Author Affiliations: sanofi pasteur, Swiftwater, Pennsylvania.
We note methodological issues with the study by Farez and Correale.1 They observed relapses of multiple sclerosis (MS) in 5 of 7 patients with MS after yellow fever (YF) vaccination and used a self-controlled case series method to elucidate a possible association. They also selected matched controls among healthy subjects and patients with MS vaccinated with inactivated influenza vaccine for comparison of immunological responses to vaccination.
The most important assumption of the self-controlled case series method is that exposures are independent of earlier events.2 This assumption is required for the conditioning argument by which the case series likelihood is derived. However, the decision to administer YF vaccination clearly is not independent of the presence of, or risk for, MS relapse. Travel to endemic areas is least likely during or soon after an MS relapse. Accordingly, the assumption that exposure (vaccination) is independent of earlier events (eg, latest relapse) is not valid. Moreover, as time passes, symptoms remit and likelihood of travel increases, but equally, the (unknown) time of next relapse also draws nearer. Thus, exposure (vaccination) is also associated with likelihood of the next event occurring within any defined postexposure window, independent of the presence or absence of a causal association between exposure and the event. These biases invalidate the analysis. Such bias is less of an issue with vaccines that are mandated at certain ages or used seasonally but still needs to be tested for (Whitaker et al2 provide a motivating example of idiopathic thrombocytopenic purpura and measles, mumps, and rubella vaccine).
Farez and Correale also compared immunological changes after YF vaccination with those after inactivated influenza vaccine and also in healthy unvaccinated controls. The differences noted are to be expected when comparing recipients of a live vaccine vs an inactivated product or no vaccine at all and have no specificity for YF vaccination. Finally, the analysis of magnetic resonance imaging changes after vaccination is unreliable because of the earlier-discussed bias and also because the controls were not matched on time since onset or severity of the disease.
We conclude that the inference of causal relationship based on “temporal relationship between events” and “strength of exacerbations” is not supported owing to invalid study design. What remains is an argument of biological plausibility—the weakest line of evidence.
Correspondence: Dr Pool, Discovery Drive, Swiftwater, PA 18370 (vitali.pool@sanofipasteur.com).
Author Contributions: Study concept and design: Pool. Analysis and interpretation of data: Pool, Gordon, and Decker. Drafting of the manuscript: Pool. Critical revision of the manuscript for important intellectual content: Gordon and Decker. Statistical analysis: Pool. Study supervision: Gordon and Decker.
Financial Disclosure: Drs Pool, Gordon, and Decker are employees of sanofi pasteur.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
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