Streptococcus pneumoniae, the pneumococcus, is an important human pathogen that causes serious diseases such as meningitis and bacteremia (infection of normally sterile sites, termed invasive pneumococcal disease or IPD), as well as pneumonia. Pneumococcus is also a common etiologic agent in milder diseases such as sinusitis and otitis media. In 2005, the World Health Organization (WHO) estimated that 1.5 million deaths each year are due to pneumococcal diseases [1]. In 2008, the WHO also estimated that about 0.5 million deaths of 8.8 million total global annual deaths among children <5 years of age were caused by pneumococcal infections [2]. Among elderly patients, the overall case fatality rate for pneumococcal bacteremia is up to 40% [3]. Deaths from pneumococcal bacteremia tend to occur quickly, often within the first week of hospitalization, even in the context of appropriate antibiotic therapy [4]. Therefore, pneumococcal vaccination is an important strategy for the prevention of pneumococcal infection. To this end, many national immunization programs (NIPs), which are government-based programs focused on reducing rates of vaccine-preventable diseases, now include pneumococcal vaccines. The pneumococcal conjugate vaccine (PCV) has been developed to overcome the limitations of the pneumococcal polysaccharide vaccine (PPV), which has poor immunogenicity in infants younger than 2 years of age [5]. Since the initial United States (US) approval of PCV7 in 2000, pneumococcal conjugate vaccines have been adopted into routine infant immunization programs in many countries [6], resulting in a significant reduction in the incidence of IPD among children [78]. In addition to poor immunogenicity among infants, there is also evidence to suggest reduced immunogenicity of PPV among elderly adults and adults with certain immune compromising conditions [9]. Unlike polysaccharide vaccines, such as PPV, which result in antibody production without immune memory, conjugate vaccines such as PCV result in memory B cell production (T-cell-dependent response) that produce a more sustained effect [910]. In accordance with this information, some NIPs now include recommendations for administration of PCV to elderly adults and adults with immune compromising conditions [11]. Reduction in disease in vaccinated individuals is referred to as the “direct” effect of a given vaccine. However, in addition to the direct effect of PCV on reducing pneumococcal disease in the vaccinated population, there has been a concordant decline in the incidence of IPD among adults who did not receive the vaccine following the introduction of PCVs into NIPs for young children [121314]. Reduction in disease within the non-vaccinated population is referred to as the “indirect”, or “herd” effect. In this review, we describe the indirect effect of PCV in pediatric NIPs on adult pneumococcal diseases, specifically how pneumococcal vaccines in NIPs for young children can decrease the incidence of adult pneumococcal disease.

PCV7 (Prevnar; Pfizer) was introduced in 2000, and included coverage for serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F [15]. PCV10 (Synflorix; GlaxoSmithKline) was licensed in 2008 and included coverage for serotypes 1, 5, and 7F in addition to those covered by PCV7. PCV13 (Prevnar13; Pfizer), licensed in 2009, expanded coverage to include serotypes 3, 6A, and 19A in addition to those covered by PCV10 [15]. PPV23 (PNEUMOVAX23; Merck) includes coverage for 12 serotypes common to PCV13 (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, 19A, and 23F) as well as 11 additional serotypes (2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, and 33F) [15]. In the future, PCVs may include coverage for up to 20 different serotypes [16].

The WHO places estimates of global coverage for pneumococcal vaccines (PPV and PCV) at 37%, with implementation in 129 countries as of the end of 2015 [17]. As of September 2016, 132 countries (68%) have introduced PCV into their routine infant immunization programs, and 6 additional countries (3.1%) plan to introduce PCV into NIPs in 2016 (Fig. 1) [18]. However, since their introduction, PCVs have been licensed and available for optional use in many countries without formal inclusion in NIPs. In Korea, PCV7 was made available as an optional vaccine in 2003 [19], and a NIP for children with PCV10 or PCV13 was implemented in 2014 [17]. The Korea National Immunization Survey found that for children born in 2009, the rate of PCV administration prior to inclusion in the NIP was about 70%. However, PCV administration varied according to region, with a rate of 71.3% in urban areas as compared to 56.8% in rural areas [20]. Notably, 2014 Korean guidelines also recommend administration of either PPV23 or PCV13 to adults ≥65 years old [21].

Understanding mechanisms for the indirect effect of pediatric vaccines on the unvaccinated adult population depends first upon understanding the mechanisms for carriage and transmission of S. pneumoniae within a population as a whole. Pneumococcus is a commensal flora of the nasopharynx, and humans are its only natural host. Thus, nasopharyngeal carriage and horizontal transmission within human populations represent the sole means for acquisition and spread of pneumococcal disease. As a result, pneumococcal colonization is an essential prerequisite for development of pneumococcal disease [222324]. Most pneumococci are characterized by a polysaccharide capsule, which is the primary determinant of virulence and invasiveness [25262728]. Additionally, the polysaccharide capsule is the basis for classification by serotypes and has been a focus for vaccine development [225262728]. Pneumococcal colonization occurs early in infancy and is most prevalent among young children, with a markedly lower rate of colonization in adults. Pre-PCV data from a large cohort of healthy Dutch children demonstrated that peak incidence of colonization was 55% at age 3, which declined to 8% after age 10 [29]. While the rates of pneumococcal carriage vary primarily by age, they may also be influenced by multiple additional factors, such as baseline serotype-specific prevalence, genetics, socioeconomic status, and demographic variables [2930]. Specifically, crowding and close contact among children (e.g. between siblings and in day care centers) have been identified as significantly affecting transmission [2931]. Consequently, rates of pneumococcal colonization vary widely across different populations. For these reasons, it is important to consider these factors and to conduct population-specific surveillance data in order to predict or evaluate the effects of a vaccine. Prior to the introduction of PCV into the NIP in Korea, the prevalence of pneumococcal carriage was 34% among children aged less than 5 years [32], and 9.6% among those aged 5 to 18 years [19].

Pneumococcal colonization is believed to represent the most important source of horizontal spreading within a community [3031]. Adults acquire nasopharyngeal colonization (and subsequently pneumococcal disease) via contact with children. In older adults, IPD exhibited distinct winter seasonality, especially surrounding winter holidays (Christmas and New Year’s) [3334]. Epidemiologic data also indicates a disproportionate effect of spikes in pediatric serotypes among older adults, particularly older women. Such data suggests the possibility of seasonal increases in transmission related to family contact between elderly adults and young children [34]. Adults with community-acquired pneumonia (CAP) who had regular contact with PCV7-vaccinated children were less likely to have CAP caused by the serotypes covered by the PCV7 vaccine than those with regular contact with unvaccinated children [35]. This can be explained by acquisition of S. pneumoniae from children colonized with similar pneumococcal serotypes via horizontal transmission. These mechanisms for pneumococcal carriage and transmission among children are therefore associated with changes in the burden of adult pneumococcal diseases.

PCVs have been associated with changes in carriage rates of vaccine type (VT) and non-VT serotypes. In a randomized trial of PCV administration to toddlers attending day care centers, the rate of carriage of VT S. pneumoniae was reduced in the vaccinated group, although that of non-VT was higher than in the control group [36]. Increases in the rate of non-VT carriage or disease after implementation of a vaccine, a phenomenon known as serotype replacement, is of significant concern with any NIP, including pneumococcal vaccines, and warrants careful consideration and surveillance.

In addition to the direct effects on carriage rates in vaccinated children, indirect effects of PCV on carriage rates in non-vaccinated adults have also been observed. The prevalence of VT carriage was lower in adults living with PCV7-vaccinated children than that in adults living with unvaccinated children [37]. In several community-based studies, reductions in the rate of carriage of VT were observed in unvaccinated children and adults after mass pediatric vaccination with PCV7 [3839] or PCV10 [40]. PCV13 also led to a reduction of nasopharyngeal pneumococcal carriage of the serotypes it uniquely covers in vaccinated children [41]. A Massachusetts-based study in the US noted a 50% decline in PCV13 serotype colonization among unvaccinated children at a time when overall vaccine coverage was 75% [42]. This finding suggests that implementation of a NIP could result in a coverage rate sufficiently high to induce an indirect effect.

To summarize the proposed mechanism by which NIP for young children can decrease the incidence of adult pneumococcal disease, PCV first leads to a reduction in VT colonization via a direct effect on vaccinated individuals [3641]. In turn, unvaccinated children and adults experience less exposure to VT serotypes [37], resulting in a reduction in VT-IPD among unvaccinated adults [43].

In 2014, the US Advisory Committee on Immunization Practices (ACIP) recommended that PCV13 should be administered to all adults 65 years of age or older, given in series with PPV23. This recommendation was, in large part, based on the result of the CAPiTA study [11]. In 2018, ACIP plans to reevaluate recommendations for routine PCV13 use among adults 65 years of age or older to incorporate available findings regarding the indirect effect of PCV13 [11]. Prior to the introduction of PCV13, the serotypes contained in PCV10, PCV13, and PPV23 accounted for 39.8%, 67.3%, and 73.4% of pneumococcal infections, respectively, among Korean adults 19 years of age or older [63]. Based on this information, the Korean Society of Infectious Diseases (KSID) recommended that either PCV13 or PPV23, but not both, should be administered to healthy adults 65 years of age or older [21].

Following implementation of a PCV-containing NIP for Korean children in 2014, serotypes causing pneumococcal diseases may be redistributed as serotype replacement occurs. Following implementation of PCVs, studies of surveillance data have noted an increase in disease caused by serotypes found solely in PPV23 [57]. This could effectively broaden the coverage range of PPV23 for adults, which would provide coverage for 11 additional non-PCV13 serotypes. A systematic review and meta-analysis suggested that the vaccine effectiveness of PPV23 in preventing IPD and all-cause CAP was similar to the estimates for PCV13, as reported in the CAPiTA trial [64]. Therefore, the role of PPV23 in adults may be more important in the context of pediatric PCV NIP. However, this theoretical benefit must be weighed against the potential for a reduced direct effect due to the relatively lower immunogenicity of PPV in certain adult populations. As post-PCV trends in indirect protection and serotype replacement are dependent on numerous factors that are specific to a given population, ongoing surveillance is necessary to evaluate the overall effects of PCV and to determine the ideal strategy for pneumococcal vaccine administration in Korean adults.