Response to Effectiveness of the 10-Valent Pneumococcal Nontypeable Haemophilus influenzae Protein D-Conjugated Vaccine (PHiD-CV) Against Carriage and Acute Otitis Media-A Double-Blind Randomized Clinical Trial in Finland.

To the Editor—We read with interest the article by Vesikari et al [1] in which a statistically significant reduction of serotype 19A carriage was observed in children 18–22 months of age who received a 3 + 1 schedule of PCV10 (3 primary infant doses with a booster dose at 12 months). Statistically significant reductions were not observed in other age groups, nor in any age group that received the 2 + 1 schedule (2 primary doses followed by a booster), which is the currently recommended regimen in most European countries, including Finland. Neither PCV7 nor PCV10 contain the epidemiologically, globally, most relevant serotype, 19A. Partial cross-reactivity between serotypes 19F and 19A, when considering antibodies measured by enzyme-linked immunosorbent assay, has led to the hypothesis that administration of PCV7 or PCV10 may lead to clinically significant cross-protection against serotype 19A pneumococcal disease. However, postmarketing surveillance in the United States and elsewhere demonstrated that there was no reduction in 19A in infants and children vaccinated with PCV7. The findings from Vesikari et al [1] are in line with other studies that have shown limited impact of PCV10 on 19A carriage in children. For example, among infants vaccinated with either PCV7 or PCV10 in a randomized controlled trial (RCT) in the Netherlands (3 + 1), serotype19A was the most common serotype colonizing the nasopharynx throughout a 12-month follow-up period, and this was found in a similar percentage of subjects in both vaccine groups [2]. In 2 other RCTs in Latin America and the Czech Republic, PCV10 vaccination (3 + 1) did not decrease carriage of 6A/19A [3, 4]. In Kenya, surveillance data before and after PCV10 introduction has shown carriage of 19A to now be higher than the pre-PCV10 period [5]. In contrast, studies of PCV13, which contains 19A in the 13-valent vaccine formulation, have consistently demonstrated reductions in carriage and invasive pneumococcal disease (IPD) by this serotype [6]. It is noteworthy that in an RCT in Israel comparing PCV7 and PCV13, the rate of nasopharyngeal acquisition of serotype 19A was significantly reduced compared with children who received PCV7 [7]. To the best of our knowledge, there have been no head-to-head carriage studies comparing PCV10 and PCV13. Some information comes from 2 immunogenicity studies (NCT01616459 and NTR3069) [8, 9] assessing anticapsular polysaccharide immunoglobulin (Ig)G antibody and opsonophagocytic activity (OPA). In NCT01616459, there was a 15-fold increase in anti-19A IgG concentration postprimary series for PCV13 and no change for PCV10. In NTR3069, infants who received PCV13 had approximately 18-, 16-, and 5-fold higher anti-19A IgG concentrations, OPA titers, and memory B cells, than those receiving PCV10. Although some studies conducted over a 2to 3-year period cited by Vesikari et al [1] have suggested PCV10 effectiveness for serotype 19A IPD, surveillance data from Finland, Brazil, Chile, and New Zealand, countries with PCV10 National Immunization Programs, have shown an increase in IPD associated with serotype 19A in both children and adults [10]. This is in contrast to countries that have used PCV13, where dramatic and sustained reductions in 19A IPD have been observed in both children and adults [6]. The evidence available to date suggest that the inclusion of serotype 19A into the vaccine formulation is required to elicit (1) levels of functional antibodies, sufficient to translate into a reduction in carriage, and ultimately (2) reductions in invasive and noninvasive disease at the population level.