This analysis is part of a larger project describing the impact of PCV dosing schedules on IPD, immunogenicity, nasopharyngeal carriage, pneumonia and indirect effects.^3–6 Details on the literature search terms and methods used in this systematic review are described elsewhere (see Methods Appendix⁸). In brief, a systematic literature review was performed to collect all available English language data published from January 1994 to September 2010 (supplemented post hoc with studies from 2011) on the effect of various PCV vaccination schedules among immunized children on immunogenicity, NP colonization, invasive pneumococcal disease, pneumonia and on indirect effects among unvaccinated populations. Articles published in 14 databases, from ad hoc unpublished sources and abstracts from meetings of the International Symposium on Pneumococci and Pneumococcal Disease (1998–2010) and the Interscience Conference on Antimicrobial Agents and Chemotherapeutics (1994–2010), were searched. We included all randomized controlled clinical trials (RCTs), nonrandomized trials, surveillance database analyses and observational studies of any PCV schedule on 1 or more outcomes of interest. Studies were included for abstraction if pneumococcal polysaccharide vaccine (PPV23) was used as a booster dose, but not as a primary dose. Titles and abstracts were reviewed twice and those with relevant content on 1 of the 5 outcomes (immunogenicity, carriage, invasive disease, pneumonia and indirect effects) underwent full review using a standardized data collection instrument. We did not search non-English language literature because of the low likelihood they would have the relevant data for this project. Details on the search methods are provided in the Methods Appendix.⁸

Citations recovered through the literature search went through several stages of independent review to determine their eligibility, as described elsewhere.⁸ Citations meeting inclusion criteria were categorized on an outcome specific basis into “study families,” where each family included abstracts or publications generated from a single protocol, population, surveillance system or other data collection system relevant to that outcome. Investigators identified the primary data from the individual studies making up each study family for inclusion in the analysis. The primary data were selected as the most current and complete data available for that study family. In some cases, these data were drawn from >1 publication within a family. We also defined “study arms” asa group of children distinguished by immunization schedule or PCV product.

We abstracted core information on the following: number of children in a “study arm”; PCV manufacturer, valency and conjugate protein; co-administered vaccines; country; age at each dose and date of study and publication. To assess indirect effects, we abstracted additional data from studies of the effects of PCV in unimmunized populations on VT-IPD, VT-NP carriage and syndromic pneumonia and included information on study design, case definitions and trends in the outcome of interest.

We included the data published during or after 1994 from clinical trials, surveillance database analyses and observational studies of PCV schedules on VT-IPD, VT-NP carriage and syndromic pneumonia. We included all licensed and unlicensed PCV products (denoted as PCV with a number indicating the valency, eg, PCV7). We excluded studies with vaccination series beginning after 12 months of life as well as the observational studies that only reported data before or after PCV introduction but not for both periods. Unless ≥50% vaccination coverage was documented, the observational studies were also excluded if vaccination was only available through a private sector or only recommended for high-risk groups. Studies that only provided incidence rates during the year of vaccine introduction, or did not specify a time period, were excluded.

For IPD, we focused the analysis on the indirect effects among adults by including studies that reported data on specific age groups between 18 and 64 years (eg, 18–35 and 36–64 years), and those that were inclusive of age groups ≥65 or <18 years (eg, the “general population”). Studies that only reported data on age groups <18 or ≥65 years were excluded.

We included PCV schedules with 2 or 3 primary doses without a booster dose (2+0 and 3+0) and with a booster dose (2+1 and 3+1). Schedules with either PCV or PPV23 boosters were included (2+PPV23 and 3+PPV23).

Because the included studies used a variety of designs and methods, we were unable to perform a formal meta-analysis. Thus, we summarized the data across studies in descriptive analyses to provide an overview of the amount and variability of data by outcome and schedule. For VT-NP carriage, each study was divided into arms, defined as a unique combination of vaccine schedule, age at NP specimen collection and vaccine product used. Studies could have multiple arms. Vaccine-type pneumococci were defined as each study defined them, based on the product used. For carriage, no studies included serotype 19A in VT and 1 included serotype 6A in VT.⁹ For IPD, no studies included serotypes 19A or 6A in VT. We defined VT-NP carriage prevalence as the percentage of those sampled who carried VT pneumococci, except in 2 studies that only reported the percentage of pneumococcal isolates found that were VT.^9,10 The syndromic pneumonia endpoint included clinical pneumonia, radiologically confirmed pneumonia and pneumococcal (eg, bacteremic) pneumonia.

For observational studies reporting VT-IPD incidence over time, we calculated percent reduction by defining baseline incidence as the mean of all data points reported prior to introduction. When annual data on post introduction incidence were available, we calculated percent reduction from baseline using the data point given for each year reported. In cases where only the average post introduction incidence rate over a period was provided, we calculated percent reduction from baseline to the reported rate and assigned it to the median year of the date range provided. When possible, incidence rates during the year of introduction were excluded from these calculations. Percent reduction reported by the study was only used if no incidence rates were provided. Therefore, the percent reduction over time presented in this review may not always be identical to that reported by the study.

We used Microsoft Access 2003 and 2007 (Microsoft Corporation, Redmond, WA) for data abstraction and SAS 9.2 and 9.3 (SAS Institute Inc., Cary, NC) to perform all analyses.

This review identified 6 studies that evaluated the indirect impact of PCV on VT-NP carriage. All but 1 study were from North America, Europe or Australia. Five studies (83%) evaluated PCV7, including one with a PPV23 booster dose; 1 study (17%) evaluated PCV9. Three studies (50%) evaluated the impact of PCV on VT-NP carriage in indigenous populations.

Two studies (3 citations) among nonhigh-risk populations evaluated the indirect effects of either a 2+0 or 2+1 schedule (Table 2) on VT-NP carriage.^41,44,45 One individual RCT in the Netherlands found no VT-NP carriage indirect effect of PCV7 given in 2+0 and 2+1 dosing schedules among parents and siblings of vaccinated and unvaccinated children.^44,45 One pre/postvaccine introduction observational study in the United Kingdom using a 2+1 schedule with catch-up through 2 years of age found a nonsignificant reduction in VT-NP carriage 2–3 years after PCV7 introduction among children and adults ≥5 years of age (Table 2).⁴¹ There were no studies that evaluated 2+0 or 2+1 schedules in high-risk populations, such as indigenous and immunocompromised populations.

One study evaluated a 3+0 (Table 2) schedule on VT-NP carriage. This individual RCT found no effect on VT-NP carriage among unvaccinated younger siblings of children vaccinated with PCV9 or placebo in The Gambia.⁴⁰ There was 1 RCT and 2 observational studies that evaluated a 3+1 or 3+PPV23 schedule in high-risk populations; no studies evaluated a 3+0 schedule in high-risk populations (Table 2). The observational carriage study in Australia among Aboriginals with 3+PPV23 found a significant indirect reduction of VT-carriage among older children, but no difference among adults.¹⁰ A cluster-randomized, placebo-controlled trial evaluated VT-carriage indirect effects among the Navajo Nation and White Mountain Apache people.^9,43 During the trial, VT-carriage was reduced among household contacts (older and younger siblings) of PCV7 vaccinees, but reached statistical significance only for daycare-attending contacts.⁹ However, at 3–15 months after completion of the trial, significant reductions were seen in VT-carriage among unvaccinated children <5 years of age and adults living in communities randomized to PCV7 compared with placebo.⁴³ Another observational study demonstrated a highly significant trend in reduction of VT-carriage prevalence among Alaskan Native adults in the 4 years following the introduction of PCV7 with a 3+1 schedule.⁴²

We identified 21 studies documenting the impact of PCV introduction on incidence of VT-IPD among adult age groups, including 4 studies that specifically reported data on VT-meningitis (Table 3). All these studies were observational studies using either population-based surveillance or sentinel site data. No clinical trials of indirect effects among adults were identified in the published literature; we are aware of 1 such unpublished trial result that showed no effect in any age group (author data).⁴⁶ Six studies provided data on a high-risk population, either indigenous (n = 4; 19.0%) or HIV-infected (n = 2, 9.5%) persons. The definition of adult age group varied across studies; however, 4 (19.0%) reported data from the total population, including children <18 and adults ≥65 years of age.

Many studies reporting indirect effects of PCV on VT-IPD occurred in the setting of a 3+1 national immunization program (n = 12; 61.9%). Six studies (12.9%), conducted in the United Kingdom, Scotland, Italy, Denmark and Norway, occurred in a 2+1 setting. Three studies, all conducted in Australia, used a 3+PPV23 (among indigenous groups) and/or 3+0 (among nonindigenous groups) dosing schedule.^23,26 No studies used a 2+0 schedule and no direct comparisons among dosing schedules were identified.

Nearly all studies (n = 20; 95.2%) demonstrated a reduction in VT-IPD among at least 1 adult age group, regardless of dosing schedule (2+1, 3+0, 3+PPV23 and 3+1). The degree of impact varied by a specific age group, the outcome measured and the number of years post introduction (Fig. 2). Reductions in VT-IPD were observed as early as 1 year after introduction. In general, reductions for all schedules were larger ≥3 years after introduction compared with reductions seen within 3 years of introduction (Fig. 3A, B).

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.

Of the observational studies, 2 studies using 2+1³⁸ and 3+0³⁴ schedules showed almost no impact on clinical or radiologically confirmed pneumonia (Table 4). Of 5 studies using a 3+1 schedule,^{11,33,35,37,39} 3 showed any impact on pneumonia (Table 4). The study conducted in Taiwan³⁵ found significant reductions in pneumonia only in adults ≥65 years of age, although the authors noted an increase in use of PPV23 among this population during the study period.

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