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Introduction As of January 2021, rotavirus vaccination programs have been implemented in 109 countries and their use has resulted in a positive impact on rotavirus-related diarrheal hospitalizations and mortality in children below five years of age. Despite these successes, several countries in Africa and Asia where disease burden is high have not yet implemented rotavirus vaccination at all or at a scale sufficient enough to demonstrate impact. This could be, among other reasons, due to poor vaccine coverage and the modest levels of efficacy and effectiveness of the vaccines in these resource-limited settings. Areas covered We review various factors related to the human host (malnutrition, maternally-derived antibodies and breastfeeding, genetic factors, blood group and co-administration with oral polio vaccine), rotavirus pathogen (force of infection, strain diversity and coinfections) and the environment (related to the human microbiome) which reflect complex and interconnected processes leading to diminished vaccine performance in resource-limited settings. Expert opinion Addressing the limiting factors for vaccine efficacy is needed but likely to take a long time to be resolved. An immediate solution is to increase the immunization coverage to higher values generating an overall effect of adequate proportion of protected population to reduce the prevalence of rotavirus disease.

Introduction Hepatitis A virus infection is more severe in adults than children. Although vaccination can protect adults, current childhood programs cover a large population more successfully. Childhood vaccination is, therefore, a solution to protecting adults if it induces lasting immunity. Fifteen-year protection has been demonstrated in children, but longer-term data are only available for adults. We aimed to predict long term persistence of antibody in children beyond 15 years and assess if immunological mechanisms triggered by vaccination support longer-term protection. Methods Long-term clinical studies using hepatitis A (HAV) or A/B vaccines (HAB) containing 720 or 1440 Enzyme-linked immunosorbent assay Units (EU) of hepatitis A virus antigen were identified. Duration of persistence of antibodies and possible protection was determined by descriptively comparing antibody geometric mean concentration (GMC) kinetics, as well as GMC (95% confidence interval) at 15 years post-vaccination across studies. Immunological mechanism studies describing hepatitis A vaccination were identified. Results One study in children 12–15 years (2-dose HAB 720) and four in adults (2-dose HAV 1440 and 3-dose HAB 720) showed comparable GMC kinetics and per year rates of change up to 15 years. At 15 years, the GMC in children [414.7 mEU/ml (336.9; 510.5)] was in the same range as in adults [range 282.6 (217.6; 367.0) to 550.1 (416.0; 727.4)]. Based on these data, mathematical model predictions from adult studies (showing > 85% protected at 50 years) were deemed likely to also apply to children. Studies identified, both humoral and cell-mediated responses are induced following vaccination. Conclusion Based on comparable antibody data in adults and children up to 15 years, similar longer-term antibody persistence is expected in children with 2-dose inactivated hepatitis A 720 containing vaccine at least up to 50 years. Accordingly, improving routine childhood hepatitis A vaccination coverage could protect against more severe disease in adulthood. Fig. 1 Plain language summary Trial Registration ClinicalTrials.gov identifiers, NCT00875485, NCT01000324, NCT01037114, NCT00289757, NCT00291876.

During the 20th century, the discovery of modern vaccines and ensuing mass vaccination dramatically decreased the incidence of many infectious diseases and in some cases eliminated them. Despite this, we are now witnessing a decrease in vaccine confidence that threatens to reverse the progress made. Considering the different extents of low vaccine confidence in different countries of the world, both developed and developing, we aim to contribute to the discussion of the reasons for this, and to propose some viable scientific solutions to build or help restore vaccine confidence worldwide.

The current COVID-19 global pandemic continues to impact healthcare services beyond those directly related to the management of SARS-CoV-2 transmission and disease. We reviewed the published literature to assess the pandemic impact on existing global immunization activities and how the impact may be addressed. Widespread global disruption in routine childhood immunization has impacted a majority of regions and countries, especially in the initial pandemic phases. While data indicate subsequent recovery in immunization rates, a substantial number of vulnerable people remain unvaccinated. The downstream impact may be even greater in resource-limited settings and economically poorer populations, and consequently there are growing concerns around the resurgence of vaccine-preventable diseases, particularly measles. Guidance on how to address immunization deficits are available and continue to evolve, emphasizing the importance of maintaining and restoring routine immunization and necessary mass vaccination campaigns during and after pandemics. In this, collaboration between a broad range of stakeholders (governments, industry, healthcare decision-makers and frontline healthcare professionals) and clear communication and engagement with the public can help achieve these goals.Key messagesThe COVID-19 pandemic has a substantial impact on essential immunization activities.Disruption to mass vaccination campaigns increase risk of VPD resurgence.Catch-up campaigns are necessary to limit existing shortfalls in vaccine uptake.Guidance to mitigate these effects continues to evolve.

Introduction: Measles, mumps, and rubella incidence decreased drastically following vaccination programs' implementation. However, measles and mumps' resurgence was recently reported, outbreaks still occur, and challenges remain to control these diseases.Areas covered: This qualitative narrative review provides an objective appraisal of the literature regarding current challenges in controlling measles, mumps, rubella infections, and interventions to address them.Expert opinion: While vaccines against measles, mumps, and rubella (including trivalent vaccines) are widely used and effective, challenges to control these diseases are mainly related to insufficient immunization coverage and changing vaccination needs owing to new global environment (e.g. traveling, migration, population density). By understanding disease transmission peculiarities by setting, initiatives are needed to optimize vaccination policies and increase vaccination coverage, which was further negatively impacted by COVID-19 pandemic. Also, awareness of the potential severity of infections and the role of vaccines should increase. Reminder systems, vaccination of disadvantaged, high-risk and difficult-to-reach populations, accessibility of vaccination, healthcare infrastructure, and vaccination services management should improve. Outbreak preparedness should be strengthened, including implementation of high-quality surveillance systems to monitor epidemiology. While the main focus should be on these public health initiatives to increase vaccination coverage, slightly more benefits could come from evolution of current vaccines.Plain Language SummaryWhat is the context? Measles, mumps, and rubella are highly contagious diseases associated with significant medical and societal burden. Effective vaccines against these diseases are available, and the implementation of vaccination programs drastically reduced disease incidence globally. However, reports of measles and mumps outbreaks in the last few years highlight remaining challenges to eliminate these diseases.What does the review highlight? We conducted a literature review to identify challenges associated with controlling measles, mumps, and rubella infections, and interventions needed to address them. We identified 11 challenges mainly related to low immunization coverage and vaccine characteristics. Societal challenges could be addressed by increasing awareness of disease severity and vaccines impact, targeting high-risk, unvaccinated, and under-vaccinated populations, improving vaccination access, setting up clear outbreak preparedness plans, and implementing country-specific vaccination policies. System weaknesses could be addressed through improving vaccination services and health infrastructure, implementing high-quality surveillance, patient invite, and reminder systems, ensuring vaccine implementation and long-term supply. Interventions related to vaccine characteristic challenges could include adaptation of vaccination schedules (shorter interval between doses, administration of a third dose) and development of vaccines against emerging strains.What is the take-home message?Policymakers should support the following strategies to increase vaccination coverage and reach elimination of measles, mumps, and rubella: strengthening health systems and vaccination access; raising awareness of disease severity and vaccination impact; limiting disease propagation owing to global changing environment and population dynamics (traveling, migration); improving surveillance systems to rapidly address the immunity gaps against disease resurgence.

Tobacco use is a major risk factor for tuberculosis (TB). Secondhand smoke (SHS) is also a risk factor for TB and to a lesser extent, Mycobacterium tuberculosis infection without disease. We investigated the added risk of M. tuberculosis infection due to SHS exposure in childhood contacts of TB cases in The Gambia. Participants were childhood household contacts aged ≤ 14 years of newly diagnosed pulmonary TB (PTB) cases. The intensity of exposure to the case was categorized according to whether contacts slept in the same room, same house, or a different house as the case. Contacts were tested with an enzyme-linked immunospot interferon gamma release assay. In multivariate regression models, M. tuberculosis infection was associated with increasing exposure to a case (odds ratios [OR]: 3.9, 95% confidence interval [CI]: 2.11–71.4, P < 0.001]) and with male gender (OR: 1.5 [95% CI: 1.12–2.11], P = 0.008). Tobacco use caused a 3-fold increase in the odds of M. tuberculosis infection in children who slept closest to a case who smoked within the same home compared with a nonsmoking case (OR: 8.0 [95% CI: 2.74–23.29] versus 2.4 [95% CI: 1.17–4.92], P < 0.001). SHS exposure as an effect modifier appears to greatly increase the risk of M. tuberculosis infection in children exposed to PTB cases. Smoking cessation campaigns may be important for reducing transmission of M. tuberculosis to children within households.

BACKGROUND: Health challenges and health systems set-ups differ, warranting contextualised healthcare interventions to move towards universal health coverage. As such, there is emphasis on generation of contextualized evidence to solve local challenges. However, weak research capacity and inadequate resources remain an impendiment to quality research in the African region. WHO African Region (WHO AFR) facilitated the adoption of a regional strategy for strengthening national health research systems (NHRS) in 2015. We assessed the progress in strengthening NHRS among the 47 member states of the WHO AFR.METHODS: We employed a cross sectional survey design using a semi structured questionnaire. All the 47member states of WHO AFR were surveyed. We assessed performance against indicators of the regional research strategy, explored facilitating factors and barriers to strengthening NHRS. Using the research barometer, which is a metric developed for the WHO AFR we assessed the strength of NHRS of member states. Data were analysed in Excel Software to calculate barometer scores for NHRS function and sub-function. Thematic content was employed in analysing the qualitative data. Data for 2014 were compared to 2018 to assess progress.RESULTS: WHO AFR member states have made significant progress in strengthening their NHRS. Some of the indicators have either attained or exceeded the 2025 targets. The average regional barometer score improved from 43% in 2014 to 61% in 2018. Significant improvements were registered in the governance of research for health (R4H); developing and sustaining research resources and producing and using research. Financing R4H improved only modestly. Among the constraints are the lengthy ethical clearance processes, weak research coordination mechanisms, weak enforcement of research laws and regulation, inadequate research infrastructure, limited resource mobilisation skills and donor dependence.CONCLUSION: There has been significant improvement in the NHRS of member states of the WHO AFRO since the last assessment in 2014. Improvement across the different objectives of the regional research strategy is however varied which compromises overall performance. The survey highlighted the areas with slow improvement that require a concerted effort. Furthermore, the study provides an opportunity for countries to share best practice in areas of excellence.

Eradication of poliomyelitis remains a public health priority due to the paralytic effects of the virus on children and impact on global health system. However, existing gaps in surveillance can hinder eradication. Improved timeliness of identification and reporting of acute flaccid paralysis (AFP) cases with further confirmation of Wild Poliovirus (WPV) in stool samples, can help Nigeria achieve the performance indicators of non-polio AFP rate of ≥ 2/100,000 population aged < 15 years and ≥80% stool sample collection adequacy. To ascertain the awareness of AFP case definition and detection by health care workers and to evaluate the impact of SMS-based reporting on the AFP surveillance system the study was conducted from November 2013 to July 2014. In Sokoto state, 112 health facilities (focal sites) were operational and participated in this study. All AFP focal points for the 112 facilities were included in the study. In addition to AFP focal points, two clinicians per facility where possible, were included in the study. The study focused exclusively on reports from focal sites. The methodology was a one group pretest-posttest design conducted in 3 phases. 1) Pre-intervention Knowledge, Attitude and Practices (KAP) survey, 2) SMS implementation and 3) Post-intervention KAP. Results were analysed using the independent sample t-test to assess the increase in knowledge, attitudes, or practice scores pre- and post- training. The study showed improved knowledge gap of health care workers on AFP surveillance between pre and post intervention. It shows that this approach of improved surveillance will be effective in countries in hard to reach, access compromised or countries/place without sufficient surveillance staff.

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.

Summary Background Vitamin D is essential in the host defence against tuberculosis (TB) as an immune modulator. The aim of this study was to determine the level of 25-hydroxyvitamin D (25 (OH) D) from adult TB index cases before and after treatment and their exposed household contacts (HHC) in The Gambia. Methods Serum from adult index TB cases and their TB-exposed household contacts (HHC) was analysed for 25(OH) D and Vitamin D binding protein (VDBP) concentrations. Tuberculin skin test (TST) status was used as a measure of Mycobacterium tuberculosis (Mtb) infectivity in the HHC. In addition, HHC who later progressed to active TB (incident cases) were assessed alongside non-progressors to determine the influence of 25 (OH) D levels on TB risk. Results Eighty-three TB cases, 46 TST+ and 52 TST− HHC were analysed. Generally levels of 25(OH) D were considered insufficient in all subjects. However, median levels of 25(OH) D and VDBP were significantly higher in TB cases compared to both TST+ and TST− HHC at recruitment and were significantly reduced after TB therapy (p

Rationale: Contacts of patients with tuberculosis (TB) constitute an important target population for preventive measures because they are at high risk of infection with Mycobacterium tuberculosis and progression to disease. Objectives: We investigated bio-signatures with predictive ability for incident TB. Methods: In a case-control study nested within the Grand Challenges 6-74 longitudinal HIV-negative African cohort of exposed household contacts, we employed RNA sequencing, PCR, and the pair ratio algorithm in a training/test set approach. Overall, 79 progressors who developed TB between 3 and 24 months after diagnosis of index case and 328 matched nonprogressors who remained healthy during 24 months of follow-up were investigated. Measurements and Main Results: A four-transcript signature derived from samples in a South African and Gambian training set predicted progression up to two years before onset of disease in blinded test set samples from South Africa, the Gambia, and Ethiopia with little population-associated variability, and it was also validated in an external cohort of South African adolescents with latent M. tuberculosis infection. By contrast, published diagnostic or prognostic TB signatures were predicted in samples from some but not all three countries, indicating site-specific variability. Post hoc meta-analysis identified a single gene pair, C1QC/TRAV27 (complement C1q C-chain / T-cell receptor-a variable gene 27) that would consistently predict TB progression in household contacts from multiple African sites but not in infected adolescents without known recent exposure events. Conclusions: Collectively, we developed a simple whole blood-based PCR test to predict TB in recently exposed household contacts from diverse African populations. This test has potential for implementation in national TB contact investigation programs.

Pneumococcal conjugate vaccines (PCVs) have been successful in preventing invasive pneumococcal disease but effectiveness has been challenged by replacement of vaccine serotypes with non-vaccine serotypes. Vaccines targeting common pneumococcal protein(s) found in most/all pneumococci may overcome this limitation. This phase II study assessed safety and immunogenicity of a new protein-based pneumococcal vaccine containing polysaccharide conjugates of 10 pneumococcal serotypes combined with pneumolysin toxoid(dPly) and pneumococcal histidine triad protein D(PhtD) (PHiD-CV/dPly/PhtD-30) in African children. 120 Gambian children (2-4 years, not previously vaccinated against Streptococcus pneumoniae) randomized (1:1) received a single dose of PHiD-CV/dPly/PhtD-30 or PCV13. Adverse events occurring over 4 d post-vaccination were reported, and blood samples obtained pre- and 1-month post-vaccination. Serious adverse events were reported for 6 months post-vaccination. Solicited local and systemic adverse events were reported at similar frequency in each group. One child (PHiD-CV/dPly/PhtD-30 group) reported a grade 3 local reaction to vaccination. Haematological and biochemical parameters seemed similar pre- and 1-month post-vaccination in each group. High pre-vaccination Ply and PhtD antibody concentrations were observed in each group, but only increased in PHiD-CV/dPly/PhtD-30 vaccinees one month post-vaccination. One month post-vaccination, for each vaccine serotype ≥96.2% of PHiD-CV/dPly/PhtD-30 vaccinees had serotype-specific polysaccharide antibody concentrations ≥0.20µg/mL except serotypes 6B (80.8%) and 23F (65.4%), and ≥94.1% had OPA titres of ≥8 except serotypes 1 (51.9%), 5 (38.5%) and 6B (78.0%), within ranges seen in PCV13-vaccinated children. A single dose of PHiD-CV/dPly/PhtD-30 vaccine, administered to Gambian children aged 2-4 y not previously vaccinated with a pneumococcal vaccine, was well-tolerated and immunogenic.

Pneumonia is a major killer of children worldwide. It is responsible for 19% of under-five-year-old mortality, of which 70% occurs in sub-Saharan Africa and South East Asia. A substantial proportion of deaths attributed to pneumonia is caused by failure to recognise factors at presentation that affect prognosis. The present study was aimed to assess for factors at presentation that determine mortality among children with WHO ARI defined severe pneumonia. This was a prospective observational study of consecutive children aged 2 to 59 months admitted with severe pneumonia at a major health centre in rural Gambia to de- termine the risk factors for mortality using logistic regression analysis. Four hundred and twenty (27.6%) out of the 1517 under- five admissions during the study period fulfilled the criteria of severe pneumonia using the WHO ARI criteria. Fifteen of the 420 cases died giving case fatality of 36 per 1000 admissions, with pneumonia accounting for 21.4% of all 70 deaths during the period. Although age ranges 12-23 months and 36-47 months, overcrowding, hypothermia at presentation, oedematous PEM, severe wasting, grunting respiration, convulsion, somnolence and hypoxaemia were significantly associated with mortality (p < 0.05); only convulsions ( OR = 16.64, 95% CI 1.028-1.033) and severe wasting (OR = 5.05, 95% CI 1.459-20.484,) were independent determinants of mortality. We conclude that children with severe pneumonia who in addition have severe wasting and convulsion are at increased risks of dying and should be managed in better equipped secondary or tertiary health facilities.

A retrospective study to identify VAPP cases from the entire Uganda was conducted between January 2003 and December 2011. Eleven of the 106 AFP cases were VAPPs. The VAPP rate ranged from 0 to 3.39 cases per 1,000,000 birth cohorts and the peak was in 2009 when there was scaling up of OPV immunization activities following an importation of wild poliovirus in the country. All the subsequent polio suspect cases since then have been vaccine-associated polio cases. Our data support the strategy to withdraw OPV and introduce IPV progressively in order to mitigate against the paralysis arising from Sabin polioviruses.

SummaryBackgroundHIV-1 infection is associated with increased risk of tuberculosis and a safe and effective vaccine would assist control measures. We assessed the safety, immunogenicity, and efficacy of a candidate tuberculosis vaccine, modified vaccinia virus Ankara expressing antigen 85A (MVA85A), in adults infected with HIV-1.MethodsWe did a randomised, double-blind, placebo-controlled, phase 2 trial of MVA85A in adults infected with HIV-1, at two clinical sites, in Cape Town, South Africa and Dakar, Senegal. Eligible participants were aged 18–50 years, had no evidence of active tuberculosis, and had baseline CD4 counts greater than 350 cells per μL if they had never received antiretroviral therapy or greater than 300 cells per μL (and with undetectable viral load before randomisation) if they were receiving antiretroviral therapy; participants with latent tuberculosis infection were eligible if they had completed at least 5 months of isoniazid preventive therapy, unless they had completed treatment for tuberculosis disease within 3 years before randomisation. Participants were randomly assigned (1:1) in blocks of four by randomly generated sequence to receive two intradermal injections of either MVA85A or placebo. Randomisation was stratified by antiretroviral therapy status and study site. Participants, nurses, investigators, and laboratory staff were masked to group allocation. The second (booster) injection of MVA85A or placebo was given 6–12 months after the first vaccination. The primary study outcome was safety in all vaccinated participants (the safety analysis population). Safety was assessed throughout the trial as defined in the protocol. Secondary outcomes were immunogenicity and vaccine efficacy against Mycobacterium tuberculosis infection and disease, assessed in the per-protocol population. Immunogenicity was assessed in a subset of participants at day 7 and day 28 after the first and second vaccination, and M tuberculosis infection and disease were assessed at the end of the study. The trial is registered with ClinicalTrials.gov, number NCT01151189.FindingsBetween Aug 4, 2011, and April 24, 2013, 650 participants were enrolled and randomly assigned; 649 were included in the safety analysis (324 in the MVA85A group and 325 in the placebo group) and 645 in the per-protocol analysis (320 and 325). 513 (71%) participants had CD4 counts greater than 300 cells per μL and were receiving antiretroviral therapy; 136 (21%) had CD4 counts above 350 cells per μL and had never received antiretroviral therapy. 277 (43%) had received isoniazid prophylaxis before enrolment. Solicited adverse events were more frequent in participants who received MVA85A (288 [89%]) than in those given placebo (235 [72%]). 34 serious adverse events were reported, 17 (5%) in each group. MVA85A induced a significant increase in antigen 85A-specific T-cell response, which peaked 7 days after both vaccinations and was primarily monofunctional. The number of participants with negative QuantiFERON-TB Gold In-Tube findings at baseline who converted to positive by the end of the study was 38 (20%) of 186 in the MVA85A group and 40 (23%) of 173 in the placebo group, for a vaccine efficacy of 11·7% (95% CI −41·3 to 44·9). In the per-protocol population, six (2%) cases of tuberculosis disease occurred in the MVA85A group and nine (3%) occurred in the placebo group, for a vaccine efficacy of 32·8% (95% CI −111·5 to 80·3).InterpretationMVA85A was well tolerated and immunogenic in adults infected with HIV-1. However, we detected no efficacy against M tuberculosis infection or disease, although the study was underpowered to detect an effect against disease. Potential reasons for the absence of detectable efficacy in this trial include insufficient induction of a vaccine-induced immune response or the wrong type of vaccine-induced immune response, or both.FundingEuropean & Developing Countries Clinical Trials Partnership (IP.2007.32080.002), Aeras, Bill & Melinda Gates Foundation, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium.

Background: The objectives of this article are to describe the process followed in development of the Swaziland’s national health research agenda (NHRA); and to provide an overview of the health research priorities that emerged from that process.Discussion: Swaziland followed a fourteen step process to develop it’s NHRA, namely: search and review of the existing health research priority setting guidelines; situation analysis included review of Swaziland’s socio-economic indicators; identification of research stakeholders; identification of the preliminary main broad research themes; development of questionnaire on ranking of main research themes; workshops with each of the eight stakeholders; ranking of major health themes and identification of sub-themes; identification of research gaps under each sub-theme and main research areas; scoring of research areas; research areas were grouped by sub-themes and ranked; collating research areas ranked as number one in each sub-theme; providing content to the agenda; preparation of the zero NHRA draft report; preparation of the first NHRA draft report taking into account critical inputs from stakeholders; and stakeholder’s final validation of the NHRA draft report. The paper provides an overview of communicable diseases, non-communicable diseases, sexual and reproductive health, injuries and health system research gaps under four categories of research: situation (burden and determinants); improvement of existing interventions; effectiveness of interventions; and feasibility of developing new capacities (tools and products).Conclusion: The National Health Research Department, with the support of the National Health Research Review Board, will be responsible for dissemination, preparation of rolling annual action plans to secure government funds for implementation of NHRA, promoting adherence among stakeholders, establishing a registry of R4H, establishing a knowledge translation platform, building of public-private-partnerships for research, mobilization of external resources, coordination and monitoring of the implementation of the NHRA. KeywordsSwaziland, National Health Research Agenda, Health Research Priorities, Research Stakeholders, Research Gaps

Background Hypertension is a leading cause of cardiovascular diseases and a growing public health problem in many developed and developing countries. However, population-based data to inform policy development are scarce in Rwanda. This nationally representative study aimed to determine population-based estimates of the prevalence and risk factors associated with hypertension in Rwanda. Methods We conducted secondary epidemiological analysis of data collected from a cross-sectional population-based study to assess the risk factors for NCDs using the WHO STEPwise approach to Surveillance of non-communicable diseases (STEPS). Adjusted odds ratios at 95% confidence interval were used to establish association between hypertension, socio-demographic characteristics and health risk behaviors. Results Of the 7116 study participants, 62.8% were females and 38.2% were males. The mean age of study participants was 35.3 years (SD 12.5). The overall prevalence of hypertension was 15.3% (16.4% for males and 14.4% for females). Twenty two percent of hypertensive participants were previously diagnosed. A logistic regression model revealed that age (AOR: 8.02, 95% CI: 5.63–11.42, p

Introduction The currently used Streptococcus pneumoniae vaccines have had a significant impact on the pneumococcal diseases caused by the serotypes they cover. Their limitations have stimulated a search for alternate vaccines that will cover all serotypes, be affordable and effective in young children. Pneumococcal protein antigens are potential vaccine candidates that may meet some of the shortfalls of the current vaccines. Thus, this study aimed to determine the relationship between antibodies against pneumococcal protein antigens and nasopharyngeal carriage in infants. Methods One hundred and twenty mother-infant pairs were enrolled into the study. They had nasopharyngeal swabs(NPS) taken at birth and every two weeks for the first eight weeks after delivery, and blood samples were obtained at birth and every four weeks for the first eight weeks after delivery. Nasopharyngeal carriage of S. pneumoniae was determined from the NPS and antibodies against the pneumococcal proteins CbpA, PspA and rPly were measured in the blood samples. Results The S. pneumoniae carriage rate in infants increased to that of mothers by eight weeks of age. The odds of carriage in infants was 6.2 times (95% CI: 2.0–18.9) higher when their mothers were also carriers. Bacterial density in infants was lower at birth compared to their mothers (p = 0.004), but increased with age and became higher than that of their mothers at weeks 4 (p = 0.009), 6 (p = 0.002) and 8 (p

Background Conserved pneumococcal proteins are potential candidates for inclusion in vaccines against pneumococcal diseases. In the first part of a two-part study, an investigational vaccine (PHiD-CV/dPly/PhtD-30) containing 10 pneumococcal serotype-specific polysaccharide conjugates (10VT) combined with pneumolysin toxoid and pneumococcal histidine triad protein D (30 μg each) was well tolerated by Gambian children. Part two, presented here, assessed the efficacy of two PHiD-CV/dPly/PhtD formulations against pneumococcal nasopharyngeal carriage (NPC) prevalence in infants. Methods In this phase 2, randomized, controlled, observer-blind trial, healthy infants aged 8–10 weeks, recruited from a peri-urban health center, were randomized (1:1:1:1:1:1) into six groups. Four groups received PHiD-CV/dPly/PhtD (10 or 30 μg of each protein), PHiD-CV, or 13-valent pneumococcal conjugate vaccine at ages 2–3–4 months (3 + 0 infant schedule) and two groups PHiD-CV/dPly/PhtD-30 or PHiD-CV at 2–4–9 months (2 + 1 infant schedule). The primary objective was impact on non-10VT NPC at ages 5–9–12 months. Secondary objectives included confirmatory analysis of protein dose superiority and safety/reactogenicity. Impact on pneumococcal NPC acquisition, bacterial load, and ply and phtD gene sequencing were explored. Results 1200 infants were enrolled between June 2011 and May 2012. Prevalences of pneumococcal (60–67%) and non-10VT (55–61%) NPC were high at baseline. Across all post-vaccination time points, efficacy of PHiD-CV/dPly/PhtD-10 and PHiD-CV/dPly/PhtD-30 against non-10VT NPC (3 + 0 schedule) was 1.1% (95% CI −21.5, 19.5) and 2.1% (−20.3, 20.3), respectively; efficacy of PHiD-CV/dPly/PhtD-30 (2 + 1 schedule) was 0.5% (−22.1, 18.9) versus PHiD-CV. No differences were observed in pneumococcal NPC acquisition, clearance, or bacterial load. Both protein-based vaccines elicited immune responses to pneumococcal proteins. Conclusions In this high carriage prevalence setting, inclusion of pneumococcal proteins in the PHiD-CV/dPly/PhtD investigational vaccine had no impact on pneumococcal NPC in infants, regardless of protein dose or schedule. Future evaluations will assess its impact against pneumococcal disease endpoints. Funding: PATH, GlaxoSmithKline Biologicals SA. ClinicalTrials.gov identifier NCT01262872 .

a b s t r a c t Major epidemics of serogroup A meningococcal meningitis continue to affect the African meningitis belt. The development of an affordable conjugate vaccine against the disease became a priority for World Health Organization (WHO) in the late 1990s. Licensing of meningococcal vaccines has been based on serological correlates of protection alone, but such correlates might differ in different geographical regions. If high pre-vaccination antibody concentrations/titers impacts on the response to vaccination and possibly vaccine efficacy, is not clearly understood. We set out to define the pre-vaccination Meningo- coccal group A (Men A) antibody concentrations/titers in The Gambia and study their impact on the immunogenicity of Men A containing vaccines. Data from subjects originally enrolled in studies to test the safety and immunogenicity of the MenA vaccine recently developed for Africa meningococcal A polysaccharide conjugated to tetanus toxoid, MenAfriVac ® (PsA-TT) were analyzed. Participants had been randomized to receive either the study vaccine PsA-TT or the reference quadrivalent plain polysaccharide vaccine containing meningococcal groups A, C, W, and Y, Mencevax ® ACWY, GlaxoSmithKline (PsACWY) in a 2:1 ratio. Venous blood sam- ples were collected before and 28 days after vaccination. Antibodies were assayed by enzyme-linked immunosorbent assay (ELISA) for geometric mean concentrations and serum bactericidal antibody (SBA) for functional antibody. The inter age group differences were compared using ANOVA and the pre and post-vaccination differences by t test. Over 80% of the ≥19 year olds had pre-vaccination antibody concentrations above putatively protective concentrations as compared to only 10% of 1-2 year olds. Ninety-five percent of those who received the study vaccine had ≥4-fold antibody responses if they had low pre-vaccination concentrations compared to 76% of those with high pre-vaccination concentrations. All subjects with low pre-vaccination titers attained ≥4-fold responses as compared to 76% with high titers where study vaccine was received. Our data confirm the presence of high pre-vaccination Men A antibody concentrations/titers within the African meningitis belt, with significantly higher concentrations in older individuals. Although all partic- ipants had significant increase in antibody levels following vaccination, the four-fold or greater response in antibody titers were significantly higher in individuals with lower pre-existing antibody titers, espe- cially after receiving PsA-TT. This finding may have some implications for vaccination strategies adopted in the future.

To the Editor: Tuberculosis continues to be a major public health problem in developing countries [1]. One of the roadblocks in reducing tuberculosis transmission is the lack of accurate laboratory-free diagnostic tests for use at the point of care. If tuberculosis is to be eliminated, we need a robust, low-cost and safe point-of-care diagnostic test, which in turn requires identification of appropriate biomarkers [2]. Rapid tests based on microfluidics (lateral flow tests) hold great promise for tuberculosis diagnostics. They are easy to use, cheap, provide an answer within minutes, do not require specialised equipment and are stable at room temperature, making them ideal for use in high tuberculosis burden, resource-poor settings. To date, however, no such test has been developed for tuberculosis due to lack of sensitivity related to the markers and/or sample type. Development of tests based on host biomarkers requires evaluation of different sample types [3]–[5] and markers other than interferon (IFN)-γ [5] to provide differential diagnosis of active tuberculosis, latent infection and other respiratory disorders. We have previously shown that a combination of three host factors in pleural fluid resulted in 96% correct classification of tuberculosis among other respiratory diseases (ORD) (including bacterial pneumonia) regardless of HIV status [6]. However, this sample type is not easy to obtain and we therefore wanted to determine if we could use ex vivo sputum, which is noninvasive and easy to obtain in adult pulmonary tuberculosis patients. Subjects were consecutively recruited from the outpatient clinic and ward at the Medical Research Council Unit, Fajara, the Gambia. All subjects were adults (≥18 years of age) with symptoms suggestive of tuberculosis. Subjects were subsequently classified into two groups: those with culture-confirmed tuberculosis and those with ORD. 75% of the tuberculosis and …

In The Gambia, Mycobacterium tuberculosis (Mtb) and Mycobacterium africanum (Maf) are major causes of tuberculosis (TB). Maf is more likely to cause TB in immune suppressed individuals, implying differences in virulence. Despite this, few studies have assessed the underlying immunity to the two pathogens in human. In this study, we analyzed T-cell responses from 19 Maf- and 29 Mtb-infected HIV-negative patients before and after TB chemotherapy following overnight stimulation of whole blood with TB-specific antigens. Before treatment, percentages of early secreted antigenic target-6(ESAT-6)/culture filtrate protein-10(CFP-10) and purified protein derivative-specific single-TNF-α-producing CD4(+) and CD8(+) T cells were significantly higher while single-IL-2-producing T cells were significantly lower in Maf- compared with Mtb-infected patients. Purified protein derivative-specific polyfunctional CD4(+) T cells frequencies were significantly higher before than after treatment, but there was no difference between the groups at both time points. Furthermore, the proportion of CD3(+) CD11b(+) T cells was similar in both groups pretreatment, but was significantly lower with higher TNF-α, IL-2, and IFN-γ production in Mtb- compared with that of Maf-infected patients posttreatment. Our data provide evidence of differences in T-cell responses to two mycobacterial strains with differing virulence, providing some insight into TB pathogenesis with different Mtb strains that could be prospectively explored as biomarkers for TB protection or susceptibility.

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.

Immunization remains the most cost effective method for the control of infectious diseases. Therefore, there is a global effort to deploy new vaccines for disease control and eradication. These new vaccines must be tested in the settings in which they will be used. This necessity has required the conduct of many vaccine trials in Africa, where several infectious diseases with significant public health impact are prevalent. However, these areas have peculiarities and are just beginning to gain expertise in the conduct of such trials. The vaccine developers and sponsors of these trials may also not be conversant with some issues unique to the trial site. The understanding gap from both partners can result in challenges if not addressed during the planning phase of the trial. This review seeks to highlight the issues surrounding the conduct of clinical trials in resource-constrained settings and suggests some ways of circumventing them.

MVA85A is a candidate boost vaccine for TB. A previously reported study showed no differences in response to MVA85A in 10 BCG vaccinated (BCG+) and 11 BCG naive (BCG-) adult Gambians. Here we evaluated the effect of pre-existing plasma cytokines in both groups before and after MVA85A vaccination on the vaccine-induced immune response. Pre-vaccination levels of IL-8 were higher in BCG+ subjects, whilst MCP-1 levels were lower compared to BCG-. Following MVA85A vaccination, concentrations of IL-8, IL-18, IL-12(p70) and MCP-1 were differentially induced between BCG+ and BCG- groups. The implications of these findings depend on their role in TB pathogenesis. © 2012 Owiafe PK, et al.

Tuberculosis (TB) kills 2 million people per year and infection with HIV is the most potent known risk factor for progression to active TB. An understanding of the immune response to TB Ags in HIV-infected patients is required to develop optimal TB vaccines and diagnostics. We assessed polyfunctional (IFN-γ+IL-2+TNF-α+) T cell responses to TB Ags in three groups of HIV-1–infected patients dependent on their TB status, CD4 counts, and anti-retroviral exposure. We found that although the proportion of IFN-γ cells in response to TB Ags was higher in patients with low CD4 counts, the responding cells changed from a polyfunctional CD4+ to a monofunctional CD8+ response. The overall polyfunctionality of the cells was restored by 12 mo of anti-retroviral therapy and primarily involved CD4+ T cells with an effector memory phenotype. These findings have major implications for diagnosis of TB and in vaccine development strategies for TB in HIV-1–infected patients.

Understanding the immunogenicity of BCG in a population where it has failed will facilitate the design of new TB vaccines. We assessed the immunogenicity of M. bovis BCG over 12 months by ELISPOT assay. Forty-one adolescents and young Gambian male adults received a tuberculin skin test (TST) which was followed one week later by BCG vaccination, but the 23 control subjects received neither of these. TST alone significantly induced PPD-specific IFN-gamma producing cells. Twenty-three percent of subjects did not respond to BCG, which was associated with higher pre-existing ex vivo response to PPD. Paradoxically, amongst BCG responders there was a correlation between pre-existing response and subsequent response to BCG. We conclude that BCG is immunogenic, but this effector response is short-lived and can be limited in higher pre-existing anti-mycobacterial immunity, suggesting a possible threshold beyond which BCG immunogenicity is inhibited.

Bacillus Camette-Guérin (BCG) vaccine is the only licensed vaccine against tuberculosis, yet its protective efficacy is highly variable between different geographical regions. We hypothesized that exposure to nontuberculous mycobacteria attenuates BCG immunogenicity by inducing mycobacterial-specific regulatory T cells (Tregs). Gambian neonates were recruited at birth and randomized to receive BCG vaccination either at birth or at 4 1/2 mo. Mycobacterial immune responses were assessed at birth, 4 1/2, and 9 mo of age. At 4 1/2 mo of age the BCG naive individuals had detectable mycobacterial responses, including increased IL-10 production suggesting environmental priming. Vaccination at birth significantly enhanced Th1, Th2, IL-6, IL-17, and Treg responses in mycobacterial cultures at 4 1/2 mo compared with the BCG naive group. Analyzing results at 4 1/2 mo postvaccination revealed lower IFN-γ, IL-6, and IL-17 responses in the delayed BCG vaccine group compared with those vaccinated at birth, but this did not relate to Treg levels prevaccination. When comparing responses pre- and post-BCG vaccination in the delayed vaccine group, there was no priming of mycobacterial IL-17. Mycobacterial responses waned over 9 mo in those vaccinated at birth, leading to comparable mycobacterial immunity in both groups at 9 mo of age. Overall, these data suggest that vaccination at birth induces a broad Th1/Th2/IL-17/Treg mycobacterial response but the Th1/Th-17 response was reduced when delaying the vaccine. The evidence did not suggest that mycobacterial specific naturally occurring Tregs accounted for this attenuated immunogenicity.

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. © 2012 Elsevier Ltd.

New tuberculosis vaccines are urgently needed to curtail the current epidemic. MVA85A is a subunit vaccine that could enhance immunity from BCG vaccination. To determine MVA85A safety and immunogenicity as well as interactions with other routine vaccines administered in infancy, we randomized healthy 4-month-old infants who had received Bacille Calmette-Guérin at birth to receive Expanded Program on Immunization (EPI) vaccines alone, EPI and MVA85A simultaneously, or MVA85A alone. Adverse events were monitored throughout. Blood samples obtained before vaccination and at 1, 4, and 20 weeks after vaccination were used to assess safety and immunogenicity. The safety profile of both low and standard doses was comparable, but the standard dose was more immunogenic and therefore was selected for the second stage of the study. In total, 72 (first stage) and 142 (second stage) infants were enrolled. MVA85A was safe and well tolerated and induced a potent cellular immune response. Coadministration of MVA85A with EPI vaccines was associated with a significant reduction in MVA85A immunogenicity, but did not affect humoral responses to the EPI vaccines. These results provide important information regarding timing of immunizations, which is required for the design of infant efficacy trials with MVA85A, and suggest that modifications to the standard EPI schedule may be required to incorporate a new generation of T cell-inducing vaccines.

Background A functional national health research system (NHRS) is crucial in strengthening a country’s health system to promote, restore and maintain the health status of its population. Progress towards the goal of universal health coverage in the post-2015 sustainable development agenda will be difficult for African countries without strengthening of their NHRS to yield the required evidence for decision-making. This study aims to develop a barometer to facilitate monitoring of the development and performance of NHRSs in the African Region of WHO. Methods The African national health research systems barometer algorithm was developed in response to a recommendation of the African Advisory Committee for Health Research and Development of WHO. Survey data collected from all the 47 Member States in the WHO African Region using a questionnaire were entered into an Excel spreadsheet and analysed. The barometer scores for each country were calculated and the performance interpreted according to a set of values ranging from 0% to 100%. Results The overall NHRS barometer score for the African Region was 42%, which is below the average of 50%. Among the 47 countries, the average NHRS performance was less than 20% in 10 countries, 20–40% in 11 countries, 41–60% in 16 countries, 61–80% in nine countries, and over 80% in one country. The performance of NHRSs in 30 (64%) countries was below 50%. Conclusion An African NHRS barometer with four functions and 17 sub-functions was developed to identify the gaps in and facilitate monitoring of NHRS development and performance. The NHRS scores for the individual sub-functions can guide policymakers to locate sources of poor performance and to design interventions to address them. Electronic supplementary material The online version of this article (doi:10.1186/s12961-016-0121-4) contains supplementary material, which is available to authorized users.

BACKGROUND: In West Africa, the carriage of Group B Streptococcus (GBS), among infants is poorly characterised. We investigated co-carriage of GBS with other respiratory pathogens in the infants' nasopharynx in The Gambia. METHODS: We assessed the carriage, serotypes and antibiotic susceptibility of Beta-haemolytic Streptococci (BHS) groups A-G; along with the carriage of Streptococcus pneumoniae; Haemophilus influenzae; Staphylococcus aureus and Moraxella catarrhalis in 1200 two-month old infants. RESULTS: The BHS prevalence was 20.0 % and GBS dominated (13.8 %), particularly serotypes V and II; serotype V being negatively associated with H. Influenzae carriage (OR 0.41 [95 % CI: 0.18-0.93], p = 0.033). Although co-colonization of GBS and other BHS was not seen, colonization with GBS was positively associated with S. aureus (OR 1.89 [95 % CI: 1.33-2.69], P < 0.001) and negatively associated with S. pneumoniae (OR 0.47 [95 % CI: 0.33-0.67], p < 0.001) and M. catarrhalis (OR 0.61 [95 % CI: 0.40-0.92], p = 0.017). ≥ 89 % of GBS isolates were susceptible to most antibiotics tested, except for tetracycline resistance, which was 89 %. CONCLUSION: This study provides baseline data on the carriage of GBS in two month old infants from West Africa. The dominant serotypes of GBS in this setting are serotypes V and II. This may be important for future GBS vaccine development for the West African sub-region.

Epidemiological differences exist between Mycobacterium africanum (Maf)- and Mycobacterium tuberculosis (Mtb)-infected patients, but to date, contributing host factors have not been characterised. We analysed clinical outcomes, as well as soluble markers and gene expression profiles in unstimulated, and ESAT6/CFP-10-, whole-Maf- and Mtb-stimulated blood samples of 26 Maf- and 49 Mtb-HIV-negative tuberculosis patients before, and after 2 and 6 months of anti-tuberculosis therapy. Before treatment, both groups had similar clinical parameters, but differed in few cytokines concentration and gene expression profiles. Following treatment the body mass index, skinfold thickness and chest X-ray scores showed greater improvement in the Mtb- compared to Maf-infected patients, after adjusting for age, sex and ethnicity (p = 0.02; 0.04 and 0.007, respectively). In addition, in unstimulated blood, IL-12p70, IL12A and TLR9 were significantly higher in Maf-infected patients, while IL-15, IL-8 and MIP-1α were higher in Mtb-infected patients. Overnight stimulation with ESAT-6/CFP-10 induced significantly higher levels of IFN-γ and TNF-α production, as well as gene expression of CCL4, IL1B and TLR4 in Mtb- compared to Maf-infected patients. Our study confirms differences in clinical features and immune genes expression and concentration of proteins associated with inflammatory processes between Mtb- and Maf-infected patients following anti-tuberculosis treatment These findings have public health implications for treatment regimens, and biomarkers for tuberculosis diagnosis and susceptibility., Author Summary In the Gambia tuberculosis is caused my two major lineages within the Mycobacterium tuberculosis complex (MTBC), M. tuberculosis lineages 4 and M. africanum lineage 6. Our analysis of 26 M. africanum- and 49 M. tuberculosis -HIV-negative tuberculosis patients’ clinic parameters and antigen-stimulated blood cytokines concentration and genes expression reveal that heterogeneous response to standard anti-tuberculosis treatment might depend on the diversity of MTBC lineages. Before treatment, the two groups of patients had similar clinical parameters, but greater improvement was observed in M. tuberculosis- compared to M. africanum -infected patients post-treatment. This was supported by higher production of inflammation-associated cytokines and genes in unstimulated blood samples from M. africanum-infected patients compared to those infected with M. tuberculosis, who instead had higher level of disease resolution cytokines. In contrast, there were lower cytokine responses in antigen-stimulated blood samples of M. africanum- compared to M. tuberculosis-infected patients post-treatment indicating a poorly recovered immune profile. Our results suggest that M. africanum patients respond relatively poorly to the standard anti-tuberculosis treatment or might have a pre-existing defective immune profile; this could explain why they succumb to less virulent mycobacteria.

Background As the World Health Organization (WHO) currently recommends that children be protected against 11 different pathogens, it is becoming increasingly necessary to administer multiple injectable vaccines during a single immunization visit. In this study we assess Gambian healthcare providers’ and infant caregivers’ attitudes and practices related to the administration of multiple injectable vaccines to a child at a single immunization visit before and after the 2015 introduction of inactivated polio vaccine (IPV). IPV introduction increased the number of injectable vaccines recommended for the 4-month immunization visit from two to three in The Gambia. Methods We conducted a cross-sectional questionnaire-based survey before and after the introduction of IPV at 4 months of age in a representative sample of all health facilities providing immunizations in The Gambia. Healthcare providers who administer vaccines at the selected health facilities and caregivers who brought infants for their 4 month immunization visit were surveyed. Findings Prior to IPV introduction, 9.9% of healthcare providers and 35.7% of infant caregivers expressed concern about a child receiving more than 2 injections in a single visit. Nevertheless, 98.8% and 90.9% of infants received all required vaccinations for the visit before and after IPV introduction, respectively. The only reason why vaccines were not received was vaccine stock-outs. Infant caregivers generally agreed that vaccinators could be trusted to provide accurate information regarding the number of vaccines that a child needed. Conclusion Healthcare providers and infant caregivers in this resource limited setting accepted an increase in the number of injectable vaccines administered at a single visit even though some expressed concerns about the increase.

CD4+ T cells are required for protection against tuberculosis (TB) disease progression, but interest in the role of antibodies in early protection, as biomarkers for disease status, and use in diagnostic tests has recently increased. In this study we analyzed plasma antibody levels in TB cases before and after treatment in both HIV-positive and -negative individuals and compared them with tuberculin skin test (TST+) (latently infected) household contacts (HHC). We also analyzed HHC that subsequently progressed to active disease within 2 years in order to see if antibodies play a role in protection against disease progression. We used a commercially available kit to 38 kDa antigen and lipoarabinomannan (LAM) and found that immunoglobulin (Ig) G levels were 4-fold higher in subjects with disease compared to latently infected controls ( ) and were 2-fold higher than pretreatment levels following successful TB treatment ( compared to both pretreated cases and latently infected controls). HIV infection resulted in low antibody levels regardless of disease status or treatment outcome. Furthermore, levels in disease progressors (incident cases) were similar to nonprogressors and were not elevated until just prior to disease progression confirming previous reports that IgG antibodies, at least in the periphery, do not confer protection against TB disease progression.

BACKGROUND Directly observed treatment short-course (DOTS) strategy is an effective mode of treating TB. We aimed to study the cost effectiveness and patients' satisfaction with home based direct observation of treatment (DOT), an innovative approach to community-based DOT (CBDOT) and hospital based DOT (HBDOT). METHODS A randomized controlled trial involving 150 newly diagnosed pulmonary TB patients in four TB clinics in Ile Ife , Nigeria, was done. They were randomly assigned to receive treatment with anti TB drugs for the intensive phase administered at home by a TB worker (CBDOT) or at the hospital (HBDOT). Outcome measures were treatment completion/default rates, cost effectiveness and patients' satisfaction with care using a 13 item patients satisfaction questionnaire (PS-13) at 2 months. This trial was registered with pactr.org: number PACTR 201503001058381. RESULTS At the end of intensive phase, 15/75 (20%) and 2/75 (3%) of patients in the HBDOT and CBDOT, respectively had defaulted from treatment, p= 0.01. Of those with pretreatment positive sputum smear, 97% (68/70) on CBDOT and 54/67 (81%) on HBDOT were sputum negative for AFB at the end of 2 months of treatment, p=0.01. The CBDOT method was associated with a higher patient satisfaction score compared with HBDOT (OR 3.1; 95% CI 1.25-7.70), p=0.001.The total cost for patients was higher in HBDOT (US$159.38) compared with the CBDOT (US$89.52). The incremental cost effectiveness ratio was US$410 per patient who completed the intensive phase treatment with CBDOT. CONCLUSIONS CBDOT is a cost effective approach associated with better compliance to treatment and better patient satisfaction compared to HBDOT.

Background The increasing emphasis on research, development and innovation for health in providing solutions to the high burden of diseases in the African Region has warranted a proliferation of studies including clinical trials. This changing public health landscape requires that countries develop adequate ethics review capacities to protect and minimize risks to study participants. Therefore, this study assessed the readiness of national ethics committees to respond to challenges posed by a globalized biomedical research system which is constantly challenged by new public health threats, rapid scientific and technological advancements affecting biomedical research and development, delivery and manufacture of vaccines and therapies, and health technology transfer. Methods This is a descriptive study, which used a questionnaire structured to elicit information on the existence of relevant national legal frameworks, mechanisms for ethical review; as well as capacity requirements for national ethics committees. The questionnaire was available in English and French and was sent to 41 of the then 46 Member States of the WHO African Region, excluding the five Lusophone Member States. Information was gathered from senior officials in ministries of health, who by virtue of their offices were considered to have expert knowledge of research ethics review systems in their respective countries. Results Thirty three of the 41 countries (80.5 %) responded. Thirty (90.9 %) of respondent countries had a national ethics review committee (NEC); 79 % of which were established by law. Twenty-five (83.3 %) NECs had secretarial and administrative support. Over 50 % of countries with NECs indicated a need for capacity strengthening through periodic training on international guidelines for health research (including clinical trials) ethics; and allocation of funds for administrative and secretariat support. Conclusions Despite the existing training initiatives, the Region still experiences a shortage of professionals trained in health research ethics/ethicists. Committees continue to face various capacity needs especially for evaluating clinical trials, for monitoring ongoing research, database management and for accrediting institutional ethics committees. Given the growing number of clinical trials involving human participants in the African Region, there is urgent need for supporting countries without NECs to establish them; capacity strengthening where they exist; and creation of a regional network and joint ethical review mechanisms, whose membership would be open to all NECs of the Region.

Zinc deficiency is widespread and tends to mirror the distribution of infectious diseases prevalent in the developing world. Despite numerous observational studies suggesting a key role for zinc in human immunity and an involvement in disease pathogenesis, the underlying mechanisms remain poorly understood, and zinc intervention trials across a range of diseases have yielded mixed results. There is suggestive evidence that zinc supplementation may reduce initial susceptibility to pneumonia (i.e. preventive), but interpretation is confounded by the use of varied and imprecise diagnostic criteria. Evidence for a therapeutic (i.e. lower pneumonia severity and duration) effect of adjunctive zinc in pre- existing disease is less secure and similarly confounded. In neither case has there been substantive research into the putative mechanisms by which zinc could be beneficial. Animal studies suggest a beneficial role for zinc in T cell immunity; with deficiency resulting in involution of the thymus, which is the seat of T cell development. Here we review the evidence that zinc may play a critical role in human infectious diseases immunity through effects on T cell generation and mediation of cytokine production. Additional mechanisms may involve a role in the removal of metabolic toxins via free radical scavenger molecules for which zinc is an essential cofactor. We review the theory and existing evidence to support that zinc supplementation promotes the induction of T cell immunity to control infection and ameliorate immunopathology including excess inflammation. This is a potential route by which respiratory tissue regeneration may be achieved following respiratory tract infections in children benefiting from zinc adjunct therapy.

Objectives/Background Mycobacterium africanum that causes 40% of tuberculosis (TB) in West Africa grows more slowly in culture and has similar transmission capacity compared with Mycobacterium tuberculosis, but M. africanum-exposed contacts progress more slowly to active disease. The presence of lipid body (LB) containing M. tuberculosis complex (MTBC) cells in sputum samples has been associated with mycobacterial transcriptomes indicating slow or no growth and persister-like antibiotic tolerance. Slow-growing bacilli have been found to display a persister-like phenotype with the accumulation of LBs and drug tolerance. Our previous study showed that the body mass index and lung damage resolution on chest X-ray were significantly improved slower in M. africanum-infected patients posttreatment than in M. tuberculosis-infected patients; however, the reason for this remains unclear. Therefore, we hypothesized that these differences could be either due to significant differences in drug resistance between the MTBC lineages or a difference in their content of persisters, as indicated by the percentage of LP-positive bacilli in sputum. Methods Sputum isolates collected before treatment from patients with TB were subjected to drug susceptibility testing using the BD BACTEC MGIT 960 SIRE kit. The percentage of acid-fast bacilli (AFB) and LB-positive bacilli in pretreatment sputum was determined by a dual staining procedure using Auramine O and LipidTOX Red neutral lipid stain, respectively, and fluorescence microscopy imaging. Results Out of the 77 isolates tested, 9 showed resistance to at least one drug and only 2 showed multidrug (rifampicin and isoniazid) resistance among M. tuberculosis-infected patients. The percentage of AFB-positive smears was similar between the two groups (p = 0.821), whereas that of LP-positive bacilli was significantly higher (p = 0.0059) in M. africanum-infected patients’ sputa (n = 24) than in M. tuberculosis-infected patients’ sputa (n = 36). In addition, the bacillary lengths were significantly higher in M. africanum-infected patients’ sputa than in M. tuberculosis-infected patients’ sputa (p = 0.0007). A high frequency of LP-positive bacilli in pretreatment sputum was associated with a poor body mass index and lung damage on chest X-ray improvement following anti-TB treatment in both the groups (r2 = 0.022; p = 0.017). Conclusion The slow clinical recovery of M. africanum-infected patients compared with M. tuberculosis-infected patients posttreatment may be at least partially associated with the persistence of drug-tolerant “fat and lazy” bacilli.

The study of the contacts of patients with tuberculosis has a long history. Where tuberculosis is endemic, regular recruitment of tuberculosis cases and their household contacts can be done for research and strategic intervention. This recruitment provides a platform whereby host, pathogen, and environmental factors related to tuberculosis can be investigated and new interventions can be assessed. We describe the types of study possible within a tuberculosis case-contact study platform and its essential components, including recruitment and follow-up of the patients with tuberculosis, their household contacts and community controls, assessments and sampling, and data management and processing. Sample handling and storage, local engagement, ethical challenges, and the strengths and weaknesses of study design are all important issues in case-contact research. A case-contact study platform is a powerful research tool to answer fundamental questions in tuberculosis and has relevance to the study of other major infectious diseases.

Background: We compared the performance of tuberculin skin test (TST), Quantiferon-TB Gold in-tube (QFT-GIT), and T-SPOT.TB in diagnosing latent tuberculosis (LTBI) among childhood TB contacts in a TB endemic setting with high BCG coverage. We evaluated the performance of interferon gamma release assays (IGRAs) and TST when combined in an algorithm. Methods: Childhood contacts of newly diagnosed TB patients were tested with TST, QFT-GIT, and T-SPOT. The level of exposure in contacts was categorized according to whether they slept in the same room, same house, or a different house as the index case. For the evaluation of combined test performance, prior estimates for prevalence of latent TB were used in Bayesian models that assumed conditional dependence between tests. Results: A total of 285 children were recruited. Overall, 26.5%, 33.0%, and 33.5% were positive for TST, T-SPOT, or QFT-GIT, respectively. All 3 tests responded to the gradient of sleeping proximity to the index case. Neither TST nor IGRA results were confounded by BCG vaccination. There was moderate agreement ( 0.40 – 0.68) between all 3 tests. Combination of either IGRA with TST increased sensitivity (by 9.3%–9.6%) especially in contacts in the highest exposure category but was associated with loss of specificity (9.9%–11.3%). Conclusion: IGRAs and TST are similar in their diagnostic performance for LTBI. An approximate 10% sensitivity benefit for using the TST and an IGRA in combination is associated with a slightly greater specificity loss. Testing strategies combining an IGRA and TST with an “or” statement may be useful only in situations where there is a high pretest probability of latent infection.

Background. Streptococcus pneumoniae is a leading cause of vaccine-preventable disease worldwide. Pneumococcal protein antigens are currently under study as components of potential vaccines that offer protection against multiple serotypes. We have therefore characterized T cell pneumococcal immunity acquired through asymptomatic carriage. Methods. Peripheral blood mononuclear cells from 40 healthy Gambian adults were stimulated with supernatants derived from S. pneumoniae strain (D39), 2 isogenic mutant strains lacking either pneumolysin or choline binding protein A, and recombinant pneumolysin. Immune responses were measured by cellular proliferation and by interleukin-10 (IL-10) and interferon-γ (IFN-γ) enzyme-linked immunosorbent spot and bioplex cytokine assays. Nasopharyngeal swabs were cultured to determine carriage rates. Results. S. pneumoniae nasopharyngeal carriage was detected in 60% of individuals. Both effector and resting (or central) CD4 - T cell memory were frequently present to a range of pneumococcal antigens. However, the level of the effector memory response did not relate to current nasopharyngeal carriage. Pneumolysin was not immunodominant in these T cell responses but induced a distinct proinflammatory profile (high IFN-7, IL-12[p40], and L-17 levels and low IL-10 and IL-13 levels). Conclusions. In this population, T cell-mediated immunological memory potentially capable of pathogen clearance and immune surveillance is common but is not associated with the absolute interruption of pneumococcal carriage. How this naturally acquired immune memory influences pneumococcal vaccine efficacy remains to be determined. © 2009 by the Infectious Diseases Society of America. All rights reserved.

Tuberculosis (TB) remains a global health problem. The solution involves development of an effective vaccine, but has been limited by incomplete understanding of what constitutes protective immunity during natural infection with Mycobacterium tuberculosis. In this study, M. tuberculosis-specific responses following an overnight whole-blood assay were assessed by intracellular cytokine staining and luminex, and compared between TB cases and exposed household contacts. TB cases had significantly higher levels of IFN-γ+TNF-α+IL-2+CD4+T cells compared with contacts. TB cases also had a significantly higher proportion of cells single-positive for TNF-α, but lower proportion of cells producing IL-2 alone and these differences were seen for both CD4+and CD8+ T cells. Cytokine profiles from culture supernatants were significantly biased toward a Th1 phenotype (IFN-γ and IL-12(p40)) together with a complete abrogation of IL-17 secretion in TB cases. Our data indicate that despite a robust response to TB antigens in active TB disease, changes in the pattern of cytokine production between TB infection and disease clearly contribute to disease progression.

Interferon gamma remains a key effector molecule that is still widely used as the most informative biomarker for screening human immune responses against tuberculosis, particularly in ELISPOT assays. We investigated the participation of CD4(+) and CD8(+) T lymphocytes in the PBMC responses to Mycobacterium tuberculosis (Mtb) specific antigens in 33 TB cases and 49 contacts. Responses to ESAT-6 were higher than CFP-10. There was no significant difference in responses to both Mtb antigens between cases and contacts. PBMCs response to ESAT-6 but not CFP-10 in cases was significantly reduced by depletion of CD4(+) cells whereas CD8(+) cell depletion had no impact. In conclusion, ESAT-6 is a more recognized antigen in this population, and CD4(+) lymphocytes are the main participants in IFN-gamma response by ELISPOT. Thus, a decline of CD4(+) T lymphocytes below a critical level might affect the sensitivity of IFN-gamma release assays for detecting Mtb infection.

TheMycobacterium bovisBCG vaccine has a poor record of efficacy in low-income tropical settings. Against this background, we evaluated the immune response of infants to mycobacterial antigens over the 2 years following BCG vaccination at birth by measuring the gamma interferon (IFN-γ), interleukin-2 (IL-2), and CD154 responses of CD4 T cells. Similar numbers of cells expressed IFN-γ in infants, 4- to 5-year-old children, and adults, while CD154 was not expressed at comparable levels until the second year of infancy. The IL-2 response remained relatively low in infants, children, and adults but correlated negatively with mother's body mass index and was highest among infants born to Mandinka mothers. Similarly, infants born in the wet season had a stronger CD154 response than those born in the dry season throughout the 2 years of the study. We conclude that the prenatal and perinatal environments have a lasting effect on the response of infants to the BCG vaccine.