Pneumococcal Vaccine Dosing Schedule Linked to Higher Risk of Acquiring Multiresistant Strain

Laurie Barclay, MD

September 18, 2010

September 7, 2010 — A 2 + 1 pneumococcal vaccine dosing schedule is linked to an increased risk of acquiring a multiresistant strain, according to the results of a study reported in the September 8 issue of the Journal of the American Medical Association.

"The rapid increase in multiresistant serotype 19A as a cause of invasive and respiratory pneumococcal disease has been associated in time with the widespread implementation of 7-valent pneumococcal conjugate vaccination (PCV-7) in several countries," write Elske J. M. van Gils, MD, from University Medical Center Utrecht in Utrecht, the Netherlands, and colleagues. "Because spontaneous fluctuations in time and antibiotic selective pressure may have induced this serotype 19A increase, controlled studies are needed to assess the role of PCV-7."

The goal of the study was to evaluate the association of PCV-7 vaccination and nasopharyngeal acquisition of serotype 19A pneumococci, as well as their clonal distribution and antibiotic susceptibility or resistance. This post hoc analysis was part of a randomized controlled trial of nasopharyngeal Streptococcus pneumoniae carriage. In the Netherlands, where rates of antibiotic resistance are low, 1003 healthy newborns were enrolled and were followed up to age 24 months.

The study was performed between July 7, 2005, and February 14, 2008, before PCV-7 implementation in infants was widespread. Infants were randomly selected to receive 2 doses of PCV-7 at 2 and 4 months; 2 + 1 doses of PCV-7 at 2, 4, and 11 months; or no dosage (unvaccinated control group). At age 6 weeks and at ages 6, 12, 18, and 24 months, nasopharyngeal swabs were obtained. The primary study endpoint was the cumulative proportion of children with nasopharyngeal acquisition of a new serotype 19A strain from ages 6 through 24 months.

Among 948 children who completed the study, nasopharyngeal serotype 19A carriage isolates were identified from 6 weeks through 24 months in 54 of 318 collected in the 2-dose group, 66 of 327 in the 2 +1-dose group, and 33 of 303 in the unvaccinated group. From ages 6 months through 24 months, the cumulative proportion testing positive for new nasopharyngeal serotype 19A acquisition was significantly higher in the group assigned the 2 + 1-dose PCV-7 schedule (16.2%; 95% confidence interval [CI], 12.6% - 20.6%) vs the unvaccinated group (9.2%; 95% CI, 6.5% - 13.0%; relative risk [RR], 1.75; 95% CI, 1.14 - 2.70). However, new nasopharyngeal serotype 19A acquisition was not significantly higher in the 2 + 1-dose PCV-7 schedule vs the group assigned a 2-dose schedule (13.2%; 95% CI, 9.9% - 17.4%; RR, 1.43; 95% CI, 0.91 - 2.25).

Of 28 different sequence types identified, 6 were new types. The groups did not differ in the proportion of children with new 19A acquisition who had used antibiotics in the last 6 months (18.7%; 95% CI, 12.8% - 26.5%). Susceptibility to penicillin was intermediate in 5 isolates, and an additional 3 isolates were nonsusceptible to erythromycin and azithromycin. All 8 of these isolates were in the vaccine groups.

"A 2 + 1-dose PCV-7 schedule was associated with an increase in serotype 19A nasopharyngeal acquisition compared with unvaccinated controls," the study authors write.

Limitations of this study include post hoc analysis, use of nasopharyngeal colonization as a marker for disease, 6-month sampling intervals, and study limited only to reduced-dose schedules and not to the full 3 + 1-schedule.

"In addition to the contributing role of antibiotic selective pressure as previously described by others, we now have demonstrated, to our knowledge for the first time, the facilitating role of PCV-7 in nasopharyngeal acquisition of serotype 19A," the study authors conclude. "In view of the proven disease potential of serotype 19A for otitis media and invasive pneumococcal disease and the observed association with antibiotic resistance, vaccines of broader coverage including protection against serotype 19A may further aid to pneumococcal disease prevention. However, we need to be aware that other serotypes with similar characteristics and disease potential may be the next in line to proliferate and therefore pneumococcal surveillance remains important after introduction of expanded pneumococcal conjugate vaccines."

The Dutch Ministry of Health supported this study. Some of the study authors have disclosed various financial relationships with GlaxoSmithKline, Wyeth/Pfizer, Baxter, and/or Novartis.

JAMA. 2010;304:1099-1106.

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