPs of ovalbumin cut the survival rate in half for the animals with tumors. A separate rodent experiment demonstrated that 100% modified N1-methylpsuedouridine LNPs impair interferon synthesis making cancer survival less likely. When Pfizer modRNA shots, which replace uridine with 100% modified N1-methylpsuedouridine, reduced interferon signaling they could switch macrophages from inflammatory M1 immune cells to non-inflammatory M2 cells that inhibit effector t-cells and have been known to stimulate tumor growth.
Of course, we would also need to consider the unintended effects of replacing the uridine base of mRNA with 100% modified N1-methylpsuedouridine in modRNA that supposedly increases its stability. Mulroney and colleagues recently discovered that the ribosomes in your cells will mistranslate the instructions given to it to synthesize the spike protein when it encounters N1-Methyl pseudouridine from the modRNA LNPs where it would otherwise encounter the nucleoside base uridine in endogenous mRNA. This mistranslation causes ribosomes attempting to synthesize the spike protein to stall and frameshift the rest of the modRNA sequence for the amino acids encoded for during translation leading to a different protein than the spike protein for the subvariant the product was developed for. Then this will elicit off-target immune responses from your body. While the authors find no evidence of adverse outcomes from mistranslation in their small sample size (n =21) they suggest “these data highlight potential off-target effects for future mRNA-based therapeutics and demonstrate the requirement for sequence optimization.” However, as (Wiseman et al., 2023) explains it would be hard to detect adverse outcomes with such a sample size, that makes an extreme selection bias highly probable, and no control group for comparison. Ribosomal frameshifting that the N1-methyl pseudouridine causes is also associated with cancer cells. This could also lead to autoimmune disorders when cells present off target proteins on the surface of dendritic cells. 47% of Pfizer modRNA compatible transcripts create R-loops, triple stranded structures of displaced DNA and DNA/RNA hybrids, that often damage DNA.
As I pointed out in a prior post you need Immunoglobulin A induced mucosal immunity to prevent infection at the actual site of infection. Circulating IgA does not enter mucosal secretions in the upper respiratory tract and neither do IgG induced in the lymphatic system.