Controlled temperature chain for vaccination in low- and middle-income countries: a realist evidence synthesis.

Objective: To evaluate the evidence describing how the controlled temperature chain approach for vaccination could lead to improved equitable immunization coverage in low- and middle-income countries. Methods: We created a theory of change construct from the Controlled temperature chain: strategic roadmap for priority vaccines 2017-2020, containing four domains: (i) uptake and demand for the approach; (ii) compliance and safe use of the approach; (iii) programmatic efficiency gains from the approach; and (iv) improved equitable immunization coverage. To verify and improve the theory of change, we applied a realist review method to analyse published descriptions of controlled temperature chain or closely related experiences. Findings: We evaluated 34 articles, describing 22 unique controlled temperature chain or closely related experiences across four World Health Organization regions. We identified a strong demand for this approach among service delivery providers; however, generating an equal level of demand among policy-makers requires greater evidence on economic benefits and on vaccination coverage gains, and use case definitions. Consistent evidence supported safety of the approach when integrated into special vaccination programmes. Feasible training and supervision supported providers in complying with protocols. Time-savings were the main evidence for efficiency gains, while cost-saving data were minimal. Improved equitable coverage was reported where vaccine storage beyond the cold chain enabled access to hard-to-reach populations. No evidence indicated an inferior vaccine effectiveness nor increased adverse event rates for vaccines delivered under the approach. Conclusion: Synthesized evidence broadly supported the initial theory of change. Addressing evidence gaps on economic benefits and coverage gains may increase future uptake.

Sustaining Maternal and Neonatal Tetanus Elimination (MNTE) in countries that have been validated for elimination - progress and challenges.

BACKGROUND: As of October 2021, 47 (80%) of the 59 countries, identified at highest risk for Maternal and Neonatal Tetanus (MNT), had been validated for elimination. We assessed sustainability of MNT elimination (MNTE) in 28 countries that were validated during 2011‒2020. METHODS: We assessed the attainment of the following MNTE sustainability indicators: 1) ≥ 90% coverage with three doses of Diphtheria-Tetanus-Pertussis vaccine (DTP3) among infants < 1 year, 2) ≥ 80% coverage with at least two doses of tetanus toxoid-containing vaccine (TTCV2 +) among pregnant women, 3) ≥ 80% protection at birth (PAB), 4) ≥ 70% skilled birth attendance (SBA), and 4) ≥ 80% first (ANC1) and fourth antenatal care (ANC4) visits. We assessed the introduction of TTCV booster doses. Data sources included the 2020 WHO /UNICEF Joint Reporting Forms, and the latest Demographic and Health Survey (DHS) or Multi-Indicator Cluster Surveys (MICS) for each country, if available. We reviewed literature and used DHS/MICS data to identify barriers to sustaining MNTE. RESULTS: Of 28 assessed countries, 7 (25%) reported ≥ 90% DTP3 coverage, 4 of 26 (16%) reported ≥ 80% TTCV2 + coverage, and 23 of 27 (85%) reported ≥ 80% PAB coverage. Based on DHS/MICS in 15 of the 28 countries, 10 (67%) achieved ≥ 70% SBA delivery, 13 (87%) achieved ≥ 80% ANC1 visit coverage, and 3 (20%) ≥ 80% ANC4 visit coverage. We observed sub-optimal coverage in many countries at the subnational level. The first, second and third booster doses of TTCV respectively have been introduced in 6 (21%), 5 (18%), and 1 (4%) of 28 countries. Only three countries conducted post-MNTE validation assessments. Barriers to MNTE sustainability included: competing program priorities, limited resources to introduce TTCV booster doses and implement corrective immunization in high-risk districts and socio-economic factors. CONCLUSIONS: Despite good performance of MNTE indicators in several countries, MNTE sustainability appears threatened in some countries. Integration and coordination of MNTE activities with other immunization activities in the context of the Immunization Agenda 2030 lifecourse vaccination strategy such as providing tetanus booster doses in school-based vaccination platforms, during measles second dose and HPV vaccination, and integrating MNTE post-validation assessments with immunization program reviews will ensure MNTE is sustained.

Linked vaccination coverage surveys plus serosurveys among Ethiopian toddlers undertaken three years apart to compare coverage and serologic evidence of protection in districts implementing the RED-QI approach.

In low and middle-income countries, estimating the proportion of vaccinated toddlers in a population is important for controlling vaccine-preventable diseases by identifying districts where immunization services need strengthening. Estimates measured before and several years after specific interventions can assess program performance. However, employing different methods to derive vaccination coverage estimates often yield differing results. METHODS: Linked vaccination coverage surveys and seroprotection surveys performed among ~300 toddlers 12-23 months of age in districts (woredas), one per region, of Ethiopia (total, ~900 toddlers) in 2013 to estimate the proportion vaccinated with tetanus toxoid (a proxy for pentavalent vaccine) and measles vaccine. The surveys were followed by implementation of the Reaching Every District using Quality Improvement (RED-QI) approach to strengthen the immunization system. Linked coverage/serosurveys were repeated in 2016 to assess effects of the interventions on vaccination coverage. Indicators included "documented coverage" (vaccination card and/or health facility register records) and "crude coverage" (documented plus parent/caretaker recall for children without cards). Seroprotection thresholds were IgG-ELISA tetanus antitoxin ≥0.05 IU/ml and plaque reduction neutralization (PRN) measles titers ≥120 mIU/ml. FINDINGS: Improved markers in 2016 over 2013 include coverage of pentavalent vaccination, vaccination timeliness, and fewer missed opportunities to vaccinate. In parallel, tetanus seroprotection increased in the 3 woredas from 59.6% to 79.1%, 72.9% to 83.7%, and 94.3 to 99.3%. In 2015, the Ethiopian government conducted supplemental measles mass vaccination campaigns in several regions including one that involved a project woreda and the campaign overlapped with the RED-QI intervention timeframe; protective measles PRN titers there rose from 31.0% to 50.0%. INTERPRETATION: The prevalence of seroprotective titers of tetanus antitoxin (stimulated by tetanus toxoid components within pentavalent vaccine) provides a reliable biomarker to identify children who received pentavalent vaccine. In the three study woredas, the RED-QI intervention appeared to improve immunization service delivery, as documented by enhanced pentavalent vaccine coverage, vaccination timeliness, and fewer missed vaccination opportunities. A measles mass vaccination campaign was followed by a markedly increased prevalence of measles PRN antibodies. Collectively, these observations suggest that wider implementation of RED-QI can strengthen immunization, and periodic linked vaccination surveys/serosurveys can monitor changes.

The effects of switching from 10 to 5-dose vials of MR vaccine on vaccination coverage and wastage: A mixed-method study in Zambia.

INTRODUCTION: Vaccines procured for low-income countries are often packaged in multi-dose vials to reduce program costs. To avoid wastage, health workers may refrain from opening a vial if few children attend an immunization session, possibly leading to lower coverage. Lowering the number of doses in a vial may increase coverage and reduce wastage. METHODS: We used a mixed methods approach to measure the effects of switching from conventional 10-dose measles containing vaccine (MCV) vials to 5-dose MCV vials on coverage and open vial wastage in 14 districts purposely selected from two provinces in Zambia. The districts were paired based on the number of health facilities and the average size of the health facility catchment population. One district from each pair was randomly allocated to receive 5-dose vials while the other continued with the conventional vials. We applied propensity score matched difference-in-difference analysis to estimate intervention effects on coverage using pre-intervention household survey and post-intervention household survey after 11 months of the intervention. The intervention effects on wastage rates were estimated from multivariate analysis of the administrative data. Key informant interviews were conducted to better understand health workers' behavior and preferences at baseline, midline and endline, and analyzed using thematic analysis techniques. RESULTS: MCV coverage rates increased across both arms for both doses. A five percentage-point intervention effect was detected for MCV1 and 3.5 percentage-point effect for MCV2. The MCV wastage rate was 47% lower in facilities using 5-dose vials (16.2%) versus 10-dose vials (30.5%). Healthcare workers reported being more willing to open a 5-dose vial than a 10-dose vial for one child, as they were less concerned about wastage. DISCUSSION: Switching 10-dose MCV vials to 5-dose vials improved coverage, decreased wastage, and improved willingness to open a vial. These findings can contribute to strategies for reducing missed opportunities for vaccination.

Lessons Learned from the CORE Group Polio Project and Their Relevance for Other Global Health Priorities.

Despite numerous setbacks, the Global Polio Eradication Initiative has implemented various community strategies with potential application for other global health issues. This article reviews strategies implemented by the CORE Group Polio Project (CGPP), including pursuit of the missed child, microplanning, independent campaign monitoring, using community health workers and community mobilizers to build community engagement, community-based surveillance, development of the capacity to respond to other health needs, targeting geographic areas at high risk, the secretariat model for non-governmental organization collaboration, and registration of vital events. These strategies have the potential for contributing to the reduction of child and maternal mortality in hard-to-reach, underserved populations around the world. Community-based surveillance as developed by the CGPP also has potential for improving global health security, now a global health priority.

Introducing rotavirus vaccine in the Universal Immunization Programme in India: From evidence to policy to implementation.

BACKGROUND: In 2016, India became one of the first countries in Asia to introduce an indigenously manufactured rotavirus vaccine. However, any new vaccine introduction needs to be meticulously planned to allow for strengthening of the existing immunization systems instead of burdening them. METHODS: The process of rotavirus vaccine introduction in India started with the establishment of National Rotavirus Surveillance Network in 2005 which generated relevant evidence to inform policy level decisions to introduce the vaccine. The preparatory activities started with assessment of health systems and closing any gaps. This was followed by development of vaccine specific training packages and cascade training for programme managers and health workers. The introduction was complemented with strong communications systems and media involvement to allow for good acceptability of the vaccine on the ground. Each step of introduction was led by the government and technically supported by development partners. RESULTS: India introduced rotavirus vaccine in a phased wise manner. In the first two phases the vaccine has been introduced in nine states of the country accounting for nearly 35% of the annual birth cohort of the country. From March 2016 to November 2017, approximately 13,260,000 rotavirus vaccine doses were administered in the country. The vaccine was well accepted by both the health workers and parents/caregivers. CONCLUSION: Rotavirus vaccine introduction in India is an excellent example of how government stewardship with well-defined roles for development partners can allow a new vaccine introduction to be used as a system strengthening activity.

The value of tailoring vial sizes to populations and locations.

BACKGROUND: Frequently, a country will procure a single vaccine vial size, but the question remains whether tailoring the use of different size vaccine vial presentations based on populations or location characteristics within a single country could provide additional benefits, such as reducing open vial wastage (OVW) or reducing missed vaccination opportunities. METHODS: Using the Highly Extensible Resource for Modeling Supply Chains (HERMES) software, we built a simulation model of the Zambia routine vaccine supply chain. At baseline, we distributed 10-dose Measles-Rubella (MR) vials to all locations, and then distributed 5-dose and 1-dose MR vials to (1) all locations, (2) rural districts, (3) rural health facilities, (4) outreach sites, and (5) locations with average MR session sizes <5 and <10 children. We ran sensitivity on each scenario using MR vial opening thresholds of 0% and 50%, i.e. a healthcare worker opens an MR vaccine for any number of children (0%) or if at least half will be used (50%). RESULTS: Replacing 10-dose MR with 5-dose MR vials everywhere led to the largest reduction in MR OVW, saving 573,892 doses (103,161 doses with the 50% vial opening threshold) and improving MR availability by 1% (9%). This scenario, however, increased cold chain utilization and led to a 1% decrease in availability of other vaccines. Tailoring 5-dose MR vials to rural health facilities or based on average session size reduced cold transport constraints, increased total vaccine availability (+1%) and reduced total cost per dose administered (-$0.01) compared to baseline. CONCLUSIONS: In Zambia, tailoring 5-dose MR vials to rural health facilities or by average session size results in the highest total vaccine availability compared to all other scenarios (regardless of OVT policy) by reducing open vial wastage without increasing cold chain utilization.

Doses per vaccine vial container: An understated and underestimated driver of performance that needs more evidence.

The widespread use of multidose vaccine containers in low and middle income countries' immunization programs is assumed to have multiple benefits and efficiencies for health systems, yet the broader impacts on immunization coverage, costs, and safety are not well understood. To document what is known on this topic, how it has been studied, and confirm the gaps in evidence that allow us to assess the complex system interactions, the authors undertook a review of published literature that explored the relationship between doses per container and immunization systems. The relationships examined in this study are organized within a systems framework consisting of operational costs, timely coverage, safety, product costs/wastage, and policy/correct use, with the idea that a change in dose per container affects all of them, and the optimal solution will depend on what is prioritized and used to measure performance. Studies on this topic are limited and largely rely on modeling to assess the relationship between doses per container and other aspects of immunization systems. Very few studies attempt to look at how a change in doses per container affects vaccination coverage rates and other systems components simultaneously. This article summarizes the published knowledge on this topic to date and suggests areas of current and future research to ultimately improve decision making around vaccine doses per container and increase understanding of how this decision relates to other program goals.

Beyond new vaccine introduction: the uptake of pneumococcal conjugate vaccine in the African Region.

The number of vaccines available to low-income countries has increased dramatically over the last decade. Overall infant immunization coverage in the WHO African region has stagnated in the past few years while countries' ability to maintain high immunization coverage rates following introduction of new vaccines has been uneven. This case study examines post-introduction coverage among African countries that introduced PCV between 2008 and 2013 and the factors affecting Pneumococcal Conjugate Vaccine (PCV) introduction. Nearly one-third of countries did not achieve 80% infant PCV3 coverage by two years post-introduction and 58% of countries experienced a decline in coverage between post introduction years two and four. Major factors affecting coverage rates included introduction without adequate preparation, insufficient supply chain capacity and management, poor communication between organizations and with the public, and data collection systems that were insufficient to meet information needs. Deliberately addressing these issues as well as longstanding weaknesses during new vaccine introduction can strengthen the immunization and broader health system. Further study is required to identify and address factors that affect maintenance of high coverage following introduction of new vaccines in the African region. Immunization with PCV is one of the most important interventions protecting against pneumonia, the second leading cause of death for children under five globally.

Immunization Coverage Surveys and Linked Biomarker Serosurveys in Three Regions in Ethiopia.

OBJECTIVE: Demographic and health surveys, immunization coverage surveys and administrative data often divergently estimate vaccination coverage, which hinders pinpointing districts where immunization services require strengthening. We assayed vaccination coverage in three regions in Ethiopia by coverage surveys and linked serosurveys. METHODS: Households with children aged 12-23 (N = 300) or 6-8 months (N = 100) in each of three districts (woredas) were randomly selected for immunization coverage surveys (inspection of vaccination cards and immunization clinic records and maternal recall) and linked serosurveys. IgG-ELISA serologic biomarkers included tetanus antitoxin ≥ 0.15 IU/ml in toddlers (receipt of tetanus toxoid) and Haemophilus influenzae type b (Hib) anti-capsular titers ≥ 1.0 mcg/ml in infants (timely receipt of Hib vaccine). FINDINGS: Coverage surveys enrolled 1,181 children across three woredas; 1,023 (87%) also enrolled in linked serosurveys. Administrative data over-estimated coverage compared to surveys, while maternal recall was unreliable. Serologic biomarkers documented a hierarchy among the districts. Biomarker measurement in infants provided insight on timeliness of vaccination not deducible from toddler results. CONCLUSION: Neither administrative projections, vaccination card or EPI register inspections, nor parental recall, substitute for objective serological biomarker measurement. Including infants in serosurveys informs on vaccination timeliness.

Strategies for Coordination of a Serosurvey in Parallel with an Immunization Coverage Survey.

A community-based immunization coverage survey is the standard way to estimate effective vaccination delivery to a target population in a region. Accompanying serosurveys can provide objective measures of protective immunity against vaccine-preventable diseases but pose considerable challenges with respect to specimen collection and preservation and community compliance. We performed serosurveys coupled to immunization coverage surveys in three administrative districts (woredas) in rural Ethiopia. Critical to the success of this effort were serosurvey equipment and supplies, team composition, and tight coordination with the coverage survey. Application of these techniques to future studies may foster more widespread use of serosurveys to derive more objective assessments of vaccine-derived seroprotection and monitor and compare the performance of immunization services in different districts of a country.

Engaging communities with a simple tool to help increase immunization coverage.

The level of vaccination coverage in a given community depends on both service factors and the degree to which the public understands and trusts the immunization process. This article describes an approach that aims to raise awareness and boost demand. Developed in India, the "My Village Is My Home" (MVMH) tool, known as Uma Imunizasaun (UI) in Timor-Leste, is a poster-sized material used by volunteers and health workers to record the births and vaccination dates of every infant in a community. Introduction of the tool in 5 districts of India (April 2012 to March 2013) and in 7 initial villages in Timor-Leste (beginning in January 2012) allowed community leaders, volunteers, and health workers to monitor the vaccination status of every young child and guided reminder and motivational visits. In 3 districts of India, we analyzed data on vaccination coverage and timeliness before and during use of the tool; in 2 other districts, analysis was based only on data for new births during use of the tool. In Timor-Leste, we compared UI data from the 3 villages with the most complete data with data for the same villages from the vaccination registers from the previous year. In both countries, we also obtained qualitative data about perceptions of the tool through interviews with health workers and community members. Assessments in both countries found evidence suggesting improved vaccination timeliness and coverage. In India, pilot communities had 80% or higher coverage of identified and eligible children for all vaccines. In comparison, overall coverage in the respective districts during the same time period was much lower, at 49% to 69%. In Timor-Leste, both the number of infants identified and immunized rose substantially with use of the tool compared with the previous year (236 vs. 155, respectively, identified as targets; 185 vs. 147, respectively, received Penta 3). Although data challenges limit firm conclusions, the experiences in both countries suggest that "My Village Is My Home" is a promising tool that has the potential to broaden program coverage by marshalling both community residents and health workers to track individual children's vaccinations. Three states in India have adopted the tool, and Timor-Leste had also planned to scale-up the initiative.

Drivers of routine immunization coverage improvement in Africa: findings from district-level case studies.

There is limited understanding of why routine immunization (RI) coverage improves in some settings in Africa and not in others. Using a grounded theory approach, we conducted in-depth case studies to understand pathways to coverage improvement by comparing immunization programme experience in 12 districts in three countries (Ethiopia, Cameroon and Ghana). Drawing on positive deviance or assets model techniques we compared the experience of districts where diphtheria-tetanus-pertussis (DTP3)/pentavalent3 (Penta3) coverage improved with districts where DTP3/Penta3 coverage remained unchanged (or steady) over the same period, focusing on basic readiness to deliver immunization services and drivers of coverage improvement. The results informed a model for immunization coverage improvement that emphasizes the dynamics of immunization systems at district level. In all districts, whether improving or steady, we found that a set of basic RI system resources were in place from 2006 to 2010 and did not observe major differences in infrastructure. We found that the differences in coverage trends were due to factors other than basic RI system capacity or service readiness. We identified six common drivers of RI coverage performance improvement-four direct drivers and two enabling drivers-that were present in well-performing districts and weaker or absent in steady coverage districts, and map the pathways from driver to improved supply, demand and coverage. Findings emphasize the critical role of implementation strategies and the need for locally skilled managers that are capable of tailoring strategies to specific settings and community needs. The case studies are unique in their focus on the positive drivers of change and the identification of pathways to coverage improvement, an approach that should be considered in future studies and routine assessments of district-level immunization system performance.

Monitoring coverage of fully immunized children.

Immunization programs monitor 3rd dose of DPT-containing vaccine coverage as a principal indicator; however, this does not inform about coverage with other vaccines. A mini-survey was conducted to assess the status of monitoring coverage of fully immunized children (FIC) in Eastern and Southern African countries. We designed and distributed a structured self-administered questionnaire to all 19 national program managers attending a meeting in March 2014 in Harare, Zimbabwe. We learned that most countries already monitor FIC coverage and managers appreciate the importance of monitoring this as a national indicator, as it aligns with the full benefits of immunization. This mini-survey concluded that at national level, FIC coverage could be used as a principal indicator; however, at global level DPT3 has some additional advantages across all countries in standardizing the capacity of the immunization program to deliver multiple doses of the same vaccine to all children by 12 months of age.

Applying an equity lens in the Decade of Vaccines.

Addressing inequities in immunisation must be the main priority for the Decade of Vaccines. Children who remain unreached are those who need vaccination - and other health services - most. Reaching these children and other underserved target groups will require a reorientation of current approaches and resource allocation. At the country level, evidence-based and context-specific strategies must be developed to promote equity in ways that strengthen the system that facilitates vaccination, are sustainable and extend benefits across the life cycle. At the global level, more attention must go on ensuring sustainable and affordable supply for low- and middle-income countries to vaccine products that are appropriate for the contexts where needs are greatest. Finally, data must be disaggregated and used at all levels to monitor and guide progress to reach the unreached.