Vaccination strategies for measles control and elimination: time to strengthen local initiatives.

BACKGROUND: Through a combination of strong routine immunization (RI), strategic supplemental immunization activities (SIA) and robust surveillance, numerous countries have been able to approach or achieve measles elimination. The fragility of these achievements has been shown, however, by the resurgence of measles since 2016. We describe trends in routine measles vaccine coverage at national and district level, SIA performance and demographic changes in the three regions with the highest measles burden. FINDINGS: WHO-UNICEF estimates of immunization coverage show that global coverage of the first dose of measles vaccine has stabilized at 85% from 2015 to 19. In 2000, 17 countries in the WHO African and Eastern Mediterranean regions had measles vaccine coverage below 50%, and although all increased coverage by 2019, at a median of 60%, it remained far below levels needed for elimination. Geospatial estimates show many low coverage districts across Africa and much of the Eastern Mediterranean and southeast Asian regions. A large proportion of children unvaccinated for MCV live in conflict-affected areas with remote rural areas and some urban areas also at risk. Countries with low RI coverage use SIAs frequently, yet the ideal timing and target age range for SIAs vary within countries, and the impact of SIAs has often been mitigated by delays or disruptions. SIAs have not been sufficient to achieve or sustain measles elimination in the countries with weakest routine systems. Demographic changes also affect measles transmission, and their variation between and within countries should be incorporated into strategic planning. CONCLUSIONS: Rebuilding services after the COVID-19 pandemic provides a need and an opportunity to increase community engagement in planning and monitoring services. A broader suite of interventions is needed beyond SIAs. Improved methods for tracking coverage at the individual and community level are needed together with enhanced surveillance. Decision-making needs to be decentralized to develop locally-driven, sustainable strategies for measles control and elimination.

Using models to shape measles control and elimination strategies in low- and middle-income countries: A review of recent applications.

After many decades of vaccination, measles epidemiology varies greatly between and within countries. National immunization programs are therefore encouraged to conduct regular situation analyses and to leverage models to adapt interventions to local needs. Here, we review applications of models to develop locally tailored interventions to support control and elimination efforts. In general, statistical and semi-mechanistic transmission models can be used to synthesize information from vaccination coverage, measles incidence, demographic, and/or serological data, offering a means to estimate the spatial and age-specific distribution of measles susceptibility. These estimates complete the picture provided by vaccination coverage alone, by accounting for natural immunity. Dynamic transmission models can then be used to evaluate the relative impact of candidate interventions for measles control and elimination and the expected future epidemiology. In most countries, models predict substantial numbers of susceptible individuals outside the age range of routine vaccination, which affects outbreak risk and necessitates additional intervention to achieve elimination. More effective use of models to inform both vaccination program planning and evaluation requires the development of training to enhance broader understanding of models and where feasible, building capacity for modelling in-country, pipelines for rapid evaluation of model predictions using surveillance data, and clear protocols for incorporating model results into decision-making.

Context matters: using reinforcement learning to develop human-readable, state-dependent outbreak response policies.

The number of all possible epidemics of a given infectious disease that could occur on a given landscape is large for systems of real-world complexity. Furthermore, there is no guarantee that the control actions that are optimal, on average, over all possible epidemics are also best for each possible epidemic. Reinforcement learning (RL) and Monte Carlo control have been used to develop machine-readable context-dependent solutions for complex problems with many possible realizations ranging from video-games to the game of Go. RL could be a valuable tool to generate context-dependent policies for outbreak response, though translating the resulting policies into simple rules that can be read and interpreted by human decision-makers remains a challenge. Here we illustrate the application of RL to the development of context-dependent outbreak response policies to minimize outbreaks of foot-and-mouth disease. We show that control based on the resulting context-dependent policies, which adapt interventions to the specific outbreak, result in smaller outbreaks than static policies. We further illustrate two approaches for translating the complex machine-readable policies into simple heuristics that can be evaluated by human decision-makers. This article is part of the theme issue 'Modelling infectious disease outbreaks in humans, animals and plants: epidemic forecasting and control'. This theme issue is linked with the earlier issue 'Modelling infectious disease outbreaks in humans, animals and plants: approaches and important themes'.

A spatial regression model for the disaggregation of areal unit based data to high-resolution grids with application to vaccination coverage mapping.

The growing demand for spatially detailed data to advance the Sustainable Development Goals agenda of 'leaving no one behind' has resulted in a shift in focus from aggregate national and province-based metrics to small areas and high-resolution grids in the health and development arena. Vaccination coverage is customarily measured through aggregate-level statistics, which mask fine-scale heterogeneities and 'coldspots' of low coverage. This paper develops a methodology for high-resolution mapping of vaccination coverage using areal data in settings where point-referenced survey data are inaccessible. The proposed methodology is a binomial spatial regression model with a logit link and a combination of covariate data and random effects modelling two levels of spatial autocorrelation in the linear predictor. The principal aspect of the model is the melding of the misaligned areal data and the prediction grid points using the regression component and each of the conditional autoregressive and the Gaussian spatial process random effects. The Bayesian model is fitted using the INLA-SPDE approach. We demonstrate the predictive ability of the model using simulated data sets. The results obtained indicate a good predictive performance by the model, with correlations of between 0.66 and 0.98 obtained at the grid level between true and predicted values. The methodology is applied to predicting the coverage of measles and diphtheria-tetanus-pertussis vaccinations at 5 × 5 km2 in Afghanistan and Pakistan using subnational Demographic and Health Surveys data. The predicted maps are used to highlight vaccination coldspots and assess progress towards coverage targets to facilitate the implementation of more geographically precise interventions. The proposed methodology can be readily applied to wider disaggregation problems in related contexts, including mapping other health and development indicators.

Correlation between measles vaccine doses: implications for the maintenance of elimination.

Measles eradication efforts have been successful at achieving elimination in many countries worldwide. Such countries actively work to maintain this elimination by continuing to improve coverage of two routine doses of measles vaccine following measles elimination. While improving measles vaccine coverage is always beneficial, we show, using a steady-state analysis of a dynamical model, that the correlation between populations receiving the first and second routine dose also has a significant impact on the population immunity achieved by a specified combination of first and second dose coverage. If the second dose is administered to people independently of whether they had the first dose, high second-dose coverage improves the proportion of the population receiving at least one dose, and will have a large effect on population immunity. If the second dose is administered only to people who have had the first dose, high second-dose coverage reduces the rate of primary vaccine failure, but does not reach people who missed the first dose; this will therefore have a relatively small effect on population immunity. When doses are administered dependently, and assuming the first dose has higher coverage, increasing the coverage of the first dose has a larger impact on population immunity than does increasing the coverage of the second. Correlation between vaccine doses has a significant impact on the level of population immunity maintained by current vaccination coverage, potentially outweighing the effects of age structure and, in some cases, recent improvements in vaccine coverage. It is therefore important to understand the correlation between vaccine doses as such correlation may have a large impact on the effectiveness of measles vaccination strategies.

Age-specific mixing generates transient outbreak risk following critical-level vaccination.

Measles elimination goals have been adopted in a range of countries, sub-regions, and regions since the WHO declared an elimination goal by 2015 or 2020. All countries attempt to achieve and maintain high coverage through routine immunization programmes. This routine strategy, however, does not ensure the elimination goal of measles. Many developed countries, such as the United States, that have succeeded in interrupting measles transmission earlier, are now experiencing outbreaks with an increasing number of cases. Using a stochastic, age-structured model of measles vaccination dynamics, we explore and characterize the transient dynamics of measles susceptibility in the years following the implementation of routine vaccination at the herd immunity threshold. We demonstrate how a population could face risks of potentially large outbreaks even within few years of vaccination. We characterize different risk profiles depending on the incidence pattern in the years prior to vaccination. These results suggest that the classic critical vaccination threshold is necessary to achieve herd immunity, but not sufficient to prevent long periods of transient, super-critical dynamics. Our results suggest the need of future work for more careful monitoring of the impacts of current immunization programmes, and developing models that take into account more complicated vaccination strategies, demographic factors, and population movements.

Optimal vaccine schedules to maintain measles elimination with a two-dose routine policy.

Measles was eliminated in the Americas in 2002 by a combination of routine immunizations and supplementary immunization activities. Recent outbreaks underscore the importance of reconsidering vaccine policy in order to maintain elimination. We constructed an age-structured dynamical model for the distribution of immunity in a population with routine immunization and without disease, and analysed the steady state for an idealized age structure and for real age structures of countries in the Americas. We compared the level of immunity maintained by current policy in these countries to the level maintainable by an optimal policy. The optimal age target for the first routine dose of measles vaccine depends on the timing and coverage of both doses. Similarly, the optimal age target for the second dose of measles vaccine depends on the timing and coverage of the first dose. The age targets for the first and second doses of measles vaccine should be adjusted for the post-elimination era, by specifically accounting for current context, including realized coverage of both doses, and altered maternal immunity. Doing so can greatly improve the proportion immune within a population, and therefore the chances of maintaining measles elimination, without changing coverage.

The effects of maternal immunity and age structure on population immunity to measles.

Measles was successfully eradicated in the Pan-American Health Region in 2002. However, maintenance of elimination in parts of Africa, Europe, the USA, and other regions is proving difficult, despite apparently high vaccine coverage. This may be due to the different age structure in developed and developing populations, as well as to differences in the duration of maternal immunity. We explore the interaction between maternal immunity and age structure and quantify the resulting immunity gap between vaccine coverage and population immunity; we use this immunity gap as a novel metric of vaccine program success as it highlights the difference between actual and estimated immunity. We find that, for some combinations of maternal immunity and age structure, the accepted herd immunity threshold is not maintainable with a single-dose vaccine strategy for any combination of target age and coverage. In all cases, the herd immunity threshold is more difficult to maintain in a population with developing age structure. True population immunity is always improved if the target age at vaccination is chosen for the specific combination of maternal immunity and age structure.

Transgenic Virus Resistance in Crop-Wild Cucurbita pepo Does Not Prevent Vertical Transmission of Zucchini yellow mosaic virus.

Zucchini yellow mosaic virus (ZYMV) is an economically important pathogen of cucurbits that is transmitted both horizontally and vertically. Although ZYMV is seed-transmitted in Cucurbita pepo, the potential for seed transmission in virus-resistant transgenic cultivars is not known. We crossed and backcrossed a transgenic squash cultivar with wild C. pepo, and determined whether seed-to-seedling transmission of ZYMV was possible in seeds harvested from transgenic backcrossed C. pepo. We then compared these transmission rates to those of non-transgenic (backcrossed and wild) C. pepo. The overall seed-to-seedling transmission rate in ZYMV was similar to those found in previous studies (1.37%), with no significant difference between transgenic backcrossed (2.48%) and non-transgenic (1.03%) backcrossed and wild squash. Fewer transgenic backcrossed plants had symptom development (7%) in comparison with all non-transgenic plants (26%) and may be instrumental in preventing yield reduction due to ZYMV. Our study shows that ZYMV is seed transmitted in transgenic backcrossed squash, which may affect the spread of ZYMV via the movement of ZYMV-infected seeds. Deep genome sequencing of the seed-transmitted viral populations revealed that 23% of the variants found in this study were present in other vertically transmitted ZYMV populations, suggesting that these variants may be necessary for seed transmission or are distributed geographically via seeds.

Think globally, act locally: the role of local demographics and vaccination coverage in the dynamic response of measles infection to control.

The global reduction of the burden of morbidity and mortality owing to measles has been a major triumph of public health. However, the continued persistence of measles infection probably not only reflects local variation in progress towards vaccination target goals, but may also reflect local variation in dynamic processes of transmission, susceptible replenishment through births and stochastic local extinction. Dynamic models predict that vaccination should increase the mean age of infection and increase inter-annual variability in incidence. Through a comparative approach, we assess national-level patterns in the mean age of infection and measles persistence. We find that while the classic predictions do hold in general, the impact of vaccination on the age distribution of cases and stochastic fadeout are mediated by local birth rate. Thus, broad-scale vaccine coverage goals are unlikely to have the same impact on the interruption of measles transmission in all demographic settings. Indeed, these results suggest that the achievement of further measles reduction or elimination goals is likely to require programmatic and vaccine coverage goals that are tailored to local demographic conditions.

Spatial dynamics of meningococcal meningitis in Niger: observed patterns in comparison with measles.

Throughout the African meningitis belt, meningococcal meningitis outbreaks occur only during the dry season. Measles in Niger exhibits similar seasonality, where increased population density during the dry season probably escalates measles transmission. Because meningococcal meningitis and measles are both directly transmitted, we propose that host aggregation also impacts the transmission of meningococcal meningitis. Although climate affects broad meningococcal meningitis seasonality, we focus on the less examined role of human density at a finer spatial scale. By analysing spatial patterns of suspected cases of meningococcal meningitis, we show fewer absences of suspected cases in districts along primary roads, similar to measles fadeouts in the same Nigerien metapopulation. We further show that, following periods during no suspected cases, districts with high reappearance rates of meningococcal meningitis also have high measles reintroduction rates. Despite many biological and epidemiological differences, similar seasonal and spatial patterns emerge from the dynamics of both diseases. This analysis enhances our understanding of spatial patterns and disease transmission and suggests hotspots for infection and potential target areas for meningococcal meningitis surveillance and intervention.

Explaining seasonal fluctuations of measles in Niger using nighttime lights imagery.

Measles epidemics in West Africa cause a significant proportion of vaccine-preventable childhood mortality. Epidemics are strongly seasonal, but the drivers of these fluctuations are poorly understood, which limits the predictability of outbreaks and the dynamic response to immunization. We show that measles seasonality can be explained by spatiotemporal changes in population density, which we measure by quantifying anthropogenic light from satellite imagery. We find that measles transmission and population density are highly correlated for three cities in Niger. With dynamic epidemic models, we demonstrate that measures of population density are essential for predicting epidemic progression at the city level and improving intervention strategies. In addition to epidemiological applications, the ability to measure fine-scale changes in population density has implications for public health, crisis management, and economic development.

The epidemiology of rubella in Mexico: seasonality, stochasticity and regional variation.

The factors underlying the temporal dynamics of rubella outside of Europe and North America are not well known. Here we used 20 years of incidence reports from Mexico to identify variation in seasonal forcing and magnitude of transmission across the country and to explore determinants of inter-annual variability in epidemic magnitude in rubella. We found considerable regional variation in both magnitude of transmission and amplitude of seasonal variation in transmission. Several lines of evidence pointed to stochastic dynamics as an important driver of multi-annual cycles. Since average age of infection increased with the relative importance of stochastic dynamics, this conclusion has implications for the burden of congenital rubella syndrome. We discuss factors underlying regional variation, and implications of the importance of stochasticity for vaccination implementation.

Measles hotspots and epidemiological connectivity.

Though largely controlled in developed countries, measles remains a major global public health issue. Regional and local transmission patterns are rooted in human mixing behaviour across spatial scales. Identifying spatial interactions that contribute to recurring epidemics helps define and predict outbreak patterns. Using spatially explicit reported cases from measles outbreaks in Niger, we explored how regional variations in movement and contact patterns relate to patterns of measles incidence. Because we expected to see lower rates of re-introductions in small, compared to large, populations, we measured the population-size corrected proportion of weeks with zero cases across districts to understand relative rates of measles re-introductions. We found that critical elements of spatial disease dynamics in Niger are agricultural seasonality, transnational contact clusters, and roads networks that facilitate host movement and connectivity. These results highlight the need to understand local patterns of seasonality, demographic characteristics, and spatial heterogeneities to inform vaccination policy.

Episodic outbreaks bias estimates of age-specific force of infection: a corrected method using measles as an example.

Understanding age-specific differences in infection rates can be important in predicting the magnitude of and mortality in outbreaks and targeting age groups for vaccination programmes. Standard methods to estimate age-specific rates assume that the age-specific force of infection is constant in time. However, this assumption may easily be violated in the face of a highly variable outbreak history, as recently observed for acute immunizing infections like measles, in strongly seasonal settings. Here we investigate the biases that result from ignoring such fluctuations in incidence and present a correction based on the epidemic history. We apply the method to data from a measles outbreak in Niamey, Niger and show that, despite a bimodal age distribution of cases, the estimated age-specific force of infection is unimodal and concentrated in young children (<5 years) consistent with previous analyses of age-specific rates in the region.

Time is of the essence: exploring a measles outbreak response vaccination in Niamey, Niger.

The current World Health Organization recommendations for response during measles epidemics focus on case management rather than outbreak response vaccination (ORV) campaigns, which may occur too late to impact morbidity and mortality and have a high cost per case prevented. Here, we explore the potential impact of an ORV campaign conducted during the 2003-2004 measles epidemic in Niamey, Niger. We measured the impact of this intervention and also the potential impact of alternative strategies. Using a unique geographical, epidemiologic and demographic dataset collected during the epidemic, we developed an individual-based simulation model. We estimate that a median of 7.6% [4.9-8.9] of cases were potentially averted as a result of the outbreak response, which vaccinated approximately 57% (84563 of an estimated 148600) of children in the target age range (6-59 months), 23 weeks after the epidemic started. We found that intervening early (up to 60 days after the start of the epidemic) and expanding the age range to all children aged 6 months to 15 years may lead to a much larger (up to 90%) reduction in the number of cases in a West African urban setting like Niamey. Our results suggest that intervening earlier even with lower target coverage (approx. 60%), but a wider age range, may be more effective than intervening later with high coverage (more than 90%) in similar settings. This has important implications for the implementation of reactive vaccination interventions as they can be highly effective if the response is fast with respect to the spread of the epidemic.

Estimating transmission intensity for a measles epidemic in Niamey, Niger: lessons for intervention.

The objective of this study is to estimate the effective reproductive ratio for the 2003-2004 measles epidemic in Niamey, Niger. Using the results of a retrospective and prospective study of reported cases within Niamey during the 2003-2004 epidemic, we estimate the basic reproductive ratio, effective reproductive ratio (RE) and minimal vaccination coverage necessary to avert future epidemics using a recent method allowing for estimation based on the epidemic case series. We provide these estimates for geographic areas within Niamey, thereby identifying neighbourhoods at high risk. The estimated citywide RE was 2.8, considerably lower than previous estimates, which may help explain the long duration of the epidemic. Transmission intensity varied during the course of the epidemic and within different neighbourhoods (RE range: 1.4-4.7). Our results indicate that vaccination coverage in currently susceptible children should be increased by at least 67% (vaccine efficacy 90%) to produce a citywide vaccine coverage of 90%. This research highlights the importance of local differences in vaccination coverage on the potential impact of epidemic control measures. The spatial-temporal spread of the epidemic from district to district in Niamey over 30 weeks suggests that targeted interventions within the city could have an impact.

Seroepidemiology of infection with hepatitis A virus and hepatitis B virus in the Seychelles.

A batch of 417 serum samples obtained from native-born subjects were tested for the presence of hepatitis B surface antigen (HBsAg) and corresponding antibody (anti-HBs), by enzyme-linked immunosorbent assay (ELISA); and antibodies to hepatitis B core antigen (anti-HBc), e-antigen (anti-HBe), and hepatitis A virus (anti-HAV), by radioimmunoassay (RIA). HBsAg was found in only two of the 417 subjects studied. Anti-HBs was detected in 112 samples (26.8%), anti-HBc in 114 (27.3%) and anti-HBe in 31 samples (7.4%). Serologic evidence of a previous or present infection by hepatitis B virus (HBV) was found in 34.5% of the samples studied. Males showed a greater prevalence of anti-HBs and anti-HBc, while anti-HBe was more common in females; however, these differences were not significant. With regard to age, a significantly higher prevalence of anti-HBs (p less than 0.05), anti-HBc (p less than 0.025) and anti-HBe (p less than 0.025) was found in the older age groups. Anti-HAV antibodies were present in 90% of the subjects studied, with no variation between the sexes. The anti-HAV rate in the group under 20 years was similar to that found in the older age groups. The total infection rate of hepatitis B virus in the Seychelles is lower than in other tropical areas, HBs antigen/antibody ratio approaching that in temperate areas. Elucidation of the reasons for the low prevalence of hepatitis B virus carriers among the Sevchelles population requires further investigation.