In a recent study, Shrestha et al. from Cleveland Clinic, one of the largest academic medical center in the U.S., analyzed the effectiveness of the bivalent mRNA vaccine, which targets both Omicron and original Wuhan variants of SARS-CoV-2, against Covid.
After adjusting for age, gender, job category, number of Covid vaccine doses received, and pandemic phase when the last Covid episode occurred, 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).
Another large cohort 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. One more 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. 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 showed 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 these studies but is likely not beneficial, judging from what the abovementioned cohort studies have found.)
Now, how do we make sense of these studies? We must first consider three factors: Group behavior, immune imprinting, and IgG4 class switch.
Part I: Group behavior
This study is observational, which by default cannot establish cause-and-effect due to inherent biases, such as differences in behavior. Obervational studies don't perform randomization to nullify the behavioral factors — as well as genetic, environmental, and countless other factors — between groups. That’s why observational studies can only support causation in light of what randomized clinical trials found.
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.”
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. admit. “A simplistic explanation might be that those who received more doses were more likely to be individuals at higher risk of COVID-19.”
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 incomplete 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.
As authors of the Qatar study noted, “This 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."
Part III: IgG4 class switch
Another possibility of repeated vaccinations increasing the risk of Covid is IgG4 class switch, which occurs 3–7 months after the second dose and persists well into 6 months after the third dose of the 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 the main drivers of antibody-dependent immune responses, including vaccinations.
A study from German showed that serum samples of vaccinees had mostly IgG1 and IgG3 with undetectable IgG4 initially, but IgG4 began increasing months later, resulting in IgG4 class switch. The study then showed that serum samples with IgG4 class switch exhibited weaker phagocytosis and complement activation than samples without IgG4 class switch.
(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.)
There’re two ways to look at this data. First, IgG4 class switch weakening antibody-dependent responses may drive vaccine ineffectiveness. Second, IgG4 class switch may be a control mechanism for limiting inflammation, thus leading to better disease outcomes (as I covered here).
The first scenario may explain why some large cohort studies find that the more vaccines we get, the higher the risk of Omicron infection (see part II on immune imprinting). The second scenario may explain why those with more vaccinations had better Covid clinical outcomes.
Making sense of this study
Current observational studies showing a higher risk of Omicron infections but a lower risk of severe diseases with more vaccinations suggest four possibilities:
- Behavioral differences lead to more infections being caught in the boosted group (speculation only).
- Immune imprinting happens with the latest Omicron variants and subvariants (supported by laboratory data).
- IgG4 class switch weakens antibody-dependent responses and inflammatory activities (supported by laboratory data).
- All of the above play a role.
I lean towards the fourth possibility that all factors may be involved. A complex topic like vaccine effectiveness often has complex underlying factors involved. So, a combination of group behavioral differences, immune imprinting, and IgG4 class switch may likely drive more infections and reinfections in the boosted group. But the upside is that the boosted group, especially senior citizens, has a lower risk of severe Covid.
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…, and those who are immunocompromised. 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. [Notwithstanding the risk of immune imprinting as well.]
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