Performance assessment and validation of a plaque reduction neutralization test (PRNT) in support to yellow fever diagnostic and vaccine clinical trials.

Yellow fever (YF) virus is a mosquito-borne virus belonging to the Flaviviridae family that circulates in tropical and subtropical areas of Africa and South America. Despite the availability of an effective vaccine, YF remains a threat to travelers, residents of endemic areas, and unvaccinated populations. YF vaccination and natural infection both induce the production of neutralizing antibodies. Serological diagnostic methods detecting YF virus-specific antibodies demonstrate high levels of cross-reactivities with other flaviviruses. To date, the plaque reduction neutralization test (PRNT) is the most specific serological test for the differentiation of flavivirus infections and is considered the reference method for detecting YF neutralizing antibodies and assessing the protective immune response following vaccination. In this study, we developed and validated a YF PRNT. We optimized different parameters including cell concentration and virus-serum neutralization time period and then assessed the intra- and inter-assay precisions, dilutability, specificity, and lower limit of quantification (LLOQ) using international standard YF serum, sera from vaccinees and human specimens collected through YF surveillance. The YF PRNT has shown good robustness and 100% of intra-assay precision, 95.6% of inter-assay precision, 100% of specificity, 100% of LLOQ, and 95.3% of dilutability. The test is, therefore, suitable for use in the YF diagnostic as well as evaluation of the YF vaccine neutralizing antibody response and risk assessment studies.

Inmunización en las Américas. Resumen 2021

Los países de las Américas, con apoyo de la Organización Panamericana de la Salud (OPS), han logrado avances notables al proporcionar a los niños y las niñas una protección general contra las enfermedades prevenibles mediante vacunación. Los niveles sostenidos de elevadas coberturas nacionales de vacunación, la erradicación de la poliomielitis, la interrupción de la transmisión endémica del virus del sarampión y las iniciativas más recientes en favor de la eliminación de la rubéola y el síndrome de rubéola congénita son hitos continentales de este progreso. En la actualidad, los países administran vacunas a grupos etarios distintos de los incluidos en los programas tradicionales de inmunización infantil. La introducción de la vacuna estacional contra la gripe en los adultos en riesgo; la vacunación de adolescentes y adultos, hombres y mujeres, para la eliminación de la rubéola, y la definición de la carga de enfermedad del cáncer cervicouterino son las actividades que apoyan la necesidad fundamental de efectuar una transición de los programas nacionales de inmunización infantil a programas de inmunización de la familia. Una de las funciones de la OPS en su apoyo a los países es difundir información que destaque el progreso de la Región y los desafíos que enfrenta. Con ese fin, publica varios documentos técnicos relacionados con la inmunización, tales como los boletines de inmunización, los módulos de capacitación en inmunización y la serie de guías prácticas sobre rubéola, sarampión, tétanos neonatal, poliomielitis, vacuna pentavalente y fiebre amarilla.

The global burden of yellow fever.

Yellow fever (YF) is a viral, vector-borne, haemorrhagic fever endemic in tropical regions of Africa and South America. The vaccine for YF is considered safe and effective, but intervention strategies need to be optimised; one of the tools for this is mathematical modelling. We refine and expand an existing modelling framework for Africa to account for transmission in South America. We fit to YF occurrence and serology data. We then estimate the subnational forces of infection for the entire endemic region. Finally, using demographic and vaccination data, we examine the impact of vaccination activities. We estimate that there were 109,000 (95% credible interval [CrI] [67,000-173,000]) severe infections and 51,000 (95% CrI [31,000-82,000]) deaths due to YF in Africa and South America in 2018. We find that mass vaccination activities in Africa reduced deaths by 47% (95% CrI [10%-77%]). This methodology allows us to evaluate the effectiveness of vaccination and illustrates the need for continued vigilance and surveillance of YF.

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.

The Public Health Benefits and Economic Value of Routine Yellow Fever Vaccination in Colombia.

OBJECTIVES: To evaluate the public health benefits and economic value of live-attenuated yellow fever (YF) 17D vaccine in Colombia. METHODS: A decision tree model was used to assess the theoretical impact of routine YF vaccination of 1-year-olds (no "catch-up") during the interepidemic period from 1980 to 2002, avoiding capturing the impact of YF vaccine introduction in 2003. The vaccine was assumed to be 99% effective, to provide lifetime protection, and to cover 85% of the target population. Costs per disability-adjusted life-year (DALY) averted were computed from payer and societal perspectives. Univariate sensitivity analyses were performed. RESULTS: During the interepidemic period, routine YF vaccination would have averted 2223 nonfatal cases of YF and 65 deaths, leading to an overall reduction of 1365 DALYs. The net cost of this vaccination would have been $25 964 813 (payer's perspective) and $16 535 465 (societal perspective). Cost per DALY averted was $19 022 and $12 114 from payer and societal perspectives, respectively (all costs in 2015 US dollars). Vaccination was considered cost-effective from both perspectives (ie, between 1- and 3-fold the gross domestic product per capita, $7158) and remains so if price per dose was $2.75 or less and $4.66 from payer and societal perspectives, respectively. Underreporting had the largest impact on the results. CONCLUSIONS: Routine toddler YF vaccination in Colombia would have been considered cost-effective in the prevaccination era. This study provides insights on the value of vaccination in an upper middle-income country.

Access to yellow fever travel vaccination centres in England, Wales, and Northern Ireland: A geographical study.

BACKGROUND: More than 700,000 trips were made by residents in England, Wales, and Northern Ireland (EWNI) in 2015 to tropical countries endemic for yellow fever, a potentially deadly, yet vaccine-preventable disease transmitted by mosquitoes. The aim of this study was to map the geographical accessibility of yellow fever vaccination centres (YFVC) in EWNI. METHODS: The location of 3208 YFVC were geocoded and the average geodetic distance to nearest YFVC was calculated for each population unit. Data on trips abroad and centres were obtained regionally for EWNI and nationally for the World Top20 countries in terms of travel. RESULTS: The mean distance to nearest YFVC was 2.4 km and only 1% of the population had to travel more than 16.1 km to their nearest centre. The number of vaccines administered regionally in EWNI was found correlated with the number of trips to yellow fever countries. The number of centres per 100,000 trips was 6.1 in EWNI, which was below United States (12.1) and above the rest of Top20 countries. CONCLUSIONS: The service availability was in line with demand regionally. With the exception of remote, rural areas, yellow fever vaccination services were widely available with only short distances to cover for the travelling public.