Since PCV13's introduction into routine infant immunization programs globally, the incidence of disease caused by PCV13 serotypes dramatically decreased among vaccinated children and among unvaccinated individuals, including adults ≥ 65 years of age who are at high risk of pneumococcal disease [17, 18]. The notable exception has been serotype 3 disease. A recent SAGE report suggests there is no difference in disease burden due to serotype 3 in countries that use PCV13 or PCV10 in the infant NIP ; however, surveillance data were not included in their assessment in the same manner as reported here. RCTs and observational studies have shown that PCV13 provides direct protection against serotype 3 IPD in children and IPD and CAP in adults [2,3,4,5,6]. By contrast, fewer data exist for PCV13's impact on serotype 3 carriage with the only RCT conducted to date showing no efficacy, although with wide confidence intervals . To better interpret the direct and potential indirect effect, if any, of PCV13 on serotype 3, we examined surveillance data from several countries. We found that countries that have introduced PCV10 in routine infant vaccination programs showed a substantial linear increase in serotype 3 pneumococcal disease among all age groups since the time of PCV10 introduction. By contrast, countries with PCV13 in their routine pediatric programs experienced a modest decline during the 3–4 years after introduction followed by an inflection upward in subsequent years, which was most pronounced in the ≥ 65 year age group. It is also possible that as every year new infants are vaccinated according to the NIP, this population could represent the reservoir and the source of transmission to the adults. However, numerous studies have shown that older children (1 to 4 years of age) are the main reservoir for PCV transmission [20,21,22]. We also found that, using a model based on 0% vaccine effectiveness against serotype 3 IPD and carriage in children, the projected trajectory of serotype 3 disease in adults more closely resembled the epidemiology in PCV10 countries (although underestimating incidence rates of serotype 3 disease observed in PCV10 countries) and differed significantly from PCV13 countries.
The initial declines in serotype 3 IPD among unvaccinated older adults in all countries implementing public PCV13 programs suggest that at least some indirect effect occurs. In theory, this seems at odds with the RCT of PCV13 vaccine efficacy against carriage, which showed no impact on serotype 3. However, confidence intervals in this study were wide (rate ratio, 0.99; 95% CI 0.48–2.06) , and the study did not assess PCV13's impact against carriage density or duration, the latter being important, as a human challenge RCT for serotype 6B has shown that the primary effect of PCV13 vs. unconjugated 23-valent pneumococcal polysaccharide vaccine was against density and not acquisition [23, 24]. In addition, although the aggregate correlate of protection of 0·35 μg/ml is used in the licensing of new PCVs, at least one study has suggested serotype-specific correlates of protection vary widely, with a very high serum IgG concentration of 2·83 μg/ml needed for protection against serotype 3—a concentration that is rarely attained from vaccination . In addition, serum IgG concentrations may not be the correct correlate for protection, but rather memory B cells, or other aspects of the immune systems such as mucosal IgA, may play a role.
If there is an indirect effect of PCV13 against serotype 3 carriage, it appears to be incomplete and possibly of relatively short duration, based on gradual increases in serotype 3 IPD that occur in unvaccinated persons within approximately 4 years. Several explanations exist. PCV13 immune responses (e.g., antibody levels) against serotype 3 may be sufficient to provide direct protection but insufficient for sustained protection against carriage, which may be mediated by additional immunological mechanisms such as memory B cells [25, 26]. This in combination with increased global circulation of serotype 3 strains with reduced antibiotic susceptibility could lead to increases in serotype 3 over time . Aging within the elderly population, including increasing prevalence of co-morbidities, could increase the percent of the population susceptible to serotype 3 diseases. Lastly, serotype 3 could consist of multiple variants. For example, it could be a serogroup with multiple serotypes (similar to the earlier experience with serotypes 6A/6C and 19A/19F) with PCV13 reducing phenotypes that are more similar to the polysaccharide used in vaccine construction. Alternatively, the polysaccharide could be consistent across different serotype 3 genotypes, but subcapsular proteins mediating immunological effects such as complement binding could differ . Regardless, a holistic analysis of surveillance data has shown that countries using PCV10 experience a substantially different population-based evolution of serotype 3 IPD than countries using PCV13, which in turn supports some degree of PCV13-induced indirect protection in addition to the previously documented direct protection against IPD and pneumonia.
A secondary conundrum is why PCV7 did not lead to the increases in serotype 3 that appear to have occurred following PCV10 introduction. While no definitive answer exists, this likely points to the multifactorial nature of serotype 3 dynamics. For example, serotype 3 has historically been antibiotic sensitive, while during the PCV10/PCV13 periods a much more antibiotic resistant clade has emerged from Asia to become the dominant strain in some locations . It is possible that PCV7 did not create the optimal circumstances for serotype 3, possibly because of more aggressive replacement by serotype 19A, which is not present in PCV7. As above, population aging and increases in co-morbidities predisposing to serotype 3 disease may have reached a critical level.
The current study relied on surveillance data, which can have numerous limitations. For example, the number of IPD cases was not available for each country; thus, we could not calculate confidence intervals. Instead, we relied on a standardized reporting of incidence per 100,000, allowing for comparisons between countries. Though we used the most robust publicly available information, including studies that used similar methodologies across multiple countries, we excluded some countries from the analysis, such as: (1) Australia, which uses a 3 + 0 schedule; (2) New Zealand, which had multiple switches between PCV10 and PCV13; (3) countries in Latin America such as Brazil, where incidence data are not available. In addition, South Africa did not meet the inclusion criteria as it is a middle income country that introduced a novel three-dose schedule, with two primary doses given to infants at 6 and 14 weeks of age and a booster given at 9 months of age . Nonetheless, in South Africa, data collected in the 1–2 years following PCV13 introduction in children showed a decrease of serotype 3 IPD in those < 2 years of age compared to the baseline years (i.e., 2005–2008 vs. 2012). Surveillance data also showed a decrease in the number of serotype 3 IPD isolates in the first 4 years following PCV13 introduction, followed by an increase [29, 41]. The trends in these countries show the epidemiology of serotype 3 IPD post PCV13 introduction is similar to that of the other countries in our analysis.
To our knowledge, only one other study has analyzed surveillance data in a similar manner. The aforementioned study by SpIDnet reported the indirect effect of all PCV10/PCV13 serotypes through 2015 . Among the sites with universal pediatric PCV13 programs, a general decrease in serotype 3 IPD was observed from 2011 to 2014, followed by an increase, resulting in an 11% decrease from baseline during the last surveillance year. In contrast, data from four sites with universal PCV10 programs showed a general increase in serotype 3 IPD IRRs starting at the time of PCV10 introduction, with an increase of 58% in 2015 (Fig. 5). As a control, the shared serotypes (1, 5, and 7F) showed a decrease in both sets of countries, whereas the other non-shared serotypes, 6A and 19A, also decreased in PCV13 countries and increased in PCV10 countries.