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Children in Australia who took the Pfizer BNT162b2 COVID-19 vaccine experienced significant drops in levels of immune proteins, or cytokines, according to a study appearing in Frontiers in Immunology.
Does that mean these children developed vaccine-acquired immune deficiency, or VAIDS, after they received the shots, as some reports speculated?
Dozens of cytokines participate in immunity, and many promote unhealthy or dangerous inflammation. To our knowledge, the 27-cytokine panel the researchers used to measure immune function was not validated to diagnose either immune deficiency or inflammation. It provides hints or clues but is not confirmatory.
Cytokines are “good” when they stimulate immunity to combat infection or attack tumors. But the same cytokines are “bad” when they promote inflammation, for example in rheumatoid arthritis or Crohn’s disease.
So, vaccinated children who experience a drop in levels of the 27 cytokines the researchers measured may be less able to fight off an infection — but we don’t know that for certain.
Researchers could have learned more by including unvaccinated children in their study, or they could have definitively settled the matter by monitoring the children longer-term for infection — neither of which they did.
Still, the study adds fuel to the ongoing controversy over COVID-19 vaccinations in children, though perhaps not in the way investigators intended.
The researchers set out to determine whether children who received the Pfizer COVID-19 vaccine were better protected against other infections besides COVID-19.
But their finding, that cytokine responses associated with fighting non-COVID-19 infections decreased, suggested the opposite.
Led by corresponding author Andrés Noé at Murdoch Children’s Research Institute in Parkville, Victoria, Australia, researchers looked for evidence that the Pfizer vaccine administered to young children might prevent not just COVID-19 but also other infectious diseases.
This phenomenon, known as a heterologous or “off-target effect,” was reported earlier for smallpox vaccination and is the subject of ongoing discussion for the bacille Calmette-Guérin vaccine, a vaccine for tuberculosis.
In both instances, vaccinated individuals experienced fewer hospitalizations for other infections not targeted by the vaccine.
Noé and co-workers did not use hospitalization as their endpoint but instead measured levels of cytokines, which are proteins that serve as chemical immune system signals.
According to the authors, their study was the first to examine this specific effect in children.
How the study was conducted
Researchers initially enrolled 51 children, ages 5-11 (median age 6.4), between Jan. 20 and Feb. 1, 2022. Of the 47 deemed eligible for the study, 18 children previously infected with COVID-19 were excluded, leaving 29 subjects.
To compare unvaccinated versus vaccinated cytokine levels, researchers drew blood samples right before the first BNT162b2 injection and 28 days after the second dose.
An additional eight samples were collected at six months post-treatment.
Researchers chose not to include an unvaccinated control group, instead using samples drawn before vaccination as the assay controls. They decided this because, in their estimation, including an unvaccinated control group was unethical.
They used a whole blood stimulation assay to measure cytokine responses to both COVID-19 and non-COVID-19 pathogen-related stimulants. This test involves adding a “challenge” to blood samples that simulate real-world exposure to an infectious microbe.
Because cytokines are present in low abundance and are rapidly degraded in blood, assays were performed within two hours of blood collection.
Researchers treated or “challenged” blood samples with 13 pathogens, including three COVID-19-related preparations and 10 other heat-killed disease-causing bacteria and viruses. Non-COVID-19 challenges included influenza virus, staphylococcus bacteria, and other common infectious microbes.
Challenges were grouped according to bacterial, viral or COVID-19-related.
The researchers looked for 27 cytokines belonging to one of three groups: inflammatory, adaptive or mixed, and chemokines.
Inflammatory cytokines promote both beneficial and disease-causing inflammation. Adaptive cytokines help fight infections. Chemokines recruit disease-fighting white blood cells to attack and remove infectious microbes.
Plain cell culture medium and medium from uninfected cells served as assay controls.
What the researchers found
Cytokine levels generally fell at 28 days after the second injection, but results were mixed.
The greatest decreases, in cytokines that fight bacteria and non-COVID-19 viruses, were evident at 28 days for all pathogen challenges.
Decreases persisted at six months post-vaccination for viral but not bacterial challenges.
The only increases in cytokine levels observed resulted from COVID-19-related challenges.
Researchers found no correlation between these effects and levels of anti-COVID-19 antibodies, meaning whatever cytokine effects they observed arose from generalized immune stimulation and not a response to spike protein, the main antigen in the vaccines.
Noé concluded that the BNT162b2 injection in children “alters cytokine responses” to stimulants other than the COVID-19 virus or spike protein, particularly one month after vaccination.
To summarize, positive cytokine responses 28 days after BNT162b2 injection were limited to those typically expected after a vaccination — to the antigen(s) against which BNT162b2 was designed.
At the same time, levels of nearly all cytokines normally employed by the immune system to fight bacterial and viral invaders fell.
The most glaring defect in Noé’s report was the absence of an unvaccinated control group.
According to the authors, including unvaccinated children was “unethical” because the Australian Technical Advisory Group on Immunisation, which advises the Australian government on vaccination policy, had established COVID-19 “vaccination” as the standard of care.
But the authors were not ethically conflicted about injecting their subjects with products that had not yet been approved or even tested in children or which, according to their own study hypothesis, might negatively affect the subjects’ ability to fight infections other than COVID-19.
Pfizer began testing its BNT162b2 product in young children on March 25, 2021, but the product was not approved in Australia for that demographic until Sept. 29, 2022 — more than six months after Noé and co-workers began injecting subjects.
BNT162b2 was approved in the U.S. for that age group in December 2022.
Also, conspicuously absent from the “discussion” section of the Noé paper was any explanation of the study’s clinical significance.
In their abstract, the authors first mention that vaccines “can have beneficial off-target (heterologous) effects that alter immune responses to, and protect against, unrelated infections.”
Later they write that BNT162b2 vaccination affects “cytokine responses to heterologous stimulants.”
But nowhere do they attempt to reconcile the two statements, to explain the clinical significance of those “alterations,” or even if the rise in cytokines to COVID-19 challenges reflects immunity from COVID-19.
Another questionable strategy was excluding children with natural immunity to COVID-19 through exposure to the virus. These potential subjects had already been recruited and had blood drawn to test for COVID-19 exposure.
Since the blood tests were run on an automated analyzer, including them could have provided additional insights without entailing significant additional work.
It would have allowed, for example, comparing cytokine levels in COVID-19-exposed and -unexposed vaccine-naive children, and eventually between children with natural versus BNT162b2-induced immunity.
Biomarkers are commonly used in biomedical research — for example, cholesterol for heart disease or C-reactive protein for inflammation. But they do not carry the same weight as “hard” endpoints like biopsy results, symptomatic illness or death.
Although Noé made no claims, positive or negative, about the clinical significance of his findings his hypothesis clearly implies that COVID-19 risk is inversely related to COVID-19-related cytokine levels: the higher the levels, the lower the risk.
If Noé’s findings suggest a lower risk for COVID-19 by virtue of a strong, persistent cytokine response, then by the same logic they show that the Pfizer BNT162b2 vaccine does the exact opposite for other dangerous infections.
But Noé was careful not to make any explicit claims on either point, concluding merely that “BNT162b2 vaccination in children alters cytokine responses to heterologous stimulants.”
In defense of his original hypothesis — that BNT162b2 confers immunity to non-COVID-19 pathogens — not all cytokine activity is beneficial or predictable in its effects.
The specific cytokines whose levels fell in response to viral and bacterial challenges might, under conditions of actual infection with live pathogens, have worked together to cause harmful or even dangerous inflammation.
Immunity is a complex phenomenon involving interactions among dozens or hundreds of molecular actors. Absent a narrow, rigorously validated and clearly defined relationship between biomarkers and actual disease — and not to “risk” or “risk factors” — drawing conclusions from biomarker studies is itself risky.
Had all cytokine levels risen along with those involved in fighting COVID-19, Noé’s conclusion might well have been different.
But even those claims would be subject to validation through a large study involving an unvaccinated control group and long follow-up to see if vaccinated children experienced fewer infections or fewer infections requiring hospitalization than controls.