Abstract
BackgroundThere is great interest in the use of reduced dosing schedules for pneumococcal conjugate vaccines, a strategy premised on maintaining an acceptable level of protection against disease and carriage of the organism. We asked about the practicality of measuring differential effectiveness against carriage in a population with and without widespread use of the vaccine for infants.MethodsWe adapted an existing transmission-dynamic, individual-based stochastic model fitted to the prevaccine epidemiology of pneumococcal carriage in the United States, and compared the observed vaccine-type carriage prevalence in different arms of a simulated trial with one, two, or three infant doses plus a 12-month booster. Using these simulations, we calculated vaccine efficacy that would be estimated at different times post-enrollment in the trial and calculated required sample sizes to see a difference in carriage prevalence.ResultsIn a pneumococcal conjugate vaccine (PCV)-naïve population, the difference in vaccine-type (VT) pneumococcal carriage prevalence between trial arms was less than 7% and varied with sampling time. In a population already receiving routine PCV administration, VT pneumococcal prevalence is nearly indistinguishable between trial arms. Relative efficacy of different dosing schedules was strongly dependent on the time between enrollment and sampling, with maximal prevalence differences reached 1–3 years post-enrollment. Moreover, vaccine efficacy estimates were typically slightly higher in trials in communities already receiving vaccination. Despite this, much larger sample sizes—by more than an order of magnitude—are required for a vaccine trial conducted in a population receiving routine PCV administration as compared to in a PCV-naïve population.ConclusionsThese findings highlight some underappreciated aspects of clinical trials of pneumococcal conjugate vaccines with efficacy endpoints, such as the context- and time-dependence of efficacy estimates. They support the wisdom of conducting comparative dose schedule trials of conjugate vaccine effects on carriage in vaccine-naïve populations.
Highlights
There is great interest in the use of reduced dosing schedules for pneumococcal conjugate vaccines, a strategy premised on maintaining an acceptable level of protection against disease and carriage of the organism
In a pneumococcal conjugate vaccine (PCV)-naïve population, the difference in vaccine serotypes (VT) pneumococcal carriage prevalence between trial arms was less than 7% and varied with sampling time (Fig. 1a-c)
This study demonstrates computationally that the presence of background herd immunity challenges the comparison of PCV dose schedules in a clinical trial
Summary
There is great interest in the use of reduced dosing schedules for pneumococcal conjugate vaccines, a strategy premised on maintaining an acceptable level of protection against disease and carriage of the organism. Mass vaccination of infants and toddlers with pneumococcal conjugate vaccines (PCVs) has led to large declines in pneumococcal disease in countries around the world [1]. These vaccines currently contain 10 or 13 different capsular polysaccharides from Streptococcus pneumoniae, each conjugated to a protein carrier. It is clear that the immunity induced by PCVs partially protects recipients against nasopharyngeal carriage of VT pneumococci [3] This is important because the nasopharyngeal pneumococcal population is the source of transmission to other hosts, so the reduced carriage has led to herd immunity that has reduced VT disease in other age groups in many populations in which infants and/or toddlers have received PCVs [4, 5]
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