Jennifer D. Loo

Systematic Review of the Effect of Pneumococcal Conjugate Vaccine Dosing Schedules on Prevention of Pneumonia

Background: Pneumonia is the leading cause of morbidity and mortality among children <5 years of age globally. Pneumococcal conjugate vaccines (PCVs) are known to provide protection against vaccine serotype pneumococcal pneumonia; uncertainty exists regarding the optimum PCV dosing schedule. Methods: We conducted a systematic review of studies published from 1994 to 2010 (supplemented post hoc with studies from 2011) documenting the effect of PCV dosing schedules on clinical and radiologically confirmed pneumonia, pneumococcal pneumonia and empyema among children of ages targeted to receive vaccine. Data on 2- and 3-dose schedules were included. Percent change of pneumonia incidence rates from baseline to most recent year post-PCV introduction was calculated. Results: We identified 42 primary citations that evaluated PCV schedules and pneumonia. Thirty-seven (88%) were from North America, Europe or Australia; 37 (88%) evaluated PCV7 and 1 (2%) PCV10. Two studies (both observational) compared multiple schedules within the study. We found evidence of reduced clinical and radiologically confirmed pneumonia incidence for all schedules, including 2+1 (1 nonrandomized trial, 5 observational studies), 3+0 (5 randomized trials, 2 observational studies) and 3+1 (5 clinical trials, 24 observational studies) schedules. The magnitude of disease impact did not differ among schedules. Evidence for impact on pneumococcal pneumonia and empyema varied. Conclusions: All schedules (2+1, 3+0 and 3+1) reduced clinical and radiologically confirmed pneumonia. Quantifying differences in pneumonia disease impact between schedules was difficult due to heterogeneity among studies in design, case definition and population. These findings support World Health Organization recommendations for 3-dose schedules administered as either 3+0 or 2+1 regimens. Pneumonia impact data are still needed on expanded serotype PCV products, developing country settings and the role for a booster dose.

Systematic Review of the Indirect Effect of Pneumococcal Conjugate Vaccine Dosing Schedules on Pneumococcal Disease and Colonization

Background: To aid decision making for pneumococcal conjugate vaccine (PCV) use in infant national immunization programs, we summarized the indirect effects of PCV on clinical outcomes among nontargeted age groups. Methods: We systematically reviewed the English literature on infant PCV dosing schedules published from 1994 to 2010 (with ad hoc addition of 2011 articles) for outcomes on children >5 years of age and adults including vaccine-type nasopharyngeal carriage (VT-NP), vaccine-type invasive pneumococcal disease (VT-IPD) and syndromic pneumonia. Results: Of 12,980 citations reviewed, we identified 21 VT-IPD, 6 VT-NP and 9 pneumonia studies. Of these 36, 21 (58%) included 3 primary doses plus PCV or pneumococcal polysaccharide vaccine (PPV23) booster schedule (3+1 or 3+PPV23), 5 (14%) 3+0, 9 (25%) 2+1 and 1 (3%) 2+0. Most (95%) were PCV7 studies. Among observational VT-IPD studies, all schedules (2+1, 3+0 and 3+1) demonstrated reductions in incidence among young adult groups. Among syndromic pneumonia observational studies (2+1, 3+0 and 3+1), only 3+1 schedules showed significant indirect impact. Of 2 VT-NP controlled trials (3+0 and 3+1) and 3 VT-NP observational studies (2+1, 3+1 and 3+PPV23), 3+1 and 3+PPV23 schedules showed significant indirect effect. The 1 study to directly compare between schedules was a VT-NP study (2+0 vs. 2+1), which found no indirect effect on older siblings and parents of vaccinated children with either schedule. Conclusions: Indirect benefit of a 3+1 infant PCV dosing schedule has been demonstrated for VT-IPD, VT-NP and syndromic pneumonia; 2+1 and 3+0 schedules have demonstrated indirect effect only for VT-IPD. The choice of optimal infant PCV schedule is limited by data paucity on indirect effects, especially a lack of head-to-head studies and studies of PCV10 and PCV13.

Systematic Review of the Effect of Pneumococcal Conjugate Vaccine Dosing Schedules on Vaccine-type Nasopharyngeal Carriage

Background: Pneumococcal conjugate vaccines (PCV) reduce nasopharyngeal carriage of vaccine type (VT) pneumococci, an important driver of vaccine programs’ overall benefits. The dosing schedule that best reduces carriage is unclear. Methods: We performed a systematic review of English language publications from 1994 to 2010 (supplemented post hoc with studies from 2011) reporting PCV effects on VT carriage to assess variability in effect by dosing schedule. Results: We identified 32 relevant studies (36 citations) from 12,980 citations reviewed. Twenty-one (66%) evaluated PCV7; none used PCV10 or PCV13. Five studies evaluated 2 primary doses and 13 three primary doses. After the first year of life, 14 evaluated 3-dose primary series with PCV booster (3+1), seven 3 doses plus 23-valent polysaccharide booster “3+1PPV23,” five “3+0,” four “2+1,” three “2+1PPV23” and two “2+0.” Four studies directly compared schedules. From these, 3 primary doses reduced VT carriage more than 2 doses at 1–7 months following the series (1 study significant; 2 borderline). In a study, the 2+1 schedule reduced VT carriage more than 2+0 at 18, but not at 24 months of age. One study of a 23-valent pneumococcal polysaccharide vaccine booster showed no effect. All 16 clinical trials with unvaccinated controls and 11 observational studies with before-after designs showed reduction in VT carriage. Conclusions: The available literature demonstrates VT-carriage reduction for 2+0, 2+1, 3+0 and 3+1 PCV schedules, but not for 23-valent pneumococcal polysaccharide vaccine booster. Comparisons between schedules show that 3 primary doses and a 2+1 schedule may reduce carriage more than 2 primary doses and a 2+0 schedule, respectively.

Systematic Review of the Effect of Pneumococcal Conjugate Vaccine Dosing Schedules on Vaccine-type Invasive Pneumococcal Disease Among Young Children

Background: Pneumococcal conjugate vaccines (PCV) are being implemented globally using a variety of different schedules. The optimal schedule to maximize protection of vaccinated children against vaccine-type invasive pneumococcal disease (VT-IPD) is not known. Methods: To assess the relative benefit of various PCV dosing schedules, we conducted a systematic review of studies published in English from 1994 to 2010 (supplemented post hoc with studies from 2011) on PCV effectiveness against VT-IPD among children targeted to receive vaccine. Data on 2-dose and 3-dose primary series, both with and without a booster (“2+0,” “2+1,” “3+0” and “3+1”), were included. For observational studies using surveillance data or case counts, we calculated percentage reduction in VT-IPD before and after PCV introduction. Results: Of 4 randomized controlled trials and 31 observational studies reporting VT-IPD among young children, none evaluated a 2+0 complete series, 7 (19%) evaluated 2+1, 4 (11%) 3+0 and 27 (75%) 3+1. Most (86%) studies were from North America or Europe. Only 1 study (observational) directly compared 2 schedules (3+0 vs. 3+1); results supported the use of a booster dose. In clinical trials, vaccine efficacy ranged from 65% to 71% with 3+0 and 83% to 94% with 3+1. Surveillance data and case counts demonstrate reductions in VT-IPD of up to 100% with 2+1 (6 studies) or 3+1 (17 studies) schedules and up to 90% with 3+0 (2 studies). Reductions were observed as early as 1 year after PCV introduction. Conclusions: These data support the use of 2+1, 3+0 and 3+1 schedules, although most data of PCV impact on VT-IPD among young children are from high-income countries using 3+1. Differences between schedules for impact on VT-IPD are difficult to discern based on available data.

Global use of Haemophilus influenzae type b conjugate vaccine

Haemophilus influenzae type b (Hib) conjugate vaccines have been underutilized globally. We report progress in global use of Hib vaccines included in national immunization schedules. The number of countries using Hib vaccine increased from 89/193 (46%) in 2004 to 158/193 (82%) by the end of 2009. The increase was greatest among low-income countries eligible for financial support from the GAVI Alliance [13/75 (17%) in 2004, 60/72 (83%) by the end of 2009], and can be attributed to various factors. Additional efforts are still needed to increase vaccine adoption in lower middle income countries [20/31 (65%) by the end of 2009].

Systematic Review of the Effect of Pneumococcal Conjugate Vaccine Dosing Schedules on Immunogenicity

Background: Despite the breadth of studies demonstrating benefits of pneumococcal conjugate vaccine (PCV), uncertainty remains regarding the optimal PCV dosing schedule in infants. Methods: We conducted a systematic literature review of PCV immunogenicity published from 1994 to 2010 (supplemented post hoc with studies from 2011). Studies included for analysis evaluated ≥2 doses of 7-valent or higher product (excluding Aventis-Pasteur PCV11) administered to nonhigh-risk infants ⩽6 months of age. Impact of PCV schedule on geometric mean antibody concentration (GMC) and proportion of subjects over 0.35 mcg/mL were assessed at various time points; the GMC 1 month postdose 3 (for various dosing regimens) for serotypes 1, 5, 6B, 14, 19F and 23F was assessed in detail using random effects linear regression, adjusted for product, acellular diphtheria-tetanus-pertussis/whole-cell diphtheria- tetanus-pertussis coadministration, laboratory method, age at first dose and geographic region. Results: From 61 studies, we evaluated 13 two-dose (2+0) and 65 three-dose primary schedules (3+0) without a booster dose, 11 “2+1” (2 primary plus booster) and 42 “3+1” schedules. The GMC after the primary series was higher following 3-dose schedules compared with 2-dose schedules for all serotypes except for serotype 1. Pre- and postbooster GMCs were generally similar regardless of whether 2 or 3 primary doses were given. GMCs were significantly higher for all serotypes when dose 3 was administered in the second year (2+1) compared with ⩽6 months of age (3+0). Conclusions: While giving the third dose in the second year of life produces a higher antibody response than when given as part of the primary series in the first 6 months, the lower GMC between the 2-dose primary series and booster may result in less disease protection for infants in that interval than those who completed the 3-dose primary series. Theoretical advantages of higher antibodies induced by giving the third dose in the second year of life, such as increased protection against serotype 1 disease, longer duration of protection or more rapid induction of herd effects, need to be evaluated in practice.

A systematic review and critical evaluation of invasive Haemophilus influenzae type B disease burden studies in Asia from the last decade: lessons learned for invasive bacterial disease surveillance.

In Asia, questions regarding the burden of Haemophilus influenzae type b (Hib) disease have delayed decision-making on introduction of Hib vaccine. However, over the past decade many studies have been published regarding Hib disease burden in Asia. We conducted a systematic literature review of all reports of Hib disease burden in Asia between 1998 and 2009, and critically reviewed their methods and data quality. We identified 94 studies from 28 countries in Asia presenting data on Hib disease burden. Of the 94 studies reviewed, 49 (52%) used a case definition consistent with World Health Organization standards, and 47 (50%) described laboratory methodology used. Twenty-seven surveillance studies presented data on incidence of Hib disease, with 8 (30%) accounting for missed cases, 6 (15%) accounting for cases with missed diagnostic tests, and 2 (7%) that considered prior antibiotic use. Of the 21 studies that provided incidence data for Hib meningitis, 10 (48%) used active, prospective, population-based surveillance, and found unadjusted incidence rates of Hib meningitis ranging from a low of 0.98 per 100,000 child-years in children aged less than 5 years in China to a high of 28 per 100,000 child-years in children less than 5 years in Mongolia. Of 49 studies that reported the etiology of bacterial meningitis, 30 (60%) identified Hib as the most common cause. This review highlights the importance of using rigorous methodologies, including standardized surveillance methods and appropriate laboratory diagnostic tests, when conducting studies measuring the burden of invasive bacterial diseases including those caused by Hib. When poorly conducted, studies can underestimate disease burden and lead to inappropriate decisions about vaccine introduction.

“It Is Good for My Family’s Health and Cooks Food in a Way That My Heart Loves”: Qualitative Findings and Implications for Scaling Up an Improved Cookstove Project in Rural Kenya

The use of indoor, three-stone fire pits in resource–poor countries is a substantial burden on human health and the environment. We conducted a pilot intervention promoting the purchase and use of an improved cookstove in rural Kenya. The goals of this qualitative inquiry were to understand the motivation to purchase and use; perceived benefits and challenges of cookstove use; and the most influential promotion activities for scaling up future cookstove promotion. Purposive sampling was used to recruit 10 cookstove promoters and 30 cookstove purchasers in the Luo community. Qualitative semi-structured interviews were transcribed and a thematic analysis conducted. Women reported the need for less firewood, fuel cost savings, reduced smoke, improved cooking efficiency, reduced eye irritation, lung congestion and coughing as major benefits of the cookstove. Cost appeared to be a barrier to wider adoption. The most persuasive promotion strategies were interpersonal communication through social networks and cooking demonstrations. Despite this cost barrier, many women still considered the improved cookstove to be a great asset within their household. This inquiry provided important guidance for future cookstove implementation projects.

The Differential Impact of Coadministered Vaccines, Geographic Region, Vaccine Product and Other Covariates on Pneumococcal Conjugate Vaccine Immunogenicity

Background: Antipneumococcal capsular polysaccharide antibody concentrations are used as predictors of vaccine efficacy against vaccine serotype (ST) pneumococcal disease among infants. While pneumococcal conjugate vaccines (PCV) are recommended globally, factors associated with optimal PCV immune response are not well described. We aimed to systematically assess local setting factors, beyond dosing schedule, which may affect PCV antibody levels. Methods: We conducted a literature review of PCV immunogenicity, abstracting data from published reports, unpublished sources, and conference abstracts from 1994 to 2010 (and ad hoc 2011 reports). Studies included in this analysis evaluated ≥ 2 primary doses of PCV before 6 months of age in non–high-risk populations, used 7-valent or higher PCV products (excluding Aventis-Pasteur and Merck products) and provided information on geometric mean concentration (GMC) for STs 1, 5, 6B, 14, 19F or 23F. Using random effects meta-regression, we assessed the impact of geographic region, coadministered vaccines and PCV product on postprimary GMC, adjusting for dosing schedule and ELISA laboratory method. Results: Of 12,980 citations reviewed, we identified 103 vaccine study arms for this analysis. Children in studies from Asia, Africa and Latin America had significantly higher GMC responses compared with those in studies from Europe and North America. Coadministration with acellular pertussis DTP compared with whole-cell DTP had no effect on PCV immunogenicity except for ST14, where GMCs were higher when coadministered with acellular pertussis DTP. Vaccine product, number of PCV doses, dosing interval, age at first dose and ELISA laboratory method also affected the GMC. Conclusions: PCV immunogenicity is associated with geographic region and vaccine product; however, the associations and magnitude varied by ST. Consideration of these factors is essential when comparing PCV immunogenicity results between groups and should be included in the evidence base when selecting optimal PCV vaccine schedules in specific settings.

Investigation of a Chlamydia pneumoniae Outbreak in a Federal Correctional Facility in Texas

BACKGROUND Chlamydia pneumoniae illness is poorly characterized, particularly as a sole causative pathogen. We investigated a C. pneumoniae outbreak at a federal correctional facility. METHODS We identified inmates with acute respiratory illness (ARI) from 1 November 2009 to 24 February 2010 through clinic self-referral and active case finding. We tested oropharyngeal and/or nasopharyngeal swabs for C. pneumoniae by real-time polymerase chain reaction (qPCR) and serum samples by microimmunofluorescence. Cases were inmates with ARI and radiologically confirmed pneumonia, positive qPCR, or serological evidence of recent infection. Swabs from 7 acutely ill inmates were tested for 18 respiratory pathogens using qPCR TaqMan Array Cards (TACs). Follow-up swabs from case patients were collected for up to 8 weeks. RESULTS Among 33 self-referred and 226 randomly selected inmates, 52 (20.1%) met the case definition; pneumonia was confirmed in 4 by radiology only, in 9 by qPCR only, in 17 by serology only, and in 22 by both qPCR and serology. The prison attack rate was 10.4% (95% confidence interval, 7.0%-13.8%). White inmates and residents of housing unit Y were at highest risk. TAC testing detected C. pneumoniae in 4 (57%) inmates; no other causative pathogens were identified. Among 40 inmates followed prospectively, C. pneumoniae was detected for up to 8 weeks. Thirteen (52%) of 25 inmates treated with azithromycin continued to be qPCR positive >2 weeks after treatment. CONCLUSIONS Chlamydia pneumoniae was the causative pathogen of this outbreak. Higher risk among certain groups suggests that social interaction contributed to transmission. Persistence of C. pneumoniae in the oropharynx creates challenges for outbreak control measures.