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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  Individual and Contextual Factors Associated with Low Childhood Immunisation Coverage in Sub-Saharan Africa: A Multilevel Analysis 
PLoS ONE  2012;7(5):e37905.
Background
In 2010, more than six million children in sub-Saharan Africa did not receive the full series of three doses of the diphtheria-tetanus-pertussis vaccine by one year of age. An evidence-based approach to addressing this burden of un-immunised children requires accurate knowledge of the underlying factors. We therefore developed and tested a model of childhood immunisation that includes individual, community and country-level characteristics.
Method and Findings
We conducted multilevel logistic regression analysis of Demographic and Health Survey data for 27,094 children aged 12–23 months, nested within 8,546 communities from 24 countries in sub-Saharan Africa. According to the intra-country and intra-community correlation coefficient implied by the estimated intercept component variance, 21% and 32% of the variance in unimmunised children were attributable to country- and community-level factors respectively. Children born to mothers (OR 1.35, 95%CI 1.18 to 1.53) and fathers (OR 1.13, 95%CI 1.12 to 1.40) with no formal education were more likely to be unimmunised than those born to parents with secondary or higher education. Children from the poorest households were 36% more likely to be unimmunised than counterparts from the richest households. Maternal access to media significantly reduced the odds of children being unimmunised (OR 0.94, 95%CI 0.94 to 0.99). Mothers with health seeking behaviours were less likely to have unimmunised children (OR 0.56, 95%CI 0.54 to 0.58). However, children from urban areas (OR 1.12, 95% CI 1.01 to 1.23), communities with high illiteracy rates (OR 1.13, 95% CI 1.05 to 1.23), and countries with high fertility rates (OR 4.43, 95% CI 1.04 to 18.92) were more likely to be unimmunised.
Conclusion
We found that individual and contextual factors were associated with childhood immunisation, suggesting that public health programmes designed to improve coverage of childhood immunisation should address people, and the communities and societies in which they live.
doi:10.1371/journal.pone.0037905
PMCID: PMC3360654  PMID: 22662247
12.  The African Vaccine-Preventable Diseases Network: a vaccine advocacy initiative 
Achieving high and equitable childhood immunisation coverage in Africa will not only protect children from disability and premature death, it will also boost productivity, reduce poverty and support the economic growth of the continent. Thus, Africa needs innovative and sustainable vaccine advocacy initiatives. One such initiative is the African Vaccine-Preventable Diseases Network, formed in 2009. This association of immunisation practitioners, vaccinologists, paediatricians, and infectious disease experts provides a platform to advocate for the introduction of newly available vaccines (e.g. 10-valent and 13-valent pneumococcal conjugate and rotavirus vaccines) into the Expanded Programme on Immunisation (EPI) as well as increased and equitable coverage for established EPI vaccines.
PMCID: PMC3201589  PMID: 22121433
Vaccine preventable diseases; vaccine; network; Africa; awareness; child health
13.  MVA85A, a novel TB vaccine, is safe in adolescents and children, and induces complex subsets of polyfunctional CD4+ T cells 
European journal of immunology  2010;40(1):279-290.
Summary
MVA85A is a new tuberculosis vaccine aimed at enhancing immunity induced by BCG. We investigated the safety and immunogenicity of MVA85A in healthy adolescents and children from a tuberculosis endemic region, who received BCG at birth.
Twelve adolescents and 24 children were vaccinated and followed up for 12 or 6 months, respectively. Adverse events were documented and vaccine-induced immune responses assessed by IFN-γ ELISpot and intracellular cytokine staining.
The vaccine was well tolerated and there were no vaccine-related serious adverse events. MVA85A induced potent and durable T cell responses. Multiple CD4+ T cell subsets, based on expression of IFN-γ, TNF-α, IL-2, IL-17 and GM-CSF, were induced. Polyfunctional CD4+ T cells co-expressing IFN-γ, TNF-α and IL-2 dominated the response in both age groups. A novel CD4+ cell subset co-expressing these three Th1 cytokines and IL-17 was induced in adolescents, while a novel CD4+ T cell subset co-expressing Th1 cytokines and GM-CSF was induced in children. Antigen-specific CD8+ T cells were not detected.
We conclude that in adolescents and children MVA85A safely induces the type of immunity thought to be important in protection against tuberculosis. This includes induction of novel Th1 cell populations which have not been previously described in humans.
doi:10.1002/eji.200939754
PMCID: PMC3044835  PMID: 20017188
MVA85A; tuberculosis; vaccine; polyfunctional; IL-17
14.  Delaying BCG vaccination from birth to 10 weeks of age may result in an enhanced memory CD4 T cell response 
Vaccine  2009;27(40):5488-5495.
Background
In most tuberculosis (TB) endemic countries, bacillus Calmette Guérin (BCG) is usually given around birth to prevent severe TB in infants. The neonatal immune system is immature. Our hypothesis was that delaying BCG vaccination from birth to 10 weeks of age would enhance the vaccine-induced immune response.
Methods
In a randomized clinical trial, BCG was administered intradermally either at birth (n=25) or at 10 weeks of age (n=21). Ten weeks after vaccination, and at 1 year of age, vaccine-specific CD4 and CD8 T cell responses were measured with a whole blood intracellular cytokine assay.
Results
Infants who received delayed BCG vaccination demonstrated higher frequencies of BCG-specific CD4 T cells, particularly polyfunctional T cells co-expressing IFN-γ, TNF-α and IL-2, and most strikingly at 1 year of age.
Conclusions
Delaying BCG vaccination from birth to 10 weeks of age enhances the quantitative and qualitative BCG-specific T cell response, when measured at one year of age.
doi:10.1016/j.vaccine.2009.06.103
PMCID: PMC2745558  PMID: 19616494
BCG; vaccination; birth; delayed; polyfunctional CD4 T cells
15.  Bacille Calmette Guerin vaccination of human newborns induces T cells with complex cytokine and phenotypic profiles 
The immune response to vaccination with Bacillus Calmette-Guerin (BCG), the only tuberculosis vaccine available, has not been fully characterized. We used multiparameter flow cytometry to examine specific T cell cytokine production and phenotypic profiles in blood from 10-week old infants, routinely vaccinated with BCG at birth. Ex vivo stimulation of whole blood with BCG for 12 hours induced expression of predominantly IFN-γ, IL-2 and TNF-α in CD4+ T cells, in 7 distinct cytokine combinations. IL-4 and IL-10 expression were detected in CD4+ T cells at low frequencies, and only in cells that did not co-express Type 1 cytokines. Specific CD8+ T cells were less frequent than CD4+ T cells, and produced mainly IFN-γ and/or IL-2, and less TNF-α, IL-4 and IL-10. Importantly, many mycobacteria-specific CD4+ and CD8+ T cells did not produce IFN-γ. The predominant phenotype of BCG-specific Type 1 T cells was that of effector cells, i.e., CD45RA–CCR7–CD27+, which may reflect persistence of M. bovis BCG in infants until 10 weeks of age. Among 5 phenotypic patterns of CD4+ T cells, central memory cells were more likely to be IL-2+, and effector cells more likely to be IFN-γ+. We concluded that neonatal vaccination with BCG induces T cells with a complex pattern of cytokine expression and phenotypes. Measuring IFN-γ production alone underestimates the magnitude and complexity of the host cytokine response to BCG vaccination, and may not be an optimal readout in studies of BCG and novel tuberculosis vaccination.
PMCID: PMC2842001  PMID: 18292584
Human; Th1/Th2 Cells; T cells; Cytokines; Memory; Vaccination
16.  Significantly skewed memory CD8+ T cell subsets in HIV-1 infected infants during the first year of life1 
Clinical immunology (Orlando, Fla.)  2008;130(3):280-289.
HIV-1 infection causes a severe T cell compromise; however, little is known about changes in naïve, memory, effector and senescent T cell subsets during the first year of life. T cell subsets were studied over the first year of life in blood from 3 infant cohorts: untreated HIV-infected, HIV-exposed but uninfected, and HIV-unexposed. In HIV-infected infants, the frequency of CCR7+CD45RA+ naïve CD8+ T cells was significantly decreased, whilst the frequency of CCR7−CD45RA− effector memory CD8+ T cells was increased, compared with the control cohorts. A larger population of CD8+ T cells in HIV-infected infants displayed a phenotype consistent with senescence. Differences in CD4+ T cell subset frequencies were less pronounced, and no significant differences were observed between exposed and unexposed HIV-uninfected infants. We concluded that the proportion of naïve, memory, effector and senescent CD8+ T cells during the first year of life is significantly altered by HIV-1 infection.
doi:10.1016/j.clim.2008.09.006
PMCID: PMC2722743  PMID: 18996749
CD4; CD8; memory; HIV-1; infants
17.  Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in healthy adults in South Africa1 
The Journal of infectious diseases  2008;198(4):544-552.
BACKGROUND
The efficacy of BCG may be enhanced by heterologous vaccination strategies that boost the BCG-primed immune response. One leading booster vaccine, MVA85A, has shown promising safety and immunogenicity in UK human trials. We investigated the safety and immunogenicity of MVA85A in mycobacteria-exposed, but Mycobacterium tuberculosis-uninfected, healthy adults from a TB-endemic region of South Africa.
METHODS
Twenty-four adults were vaccinated with MVA85A. All subjects were followed up for one year for adverse events and for immunological assessment.
RESULTS
MVA85A vaccination was well tolerated and induced potent T cell responses, measured by IFN-γ ELISPOT assay, which exceeded pre-vaccination levels up to 364 days after vaccination. BCG-specific CD4+ T cells boosted by MVA85A comprised of multiple populations expressing combinations of IFN-γ, TNF-α, IL-2 and IL-17, as measured by polychromatic flow cytometry. IFN-γ expressing and polyfunctional IFN-γ+TNF-α+IL-2+ CD4+ T cells were boosted during the peak BCG-specific response 7 days post-vaccination.
CONCLUSION
The excellent safety profile and quantitative and qualitative immunogenicity data strongly support further trials to assess the efficacy of MVA85A as a boosting vaccine in TB endemic countries.
doi:10.1086/590185
PMCID: PMC2822902  PMID: 18582195
Vaccination; tuberculosis; T cells; MVA85A; South Africa
18.  Infant HIV-1 Infection Severely Impairs the Bacille Calmette-Guerin Vaccine-Induced Immune Response1 
The Journal of infectious diseases  2009;199(7):982-990.
Background
World-wide, most infants born to HIV-infected mothers receive BCG. Tuberculosis is a major cause of death of HIV-infected infants in sub-Saharan Africa, and should be prevented. However, BCG may itself cause disease (BCGosis) in these infants. Information regarding the immunogenicity of BCG is imperative for the risk/benefit assessment of BCG vaccination in HIV-infected infants; however, no such data exists.
Methods
We compared BCG-induced CD4 and CD8 T cell responses, assessed by flow cytometry, in HIV-infected (n = 20), HIV-exposed but uninfected (n = 25), and HIV-unexposed (n = 23) infants, over their first year of life.
Results
BCG vaccination of the 2 HIV-uninfected groups induced a robust response, characterized by IFN-γ, TNF-α, and/or IL-2-expressing CD4 T cells. In contrast, HIV-infected infants had a markedly lower response, throughout the first year of life. These infants also had significantly reduced numbers of IFN-γ, TNF-α and IL-2 co-expressing polyfunctional CD4 T cells, thought to indicate T cell quality.
Conclusions
HIV-1 infection severely impairs the BCG-specific T cell response during the first year of life. BCG may therefore provide little, if any, vaccine-induced benefit in HIV-infected infants. Considering the significant risk of BCGosis, these data strongly support not giving BCG to HIV-infected infants.
doi:10.1086/597304
PMCID: PMC2815505  PMID: 19236280
Tuberculosis; BCG; HIV; infants; T cells; immune response; polyfuntional; Th1; Th17
19.  Rifampin pharmacokinetics in children, with and without human immunodeficiency virus infection, hospitalized for the management of severe forms of tuberculosis 
BMC Medicine  2009;7:19.
Background
Rifampin is a key drug in antituberculosis chemotherapy because it rapidly kills the majority of bacilli in tuberculosis lesions, prevents relapse and thus enables 6-month short-course chemotherapy. Little is known about the pharmacokinetics of rifampin in children. The objective of this study was to evaluate the pharmacokinetics of rifampin in children with tuberculosis, both human immunodeficiency virus type-1-infected and human immunodeficiency virus-uninfected.
Methods
Fifty-four children, 21 human immunodeficiency virus-infected and 33 human immunodeficiency virus-uninfected, mean ages 3.73 and 4.05 years (P = 0.68), respectively, admitted to a tuberculosis hospital in Cape Town, South Africa with severe forms of tuberculosis were studied approximately 1 month and 4 months after commencing antituberculosis treatment. Blood specimens for analysis were drawn in the morning, 45 minutes, 1.5, 3.0, 4.0 and 6.0 hours after dosing. Rifampin concentrations were determined by liquid chromatography tandem mass spectrometry. For two sample comparisons of means, the Welch version of the t-test was used; associations between variables were examined by Pearson correlation and by multiple linear regression.
Results
The children received a mean rifampin dosage of 9.61 mg/kg (6.47 to 15.58) body weight at 1 month and 9.63 mg/kg (4.63 to 17.8) at 4 months after commencing treatment administered as part of a fixed-dose formulation designed for paediatric use. The mean rifampin area under the curve 0 to 6 hours after dosing was 14.9 and 18.1 μg/hour/ml (P = 0.25) 1 month after starting treatment in human immunodeficiency virus-infected and human immunodeficiency virus-uninfected children, respectively, and 16.52 and 17.94 μg/hour/ml (P = 0.59) after 4 months of treatment. The mean calculated 2-hour rifampin concentrations in these human immunodeficiency virus-infected and human immunodeficiency virus-uninfected children were 3.9 and 4.8 μg/ml (P = 0.20) at 1 month after the start of treatment and 4.0 and 4.6 μg/ml (P = 0.33) after 4 months of treatment. These values are considerably less than the suggested lower limit for 2-hour rifampin concentrations in adults of 8.0 μg/ml and even 4 μg/ml
Conclusion
Both human immunodeficiency virus-infected and human immunodeficiency virus-uninfected children with tuberculosis have very low rifampin serum concentrations after receiving standard rifampin dosages similar to those used in adults. Pharmacokinetic studies of higher dosages of rifampin are urgently needed in children to assist in placing the dosage of rifampin used in childhood on a more scientific foundation.
doi:10.1186/1741-7015-7-19
PMCID: PMC2679060  PMID: 19386087
20.  Distinct, specific IL-17 and IL-22-producing CD4+ T cell subsets contribute to the human anti-mycobacterial immune response1 
We investigated whether the pro-inflammatory T cell cytokines interleukin-17 (IL-17) and IL-22 are induced by human mycobacterial infection. Remarkably, >20% of specific cytokine-producing CD4+ T cells in peripheral blood of healthy, mycobacteria-exposed adults expressed IL-17 or IL-22. Specific IL-17 and IL-22 producing CD4+ T cells were distinct from each other and from Th1 cytokine-producing cells. These cells had phenotypic characteristics of long-lived central memory cells. In patients with tuberculosis disease, peripheral blood frequencies of these cells were reduced, while bronchoalveolar lavage fluid (BALF) contained higher levels of IL-22 protein, compared with healthy controls. IL-17 was not detected in this fluid, which may be due to suppression by Th1 cytokines, as PBMC IL-17 production was inhibited by IFN-γ in vitro. However, Th1 cytokines had no effect on IL-22 production in vitro. Our results imply that the magnitude and complexity of the anti-mycobacterial immune response have historically been underestimated. IL-17 and IL-22-producing CD4+ T cells may play important roles in the human immune response to mycobacteria.
PMCID: PMC2219462  PMID: 18209095
human; T cells; cytokines; bacterial infection
21.  Culture-confirmed childhood tuberculosis in Cape Town, South Africa: a review of 596 cases 
Background
The clinical, radiological and microbiological features of culture-confirmed childhood tuberculosis diagnosed at two referral hospitals are described.
Methods
Cultures of Mycobacterium tuberculosis from children less than 13 years of age at Tygerberg and Red Cross Children's Hospitals, Cape Town, South Africa, were collected from March 2003 through February 2005. Folder review and chest radiography were performed and drug susceptibility tests done.
Results
Of 596 children (median age 31 months), 330 (55.4%) were males. Of all children, 281 (47.1%) were HIV-uninfected, 133 (22.3%) HIV-infected and 182 (30.5%) not tested. Contact with infectious tuberculosis adults was recorded in 295 (49.5%) children. Missed opportunities for chemoprophylaxis were present in 117/182 (64.3%) children less than 5 years of age.
Extrathoracic TB was less common in HIV-infected than in HIV-uninfected children (49/133 vs. 156/281; odds ratio 0.50, 95% confidence interval 0.32–0.78). Alveolar opacification (84/126 vs. 128/274; OR 1.85, 95%CI 1.08–3.19) and cavitation (33/126 vs. 44/274; OR 2.28, 95%CI 1.44–3.63) were more common in HIV-infected than in HIV-uninfected children. Microscopy for acid-fast bacilli on gastric aspirates and sputum was positive in 29/142 (20.4%) and 40/125 (32.0%) children, respectively. Sixty-seven of 592 (11.3%) children's isolates showed resistance to isoniazid and/or rifampicin; 43 (7.3%) were isoniazid-monoresistant, 2 (0.3%) rifampicin-monoresistant and 22 (3.7%) multidrug-resistant. Death in 41 children (6.9%) was more common in HIV-infected children and very young infants.
Conclusion
HIV infection and missed opportunities for chemoprophylaxis were common in children with culture-confirmed TB. With cavitating disease and sputum or gastric aspirates positive for acid-fast bacilli, children may be infectious. Transmission of drug-resistant TB is high in this setting.
doi:10.1186/1471-2334-7-140
PMCID: PMC2225409  PMID: 18047651
22.  A prospective, cross-sectional study of anaemia and peripheral iron status in antiretroviral naïve, HIV-1 infected children in Cape Town, South Africa 
Background
Anaemia is a common manifestation of paediatric HIV infection. Although there are many causes, anaemia of chronic diseases is the most frequent type. In poor countries iron deficiency is widespread. It is probable that many HIV-infected children in these countries are also iron deficient. This study describes the relationship between paediatric HIV infection and anaemia, and documents the peripheral iron status of antiretroviral naive, HIV-infected children.
Methods
Sixty children were evaluated prospectively. Investigations included CD4+ count, haemoglobin concentration (Hb), red blood cell (RBC) morphology, and iron studies.
Results
Anaemia was present in 73% of children. Compared to mild HIV infection, median Hb was lower in children with moderate clinical infection (104 g/L v 112 g/L, p = 0.04) and severe clinical infection (96 g/L v 112 g/L, p = 0.006), and more children with severe infection were anaemic (92% v 58%, 0.04). There was a significant relationship between immunological status and Hb. 68% had abnormal RBC morphology. Significantly more children with moderate and severe disease, and severe immunosuppression had abnormal RBC morphology. 52% were iron-depleted, 20% had iron-deficient erythropoiesis and 18% iron deficiency anaemia (IDA). 16% (7/44) of anaemic children had microcytosis and hypochromia. Median soluble transferrin receptor concentration was significantly higher in those with microcytic hypochromic anaemia (42.0 nmol/L v 30.0 nmol/L, p = 0.008).
Conclusions
Both the proportion of anaemic children and the median Hb were associated with disease status. Iron depletion and IDA are major problems in HIV-infected children in South Africa.
doi:10.1186/1471-2334-2-3
PMCID: PMC65689  PMID: 11866864
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.  'Communicate to vaccinate' (COMMVAC). building evidence for improving communication about childhood vaccinations in low- and middle-income countries: protocol for a programme of research 
Background
Effective provider-parent communication can improve childhood vaccination uptake and strengthen immunisation services in low- and middle-income countries (LMICs). Building capacity to improve communication strategies has been neglected. Rigorous research exists but is not readily found or applicable to LMICs, making it difficult for policy makers to use it to inform vaccination policies and practice.
The aim of this project is to build research knowledge and capacity to use evidence-based strategies for improving communication about childhood vaccinations with parents and communities in LMICs.
Methods and design
This project is a mixed methods study with six sub-studies. In sub-study one, we will develop a systematic map of provider-parent communication interventions for childhood vaccinations by screening and extracting data from relevant literature. This map will inform sub-study two, in which we will develop a taxonomy of interventions to improve provider-parent communication around childhood vaccination. In sub-study three, the taxonomy will be populated with trial citations to create an evidence map, which will also identify how evidence is linked to communication barriers regarding vaccination.
In the project's fourth sub-study, we will present the interventions map, taxonomy, and evidence map to international stakeholders to identify high-priority topics for systematic reviews of interventions to improve parent-provider communication for childhood vaccination. We will produce systematic reviews of the effects of high-priority interventions in the fifth sub-study. In the sixth and final sub-study of the project, evidence from the systematic reviews will be translated into accessible formats and messages for dissemination to LMICs.
Discussion
This project combines evidence mapping, conceptual and taxonomy development, priority setting, systematic reviews, and knowledge transfer. It will build and share concepts, terms, evidence, and resources to aid the development of communication strategies for effective vaccination programmes in LMICs.
doi:10.1186/1748-5908-6-125
PMCID: PMC3259054  PMID: 22132930

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