Pneumococcal conjugate vaccines in Latin America: are PCV10 and PCV13 similar in terms of protection against serotype 19A?

KEYWORDS:

• Pneumococcal conjugate vaccine
• effectiveness
• serotype 19A
• Latin America

1. Introduction

Pneumococcal disease is endemic globally, and to date, more than 90 distinct capsular types have been described. Of note, serotype 19A has been commonly associated with nasopharyngeal carriage (NPC), mucosal disease, and invasive pneumococcal disease (IPD). Clinically significant resistance to antimicrobial drugs among serotype 19A strains is a major concern [1].

The 10-valent pneumococcal conjugate vaccine (PCV10; Synflorix®, GlaxoSmithKline Biologicals S.A.) does not contain serotype 19A in its formulation but contains the antigenically related serotype 19F. Immunological cross-reactivity between serotypes 19F and 19A has led to the hypothesis that PCV10 may provide a clinically significant cross-protection against serotype 19A pneumococcal disease [2], a controversial issue today. The 13-valent conjugate vaccine (PCV13; Prevnar 13/Prevenar 13® Wyeth/Pfizer Vaccines) contains all of the polysaccharide antigens included in PCV10 along with serotypes 3, 6A, and 19A [3].

2. Direct protection versus cross-protection

PCV13 elicits substantially greater levels of opsonic activity against serotype 19A when compared with PCV10. Opsonophagocytic activity (OPA) geometric mean titer ratios with PCV13 vaccination are 51- and 46-folds greater than PCV10 after the infant series and toddler doses, respectively, although the assays were not performed in the same study [4,5]. There have been two direct comparisons of PCV10 and PCV13: (1) a Netherlands study where children were vaccinated with either vaccine at 2, 3, 4, and 11 months of age [6] and (2) a phase II study to assess noninferiority of immune response to investigational 11-valent and 12-valent vaccines compared to PCV10 and PCV13; here, infants received three doses of the respective vaccines at 2, 3, and 4 months of age [7]. In both studies, three parameters were assessed: anticapsular polysaccharide IgG antibody, OPA, and memory B cells. In the Netherlands’ study, 1 week after the fourth dose, infants who received PCV13 had approximately 18-, 16-, and 5-folds higher anti-19A IgG concentrations, OPA titers, and memory B cell responses, respectively, than those receiving PCV10. In the phase II study, there was a 15-fold increase in anti-19A IgG concentration post-primary series for PCV13 and no change for PCV10.

3. Real-world data

3.1. 19A nasopharyngeal carriage

Reduction of NPC of pneumococcal serotypes included in PCVs plays an important role in the reduction of transmission to susceptible individuals; PCVs can protect by direct and indirect methods. Although a serologic correlate of protection does not exist for the prevention of nasopharyngeal colonization, it is generally agreed that higher IgG antibody concentrations are needed for protection against carriage than for invasive disease [8]. In a randomized, double-blind study conducted in Israel, NPC rates of serotype 19A up to 12 months after PCV13 booster dose were significantly reduced compared with children who received PCV7 [9]. Comparing 2013–2014 to the pre-PCV7 period, carriage of PCV7 serotypes was reduced 74.9%, carriage of the six additional PCV13 serotypes decreased 72.0%, and overall carriage was reduced 11.5% [9]. Similarly, in a United Kingdom study a significant decrease in the childhood carriage prevalence of PCV13-covered serotypes 7F (p = 0.0177), 19A (p < 0.0001), and 3 (p = 0.0024) has been found compared with the pre-PCV13 era [10]. A recently published experience from France supports similar conclusions with broad use of PCV13 (49.2% reduction in carriage of six additional PCV13 serotypes) in children receiving ≥1 dose PCV13 versus PCV7 schedule with significant reduction in carriage of serotypes 19A, 7F, and 6C [11].

In contrast, there is limited evidence that PCV10 has an impact on NPC for serotype 19A. Among infants vaccinated with either PCV7 or PCV10 (3 + 1 schedule) in a randomized controlled trial in the Netherlands, serotype19A was the most common serotype colonizing the nasopharynx throughout a 12-month follow-up period, and it was found in a similar percentage of subjects (6–11%) in both vaccine groups [12]. In a randomized, controlled study conducted in Argentina, Panama, and Colombia, PCV10 vaccination (at 2, 4, 6, and 15–18 months) resulted in a nonsignificant trend toward decreased carriage of 19A serotype [13]. In a Finland study, a statistically significant reduction of serotype 19A carriage was observed only at one time point (18–22 months of age) in children who received a 3 + 1 schedule. Statistically significant reductions were not observed in other age groups, or in any age group that received a 2 + 1 schedule, which is the currently recommended regimen in most of the countries [14].

In March 2010, Brazil introduced the PCV10 in the routine infant immunization program using a 4-dose schedule and catch-up for children <23 months. Carriage of serotypes 6A and 19A did not change significantly. No direct protection of PCV10 against carriage of vaccine-related serotypes has been found by the authors [15]. Finally, a nonsignificant reduction for 19A NPC in children ≥3 year of has been found in Iceland after PCV10 introduction in 2011 [16].

3.2. 19A effectiveness and surveillance data

Introduction of PCV13 into the routine infant immunization programs of numerous countries has resulted in significant declines of serotype 19A cases in all age groups: ≤5 years of age (direct protection) and >5 years of age (indirect protection). In the United States, the number of cases of serotype 19A IPD has significantly decreased (in the period ending June 2013) from pre-PCV13 levels in children <5 of age and those >5 years of age according to data from the ABCs program [17]. More recent data published on the CDC (Centers for Disease Control and Prevention) page show that the overall IPD incidence declined from 100 cases per 100,000 in 1998 to 9 cases per 100,000 in 2015; IPD caused by PCV13 serotypes declined from 91 cases per 100,000 in 1998 to 2 cases per 100,000 in 2015. Although data for individual serotypes were not published, IPD associated with the six additional serotypes included in PCV13 (i.e. 1, 5, 7F, 3, 6A, and 19A) declined by 93% (95% CI, 91, 94) since PCV13 introduction.

Similarly, significant decreases in serotype 19A have been observed in several European countries after the introduction of PCV13. A study of IPD in England and Wales found that the incidence rate of serotype 19A-associated IPD decreased between pre- and post-PCV13 periods had a significant reduction of 91% in children <5 years of age, 54% in those 5–64 years of age, and 65% in those ≥65 years of age [18]. Decreases in IPD associated with serotype 19A after the introduction of PCV13 have also been documented in Norway and Denmark, where the incidence decreased toward pre-PCV7 levels [19].

Related to PCV10, a case-control study conducted in Brazil [20] after the vaccine introduction into NIPs showed effectiveness against IPD due to 19A of 82.2% (95% CI, 10.7, 96.4) between 2010 and 2012 in young children only. However, surveillance data reported from these countries have showed that serotype 19A IPD cases have increased after PCV10 introduction. In Finland, the number of 19A IPD cases in children <5 years of age has fluctuated between 0 and 11 cases per year after PCV10 introduction. In 2015, serotype 19A caused 13 cases, representing 57% of the total number of IPD cases in those children <5 years of age (23 cases). Unfortunately, there is not publically available serotype-specific incidence data from Finland; however, following universal PCV10 immunization the number of cases of serotype 19A invasive infections increased in both age groups (less than 1 year old and 2–4 years old). Therefore, when we analyzed IPD rates serotype 19A is the most prevalent, it is 8.8 cases/100.000 person-years and 5 cases/100.000 person-years out of 9.7/100.000 person-years and 6.6/100.000 person years in children less than 1 year old and 2–4 years old, respectively [21].

Surveillance data from Brazil have demonstrated an increase in the number of cases of 19A IPD in all age groups since the introduction of PCV10 in 2010. Specifically, the number of cases in children <5 years of age from 2011 to 2014 was higher than prior to PCV10 introduction, with 5 cases being reported in 2009 and 37 cases in 2014 [22]. In Chile the inclusion of the PCV10 in 2011 was followed by a reduction of hospital admissions and pneumonia-related deaths in this age group. However, a progressive increase of serotype 19A pneumococcal isolates has been observed. According to the analysis of pneumococcal strains performed by laboratory of the Institute of Public Health, the relative proportion of serotype 19A isolates increased from <5% before 2010 to 12–23% in years 2014–2015. Serotype 19A represented 4–8% of the isolates in the pre-vaccine era among children less than 2 years, increasing to 25% during 2014. Among children, most invasive infections secondary to serotype 19A have occurred in patients fully vaccinated with PCV10. In 2015, serotype 19A accounted for 23% (7/31) of IPD cases in children <2 years old [23].

The higher and specific immune response that PCV13 induces because it contains serotype 19A seems to be the explanation for the difference in effectiveness rates, compared to PCV10 in terms of 19A NPC and IPD reduction. In order to have more data to support this rationale, epidemiological surveillance of serotype 19A cases in countries with PCV13 and PCV10 is strongly recommended. Although in Latin America and the Caribbean laboratory-based surveillance by SIREVA network revealed that prior to year 2010, serotype 19A was responsible for less than 5% of IPD in children younger than 6 years of age among referral hospitals in the region [24], the real and current burden of these infections is unknown. Even more, few studies have addressed the clinical characteristics and rates of complications and outcomes of serotype 19A noninvasive and invasive infections among Latin American children [25]. This is certainly and urgently needed in the era of emerging pneumococcal serotypes. Nevertheless, the first reports on decrease of PCV-13 invasive infections have been already published following PCV-13 introduction in Mexico [26].

4. Conclusions

The purpose of this editorial is to alert about the importance of increasing and improving 19A serotype surveillance in Latin American countries that have already introduced PCV10 and PCV13 in their immunization programs. Since, the first reports suggesting 19A decreases after transition from PCV7 to PCV10 [27], most recent preliminary data from Brazil, Colombia, and specially Chile, suggest a potential increase in 19A serotype infections. At this moment with the available evidence, PCV13 seems to offer better and longer protection than PCV10 against invasive serotype 19A infections as well as NPC reduction.

Declaration of interest

M.L Avila-Agüero has been invited as a speaker and participated in advisory boards on pneumococcal disease and vaccines by Pfizer and GSK and coordinates the GREEN group (Grupo Regional de Estudio de la Enfermedad Neumocóccica). R Ulloa-Gutierrez has been invited as a speaker and participated in advisory boards on pneumococcal disease and vaccines by Pfizer and GSK. LH Falleiros-Arlant is a co-coordinator of GREEN. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Acknowledgment

The authors acknowledge Dr Alejandro Cane from Pfizer for providing scientific data.

Additional information

Funding

This manuscript was not funded.