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A call for caution in use of pertussis vaccine effectiveness studies to estimate waning immunity: a Canadian Immunization Research Network study

Crowcroft NS, Schwartz KL, Savage RD, Chen C, Johnson C, Li Y, Marchand-Austin A, Bolotin S, Deeks SL, Jamieson FB, Drews SJ, Russell ML, Svenson LW, Simmonds K, Righolt CH, Bell C, Mahmud SM, Kwong JC. Clin Infect Dis. 2020; May 8 [Epub ahead of print]. DOI:

Background — Vaccine effectiveness (VE) studies provide essential evidence on waning vaccine-derived immunity, a major threat to pertussis control. We evaluated how study design affects estimates by comparing two case-control studies conducted in Ontario, Canada.

Methods — We compared results from a test-negative design (TND) with a frequency-matched design (FMD) case-control study using pertussis cases from 2005-15. In the first study, we identified test-negative controls from the public health laboratory that diagnosed cases and in the second, randomly selected controls from patients attending the same physicians that reported cases, frequency-matched on age and year. We compared characteristics of cases and controls using standardized differences.

Results — In both designs, VE estimates for the early years post-immunization were consistent with clinical trials (TND 84%, FMD 89% at 1-3 years post-vaccination), but diverged as time since last vaccination increased (TND 41% and FMD 74% by 8 years post-vaccination). Overall, we observed lower VE and faster waning in the TND than the FMD. In the TND but not the FMD, controls differed from cases in important confounders, being younger, having more comorbidities and higher healthcare use. Differences between the controls of each design were greater than differences between cases. TND controls were more likely to be unvaccinated or incomplete vaccinated than FMD controls (p<0.001).

Conclusions — The FMD adjusted better for healthcare-seeking behaviour than the TND. Duration of protection from pertussis vaccines is unclear because estimates vary by study design. Caution should be exercised by experts, researchers and decision-makers when evaluating evidence on optimal timing of boosters.

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