Age-specific prevalence of IgG against measles/rubella and the impact of routine and supplementary immunization activities - a multistage random cluster sampling study with mathematical modelling.

BACKGROUND: Vietnam continues to have measles and rubella outbreaks following supplementary immunization activities (SIA) and routine immunization despite both having high reported coverage. To evaluate immunization activities, age-specific immunity against measles and rubella, and the number of averted Congenital Rubella Syndrome (CRS) cases, must be estimated. METHODS: Dried blood spots were collected from 2,091 randomly selected individuals aged 1-39 years. Measles and rubella virus-specific immunoglobulin G (IgG) were measured by enzyme immunoassay. Results were considered positive at ≥120 mIU/mL for measles and ≥10 IU/mL for rubella. The number of CRS cases averted by immunization since 2014 were estimated using mathematical modelling. RESULTS: OVERALL IGG SEROPREVALENCE WAS 99.7% (95%CI: 99.2-99.9) FOR MEASLES AND 83.6% (95%CI: : 79.3-87.1) for rubella. Rubella IgG seroprevalence was higher among age groups targeted in the SIA than in non-targeted young adults (95.4% [95%CI: 92.9-97.0] vs. 72.4% [95%CI: 63.1-80.1]; P < 0.001). The estimated number of CRS cases averted in 2019 by immunization activities since 2014 ranged from 126 (95%CI: 0-460) to 883 (95%CI: 0-2271) depending on the assumed post-vaccination reduction in the force of infection. CONCLUSIONS: The results suggest the SIA was effective, while young adults born before 1998 who remain unprotected for rubella require further vaccination.

Estimating the health effects of COVID-19-related immunisation disruptions in 112 countries during 2020-30: a modelling study.

BACKGROUND: There have been declines in global immunisation coverage due to the COVID-19 pandemic. Recovery has begun but is geographically variable. This disruption has led to under-immunised cohorts and interrupted progress in reducing vaccine-preventable disease burden. There have, so far, been few studies of the effects of coverage disruption on vaccine effects. We aimed to quantify the effects of vaccine-coverage disruption on routine and campaign immunisation services, identify cohorts and regions that could particularly benefit from catch-up activities, and establish if losses in effect could be recovered. METHODS: For this modelling study, we used modelling groups from the Vaccine Impact Modelling Consortium from 112 low-income and middle-income countries to estimate vaccine effect for 14 pathogens. One set of modelling estimates used vaccine-coverage data from 1937 to 2021 for a subset of vaccine-preventable, outbreak-prone or priority diseases (ie, measles, rubella, hepatitis B, human papillomavirus [HPV], meningitis A, and yellow fever) to examine mitigation measures, hereafter referred to as recovery runs. The second set of estimates were conducted with vaccine-coverage data from 1937 to 2020, used to calculate effect ratios (ie, the burden averted per dose) for all 14 included vaccines and diseases, hereafter referred to as full runs. Both runs were modelled from Jan 1, 2000, to Dec 31, 2100. Countries were included if they were in the Gavi, the Vaccine Alliance portfolio; had notable burden; or had notable strategic vaccination activities. These countries represented the majority of global vaccine-preventable disease burden. Vaccine coverage was informed by historical estimates from WHO-UNICEF Estimates of National Immunization Coverage and the immunisation repository of WHO for data up to and including 2021. From 2022 onwards, we estimated coverage on the basis of guidance about campaign frequency, non-linear assumptions about the recovery of routine immunisation to pre-disruption magnitude, and 2030 endpoints informed by the WHO Immunization Agenda 2030 aims and expert consultation. We examined three main scenarios: no disruption, baseline recovery, and baseline recovery and catch-up. FINDINGS: We estimated that disruption to measles, rubella, HPV, hepatitis B, meningitis A, and yellow fever vaccination could lead to 49 119 additional deaths (95% credible interval [CrI] 17 248-134 941) during calendar years 2020-30, largely due to measles. For years of vaccination 2020-30 for all 14 pathogens, disruption could lead to a 2·66% (95% CrI 2·52-2·81) reduction in long-term effect from 37 378 194 deaths averted (34 450 249-40 241 202) to 36 410 559 deaths averted (33 515 397-39 241 799). We estimated that catch-up activities could avert 78·9% (40·4-151·4) of excess deaths between calendar years 2023 and 2030 (ie, 18 900 [7037-60 223] of 25 356 [9859-75 073]). INTERPRETATION: Our results highlight the importance of the timing of catch-up activities, considering estimated burden to improve vaccine coverage in affected cohorts. We estimated that mitigation measures for measles and yellow fever were particularly effective at reducing excess burden in the short term. Additionally, the high long-term effect of HPV vaccine as an important cervical-cancer prevention tool warrants continued immunisation efforts after disruption. FUNDING: The Vaccine Impact Modelling Consortium, funded by Gavi, the Vaccine Alliance and the Bill & Melinda Gates Foundation. TRANSLATIONS: For the Arabic, Chinese, French, Portguese and Spanish translations of the abstract see Supplementary Materials section.

Estimates of the global burden of Congenital Rubella Syndrome, 1996-2019.

OBJECTIVES: Many countries introduced rubella-containing vaccination (RCV) after 2011, following changes in recommended World Health Organization (WHO) vaccination strategies and external support. We evaluated the impact of these introductions. METHODS: We estimated the country-specific, region-specific, and global Congenital Rubella Syndrome (CRS) incidence during 1996-2019 using mathematical modeling, including routine and campaign vaccination coverage and seroprevalence data. RESULTS: In 2019, WHO African and Eastern Mediterranean regions had the highest estimated CRS incidence (64 [95% confidence intervals (CI): 24-123] and 27 [95% CI: 4-67] per 100,000 live births respectively), where nearly half of births occur in countries that have introduced RCV. Other regions, where >95% of births occurred in countries that had introduced RCV, had a low estimated CRS incidence (<1 [95% CI: <1 to 8] and <1 [95% CI: <1 to 12] per 100,000 live births in South-East Asia [SEAR] and the Western Pacific [WPR] respectively, and similarly in Europe and the Americas). The estimated number of CRS births globally declined by approximately two-thirds during 2010-2019, from 100,000 (95% CI: 54,000-166,000) to 32,000 (95% CI: 13,000-60,000), representing a 73% reduction since 1996, largely following RCV introductions in WPR and SEAR, where the greatest reductions occurred. CONCLUSIONS: Further reductions can occur by introducing RCV in remaining countries and maintaining high RCV coverage.

Comparison of population-based measles-rubella immunoglobulin G antibody prevalence between 2014 and 2019 in Lao People's Democratic Republic: Impacts of the national immunization program.

OBJECTIVES: We evaluated the effectiveness of the Lao People's Democratic Republic's measles-rubella immunization program using the seroprevalence from two cross-sectional surveys. METHODS: The nationwide surveys occurred in 2014 and 2019 using a multistage cluster sampling, both requiring samples from 2184 individuals from 52 randomly selected villages. Immunoglobulin G titers, measured using enzyme-linked immunosorbent assay, were considered positive at ≥120 mIU/ml (measles) and ≥10 IU/ml (rubella). We calculated the vaccination-related reduction in the force of rubella infection and the number of congenital rubella syndrome cases averted in 2019. RESULTS: We collected 2135 (women: 55.2%, mean age: 23.2 years) and 2001 (52.7%, 23.1 years) samples in 2014 and 2019, respectively. During 2014-2019, immunoglobulin G prevalence increased from 83.9% (95% confidence interval [CI]: 83.8-84.0) to 98.3% (97.7-98.8) for measles and from 75.4% (75.3-75.5) to 87.8% (86.4-89.2) for rubella. The most plausible reduction in the average force of rubella infection was 100% (95% CI: 28-100) since vaccination started, averting 78 (95% CI: 42-128) congenital rubella syndrome cases in 2019. CONCLUSION: This is the first population-based study for measles and rubella at two different time points in developing countries. Measles and rubella seroprevalence increased significantly during 2014-2019, greatly exceeding the immunity thresholds for their elimination.

Feasibility of measles and rubella vaccination programmes for disease elimination: a modelling study.

BACKGROUND: Marked reductions in the incidence of measles and rubella have been observed since the widespread use of the measles and rubella vaccines. Although no global goal for measles eradication has been established, all six WHO regions have set measles elimination targets. However, a gap remains between current control levels and elimination targets, as shown by large measles outbreaks between 2017 and 2019. We aimed to model the potential for measles and rubella elimination globally to inform a WHO report to the 73rd World Health Assembly on the feasibility of measles and rubella eradication. METHODS: In this study, we modelled the probability of measles and rubella elimination between 2020 and 2100 under different vaccination scenarios in 93 countries of interest. We evaluated measles and rubella burden and elimination across two national transmission models each (Dynamic Measles Immunisation Calculation Engine [DynaMICE], Pennsylvania State University [PSU], Johns Hopkins University, and Public Health England models), and one subnational measles transmission model (Institute for Disease Modeling model). The vaccination scenarios included a so-called business as usual approach, which continues present vaccination coverage, and an intensified investment approach, which increases coverage into the future. The annual numbers of infections projected by each model, country, and vaccination scenario were used to explore if, when, and for how long the infections would be below a threshold for elimination. FINDINGS: The intensified investment scenario led to large reductions in measles and rubella incidence and burden. Rubella elimination is likely to be achievable in all countries and measles elimination is likely in some countries, but not all. The PSU and DynaMICE national measles models estimated that by 2050, the probability of elimination would exceed 75% in 14 (16%) and 36 (39%) of 93 modelled countries, respectively. The subnational model of measles transmission highlighted inequity in routine coverage as a likely driver of the continuance of endemic measles transmission in a subset of countries. INTERPRETATION: To reach regional elimination goals, it will be necessary to innovate vaccination strategies and technologies that increase spatial equity of routine vaccination, in addition to investing in existing surveillance and outbreak response programmes. FUNDING: WHO, Gavi, the Vaccine Alliance, US Centers for Disease Control and Prevention, and the Bill & Melinda Gates Foundation.

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.

Estimates of the basic reproduction number for rubella using seroprevalence data and indicator-based approaches.

The basic reproduction number (R0) of an infection determines the impact of its control. For many endemic infections, R0 is often estimated from appropriate country-specific seroprevalence data. Studies sometimes pool estimates from the same region for settings lacking seroprevalence data, but the reliability of this approach is unclear. Plausibly, indicator-based approaches could predict R0 for such settings. We calculated R0 for rubella for 98 settings and correlated its value against 66 demographic, economic, education, housing and health-related indicators. We also trained a random forest regression algorithm using these indicators as the input and R0 as the output. We used the mean-square error to compare the performances of the random forest, simple linear regression and a regional averaging method in predicting R0 using 4-fold cross validation. R0 was <5, 5-10 and >10 for 81, 14 and 3 settings respectively, with no apparent regional differences and in the limited available data, it was usually lower for rural than urban areas. R0 was most correlated with educational attainment, and household indicators for the Pearson and Spearman correlation coefficients respectively and with poverty-related indicators followed by the crude death rate considering the Maximum Information Coefficient, although the correlation for each was relatively weak (Pearson correlation coefficient: 0.4, 95%CI: (0.24,0.48) for educational attainment). A random forest did not perform better in predicting R0 than simple linear regression, depending on the subsets of training indicators and studies, and neither out-performed a regional averaging approach. R0 for rubella is typically low and using indicators to estimate its value is not straightforward. A regional averaging approach may provide as reliable an estimate of R0 for settings lacking seroprevalence data as one based on indicators. The findings may be relevant for other infections and studies estimating the disease burden and the impact of interventions for settings lacking seroprevalence data.

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.

The impact of testing and infection prevention and control strategies on within-hospital transmission dynamics of COVID-19 in English hospitals.

Nosocomial transmission of SARS-CoV-2 is a key concern, and evaluating the effect of testing and infection prevention and control strategies is essential for guiding policy in this area. Using a within-hospital SEIR transition model of SARS-CoV-2 in a typical English hospital, we estimate that between 9 March 2020 and 17 July 2020 approximately 20% of infections in inpatients, and 73% of infections in healthcare workers (HCWs) were due to nosocomial transmission. Model results suggest that placing suspected COVID-19 patients in single rooms or bays has the potential to reduce hospital-acquired infections in patients by up to 35%. Periodic testing of HCWs has a smaller effect on the number of hospital-acquired COVID-19 cases in patients, but reduces infection in HCWs by as much as 37% and results in only a small proportion of staff absences (approx. 0.3% per day). This is considerably less than the 20-25% of staff that have been reported to be absent from work owing to suspected COVID-19 and self-isolation. Model-based evaluations of interventions, informed by data collected so far, can help to inform policy as the pandemic progresses and help prevent transmission in the vulnerable hospital population. This article is part of the theme issue 'Modelling that shaped the early COVID-19 pandemic response in the UK'.

Estimating the health impact of vaccination against ten pathogens in 98 low-income and middle-income countries from 2000 to 2030: a modelling study.

BACKGROUND: The past two decades have seen expansion of childhood vaccination programmes in low-income and middle-income countries (LMICs). We quantify the health impact of these programmes by estimating the deaths and disability-adjusted life-years (DALYs) averted by vaccination against ten pathogens in 98 LMICs between 2000 and 2030. METHODS: 16 independent research groups provided model-based disease burden estimates under a range of vaccination coverage scenarios for ten pathogens: hepatitis B virus, Haemophilus influenzae type B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, Streptococcus pneumoniae, rotavirus, rubella, and yellow fever. Using standardised demographic data and vaccine coverage, the impact of vaccination programmes was determined by comparing model estimates from a no-vaccination counterfactual scenario with those from a reported and projected vaccination scenario. We present deaths and DALYs averted between 2000 and 2030 by calendar year and by annual birth cohort. FINDINGS: We estimate that vaccination of the ten selected pathogens will have averted 69 million (95% credible interval 52-88) deaths between 2000 and 2030, of which 37 million (30-48) were averted between 2000 and 2019. From 2000 to 2019, this represents a 45% (36-58) reduction in deaths compared with the counterfactual scenario of no vaccination. Most of this impact is concentrated in a reduction in mortality among children younger than 5 years (57% reduction [52-66]), most notably from measles. Over the lifetime of birth cohorts born between 2000 and 2030, we predict that 120 million (93-150) deaths will be averted by vaccination, of which 58 million (39-76) are due to measles vaccination and 38 million (25-52) are due to hepatitis B vaccination. We estimate that increases in vaccine coverage and introductions of additional vaccines will result in a 72% (59-81) reduction in lifetime mortality in the 2019 birth cohort. INTERPRETATION: Increases in vaccine coverage and the introduction of new vaccines into LMICs have had a major impact in reducing mortality. These public health gains are predicted to increase in coming decades if progress in increasing coverage is sustained. FUNDING: Gavi, the Vaccine Alliance and the Bill & Melinda Gates Foundation.

Transmission dynamics and control measures of COVID-19 outbreak in China: a modelling study.

COVID-19 is reported to have been brought under control in China. To understand the COVID-19 outbreak in China and provide potential lessons for other parts of the world, in this study we apply a mathematical model with multiple datasets to estimate the transmissibility of the SARS-CoV-2 virus and the severity of the illness associated with the infection, and how both were affected by unprecedented control measures. Our analyses show that before 19th January 2020, 3.5% (95% CI 1.7-8.3%) of  infected people were detected; this percentage increased to 36.6% (95% CI 26.1-55.4%) thereafter. The basic reproduction number (R0) was 2.33 (95% CI 1.96-3.69) before 8th February 2020; then the effective reproduction number dropped to 0.04(95% CI 0.01-0.10). This estimation also indicates that control measures taken since 23rd January 2020 affected the transmissibility about 2 weeks after they were introduced. The confirmed case fatality rate is estimated at 9.6% (95% CI 8.1-11.4%) before 15 February 2020, and then it reduced to 0.7% (95% CI 0.4-1.0%). This shows that SARS-CoV-2 virus is highly transmissible but may be less severe than SARS-CoV-1 and MERS-CoV. We found that at the early stage, the majority of R0 comes from undetected infectious people. This implies that successful control in China was achieved through reducing the contact rates among people in the general population and increasing the rate of detection and quarantine of the infectious cases.

Estimating the immunogenicity of measles-rubella vaccination administered during a mass campaign in Lao People's Democratic Republic using multi-valent seroprevalence data.

Measles and rubella are important causes of morbidity and mortality globally. Despite high coverage reported for measles vaccination, outbreaks continue to occur in some countries. The reasons for these outbreaks are poorly understood. We apply Bayesian methods to multi-valent seroprevalence data for measles and rubella, collected 2 years and 3 months after a mass measles-rubella vaccination campaign in Lao PDR to estimate the immunogenicity and vaccination coverage. When the vaccination coverage was constrained to exceed 95% or 90%, consistent with officially-reported values, the immunogenicity of the measles vaccine component was unexpectedly low (75% (95% CR: 63-82%) and 79% (CR: 70-87%) respectively. The estimated immunogenicity increased after relaxing constraints on the vaccination coverage, with best-fitting values of 83% (95% CR: 73-91%) and 97% (95% CR: 90-100%) for the measles and rubella components respectively, with an estimated coverage of 83% (95% CR: 80-88%). The findings suggest that, if the vaccine coverage was as high as that reported, continuing measles outbreaks in Lao PDR, and potentially elsewhere, may be attributable to suboptimal immunogenicity attained in mass campaigns. Vaccine management in countries with high reported levels of coverage and ongoing measles outbreaks needs to be reviewed if measles elimination targets are to be achieved.

Mycobacterium tuberculosis transmission in an ethnically-diverse high incidence region in England, 2007-11.

BACKGROUND: Transmission patterns in high tuberculosis incidence areas in England are poorly understood but need elucidating to focus contact tracing. We study transmission within and between age, ethnic and immigrant groups using molecular data from the high incidence West Midlands region. METHODS: Isolates from culture-confirmed tuberculosis cases during 2007-2011 were typed using 24-locus Mycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeats (MIRU-VNTR). We estimated the proportion of disease attributable to recent transmission, calculated the proportion of isolates matching those from the two preceding years ("retrospectively clustered"), and identified risk factors for retrospective clustering using multivariate analyses. We calculated the ratio (RCR) between the observed and expected proportion clustered retrospectively within or between age, ethnic and immigrant groups. RESULTS: Of the 2159 available genotypes (79% of culture-confirmed cases), 34% were attributed to recent transmission. The percentage retrospectively clustered decreased from 50 to 24% for 0-14 and ≥ 65 year olds respectively (p = 0.01) and was significantly lower for immigrants than the UK-born. Higher than expected clustering occurred within 15-24 year olds (RCR: 1.4 (95% CI: 1.1-1.8)), several ethnic groups, and between UK-born or long-term immigrants with the UK-born (RCR: 1.8 (95% CI: 1.1-2.4) and 1.6 (95% CI: 1.2-1.9) respectively). CONCLUSIONS: This study is the first to consider "who clusters with whom" in a high incidence area in England, laying the foundation for future whole-genome sequencing work. The higher than expected clustering seen here suggests that preferential mixing between some age, ethnic and immigrant groups occurs; prioritising contact tracing to groups with which cases are most likely to cluster retrospectively could improve TB control.

Positively interacting strains that co-circulate within a network structured population induce cycling epidemics of Mycoplasma pneumoniae.

Mycoplasma pneumoniae (MP) is considered a common cause of pneumonia, causing about 15-20% of adult community-acquired pneumonia (CAP) and up to 40% of cases in children. It has often been observed that MP epidemics last approximately 1-2 years and occur every 3-7 years, with the dominant strains alternating between epidemics. However, the underlying mechanism by which these cycles and changes in the dominant strains occur remains unclear. The traditional models for the periodicity of MP epidemics neglected two phenomena: structured contact patterns among people and co-circulating strains of MP. We also believe that the two distinctive aspects of MP epidemics: prevalent serotype shifts among epidemics and incidence cycling of MP, are interconnected. We propose a network transmission model that assumes two strains of MP are transmitted within a network structured population and they can interact as secondary infections with primary infections. Our studies show that multiple strains that co-circulate within a network structured population and interact positively generate the observed patterns of recurrent epidemics of MP. Hence our study provides a possible mechanism for the cycling epidemics of MP, and could provide useful information for future vaccine design and vaccine evaluation/monitoring processes.

The impact of Measles-Rubella vaccination on the morbidity and mortality from Congenital Rubella Syndrome in 92 countries.

Since 2011, GAVI, The Vaccine Alliance, has funded eligible countries to introduce rubella-containing vaccination (RCV) into their national schedule. Two key indicators used to monitor the impact - the future deaths and DALYs (Disability Adjusted Life Years) averted through vaccination conducted in specific periods - are poorly understood for rubella and Congenital Rubella Syndrome (CRS). We calculate these indicators using an age-structured dynamic transmission model for rubella, with historical vaccination coverage projections during 2001-30 in 92 low and middle-income countries considered most likely to require global support to achieve the Global Vaccine Action Plan's objectives. 131,000 CRS deaths and 12.5 million DALYs may be prevented with immunization campaigns at best-estimate coverage during 2001-30, relative to those without additional support. The impact depended on the time period considered and the method for attributing deaths averted to vaccination in specific periods. The analyses support ongoing activities to reduce CRS-related morbidity and mortality.

Should NICE reconsider the 2016 UK guidelines on TB contact tracing? A cost-effectiveness analysis of contact investigations in London.

BACKGROUND: In January 2016, clinical TB guidance in the UK changed to no longer recommend screening contacts of non-pulmonary, non-laryngeal (ETB) index cases. However, no new evidence was cited for this change, and there is evidence that screening these contacts may be worthwhile. The objective of this study was to estimate the cost-effectiveness of screening contacts of adult ETB cases and adult pulmonary or laryngeal TB (PTB) cases in London, UK. METHODS: We carried out a cross-sectional analysis of data collected on TB index cases and contacts in the London TB register and an economic evaluation using a static model describing contact tracing outcomes. Incremental cost-effectiveness ratios (ICERs) were calculated using no screening as the baseline comparator. All adult TB cases (≥15 years old) in London from 2012 to 2015, and their contacts, were eligible (2465/5084 PTB and 2559/6090 ETB index cases were included). RESULTS: Assuming each contact with PTB infects one person/month, the ICER of screening contacts of ETB cases was £78 000/quality-adjusted life-years (QALY) (95% CI 39 000 to 140 000), and screening contacts of PTB cases was £30 000/QALY (95% CI 18 000 to 50 000). The ICER of screening contacts of ETB cases was £30 000/QALY if each contact with PTB infects 3.4 people/month. Limitations of this study include the use of self-reported symptomatic periods and lack of knowledge about onward transmission from PTB contacts. CONCLUSIONS: Screening contacts of ETB cases in London was almost certainly not cost-effective at any conventional willingness-to-pay threshold in England, supporting recent changes to National Institute for Health and Care Excellence national guidelines.

Transmission events revealed in tuberculosis contact investigations in London.

Contact tracing is a key part of tuberculosis prevention and care, aiming to hasten diagnosis and prevent transmission. The proportion of case-contact pairs for which recent transmission occurred and the typical timespans between the index case and their contact accessing care are not known; we aimed to calculate these. We analysed individual-level TB contact tracing data, collected in London from 20/01/2011-31/12/2015, linked to tuberculosis surveillance and MIRU-VNTR 24-locus strain-typing information. Of pairs of index cases and contacts diagnosed with active tuberculosis, 85/314 (27%) had strain typing data available for both. Of these pairs, 79% (67/85) shared indistinguishable isolates, implying probable recent transmission. Of pairs in which both contact and the index case had a social risk factor, 11/11 (100%) shared indistinguishable isolates, compared to 55/75 (75%) of pairs in which neither had a social risk factor (P = 0.06). The median time interval between the index case and their contact accessing care was 42 days (IQR: 16, 96). As over 20% of pairs did probably not involve recent transmission between index case and contact, the effectiveness of contact tracing is not necessarily limited to those circumstances where the index case has transmitted disease to their close contacts.

Evaluation of nationwide supplementary immunization in Lao People's Democratic Republic: Population-based seroprevalence survey of anti-measles and anti-rubella IgG in children and adults, mathematical modelling and a stability testing of the vaccine.

BACKGROUND: Measles outbreaks have occurred in some countries despite supplementary immunization activities (SIA) using measles-containing vaccine with high vaccination coverage. We conducted a cross-sectional seroprevalence survey to estimate population immunity in Lao People's Democratic Republic where repeated mass immunization has failed to eliminate measles. METHODS AND FINDINGS: In this nationwide multistage cluster sampling survey conducted in 2014 based on probability proportionate to size sampling, blood samples were collected from 2,135 children and adults living in 52 randomly selected villages. Anti-measles and anti-rubella IgG were measured, and IgG prevalence was calculated. We applied mathematical modelling to estimate the number of cases of congenital rubella syndrome (CRS) in 2013 that were averted by the 2011 SIA. A stability testing was applied to the MR vaccine at 4°C, 25°C, and 35°C to examine stability differences between measles and rubella vaccine components. Measles IgG prevalence was significantly lower in the target age groups (5-21 years) of the 2011 SIA using a combination vaccine for measles and rubella vaccine (MR vaccine) than in young adults (22-39 years) (86.8% [95% CI: 83.0-90.6] vs. 99.0% [98.3-99.8]; p<0.001), whereas rubella IgG prevalence was significantly higher (88.2% [84.5-91.8] vs. 74.6% [70.7-78.5]; p<0.001). In the SIA target age groups, prevalence of measles IgG, but not rubella IgG, increased with age. CRS cases prevented in 2013 ranged from 16 [0-50] to 92 [32-180] if the force of infection had remained unchanged or had been reduced by 75%, respectively. In freeze-dried conditions, the measles vaccine component was more heat sensitive than the rubella component. CONCLUSIONS: Inconsistent IgG prevalence between measles and rubella in Lao PDR can be partly explained by different stability of the measles and rubella vaccine components under heat exposure. Suboptimal vaccine handling may cause insufficient immunogenicity for measles, which subsequently leads to an outbreak despite high SIA coverage, while direct evidence is lacking. Temperature monitoring of the vaccine should be conducted.

The duration of protection of school-aged BCG vaccination in England: a population-based case-control study.

Background: Evidence of protection from childhood Bacillus Calmette-Guerin (BCG) against tuberculosis (TB) in adulthood, when most transmission occurs, is important for TB control and resource allocation. Methods: We conducted a population-based case-control study of protection by BCG given to children aged 12-13 years against tuberculosis occurring 10-29 years later. We recruited UK-born White subjects with tuberculosis and randomly sampled White community controls. Hazard ratios and 95% confidence intervals (CIs) were estimated using case-cohort Cox regression, adjusting for potential confounding factors, including socio-economic status, smoking, drug use, prison and homelessness. Vaccine effectiveness (VE = 1 - hazard ratio) was assessed at successive intervals more than 10 years following vaccination. Results: We obtained 677 cases and 1170 controls after a 65% response rate in both groups. Confounding by deprivation, education and lifestyle factors was slight 10-20 years after vaccination, and more evident after 20 years. VE 10-15 years after vaccination was 51% (95% CI 21, 69%) and 57% (CI 33, 72%) at 15-20 years. Subsequently, BCG protection appeared to wane; 20-25 years VE = 25% (CI -14%, 51%) and 25-29 years VE = 1% (CI -84%, 47%). Based on multiple imputation of missing data (in 17% subjects), VE estimated in the same intervals after vaccination were similar [56% (CI 33, 72%), 57% (CI 36, 71%), 25% (-10, 48%), 21% (-39, 55%)]. Conclusions: School-aged BCG vaccination offered moderate protection against tuberculosis for at least 20 years, which is longer than previously thought. This has implications for assessing the cost-effectiveness of BCG vaccination and when evaluating new TB vaccines.