Of the 12 studies, 9 (75.0%) using a 3+1 or 3+PPV23 schedule took place in countries where catch-up campaigns were implemented during national introduction. Reductions in VT-IPD among healthy adult groups in countries using 3+1 schedules ranged from 13% in Spain, 6 years after PCV introduction, to 92% in the United States, 7 years after introduction.11,25 Vaccine-type meningitis was reduced by 73% among the general population in Canada and by 67% among adults ages 18–39 years in the United States, both within 5 years after PCV introduction.12,19 One study conducted in the United States demonstrated a 67% reduction in VT-IPD among Alaskan Natives ages 18–44 years, also within 5 years after introduction.
Two studies identified in this review did not show a reduction in VT-IPD among a reported adult group using a 3+1 schedule. In Spain, a 25% increase in VT-meningitis was observed among all adults, which was accompanied by a 13% reduction in VT-IPD among adults ages 18–64 years.11 Factors cited as possibly contributing to this finding included a low PCV coverage (50% within 6 years after introduction for high-risk groups) and an increase in in-migration to the area that could have impacted the indirect effects of vaccine introduction. In the Netherlands, no change (0%) in VT-IPD was observed among 5–49 year olds 2 years following introduction.27 Authors attributed the apparent absence of herd immunity despite high vaccine uptake among children (94%) to the lack of a catch-up campaign and short evaluation period.
We identified 2 studies reporting indirect effects of PCV on VT-IPD among adults with HIV. Both studies took place in settings using a 3+1 schedule. In the United States, Cohen et al. reported a 91% reduction in the incidence of VT-IPD among HIV-infected persons, from 681 per 100,000 persons 18–64 years of age living with AIDS in 1998/1999 to 64 per 100,000 persons in 2007. In Spain, Grau et al. reported a 67% reduction in VT-IPD among 4011 HIV-infected adults receiving care at a teaching hospital in Barcelona 6 years after vaccine introduction.
Of the 5 countries reporting data on the indirect effects of PCV on adult groups using a 2+1 schedule, all except Italy implemented some type of catch-up campaign among young children. Reported indirect effects on VT-IPD with a 2+1 schedule ranged from 15% among the general population in Italy to 88% among 15–44 year olds in England and Wales.14,24 A 70% reduction in VT-meningitis was also observed among adults 5–64 years of age in England and Wales within 4 years after vaccine introduction.24
The 3 studies using either a 3+0 or a 3+PPV23 schedule all took place in Australia, where catch-up campaigns were conducted for both indigenous and nonindigenous children.23,26 These studies demonstrated similar reductions in VT-IPD among indigenous (range 43–75%) and nonindigenous adults (range 35–62%) over 15 years of age, although 1 study demonstrated a 6% increase in VT-IPD among indigenous adults 15–29 years of age. In this study, other indigenous adults 30–49 and 50–64 years of age experienced reductions of 54% and 43%, respectively.23
Nine observational studies in this review evaluated the impact of PCV dosing schedules on clinical or radiologically confirmed pneumonia in older children or adults (Table 4). Most studies (n = 7, 78%) were conducted in Europe, North America or Australia; the remaining 2 studies were from South Africa32 and Taiwan.35 There were no studies that evaluated indirect pneumonia effects on high-risk populations. Additionally, no studies directly compared various dosing schedules on indirect populations and no RCTs have evaluated the impact of PCV on pneumonia in unvaccinated populations.
This analysis also found 2 case-control studies evaluating PCV impact on pneumonia in unvaccinated populations (Table 5). One study, conducted in South Africa, evaluated the impact of a 3+0 schedule on adults residing with children enrolled in an RCT for PCV9.32 This study found no impact against pneumonia in adults during the clinical trial. The authors noted possible reasons for a lack of impact, including a large burden of HIV among adults in South Africa, timing of doses given in the infant schedule, the lack of a booster dose and <20% coverage in <5 year olds in the community during the trial. Another case-control study conducted in the United States after implementation of PCV7 into the national immunization program showed an 80% reduction in the odds of getting bacteremic pneumococcal pneumonia in adults that resided with a vaccinated child.36
Our review identified a substantial body of research evaluating whether PCV use in young children leads to indirect effects in other age groups, although there are more data supporting some schedules than others. Most of the data were from studies evaluating 2 or 3 primary dose schedules with a booster dose (2+1, 3+1 or 3+PPV23), and among these, studies evaluating a 3+1 dosing schedule were most common. While studies have evaluated pneumonia, VT-NP carriage and VT-IPD, the demonstration of indirect effects was most consistent across studies and for all schedules for VT-IPD.
Because the first countries to introduce PCV used a 3+1 schedule, most of the available literature on indirect effects is for that schedule. The weight of evidence suggests that the use of a 3+1 schedule as part of a routine vaccination program for all infants will result in reduction of carriage and disease in age groups not targeted to receive PCV. Of 12 studies that we identified evaluating the 3+1 schedule for VT-IPD, only 2 showed no evidence of reductions in VT-IPD in unimmunized age groups; both took place in countries without catch-up campaigns and vaccine coverage in the population may have been insufficient to demonstrate indirect effects.11,27 VT-NP carriage studies have also shown indirect effects with 3+1 schedules. The impact on VT-NP carriage was observed in high-risk populations; no NP carriage studies with indirect effects were conducted in general populations. Studies of syndromic pneumonia only showed an impact with 3+1 schedules. Among 6 studies evaluating the 3+1 schedule, only 2, from Spain11 and the United States,37 observed increases in overall trends of pneumonia (pneumococcal, clinical and radiologically confirmed), with authors of both studies speculating that the overall increases were due to increases in nonvaccine serotype disease, although other secular trends could have contributed.
A smaller but growing number of studies have examined 3-dose (2+1 and 3+0) schedules. Most policy makers recently adopting PCV have used 1 of these schedules and the World Health Organization recently updated their recommendation for PCV to be used on either of these 3-dose schedules.47 Our review did not find sufficient data to directly compare these 2 schedules or to make conclusions regarding the impact of these schedules on VT-NP carriage or syndromic pneumonia; statistically significant indirect effects for pneumonia and VT-NP carriage using 2+1 and 3+0 schedules were not observed in any of the 6 studies of these outcomes identified by our review, although many of these studies were conducted early in the immunization programs or evaluated nonspecific endpoints. Despite these limitations, both 3-dose schedules appear to have indirect effects on VT-IPD when introduced nationally. Substantial reductions in VT-IPD were observed among young adult groups in 5 European countries using a 2+1 national immunization schedule.14–16,22,24,30 In countries with catch-up campaigns, this reduction was observed as early as 1 year after vaccine introduction. Two studies evaluated 3+0 schedules for indirect effects on VT-IPD and both found significant reductions. One 3+0 study in Australia did find 3–11% reductions in pneumonia; however, these findings were only borderline significant.34 Additionally, a 3+PPV23 schedule in Australia showed a decrease in VT-NP carriage among older children but not among adults.10 However, other studies suggest that PPV23 boosters do not affect VT-carriage,48 and thus a 3+PPV23 schedule likely approximates a 3+0 schedule in terms of benefits against VT-carriage.
This review also found studies of indirect effects of PCV on high-risk populations, including 9 studies evaluating PCV on either VT-NP carriage9,10,42,43 or VT-IPD13,17,18,23,28,31; no studies evaluated pneumonia and all used 3+1 or 3+PPV23 schedules. Seven studies focused on the impact of PCV on indigenous populations, including Australian Indigenous, Alaskan Native and American Indian populations, and 2 focused on HIV-infected populations. Despite these varying populations, the findings were consistent. All studies noted reductions in disease in older children and adults, suggesting indirect impact of PCV on high-risk populations. These observations may be of relevance to countries with a high burden of HIV or vulnerable populations at higher risk of pneumococcal disease.
While the strength of this analysis is the diversity of settings and study designs included, both for high-risk and nonhigh-risk populations, there are some limitations to our analysis. The heterogeneity of the data did not allow for direct comparisons among schedules and since many factors contribute to the indirect impact of a vaccine schedule, this analysis was unable to fully address the wide variability in study settings and factors that may contribute to the relative impact of PCV schedules (eg, vaccine coverage, presence of a catch up campaign, proportion of the population under 5 years of age, HIV prevalence). Additionally, few data points exist for most of the outcomes we evaluated. Only 1 study directly compared impact among dosing schedules; this VT-NP study from the Netherlands showed no impact of either a 2+0 or a 2+1 schedule on NP carriage in older siblings and parents of vaccinated and unvaccinated children participating in an individual RCT. This study was the only study to evaluate a 2+0 schedule.44,45 Furthermore, some of the studies presented here were small and/or were substudies of clinical trials and therefore may not accurately represent the herd protection of vaccine introduction in a broad population. Many of the studies took place over relatively short periods; since full realization of herd effects in a population may take years,1 study periods of just a few years likely underestimate the measured herd effects in some studies. As PCV introductions in lower- and middle-income countries have only recently occurred,49 almost all data on impact from routine use came from high-income, early introducing countries with more mature immunization programs, which may be more likely to show indirect effects; however, a number of studies are ongoing and data will likely be available soon on the impact of routine use of PCV on unvaccinated older children and adults in lower- and middle-income settings.
The findings of our review suggest to policy makers that, should they adopt either a 3- or 4-dose PCV schedule, indirect effects are likely to add to the overall benefits seen from their program. The evidence to date is strong for the 3+1 schedule and is growing for the 3-dose schedules (2+1 and 3+0). More data to support evidence of herd effects from countries using either the 2+1 or 3+0 schedule would be useful, in particular for the outcomes of VT-NP carriage and pneumonia, from developing country settings where transmission may be more intense and across a wider age range than in high-income populations and for the new generation of conjugate vaccines (PCV10 and PCV13). Because studies of PCV effect on NP carriage in vaccinated children show that 3- and 4-dose schedules reduce colonization,4 we anticipate that with time and more study, vaccination of infants using all of these schedules will be found to prevent a variety of disease syndromes and colonization in unvaccinated age groups. For policy makers trying to determine the best schedule to adopt for their national PCV program, the evidence summarized here on indirect effects should provide an adjunct to data on the direct benefits of various PCV schedules for infants and to programmatic and epidemiologic factors specific to their situation that would drive their decisions on PCV use.
The authors gratefully acknowledge the tremendous support for abstracting data from the following: Becky Roberts, Karrie-Ann Toews and Carolyn Wright from the Centers for Disease Control and Prevention, Respiratory Diseases Branch; Catherine Bozio, Rose Chang, Jamie Felzer, Amy Fothergill, Sara Gelb, Kristen Hake, Sydney Hubbard, Grace Hunte and Shuling Liu from Emory University Rollins School of Public Health; Bethany Baer, Subash Chandir, Stephanie Davis, Sylvia Kauffman, Min Joo Kwak, Paulami Naik and Meena Ramakrishnan from The Johns Hopkins Bloomberg School of Public Health and T. Scott Johnson from Biostatistics Consulting.
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