Report from the World Health Organization's immunization and vaccines related implementation research advisory committee (IVIR-AC) meeting, Geneva, 11-13 September 2023.

Evaluating vaccine-related research is critical to maximize the potential of vaccination programmes. The WHO Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC) provides an independent review of research that estimates the performance, impact and value of vaccines, with a particular focus on transmission and economic modelling. On 11-13 September 2023, IVIR-AC was convened for a bi-annual meeting where the committee reviewed research and presentations across eight different sessions. This report summarizes the background information, proceedings and recommendations from that meeting. Sessions ranged in topic from timing of measles supplementary immunization activities, analyses of conditions necessary to meet measles elimination in the South-East Asia region, translating modelled evidence into policy, a risk-benefit analysis of dengue vaccine, COVID-19 scenario modelling in the African region, therapeutic vaccination against human papilloma virus, the Vaccine Impact Modelling Consortium, and the Immunization Agenda 2030 vaccine impact estimates.

Population-Level Risk Factors Related to Measles Case Fatality: A Conceptual Framework Based on Expert Consultation and Literature Review.

A better understanding of population-level factors related to measles case fatality is needed to estimate measles mortality burden and impact of interventions such as vaccination. This study aimed to develop a conceptual framework of mechanisms associated with measles case fatality ratios (CFRs) and assess the scope of evidence available for related indicators. Using expert consultation, we developed a conceptual framework of mechanisms associated with measles CFR and identified population-level indicators potentially associated with each mechanism. We conducted a literature review by searching PubMed on 31 October 2021 to determine the scope of evidence for the expert-identified indicators. Studies were included if they contained evidence of an association between an indicator and CFR and were excluded if they were from non-human studies or reported non-original data. Included studies were assessed for study quality. Expert consultation identified five mechanisms in a conceptual framework of factors related to measles CFR. We identified 3772 studies for review and found 49 studies showing at least one significant association with CFR for 15 indicators (average household size, educational attainment, first- and second-dose coverage of measles-containing vaccine, human immunodeficiency virus prevalence, level of health care available, stunting prevalence, surrounding conflict, travel time to major city or settlement, travel time to nearest health care facility, under-five mortality rate, underweight prevalence, vitamin A deficiency prevalence, vitamin A treatment, and general malnutrition) and only non-significant associations for five indicators (antibiotic use for measles-related pneumonia, malaria prevalence, percent living in urban settings, pneumococcal conjugate vaccination coverage, vitamin A supplementation). Our study used expert consultation and a literature review to provide additional insights and a summary of the available evidence of these underlying mechanisms and indicators that could inform future measles CFR estimations.

Estimating vaccine coverage in conflict settings using geospatial methods: a case study in Borno state, Nigeria.

Reliable estimates of subnational vaccination coverage are critical to track progress towards global immunisation targets and ensure equitable health outcomes for all children. However, conflict can limit the reliability of coverage estimates from traditional household-based surveys due to an inability to sample in unsafe and insecure areas and increased uncertainty in underlying population estimates. In these situations, model-based geostatistical (MBG) approaches offer alternative coverage estimates for administrative units affected by conflict. We estimated first- and third-dose diphtheria-tetanus-pertussis vaccine coverage in Borno state, Nigeria, using a spatiotemporal MBG modelling approach, then compared these to estimates from recent conflict-affected, household-based surveys. We compared sampling cluster locations from recent household-based surveys to geolocated data on conflict locations and modelled spatial coverage estimates, while also investigating the importance of reliable population estimates when assessing coverage in conflict settings. These results demonstrate that geospatially-modelled coverage estimates can be a valuable additional tool to understand coverage in locations where conflict prevents representative sampling.

Estimating national-level measles case-fatality ratios in low-income and middle-income countries: an updated systematic review and modelling study.

BACKGROUND: To understand the current measles mortality burden, and to mitigate the future burden, it is crucial to have robust estimates of measles case fatalities. Estimates of measles case-fatality ratios (CFRs) that are specific to age, location, and time are essential to capture variations in underlying population-level factors, such as vaccination coverage and measles incidence, which contribute to increases or decreases in CFRs. In this study, we updated estimates of measles CFRs by expanding upon previous systematic reviews and implementing a meta-regression model. Our objective was to use all information available to estimate measles CFRs in low-income and middle-income countries (LMICs) by country, age, and year. METHODS: For this systematic review and meta-regression modelling study, we searched PubMed on Dec 31, 2020 for all available primary data published from Jan 1, 1980 to Dec 31, 2020, on measles cases and fatalities occurring up to Dec 31, 2019 in LMICs. We included studies that previous systematic reviews had included or which contained primary data on measles cases and deaths from hospital-based, community-based, or surveillance-based reports, including outbreak investigations. We excluded studies that were not in humans, or reported only data that were only non-primary, or on restricted populations (eg, people living with HIV), or on long-term measles mortality (eg, death from subacute sclerosing panencephalitis), and studies that did not include country-level data or relevant information on measles cases and deaths, or were for a high-income country. We extracted summary data on measles cases and measles deaths from studies that fitted our inclusion and exclusion criteria. Using these data and a suite of covariates related to measles CFRs, we implemented a Bayesian meta-regression model to produce estimates of measles CFRs from 1990 to 2019 by location and age group. This study was not registered with PROSPERO or otherwise. FINDINGS: We identified 2705 records, of which 208 sources contained information on both measles cases and measles deaths in LMICS and were included in the review. Between 1990 and 2019, CFRs substantially decreased in both community-based and hospital-based settings, with consistent patterns across age groups. For people aged 0-34 years, we estimated a mean CFR for 2019 of 1·32% (95% uncertainty interval [UI] 1·28-1·36) among community-based settings and 5·35% (5·08-5·64) among hospital-based settings. We estimated the 2019 CFR in community-based settings to be 3·03% (UI 2·89-3·16) for those younger than 1 year, 1·63% (1·58-1·68) for age 1-4 years, 0·84% (0·80-0·87) for age 5-9 years, and 0·67% (0·64-0·70) for age 10-14 years. INTERPRETATION: Although CFRs have declined between 1990 and 2019, there are still large heterogeneities across locations and ages. One limitation of this systematic review is that we were unable to assess measles CFR among particular populations, such as refugees and internally displaced people. Our updated methodological framework and estimates could be used to evaluate the effect of measles control and vaccination programmes on reducing the preventable measles mortality burden. FUNDING: Bill & Melinda Gates Foundation; Gavi, the Vaccine Alliance; and the US National Institutes of Health.

Meningococcal A conjugate vaccine coverage in the meningitis belt of Africa from 2010 to 2021: a modelling study.

Background: As of the end of 2021, twenty-four countries in the African meningitis belt have rolled out mass campaigns of MenAfriVac®, a meningococcal A conjugate vaccine (MACV) first introduced in 2010. Twelve have completed introduction of MACV into routine immunisation (RI) schedules. Although select post-campaign coverage data are published, no study currently comprehensively estimates MACV coverage from both routine and campaign sources in the meningitis belt across age, country, and time. Methods: In this modelling study, we assembled campaign data from the twenty-four countries that had introduced any immunisation activity during or before the year 2021 (Benin, Burkina Faso, Burundi, Cameroon, Central African Republic, Chad, Côte d'Ivoire, Democratic Republic of the Congo, Ethiopia, Eritrea, the Gambia, Ghana, Guinea, Guinea Bissau, Kenya, Mali, Mauritania, Niger, Nigeria, Senegal, South Sudan, Sudan, Togo and Uganda) via WHO reports and RI data via systematic review. Next, we modelled RI coverage using Spatiotemporal Gaussian Process Regression. Then, we synthesized these estimates with campaign data into a cohort model, tracking coverage for each age cohort from age 1 to 29 years over time for each country. Findings: Coverage in high-risk locations amongst children aged 1-4 in 2021 was estimated to be highest in Togo with 96.0% (95% uncertainty interval [UI] 92.0-99.0), followed by Niger with 87.2% (95% UI 85.3-89.0) and Burkina Faso, with 86.4% (95% UI 85.1-87.6). These countries had high coverage values driven by an initial successful mass immunisation campaign, followed by a catch-up campaign, followed by introduction of RI. Due to the influence of older mass vaccination campaigns, coverage proportions skewed higher in the 1-29 age group than the 1-4 group, with a median coverage of 82.9% in 2021 in the broader age group compared to 45.6% in the narrower age group. Interpretation: These estimates highlight where gaps in immunisation remain and emphasise the need for broader efforts to strengthen RI systems. This methodological framework can be applied to estimate coverage for any vaccine that has been delivered in both routine and supplemental immunisation activities. Funding: Bill and Melinda Gates Foundation.

Exploring the subnational inequality and heterogeneity of the impact of routine measles immunisation in Africa.

Despite vaccination being one of the most effective public health interventions, there are persisting inequalities and inequities in immunisation. Understanding the differences in subnational vaccine impact can help improve delivery mechanisms and policy. We analyse subnational vaccination coverage of measles first-dose (MCV1) and estimate patterns of inequalities in impact, represented as deaths averted, across 45 countries in Africa. We also evaluate how much this impact would improve under more equitable vaccination coverage scenarios. Using coverage data for MCV1 from 2000-2019, we estimate the number of deaths averted at the first administrative level. We use the ratio of deaths averted per vaccination from two mathematical models to extrapolate the impact at a subnational level. Next, we calculate inequality for each country, measuring the spread of deaths averted across its regions, accounting for differences in population. Finally, using three more equitable vaccination coverage scenarios, we evaluate how much impact of MCV1 immunisation could improve by (1) assuming all regions in a country have at least national coverage, (2) assuming all regions have the observed maximum coverage; and (3) assuming all regions have at least 80% coverage. Our results show that progress in coverage and reducing inequality has slowed in the last decade in many African countries. Under the three scenarios, a significant number of additional deaths in children could be prevented each year; for example, under the observed maximum coverage scenario, global MCV1 coverage would improve from 76% to 90%, resulting in a further 363(95%CrI:299-482) deaths averted per 100,000 live births. This paper illustrates that estimates of the impact of MCV1 immunisation at a national level can mask subnational heterogeneity. We further show that a considerable number of deaths could be prevented by maximising equitable access in countries with high inequality when increasing the global coverage of MCV1 vaccination.

Declines in Pneumonia Mortality Following the Introduction of Pneumococcal Conjugate Vaccines in Latin American and Caribbean Countries.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) are recommended for use in pediatric immunization programs worldwide. Few data are available on their effect against mortality. We present a multicountry evaluation of the population-level impact of PCVs against death due to pneumonia in children < 5 years of age. METHODS: We obtained national-level mortality data between 2000 and 2016 from 10 Latin American and Caribbean countries, using the standardized protocol. Time series models were used to evaluate the decline in all-cause pneumonia deaths during the postvaccination period while controlling for unrelated temporal trends using control causes of death. RESULTS: The estimated declines in pneumonia mortality following the introduction of PCVs ranged from 11% to 35% among children aged 2-59 months in 5 countries: Colombia (24% [95% credible interval {CrI}, 3%-35%]), Ecuador (25% [95% CrI, 4%-41%]), Mexico (11% [95% CrI, 3%-18%]), Nicaragua (19% [95% CrI, 0-34%]), and Peru (35% [95% CrI, 20%-47%]). In Argentina, Brazil, and the Dominican Republic, the declines were not detected in the aggregated age group but were detected in certain age strata. In Guyana and Honduras, the estimates had large uncertainty, and no declines were detected. Across the 10 countries, most of which have low to moderate incidence of pneumonia mortality, PCVs have prevented nearly 4500 all-cause pneumonia deaths in children 2-59 months since introduction. CONCLUSIONS: Although the data quality was variable between countries, and the patterns varied across countries and age groups, the balance of evidence suggests that mortality due to all-cause pneumonia in children declined after PCV introduction. The impact could be greater in populations with a higher prevaccine burden of pneumonia.

Progression from latent infection to active disease in dynamic tuberculosis transmission models: a systematic review of the validity of modelling assumptions.

Mathematical modelling is commonly used to evaluate infectious disease control policy and is influential in shaping policy and budgets. Mathematical models necessarily make assumptions about disease natural history and, if these assumptions are not valid, the results of these studies can be biased. We did a systematic review of published tuberculosis transmission models to assess the validity of assumptions about progression to active disease after initial infection (PROSPERO ID CRD42016030009). We searched PubMed, Web of Science, Embase, Biosis, and Cochrane Library, and included studies from the earliest available date (Jan 1, 1962) to Aug 31, 2017. We identified 312 studies that met inclusion criteria. Predicted tuberculosis incidence varied widely across studies for each risk factor investigated. For population groups with no individual risk factors, annual incidence varied by several orders of magnitude, and 20-year cumulative incidence ranged from close to 0% to 100%. A substantial proportion of modelled results were inconsistent with empirical evidence: for 10-year cumulative incidence, 40% of modelled results were more than double or less than half the empirical estimates. These results demonstrate substantial disagreement between modelling studies on a central feature of tuberculosis natural history. Greater attention to reproducing known features of epidemiology would strengthen future tuberculosis modelling studies, and readers of modelling studies are recommended to assess how well those studies demonstrate their validity.

Electronically Available Comorbid Conditions for Risk Prediction of Healthcare-Associated Clostridium difficile Infection.

OBJECTIVE To analyze whether electronically available comorbid conditions are risk factors for Centers for Disease Control and Prevention (CDC)-defined, hospital-onset Clostridium difficile infection (CDI) after controlling for antibiotic and gastric acid suppression therapy use. PATIENTS Patients aged ≥18 years admitted to the University of Maryland Medical Center between November 7, 2015, and May 31, 2017. METHODS Comorbid conditions were assessed using the Elixhauser comorbidity index. The Elixhauser comorbidity index and the comorbid condition components were calculated using the International Classification of Disease, Tenth Revision, Clinical Modification (ICD-10-CM) codes extracted from electronic medical records. Bivariate associations between CDI and potential covariates for multivariable regression, including antibiotic use, gastric acid suppression therapy use, as well as comorbid conditions, were estimated using log binomial multivariable regression. RESULTS After controlling for antibiotic use, age, proton-pump inhibitor use, and histamine-blocker use, the Elixhauser comorbidity index was a significant risk factor for predicting CDI. There was an increased risk of 1.26 (95% CI, 1.19-1.32) of having CDI for each additional Elixhauser point added to the total Elixhauser score. CONCLUSIONS An increase in Elixhauser score is associated with CDI. Our study and other studies have shown that comorbid conditions are important risk factors for CDI. Electronically available comorbid conditions and scores like the Elixhauser index should be considered for risk-adjustment of CDC CDI rates. Infect Control Hosp Epidemiol 2018;39:297-301.

Guidance on Frequency and Location of Environmental Sampling for Acinetobacter baumannii.

We assessed various locations and frequency of environmental sampling to maximize information and maintain efficiency when sampling for Acinetobacter baumannii. Although sampling sites in closer proximity to the patient were more likely positive, to fully capture environmental contamination, we found value in sampling all sites and across multiple days. Infect Control Hosp Epidemiol 2018;39:339-342.