The contribution of the polio eradication initiative to narrowing the gaps in the health workforce in the African Region.

INTRODUCTION: The Global Polio Eradication Initiative (GPEI) massively invested to overcome the crippling disease in countries of the WHO African Region. In the context of economic crisis, almost all countries in the Region lack an adequate health workforce. Large amounts were invested by GPEI in human resources. This paper shows how the human resources funded by polio contributed to narrowing the gaps in health workforce and helped strengthening and supporting other priority health programmes in Angola, Chad, DRC, Nigeria, Tanzania, and Togo. METHODS: The health workforce strengthening methods used in the five different countries included the following: policy development and strategic planning, microplanning, capacity building of public health and community workers, implementation and services, monitoring and evaluation, advocacy and social mobilization, and programme review. RESULTS: Staff funded by polio helped with achieving good coverage in vitamin A and insecticide-treated mosquito nets (Angola, Chad); improvement of EPI and integrated disease surveillance indicators, improved quality of data (all five countries), administrative support, smooth introduction of new vaccines, increased case detection, and early isolation of patients suffering from the Guinea worm (Chad); reduction of cholera, extension of directly observed TB short course treatment (Democratic Republic of Congo); significant staff performance improvement (Nigeria). DISCUSSION: GPEI investment achieved far beyond its primary goal, and contributed to narrowing the gaps in the health workforce in countries of the African Region, as demonstrated by the best practice documentation exercise. We recommend that expertise and experience of polio funded staff should be leveraged to strengthen, expand and support other public health programmes.

Differential gene expression of activating Fcγ receptor classifies active tuberculosis regardless of human immunodeficiency virus status or ethnicity.

New diagnostics and vaccines for tuberculosis (TB) are urgently needed, but require an understanding of the requirements for protection from/susceptibility to TB. Previous studies have used unbiased approaches to determine gene signatures in single-site populations. The present study utilized a targeted approach, reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA), to validate these genes in a multisite study. We analysed ex vivo whole blood RNA from a total of 523 participants across four sub-Saharan countries (Ethiopia, Malawi, South Africa, and The Gambia) with differences in TB and human immunodeficiency virus (HIV) status. We found a number of genes that were expressed at significantly lower levels in participants with active disease than in those with latent TB infection (LTBI), with restoration following successful TB treatment. The most consistent classifier of active disease was FCGR1A (high-affinity IgG Fc receptor 1 (CD64)), which was the only marker expressed at significantly higher levels in participants with active TB than in those with LTBI before treatment regardless of HIV status or genetic background. This is the first study to identify a biomarker for TB that is not affected by HIV status or geo-genetic differences. These data provide valuable clues for understanding TB pathogenesis, and also provide a proof-of-concept for the use of RT-MLPA in rapid and inexpensive validation of unbiased gene expression findings.

Diagnostic utility of QuantiFERON-TB gold in-tube in active pulmonary Tuberculosis in Nigeria.

BACKGROUND: The high positive responses obtained in active TB indicate that IGRAs may be useful in diagnosing active TB. This study aimed at evaluating the usefulness of Quantifer on-TB Gold-in Tube test (QFT-IT) in the diagnosis of active TB among Nigerians. METHODS: This study prospectively enrolled sputum smear positive TB cases and healthy disease free controls. Basic demographic and clinical data were collected using a structured questionnaire. Venous blood was collected into the QTF-IT tubes, incubated for 16-24 hours, serum harvested and stored at -200C till analysed in a batch. Tuberculin skin test (TST) was also done using 5TU and read within 48-72 hours. The performances of QFT-IT and TST among the cases and controls were compared. RESULTS: Sixty one TB cases and 41 controls were enrolled. The mean (SD) age of the TB cases was higher than the controls, 35.14+4.3 yrs v 27.8 + 2.1, p<0.001. Forty three (70.5%), 13 (21.3%) and 5 (8.2%) of the cases had a positive, negative and indeterminate QFT-IT results respectively compared with 14 (34.1%), 25 (61%), and 2 (4.9%) of the controls respectively, p values <0.001, 0.005 and 0.05 respectively. Fifty eight(95%) and 29(70.7%) of the TB cases and controls had a positive TST result respectively while 3 (5%) and 12( 29.3%) of the TB cases and controls had a negative TST result respectively, p values 0.003 each .QFT-IT had a sensitivity of 76% (95% CI 61.8 -85.2%) while the sensitivity of TST was 96.6% (95% CI 88.5 -98.3%), p = 0.07. The specificity of QFT-IT was 63.7% (95% CI 46-76%) and 30% (95% CI 20- 56%) for TST, p =0.001. Positive Likelihood ratio was 1.7 (95% CI 1.06-2.85) for QFT-IT and 1.4 (95%CI 1.06-1.8) for TST, p =0.002. Among the cases, both TST and QFT-IT were positive in 43(70.5%) and both negative in 1 (1.6%), and overall test .agreement was 77.7% (Kappa =0.13; p= 0.07). Female sex and higher total lymphocytes count were significantly associated with a positive QFT results. CONCLUSION: IGRA has a higher specificity and positive likelihood ratio in TB cases. Our findings indicate that QFT-IT may be a good adjunct tool to diagnose TB disease.

Human immune responses to vaccines in the first year of life: biological, socio-economic and ethical issues - a viewpoint.

Human newborns are vulnerable to infectious diseases that account for majority of the morbidity and mortality, particularly in first year of life. Vaccines have become the most effective public health intervention strategy to curtail the prevalence of these infectious diseases. Although vaccines against a number of diseases exist, there are no vaccines against many other diseases that commonly affect children. The adequate assessment of immune responses to vaccines is an important step in the development of vaccines. However, a number of biological and "non-medical" socio-economic and ethical factors could influence either the administration and/or evaluation of vaccines in infants. Recognition and understanding of these determinants are crucial in planning interventions and for logical interpretations of results.

A new TB vaccine, MVA85A, induces durable antigen-specific responses 14 months after vaccination in African infants.

This study aimed to evaluate the durability of the immunogenicity of MVA85A beyond infancy. Participants in an immunogenicity study of MVA85A administered at age of 4 months had additional evaluation 14 months after initial vaccination for IFN-γ ELISPOT responses to Ag85A peptide and ESAT6/CFP-10 and tuberculin skin test (TST). 112 children participated in this study. The anthropometry, biochemical and haematological safety profile were similar between the MVA85A recipients and controls. MVA85A recipients still had significantly higher immune responses to Ag85A compared to the controls. The majority of these children had negative responses to the TST as well as the ESAT6/CFP-10 antigens. In summary, MVA85A-vaccinated children had a persistently higher Ag85A immune response 14 months following vaccination than controls. All the children had negligible evidence of latent infection with M. tuberculosis (Mtb), suggesting that deploying a prophylactic vaccine against Mtb infection at this age could still be effective in this setting.

Identification of biomarkers for tuberculosis disease using a novel dual-color RT-MLPA assay.

Owing to our lack of understanding of the factors that constitute protective immunity during natural infection with Mycobacterium tuberculosis (Mtb), there is an urgent need to identify host biomarkers that predict long-term outcome of infection in the absence of therapy. Moreover, the identification of host biomarkers that predict (in)adequate response to tuberculosis (TB) treatment would similarly be a major step forward. To identify/monitor multi-component host biomarker signatures at the transcriptomic level in large human cohort studies, we have developed and validated a dual-color reverse-transcriptase multiplex ligation-dependent probe amplification (dcRT-MLPA) method, permitting rapid and accurate expression profiling of as many as 60-80 transcripts in a single reaction. dcRT-MLPA is sensitive, highly reproducible, high-throughput, has an extensive dynamic range and is as quantitative as QPCR. We have used dcRT-MLPA to characterize the human immune response to Mtb in several cohort studies in two genetically and geographically diverse populations. A biomarker signature was identified that is strongly associated with active TB disease, and was profoundly distinct from that associated with treated TB disease, latent infection or uninfected controls, demonstrating the discriminating power of our biomarker signature. Identified biomarkers included apoptosis-related genes and T-cell/B-cell markers, suggesting important contributions of adaptive immunity to TB pathogenesis.

Antibody and T-cell responses during acute and convalescent stages of invasive pneumococcal disease.

OBJECTIVE: To understand the pattern of immune responses to pneumococcal proteins during invasive disease as a guide to their development as vaccine candidates. METHODS: The antibody concentration and avidity, as well as frequency of interferon-gamma (IFN-γ)-, interleukin-10 (IL-10)-, and tumor necrosis factor-alpha (TNF-α)-containing CD4+ T-lymphocytes in response to pneumolysin, pneumococcal surface protein A (PspA), and choline-binding protein A (CbpA), during and after invasive pneumococcal disease (IPD) in 20 children were compared to those of 20 healthy matched controls. RESULTS: During the acute phase of IPD, the concentrations of antibodies against these three pneumococcal proteins were lower, whereas the frequencies of IL-10- and TNF-α-producing CD4+ T-cells were higher, compared to values obtained during convalescence and in healthy controls (p < 0.01). In addition, the concentrations of antibodies against the capsular polysaccharides for the serotypes isolated from these patients, were all below the detection level of the assay during both the acute and convalescent phases of IPD. CONCLUSION: These data indicate that the recognition of these antigens by the immune system occurs in variable proportions according to the stage of infection, implying the important role of these in the pathogenesis of IPD, and support their usefulness in vaccine development.

Absence of association between delayed type hypersensitivity to tuberculin and atopy in children in The Gambia.

BACKGROUND: An inverse association between delayed type hypersensitivity to tuberculin and atopy has been observed in children, suggesting that exposure to mycobacteria may influence the immune response to allergens. OBJECTIVE: To investigate the relationship between tuberculin responses and atopy in children living in three different environments in The Gambia. METHODS: In this cross-sectional study a total of 507 school-aged children were recruited from rural, urban poor or urban affluent communities. They were assessed for skin responses to five common allergens and tuberculin, presence of bacille Calmette-Guérin (BCG) scar, presence of intestinal parasites, and total serum IgE. Atopy was defined as the presence of a skin prick test response > or = 3 x 3 mm to at least one allergen. RESULTS: The overall prevalence of atopy was 33% but there was a significant variation among the three study groups. The prevalence of atopy was 22% in urban poor, 36% in urban affluent, and 43% in rural children. Controlling for potential confounding factors, children in the rural community had a significantly higher odds ratio, 3.3 (95% confidence interval 1.8-6.0) of being atopic than children from the urban poor community. No association between atopy and tuberculin response or BCG scar was observed in any of the three groups. Serum IgE levels were higher among children of the urban poor group but were not associated with tuberculin response or BCG scar in any of the groups. CONCLUSION: Environmental factors have an important influence on the development of atopy in children in The Gambia but delayed type hypersensitivity to tuberculin is not a protective factor.

The epidemiology and consequences of maternal malaria: a review of immunological basis.

Millions of women who become pregnant in malaria-endemic areas are at increased risk of contracting malaria infection that jeopardises the outcome of pregnancy. The complication of this infection for mother and baby are considerable. In absence of any other reason, it was thought that the increased risk of infection during pregnancy was related to suppression of pre-existing malaria immunity. Although this concept is plausible, the significantly higher risk of maternal malaria and consequences in primigravidae compared with multigravidae suggests that there are more to mere immunosuppression in pregnancy. The mechanisms underlying some of the striking epidemiological and clinical features of malaria in pregnancy could be related to differences in the strains of parasite populations infecting pregnant women occasioned by the cyto-adherent properties of human placenta, presence or absence of anti-adhesion antibodies acquired from previous pregnancies or the elevated production of some pro-inflammatory cytokines in response to parasitisation of human placenta. Malaria infection of placenta causes a shift from Th2 to Th1 cytokine profile that may be detrimental to pregnancy. The increased susceptibility in the first pregnancy can be explained by the absence of anti-adhesion antibody in the primigravida that is being exposed for the first time to a different strain of malaria parasite sub-population that adhere exclusively to chondroitin sulphate A and hyaluronic acid (HA) in the placenta. In reviewing the epidemiology and consequences of maternal malaria, we have highlighted possible immunological and molecular basis that could account for the higher impact of malaria in pregnancy especially among primigravidae. These factors could be the basis for future research and vaccine formulation.

T cell responses to vaccines in infants: defective IFNgamma production after oral polio vaccination.

The immaturity of the neonatal immune system is associated with an increased susceptibility to infections. Studies in mice indicate that neonatal immune responses are biased towards the T helper 2 type, but little is known about helper T cell responses in human newborns. In this study, the oral polio vaccine was used as a model of early immunization to investigate the capacity of young infants to develop cellular immune responses. We show that neonatal immunization with oral polio vaccine induces the production of high titres of neutralizing antibodies but reduced proliferative and IFNgamma responses to polio antigens compared to immune adults. These data suggest that specific strategies will be required to immunize newborns against pathogens controlled by Th1 type immune responses.