More Vaccine Doses, More Covid Infections

Two new studies detail immune dysregulation, promoting 'herd opportunity'

Why do the most vaccinated people seem to get Covid more often? Two new studies help us understand the paradox we first noticed in the fall of 2021.

The first study comes from the Cleveland Clinic and is relatively simple. How many vaccine doses had each of its employees received, and how many Covid-19 infections did they suffer?

The second is a far more technical study of antibody responses as doses increase.

Combined, these studies suggest multiple, potentially reinforcing mechanisms – immune imprinting and immune tolerance – could make the mRNA vaccines less effective the more doses you take. These phenomena are well known to immunologists and may be counterintuitive to laymen. Yet regular people seem to be picking up on it faster than the public health community.

Immune Imprinting

The Cleveland Clinic followed 51,011 employees and found remarkably consistent negative efficacy with regard to Covid infection. In fact, each vaccine dose deepened one’s vulnerability of contracting Covid. Like stair steps, 4 doses is worse than 3, is worse than 2, is worse than 1, is worse than none.

The Cleveland Clinic followed 51,011 employees and found each vaccine dose “boosted” one’s chances of catching Covid.

One potential explanation for this effect is immune imprinting, also known as original antigenic sin (OAS) or linked-epitope suppression. The first exposure to an antigen (in this case the Wuhan Spike protein) trains your immune system to respond specifically to that version. When a related but slightly different pathogen appears – say, a new SARS-CoV-2 variant – your body many produce antibodies to the original version, not the current one. Repeated exposures to a an antigen, as with boosters, may reinforce – or imprint – that memory and make it more difficult to recognize and respond to variants. Those with recovered natural immunity may enjoy a broader immune profile and be better equipped to fight new variants.

The Cleveland Clinic figures confirm in more detail the consistent pattern we first picked up in the UK’s weekly reports. Beginning in the fall of 2021, we noticed that for some age groups, the vaccinated appeared to be suffering more Covid infections than the unvaccinated. Over time, the pattern intensified and spread to all adult age cohorts. By the spring of 2022, the UK data showed the triple-vaccinated were three to four times more likely to contract Covid than the unvaccinated. Well, that’s exactly what the new Cleveland Clinic study shows – an approximate 3x negative effect on infection.

Some critics insist the Cleveland results are just statistical snap-shot artifact. Yet numerous other studies, such as this one from Qatar, show similar results and suggest imprinting is a factor.¹ The totality of evidence over long periods, moreover, says this is not a snap-shot but a reliable pattern. The fact that the most heavily vaccinated places continue to suffer the most Covid infections (see Japan’s experience below) point toward a fundamental immunological phenomenon.

Immune Tolerance

In our November 2021 report on the Counterintuitive Dynamics of Covid-19, we noted the FDA’s two senior vaccine scientists had just resigned because they thought the booster train was hurtling off the tracks. We wondered whether mRNA boosters were a good idea:

Boosters may be appropriate for some high-risk people. But many questions remain: How much Spike protein can our bodies take? More is not always better – do we develop “high zone tolerance”?

Tolerance is a common biological process in which we learn to ignore foreign substances. We want our bodies to fight viruses and cancers. But we don’t want our bodies to fight food or other common substances like pollen or cat dander. If we did fight every foreign substance, we’d be in a constant state of irritated inflammation, and we couldn’t eat.

The second new paper, published in Science Immunology, shows that as we take more doses of mRNA vaccine, our antibody response changes. Among four main subtypes, or classes, of antibodies, they switch in relative proportion. With more doses, we produce fewer neutralizing antibodies which fight and far more non-neutralizing antibodies which tolerate. The team from Friedrich-Alexander-Universität in Germany found that the most potent neutralizing antibodies – IgG1 and IgG3 – fell dramatically in their capacity “to mediate antibody-dependent cellular phagocytosis and complement deposition” – in other words, to clear virus. The tolerizing IgG4 antibodies, meanwhile, exploded to 19.27% on average from a mere 0.04% of the antibody pool.

Unfortunately, IgG4 dysregulation can cause all sorts of problems. Jessica Rose covers the paper, “Class switch towards non-inflammatory, spike-specific IgG4 antibodies after repeated SARS-CoV-2 mRNA vaccination,” and the broader IgG4 topic here. She then examines IgG4’s potential relationship with fibrosis here and the implications for cancer here. Despite these good reviews, we should acknowledge a possible chicken-egg causal question and refrain from premature alarm.

The antibody “class switch” may be an important factor not only in the dose-dependent failure of vaccines to prevent infection but also in a host of other newly prolific immune dysregulatory problems, from viral reactivation to fast-moving cancers.

Japan’s Experience

These two effects – immune imprinting and immune tolerance – may also help explain why Japan is now suffering record Covid-19 cases and deaths. Japan is one of the world’s most vaccinated nations, with 370 million total doses, or 2.99 per capita. An average of three means many Japanese have taken four, five, or six doses. And yet a country which survived Covid-19 far better than most other high-income nations, especially in the first year, is now doing worse than ever.

Japan has survived Covid-19 better than many high-income nations, especially in the first year. Yet its extraordinarily high vaccination rate does not seem to have helped. In late 2022, Japan suffers record high case and death rates.

These unintended (but not unknown) vaccine-induced phenomena seem to have prolonged the pandemic. The toy model below shows how a vaccine which modestly protects against individual disease and death could – if it does not prevent but indeed promotes infection – result in more overall disease and death. Instead of achieving herd immunity by virtue of mass recovery from natural infection, mass vaccination using these technologies has produced herd opportunity for the virus.

Yes, this result is counterintuitive. But think about it. If the vaccines promote an explosion of infections and reinfections over a much longer time period, but only reduce the mortality rate of individual cases by a small amount, the net effect can be negative.

The FDA Bails on Boosters

Even Peter Marks of the FDA, one of the biggest vaccine promoters, is now writing in the pages of JAMA that continued boosting is not viable:

Continuing along the current path of the generation and administration of variant-specific vaccine boosters is inadequate as a long-term strategy for addressing COVID-19 in populations globally.

There is also a risk that eventually a variant will emerge that will escape the protection provided by the current generation of vaccines against severe disease.

This is indeed a great worry – that today’s apparent vaccine-enhancement of infection could become tomorrow’s vaccine-enhancement of disease.

UPDATE: Wall Street Journal editorial board member Allysia Finley has just written a great column on vaccine-driven evolution and immune imprinting: Are Vaccines Fueling New Covid Variants?

1. See, for example, (a) Röltgen, et al, Immune Imprinting, Breadth of Variant Recognition, and Germinal Center Response in Human SARS-CoV-2 Infection and Vaccination, Cell; (b) Chemaitelly, et al, COVID-19 primary series and booster vaccination and immune imprinting; (c) Wang, Ho, et al, Antibody responses to Omicron BA.4/BA.5 bivalent mRNA vaccine booster shot; (d) Cao, et al, Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution, Nature; (e) Collier, et al, Immunogenicity of the BA.5 Bivalent mRNA Vaccine Boosters. The last of these concludes: “Our findings suggest that immune imprinting by prior antigenic exposure may pose a greater challenge than currently appreciated for inducing robust immunity to SARS-CoV-2 variants.”