Study Overview and Findings

A research team led by Li et al. from Taiwan and the U.S. used the TriNetX network, which contains medical records for over 90 million individuals in the U.S. After excluding participants who were (i) under 18, (ii) had a history of RVO in the previous six months, (iii) were taking specific medications four weeks prior, and (iv) had prior COVID-19, they were left with 745,041 vaccinated and 3,874,458 unvaccinated individuals.

Li et al. matched 739,066 vaccinated individuals to unvaccinated counterparts at a 1:1 ratio, ensuring that age, sex, and other baseline characteristics were similar. This matching allows for more reliable conclusions regarding the effects of vaccination, minimizing the influence of confounding variables.

The study revealed two primary findings:

• The vaccinated group faced a 3.54-fold and 2.19-fold higher risk of RVO than the unvaccinated group at 12 weeks and 2 years of follow-up, respectively. This association was consistent across age, sex, and race, and was significant for all RVO subtypes.
• Subgroup analyses indicated a significant increase in RVO risk after both the first and second doses of the Pfizer or Moderna mRNA vaccines over a two-year period, while no significant association was found with Johnson & Johnson's DNA vaccine.

The study's analyses substantiate these conclusions, making it a scientifically robust piece of research. However, it is crucial to contextualize the findings regarding mechanistic explanations, potential confounding variables, and effect size—areas that the study did not fully address.

Contextualizing the Mechanism

First, the exact mechanism by which mRNA vaccines might lead to RVO remains unclear. The authors speculate that it could be similar to vaccine-induced thrombotic thrombocytopenia (VITT), a condition involving activation of platelet factor 4 (PF4) due to vaccination. This hypothesis is plausible since both RVO and VITT are vascular complications.

However, VITT has been primarily associated with AstraZeneca’s and Johnson & Johnson’s DNA vaccines, not mRNA vaccines. Multiple large-scale studies have shown no significant risk of thrombotic or thrombocytopenic events from mRNA vaccines, as detailed in my previous paper published in Vaccines.

Thus, without a well-defined biological mechanism linking RVO to the mRNA vaccine, uncertainty remains about whether such a relationship exists.

Understanding Unmeasured Confounding

If a clear mechanistic basis is lacking, what explains the observed RVO risk among mRNA vaccine recipients?

One possible explanation is unmeasured confounding. This refers to variables not considered in the study that may have influenced results, including behavioral and genetic factors that are difficult to quantify.

A recognized form of unmeasured confounding is "healthy vaccinee bias," where healthier individuals are more likely to get vaccinated, while those with health issues may postpone vaccination. This could lead to an artificially healthier vaccinated group, which might correlate with outcomes unrelated to the vaccine, such as lower overall mortality rates.

Conversely, those with health concerns may feel a stronger urgency to get vaccinated. Individuals at risk for RVO often share risk factors with those at risk for severe COVID-19, such as diabetes and hypertension.

Despite the study's efforts to match vaccinated and unvaccinated groups based on underlying health conditions, it’s possible that the vaccinated group included more individuals with subclinical health issues.

Li et al. acknowledged this limitation, noting that “while multiple confounding variables were accounted for, residual confounding variables may still exist and bias the results.”

As such, observational studies cannot establish causation—only randomized controlled trials (RCTs) can do this. In RCTs, participants are randomly assigned to either the vaccine or placebo groups, effectively controlling for confounding variables. However, conducting a new RCT on mRNA vaccines would be unethical at this point, as it would involve withholding vaccination from individuals who are already at risk.

Evaluating Effect Size

Despite the uncertainties, it is plausible that the correlation observed is genuine, indicating that mRNA vaccines might elevate RVO risk.

The evidence for this assertion is reinforced by another large study conducted by Dorney et al. in Ohio, which found a 2.25-fold increased risk of RVO following the second mRNA vaccine dose compared to the first. This study also utilized the TriNetX database, suggesting that both studies could be interpreted as drawing from a single dataset rather than two separate studies.

However, Dorney et al.'s research found no significant difference in RVO risk among recipients of the first dose of the COVID mRNA vaccine, the influenza vaccine, and the Tdap vaccine. This implies that the first mRNA vaccine dose did not pose a risk, contrasting with Li et al.'s findings, despite both studies using the same data source. The reasons for these discrepancies remain unclear.

Considering effect sizes, Li et al.’s study reported significant risk increases, but the absolute numbers were modest: 782 out of 739,066 vaccinated individuals (0.106%) and 209 out of 739,066 unvaccinated individuals (0.028%) developed RVO after two weeks. This translates to an excess of 573 cases, meaning one additional case of RVO would occur for every 1,300 vaccinated individuals.

Using Dorney et al.’s findings, 45 out of 1.18 million (0.004%) who received the first mRNA dose developed RVO, a rate comparable to other vaccines. After the second dose, 93 out of 1.18 million (0.008%) developed RVO, resulting in an excess of 48 cases, or one additional case for every 25,000 vaccine recipients.

On average, combining findings from both studies suggests one extra RVO case for every 13,150 vaccinated individuals—not a particularly high risk.

Conclusion

The risk of RVO following mRNA vaccination must be assessed in the context of the vaccine's benefits compared to the risks associated with COVID-19 itself. Vaccines provide significant advantages, particularly in reducing severe COVID-19 cases and associated complications like long COVID and cardiovascular issues.

RVO itself is also a potential complication of COVID-19. A 2023 study published in JAMA Ophthalmology reported a 1.5-fold increased risk of RVO following COVID-19. While this risk appears lower than that of the vaccine based on Li et al. and Dorney et al., comparing studies with different methodologies and sample sizes can be problematic.

Unfortunately, neither Li et al. nor Dorney et al. compared RVO risk between COVID-infected and uninfected individuals, limiting our understanding of the actual significance of their findings.

In summary, emerging data suggests a potential link between mRNA vaccines and RVO. However, as these findings stem from a single database, it is premature to draw firm conclusions, especially considering the lack of a solid mechanistic basis and the potential for unmeasured confounding.

Even if an association does exist, the effect size appears minimal and is unlikely to outweigh the benefits of vaccination, particularly for individuals at risk of severe COVID-19.

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