Validation of the Micronutrient and Environmental Enteric Dysfunction Assessment Tool and evaluation of biomarker risk factors for growth faltering and vaccine failure in young Malian children.

Environmental enteric dysfunction (EED) is an intestinal disorder common among children in low-resource settings and is associated with increased risk of growth stunting, cognitive deficits, and reduced oral vaccine immunogenicity. The Micronutrient and EED Assessment Tool (MEEDAT) is a multiplexed immunoassay that measures biomarkers previously associated with child growth faltering and/or oral vaccine immunogenicity: intestinal fatty acid-binding protein (I-FABP), soluble CD14 (sCD14), insulin-like growth factor 1 (IGF-1), and fibroblast growth factor 21 (FGF21). MEEDAT also measures systemic inflammation (α1-acid glycoprotein, C-reactive protein), ferritin, soluble transferrin receptor, retinol binding protein 4, thyroglobulin, and Plasmodium falciparum antigenemia (histidine-rich protein 2). The performance of MEEDAT was compared with commercially available enzyme-linked immunosorbent assays (ELISAs) using 300 specimens from Malian infant clinical trial participants. Regression methods were used to test if MEEDAT biomarkers were associated with seroconversion to meningococcal A conjugate vaccine (MenAV), yellow fever vaccine (YFV), and pentavalent rotavirus vaccine (PRV) after 28 days, or with growth faltering over 12 weeks. The Pearson correlations between the MEEDAT and ELISA results were 0.97, 0.86, 0.80, and 0.97 for serum I-FABP, sCD14, IGF-1, and FGF21, respectively. There were significant associations between I-FABP concentration and the probability of PRV IgG seroconversion and between IGF-1 concentration and the probability of YFV seroconversion. In multivariable models neither association remained significant, however there was a significant negative association between AGP concentration and YFV seroconversion. GLP-2 and sCD14 concentrations were significantly negatively associated with 12-week change in weight-for-age z-score and weight-for-height z-score in multivariable models. MEEDAT performed well in comparison to commercially-available ELISAs for the measurement of four analytes for EED and growth hormone resistance. Adoption of MEEDAT in low-resource settings could help accelerate the identification of interventions that prevent or treat child stunting and interventions that boost the immunogenicity of child vaccinations.

Eliminating yellow fever epidemics in Africa: Vaccine demand forecast and impact modelling.

BACKGROUND: To counter the increasing global risk of Yellow fever (YF), the World Health Organisation initiated the Eliminate Yellow fever Epidemics (EYE) strategy. Estimating YF burden, as well as vaccine impact, while accounting for the features of urban YF transmission such as indirect benefits of vaccination, is key to informing this strategy. METHODS AND FINDINGS: We developed two model variants to estimate YF burden in sub-Saharan Africa, assuming all infections stem from either the sylvatic or the urban cycle of the disease. Both relied on an ecological niche model fitted to the local presence of any YF reported event in 34 African countries. We calibrated under-reporting using independent estimates of transmission intensity provided by 12 serological surveys performed in 11 countries. We calculated local numbers of YF infections, deaths and disability-adjusted life years (DALYs) lost based on estimated transmission intensity while accounting for time-varying vaccination coverage. We estimated vaccine demand and impact of future preventive mass vaccination campaigns (PMVCs) according to various vaccination scenarios. Vaccination activities conducted in Africa between 2005 and 2017 were estimated to prevent from 3.3 (95% CI 1.2-7.7) to 6.1 (95% CI 2.4-13.2) millions of deaths over the lifetime of vaccinees, representing extreme scenarios of none or maximal herd effects, respectively. By prioritizing provinces based on the risk of urban YF transmission in future PMVCs, an average of 37.7 million annual doses for PMVCs over eight years would avert an estimated 9,900,000 (95% CI 7,000,000-13,400,000) infections and 480,000 (180,000-1,140,000) deaths over the lifetime of vaccinees, corresponding to 1.7 (0.7-4.1) deaths averted per 1,000 vaccine doses. CONCLUSIONS: By estimating YF burden and vaccine impact over a range of spatial and temporal scales, while accounting for the specificity of urban transmission, our model can be used to inform the current EYE strategy.

Differences between coverage of yellow fever vaccine and the first dose of measles-containing vaccine: A desk review of global data sources.

INTRODUCTION: The strategy to Eliminate Yellow Fever Epidemics (EYE) is a global initiative that includes all countries with risk of yellow fever (YF) virus transmission. Of these, 40 countries (27 in Africa and 13 in the Americas) are considered high-risk and targeted for interventions to increase coverage of YF vaccine. Even though the World Health Organization (WHO) recommends that YF vaccine be given concurrently with the first dose of measles-containing vaccine (MCV1) in YF-endemic settings, estimated coverage for MCV1 and YF vaccine have varied widely. The objective of this study was to review global data sources to assess discrepancies in YF vaccine and MCV1 coverage and identify plausible reasons for these discrepancies. METHODS: We conducted a desk review of data from 34 countries (22 in Africa, 12 in Latin America), from 2006 to 2016, with national introduction of YF vaccine and listed as high-risk by the EYE strategy. Data reviewed included procured and administered doses, immunization schedules, routine coverage estimates and reported vaccine stock-outs. In the 30 countries included in the comparitive analysis, differences greater than 3 percentage points between YF vaccine and MCV1 coverage were considered meaningful. RESULTS: In America, there were meaningful differences (7-45%) in coverage of the two vaccines in 6 (67%) of the 9 countries. In Africa, there were meaningful differences (4-27%) in coverage of the two vaccines in 9 (43%) of the 21 countries. Nine countries (26%) reported MVC1 stock-outs while sixteen countries (47%) reported YF vaccine stock-outs for three or more years during 2006-2016. CONCLUSION: In countries reporting significant differences in coverage of the two vaccines, differences may be driven by different target populations and vaccine availability. However,these were not sufficient to completely explain observed differences. Further follow-up is needed to identify possible reasons for differences in coverage rates in several countries where these could not fully be explained.

Serologic assessment of yellow fever immunity in the rural population of a yellow fever-endemic area in Central Brazil.

INTRODUCTION: The yellow fever epidemic that occurred in 1972/73 in Central Brazil surprised the majority of the population unprotected. A clinical-epidemiological survey conducted at that time in the rural area of 19 municipalities found that the highest (13.8%) number of disease cases were present in the municipality of Luziânia, State of Goiás. METHODS: Thirty-eight years later, a new seroepidemiological survey was conducted with the aim of assessing the degree of immune protection of the rural population of Luziânia, following the continuous attempts of public health services to obtain vaccination coverage in the region. A total of 383 volunteers, aged between 5 and 89 years and with predominant rural labor activities (75.5%), were interviewed. The presence of antibodies against the yellow fever was also investigated in these individuals, by using plaque reduction neutralization test, and correlated to information regarding residency, occupation, epidemiological data and immunity against the yellow fever virus. RESULTS: We found a high (97.6%) frequency of protective titers (>1:10) of neutralizing antibodies against the yellow fever virus; the frequency of titers of 1:640 or higher was 23.2%, indicating wide immune protection against the disease in the study population. The presence of protective immunity was correlated to increasing age. CONCLUSIONS: This study reinforces the importance of surveys to address the immune state of a population at risk for yellow fever infection and to the surveillance of actions to control the disease in endemic areas.

Serologic assessment of yellow fever immunity in the rural population of a yellow fever-endemic area in Central Brazil

Introduction The yellow fever epidemic that occurred in 1972/73 in Central Brazil surprised the majority of the population unprotected. A clinical-epidemiological survey conducted at that time in the rural area of 19 municipalities found that the highest (13.8%) number of disease cases were present in the municipality of Luziânia, State of Goiás. Methods Thirty-eight years later, a new seroepidemiological survey was conducted with the aim of assessing the degree of immune protection of the rural population of Luziânia, following the continuous attempts of public health services to obtain vaccination coverage in the region. A total of 383 volunteers, aged between 5 and 89 years and with predominant rural labor activities (75.5%), were interviewed. The presence of antibodies against the yellow fever was also investigated in these individuals, by using plaque reduction neutralization test, and correlated to information regarding residency, occupation, epidemiological data and immunity against the yellow fever virus. Results We found a high (97.6%) frequency of protective titers (>1:10) of neutralizing antibodies against the yellow fever virus; the frequency of titers of 1:640 or higher was 23.2%, indicating wide immune protection against the disease in the study population. The presence of protective immunity was correlated to increasing age. Conclusions This study reinforces the importance of surveys to address the immune state of a population at risk for yellow fever infection and to the surveillance of actions to control the disease in endemic areas. .

Is it time for a new yellow fever vaccine?

An inexpensive live attenuated vaccine (the 17D vaccine) against yellow fever has been effectively used to prevent yellow fever for more than 70 years. Interest in developing new inactivated vaccines has been spurred by recognition of rare but serious, sometimes fatal adverse events following live virus vaccination. A safer inactivated yellow fever vaccine could be useful for vaccinating people at higher risk of adverse events from the live vaccine, but could also have broader global health utility by lowering the risk-benefit threshold for assuring high levels of yellow fever vaccine coverage. If ongoing trials demonstrate favorable immunogenicity and safety compared to the current vaccine, the practical global health utility of an inactivated vaccine is likely to be determined mostly by cost.