Research suggests Pfizer-BioNTech COVID-19 vaccine reprograms innate immune responses

Researchers in The Netherlands and Germany have warned that Pfizer-BioNTech’s coronavirus disease 2019 (COVID-19) vaccine induces complex reprogramming of innate immune responses that should be considered in the development and use of mRNA-based vaccines.

Jorge Domínguez-Andrés and colleagues say that while the vaccine has been shown to be up to 95% effective in preventing infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and subsequent COVID-19, little is known about the broad effects the vaccine may have on the innate and adaptive immune responses.

In the current study (not peer-reviewed*), the research team from Radboud University Medical Center and Erasmus MC in the Netherlands, and the Helmholtz-Centre for Infection Research (HZI), Hannover Medical School (MHH), and the University of Bonn, in Germany, confirmed the efficacy of BNT162b2 vaccination at inducing effective humoral and cellular immunity against several SARS-CoV-2 variants.

However, they also showed that the vaccine altered the production of inflammatory cytokines by innate immune cells following stimulation with both specific (SARS-CoV-2) and non-specific (viral, fungal and bacterial) stimuli.

Following vaccination, innate immune cells had a reduced response to toll-like receptor 4 (TLR4), TLR7 and TLR8 – all ligands that play an important role in the immune response to viral infection.

Neta and colleagues also found that cytokine responses to fungi were increased following vaccination.

The mRNA BNT162b2 vaccine induces complex functional reprogramming of innate immune responses, which should be considered in the development and use of this new class of vaccines,” writes the team.

A pre-print version of the research paper is available on the medRxiv* server. A preprint is a version of a scholarly or scientific paper that precedes formal peer review and publication in a peer-reviewed scholarly or scientific journal.

The accelerated development of new vaccine technologies

Since the COVID-19 pandemic began in late December 2019, researchers across the globe have been racing to develop vaccines to help combat the global healthcare crisis.

The scale of the pandemic has led to the accelerated development of new mRNA-based vaccines, the first of which to be registered was the BNT162b2 vaccine from Pfizer-BioNTech.

This vaccine is based on a lipid nanoparticle–formulated, nucleoside-modified mRNA that encodes the spike protein of the SARS-CoV-2 strain that was isolated early on in the pandemic in Wuhan, China.

The spike protein is the main structure the virus uses to infect host cells, and its receptor-binding domain (RBD) is a primary target of neutralizing antibodies following natural infection or vaccination.

Several phase 3 trials have shown that BNT162b2 elicits broad humoral (antibody) and cellular responses that protect against COVID-19. However, many challenges remain while this and other mRNA-based vaccines are rolled out globally, with the emergence of new variants being of particular concern.

The variants that have emerged in the UK (B.1.1.7 lineage), South Africa (B.1.351), and Brazil (P.1) contain multiple mutations in the spike that could impact disease severity, viral transmissibility, and vaccine effectiveness.

The capacity of BNT162b2 to induce effective humoral and cellular immunity against the new SARS-CoV-2 variants is only now beginning to be understood,” says Domínguez-Andrés and colleagues.

Furthermore, an unexplored area is whether BNT162b2 vaccination has long-term effects on innate immune responses:

This could be very relevant in COVID-19, in which dysregulated inflammation plays an important role in the pathogenesis and severity of the disease,” writes the team. “Multiple studies have shown that long-term innate immune responses can be either increased (trained immunity) or down-regulated (innate immune tolerance) after certain vaccines or infections.”

What did the researchers do?

The researchers showed that one dose of the BNT162b2 vaccine induces high concentrations of anti-spike and anti-spike RBD antibodies, while a second dose three weeks later elicits even higher levels.

All the post-vaccine serum samples tested effectively neutralized the B.1.1.7 variant, but 37.5% showed decreased neutralizing activity against the B.1.351 variant.

These data support the evidence that B.1.351, and possibly other variants, may be able to escape vaccine-induced humoral immunity to a certain extent,” say the researchers.

What about the cellular response?

Vaccination with BNT162b2 has been reported to activate SARS-CoV-2-specific CD4+ and CD8+ T cells, and to increase the production of immune-modulatory cytokines such as interferon-γ (IFN-γ).

Domínguez-Andrés and colleagues, therefore, assessed the secretion of IFN-γ from peripheral blood mononuclear cells (PBMCs) in response to different SARS-CoV-2 strains before and after BNT162b2 vaccination.

TNF-α and IFN-α production in response to heterologous stimuli in PBMCs isolated from vaccinated subjects. (A) Description of the study: vaccination and blood collection days. (B-G) Fold change values of TNF-α production are calculated individually for each subject by division of t2:t1 and t3:t1. Data are presented as fold changes ± SEM (n=15-16) and analysed by Wilcoxon’s matched-pairs signed-rank test comparing each ratio to
TNF-α and IFN-α production in response to heterologous stimuli in PBMCs isolated from vaccinated subjects. (A) Description of the study: vaccination and blood collection days. (B-G) Fold change values of TNF-α production are calculated individually for each subject by division of t2:t1 and t3:t1. Data are presented as fold changes ± SEM (n=15-16) and analysed by Wilcoxon’s matched-pairs signed-rank test comparing each ratio to t1=1 (red line). (H-I) IFN-α production (pg/ml) at t1, t2 and t3. Data are presented as cytokine concentration ± SEM (n=15-16) and analysed by Wilcoxon’s matched-pairs signed-rank test.

Vaccination increased IFN-γ production by at least 50% in 37.5% of the samples stimulated with the standard SARS-CoV-2 strain, in 50% stimulated with the B.1.1.7 or B.1.351 variant, but only in 18.8% of samples stimulated with the Bavarian variant.

These findings argue that BNT162b2 vaccination induces better humoral than cellular immune responses,” say the researchers.

Cytokine responses to certain stimuli were reduced following vaccination

Interestingly, BNT162b2 vaccination decreased IFN-γ production following stimulation with the TLR7 and TLR8 agonist R848. The TLR7 and TLR8 ligands are key players in the immune response to viral infection.

Vaccination also decreased production of the pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1β following stimulation with either the standard SARS-CoV-2 strain or different Toll-like receptor ligands.

In contrast, responses to the fungal pathogen Candida albicans were higher after vaccination.

In addition, the production of the anti-inflammatory cytokine interleukin-1Ra was reduced in response to Toll-like receptor 4 and C. albicans. This also suggests a shift towards increased inflammatory responses to fungi following vaccination, say the researchers.

These results collectively demonstrate that the effects of the BNT162b2 vaccine go beyond the adaptive immune system,” writes the team. “The BNT162b2 vaccine induces reprogramming of innate immune responses as well, and this needs to be taken into account.”

What do the authors advise?

The researchers say that in combination with strong adaptive immune responses, the reprogramming of innate responses could either contribute to a more balanced inflammatory reaction to SARS-CoV-2 infection or a weakened innate immune response.

The effect of the BNT162b2 vaccination on innate immune responses could also interfere with the responses to other vaccinations, adds the team.

Our findings need to be confirmed by conducting larger cohort-studies with populations with diverse backgrounds, while further studies should examine the potential interactions between BNT162b2 and other vaccines,” concludes Domínguez-Andrés and colleagues.

* Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Sally Robertson

Written by

Sally Robertson

Sally first developed an interest in medical communications when she took on the role of Journal Development Editor for BioMed Central (BMC), after having graduated with a degree in biomedical science from Greenwich University.

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Comments

  1. Tony Edwards Tony Edwards United States says:

    Can someone summarize this study in plain layman's english?

    • Matt K Matt K United States says:

      The vaccine causes the test subjects in this research to have a lower response rate to fungal infections.

      The vaccine does produce a strong response to COVID-19 but can also potentially cause a lowered immune response to COVID-19.

      The vaccine effects your innate immune response and could impact your immune systems response to other vaccines (ie a severe response or lowered response)

      Most importantly it lowers your bodies ability to fight fungal infections and possibly other bacterial infections.

      Google “India fungal eye infections” I’m curious if those people were vaccinated...

      • Jason Adamcewicz Jason Adamcewicz Canada says:

        My understanding of the article is that the vaccine produces stronger/enhanced immune response to fungi, particularly candida albicans. Regarding other viruses, bacteria and fungi, it states that inflammatory cytokine production was "altered." The word "reduced" was used but it was to describe anti-inflammatory response to fungi, ie. increased inflammatory response which is another way of saying stronger immune response.

        I believe Indians with those fungal infections were naturally infected, not vaccinated, but the connection to what this article suggests has me concerned, as vaccination is meant to mimic infection in some ways. As someone who's suffered with chronic sinusitis of unknown cause (never been swabbed for fungal or bacterial cultures) for a long time, and having just received first Moderna dose, I am quite concerned.

        • Rick Boden Rick Boden Canada says:

          I'm responding to your post because I also have chronic sinusitis and suffered badly this winter to the extent it affected my sleep.  Nothing scientific about this but shortly after receiving the Pfizer shot, the symptoms almost completely disappeared.  Could be the changing season, who knows.

      • Robin Birck Robin Birck United States says:

        I agree I’m very interested in the increased prevalence of “black fungus” infections in covid patients in India and how it relates. But isn’t this study saying there’s an increased response to fungus? “In contrast, responses to the fungal pathogen Candida albicans were higher after vaccination.”

      • Jason A. Jason A. Canada says:

        My understanding of the article is that the vaccine produces stronger/enhanced immune response to fungi, particularly candida albicans. Regarding other viruses, bacteria and fungi, it states that inflammatory cytokine production was "altered." The word "reduced" was used but it was to describe anti-inflammatory response to fungi, ie. increased inflammatory response which is another way of saying stronger immune response.

        I believe Indians with those fungal infections were naturally infected, not vaccinated, but the connection to what this article suggests has me concerned, as vaccination is meant to mimic infection in some ways. As someone who's suffered with chronic sinusitis of unknown cause (never been swabbed for fungal or bacterial cultures) for a long time, and having just received first Moderna dose, I am quite concerned.

  2. Gail Ferraiolo Gail Ferraiolo United States says:

    MNRA synthetic experimental gene therapy

  3. Nick Straker Nick Straker United Kingdom says:

    Those taking an MRNA "vaccine" are potentially permanently altering their body's immune system in ways which are not fully tested, researched or understood.

    For those with serious co morbidity issues this may be deemed a risk worth taking - for the 99.75+% of others aged 75 and under who could expect to survive covid 19 (the majority of whom will be largely if not wholly asymptomatic) it might reasonably be asked if the risk / reward ratio of participating in the MRNA trial is a reasonable one.

  4. Annalisse Mayer Annalisse Mayer United States says:

    Medical science is getting increasingly sophisticated.  Have they performed this type of test on other vaccines?  How about other medical treatments, e.g. newly developed designer drugs for HIV or cancer?

    A lot of things can influence immune response.  For instance, I've seen reports of research indicating that physical affection increases immune response -- while stress and lack of sleep reduce immune response.  Is alleged response reported here statistically significant? Or just background noise?

  5. Carolyn Schuster Carolyn Schuster United States says:

    Try linking this article on Facebook. I tried as did others and the link wont work, it says, Page deleted" or "page not found". Very concerning

  6. Peter Rempel Peter Rempel Canada says:

    "Following vaccination, innate immune cells had a reduced response to toll-like receptor 4 (TLR4), TLR7 and TLR8 – all ligands that play an important role in the immune response to viral infection."
    Since my first Pfizer shot I have developed a raging herpes1 viral infection in both eyes. I have a past history of mild HSV1 but it has been dormant for a while. This could be coincidental but your research article has created some concern.

  7. Lex LExe Lex LExe Germany says:

    Over 56% of the test candidates involved had been vaccinated with BCG 12 months previously.
    Unfortunately, it is not clear from the study what the distribution of the reduced immune response to the previous vaccination is.
    A reduced response of the toll like receptors is even desired on certain time!
    For this reason it would be interesting, how it looks 2 or 3 months after the 2nd vaccination?
    Unfortunately, there is no data on this either.
    Therefore, as an absolute layman, I can not classify this study as very questionable.

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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