Effectiveness of pneumococcal vaccines in preventing pneumonia in adults, a systematic review and meta-analyses of observational studies

Introduction S. pneumoniae can cause a wide spectrum of diseases, including invasive pneumococcal disease and pneumonia. Two types of pneumococcal vaccines are indicated for use in adults: 23-valent pneumococcal polysaccharide vaccines (PPV23) and a 13-valent pneumococcal conjugate vaccine (PCV13). Objective To systematically review the literature assessing pneumococcal vaccine effectiveness (VE) against community-acquired pneumonia (CAP) in adults among the general population, the immunocompromised and subjects with underlying risk factors in real-world settings. Methods We searched for peer-reviewed observational studies published between 1980 and 2015 in Pubmed, SciELO or LILACS, with pneumococcal VE estimates against CAP, pneumococcal CAP or nonbacteremic pneumococcal CAP. Meta-analyses and meta-regression for VE against CAP requiring hospitalization in the general population was performed. Results 1159 unique articles were retrieved of which 33 were included. No studies evaluating PCV13 effectiveness were found. Wide ranges in PPV23 effectiveness estimates for any-CAP were observed among adults ≥65 years (-143% to 60%). The meta-analyzed VE estimate for any-CAP requiring hospitalization in the general population was 10.2% (95%CI: -12.6; 33.0). The meta-regression indicates that VE against any-CAP requiring hospitalization is significantly lower in studies with a maximum time since vaccination ≥60 months vs. <60 months and in countries with the pediatric PCV vaccine available on the private market. However, these results should be interpreted cautiously due to the high influence of two studies. The VE estimates for pneumococcal CAP hospitalization ranged from 32% (95%CI: -18; 61) to 51% (95%CI: 16; 71) in the general population. Conclusions Wide ranges in PPV23 effectiveness estimates for any-CAP were observed, likely due to a great diversity of study populations, circulation of S. pneumoniae serotypes, coverage of pediatric pneumococcal vaccination, case definition and time since vaccination. Despite some evidence for short-term protection, effectiveness of PPV23 against CAP was not consistent in the general population, the immunocompromised and subjects with underlying risk factors.

Systematic literature review and meta-analysis on the impact and effectiveness of pneumococcal vaccines against non-IPD in adults Protocol Version (1). In general, immunity following infection is serotype-specific, but crossprotection between related serotypes can occur (2).
Transmission is by aerosol, droplets or direct contact with respiratory secretions of someone carrying the organism. Transmission usually requires either frequent or prolonged close contact. There is a seasonal variation in pneumococcal disease, with peak levels in the winter months (1).
Pneumococcal infection and disease can affect a variety of organ systems resulting in a number of disease syndromes. Although temporary colonization of the nasopharyngeal mucosa, which is the primary focus of infection, rarely results in disease, certain pneumococcal serotypes may occasionally invade the blood stream causing bacteremia and possibly infection of secondary sites such as the meninges (meningitis). In other instances, contiguous spread from the nasopharynx may cause diseases such as otitis media or sinusitis. Pneumonia is often caused by aspiration of pneumococci from the nasopharynx. When associated with bacteremia, pneumonia is classified as invasive pneumococcal disease (2).  (3). The vaccine does not protect against pneumococcal infection due to capsular types not contained in the vaccine, but the 23 types included account for about 96% of the pneumococcal isolates that cause serious infection in the UK, although serotype replacement has been described (1). PPV23 is considered safe both in terms of severe immediate reactions and potential long-term adverse consequences (2).
Pfizer has requested P-95 to carry out a systematic review of the literature and a metaanalysis of observational studies to determine the impact and effectiveness of pneumococcal vaccines in preventing pneumococcal non-invasive disease, pneumococcal pneumonia, all-cause pneumonia, and all-cause diseases in adults.

Objectives
The objectives of this project are: 1. To perform a systematic literature review of the available published peerreviewed and grey literature reports on observational studies assessing the a. Effectiveness of pneumococcal vaccines used in adults, and b. Impact of adult pneumococcal vaccination programs in preventing pneumococcal non-invasive disease, pneumococcal pneumonia, allcause pneumonia, and any-cause diseases (including sequellae/complications of pneumonia). 2. To perform a meta-analysis, dependent on the availability and quality of estimates that would allow for a meta-analysis.

Inclusion criteria
The following criteria for inclusion will be used to select studies to be included in the review: i.

Exclusion criteria
Studies with any of the following criteria will be excluded from the review: i. No primary data. Review papers will be excluded. However, original studies included or discussed in the review, systematic or narrative, will be included. ii. Studies restricted to children, i.e. with populations <16 years old. iii.
Randomized controlled trials, economic evaluation studies, transmission modeling studies. iv.
Studies focusing exclusively on invasive pneumococcal disease (defined as isolation of Streptococcus pneumoniae from a normally sterile body site (5)) and not including outcomes of interest as defined in section 3.5.1. v.
Studies on S. pneumoniae asymptomatic carriage vi.

Electronic databases and search strategy
We will conduct a literature search in MEDLINE (via PubMed), SCIELO and LILACS to obtain peer-reviewed, scientific publications of interest to the review. A detailed search strategy was developed for each bibliographic database (Annex 1).

Grey literature selection
We will search for grey literature using a general search engine (e.g. Google) using target expressions, as well as target searches in public health institutions websites, namely the US CDC, Health Canada, Public health expertise and reference centre Québec, Public Health England, France InVS, Germany RKI, Australia Department of Health, Public Health Association of New Zealand, ECDC, WHO, Cochrane collaboration (Annex 2). Conference abstracts will not be included.

Data management and storage
The results of the literature search will be imported into Endnote and MS Excel, where a track record of the selection process will be maintained with the reasons for exclusion/inclusion at each step (population, outcome, exposure, design).

Selection of studies
The selection process will take place in two steps. In the first step, two reviewers will independently review the titles and abstracts obtained from the electronic searches and apply the inclusion/exclusion criteria, differences will be resolved between the two reviewers. A third reviewer will resolve any remaining disagreements. The second selection step will be based on the full-text review of the articles retrieved in the first step. The flow of articles will be documented in a flowchart in the form of a PRISMA diagram in the report (6).

Reference checking and hand searching
Additionally, we will hand search the reference list of relevant studies retrieved from the electronic database search to identify additional studies.

Data collection
Data from the full-text selected papers will be extracted using a standard extraction form to ensure we gather all relevant data systematically and stored in MS Excel compatible format. A separate extraction table will be developed for each clinical outcome. The template will be piloted with 10 studies and modifications made if necessary. Data extraction will be carried out by a single reviewer; re-extraction of 10% of the papers will be done by a second reviewer.

Data items
The following information will be extracted:  Serotypes (vaccine-type vs. non-vaccine-type) and method for serotype ascertainment (antigen test; brand and type)  Uptake/coverage for pneumococcal vaccines and for influenza vaccines  Study evidence grade  Comments One study may contribute more than one data point.

Clinical outcomes
 Pneumococcal pneumonia o Non-bacteremia pneumonia o All pneumococcal pneumonia combined (i.e. bacteremic and nonbacteremic pneumonia)  All-cause pneumonia  Other non-IPD disease  Any-cause disease (including, but not limited to, e.g.: stroke, myocardial infarction, COPD exacerbation, asthma exacerbation, myocarditis, pericarditis, LRTI)  Mortality or case fatality rate The community-acquired pneumonia diagnosis categories used by Hak et al. in preparation for the CAPITA study can serve as a framework on the way different types of pneumonia will be classified (7).

Effect measures
The framework by Halloran et al. 2010 [8] will be used to define effectiveness and impact. Effectiveness has been split into direct effects (measured by comparing vaccinated and unvaccinated persons belonging to the same population and exposed to the same vaccination program) and indirect effects (population-level effects of widespread vaccination, as a result of reduced transmission; i.e. herd immunity); and the impact expresses the overall effect of the vaccination program on an entire population, including vaccinated and unvaccinated individuals (8,9).
Example of effect measures for effectiveness are vaccine effectiveness (VE), relative risks (RR), odds ratios (OR), hazard ratio (HR). Examples of effect measures for impact are incidence rate ratios (IRR) and incidence rate differences.
Data will be extracted as reported in the publication and we will attempt to reclassify as per Halloran et al. 2010 [8] and Hanquet et al. 2013 [9].

Quality assessment
The GRADE framework and the Newcastle-Ottawa checklist for cohort and case-control studies, developed for assessing the quality of non-randomized studies in meta-analysis, will be used to assess the study limitations (risk of bias), and to inform the decision on whether to pursue meta-analysis (10)(11)(12). See Annex 3 for more details.

Analyses and reporting
The systematic review will be reported following the PRISMA statement (6). A flowchart will document the selection process. The differences between effectiveness and impact will be clearly defined.
The studies characteristics and effect measures will be summarized in tables. VE will be reported by study design and effect measure, for each clinical outcome and population, and the vaccine used will be specified. Impact will be reported by effect measure, for each clinical outcome, and the study period and the vaccine used will be specified.
A forest plot will display the estimates by type of vaccine used, study design and/or effect measure, and clinical outcome.

Decision criteria
Where data from more than one study on a given outcome is available, meta-analysis will be considered. The decision on whether or not to perform a meta-analysis of the results will depend on the factors listed below: -Availability of effect measures that allow for meta-analysis -Assessment of heterogeneity of study designs, effect measures, case definitions, study population -Evidence of sufficient quality (see section 3.6)

Analysis
When the above requirements are fulfilled, meta-analysis will be performed using a random effects model to account for between-study heterogeneity. I 2 will be used to quantify the extent of heterogeneity. The results of the meta-analysis will be graphically displayed using forest plots. Meta-analyses will be performed using R and/or SAS 9.4.
Forest plots with summary estimates will be created for each vaccine type, by clinical outcome, and organized by study design/effect measure and population.
A detailed meta-analysis analysis plan will be developed following a decision to perform the meta-analysis.  (12) NEWCASTLE -OTTAWA QUALITY ASSESSMENT SCALE COHORT STUDIES Note: A study can be awarded a maximum of one star for each numbered item within the Selection and Outcome categories. A maximum of two stars can be given for Comparability Selection 1) Representativeness of the exposed cohort a) truly representative of the average ______________ (describe) in the community * b) somewhat representative of the average ______________ in the community * c) selected group of users e.g. nurses, volunteers d) no description of the derivation of the cohort 2) Selection of the non exposed cohort a) drawn from the same community as the exposed cohort * b) drawn from a different source c) no description of the derivation of the non exposed cohort 3) Ascertainment of exposure a) secure record (e.g. surgical records) * b) structured interview * c) written self report d) no description 4) Demonstration that outcome of interest was not present at start of study a) yes * b) no Comparability 1) Comparability of cohorts on the basis of the design or analysis a) study controls for _____________ (select the most important factor) * b) study controls for any additional factor * (This criteria could be modified to indicate specific control for a second important factor.) Outcome 1) Assessment of outcome a) independent blind assessment * b) record linkage * c) self report d) no description 2) Was follow-up long enough for outcomes to occur a) yes (select an adequate follow up period for outcome of interest) * b) no 3) Adequacy of follow up of cohorts a) complete follow up -all subjects accounted for * b) subjects lost to follow up unlikely to introduce bias -small number lost -> ____ % (select an adequate %)follow up, or description provided of those lost) * c) follow up rate < ____% (select an adequate %) and no description of those lost d) no statement NEWCASTLE -OTTAWA QUALITY ASSESSMENT SCALE CASE CONTROL STUDIES Note: A study can be awarded a maximum of one star for each numbered item within the Selection and Exposure categories. A maximum of two stars can be given for Comparability.
Selection 1) Is the case definition adequate? a) yes, with independent validation * b) yes, e.g. record linkage or based on self reports c) no description 2) Representativeness of the cases a) consecutive or obviously representative series of cases * b) potential for selection biases or not stated 3) Selection of Controls a) community controls * b) hospital controls c) no description 4) Definition of Controls a) no history of disease (endpoint) * b) no description of source Comparability 1) Comparability of cases and controls on the basis of the design or analysis a) study controls for _______________ (Select the most important factor.) * b) study controls for any additional factor * (This criteria could be modified to indicate specific control for a second important factor.) Exposure 1)Ascertainment of exposure a) secure record (e.g. surgical records) * b) structured interview where blind to case/control status * c) interview not blinded to case/control status d) written self report or medical record only e) no description 2) Same method of ascertainment for cases and controls a) yes * b) no 3) Non-Response rate a) same rate for both groups * b) non respondents described c) rate different and no designation