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1.  Public stewardship of private for-profit healthcare providers in low- and middle-income countries 
Background
Governments use different approaches to ensure that private for-profit healthcare services meet certain quality standards. Such government guidance, referred to as public stewardship, encompasses government policies, regulatory mechanisms, and implementation strategies for ensuring accountability in the delivery of services. However, the effectiveness of these strategies in low- and middle-income countries (LMICs) have not been the subject of a systematic review.
Objectives
To assess the effects of public sector regulation, training, or co-ordination of the private for-profit health sector in low- and middle-income countries.
Search methods
For related systematic reviews, we searched the Cochrane Database of Systematic Reviews (CDSR) 2015, Issue 4; Database of Abstracts of Reviews of Effectiveness (DARE) 2015, Issue 1; Health Technology Assessment Database (HTA) 2015, Issue 1; all part of The Cochrane Library, and searched 28 April 2015. For primary studies, we searched MEDLINE, Epub Ahead of Print, In-Process & Other Non-Indexed Citations, MEDLINE Daily and MEDLINE 1946 to Present, OvidSP (searched 16 June 2016); Science Citation Index and Social Sciences Citation Index 1987 to present, and Emerging Sources Citation Index 2015 to present, ISI Web of Science (searched 3 May 2016 for papers citing included studies); Cochrane Central Register of Controlled Trials (CENTRAL), 2015, Issue 3, part of The Cochrane Library (including the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register) (searched 28 April 2015); Embase 1980 to 2015 Week 17, OvidSP (searched 28 April 2015); Global Health 1973 to 2015 Week 16, OvidSP (searched 30 April 2015); WHOLIS, WHO (searched 30 April 2015); Science Citation Index and Social Sciences Citation Index 1975 to present, ISI Web of Science (searched 30 April 2015); Health Management, ProQuest (searched 22 November 2013). In addition, in April 2016, we searched the reference lists of relevant articles, WHO International Clinical Trials Registry Platform, Clinicaltrials.gov, and various electronic databases of grey literature.
Selection criteria
Randomised trials, non-randomised trials, interrupted time series studies, or controlled before-after studies.
Data collection and analysis
Two authors independently assessed study eligibility and extracted data, comparing their results and resolving discrepancies by consensus. We expressed study results as risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CI), where appropriate, and assessed the certainty of the evidence using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). We did not conduct meta-analysis because of heterogeneity of interventions and study designs.
Main results
We identified 20,177 records, 50 of them potentially eligible. We excluded 39 potentially eligible studies because they did not involve a rigorous evaluation of training, regulation, or co-ordination of private for-profit healthcare providers in LMICs; five studies identified after the review was submitted are awaiting assessment; and six studies met our inclusion criteria. Two included studies assessed training alone; one assessed regulation alone; three assessed a multifaceted intervention involving training and regulation; and none assessed co-ordination. All six included studies targeted private for-profit pharmacy workers in Africa and Asia.
Three studies found that training probably increases sale of oral rehydration solution (one trial in Kenya, 106 pharmacies: RR 3.04, 95% CI 1.37 to 6.75; and one trial in Indonesia, 87 pharmacies: RR 1.41, 95% CI 1.03 to 1.93) and dispensing of anti-malarial drugs (one trial in Kenya, 293 pharmacies: RR 8.76, 95% CI 0.94 to 81.81); moderate-certainty evidence.
One study conducted in the Lao People's Democratic Republic shows that regulation of the distribution and sale of registered pharmaceutical products may improve composite pharmacy indicators (one trial, 115 pharmacies: improvements in four of six pharmacy indicators; low-certainty evidence).
The outcome in three multifaceted intervention studies was the quality of pharmacy practice; including the ability to ask questions, give advice, and provide appropriate treatment. The trials applied regulation, training, and peer influence in sequence; and the study design does not permit separation of the effects of the different interventions. Two trials conducted among 136 pharmacies in Vietnam found that the multifaceted intervention may improve the quality of pharmacy practice; but the third study, involving 146 pharmacies in Vietnam and Thailand, found that the intervention may have little or no effects on the quality of pharmacy practice (low-certainty evidence).
Only two studies (both conducted in Vietnam) reported cost data, with no rigorous assessment of the economic implications of implementing the interventions in resource-constrained settings. No study reported data on equity, mortality, morbidity, adverse effects, satisfaction, or attitudes.
Authors' conclusions
Training probably improves quality of care (i.e. adherence to recommended practice), regulation may improve quality of care, and we are uncertain about the effects of co-ordination on quality of private for-profit healthcare services in LMICs. The likelihood that further research will find the effect of training to be substantially different from the results of this review is moderate; implying that monitoring of the impact is likely to be needed if training is implemented. The low certainty of the evidence for regulation implies that the likelihood of further research finding the effect of regulation to be substantially different from the results of this review is high. Therefore, an impact evaluation is warranted if government regulation of private for-profit providers is implemented in LMICs. Rigorous evaluations of these interventions should also assess other outcomes such as impacts on equity, cost implications, mortality, morbidity, and adverse effects.
Government regulation, training, or co-ordination of private for-profit health care in low- and middle-income countries
What is the aim of this review?
The aim of this Cochrane review was to evaluate the effect of government regulation, training, or co-ordination of private for-profit health care in low- and middle-income countries.
We collected and analysed all relevant studies to answer this question and included six studies in the review.
Why do governments regulate, train or co-ordinate private healthcare providers?
In many low- and middle-income countries, the public sector is not able to provide high quality healthcare services to all citizens, and private healthcare providers therefore play a major role. However, there is concern that health care provided by the private sector is not always of high quality and that recommended practices and guidelines are not always followed. Governments therefore use different approaches to ensure that private for-profit healthcare services meet certain quality standards. This type of government guidance is referred to as 'public stewardship' and can for instance involve training and education for private for-profit healthcare providers; introduction of regulations where quality standards are set and enforced; and co-ordination between private for-profit and public sector healthcare providers, for instance, creating referral systems between the private for-profit and public sectors.
What happens when governments regulate, train or co-ordinate private, for-profit health care providers?
Training In two studies in Kenya and Indonesia, the Ministry of Health offered private drug sellers short training sessions on prescribing and dispensing drugs. These sellers were compared to drug sellers who were not offered training. The studies suggested that training probably improves the quality of healthcare services.
Regulation In one study in the Lao People's Democratic Republic, the Ministry of Health supervised private pharmacy services in certain districts over a three-month period, applied sanctions when rules were broken, and offered information about areas needing improvement. These districts were compared to districts without this enhanced supervision. The study suggested that this enhanced regulation may make little or no difference to quality of care.
Training and regulation In three studies in Vietnam and Thailand, private pharmacies in some districts received educational visits as well as visits from pharmacy inspectors to enforce regulations. These districts were compared to districts that did not receive any visits. The studies suggested that these types of visits may improve quality of care.
Co-ordination The review did not find any eligible study that assessed the effects of co-ordination on quality of care.
How up-to-date is this review?
The review authors searched for studies that had been published up to June 2016.
doi:10.1002/14651858.CD009855.pub2
PMCID: PMC5014877  PMID: 27510030
2.  Human newborn bacille Calmette–Guérin vaccination and risk of tuberculosis disease: a case-control study 
BMC Medicine  2016;14:76.
Background
An incomplete understanding of the immunological mechanisms underlying protection against tuberculosis (TB) hampers the development of new vaccines against TB. We aimed to define host correlates of prospective risk of TB disease following bacille Calmette–Guérin (BCG) vaccination.
Methods
In this study, 5,726 infants vaccinated with BCG at birth were enrolled. Host responses in blood collected at 10 weeks of age were compared between infants who developed pulmonary TB disease during 2 years of follow-up (cases) and those who remained healthy (controls).
Results
Comprehensive gene expression and cellular and soluble marker analysis failed to identify a correlate of risk. We showed that distinct host responses after BCG vaccination may be the reason: two major clusters of gene expression, with different myeloid and lymphoid activation and inflammatory patterns, were evident when all infants were examined together. Cases from each cluster demonstrated distinct patterns of gene expression, which were confirmed by cellular assays.
Conclusions
Distinct patterns of host responses to Mycobacterium bovis BCG suggest that novel TB vaccines may also elicit distinct patterns of host responses. This diversity should be considered in future TB vaccine development.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-016-0617-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-016-0617-3
PMCID: PMC4869393  PMID: 27183822
Tuberculosis; Vaccine; Correlates of risk; Systems biology
3.  The Role of Clinical Symptoms in the Diagnosis of Intrathoracic Tuberculosis in Young Children 
Supplemental Digital Content is available in the text.
Background:
Childhood tuberculosis (TB) is usually Mycobacterium tuberculosis (MTB) culture negative. Furthermore, clinical presentation may be altered by active case finding, isoniazid prophylaxis and early treatment. We aimed to establish the value of presenting symptoms for intrathoracic TB case diagnosis among young children.
Methods:
Healthy, HIV-uninfected, South African infants in an efficacy trial of a novel TB vaccine (MVA85A) were followed for 2 years for suspected TB. When suspected, investigation followed a standardized algorithm comprising symptom history, QuantiFERON Gold-in-Tube, chest radiography (CXR), MTB culture and Xpert MTB/RIF from paired gastric lavage and induced sputa. Adjusted odds ratios and 95% confidence intervals describe the associations between symptoms and positive MTB culture or Xpert MTB/RIF, and CXR compatible with intrathoracic TB.
Results:
Persistent cough was present in 172/1017 (16.9%) of the children investigated for TB. MTB culture/Xpert MTB/RIF was positive in 38/1017 children (3.7%); and CXR was positive, that is, compatible with intrathoracic TB, in 131/1017 children (12.9%). Children with persistent cough had more than triple the odds of a positive MTB culture/Xpert MTB/RIF (adjusted odds ratios: 3.3, 95% confidence interval: 1.5–7.0) and positive CXR (adjusted odds ratios: 3.5, 95% confidence interval: 2.2–5.5). Persistent cough was the only symptom that differentiated children with severe (56.5%) from nonsevere intrathoracic TB disease (28.2%; P = 0.001).
Conclusion:
Persistent cough was the cardinal diagnostic symptom associated with microbiologic and radiologic evidence, and disease severity, of intrathoracic TB. Symptom-based definitions of TB disease for diagnostic, preventive and therapeutic studies should prioritize persistent cough above other symptoms compatible with childhood TB.
doi:10.1097/INF.0000000000000847
PMCID: PMC4604651  PMID: 26226446
diagnosis; tuberculosis; culture; children; symptoms
4.  The Role of Clinical Symptoms in the Diagnosis of Intrathoracic Tuberculosis in Young Children 
Background
Childhood tuberculosis (TB) is usually Mycobacterium tuberculosis (MTB) culture negative. Further, clinical presentation may be altered by active case-finding, isoniazid prophylaxis, and early treatment. We aimed to establish the value of presenting symptoms for intrathoracic TB case diagnosis among young children.
Methods
Healthy, HIV-uninfected, South African infants in an efficacy trial of a novel TB vaccine (MVA85A) were followed for two years for suspected TB. When suspected, investigation followed a standardized algorithm comprising symptom history, QuantiFERON Gold-in-Tube (QFT), chest radiography (CXR), MTB culture and Xpert MTB/RIF from paired gastric lavage and induced sputa. Adjusted odds ratios (AOR) and 95% confidence intervals (CI) describe the associations between symptoms and positive MTB culture or Xpert MTB/RIF; and CXR compatible with intrathoracic TB.
Results
Persistent cough was present in 172/1,017 (16.9%) of the children investigated for TB. MTB culture/Xpert MTB/RIF was positive in 38/1,017 children (3.7%); and CXR was positive, i.e. compatible with intrathoracic TB, in 131/1,017 children (12.9%). Children with persistent cough had more than triple the odds of a positive MTB culture/Xpert MTB/RIF (AOR 3.3; CI 1.5 - 7.0) and positive CXR (AOR 3.5; CI 2.2 - 5.5). Persistent cough was the only symptom that differentiated children with severe (56.5%) from non-severe intrathoracic TB disease (28.2%) (p=0.001).
Conclusion
Persistent cough was the cardinal diagnostic symptom associated with microbiologic and radiologic evidence, and disease severity, of intrathoracic TB. Symptom-based definitions of TB disease for diagnostic, preventive and therapeutic studies should prioritize persistent cough above other symptoms compatible with childhood TB.
doi:10.1097/INF.0000000000000847
PMCID: PMC4604651  PMID: 26226446
Diagnosis; tuberculosis; culture; children; symptoms
5.  Varicella zoster virus-associated morbidity and mortality in Africa: a systematic review protocol 
BMJ Open  2016;6(4):e010213.
Introduction
Varicella zoster virus (VZV) causes varicella (chicken pox) and herpes zoster (shingles). Worldwide, these diseases are associated with significant morbidity. Most of the epidemiological data on VZV come from high income countries. There are few data on VZV in Africa, where tropical climates and high HIV/AIDS prevalence rates are expected to impact the epidemiology of VZV. Safe and effective vaccinations for both varicella and herpes zoster exist, but are not routinely used in Africa. There are very few data available on VZV disease burden in Africa to guide the introduction of these vaccines on the continent. Our aim is to conduct a systematic review of the VZV-associated morbidity and mortality in Africa, which will provide critical information that could be used to develop vaccination policies against these diseases in Africa.
Methods and analysis
Electronic databases will be searched and all studies published after 1974 that meet predefined criteria will be assessed. The primary outcomes for the study are VZV incidence/prevalence, hospitalisation rates and total death rates. The secondary outcome for this study is the proportion of VZV hospitalisations and/or deaths associated with HIV/AIDS. Two reviewers will screen the titles and abstracts, and then independently review the full texts, to determine if studies are eligible for inclusion. A risk of bias and quality assessment tool will be used to score all included studies. Following standardised data extraction, a trend analysis using R-programming software will be conducted to investigate the trend of VZV. Depending on the characteristics of included studies, subgroup analyses will be performed. This review will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.
Ethics and dissemination
As this is a protocol for a systematic review, which will use already published data, no ethics approval is required. Findings will be disseminated in peer-reviewed journals.
Trial registration number
CRD42015026144.
doi:10.1136/bmjopen-2015-010213
PMCID: PMC4838733  PMID: 27098823
Varicella zoster virus; chicken pox; shingles; Africa; incidence
6.  Qualification of a whole blood intracellular cytokine staining assay to measure mycobacteria-specific CD4 and CD8 T cell immunity by flow cytometry☆ 
Background
Qualified or validated assays are essential in clinical trials. Short-term stimulation of whole blood and intracellular cytokine staining assay is commonly used to measure immunogenicity in tuberculosis vaccine clinical trials. Previously, the short-term stimulation process of whole blood with BCG was optimized. We aimed to qualify the intracellular cytokine staining process and assess the effects of long-term cryopreservation. Our hypotheses were that the assay is robust in the measurement of the mycobacteria-specific T cells, and long-term cryopreservation of fixed cells from stimulated whole blood would not compromise reliable measurement of mycobacteria induced CD4 T cell immunity.
Methods
Whole blood from healthy adults was collected in sodium heparinized tubes. The blood was left unstimulated or stimulated with mycobacterial antigens or mitogens for 12 h. Cells were harvested, fixed and multiple aliquots from each participant cryopreserved. Later, mycobacteria-specific CD4 and CD8 T cells expressing IFN-γ, TNF-α, IL-2 and IL-17 were quantitated by flow cytometry. Assay performance characteristics evaluated included limit of quantification and detection, reproducibility, precision, robustness, specificity and sensitivity. To assess the effects of long-term cryopreservation, fixed cells from the stimulated bloods were analysed one week post-cryopreservation and at 3-month intervals over a 3-year period.
Results
The limit of quantification for the different cytokines was variable: 0.04% for frequencies of IFN-γ- and IL-2-expressing T cells and less than 0.01% for TNF-α- and IL-17-expressing T cells. When measurement of the mycobacteria-specific T cells was assessed at levels above the detection limit, the whole blood intracellular cytokine assay showed high precision that was operator-independent. The assay was also robust: variation in staining conditions including temperature (4 °C or 20–23 °C) and time (45, 60 or 90 min) did not markedly affect quantification of specific T cells. Finally, prolonged periods of cryopreservation also did not significantly influence quantification of mycobacteria-specific CD4 T cells.
Conclusions
The whole blood intracellular cytokine assay is robust and reliable in quantification of the mycobacteria-specific T cells and is not significantly affected by cryopreservation of fixed cells.
doi:10.1016/j.jim.2014.12.003
PMCID: PMC4339399  PMID: 25523923
Qualification; Whole blood; Intracellular cytokine staining assay; Flow cytometry
7.  Epidemiology of hepatitis A virus in Africa among persons aged 1–10 years: a systematic review protocol 
Systematic Reviews  2015;4:129.
Background
Africa is considered an area of high endemicity for hepatitis A virus infection. However, in the past two decades, tremendous progress has been made in improving water sources and sanitation which are risk factors for hepatitis A virus infection. Recent studies suggest that several African countries could be in epidemiological transitions due to the evident socio-economic development. As a result, there may be a decrease in the exposure to and infection with hepatitis A virus at an early age. Understanding and mapping the shifting epidemiology is vital in developing control measures against the disease. We are conducting a comprehensive systematic review study to document the current burden of hepatitis A virus infection in Africa.
Methods
Our population of interest is children between 1 and 10 years in any African country. We will select cross-sectional, case-control, and cohort studies that have tested hepatitis A virus infection by serological confirmation of antibodies against the virus. We will search for eligible studies published without language restrictions from PubMed, Scopus, Africa-wide, Web of Science, and WHOLIS as well as the reference lists of the relevant articles. Two authors will independently review the search outputs, select eligible articles, and extract pre-defined study outcomes. Inconsistencies will be resolved by discussion and consensus among the authors.
Data will be extracted using a standardised data collection form. Trends in the prevalence and/or incidence will be evaluated by urban and rural setting if sufficient data is available. Where there is sufficient homogeneity between studies, meta-analysis will also be conducted, otherwise the results will be presented in a narrative format.
Discussion
The systematic review will generate up-to-date information on the current burden of hepatitis A virus in Africa. This information may have implications on policy for hepatitis A vaccination on individual African countries.
Systematic review registration
CRD42015023764
doi:10.1186/s13643-015-0112-5
PMCID: PMC4589083  PMID: 26419360
8.  The burden of pertussis in low- and middle-income countries since the inception of the Expanded Programme on Immunization (EPI) in 1974: a systematic review protocol 
Systematic Reviews  2015;4:62.
Background
Vaccine against pertussis has been in use for several decades. Despite the widespread use of pertussis vaccine, evidence shows resurgence of pertussis in high-income countries. Pertussis surveillance data is largely missing from low- and middle-income countries (LMICs). Without data on trends of pertussis, it is difficult to review and amend pertussis control policies in any country. We propose conducting a systematic review to evaluate the burden and trends of pertussis in LMICs since 1974.
Methods/design
Common and medical subject heading (MeSH) terms for pertussis and LMICs will be used to search electronic databases for the relevant literature published between 1974 and December 2014. Only studies from LMICs that fulfils World Health Organisation (WHO) or CDC pertussis case definitions will be included. The studies must have a clear numerator and denominator in a well-defined population.
Risk of bias will be evaluated by assessing all qualifying full-text articles for quality and eligibility using a modified quality score assessment tool.
Standardised data extraction will be carried out after which descriptions of trends in the prevalence, incidence, as well as mortality rate and case fatality rate, will be done. Where sufficient data is available, the results will be stratified by age group, geography, location, vaccination and HIV status.
Discussion
The systematic review proposed by this protocol seeks to address the knowledge gap in the epidemiology of pertussis in LMICs for the first time. It is anticipated that the background epidemiological trends of pertussis in LMICs that our study will provide could be used in the planning for the control of pertussis.
Systematic review registration
PROSPERO CRD42015015159
doi:10.1186/s13643-015-0053-z
PMCID: PMC4419482  PMID: 25930111
Pertussis; Whooping cough; Burden; Prevalence; Incidence; LMICs
9.  Increasing the value of health research in the WHO African Region beyond 2015—reflecting on the past, celebrating the present and building the future: a bibliometric analysis 
BMJ Open  2015;5(3):e006340.
Objective
To assess the profile and determinants of health research productivity in Africa since the onset of the new millennium.
Design
Bibliometric analysis.
Data collection and synthesis
In November 2014, we searched PubMed for articles published between 2000 and 2014 from the WHO African Region, and obtained country-level indicators from World Bank data. We used Poisson regression to examine time trends in research publications and negative binomial regression to explore determinants of research publications.
Results
We identified 107 662 publications, with a median of 727 per country (range 25–31 757). Three countries (South Africa, Nigeria and Kenya) contributed 52% of the publications. The number of publications increased from 3623 in 2000 to 12 709 in 2014 (relative growth 251%). Similarly, the per cent share of worldwide research publications per year increased from 0.7% in 2000 to 1.3% in 2014. The trend analysis was also significant to confirm a continuous increase in health research publications from Africa, with productivity increasing by 10.3% per year (95% CIs +10.1% to +10.5%). The only independent predictor of publication outputs was national gross domestic product. For every one log US$ billion increase in gross domestic product, research publications rose by 105%: incidence rate ratio (IRR=2.05, 95% CI 1.39 to 3.04). The association of private health expenditure with publications was only marginally significant (IRR=1.86, 95% CI 1.00 to 3.47).
Conclusions
There has been a significant improvement in health research in the WHO African Region since 2000, with some individual countries already having strong research profiles. Countries of the region should implement the WHO Strategy on Research for Health: reinforcing the research culture (organisation); focusing research on key health challenges (priorities); strengthening national health research systems (capacity); encouraging good research practice (standards); and consolidating linkages between health research and action (translation).
doi:10.1136/bmjopen-2014-006340
PMCID: PMC4360830  PMID: 25770227
PUBLIC HEALTH; EPIDEMIOLOGY
10.  A bibliometric analysis of cancer research in South Africa: study protocol 
BMJ Open  2015;5(2):e006913.
Introduction
Cancer is an important and growing public health burden in South Africa (SA). Over the past few decades, there has been considerable scientific activity in cancer in SA. However, there has been limited analysis of cancer scientific publications. In this paper, we present a protocol for bibliometric analysis of cancer research conducted in SA.
Methods and analysis
A comprehensive search of the journal databases PubMed, SCOPUS, Web of Science and EBSCO will be conducted to identify and retrieve data from primary peer-reviewed cancer research articles using a set of consensus search words. Articles that involve cancer research conducted in SA or using biological or clinical data from South African participants and published between 2004 and 2014 will be included in the study. Two independent researchers will screen the articles for eligibility. Bibliometric indicators and study characteristics will be extracted, entered into a database and analysed. The cancer disease site will be recorded and research will be classified using the Common Scientific Outline system. Data obtained will be analysed to determine SA's publication productivity index in cancer research. Annual trends in bibliometric indicators and the type of cancer research will be determined. The degree of collaboration in research conducted in SA will be analysed using co-authorship matrix software. A publication to disease type ratio will be used to assess scientific production relative to disease burden.
Ethics and dissemination
As this analysis will draw on publicly available data and does not directly involve human participants, ethical review is not required. We anticipate that the bibliometric analysis will identify the trends in cancer research productivity and the extent to which cancer research is aligned to the local burden of disease. Results will be published in peer-reviewed journals and presented in a user-friendly format to relevant policymakers and funders.
doi:10.1136/bmjopen-2014-006913
PMCID: PMC4330326  PMID: 25678542
ONCOLOGY; PUBLIC HEALTH; MEDICAL HISTORY
11.  Safety of licensed vaccines in HIV-infected persons: a systematic review protocol 
Systematic Reviews  2014;3:101.
Background
Safety of vaccines remains a cornerstone of building public trust on the use of these cost-effective and life-saving public health interventions. In some settings, particularly Sub-Saharan Africa, there is a high prevalence of HIV infection and a high burden of vaccine-preventable diseases. There is evidence suggesting that the immunity induced by some commonly used vaccines is not durable in HIV-infected persons, and therefore, repeated vaccination may be considered to ensure optimal vaccine-induced immunity in this population. However, some vaccines, particularly the live vaccines, may be unsafe in HIV-infected persons. There is lack of evidence on the safety profile of commonly used vaccines among HIV-infected persons. We are therefore conducting a systematic review to assess the safety profile of routine vaccines administered to HIV-infected persons.
Methods/Design
We will select studies conducted in any setting where licensed and effective vaccines were administered to HIV-infected persons. We will search for eligible studies in PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, Africa-Wide, PDQ-Evidence and CINAHL as well as reference lists of relevant publications. We will screen search outputs, select studies and extract data in duplicate, resolving discrepancies by discussion and consensus.
Discussion
Globally, immunisation is a major public health strategy to mitigate morbidity and mortality caused by various infectious disease-causing agents. In general, there are efforts to increase vaccination coverage worldwide, and for these efforts to be successful, safety of the vaccines is paramount, even among people living with HIV, who in some situations may require repeated vaccination. Results from this systematic review will be discussed in the context of the safety of routine vaccines among HIV-infected persons. From the safety perspective, we will also discuss whether repeat vaccination strategies may be feasible among HIV-infected persons.
Systematic review registration
PROSPERO CRD42014009794.
doi:10.1186/2046-4053-3-101
PMCID: PMC4163552  PMID: 25212760
12.  Knowledge, attitudes and practices on adolescent vaccination among parents, teachers and adolescents in Africa: a systematic review protocol 
Systematic Reviews  2014;3:100.
Background
Vaccines are the most successful and cost-effective public health interventions available to avert vaccine-preventable diseases and deaths. Despite progress in the field of adolescent health, many young people in Africa still get sick and die from vaccine-preventable diseases due to lack of vaccination. Parents, adolescents and teachers are key players with regard to implementation of adolescent vaccination policies. Therefore, understanding their knowledge, attitudes and practices towards adolescent vaccination may provide clues on what can be done to improve vaccine uptake among adolescents. The aim of this study is to conduct a qualitative and quantitative systematic review on knowledge, attitudes and practices on adolescent vaccination among parents, teachers and adolescents in Africa.
Methods
We will include both quantitative and qualitative primary studies. Eligible quantitative studies include both intervention and observational studies. Qualitative studies to be included are focus group discussions, direct observations, in-depth interviews and case ethnographic studies. We will search PubMed, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, WHOLIS, Africa Wide and CINAHL for eligible studies with no time and language limits. We will also check reference lists of included studies for other eligible reports. Two authors will independently screen the search output, select studies and extract data, resolving discrepancies by consensus and discussion. We will analyse qualitative data using thematic analysis where applicable, and quantitative studies findings will be presented in a narrative synthesis form based on the outcomes.
Discussion
The findings from this systematic review will guide the identification of gaps on knowledge, attitudes and practices among the key role players on adolescent vaccination. We anticipate that our findings will guide the development of adolescent-focused vaccination policy in Africa, which is virtually non-existent at present.
Systematic review registration
This review is registered with PROSPERO, registration number CRD42014010395.
doi:10.1186/2046-4053-3-100
PMCID: PMC4161692  PMID: 25200458
Adolescents; Parents; Teachers; Knowledge attitudes and practice; Vaccination barriers; Africa
13.  The use of supplementary immunisation activities to improve uptake of current and future vaccines in low-income and middle-income countries: a systematic review protocol 
BMJ Open  2014;4(2):e004429.
Introduction
Immunisation coverage data in low-income and middle-income countries (LMICs) suggest that more strategies need to be implemented to achieve and sustain optimal vaccine uptake. Among possible strategies to improve immunisation coverage are supplementary immunisation activities (SIAs). We are therefore interested in conducting a systematic review to assess whether SIAs complement routine immunisation programmes to improve vaccination coverage and prevent disease outbreaks.
Methods
Our systematic review will focus on studies conducted in LMICs. With the help of an information specialist, we will search for eligible studies in PubMed, Web of Science, Scopus, Africa-Wide, Cochrane Library, WHOLIS, CINAHL, PDQ-Evidence as well as reference lists of relevant publications. Additionally, we will contact relevant organisations such as WHO and GAVI. Two authors will independently extract data from eligible studies and independently assess risk of bias by assessing the adequacy of study characteristics. The primary meta-analysis will use random effects models due to expected interstudies heterogeneity. Dichotomous data will be analysed using relative risk and continuous data using weighted mean differences (or standardised mean differences), both with 95% CIs.
Discussion
The findings from this systematic review will be discussed in the context of strengthening routine childhood immunisation services, routine adolescent immunisation services and introduction of future vaccines against tuberculosis and HIV/AIDS.
Study strengths
Unbiased selection of many studies conducted in different settings. This will strengthen the validity of the review results.
Study limitations
Heterogeneity of the study settings of the low-income, lower-middle-income and upper-middle-income countries as well as heterogeneity in study designs.
doi:10.1136/bmjopen-2013-004429
PMCID: PMC3932000  PMID: 24549166
PUBLIC HEALTH; PREVENTIVE MEDICINE
14.  Induction and Regulation of T-Cell Immunity by the Novel Tuberculosis Vaccine M72/AS01 in South African Adults 
Rationale: Tuberculosis (TB) is a major cause of morbidity and mortality worldwide, thus there is an urgent need for novel TB vaccines.
Objectives: We investigated a novel TB vaccine candidate, M72/AS01, in a phase IIa trial of bacille Calmette-Guérin–vaccinated, HIV-uninfected, and Mycobacterium tuberculosis (Mtb)–infected and -uninfected adults in South Africa.
Methods: Two doses of M72/AS01 were administered to healthy adults, with and without latent Mtb infection. Participants were monitored for 7 months after the first dose; cytokine production profiles, cell cycling, and regulatory phenotypes of vaccine-induced T cells were measured by flow cytometry.
Measurements and Main Results: The vaccine had a clinically acceptable safety profile, and induced robust, long-lived M72-specific T-cell and antibody responses. M72-specific CD4 T cells produced multiple combinations of Th1 cytokines. Analysis of T-cell Ki67 expression showed that most vaccination-induced T cells did not express Th1 cytokines or IL-17; these cytokine-negative Ki67+ T cells included subsets of CD4 T cells with regulatory phenotypes. PD-1, a negative regulator of activated T cells, was transiently expressed on M72-specific CD4 T cells after vaccination. Specific T-cell subsets were present at significantly higher frequencies after vaccination of Mtb-infected versus -uninfected participants.
Conclusions: M72/AS01 is clinically well tolerated in Mtb-infected and -uninfected adults, induces high frequencies of multifunctional T cells, and boosts distinct T-cell responses primed by natural Mtb infection. Moreover, these results provide important novel insights into how this immunity may be appropriately regulated after novel TB vaccination of Mtb-infected and -uninfected individuals.
Clinical trial registered with www.clinicaltrials.gov (NCT 00600782).
doi:10.1164/rccm.201208-1385OC
PMCID: PMC3778736  PMID: 23306546
tuberculosis; vaccine; T cell; cytokine; proliferation
15.  Trends in the types and quality of childhood immunisations research output from Africa 1970–2010: mapping the evidence base 
Background
Over the past four decades, extraordinary progress has been made in establishing and improving childhood immunization programmes around Africa. In order to ensure effective and sustainable positive growth of these childhood immunisations programmes, the development, adaptation and implementation of all interventions (programme activities, new vaccines, new strategies and policies) should be informed by the best available local evidence.
Methods
An assessment of the peer-reviewed literature on childhood immunization research published in English from 1970 to 2010 was conducted in PubMed and Africa-Wide databases. All study types were eligible for inclusion. A standard form was used to extract information from all studies identified as relevant and entered into a Microsoft Access database for analysis.
Results
Our initial search yielded 5436 articles from the two databases, from which 848 full text articles were identified as relevant. Among studies classified as clinical research (417), 40% were clinical trials, 24% were burden of disease/epidemiology and 36% were other clinical studies. Among studies classified as operational research (431), 77% related to programme management, 18% were policy related and 5% were related to vaccine financing. Studies were conducted in 48 African countries with six countries (South Africa, The Gambia, Nigeria, Senegal, Guinea-Bissau and Kenya) accounting for 56% of the total research output. Studies were published in 152 different journals with impact factors ranging from 0.192 to 53.29; with a median impact factor of 3.572.
Conclusion
A similar proportion of clinical versus operational research output was found. However, an uneven distribution across Africa was observed with only six countries accounting for over half of the research output. The research conducted was of moderate to high quality, with 62% being published in journals with 2010 impact factors greater than two. Urgent attention should be given to the development of research capacity in low performing countries around Africa, with increased focus on the process of turning immunisations programme research evidence into policy and practice, as well as increased focus on issues relating to vaccine financing and sustainability in Africa.
doi:10.1186/1472-6963-14-52
PMCID: PMC3918141  PMID: 24495533
Expanded Programme on Immunisations (EPI); Immunisations programmes; Childhood immunisations; Vaccines; Children; Africa
16.  Mobile phone text messaging for promoting adherence to anti-tuberculosis treatment: a systematic review 
BMC Infectious Diseases  2013;13:566.
Background
Mobile phone text messaging (SMS) has the potential to promote adherence to tuberculosis treatment. This systematic review aims to synthesize current evidence on the effectiveness of SMS interventions in improving patients’ adherence to tuberculosis treatment.
Methods
We searched electronic databases (PubMed, EMBASE, Science Citation Index), reference lists of relevant articles, conference proceedings, and selected websites for eligible studies available by 15 February 2013; regardless of language or publication status. Two authors independently screened selected eligible studies, and assessed risk of bias in included studies; resolving discrepancies by discussion and consensus.
Results
We identified four studies that compared the outcomes of the SMS intervention group with controls. Only one of the four studies was a randomized controlled trial. This was conducted in Argentina and the SMS intervention did not significantly improve adherence to tuberculosis treatment compared to self-administration of tuberculosis treatment (risk ratio [RR] 1.49, 95% confidence intervals [CI] 0.90 to 2.42). One of the non-randomized studies, conducted in South Africa, which compared SMS reminders to directly observed therapy short course (DOTS) reported similar rates of tuberculosis cure (62.35% vs. 66.4%) and treatment success (72.94% vs. 69.4%). A second study from South Africa, utilized SMS reminders when patients delayed in opening their pill bottles and reported increased tuberculosis cure (RR 2.32, 95% CI 1.60 to 3.36) and smear conversion (RR 1.62, 95% CI 1.09 to 2.42) rates compared to DOTS. In the third non-randomized study, conducted in Kenya, use of SMS reminders increased rates of clinic attendance on scheduled days compared to standard care (RR 1.56, 95% CI 1.06 to 2.29). Using the GRADE approach, we rate the quality of the evidence as low, mainly because of the high risk of bias and heterogeneity of effects across studies.
Conclusions
This systematic review indicates that there is a paucity of high-quality data on the effectiveness of SMS interventions for improving patients’ adherence to tuberculosis treatment. The low quality of the current evidence implies that further studies (in particular randomized trials) on the subject are needed. In the interim, if the intervention is implemented outside research settings an impact evaluation is warranted.
doi:10.1186/1471-2334-13-566
PMCID: PMC4219402  PMID: 24295439
Mobile phone; Text messages; Tuberculosis treatment; Anti-tubercular agents; Adherence; Compliance
17.  Understanding interventions for improving routine immunization coverage in children in low- and middle-income countries: a systematic review protocol 
Systematic Reviews  2013;2:106.
Background
Virtually all low- and middle-income countries are dependent on the World Health Organization’s Expanded Program on Immunization for delivery of vaccines to children. The Expanded Program on Immunization delivers routine immunization services from health facilities free of charge. Understanding interventions for improving immunization coverage remains key in achieving universal childhood immunization.
Methods
We will conduct a systematic review that aims to assess the effectiveness of the full range of potential interventions to improve routine immunization coverage in children in low- and middle-income countries. We will include intervention studies, as well as observational studies. We will search the Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, electronic databases for eligible studies published by 31 August 2013. At least two authors will independently screen search outputs, select studies, extract data and assess the risk of bias (using separate criteria for interventions and observational studies); resolving any disagreements by discussion and consensus. The use of logic models and the Cochrane Complexity Matrix will be explored in order to better understand and contextualize studies. We will express the result of each study as a risk ratio with its corresponding 95% confidence intervals for dichotomous data, or mean difference with its standard deviation for continuous data. We will conduct meta-analysis for the same type of participants, interventions, study designs, and outcome measures where homogeneity of data allows. Use of harvest plots may be explored as an alternative. Heterogeneity will be assessed using the χ2 test of heterogeneity, and quantified using the I2 statistic. This protocol has not been registered with PROSPERO.
Discussion
This review will allow us to document evidence across a broad range of intervention types for improving routine immunization coverage in children and also distinguish between those that are well supported by evidence (to direct policy recommendations) and those that are not well supported (to direct research agenda).
doi:10.1186/2046-4053-2-106
PMCID: PMC3843560  PMID: 24262139
Expanded Program on Immunization (EPI); Routine immunization; Routine vaccination; Children; Low- and middle-income countries
18.  Strengthening the Expanded Programme on Immunization in Africa: Looking beyond 2015 
PLoS Medicine  2013;10(3):e1001405.
Shingai Machingaidze and colleagues reflect on the successes and shortfalls of the Expanded Programme on Immunization (EPI) in Africa, and the considerable challenges that must now be addressed to improve immunization systems.
doi:10.1371/journal.pmed.1001405
PMCID: PMC3601964  PMID: 23526886
19.  A bibliometric analysis of childhood immunization research productivity in Africa since the onset of the Expanded Program on Immunization in 1974 
BMC Medicine  2013;11:66.
Background
The implementation of strategic immunization plans whose development is informed by available locally-relevant research evidence should improve immunization coverage and prevent disease, disability and death in Africa. In general, health research helps to answer questions, generate the evidence required to guide policy and identify new tools. However, factors that influence the publication of immunization research in Africa are not known. We, therefore, undertook this study to fill this research gap by providing insights into factors associated with childhood immunization research productivity on the continent. We postulated that research productivity influences immunization coverage.
Methods
We conducted a bibliometric analysis of childhood immunization research output from Africa, using research articles indexed in PubMed as a surrogate for total research productivity. We used zero-truncated negative binomial regression models to explore the factors associated with research productivity.
Results
We identified 1,641 articles on childhood immunization indexed in PubMed between 1974 and 2010 with authors from Africa, which represent only 8.9% of the global output. Five countries (South Africa, Nigeria, The Gambia, Egypt and Kenya) contributed 48% of the articles. After controlling for population and gross domestic product, The Gambia, Guinea-Bissau and Sao Tome and Principe were the most productive countries. In univariable analyses, the country's gross domestic product, total health expenditure, private health expenditure, and research and development expenditure had a significant positive association with increased research productivity. Immunization coverage, adult literacy rate, human development index and physician density had no significant association. In the multivarable model, only private health expenditure maintained significant statistical association with the number of immunization articles.
Conclusions
Immunization research productivity in Africa is highly skewed, with private health expenditure having a significant positive association. However, the current contribution of authors from Africa to global childhood immunization research output is minimal. The lack of association between research productivity and immunization coverage may be an indication of lack of interactive communication between health decision-makers, program managers and researchers; to ensure that immunization policies and plans are always informed by the best available evidence.
doi:10.1186/1741-7015-11-66
PMCID: PMC3599719  PMID: 23497441
Africa; bibliometrics; childhood immunization; Expanded Program on Immunization; low and middle-income counries; research; sub-Saharan Africa
20.  Mobile phone text messaging for promoting adherence to anti-tuberculosis treatment: a systematic review protocol 
Systematic Reviews  2013;2:6.
Background
In 2010, there were approximately 8.8 million incident cases of tuberculosis (TB) worldwide. The treatment of TB is at least six months long and may be complicated by a high pill burden. In addition, TB patients often do not take their medication on schedule simply because they forget. Mobile phone text messaging has the potential to help promote TB treatment adherence. We, therefore, propose to conduct a review of current best evidence for the use of mobile phone text messaging to promote patient adherence to TB treatment.
Methods
This is a systematic review of the literature. We will preferably include randomized controlled trials (RCTs). However, non-randomized studies (NRS) will be considered if there is an inadequate number of RCTs.
We will search PubMed, EMBASE, CINAHL, CENTRAL, Science Citation Index, Africa-Wide Information, and WHOLIS electronic databases for eligible studies available by 30 November 2012 regardless of language or publication status. We will also check reference lists for additional studies, identify abstracts from conference proceedings and communicate with authors for any relevant material.
At least two authors will independently screen search outputs, select studies, extract data and assess the risk of bias (using separate criteria for RCTs and NRS); resolving discrepancies by discussion and consensus. We will assess clinical heterogeneity by examining the types of participants, interventions and outcomes in each study and pool studies judged to be clinically homogenous. We will also assess statistical heterogeneity using the chi-square test of homogeneity and quantify it using the I-square statistic. If study results are found to be statistically homogeneous (that is heterogeneity P > 0.1), we will pool them using the fixed-effect meta-analysis. Otherwise, we will use random-effects meta-analysis. We will calculate risk ratios and their corresponding 95% confidence intervals for dichotomous outcomes, and mean differences for continuous outcomes. For other outcomes without quantitative data, a descriptive analysis will be used.
Discussion
Our results can be used by researchers and policy-makers to help inform them of the efficacy of mobile phone text messaging interventions to promote patient adherence to TB treatment.
doi:10.1186/2046-4053-2-6
PMCID: PMC3564775  PMID: 23324135
Mobile phone; Text messages; Tuberculosis treatment; Anti-tubercular agents; Adherence; Compliance
21.  HIV-Specific Gag Responses in Early Infancy Correlate with Clinical Outcome and Inversely with Viral Load 
AIDS Research and Human Retroviruses  2011;27(12):1311-1316.
Abstract
Many HIV-infected infants progress to AIDS during the first year of life when antiretroviral therapy (ART) is not given. The immune determinants of progression to AIDS are not known. We hypothesized that distinct HIV-specific T cell responses correlate with viral load and survival over the first year of life. Whole blood of infants at 3, 6, 9, and 12 months of age was incubated with HIV antigens Gag and Env. The frequency of specific T cells producing interferon (IFN)-γ was then measured by flow cytometry. Viral load and CD4% in HIV+ infants were determined at each time point. ART was not available for this population at the time of sample collection. Those infants who survived to 12 months of age (n=12) had lower viral loads and higher Gag-specific CD8+ T cell responses at 3 months, compared with infants who died (n=8). Furthermore, the frequency of Gag-specific CD4+ T cells correlated inversely with viral load at 3 and 6 months of age. Together these data indicate that the early presence of quantitatively higher Gag-specific T cell responses in HIV-infected infants is associated with lower viral loads and decreased mortality in the first year of life. Our data support the design of a vaccine that preferentially elicits Gag responses, which may result in lower levels of viremia and possibly improve outcome.
doi:10.1089/aid.2011.0081
PMCID: PMC3227240  PMID: 21476948
22.  Vaginal microbicides for reducing the risk of sexual acquisition of HIV infection in women: systematic review and meta-analysis 
BMC Infectious Diseases  2012;12:289.
Background
Each year more than two million people are newly infected with HIV worldwide, a majority of them through unprotected vaginal sex. More than half of new infections in adults occur in women. Male condoms and male circumcision reduce the risk of HIV acquisition; but the uptake of these methods is out of the control of women. We therefore aimed to determine the effectiveness of vaginal microbicides (a potential female-controlled method) for prevention of sexual acquisition of HIV in women.
Methods
We conducted a comprehensive search of peer-reviewed and grey literature for publications of randomised controlled trials available by September 2012. We screened search outputs, selected studies, assessed risk of bias, and extracted data in duplicate; resolving differences by discussion and consensus.
Results
We identified 13 eligible trials that compared vaginal microbicides to placebo. These studies enrolled 35,905 sexually active HIV-negative women between 1996 and 2011; in Benin, Cameroon, Cote d’Ivoire, Ghana, Kenya, Malawi, Nigeria, South Africa, Tanzania, Uganda, Zambia, Zimbabwe, India, Thailand, and the United States of America. A small trial of 889 women found that tenofovir (a nucleotide reverse transcriptase inhibitor) significantly reduces the risk of HIV acquisition (risk ratio [RR] 0.63, 95% confidence intervals [CI] 0.43 to 0.93). Effectiveness data are not yet available from follow-up tenofovir trials being conducted in South Africa, Uganda, and Zimbabwe (1 trial) and multiple sites in South Africa (1 trial). We found no evidence of a significant effect for nonoxynol-9 (5 trials), cellulose sulphate (2 trials), SAVVY (2 trials), Carraguard (1 trial), PRO 2000 (2 trials), and BufferGel (1 trial) microbicides. The pooled RR for the effect of current experimental vaginal microbicides on HIV acquisition in women was 0.97, 95%CI 0.87 to 1.08. Although study results were homogeneous across the different drug classes (heterogeneity P = 0.17, I2 = 27%), the overall intervention effect was not statistically significant. Nonoxynol-9 significantly increased the risk of having adverse genital lesions but no other microbicide led to significant increases in adverse events.
Conclusions
There is not enough evidence at present to recommend vaginal microbicides for HIV prevention. Further high-quality research is needed to confirm the beneficial effects of tenofovir as well as continue the development and testing of new microbicides.
doi:10.1186/1471-2334-12-289
PMCID: PMC3531270  PMID: 23130761
23.  A Phase IIa Trial of the New Tuberculosis Vaccine, MVA85A, in HIV- and/or Mycobacterium tuberculosis–infected Adults 
Rationale: Novel tuberculosis (TB) vaccines should be safe and effective in populations infected with Mycobacterium tuberculosis (M.tb) and/or HIV for effective TB control.
Objective: To determine the safety and immunogenicity of MVA85A, a novel TB vaccine, among M.tb- and/or HIV-infected persons in a setting where TB and HIV are endemic.
Methods: An open-label, phase IIa trial was conducted in 48 adults with M.tb and/or HIV infection. Safety and immunogenicity were analyzed up to 52 weeks after intradermal vaccination with 5 × 107 plaque-forming units of MVA85A. Specific T-cell responses were characterized by IFN-γ enzyme-linked immunospot and whole blood intracellular cytokine staining assays.
Measurements and Main Results: MVA85A was well tolerated and no vaccine-related serious adverse events were recorded. MVA85A induced robust and durable response of mostly polyfunctional CD4+ T cells, coexpressing IFN-γ, tumor necrosis factor-α, and IL-2. Magnitudes of pre- and postvaccination T-cell responses were lower in HIV-infected, compared with HIV-uninfected, vaccinees. No significant effect of antiretroviral therapy on immunogenicity of MVA85A was observed.
Conclusions: MVA85A was safe and immunogenic in persons with HIV and/or M.tb infection. These results support further evaluation of safety and efficacy of this vaccine for prevention of TB in these target populations.
doi:10.1164/rccm.201108-1548OC
PMCID: PMC3326425  PMID: 22281831
tuberculosis; HIV-1; vaccine; MVA85A; clinical trial
24.  Advances in childhood immunisation in South Africa: where to now? Programme managers’ views and evidence from systematic reviews 
BMC Public Health  2012;12:578.
Background
The Expanded Programme on Immunisation (EPI) is one of the most powerful and cost-effective public health programmes to improve child survival. We assessed challenges and enablers for the programme in South Africa, as we approach the 2015 deadline for the Millennium Development Goals.
Methods
Between September 2009 and September 2010 we requested national and provincial EPI managers in South Africa to identify key challenges facing EPI, and to propose appropriate solutions. We collated their responses and searched for systematic reviews on the effectiveness of the proposed solutions; in the Health Systems Evidence, Cochrane Library, and PubMed electronic databases. We screened the search outputs, selected systematic reviews, extracted data, and assessed the quality of included reviews (using AMSTAR) and the quality of the evidence (using GRADE) in duplicate; resolving disagreements by discussion and consensus.
Results
Challenges identified by EPI managers were linked to healthcare workers (insufficient knowledge of vaccines and immunisation), the public (anti-immunisation rumours and reluctance from parents), and health system (insufficient financial and human resources). Strategies proposed by managers to overcome the challenges include training, supervision, and audit and feedback; strengthening advocacy and social mobilisation; and sustainable EPI funding schemes, respectively. The findings from reliable systematic reviews indicate that interactive educational meetings, audit and feedback, and supportive supervision improve healthcare worker performance. Structured and interactive communication tools probably increase parents’ understanding of immunisation; and reminders and recall, use of community health workers, conditional cash transfers, and mass media interventions probably increase immunisation coverage. Finally, a national social health insurance scheme is a potential EPI financing mechanism; however, given the absence of high-quality evidence of effects, its implementation should be pilot-tested and the impacts and costs rigorously monitored.
Conclusion
In line with the Millennium Development Goals, we have to ensure that our children’s right to health, development and survival is respected, protected and promoted. EPI is central to this vision. We found numerous promising strategies for improving EPI performance in South Africa. However, their implementation would need to be tailored to local circumstances and accompanied by high-quality monitoring and evaluation. The strength of our approach comes from having a strong framework for interventions before looking for systematic reviews. Without a framework, we would have been driven by what reviews have been done and what is easily researchable; rather than the values and preferences of key immunisation stakeholders.
doi:10.1186/1471-2458-12-578
PMCID: PMC3418205  PMID: 22849711
25.  Higher human CD4 T cell response to novel Mycobacterium tuberculosis latency associated antigens Rv2660 and Rv2659 in latent infection compared with tuberculosis disease 
Vaccine  2010;29(1):51-57.
One third of the world’s population is infected with Mycobacterium tuberculosis (M.tb). A vaccine that would prevent progression to TB disease will have a dramatic impact on the global TB burden. We propose that antigens of M.tb that are preferentially expressed during latent infection will be excellent candidates for post-exposure vaccination. We therefore assessed human T cell recognition of two such antigens, Rv2660 and Rv2659. Expression of these was shown to be associated with non-replicating persistence in vitro. After six days incubation of PBMC from persons with latent tuberculosis infection (LTBI) and tuberculosis (TB) disease, Rv2660 and Rv2659 induced IFN-γ production in a greater proportion of persons with LTBI, compared with TB diseased patients. Persons with LTBI also had increased numbers of viable T cells, and greater specific CD4+ T cell proliferation and cytokine expression capacity. Persons with LTBI preferentially recognize Rv2659 and Rv2660, compared with patients with TB disease. These results suggest promise of these antigens for incorporation into post-exposure TB vaccines.
doi:10.1016/j.vaccine.2010.10.022
PMCID: PMC3376751  PMID: 20974305
Mycobacterium tuberculosis; LTBI; TB disease; latency antigens; post-infection vaccine

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