The impact of alternative delivery strategies for novel tuberculosis vaccines in low-income and middle-income countries: a modelling study.

BACKGROUND: Tuberculosis is a leading infectious cause of death worldwide. Novel vaccines will be required to reach global targets and reverse setbacks resulting from the COVID-19 pandemic. We estimated the impact of novel tuberculosis vaccines in low-income and middle-income countries (LMICs) in several delivery scenarios. METHODS: We calibrated a tuberculosis model to 105 LMICs (accounting for 93% of global incidence). Vaccine scenarios were implemented as the base-case (routine vaccination of those aged 9 years and one-off vaccination for those aged 10 years and older, with country-specific introduction between 2028 and 2047, and 5-year scale-up to target coverage); accelerated scale-up similar to the base-case, but with all countries introducing vaccines in 2025, with instant scale-up; and routine-only (similar to the base-case, but including routine vaccination only). Vaccines were assumed to protect against disease for 10 years, with 50% efficacy. FINDINGS: The base-case scenario would prevent 44·0 million (95% uncertainty range 37·2-51·6) tuberculosis cases and 5·0 million (4·6-5·4) tuberculosis deaths before 2050, compared with equivalent estimates of cases and deaths that would be predicted to occur before 2050 with no new vaccine introduction (the baseline scenario). The accelerated scale-up scenario would prevent 65·5 million (55·6-76·0) cases and 7·9 million (7·3-8·5) deaths before 2050, relative to baseline. The routine-only scenario would prevent 8·8 million (95% uncertainty range 7·6-10·1) cases and 1·1 million (0·9-1·2) deaths before 2050, relative to baseline. INTERPRETATION: Our results suggest novel tuberculosis vaccines could have substantial impact, which will vary depending on delivery strategy. Including a one-off vaccination campaign will be crucial for rapid impact. Accelerated introduction-at a pace similar to that seen for COVID-19 vaccines-would increase the number of lives saved before 2050 by around 60%. Investment is required to support vaccine development, manufacturing, prompt introduction, and scale-up. FUNDING: WHO (2020/985800-0). TRANSLATIONS: For the French, Spanish, Italian and Dutch translations of the abstract see Supplementary Materials section.

The cost and cost-effectiveness of novel tuberculosis vaccines in low- and middle-income countries: A modeling study.

BACKGROUND: Tuberculosis (TB) is preventable and curable but eliminating it has proven challenging. Safe and effective TB vaccines that can rapidly reduce disease burden are essential for achieving TB elimination. We assessed future costs, cost-savings, and cost-effectiveness of introducing novel TB vaccines in low- and middle-income countries (LMICs) for a range of product characteristics and delivery strategies. METHODS AND FINDINGS: We developed a system of epidemiological and economic models, calibrated to demographic, epidemiological, and health service data in 105 LMICs. For each country, we assessed the likely future course of TB-related outcomes under several vaccine introduction scenarios, compared to a "no-new-vaccine" counterfactual. Vaccine scenarios considered 2 vaccine product profiles (1 targeted at infants, 1 at adolescents/adults), both assumed to prevent progression to active TB. Key economic inputs were derived from the Global Health Cost Consortium, World Health Organization (WHO) patient cost surveys, and the published literature. We estimated the incremental impact of vaccine introduction for a range of health and economic outcomes. In the base-case, we assumed a vaccine price of $4.60 and used a 1× per-capita gross domestic product (GDP) cost-effectiveness threshold (both varied in sensitivity analyses). Vaccine introduction was estimated to require substantial near-term resources, offset by future cost-savings from averted TB burden. From a health system perspective, adolescent/adult vaccination was cost-effective in 64 of 105 LMICs. From a societal perspective (including productivity gains and averted patient costs), adolescent/adult vaccination was projected to be cost-effective in 73 of 105 LMICs and cost-saving in 58 of 105 LMICs, including 96% of countries with higher TB burden. When considering the monetized value of health gains, we estimated that introduction of an adolescent/adult vaccine could produce $283 to 474 billion in economic benefits by 2050. Limited data availability required assumptions and extrapolations that may omit important country-level heterogeneity in epidemiology and costs. CONCLUSIONS: TB vaccination would be highly impactful and cost-effective in most LMICs. Further efforts are needed for future development, adoption, and implementation of novel TB vaccines.

Vaccine equity in low and middle income countries: a systematic review and meta-analysis.

BACKGROUND: Evidence to date has shown that inequality in health, and vaccination coverage in particular, can have ramifications to wider society. However, whilst individual studies have sought to characterise these heterogeneities in immunisation coverage at national level, few have taken a broad and quantitative view of the contributing factors to heterogeneity in immunisation coverage and impact, i.e. the number of cases, deaths, and disability-adjusted life years averted. This systematic review aims to highlight these geographic, demographic, and sociodemographic characteristics through a qualitative and quantitative approach, vital to prioritise and optimise vaccination policies. METHODS: A systematic review of two databases (PubMed and Web of Science) was undertaken using search terms and keywords to identify studies examining factors on immunisation inequality and heterogeneity in vaccination coverage. Inclusion criteria were applied independently by two researchers. Studies including data on key characteristics of interest were further analysed through a meta-analysis to produce a pooled estimate of the risk ratio using a random effects model for that characteristic. RESULTS: One hundred and eight studies were included in this review. We found that inequalities in wealth, education, and geographic access can affect vaccine impact and vaccination dropout. We estimated those living in rural areas were not significantly different in terms of full vaccination status compared to urban areas but noted considerable heterogeneity between countries. We found that females were 3% (95%CI[1%, 5%]) less likely to be fully vaccinated than males. Additionally, we estimated that children whose mothers had no formal education were 28% (95%CI[18%,47%]) less likely to be fully vaccinated than those whose mother had primary level, or above, education. Finally, we found that individuals in the poorest wealth quintile were 27% (95%CI [16%,37%]) less likely to be fully vaccinated than those in the richest. CONCLUSIONS: We found a nuanced picture of inequality in vaccination coverage and access with wealth disparity dominating, and likely driving, other disparities. This review highlights the complex landscape of inequity and further need to design vaccination strategies targeting missed subgroups to improve and recover vaccination coverage following the COVID-19 pandemic. TRIAL REGISTRATION: Prospero, CRD42021261927.

Progress Toward Regional Measles Elimination - Worldwide, 2000-2021.

All six World Health Organization (WHO) regions have committed to eliminating measles.* The Immunization Agenda 2021-2030 (IA2030)† aims to achieve the regional targets as a core indicator of impact and positions measles as the tracer of a health system's ability to deliver essential childhood vaccines. IA2030 highlights the importance of ensuring rigorous measles surveillance systems to document immunity gaps and achieve 95% coverage with 2 timely doses of measles-containing vaccine (MCV) among children. This report describes progress toward measles elimination during 2000-2021 and updates a previous report (1). During 2000-2021, estimated global coverage with a first MCV dose (MCV1) increased from 72% to a peak of 86% in 2019, but decreased during the COVID-19 pandemic to 83% in 2020 and to 81% in 2021, the lowest MCV1 coverage recorded since 2008. All countries conducted measles surveillance, but only 47 (35%) of 135 countries reporting discarded cases§ achieved the sensitivity indicator target of two or more discarded cases per 100,000 population in 2021, indicating surveillance system underperformance in certain countries. Annual reported measles incidence decreased 88% during 2000-2016, from 145 to 18 cases per 1 million population, then rebounded to 120 in 2019 during a global resurgence (2), before declining to 21 in 2020 and to 17 in 2021. Large and disruptive outbreaks were reported in 22 countries. During 2000-2021, the annual number of estimated measles deaths decreased 83%, from 761,000 to 128,000; an estimated 56 million measles deaths were averted by vaccination. To regain progress and achieve regional measles elimination targets during and after the COVID-19 pandemic, accelerating targeted efforts is necessary to reach all children with 2 MCV doses while implementing robust surveillance and identifying and closing immunity gaps to prevent cases and outbreaks.

COVID-19 impact on routine immunisations for vaccine-preventable diseases: Projecting the effect of different routes to recovery.

Over the past two decades, vaccination programmes for vaccine-preventable diseases (VPDs) have expanded across low- and middle-income countries (LMICs). However, the rise of COVID-19 resulted in global disruption to routine immunisation activities. Such disruptions could have a detrimental effect on public health, leading to more deaths from VPDs, particularly without mitigation efforts. Hence, as routine immunisation activities resume, it is important to estimate the effectiveness of different approaches for recovery. We apply an impact extrapolation method developed by the Vaccine Impact Modelling Consortium to estimate the impact of COVID-19-related disruptions with different recovery scenarios for ten VPDs across 112 LMICs. We focus on deaths averted due to routine immunisations occurring in the years 2020-2030 and investigate two recovery scenarios relative to a no-COVID-19 scenario. In the recovery scenarios, we assume a 10% COVID-19-related drop in routine immunisation coverage in the year 2020. We then linearly interpolate coverage to the year 2030 to investigate two routes to recovery, whereby the immunization agenda (IA2030) targets are reached by 2030 or fall short by 10%. We estimate that falling short of the IA2030 targets by 10% leads to 11.26% fewer fully vaccinated persons (FVPs) and 11.34% more deaths over the years 2020-2030 relative to the no-COVID-19 scenario, whereas, reaching the IA2030 targets reduces these proportions to 5% fewer FVPs and 5.22% more deaths. The impact of the disruption varies across the VPDs with diseases where coverage expands drastically in future years facing a smaller detrimental effect. Overall, our results show that drops in routine immunisation coverage could result in more deaths due to VPDs. As the impact of COVID-19-related disruptions is dependent on the vaccination coverage that is achieved over the coming years, the continued efforts of building up coverage and addressing gaps in immunity are vital in the road to recovery.

Effect of evidence updates on key determinants of measles vaccination impact: a DynaMICE modelling study in ten high-burden countries.

BACKGROUND: Model-based estimates of measles burden and the impact of measles-containing vaccine (MCV) are crucial for global health priority setting. Recently, evidence from systematic reviews and database analyses have improved our understanding of key determinants of MCV impact. We explore how representations of these determinants affect model-based estimation of vaccination impact in ten countries with the highest measles burden. METHODS: Using Dynamic Measles Immunisation Calculation Engine (DynaMICE), we modelled the effect of evidence updates for five determinants of MCV impact: case-fatality risk, contact patterns, age-dependent vaccine efficacy, the delivery of supplementary immunisation activities (SIAs) to zero-dose children, and the basic reproduction number. We assessed the incremental vaccination impact of the first (MCV1) and second (MCV2) doses of routine immunisation and SIAs, using metrics of total vaccine-averted cases, deaths, and disability-adjusted life years (DALYs) over 2000-2050. We also conducted a scenario capturing the effect of COVID-19 related disruptions on measles burden and vaccination impact. RESULTS: Incorporated with the updated data sources, DynaMICE projected 253 million measles cases, 3.8 million deaths and 233 million DALYs incurred over 2000-2050 in the ten high-burden countries when MCV1, MCV2, and SIA doses were implemented. Compared to no vaccination, MCV1 contributed to 66% reduction in cumulative measles cases, while MCV2 and SIAs reduced this further to 90%. Among the updated determinants, shifting from fixed to linearly-varying vaccine efficacy by age and from static to time-varying case-fatality risks had the biggest effect on MCV impact. While varying the basic reproduction number showed a limited effect, updates on the other four determinants together resulted in an overall reduction of vaccination impact by 0.58%, 26.2%, and 26.7% for cases, deaths, and DALYs averted, respectively. COVID-19 related disruptions to measles vaccination are not likely to change the influence of these determinants on MCV impact, but may lead to a 3% increase in cases over 2000-2050. CONCLUSIONS: Incorporating updated evidence particularly on vaccine efficacy and case-fatality risk reduces estimates of vaccination impact moderately, but its overall impact remains considerable. High MCV coverage through both routine immunisation and SIAs remains essential for achieving and maintaining low incidence in high measles burden settings.

Progress Toward Regional Measles Elimination - Worldwide, 2000-2020.

In 2012, the World Health Assembly endorsed the Global Vaccine Action Plan,* with the objective of eliminating measles† in five of the six World Health Organization (WHO) regions by 2020 (1). The Immunization Agenda 2021-2030 (IA2030)§ uses measles incidence as an indicator of the strength of immunization systems. The Measles-Rubella Strategic Framework 2021-2030¶ and the Measles Outbreaks Strategic Response Plan 2021-2023** are aligned with the IA2030 and highlight robust measles surveillance systems to document immunity gaps, identify root causes of undervaccination, and develop locally tailored solutions to ensure administration of 2 doses of measles-containing vaccine (MCV) to all children. This report describes progress toward World Health Assembly milestones and measles elimination objectives during 2000-2020 and updates a previous report (2). During 2000-2010, estimated MCV first dose (MCV1) coverage increased globally from 72% to 84%, peaked at 86% in 2019, but declined to 84% in 2020 during the COVID-19 pandemic. All countries conducted measles surveillance, although fewer than one third achieved the sensitivity indicator target of ≥2 discarded†† cases per 100,000 population in 2020. Annual reported measles incidence decreased 88% during 2000-2016, from 145 to 18 cases per 1 million population, rebounded to 120 in 2019, before falling to 22 in 2020. During 2000-2020, the annual number of estimated measles deaths decreased 94%, from 1,072,800 to 60,700, averting an estimated 31.7 million measles deaths. To achieve regional measles elimination targets, enhanced efforts are needed to reach all children with 2 MCV doses, implement robust surveillance, and identify and close immunity gaps.

Lives saved with vaccination for 10 pathogens across 112 countries in a pre-COVID-19 world.

Background: Vaccination is one of the most effective public health interventions. We investigate the impact of vaccination activities for Haemophilus influenzae type b, hepatitis B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, rotavirus, rubella, Streptococcus pneumoniae, and yellow fever over the years 2000-2030 across 112 countries. Methods: Twenty-one mathematical models estimated disease burden using standardised demographic and immunisation data. Impact was attributed to the year of vaccination through vaccine-activity-stratified impact ratios. Results: We estimate 97 (95%CrI[80, 120]) million deaths would be averted due to vaccination activities over 2000-2030, with 50 (95%CrI[41, 62]) million deaths averted by activities between 2000 and 2019. For children under-5 born between 2000 and 2030, we estimate 52 (95%CrI[41, 69]) million more deaths would occur over their lifetimes without vaccination against these diseases. Conclusions: This study represents the largest assessment of vaccine impact before COVID-19-related disruptions and provides motivation for sustaining and improving global vaccination coverage in the future. Funding: VIMC is jointly funded by Gavi, the Vaccine Alliance, and the Bill and Melinda Gates Foundation (BMGF) (BMGF grant number: OPP1157270 / INV-009125). Funding from Gavi is channelled via VIMC to the Consortium's modelling groups (VIMC-funded institutions represented in this paper: Imperial College London, London School of Hygiene and Tropical Medicine, Oxford University Clinical Research Unit, Public Health England, Johns Hopkins University, The Pennsylvania State University, Center for Disease Analysis Foundation, Kaiser Permanente Washington, University of Cambridge, University of Notre Dame, Harvard University, Conservatoire National des Arts et Métiers, Emory University, National University of Singapore). Funding from BMGF was used for salaries of the Consortium secretariat (authors represented here: TBH, MJ, XL, SE-L, JT, KW, NMF, KAMG); and channelled via VIMC for travel and subsistence costs of all Consortium members (all authors). We also acknowledge funding from the UK Medical Research Council and Department for International Development, which supported aspects of VIMC's work (MRC grant number: MR/R015600/1).JHH acknowledges funding from National Science Foundation Graduate Research Fellowship; Richard and Peggy Notebaert Premier Fellowship from the University of Notre Dame. BAL acknowledges funding from NIH/NIGMS (grant number R01 GM124280) and NIH/NIAID (grant number R01 AI112970). The Lives Saved Tool (LiST) receives funding support from the Bill and Melinda Gates Foundation.This paper was compiled by all coauthors, including two coauthors from Gavi. Other funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Cost of vaccine delivery strategies in low- and middle-income countries during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has disrupted immunization services critical to the prevention of vaccine-preventable diseases in many low- and middle- income countries around the world. These services will need to be modified in order to minimize COVID-19 transmission and ensure the safety of health workers and the community. Additional budget will be required to implement these modifications that ensure safe delivery. METHODS: Using a simple modeling analysis, we estimated the additional resource requirements associated with modifications to supplementary immunization activities (campaigns) and routine immunization services via fixed sites and outreach in 2020 US dollars. We considered the following four categories of costs: (1) personal protective equipment (PPE) & infection prevention and control (IPC) measures for immunization sessions; (2) physical distancing and screening during immunization sessions; (3) delivery strategy changes, such as changes in session sizes and frequency; and (4) other operational cost increases, including additional social mobilization, training, and hazard pay to compensate health workers. RESULTS: We found that implementing a range of measures to protect health workers and communities from COVID-19 transmission could result in a per-facility start-up cost of $466-799 for routine fixed-site delivery and $12-220 for routine outreach delivery, and $12-108 per immunization campaign site. A recurrent monthly cost of $137-1,024 for fixed-site delivery and $152-848 for outreach delivery per facility could be incurred, and a $0.32-0.85 increase in the cost per dose during campaigns. CONCLUSIONS: By illustrating potential cost implications of providing immunization services through a range of strategies in a safe manner, these estimates can provide a benchmark for program managers and policy makers on the additional budget required. These findings can help country practitioners and global development partners planning the continuation of immunization services in the context of COVID-19.