Overview

The authors seek to investigate the challenges and usefulness of self-reported healthcare registries for the vaccine post-marketing monitoring of rare adverse events in Danish children. For this, the authors performed telephone interviews with the parents of 21 Danish children aged 5-17. Each of the children had experienced new onset symptoms following Pfizer BNT162b2 vaccination. The parents, who were invited to respond to the interview through social media, have associated such symptoms to the Pfizer BNT162b2 vaccination. The symptoms appeared to be mostly caused by autoimmune illnesses and long-lasting infectious. The authors conclude that the study was not able to establish causal relations between COVID-19 vaccines and the reported post-vaccine symptoms.

This review follows the plus-delta-interpretation format. Each of these three aspects are described separately in what follows.

Plus

The paper is an important contribution for the development of self-reported registers as a complementary tool for the monitoring of adverse events following vaccination. This work seems to align with the philosophy of recent Governmental initiatives to incorporate social media interactions in the efforts to identify possible threats, e.g. the v-safe, a smartphone-based, text-messaging system created by the United States CDC to actively monitor the safety of select vaccines in the United States.

The experiment conducted by the authors is an example of how real-world data information could be used for a qualitative mapping of possible confounding variables, such as autoimmune illnesses and concomitant infectious. This type of analysis may be useful in the identification of appropriate risk sets/covariates groups in the design of active post-market vaccine safety surveillance of adverse events.

The way the authors performed the descriptive analysis of the reported overall participants conditions, considering the timing, nature and disease category of such environments can guide future investigations and analysis of self-reported registers.

Delta

In addition to the arguments and rationales discussed by the authors in the Study Limitations section, it would be important to state clearly that causal relationships are difficult to access through observational studies, like the one of the present paper, due to possible selection bias.

The paper would benefit from a discussion about the concept of relative risk due to the vaccine with respect to the overall diseases rates in the reference non-vaccinated population accounting for the baseline rate. This could help readers to understand why focusing the analysis only in the affected individuals (case-only approach) can lead to false causal inferences. The case-only approach ignores the baseline rates of the events in the overall population, creating severe statistical illusions known as “collider stratification bias” and “selective survival bias."

As a side note for future similar studies, the individuals data on their medical history should also be provided by the official/Governmental registers to complement the information provided by the parents.

Interpretation

The main contribution of the paper is to show how self-reported registers on adverse events after vaccination shots can be used to formulate questions on the possible interactions between the vaccines and the reported events, and to identify possible gaps in the current literature, such as potential confounding covariates. The following interpretations can be extracted from the general results and conclusions:  

- Although it is not possible to establish a causal relationship between COVID-19 vaccines and the risk of adverse events, this observational case-only study with self-reported information is useful to draw possible parallels with the events observed during the Phase III Clinical Trials and with the results of post-market surveillance literature. A post-hoc literature search, like the one conducted by the authors, is useful for a qualitative investigation on this matter.

- The self-reported study is useful for mapping metadata characteristics, such as the possibility of grouping rare diseases when conducting register studies. This would reduce the variation in the timing and diagnostic coding.

- The association between vaccines and autoimmune diseases is a critical topic that needs care attention in future works based on self-reported registers.

- About 50% of the individuals of the dataset showed the first symptoms several months following immunization. Nevertheless, the parents associated the occurrences to the COVID-19 vaccine. This is an indication that a portion of the population believes in long-term non-desirable effects from vaccines, which is an important topic to be further discussed in the literature. In addition, this also shows the importance of having Government campaigns to inform the population about vaccine safety.

- Multiple concomitant vaccines (e.g., HPV, flu, COVID-19), and the occurrence of a positive test for COVID-19 after immunization, but prior to onset of symptoms, are critical confounding covariates.