Streptococcus pneumoniae serotype 19A: worldwide epidemiology

ABSTRACT

Introduction: Streptococcus pneumoniae causes mucosal and invasive diseases with high morbidity and mortality. Introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) into routine infant immunization programs worldwide resulted in serotype 19A becoming a leading cause of the remaining pneumococcal disease burden in vaccinated and nonvaccinated individuals. This article reviews the impact of the latest generation PCVs (10-valent PCV, PCV10, and 13-valent PCV, PCV13) on serotype 19A.

Areas covered: This article covers immune responses elicited by PCV7, PCV10 and PCV13 against serotype 19A and their impact on nasopharyngeal (NP) carriage and disease in vaccinated and unvaccinated populations using data from surveillance systems, randomized controlled trials, and observational studies.

Expert commentary: As expected from a PCV containing serotype 19A, PCV13 elicits significantly higher functional immune responses against serotype 19A than PCV7 and PCV10. Higher responses are likely to be linked to both direct impact in vaccinated populations and reductions in 19A NP carriage in children, thus inducing herd protection and reducing 19A invasive pneumococcal disease (IPD) in nonvaccinated children and adults. In contrast, PCV7 and PCV10 have shown mixed evidence of direct short-lived cross-protection and little to no impact on 19A carriage, resulting in continued transmission and disease.

KEYWORDS:

• Antimicrobial resistance
• epidemiology
• nasopharyngeal carriage
• invasive pneumococcal disease
• pneumococcal conjugate vaccines
• Streptococcus pneumoniae
• serotype 19A

1. Introduction

Encapsulated Streptococcus pneumoniae are a leading cause of meningitis, bacteremia, pneumonia, otitis media, and other human diseases. Transmission occurs through airborne droplets containing viable bacteria [1]. Nasopharyngeal colonization (NPC) is considered a prerequisite for the establishment of pneumococcal disease [2] and development of antimicrobial resistance [3,4]. Most children become transiently colonized by S. pneumoniae at some point during infancy through 6 years of age [5,6]. Colonization generally peaks at approximately 3 years of age and declines thereafter [7–9]. Most adults acquire S. pneumoniae from children, but observed rates of adult colonization are generally lower than those in children [10].

Asymptomatic colonization with S. pneumoniae can lead to mucosal diseases including nonbacteremic pneumonia [11], acute otitis media (AOM) [12], and sinusitis [13], as well as invasive pneumococcal disease (IPD) including meningitis, bacteremia, and bacteremic pneumonia [2]. New acquisition of a serotype is generally a prerequisite for mucosal disease and IPD [14]. Complex relationships exist between the biochemical properties of individual serotype pneumococcal polysaccharides, the likelihood of successful colonization [15], and the invasiveness of a particular serotype [16]. The most common serotypes observed in different countries and/or geographic regions are generally similar; however, there may be large variations in relative serotype prevalence in these areas, particularly between developed and developing countries [17–25].

Two classes of vaccines have been developed to prevent pneumococcal disease. A 23-valent pneumococcal polysaccharide vaccine (PPV23) was licensed by the US FDA in 1983 [26]; PPV23 is poorly immunogenic in children <2 years of age [27] and thus it is not recommended for routine infant immunization programs and is not included in this review. More recently, pneumococcal vaccines in which capsular polysaccharides are conjugated to carrier proteins to enhance immunogenicity have been developed. These include pneumococcal conjugate vaccines (PCVs) containing 7 (PCV7, Prevnar/Prevenar®, Wyeth Lederle Vaccines) [28], 10 (PCV10, Synflorix®, GlaxoSmithKline Biologicals S.A.) [29], and 13 (PCV13, Prevnar 13/Prevenar 13®, Wyeth/Pfizer Vaccines) [30] pneumococcal polysaccharide antigens (Supplementary Figure 1). As of December 2016, 138 countries have introduced PCVs into their infant National Immunization Program (NIP) (96 with PCV13, 33 with PCV10, and 8 with both PCV10 and PCV13) [31].

Widespread use of PCV7 successfully reduced pneumococcal disease associated with the serotypes contained within this vaccine; over the years, nonvaccine serotype prevalence became increasingly important [32,33]. Serotype 19A emerged as a predominant serotype in several countries in both children and adults after the introduction of PCV7 [17,32,34–41], as well as in other countries with no PCV7 vaccination programs [42]. Though the reasons are not fully understood, fluctuations in serotype distribution in the absence of PCVs have been reported for several countries, possibly due to migration or antibiotic pressure [43–46]. Importantly, serotype 19A has demonstrated increased potential to cause invasive disease relative to other serotypes [47,48]. Possible factors contributing to serotype 19A emergence after PCV7 introduction in the USA included high rates of 19A carriage and penicillin nonsusceptibility (Supplementary Table 1), as well as capsular switching [49], i.e., an interstrain genetic recombination resulting in the acquisition of a new capsular serotype [49,50]. The recognition of 19A as a predominant serotype associated with mucosal and invasive diseases [51–53], together with the high rate of antibiotic resistance observed among serotype 19A isolates [54], makes understanding serotype 19A epidemiology and the effectiveness of PCVs to reduce serotype 19A circulation of great clinical importance.

Several years after PCV7 introduction, 2 other PCVs were licensed. PCV10, containing the 7 serotypes in PCV7 with the additional serotypes 1, 5, and 7F, was licensed in Europe in 2009 for use in children between the ages of 6 months and 5 years [55]. PCV13, containing all of the polysaccharide antigens common to PCV7 and PCV10 along with serotypes 3, 6A, and 19A [56], was approved for use in children in Europe in 2009 and the USA in 2010 [57,58]. Like PCV7, PCV10 does not contain serotype 19A; however, both vaccines contain the cross-reactive serotype 19F. Immunological cross-reactivity between serotypes 19F and 19A could theoretically result in cross-protection against pneumococcal disease caused by serotype 19A [59].

This article describes functional immune responses elicited by licensed PCVs as predictors of protection against NPC and disease caused by 19A in vaccinated and unvaccinated individuals, and reviews changes in 19A epidemiology in vaccinated and unvaccinated individuals derived from published data collected from surveillance systems in countries where these vaccines have been introduced.

2. Immune responses against serotype 19A elicited by PCVs

Protection against pneumococcal disease by PCVs is conferred by serotype-specific antibodies that bind to the pneumococcal polysaccharide capsule. Capsular polysaccharide-binding immunoglobulin G (IgG) antibody concentrations are measured by a World Health Organization (WHO) standardized enzyme-linked immunosorbent assay (ELISA) that uses serotype-specific capsular polysaccharides as substrate and measures IgG concentrations through an established standard. WHO (TRS 927) suggests a single ELISA IgG antibody concentration of 0.35 µg/mL, measured 1 month after the infant series, as the reference antibody concentration for assessment of vaccine efficacy against IPD [60] . Laboratories that employ the GSK 22F ELISA use a threshold concentration of 0.2 µg/mL that is considered equivalent to the 0.35 µg/mL in the standard ELISA [61,62]. Anticapsular polysaccharide antibody mediates protection against pneumococcal disease via opsonophagocytosis, which leads to bacterial killing by phagocytic cells [63]. The opsonic activity of vaccine-elicited immune responses is determined using serotype-specific functional opsonophagocytic activity (OPA) assays [64,65]. Unlike the IgG ELISA, the OPA tests are not standardized to an external specification. Although IgG concentrations determined by ELISA can be compared across serotypes, this cannot be done for OPA assays, as the values generated are not biologically equivalent among the different serotypes and therefore can only be compared within a given serotype. Furthermore, standardization between various laboratories is lacking. The WHO consensus statement argues that although an OPA titer ≥1:8 indicates the presence of functional antibodies, a titer that may correlate with protection against IPD caused by any one serotype is unknown. For these reasons, it is recommended that comparisons of OPA titers common to any new vaccine and the licensed comparator should focus on serotype-specific geometric mean titer (GMT) ratios between the vaccines being compared.

Following PCV7 vaccination, OPA and IgG values show a strong correlation for PCV7 serotypes [66]. However, there is no correlation between these assay values for serotype 19A in PCV7 antisera. Although serotype 19F in PCV7 elicits cross-reactive polysaccharide-binding IgG antibody to serotype 19A, these cross-reactive antibodies do not mediate opsonic activity; that is, no corresponding functional (OPA) response to serotype 19A in PCV7 recipients is observed (Supplementary Figure 2). Thus, despite the ability of PCV7 to raise IgG antibodies to serotype 19A, these antibodies appear clinically nonfunctional, and cross-protection cannot be achieved.

A similar phenomenon is apparent with PCV10, which also lacks serotype 19A in its formulation. Measurements of serotype-specific total IgG comparing PCV7 with PCV10, using IgG threshold cut-offs of 0.35 µg/mL and 0.2 µg/mL, respectively, as described above, are shown in Table 1[67–73].

Table 1. Randomized controlled trials assessing the immunogenicity of PCVs against serotype 19A.

	PCV7				PCV10
	IgG GMC, μg/mL (95% CI)		OPA GMT (95% CI)		IgG GMC, μg/mL (95% CI)		OPA GMT (95% CI)
Study	Post-primary	Post-final	Post-primary	Post-final	Post-primary	Post-final	Post-primary	Post-final
Vesikari et al. [67]^a,b	0.11 (0.09, 0.13)	0.47 (0.37, 0.62)	4.5 (3.9, 5.3)	11.1 (7.3, 17.0)	0.08 (0.07, 0.09)	0.85 (0.73, 1.00)	8.6 (7.1, 10.5)	29.2 (22.3, 38.3)
Kim et al. [68]^a,c	0.12 (0.10, 0.14)	0.32 (0.24, 0.43)	5.3 (4.2, 6.7)	15.5 (8.1, 29.9)	0.29 (0.25, 0.33)	1.54 (1.27, 1.87)	10.9 (8.4, 14.3)	64.9 (44.6, 94.5)
Bermal et al. [69,70]^a,d	0.18 (0.15, 0.22)	0.58 (0.37, 0.91)	4.2 (3.8, 4.7)	8.7 (5.4, 14.2)	0.36 (0.31, 0.41)	3.22 (2.46, 4.21)	10.6 (7.9, 14.2)	89.3 (58.9, 135.4)
Bermal et al. [69,70]^a,e	0.12 (0.10, 0.15)	0.38 (0.25, 0.58)	4.0 (4.0, 4.0)	20.3 (8.8, 46.8)	0.29 (0.25, 0.34)	1.75 (1.27, 2.43)	10.1 (7.8, 13.1)	70.7 (45.3, 110.4)
105539 [71]^a,f	NS	NS	NS	NS	0.19 (0.16, 0.24)	0.87 (0.69, 1.11)	15.8 (11.2, 22.3)	27.2 (18.0, 41.2)
Wysocki et al. [72]^a,g	0.12 (0.1, 0.14)	0.35 (0.29, 0.42)	4.1 (3.9, 4.2)	8.7 (6.6, 11.4)	0.27 (0.22, 0.32)	1.19 (0.96, 1.47)	11.2 (8.1, 15.4)	48 (32.1, 71.9)
					0.22 (0.19, 0.27)	1.12 (0.89, 1.42)	8.4 (6.4, 11.0)	46.6 (30.8, 70.4)
					0.18 (0.15, 0.22)	0.75 (0.6, 0.94)	7.1 (5.6, 9.0)	18.9 (13.0, 27.4)
van den Bergh et al. [73]^a,h	0.08 (0.07, 0.10)	NS	4.9 (4.4, 5.4)	NS	0.10 (0.09, 0.13)	NS	9.0 (6.9, 11.7)	NS
					0.09 (0.08, 0.11)	NS	8.0 (6.3, 10.2)	NS
	PCV7				PCV13
Kieninger et al. [76]^i	0.64 (0.58, 0.71)	3.79 (3.40, 4.21)	7 (5, 9)	59 (37, 94)	3.26 (2.97, 3.59)	9.58 (8.68, 10.58)	442 (361, 543)	1349 (1089, 1672)
Yeh et al. [77]^j	0.89 (0.79, 0.99)	3.54 (3.15, 3.98)	7 (5, 8)	268 (164, 436)	2.07 (1.87, 2.30)	8.55 (7.64, 9.56)	152 (105, 220)	1024 (774, 1355)

CRM: cross-reactive material; DTPa-HBV-IPV: diphtheria-tetanus-acellular pertussis/hepatitis B/inactivated polio vaccine; DTPw-HBV: diphtheria-tetanus-whole-cell pertussis/hepatitis B vaccine; ELISA: enzyme-linked immunosorbent assay; GMC: geometric mean concentration; GMT: geometric mean titer; Hib: Haemophilus influenzae type B; IgG: immunoglobulin G; IPV: inactivated polio vaccine; MenC: meningococcal serogroup C; NS: not studied; OPA: opsonophagocytic activity; PCV7: 7-valent pneumococcal conjugate vaccine; PCV10: 10-valent pneumococcal conjugate vaccine; TT: tetanus toxoid.

^aImmune responses were measured 1-month post-primary and post-final dose using 22F-inhibition ELISA. In this assay, a reference antibody concentration of 0.2 μg/mL is equivalent to 0.35 μg/mL when using the non-22F ELISA at the World Health Organization reference laboratory [60,78].

^bFinnish, French, and Polish infants received 3 primary doses of PCV10 or PCV7 at 2, 3, and 4 months of age and a final dose at 12–18 months.

^cKorean infants received 3 primary doses of PCV10 or PCV7 at 2, 4, and 6 months and a final dose at 12–18 months of age, both coadministered with Hib vaccine.

^dFilipino infants received 3 primary doses of PCV10 or PCV7 at 6, 10, and 14 weeks of age and a final dose at 12–18 months of age. The final dose was coadministered with DTPw-HBV/Hib and poliovirus vaccines.

^ePolish infants received 3 primary doses of PCV10 or PCV7 at 2, 4, and 6 months of age and a final dose at 12–18 months of age. The final dose was co-administered with DTPw-HBV/Hib and poliovirus vaccines.

^fDanish, Norwegian, Slovakian, and Swedish infants received 3 primary doses of PCV10 at 2, 3, and 4 months of age and a final dose at 11 months of age.

^gGerman, Polish, and Spanish infants received either PCV10 coadministered with: (1) DTPa-HBV-IPV/Hib and MenC-CRM; (2) DTPaHBV-IPV/Hib and MenC-TT; (3) DTPa-HBV-IPV and Hib-MenC-TT; (4) or PCV7 coadministered with DTPa-HBV-IPV and Hib-MenC-TT at 2, 4, and 6 months of age with a final dose at 11–18 months of age.

^hInfants from a single center in the Netherlands received either: (1) PCV10 and DTPa-HBV-IPV/Hib; (2) PCV10 and DTPa-IPV/Hib; or (3) PCV7 at 2, 3, and 4 months of age.

ⁱGerman infants received 3 primary doses of PCV13 or PCV7 at 2, 3, and 4 months of age and a final dose at 11–12 months of age.

^jAmerican infants received 3 primary doses of PCV13 or PCV7 at 2, 3, and 4 months of age and a final dose at 12–15 months of age.

In each of these studies, with the exception of a study in Finland [67], PCV10 elicited higher IgG geometric mean concentrations (GMCs) specific for serotype 19A compared with PCV7 after the primary series and elicited higher IgG GMCs specific for serotype 19A compared with PCV7 after the final dose. In serotype 19A-specific OPA assays, GMTs in subjects who received PCV10 were numerically higher than in subjects who received PCV7, but the percentage of children with OPA levels considered protective (≥1:8) after PCV10 administration never exceeded 40% after the primary series [74]. These results are similar to those in an earlier study in which infants were immunized with three experimental 4-valent or 7-valent PCVs containing serotype 19F (but not 19A) [75]. OPA levels specific for serotype 19A were low in infants who were given these experimental vaccines.

In contrast, PCV13 elicits a substantially higher level of opsonophagocytic activity against serotype 19A when compared with PCV7 and PCV10 (Table 1).

When infants received PCV13 or PCV7 at 2, 3, and 4 months of age and a fourth dose at 11 to 12 months of age, OPA GMTs with PCV13 vaccination were 63- and 23-fold greater than with PCV7 for serotype 19A after the infant series and the toddler dose, respectively [76]. In a separate study where infants received PCV13 or PCV7 at 2, 3, and 4 months of age and a final dose at 12–15 months of age, serotype 19A OPA GMTs with PCV13 vaccination were 22- and 2-fold greater than with PCV7 after the infant series and the toddler dose, respectively [77]. Importantly, as noted in PCV13 global registration studies [79–81], a clear association is apparent between IgG and OPA responses following vaccination with PCV13 for serotype 19A [82].

As recently reviewed by Avila-Aguero [83], few studies directly compared PCV10 and PCV13 (NCT01616459 and NTR3069). In one phase II study, children in the Netherlands were vaccinated with PCV10 or PCV13 at 2, 3, 4, and 11 months of age [84,85]. In another phase II study designed to evaluate noninferiority of the immune response elicited by investigational 11- and 12-valent vaccines relative to PCV10 and PCV13, subjects received 4 doses of the respective vaccines at 2, 3, 4 (primary series) and 12–15 months of age (booster dose) [86]. In the phase II study (NCT01616459), anti-19A IgG concentration postprimary series increased 15-fold for PCV13, whereas PCV10 anti-19A IgG concentrations did not change, remaining at 0.18 µg/mL postprimary series (Figure 1(a) [86]). In the study in the Netherlands (NTR3069), 1 week after the booster dose, PCV13 recipients had significantly higher anti-19A IgG and OPA titers, and memory B cell responses than PCV10 recipients (Figure 1(b) [84,85]).

Figure 1. Immune responses specific for serotype 19A after vaccination with PCV10 or PCV13. (a) Anti-serotype 19A geometric mean concentrations from study NCT01616459 [86]. Children in Europe were administered PCV10 or PCV13 at 2, 3, and 4 months of age (primary series). Samples for immunogenicity analysis were taken before and 1 month after the primary vaccination series. Data adapted from GlaxoSmithKline study NTC0161459 [86]. (b) Anti-serotype 19A responses from study NTR3069. Children in the Netherlands were administered PCV10 or PCV13 at 2, 3, 4, (primary series) and 11 months (booster) of age. Samples for immunogenicity analyses were taken 1 week after the booster dose. Data adapted from van Westen et al [84] and Wijmenga-Monsuur et al [85].

ASCs: antibody-secreting cells; IgG: immunoglobulin G; OPA: opsonophagocytic activity assay; PBMCs: peripheral blood mononuclear cells; PCV10: 10-valent pneumococcal conjugate vaccine; PCV13: 13-valent pneumococcal conjugate vaccine.

Mixed PCV dosing schedules have also been evaluated. For example, in a study by Truck et al. [87] children previously vaccinated with PCV13 at 2 and 4 months of age were randomized to receive either a PCV13 or a PCV10 booster at 12 months of age. Although some increase in 19A antibody was seen in PCV10 recipients, at 1 month post booster, IgG GMCs and OPA titers were significantly lower than in PCV13 booster recipients. At 1 year post booster, there was no significant difference in serotype 19A IgG concentrations between subjects in the 2 vaccine groups, but OPA titers remained significantly higher in the PCV13 group. Another study assessed noninferiority of OPA responses for serotype 19A 1 month after a booster dose in subjects primed (primary series) with PCV10 versus those primed with PCV13 [88]. Noninferiority of OPA responses was achieved if the lower limit of the 2-sided 95% CI for the OPA GMT ratio (PCV10/PCV13) was >0.5. At 1 month after the booster, the noninferiority criterion was met for 19A, with a GMT ratio of 0.9 (0.63–1.3) for those who received 3 doses of PCV10 followed by 1 dose of PCV13, compared with children who received 4 doses of PCV13. The noninferiority criterion was also met in the 2 + 1 series. However, 1 year after the booster dose, the GMT ratio was 0.75 (0.35–1.6) for the 3 + 1 series and 0.82 (0.41–1.7) for the 2 + 1 series. When applying the noninferiority criterion for the primary end point to 12 months following the booster dose for serotype 19A, the PCV10 OPA response was inferior to PCV13 in both the 3 + 1 and the 2 + 1 series.

3. Impact of PCVs on nasopharyngeal carriage of serotype 19A

By reducing carriage of vaccine serotypes, PCVs reduce pneumococcal transmission and thus provide protection by both direct and indirect (i.e. herd) effects. PCVs have the ability to reduce vaccine-type (VT) carriage [89–109]; however, a reduction in VT carriage is often associated with an increase of non-VT carriage. This replacement in the NP niche leads to increased colonization of non-VT strains [91–97,99–103,106–108]. In most cases, the PCV-induced replacement of VT pneumococci in carriage is associated with an overall decrease in pneumococcal disease, indicating that in general, replacement serotype strains are less invasive and have a lower disease potential [33,110–112].

A serologic immunological threshold has not been defined for the prevention of NPC, but some studies have suggested that higher IgG antibody concentrations are needed compared with the thresholds established for protection against invasive disease [113–116]. Therefore, functional anti-serotype 19A antibody levels elicited by PCVs (presented in Table 1) may correlate with the ability to reduce NPC with serotype 19A and to induce herd protection, although the relation between functional antibody levels in serum and carriage (on mucosal surfaces) may be indirect. In addition, reduced serotype 19A NPC may not be solely related to opsonophagocytosis.

There is no evidence that PCV7 reduces NPC of serotype 19A. In a US study conducted among children 6–59 months of age, serotype 19A accounted for 8% of NP isolates before PCV7 implementation and 21% of isolates after PCV7 implementation [35]. Additionally, in an Israeli study, PCV7 administered at ages 2, 4, 6, and 13 months had no effect on serotype 19A carriage prevalence at age 24 months (Figure 2(a) [117]).

Figure 2. Randomized controlled trials assessing the impact of PCVs on NP carriage related to serotype 19A or cross-reactive serotypes in (a) Israel, data adapted from Dagan et al. [117] (Dagan, Ron and Patterson, Scott; Comparative Immunogenicity and Efficacy of 13-Valent and 7-Valent Pneumococcal Conjugate Vaccines in Reducing Nasopharyngeal Colonization: A Randomized Double-Blind Trial, Clinical Infectious Diseases, 2013, Vol 57/Issue 7: 952–962, by permission of Oxford University Press); (b) the Netherlands, data adapted from van den Bergh et al [118]; and (c) Argentina/Panama/Colombia (COMPAS) [120].

NP: nasopharyngeal; PCV7: 7-valent pneumococcal conjugate vaccine; PCV10: 10-valent pneumococcal conjugate vaccine; PCV13: 13-valent pneumococcal conjugate vaccine.*Significant difference in carriage, PCV7 vs. PCV13. ^†Any serotype belonging to the same serogroup as the PCV10 vaccine serotypes, but different from vaccine serotypes.

As with PCV7, most studies have shown vaccination with PCV10 does not reduce serotype 19A NPC. Among infants vaccinated at 2, 3, 4, and 11–13 months with PCV7 or PCV10 in a randomized controlled trial (RCT) in the Netherlands, serotype 19A was the most common colonizing serotype across 4 time points during the full 12-month follow-up period and across all visits (28.1% in PCV10 recipients and 30.8% in PCV7 recipients) (Figure 2(b) [118]). In the winter of 2012/2013 in the Netherlands, no statistically significant reduction in serotype 19A carriage was observed in children vaccinated with PCV10 [119]. In the Clinical Otitis Media and Pneumonia Study (COMPAS), there was no significant difference between PCV10 recipients and the control group with respect to carriage of cross-reactive serotypes (Figure 2(c) [120]).

In Finland, a large cluster RCT compared 3 + 1 and 2 + 1 schedules of PCV10 versus control [105,121]. Serotype 19A carriage decreased significantly only in children 18–22 months of age who received a 3 + 1 schedule, and in no other age group (Figure 3(a) [105]). With the 2 + 1 schedule, no significant reductions of 19A carriage were observed in any age group (Figure 3(b)) [105].

Figure 3. Impact of PCV10 on serotype 19A carriage in a randomized controlled trial conducted in Finland; data adapted from Vesikari et al [105] and from GSK study report 112,595 [121]. (a) 3 + 1 regimen vs. control (hepatitis B virus vaccine or hepatitis A virus vaccine; NP swabs were collected before vaccine dose 1, 1 month after dose 3, before the booster dose, 3 months after the booster dose, and 10 months after the booster dose. (b) 2 + 1 regimen vs. control; NP swabs were collected before vaccine dose 1, 1 month after dose 2, before the booster dose, 3 months after the booster dose, and 10 months after the booster dose.

PCV10: 10-valent pneumococcal conjugate vaccine.

Additional studies assessing PCV10 effects on serotype 19A carriage were conducted in the Czech Republic (PCV10 given at 3, 4, 5, and 12–15 months of age [122]), in Kenya (PCV10 introduced in 2011 in a 3 + 0 schedule at 6, 10, and 14 weeks of age with a 2-dose catch-up for infants 12 months to 5 years [102]), and in New Zealand (PCV10 replaced PCV7 in 2011 [96]). All of these studies showed small or even negative effects of PCV10 on serotype 19A carriage (Table 2).

Table 2. Studies examining the effect of PCVs on serotype 19A.

Citation	Study location	Year after vaccine introduction	Variable measured (isolates, serotype 19A prevalence, or vaccine effectiveness)	Findings
Carriage/Colonization
PCV7/PCV13
Dagan et al. [117]	Israel	–	NP isolates from children aged ≤24 mo	PCV7 vaccinated = 22.9%
				PCV13 vaccinated = 12.6%
Lee et al. [95]	USA	1	NP isolates from children aged <7 y seen for well child or acute care visits	Decline in carriage in 2011 compared with 2009
Loughlin et al. [98]	USA	1–2	NP isolates from children aged <5 y seen for well child or urgent care visits	Year 1 = 3 per 100 children Year 2 = <1 per 100 children
Zucotti et al. [104]	Italy	1	NP isolates each from healthy children unimmunized, or vaccinated with PCV7 or PCV13 (5 September–6 December 2011)	Unimmunized = 9%
				PCV7 vaccinated = 12%
				PCV13 vaccinated = 0%
Cohen et al. [123]	France	1	NP isolates from children with AOM (October 2010–May 2011)	PCV7 vaccinated = 15.4% PCV13 vaccinated = 7.5% (P < 0.001)
Dunais et al. [96]	France	2	Serotype 19A prevalence	Pre-PCV13 (2008) = 15.5%
				Post-PCV13 (2012) = 6.5%
Desai et al [94]	USA	3	Serotype 19A prevalence	Pre-PCV13 (July–December 2010) = 25.8%
				Post-PCV13 (January–June 2013) = 3.0% (P < 0.0001)
PCV10
Prymula et al. [122]	Czech Republic	NA	Vaccine efficacy (NP isolates from healthy children 1 y after booster dose)	Vaccine efficacy (95% CI) for carriage of cross-reactive serotypes = 18.6% (−105.5%, 68.5%)
van den Bergh et al. [118]	The Netherlands	NA	Serotype 19A prevalence (NP swabs from children aged <2 y)	Serotype 19A was predominant colonizing serotype.
				PCV7 vaccinated = 30.8% across all visits;
				PCV10-vaccinated = 28.1% across all visits
Vesikari et al. [105,121]	Finland	NA	NP isolates from children aged <22 mo	Statistically significant decrease in serotype 19A carriage in children 18–22 mo of age vaccinated on a 3 + 1 schedule vs. nonvaccinated children
				Statistically significant reductions not observed in other age groups or in any age group vaccinated on a 2 + 1 schedule
Hammitt et al. [102]	Kenya	2	NP isolates from residents of Kilifi, Kenya before and after vaccine introduction	Serotype 19A carriage prevalence increased in the period after vaccine introduction
Wyllie et al. [119]	The Netherlands	1–2	Serotype 19A carriage	Nonstatistically significant reduction (P = 0.22) in serotype 19A carriage in children vaccinated with PCV10
Brandileone et al. [91]	Brazil	3	NP isolates from children 12–23 mo of age pre- and post-PCV10 introduction	No significant change in carriage of serotype 19A (P = 0.4562)
PCV7/PCV10
Best et al. [97]	New Zealand	3	NP and middle ear fluid isolates for 2 cohorts of children aged <36 mo comparing the PCV7 era (2011) with the PCV10 era (2014)	Serotype 19A was the most prominent S pneumoniae serotype in NP samples in the PCV10 era
Mucosal Disease
PCV7/PCV13
Ben-Shimol et al. [124]	Israel	3	Serotype 19A isolates from middle ear fluid cultures from children aged <2 y with otitis media (July 2004–June 2013)	IRR (95% CI): PCV13 period vs. PCV7 period = 0.09 (0.04, 0.20)
				PCV13 period vs. pre-PCV7 period = 0.15 (0.06, 0.35)
Olarte et al. [51]	USA	3	Serotype 19A isolates in patients with chronic sinusitis who underwent endoscopic sinus surgery	Pre-PCV13 (2008–2010) = 38% Post-PCV13 (2011–2013) = 11% (P = 0.007)
Kaplan et al. [53]	USA	1–3	Serotype 19A isolates from middle ear or mastoid cultures	2011 = 33.6% of isolates
				2013 = 10.2% of isolates
PCV7/PCV10
Best et al. [97]	New Zealand	3	Serotype 19A isolates from middle ear fluid for 2 cohorts of children aged <36 mo comparing the PCV7 era (2011) with the PCV10 era (2014)	Serotype 19A was the most prominent S pneumoniae serotype in middle ear fluid in the PCV10 era
Invasive Pneumococcal Disease
PCV7/PCV13
Olarte et al. [125]	USA	3	Serotype 19A isolates from pediatric patients with pneumococcal meningitis	Pre-PCV13 = 27.03%; Post-PCV13 = 14.93% (P = 0.08)
Kaplan et al. [126]	USA	1–2	Serotype 19A prevalence	Pre-PCV13 (2007–2009) = 40.07%
				Post-PCV13 (2011) = 28.57%
Iroh Tam et al. [127]	USA	2	Serotype 19A prevalence	Pre-PCV13 (2007–2009) = 39.88%;
				Post-PCV13 (2010–2012) = 20.00% (P < 0.0001)
Moore et al. [128]	USA	3	Serotype 19A prevalence	Age <5 y  Pre-PCV13 (2009–2010) = 52.84%
				Post-PCV13 (2012–2013) = 11.11%
				Age 5–17 y Pre-PCV13 = 16.67%
				Post-PCV13 = 13.73%
				Age 18–49 y Pre-PCV13 = 22.93%
				Post-PCV13 = 10.63%
				Age 50–64 y Pre-PCV13 = 20.14%
				Post-PCV13 = 10.42%
				Age ≥65 y Pre-PCV13 = 20.00%
				Post-PCV13 = 7.75%
Farnham et al. [129]	USA	2	Serotype 19A prevalence	Change in IPD incidence from pre-PCV13 period to post-PCV13 period: −79.69%, P = 0.001
Moore et al. [130]	USA	1–4	Vaccine effectiveness (95% CI) among children aged 2–59 mo	85.6% (70.6%, 93.5%)
Demczuk et al. [112]	Canada	2	IPD isolates	Pre-PCV13 (2010) = 19.12%;
				Post-PCV13 (2012) = 13.89% (P < 0.001)
Andrews et al. [131]	England, Wales, Northern Ireland	3–5	Vaccine effectiveness (95% CI)	67% (33%, 84%)
Waight et al. [132]	England and Wales	4	Serotype 19A prevalence	Age <5 y = 0.09 (0.03, 0.25) (P < 0.0001) Age 5–64 y = 0.46 (0.35, 0.68) (P < 0.0001) Age ≥65 y = 0.35 (0.25, 0.47) (P < 0.0001)
			IRR (95% CI) between post-PCV13 period and pre-PCV13 period
Harboe et al. [133]	Denmark	3	Serotype 19A prevalence Pre-PCV7 (January 2000–December 2007) PCV7 (January 2008–December 2010) Post-PCV13 (January 2011–December 2013)	Decline in incidence post-PCV13 toward pre-PCV7 levels
Ben-Shimol et al. [134]	Israel	2–3	IPD incidence (per 100,000) in children aged ≤5 y	Pre-PCV7 period (2004–2008) = 5.1 PCV7 period (2010–2011) = 5.0 Post-PCV13 period (2012–2013) = 1.6 (both differences P < 0.05)
Wei et al. [135]	Taiwan	1	IPD incidence (per 100,000 person-years) in children aged <5 y	2008–2010 = 1.7 2011–2012 = 10.3 2013 = 5.6
Von Gottberg et al. [136]	South Africa	1	IPD incidence (per 100,000 person-years) in children aged <2 y	70% decrease from pre-PCV7 period (2005–2008) to 1 y after PCV13 introduction (2012)
Lepoutre et al. [137]	France	2	IPD incidence	83% decrease from pre-PCV13 period (2008–2009) to post-PCV13 period (2012)
Picazo et al. [138]	Spain	2	IPD incidence (per 100,000 persons) Pre-PCV13 period (2007–2010) Post-PCV13 period (2011–2012)	Age <12 mo Pre-PCV13 period = 16.47Post-PCV13 period = 2.72 Age ≥12 to <24 mo Pre-PCV13 period = 16.73 Post-PCV13 period = 2.66 Age ≥24 to <60 mo Pre-PCV13 period = 3.99 Post-PCV13 period =0.45
Deceuninck et al. [139]	Canada	8 PCV7 = 3 PCV10 = 2 PCV13 = 2	Vaccine effectiveness (95% CI) in children aged 2–59 mo	PCV7 = 42% (−9%, 69%) (P = 0.093); PCV13 = 74% (11%, 92%) (P = 0.032)
PCV10
Domingues et al. [140]	Brazil	1–2	Vaccine effectiveness (95% CI) in children aged ≥2 mo	82.2% (10.7%, 96.4%)
Jokinen et al. [141]	Finland	1–3	Vaccine effectiveness (95% CI) in children aged 3–42 mo	2011–2013 for 19A = 62% (20%, 85%) 2013 for 6A+19A = 8% (–107%, 62%)
Deceuninck et al. [139]	Canada	8 PCV7 = 3 PCV10 = 2 PCV13 = 2	Vaccine effectiveness (95% CI) in children aged 2–59 mo	71% (24%, 89%) (P = 0.013)

AOM: acute otitis media; IPD: invasive pneumococcal disease; IRR: incidence rate ratio; NA: not applicable; NP: nasopharyngeal; PCV7: 7-valent pneumococcal conjugate vaccine; PCV10: 10-valent pneumococcal conjugate vaccine; PCV13: 13-valent pneumococcal conjugate vaccine.

These data for PCV7 and PCV10 are in contrast to data for PCV13. For example, in the aforementioned randomized double-blinded study in Israel, the rate of NP acquisition of serotype 19A up to 1 year after the PCV13 booster dose was statistically significantly lower among PCV13 recipients compared with PCV7 recipients [117]. Other studies have demonstrated reductions of serotype 19A carriage with PCV13 use compared with the years before PCV13 introduction [94–96,98] or compared with subjects vaccinated with PCV7 (Table 2) [104,117,123].

4. PCV impact against serotype 19A disease

Several countries across North America [128,142], Latin America [143,144], Europe [132,145–147], and Asia Pacific [148] have robust surveillance programs for IPD, either population based or sentinel, with publicly available data. These include Finland [146], New Zealand [148], Brazil [143], Canada (Quebec) [142], the USA [128], England and Wales [132], Norway [147], and Chile [144]. From these, 2 areas have used all 3 PCVs in their NIP (New Zealand and Quebec, Canada) although never at the same time. The others have either sequentially used PCV7 followed by PCV13 (Norway, the USA, and England and Wales), or only PCV10 (Finland, Brazil, and Chile). All of these countries routinely vaccinate children <2 years of age within their National Immunization Programs in 3 + 1 or 2 + 1 schedules, except the USA, which also vaccinates adults ≥65 years of age with PCV13 since 2014. The USA, UK, and Canada continue to vaccinate adults ≥65 years of age with PPV23, which contains serotype 19A. However, the protection afforded by PPV23 is acknowledged to be generally short lived, and effectiveness starts to wane after approximately 3 years [149]. In these countries, IPD surveillance data exist for all ages. Herein, the total number of serotype 19A IPD cases per year are presented by age group: ≤5 years of age (to assess direct protection) and >5 years of age (to assess indirect protection). For some of these countries, incidence, a better measure of impact, was not reported. Therefore, to account for improved surveillance over time, which could lead to increased reporting in the number of cases in the years following PCV introduction, serotype 19A cases are also presented as a proportion of the total number of IPD cases reported in a given year.

4.1. PCV7

Surveillance data demonstrate that PCV7 provides predictable protection against VT IPD. However, surveillance data did not show a decline in 19A disease after the introduction of PCV7. In fact, an increase in serotype 19A IPD was noted in a number of countries [21,134,139,150–153]. Serotype 19F, a component of PCV7, can elicit polysaccharide binding antibodies that are cross-reactive with serotype 19A, as previously mentioned, and at the time of PCV7 introduction, it was hypothesized that inclusion of serotype 19F in PCV7 may also reduce serotype 19A disease [154].

The US Centers for Disease Control and Prevention’s Active Bacterial Core surveillance (ABCs) is an active laboratory and population-based system that collects surveillance data for invasive bacterial infections in the USA with a current surveillance population between 19 and 42 million [155]. A detailed synopsis of IPD trends reported through ABCs during the entire conjugate vaccine era (1998–2015) is provided at http://www.cdc.gov/abcs/reports-findings/survreports/spneu-types.html. A matched case–control study using ABCs data described a nonsignificant shift toward cross-protection for PCV7 against serotype 19A IPD between January 2001 and May 2004 in children 3–59 months of age [156]. However, during the PCV7 period, serotype 19A IPD incidence among children <5 years of age was 2.6 per 100,000 in 1999–2000, increased to 6.5 per 100,000 in 2003–2004 [157], and increased to 9.4 per 100,000 in 2007 [150]. By 2006–2007, 19A was the most prevalent serotype in the USA associated with IPD [158] and was the most prevalent penicillin nonsusceptible serotype between 2004 and 2011 [159].

In the Canadian province of Quebec, a PCV7 vaccination program was implemented in December 2004 with doses administered at 2, 4, and 12 months of age [139]. Since vaccine introduction, >90% of children received the recommended number of doses. Beginning in January 2005, children <5 years old in Quebec have been prospectively enrolled in a nonmatched, case-control study. In this study, vaccine effectiveness of PCV7 was high for serotype 19A IPD (computed from a logistic regression model weighted for sampling fraction of controls and adjusted for season, year, age, and underlying medical conditions such as severe prematurity and asthma) at 42% (95% CI: −9%, 69%; P = 0.093) [139]. Though not statistically significant, the 42% effectiveness for PCV7 against serotype 19A IPD does not seem biologically plausible, given that surveillance data from the National Institute for Health and Welfare of Quebec showed that the number and proportion of cases in children <5 years of age steadily increased between the time PCV7 was introduced in 2004 (8 cases) and replaced by PCV10 in 2009 (36 cases) (Figure 4(a) [142]). Additionally, no demonstrable herd effect was observed with PCV7 for serotype 19A IPD.

Figure 4. Surveillance data for serotype 19A invasive pneumococcal disease in individuals <5 years or ≥5 years of age from countries that introduced PCV7, PCV10, and PCV13 into their national immunization programs. Data for Canada (Quebec; panels a and c) are adapted from the National Institute for Health and Welfare [142]. New Zealand data (panels b and d) are adapted from Public Health Surveillance [171,174]. Data for children <5 years of age are shown in panels a and b, and for individuals ≥5 years old in panels c and d.

IPD: invasive pneumococcal disease; PCV7: 7-valent pneumococcal conjugate vaccine; PCV10: 10-valent pneumococcal conjugate vaccine; PCV13: 13-valent pneumococcal conjugate vaccine.

Other countries that introduced PCV7 observed increased rates of serotype 19A disease in vaccinated populations, indicating a lack of serotype 19F cross-protection against 19A. For example, in the UK, PCV7 was introduced in September 2006 with a catch-up for all children <2 years of age, and reached coverage of >90% [160]. Nearly all (>90%) of approximately 5000 annual IPD cases occurring in England and Wales that are reported to Public Health England are serotyped, providing one of the largest datasets in the world [132]. After introduction of PCV7, serotype 19A IPD increased annually between 2007 and 2010 in infants <90 days of age [151]. In Belgium, serotype 19A IPD prevalence increased in individuals <18 years of age after PCV7 introduction in 2004 [21]; in France pneumococcal meningitis and bacteremia associated with serotype 19A in children <2 years of age [152] increased after PCV7 introduction in 2006. In Japan, 19A was the most prevalent serotype associated with cases of AOM in children <4 years of age during the PCV7 period [153].

4.2. PCV10

A similar phenomenon to that which occurred after PCV7 introduction became apparent in countries that introduced PCV10 in their routine immunization programs. For example, PCV10 was introduced into the Finnish NIP in September 2010 under a 2 + 1 schedule (3, 5, and 12 months of age) following a large cluster-randomized effectiveness study that took place between 2009 and 2012. In this study, approximately 15,000 children <1.5 years of age received PCV10 (approximately 25% of the corresponding birth cohort) under a 2 + 1 schedule with catch-up [161]. In Finland, surveillance data are based on notifications of IPD from clinical laboratories to the Finnish National Institute for Health and Welfare as well as analyses performed at national laboratories [162]. As shown in Figure 5(a) [146], the number of 19A IPD cases in children <5 years of age decreased between 2004 and 2010, before PCV10 introduction, and there has been an overall increasing trend since the introduction of PCV10 in the infant NIP. By 2015, in children <5 years of age, serotype 19A represented over half the total number of IPD cases. In those >5 years of age, the number of 19A IPD cases has steadily increased since PCV10 introduction, with 28, 38, 59, 87, and 127 cases reported in 2011, 2012, 2013, 2014, and 2015, respectively (Figure 5(d) [146]), indicating a lack of a herd effect.

Figure 5. Surveillance data for serotype 19A invasive pneumococcal disease  from countries that introduced only PCV10 into their national immunization programs. Data for Finland (panels a and d) are adapted from National Institute of Health and Welfare [141,146]; data for Brazil (panels b and e) are adapted from Cassiolato et al [163]. Data for Chile (panels c and f) are adapted from the Institute of Public Health [144]. Data for children <5 years of age are shown in panels a and b, and for individuals ≥5 years old in panels d and e. Panels c and f (Chile) show data for individuals <2 years and ≥2 years of age, respectively.

IPD: invasive pneumococcal disease; PCV10: 10-valent pneumococcal conjugate vaccine.

The data from the surveillance in Finland are consistent with a population-based study that took place between 2010 and 2013 to evaluate PCV10 for direct and indirect effects on IPD incidence among children ≤5 years of age during the initial 3 years after PCV10 was introduced in the NIP [141]. In this study, children in the vaccine-eligible cohort (all children born 1 June 2010 or later) were followed starting at age 3 months until the end of 2013. Children vaccinated with PCV10 in the aforementioned large cluster-randomized effectiveness study were excluded. The relative rate reduction in 19A between 2010 and 2013 was 62% (95% CI: 20%, 85%). To investigate temporal effects of NIP introduction, a subanalysis compared IPD rates in the target cohort in 2013 with rates in the reference cohorts. The point estimate for the reduction in PCV10-related serotypes 6A and 19A was 8% (95% CI: −107%, 62%), which is consistent with the surveillance data collected during that time period, whereby the number of cases among children <5 years of age went from 0 in 2012 to 9 in 2013. The calculated values for 6A or 19A, separately, were not provided.

In March 2010, PCV10 was introduced for routine immunization of infants through Brazil’s NIP, which offers publicly funded vaccines to all Brazilian children. Three primary doses are given to infants at ages 2, 4, and 6 months and a booster dose at 12 months, with a catch-up program in place for children up to the age of 24 months [140]. Surveillance data from Brazil is conducted by SIREVA II, a Latin American laboratory-based surveillance network [143]. As shown in Figure 5(b), serotype 19A represented 2.7% of all IPD cases in Brazil prior to PCV10 introduction (2010) in children <5 years of age and rose to 24.4% of all cases by 2014 [163]. There is also no evidence of a herd effect, as the number of 19A IPD cases in those ≥5 years of age is also increasing (Figure 5(e)). In addition, a recent study in Brazil, which used data from the national surveillance system for notifiable diseases and the national reference laboratory for S pneumoniae, showed a significant increase of 62.8% (all age groups) in the incidence rates of IPD caused by serotypes included in PCV13 but not in PCV10 (i.e. serotypes 3, 6A, and 19A) [164].

Unlike Finland, the findings of a case-controlled and indirect cohort study conducted in Brazil were not consistent with the surveillance data (Figure 5(b)) [140,165]. The case-controlled study evaluated IPD in children age-eligible for at least 1 PCV10 dose through laboratory-based and hospital-based surveillance in 10 states in Brazil from 1 March 2010, until 31 December 2012. The study identified 4 age-matched and neighborhood-matched controls for each case. PCV10 effectiveness, calculated as (1 – adjusted matched odds ratio) × 100% for VT and non-VT, yielded a point estimate of 82.2% (95% CI: 10.7%, 96.4%) against serotype 19A IPD in children [140]. In the indirect cohort study [165], cases were also identified through laboratory-based surveillance and were previously enrolled in the aforementioned case-controlled study [140]. Adjusted vaccine effectiveness against serotype 19A IPD was 71.3% (95% CI: 16.6%, 90.1%) for at least 1 dose and 63.4% (95% CI: –16.8%, 88.6%) for an up-to-date schedule (whereby partially vaccinated children were excluded from the analysis) [165].

In Chile, PCV10 was introduced into the NIP for the childhood vaccination schedule in January 2011. Vaccination is mandatory and provided free of charge to infants ≤12 months of age under a 3 + 1 schedule with no catch-up program. In a 2011 birth cohort of >247,000 children, vaccine uptake was estimated at 95.3% [166]. Since PCV10 introduction, data collected by the Chilean Ministry of Health have shown the number of 19A IPD cases has steadily increased since 2011 in all age groups [144] (Figure 5(c,f)). In 2014, serotype 19A accounted for 25% and 13% of IPD cases in those <2 and those ≥2 years of age, respectively. In a recent statement issued by the Advisory Immunization Committee of the Chilean Society of Infectious Diseases, among children younger than 2 years of age, serotype 19A was identified in 4% to 8% of isolates before PCV10 implementation and increased to 25% in 2014 [167]. Most of the cases of 19A IPD occurred in children who received all recommended doses of PCV10. The magnitude and clinical relevance of serotype 19A emergence in Chile has resulted in a call to change from PCV10 to PCV13 by this advisory committee [167].

In New Zealand, PCV10 replaced PCV7 in October 2011 with no catch-up program [168]. Between October 2011 and September 2014, 90%–94% of children aged 12 months had received all recommended infant immunizations, including pneumococcal vaccination [169]. Surveillance data are collected by laboratories of the Institute of Environmental Science and Research Ltd. and recorded on EpiSurv, the national communicable disease database [170]. As shown in Figure 4(b), the overall number and proportion of 19A IPD cases increased since PCV10 was introduced, with 55 total cases in 2010 and 87 cases in 2014 [171]. Between 2010 and 2013, an increasing proportion of penicillin-resistant IPD isolates have been serotype 19A; serotype 19A was the most common penicillin-resistant serotype in 2013 (49.3% of penicillin-resistant isolates) [172]. In July 2014, New Zealand decided to replace PCV10 with PCV13 [74,173]; however, PCV10 was used until late 2014. PCV13 use began in late 2014, and within only 1 year, the number of cases of 19A IPD in those <5 years of age had declined approximately fourfold (Figure 4(b)) [174]. However, 19A IPD cases continued to rise among those aged ≥5 years (Figure 4(d)), suggesting that herd effects may take longer to emerge.

In Quebec, PCV7 was replaced by PCV10 in June 2009 and by PCV13 in January 2011 with no catch-up doses for either vaccine. Surveillance data from the Institut National de Santé Publique du Québec show that between 2004 and 2014, the number of serotype 19A IPD cases peaked around 2009–2010 (Figure 4(a,c). The number of cases of serotype 19A IPD dropped steadily since 2010. In the aforementioned case-controlled study conducted in Quebec, vaccine effectiveness for PCV10 was 71% (95% CI: 24%, 89%; P = 0.013) against serotype 19A IPD [139], which was similar to PCV13 in the same study (74% [95% CI: 11%, 92%, P = 0.032]). The implementation of PCV13 after 18 months of PCV10 use in Quebec makes the interpretation of these similar effectiveness estimates difficult.

Lastly, 3 years after PCV10 introduction in the Netherlands, sentinel laboratory surveillance system data have shown no cross-protection against serotype 19A [175]. Most recently, a publication from the Dutch National Institute for Public Health and the Environment (RIVM) noted that the incidence of serotype 19A decreased after the introduction of PCV10 in 2011–2013 but increased slightly (among those <5 and 50–64 years of age) or stabilized (among those 5–49 and >65 years of age) in 2014–2015 and 2015–2016. In this report, the RIVM noted an ‘absence of cross-protection of PCV10 against serotype 19A’ [176].

4.3. PCV13

In contrast with the experience with PCV7 and PCV10, implementation of PCV13 immunization in the routine infant programs of several countries has resulted in dramatic and sustained declines in the incidence of serotype 19A in all age groups. PCV13 efficacy and effectiveness studies for IPD and mucosal disease caused by serotype 19A are summarized in Table 2.

As an example, in the USA, PCV13 was introduced in 2010 in a 3 + 1 schedule [128]. The number of cases of serotype 19A IPD decreased from pre-PCV13 levels in all age groups (Figure 6(a,c) [128]). IPD caused by the 6 additional PCV13 serotypes (i.e. 1, 5, 7F, 3, 6A, and 19A) collectively declined by 93% (95% CI: – 94%, – 91%). A more recent case-controlled study conducted by the CDC found significant PCV13 effectiveness against serotype 19A in children 2–59 months of age (Table 2) [130]; the same study also identified a statistically significant effectiveness against antibiotic nonsusceptible IPD of 65.6% (95% CI: 44.9%, 78.7%), though serotype-specific data were not reported. These findings were similar to past experience with PCV7 [89,177].

Figure 6. Surveillance data for serotype 19A invasive pneumococcal disease in individuals <5 years or ≥5 years of age in countries that switched from PCV7 to PCV13 in their national immunization programs. Data for the USA (panels a and c) are from the Centers for Disease Control and Prevention Active Bacterial Core Surveillance and adapted from Moore et al. [128]. Data for Norway (panels b and d) are from the Norwegian Institute of Public Health and adapted from Steens et al [147]. Data for children <5 years of age are shown in panels a and b, and for individuals ≥5 years old in panels c and d.

IPD: invasive pneumococcal disease; PCV7: 7-valent pneumococcal conjugate vaccine; PCV13: 13-valent pneumococcal conjugate vaccine.

Significant PCV13 vaccine effectiveness has also been demonstrated in Quebec among children 2–59 months of age following PCV13 introduction in January 2011 (Table 2), with an effectiveness estimate similar to that of PCV10 [139]. Surveillance data have shown that serotype 19A IPD cases in Quebec have continued to decrease after the introduction of PCV13 in all age groups (Figure 4(a,c) [142].

In the UK, PCV13 was introduced in April 2010 in a 2 + 1 schedule with no catch-up [132]. A study using the Public Health England surveillance dataset found that the incidence rate of serotype 19A IPD decreased by 91% in children <5 years of age post-PCV13 compared with the pre-PCV13 time period (Table 2) [132]. In Norway, PCV7 was introduced in 2006, and PCV13 was introduced in 2011 in a 2 + 1 schedule [147]. Under the Infectious Disease Control Act, all clinicians and laboratories in Norway are obligated to notify cases of IPD to the Norwegian Institute of Public Health. Although the number of cases in Norway for children <5 years of age dropped to zero in 2012 [147], just 1 year after PCV13 introduction (Figure 6(b,d)), data for later years have not been published and are needed to confirm these findings. Decreased serotype 19A IPD has also been reported in Denmark [133].

Decreases in IPD associated with serotype 19A in children and adults after the introduction of PCV13 have also been documented in other countries outside North America and Europe. In Israel, the incidence rate ratio of serotype 19A IPD significantly declined compared with the period of PCV7 use and the pre-PCV7 period in children <5 years (both differences P < 0.05) [134]. In Taiwan, PCV7 was introduced in late 2005; a PCV13 catch-up immunization program for children 2–5 years of age was launched in 2013 [135]. With the launch of the catch-up program, serotype 19A IPD incidence in this age group decreased from 12.9 cases per 100,000 during 2011–2012 to 6.0 cases per 100,000 in 2013 [135]. IPD incidence rates further decreased to 2.5 cases per 100,000 when the catch-up program was extended to children aged 1 year in 2014 [178]. In South Africa, the rate of serotype 19A IPD decreased by 70% in children <2 years in the year after PCV13 introduction compared with the period before PCV7 introduction [136].

5. Antibiotic resistance

The relevance of antimicrobial resistance (AMR) for human and animal health has recently been highlighted by national and international public health authorities. Clinically significant resistance to antimicrobial agents by serotype 19A became a major concern after the introduction of PCV7 [37,179–181] (Supplementary Table 1). As reviewed by Dagan and Klugman [177], after the introduction of PCV7 there was an initial decrease in AMR, followed by an early increase in antimicrobial-resistant serotype 19A. The same effect has now been observed in Chile after PCV10 introduction, where fully vaccinated children have shown increased rates of IPD caused by resistant clones of serotype 19A [167].

Similar outcomes have been observed in Brazil and New Zealand. In Brazil, molecular findings have suggested an increase in serotype 19A multidrug-resistant CC320 after PCV10 introduction [182]. In New Zealand, where PCV10 replaced PCV7 in October 2011 with no catch-up program, an increasing proportion of penicillin-resistant IPD isolates during 2010–2013 have been serotype 19A; serotype 19A was the most common penicillin-resistant serotype in 2013 (49.3% of penicillin-resistant isolates) [171].

Countries such as France, Israel, and the USA, which have introduced PCV13 into the infant NIP, have seen reductions in AMR due to the relevant serotypes, particularly antimicrobial-resistant serotype 19A [130,183–189]. In contrast with the emergence of antimicrobial-resistant serotype 19A after the introduction of PCV7 or PCV10, to date no single serotype 19A-like antimicrobial-resistant pneumococcal serotype has emerged globally in countries using PCV13. Rather, country-specific patterns of antimicrobial-resistant serotypes have waxed and waned.

6. Expert commentary

In children vaccinated with PCV7/PCV10, early effectiveness against serotype 19A IPD has been suggested in case-control, indirect cohort, or population-based studies in the USA [156], Brazil [140,165,190], Quebec [139], and Finland [141], respectively. However, continued surveillance data suggest not only a waning of this early effect, but an increasing number of 19A cases, consistent with the reemergence of this serotype. Following the introduction of PCV7 into routine pediatric vaccination programs, serotype 19A IPD ultimately emerged, along with the highly antibiotic-resistant clonal complex (CC) CC320/271 in children <5 years of age [191]. Similarly, recent data from Brazil and Chile, where PCV10 has been used in children since 2010 and 2011, respectively, are also showing an increase in serotype 19A multidrug-resistant CC320 in children [166,167,192] and adults [182]. Additionally, neither PCV7 nor PCV10 have conclusively shown any reductions of 19A carriage, resulting in no evidence of herd protection and increasing rates of 19A in nonvaccinated individuals in those countries where these vaccines have been introduced. In contrast, after several years of PCV13 use in numerous pediatric routine vaccination programs, there is conclusive evidence of a large reduction in IPD caused by 19A in vaccinated and nonvaccinated individuals [128,142,147].

Notably, serotype 19A IPD incidence increased in adults after PCV7 introduction in several countries despite adult use of PPV23, which contains serotype 19A polysaccharide. For example, PPV23 has been used in US adults since 1983 and vaccine coverage in those ≥65 years of age has been approximately 64% to 70% since 2005 [26,193]. Following introduction of PCV7 into the infant NIP in 2000, serotype 19A IPD rose substantially in adults despite relatively high PPV23 vaccine coverage; a decrease in serotype 19A was only observed after PCV13 introduction in children [128]. Similar rises in serotype 19A IPD were also observed in the UK following PCV7 introduction in children in 2006 despite PPV23 use in adults since 1992 and a comprehensive immunization campaign for PPV23 that was initiated in 2003 [132,194,195]. By 2007 PPV23, uptake rates were 70.1% in those 65–74 years of age, 77.3% in those 75–79 years of age, and 75.8% in those ≥80 years of age [196]. Thus, the observed reductions in serotype 19A in adults have been attributed to the herd effect from PCV13 use in children, rather than to direct vaccination with PPV23 [128,132]. Only 2 studies have assessed serotype-specific effectiveness of PPV23 for serotype 19A; reported vaccine effectiveness estimates ranged from 6% to 85%, without either estimate achieving statistical significance [194,197].

The most probable explanation for the reported differences in vaccine effectiveness for PCVs against serotype 19A is related to the functional antibody responses elicited by the various vaccines. In particular, functional antibody levels as measured by OPA against serotype 19A are substantially lower in vaccines containing only the cross-reactive serotype 19F (PCV7 and PCV10) compared with PCV13, which includes serotype 19A in its formulation. Differences in immunological responses between different PCVs are not exclusively related to the amount of antibodies generated but also the long-term duration of such antibody levels. For example, in a non-inferiority study assessing OPA responses, the long-term antibody response for 19A was less robust when PCV10 was followed by a booster dose of PCV13 compared with a series of PCV13 alone [88].

Although direct comparison of the immune responses to vaccination with PCVs across studies has limitations due to differing assays, study populations, and vaccination schedules, the only head-to-head comparisons of PCV10 and PCV13 showed statistically significantly higher GMCs, plasma cells, and memory B cells for PCV13 compared with PCV10 for serotype 19A [84,85,198]. In a postlicensure indirect cohort study that investigated the serotype-specific effectiveness of PCV13 and correlates of protection after institution of a 2 + 1 NIP, the calculated correlate for serotype 19A was 1.00 µg/mL (95% CI: 0.60, 2.47), substantially higher than the established WHO threshold at 0.35 µg/mL, and OPA antibody titers of ≥8 did not predict protection [131]. In light of this, although immunogenicity data provide evidence for the generation of some degree of cross-reactive antibodies to 19A for PCV10, continued monitoring of incidence data generated by robust surveillance systems may be the best means of documenting the long-term effectiveness of these vaccines in reducing pneumococcal disease associated with serotype 19A in vaccinated and nonvaccinated individuals.

The choice of PCVs in a given country must be considered using several factors, such as the country-specific prevalence of VT IPD, pneumococcal AOM, radiologically confirmed pneumonia, herd protection, and the cost of the vaccine. A recent systematic review by de Oliveira and colleagues on hospitalization and mortality in Latin American children <5 years of age concluded that PCV13 averted too few cases of serotype 19A to provide an advantage relative to PCV10 [199]. In contrast, Avila-Aguero and colleagues reviewed the evidence from surveillance systems from Brazil, Colombia, and Chile and came to the opposite conclusion, noting the available evidence suggests PCV13 offers better and longer protection than PCV10 against serotype 19A IPD and carriage in children [83]. Both Olivera and Avila-Aguero highlighted the importance of increasing and improving surveillance in Latin American countries. As many countries do not have the ability to implement robust surveillance systems, it is important to consider the evidence of PCV impact on serotype 19A globally, particularly for non-vaccinated individuals. For example, the European Centers for Disease Prevention and Control (ECDC) recently reported results from active surveillance of 13 sites in 8 European countries. Countries with universal PCV13 infant vaccination programs reported an overall 40% reduction in serotype 19A IPD incidence (2015 vs. 2009) in those ≥65 years of age, whereas countries using PCV10 reported a 227% increase in serotype 19A IPD incidence [200] in those ≥65 years of age. The ECDC recommended that ‘trends in IPD serotypes, in particular serotype 19A, must be kept under close monitoring in future years’ [201].

Beyond epidemiological surveillance data, countries also consider cost-effectiveness estimates to inform decisions about which vaccine to introduce into their NIPs; these estimates have included the evolution of serotype 19A in the local epidemiology. For example, in 2011, Colombia introduced PCV10 after publication of a cost-effectiveness study evaluating PCV7, PCV10, and PCV13 [202,203]. Following PCV10 introduction, however, serotype 19A IPD prevalence increased [143]. A more recent cost-effectiveness analysis in Colombia that imputed data from the regional vaccine system found that PCV13 was cost saving compared with PCV10 despite having higher vaccine pricing [204]. This study was consistent with other cost-effectiveness analyses of PCV13 performed in different countries [205–208], which found PCV13 to be more cost effective compared with PCV10 due to prevention of more IPD cases and deaths. The importance of the burden of disease attributed to serotype19A in particular was highlighted in a cost-effectiveness study in Australia, where the authors suggested that the high proportion of serotype 19A IPD would be of critical importance to vaccination policy [206].

It is important to understand current levels of serotype 19A circulation when considering changes to a PCV program. If circulation of serotype 19A were to approach elimination after PCV13 introduction, changing the recommended PCV to a vaccine that does not contain 19A may have undesirable consequences, such as the reemergence of the serotype as a frequent cause of disease. Most cost-effectiveness and epidemiologic impact models have been developed to evaluate the impact of introducing a PCV immunization program, and none have evaluated the impact of switching between two program strategies. Recently, disease reemergence was evaluated in two decision-analytic models that estimated the public health and economic impacts of switching infant vaccination from PCV13 to PCV10 in Canada and Spain. In both settings, real-world longitudinal data were used from countries using PCV13 or PCV10 and future disease was modeled for up to 10 years following the change in vaccine. In both analyses, the higher cost of PCV13 was offset by savings resulting from avoided medical costs due to the greater number of disease cases averted [209,210].

In conclusion, in countries where PCV7 and PCV10 have been introduced into routine pediatric immunization programs, the long-term cross-protective impact against serotype 19A in vaccinated individuals afforded by these vaccines is highly questionable. Furthermore, their inability to have an effect on serotype 19A carriage has resulted in no evidence of herd protection and often in increasing rates of 19A in nonvaccinated individuals. In contrast, after several years of PCV13 use in numerous routine vaccination programs, there is conclusive evidence of a reduction in IPD caused by 19A in vaccinated and nonvaccinated individuals.

7. Five-year view

The increase in serotype 19A IPD to date in several countries following the implementation of PCV7 or PCV10 highlights the need for continued surveillance after the introduction of any PCV to monitor emergence of nonvaccine serotypes in both vaccinated and nonvaccinated individuals. The evolution of vaccine and nonvaccine serotypes over time ultimately will determine the real-world long-term impact of the current PCVs and inform the development of next-generation PCVs.

8. Key issues

• Early effectiveness in vaccinated children using PCV7 or PCV10 against IPD caused by serotype 19A has been shown in case-control studies in the USA, Brazil, Quebec, and Finland.

• Continued surveillance data suggest a waning of the early cross-protection afforded by PCV7 and PCV10.

• Neither PCV7 nor PCV10 conclusively show any reductions of 19A carriage, resulting in no evidence of herd protection and increasing rates of 19A in nonvaccinated individuals in many countries.

• After several years of PCV13 use in numerous routine vaccination programs, conclusive evidence shows a reduction in carriage and IPD caused by 19A in vaccinated and nonvaccinated individuals.

• The inclusion of serotype 19A into a conjugate vaccine formulation is required to elicit appropriate levels of functional antibodies, which translates into protective effectiveness against invasive and noninvasive diseases in vaccinated and nonvaccinated individuals.

Declaration of interest

All authors are employees of Pfizer Inc and may hold stock or stock options. 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.

Acknowledgments

Medical writing support was provided by Daniel E. McCallus, PhD, and Jill E. Kolesar, PhD, of Complete Healthcare Communications, LLC.

Supplemental data

Supplemental data for this article can be accessed here.

Additional information

Funding

This manuscript (including medical writing support) was sponsored by Pfizer Inc.