Current data on booster effectiveness
As mRNA vaccines were efficacious in prior clinical trials, bivalent mRNA vaccines were approved for use without demonstration of efficacy in clinical trials. Only safety data was required for approval.
So, in a recent study, Shrestha et al. from Cleveland Clinic analyzed the effectiveness of the bivalent mRNA vaccine, which targets both Omicron BA.1/2 and original Wuhan variants of SARS-CoV-2, against Covid infections, in a large observational study.
They recruited 51,011 employers (median age of 42 years, 41% had prior Covid, and 87% had at least one Covid vaccine dose) at Cleveland Clinic. About 21% (n = 10,804) got the bivalent mRNA vaccine (89% from Pfizer and 11% from Moderna), and 5% (n = 2,452) got Covid.
After adjusting for age, gender, number of Covid vaccine doses received, and other factors, the bivalent mRNA vaccine reduced the risk of Covid by 30%. But further analysis showed that, in the authors’ words, “the greater the number of vaccine doses previously received, the higher the risk of COVID-19” (Figure 1).
As usual, people have exploited this graph as proof that repeated vaccinations weaken your immunity against Covid, which is indeed convincing. But there’s more to this plot than meets the eye. And a few factors must be considered before drawing conclusions from this plot.
Worryingly, at least two cohort studies other than Shrestha et al.’s have also found evidence of increasing infections with more vaccinations.
- A nationwide study from Qatar reported a 38% higher risk of Omicron reinfection (likely BA.4/5) from triple- than double-vaccinated persons. But the double- and triple-vaccinated persons still had a 57% and 47% decreased risk of Omicron reinfection compared to unvaccinated persons. None of the reinfection cases were severe, however.
- Another large cohort study from Cleveland Clinic found that those who got 2–3 doses of mRNA vaccine had a 54% higher risk of reinfection (likely BA.4/5) than those who got only 1 dose.
But thankfully, the mRNA vaccine boosters still protect against severe Covid, especially in older individuals.
For instance, in a newly released preprint, a large cohort study from Israel showed that among seniors 65 years and above, those who got the bivalent mRNA booster had 81% and 86% reduced risks of Covid hospitalizations and deaths than those who only got 2–3 monovalent (original vaccine targeting the Wuhan variant) mRNA doses (Figure 2).
Recent reports from the CDC produced similar findings: bivalent mRNA booster reduced the risk of Covid hospitalizations by 57% compared to no vaccination and 38–45% compared to monovalent vaccination among adults (≥18 years). This effect is greater in older adults (≥65 years) at 73% reduced risk compared to monovalent vaccination only.
(Bivalent booster protection against Covid infection was not analyzed in the Israel and CDC studies but is likely not beneficial, judging from what the abovementioned cohort studies have found.)
Now, how do we make sense of the situation of increased infections but decreased disease severity with more vaccinations? We must consider three factors: Group behavior, immune imprinting, and IgG4 class switch.
Part I: Group behavioral differences
First, all these cohort studies are observational, which by default cannot establish cause-and-effect due to inherent biases. Why? Observational studies don’t perform randomization to nullify the countless factors that might differ between groups, such as genetics and behavior.
For example, Shrestha et al. admitted “Those who chose to receive the bivalent vaccine might have been more worried about infection and might have been more likely to get tested when they had symptoms, thereby disproportionately detecting more incident infections among those who received the bivalent vaccine.” But they also acknowledged that “If individuals received the bivalent vaccine thinking it would reduce their risk of infection, they would have been less inclined to get tested.”
There’s also the healthy vaccinee effect, where ill individuals are likely to delay or not get the vaccine — resulting in less favorable outcomes in the unvaccinated or unboosted group — which is a major confounding variable across vaccine observational studies.
Moreover, association or correlation does not mean causation. For example, severe Covid is associated with corticosteroid use. But this is because corticosteroids are used to treat severe Covid, not because they cause severe Covid. Another example is that ice cream sales correlated with shark attacks because people are more likely to have ice cream outside and swim in the ocean during hot weather.
“The association of increased risk of COVID-19 with higher numbers of prior vaccine doses in our study, was unexpected,” Shrestha et al. stated. “A simplistic explanation might be that those who received more doses were more likely to be individuals at higher risk of COVID-19.”
But because the mRNA vaccine boosters protect against severe Covid, it doesn’t matter which group gets tested more to see an effect. After all, severe cases will end up in the hospital regardless of testing frequency.
Part II: Immune Imprinting
A contrary explanation is that more vaccinations actually increase the risk of Covid infections, which, if true, may be due to immune imprinting (also known as original antigenic sin). The authors did not discuss this possibility but they should, given that it’s a worthy consideration.
Immune imprinting happens when old antibodies, generated from older variants, still get deployed against newer variants of the virus. Such old antibodies are not only ineffective but may also hinder the formation of newer, more effective antibodies. Basically, the immune system insists on doing what it learned initially, despite that the same trick may not work twice, and then refuses to learn new tricks.
Immune imprinting has been seen with several vaccines.
For example, seasonal flu shots are only 40%–60% effective. One reason governing such poor vaccine effectiveness is immune imprinting, where prior influenza vaccines hampered the effectiveness of newer ones.
Another example is the human papillomavirus (HPV) vaccine, where those previously vaccinated against HPV mounted poorer immune responses to the updated HPV vaccine than those not previously vaccinated.
Regarding Covid vaccines, a study in Science found that among triple vaccinated individuals who got Omicron, those infected with the prior Wuhan variant mounted lower antibody and T-cell responses than those never infected. In other words, Wuhan + triple vaccination + Omicron had weaker antibody responses than triple vaccination + Omicron.
Another study in Science found that over 80% of antibodies of Omicron breakthrough cases (vaccinated + Omicron) reacted with older variants of SARS-CoV-2. But unvaccinated, never-infected individuals who just caught Omicron had more Omicron-specific antibodies.
Authors of the Qatar nationwide study also noted that their finding “suggests that the immune response against the primary omicron infection was compromised by differential immune imprinting in those who received a third booster dose, consistent with emerging laboratory science data” (which are the two studies published in Science).
But despite that immune imprinting resulting in non-specific antibodies against Omicron, such antibodies may still get deployed faster than unvaccinated or less vaccinated persons, thus curbing disease severity.
Part III: IgG4 class switch
Another possibility of repeated vaccinations increasing the risk of Covid infections is IgG4 class switch, which occurs 3–7 months after the second dose and persists well into 6 months after the third dose of mRNA vaccine.
Unlike immune imprinting, post-mRNA vaccine IgG4 class switch has only been discovered recently, which I covered here.
In brief, IgG (immunoglobulins or antibodies) have four subclasses: IgG1, IgG2, IgG3, and IgG4. IgG1 and IgG3 are pro-inflammatory and the main drivers of antibody-dependent immune responses. Whereas IgG2 and IgG4 are less effective at mediating antibody-dependent responses, but more effective at mediating anti-inflammatory responses.
A hallmark study from German showed that serum samples of individuals with repeated mRNA vaccination had mostly IgG1 and IgG3 initially, but IgG4 began to increase months later, resulting in an IgG4 class switch. The study then showed that serum samples with IgG4 class switch had weaker phagocytic and complement activation activities than samples without IgG4 class switch, raising concerns about vaccine effectiveness.
(Phagocytosis is the process of phagocyte immune cells ingesting foreign materials, including virus-infected cells. The complement system is a part of the immune system that enhances other immune functions.)
We can look at this data in two ways:
- First, IgG4 class switch weakening antibody-dependent responses may drive vaccine ineffectiveness, leading to increased infections.
- Second, IgG4 class switch may be a control mechanism for limiting inflammation, thus leading to better disease outcomes.
The first scenario may explain why some extensive cohort studies find that the more vaccines we get, the higher the risk of Omicron infections and reinfections. The second scenario may explain why those with more vaccinations had better Covid clinical outcomes.
Making sense of the situation
Overall, current observational studies are showing the more mRNA vaccines gotten, the higher the risk of Omicron infections and reinfections, but still a lower risk of severe Covid, especially in senior citizens.
This odd situation is likely due to a combination of factors, including group behavioral differences, immune imprinting, and IgG4 class switch.
After all, a complex topic like vaccine effectiveness often involves complex underlying factors, which may not be obvious in plain sight.
What does this mean for the risk-benefit equation of Covid vaccines?
Paul A. Offit, MD, professor of vaccinology and pediatrics, physician and director of the Vaccine Education Center at Children’s Hospital of Philadelphia, co-inventor of rotavirus vaccine, said it well in a 2023 perspective piece in The New England Journal of Medicine:
"…booster dosing is probably best reserved for the people most likely to need protection against severe disease — specifically, older adults, people with multiple coexisting conditions… In the meantime, I believe we should stop trying to prevent all symptomatic infections in healthy, young people by boosting them with vaccines containing mRNA from strains that might disappear a few months later."
In essence, those at low risk of severe Covid will benefit less from repeated mRNA vaccinations. Such benefits may not always outweigh the risks associated, such as myocarditis (heart inflammation), POTS (postural autonomic tachycardia syndrome), and immune imprinting. Plus, Omicron is also less severe and less likely to cause long-Covid than prior variants, and we also have effective treatments for Covid. So, aside from the first 2–3 doses, it seems hard to justify further dosing in healthy individuals.
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