Aimed to see the impact of PCV-10 on IPD cases in a rural population-based site, Sylhet.
Johns Hopkins University (BMGF grant)
Background and rationale::
In 2006, the World Health Organization (WHO) recommended that pneumococcal conjugate vaccines (PCVs) should be included in the routine infant immunization program of all countries and concomitant impact assessments of routine use of PCV should be conducted in each of the country programs (WHO, 2007). Recently, the Ministry of Health and Family Welfare (MOHFW) of the Government of Bangladesh (GoB) decided to introduce PCV10 into the national routine immunization program beginning in September 2014, making it only the second South Asian country to do so. The vaccine will be introduced in two phases, and Sylhet Division, where our study site is located, will likely be included in the second phase beginning in early 2015. The first dose of PCV10 will be provided to all infants coming for the first dose of pentavalent vaccine, and routine PCV10 immunization will continue for this cohort. In addition, the Bangladesh MOHFW has agreed to provide catch-up immunization to all children younger than 2 years of age in the study area. This decision offers a unique and time-limited opportunity to conduct a PCV impact evaluation. Before-after studies are being planned in urban areas in Dhaka, Bangladesh. Although Bangladesh has high-quality pre-PCV data on invasive pneumococcal disease (IPD) from urban settings (Brooks et al., 2007; Saha et al., 2009) allowing before-after studies, data is limited on culture-positive IPD from rural areas where majority of child deaths occur (Arifeen et al., 2009). Because IPD is a relatively rare outcome, more than one year of pre-PCV data would be needed to ensure measurement of a stable baseline incidence rate. This precludes conducting a community-based vaccine impact study with IPD as an outcome using a pre-post design in rural settings. However, a well-designed population-based case-control study can be valuable in situations where baseline data are scarce. Case-control studies have been used for post-licensure evaluation of vaccine effectiveness for many years (Mills et al., 1996). The reason for proposing a case-control study with IPD as the outcome is to provide a set of studies (the before-after studies being planned by other investigators for two other sites in Bangladesh and the case-control study described in this proposal) that, taken together, would provide solid evidence of the vaccine’s effect in Bangladesh, as each study on its own has limitations due to sample size or study design. In addition to IPD, The World Health Organization, in its manual “Measuring Impact of Streptococcus pneumoniae and Haemophilus influenzae type b conjugate vaccination” has recommended several other outcomes for studying PCV vaccine impact, such as radiologically confirmed pneumonia, clinical pneumonia syndrome and all-cause child mortality (WHO, 2012). The infrastructure that will be established in our study site for conducting objective 1 and 2 study activities will create an opportunity to study the impact of the vaccine on other important outcomes with little incremental cost. Thus we have proposed to study impact of the PCV vaccine on radiologically confirmed pneumonia, clinical pneumonia and all-cause mortality using a variety of study designs. Radiologically confirmed pneumonia is a much more common outcome and has been widely used to evaluate PCV impact in variety of settings. Furthermore, a stable incidence rate estimate can be established in a sub-cohort within our study area in a single year prior to vaccine introduction. Subsequently we plan to conduct a supplemental incident case control study in 3-35 months old children using radiologically confirmed pneumonia as an outcome. We will also precisely estimate the incidences of clinically and radiologically confirmed pneumonia in a sub-cohort of 2-35 month old children over time and examine the decline of incidences after vaccine introduction. We will also have the data to monitor the decline of all-cause mortality after vaccine introduction in our study population. We believe that an incident case-control study in Sylhet, Bangladesh field site with IPD and radiologically confirmed pneumonia as the primary outcomes as well as pre-post study for measuring impact on clinically and radiologically confirmed pneumonia and all-cause mortality will substantially strengthen the evidence base of the impact of PCV in Bangladesh and throughout South Asia.
Rationale for collecting nasal swabs to evaluate the effect of PCV10 use on nasopharyngeal (NP) colonization: Nasopharyngeal colonization represents an important outcome that has the potential for providing additional information in evaluating the global rollout of pneumococcal vaccine. (Satzke 2014) Loughlin et al (2014) have recently demonstrated the potential of analysis of a rolling time trend of vaccine-type pneumococcal carriage rates in immunized and non-immunized pediatric populations to distinguish the direct and indirect effects of PCV on carriage of vaccine serotypes. The Bill and Melinda Gates Foundation is interested in replicating this work in several developing country settings, and has asked us to do so in Bangladesh. We will have available screened cohorts of children with ultrasound-confirmed pneumonia, which the Loughlin findings suggested should be enriched for pneumococcal carriers, and therefore among whom the differential impact of vaccination status on carriage of vaccine serotype and non-vaccine serotype pneumococci can be readily assessed. These issues are simpler to study in the context of NP carriage than in the context of IPD, since the rates of pneumococcal NP colonization are much higher and it is much simpler to isolate pneumococcus from NP swabs. NP colonization studies are straightforward to conduct in a clinical field setting, can be implemented more quickly to establish baseline data, have standardized clinical and laboratory methods (O’Brien & Nohynek, 2003; Satzke 2013). An evaluation of colonization in Bangladesh will be an important additional measure of whether PCVs are working as expected in a setting with high rates of malnutrition, high—near 50% (Saha 2003) –colonization rates, and high transmission of pneumococci. The results will inform the decision-making in other Asian countries on the introduction of the PCV vaccine. This is particularly important in countries like India where it has been difficult to conduct high-quality surveillance for IPD for various reasons including the widespread use of antibiotics prior to seeking care.
We hypothesize that PCV immunization will have the immediate direct effect (i.e., among vaccinated infants) of reducing acquisition of circulating vaccine-type pneumococcal strains. PCVs have been repeatedly shown to reduce NP colonization with vaccine serotypes in children who have received vaccine (Dagan, Muallem, Melamed, Leroy, & Yagupsky, 1997; Dagan R, 2000; Mbelle et al., 1999; O’Brien et al., 2007; Obaro et al., 2000; Prymula et al., 2009). This reduction in colonization is thought to be an important driver in the ability of PCVs to prevent disease among vaccinated children.
Increasing coverage of the vaccine in the community may also reduce the overall prevalence of VT pneumococcal strains in the community, thereby having an indirect effect of reducing transmission to children participating in the study. This indirect effect, also known as herd immunity, is separate from the direct effect of the vaccine on immunized children’s immune systems which allows them to prevent acquiring whatever virus is circulating. Numerous investigations have demonstrated an indirect effect of pediatric PCV vaccination in both young children (Loughlin 2014) and other age groups (Davis 2013). We hypothesize that this indirect effect will be evident in the study cohort at a later time point when the vaccine coverage attains a high level than the direct effect.
We propose to collect NP specimens on all cases of ultrasound-confirmed pneumonia among 3-35 month-old children resident in our study area during the course of the main time-trend study of rates of ultrasound-confirmed pneumonia. We will culture these swabs in order to detect carriage of Streptococcus pneumonia; and will serotype all cultured specimens. These procedures will enable us to assess the differential effect of vaccination status on carriage of vaccine-type pneumococci among vaccinated and unvaccinated children with pneumonia.
As the MOHFW is set to introduce PCV in March 2015, we propose to conduct a one-year pre-PCV observational surveillance of IPD and clinically and radiologically-confirmed pneumonia. This surveillance will be instrumental in several contexts for this study. It will generate population-based pre-PCV incidence rates of IPD and clinically and radiologically-confirmed pneumonia from high burden rural Bangladeshi children, data which are not currently available. It will guide the design of the main case-control studies with precise baseline rates for determining sample size and study duration. For the pre-post studies this will create the pre-PCV estimates for comparison with post-PCV estimates. It will also help establish IPD surveillance in the study area that will be continued through the case-control study and minimize the start-up activities for it.
During this period we will also conduct a number of other preparatory activities for the main case-control study, including validation of immunization data maintained in the home and at village immunization clinics.
The incident case-control studies will be conducted in the context of routine immunization which will provide PCV10 to infants coming for the first dose of pentavalent vaccine We also propose an immunogenicity study, taking advantage of the opportunity created by the larger case-control study. Very few data are available on the immunogenicity of PCV in South Asia. The immunogenicity study can be done at a very modest incremental cost using the infrastructure we will have established for the IPD surveillance and the case-control study.
The validation of CHW screening for clinical pneumonia and meningitis is important not only for those conducting vaccine impact studies, but also for implementation of community case management of pneumonia. This study will be carried out in the context of routine quality assurance of the CHW screening of children screened as healthy and clinical confirmation of pneumonia in children screened as possible pneumonia cases.
In Bangladesh, the study will be conducted by the Projahnmo study group which is a partnership of Johns Hopkins University with Bangladesh Ministry of Health and Family Welfare, icddr,b, and two local NGOs: Child Health Research Foundation (CHRF) and Shimantik. This collaboration with national institutions, particularly the MOHFW will facilitate the implementation of the study and the utilization of the study results at the country level.