Comparison of haematology and biochemistry parameters in healthy South African infants with laboratory reference intervals.

OBJECTIVE: Paediatric laboratory reference intervals used in Africa and Asia may be derived from historical intervals of predominantly Caucasian infants in Europe or North America. These intervals may therefore not be compatible with the range of normality for developing country populations. We aimed to compare haematology and biochemistry parameters in healthy South African infants with local laboratory reference intervals. METHODS: We compared the baseline haematology and biochemistry results of 634 (316 male and 318 female) HIV-unexposed infants, aged 3-6 months, living in a rural area of the Western Cape Province, South Africa, against laboratory reference intervals supplied by the South African National Health Laboratory Services (NHLS). We calculated the percentage of observed values out of bound (in terms of lower and upper limits) compared to laboratory reference intervals. RESULTS: Of the 634 healthy infants screened, 316 (49.84%) were male and 318 (50.16%) female. A majority (91.05%) had platelet counts above the laboratory reference interval upper limit (350 × 109 cells/l), while over half, 54.85% and 56.98% had mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) values below the lower limits of 77.0-105.0 fl and 26.0-34.0 pg, respectively. A small proportion were outside the reference limits for haematocrit, namely 15.71% below and 7.14% above the normal limits of 0.31-0.38 l/l. For male and female infants, 33.65% and 18.04% of alkaline phosphatase (ALP) values and 7.01% and 14.56% of alanine transaminase (ALT) values were above the upper limits, respectively. For male infants, 10.83% of gamma-glutamyl transferase (GGT) values, and for female infants, 31.11% of GGT values were below the lower limits of 12 U/l for males and 15 U/l for females. We observed no significant deviations (>10% out of bound) from NHLS reference intervals in the remaining haematology and biochemistry parameters measured. CONCLUSIONS: Haematology and biochemistry parameters in apparently healthy South African infants deviate frequently from national laboratory reference intervals, including abnormalities consistent with subclinical hypochromic microcytic anaemia. It is important that clinical laboratory reference intervals for children are derived locally, rather than being adopted from Caucasian norms in developed countries, because clinical trials of vaccines, drugs and diagnostics are increasingly conducted in sub-Saharan Africa.

A controlled trial of sputum induction and routine collection methods for TB diagnosis in a South African community.

The diagnostic yield of pulmonary tuberculosis (TB) by sputum induction (SI) at the first point of contact with health services, conducted in all patients with suspected TB regardless of the ability to expectorate spontaneously, has not been evaluated. We compared the diagnostic yield of SI to routine sputum collection in a South African community setting. Ambulatory patients with suspected TB provided a 'spot' expectorated sputum sample, an SI sample by hypertonic (5 %) saline nebulization, and early morning expectorated sputum sample. The diagnostic yield of sputum smear microscopy and liquid culture (denominator all subjects with any positive Mycobacterium tuberculosis culture), and time-to-positivity of culture were compared between SI and expectorated samples. A total of 555 subjects completed the SI procedure, of whom 132 (24 %) were human immunodeficiency virus (HIV)-infected. One hundred and twenty-nine samples (129, 23 %) were M. tuberculosis culture-positive. The time-to-positivity of Mycobacteria Growth Indicator Tube (MGIT) culture was shorter for SI (median difference 2 days, p = 0.63) and for early morning expectorated sputum (median difference 2 days, p = 0.02) compared to spot expectorated sputum. However, there was no difference in the culture-positive diagnostic yield between SI and spot expectorated sputum [difference +0.7 %; confidence interval (CI) -7.0 to +8.5 %, p = 0.82] or SI and early morning expectorated sputum (difference +4.7 %; CI -3.2 to +12.5 %, p = 0.20) for all subjects or for HIV-infected subjects. SI reduces the time to positive M. tuberculosis culture, but does not increase the rate of positive culture compared to routine expectorated sputum collection. SI cannot be recommended as the routine collection method at first contact among ambulatory patients with suspected TB in high-burden communities.

District Health System performance in South Africa: Are current monitoring systems optimal?

In this article, we review the monitoring and evaluation system that is used to measure the performance of primary healthcare delivered through the district health system and district management teams. We then review some global frameworks, especially linked to the World Health Organization, and look at some of the differences between what is internationally recommended and what we do in South Africa. We end with some recommendations to improve the system.

Sputum induction for the diagnosis of pulmonary tuberculosis: a systematic review and meta-analysis.

Sputum induction (SI) has been proposed as the optimal sample collection method for patients with paucibacillary tuberculosis (TB). Studies reporting the culture of Mycobacterium tuberculosis from SI were reviewed. A random-effects meta-analysis of diagnostic yield (numerator M. tuberculosis SI culture-positive cases; denominator all culture-positive cases) was conducted. Diagnostic yields (95% confidence intervals, CIs) were displayed as Forest plots. Heterogeneity was evaluated using Chi-squared and I-squared tests and meta-regression analysis. Ninety publications were screened, 28 full-text papers reviewed, and 17 analyzed. Collectively, n=627 SI culture-positive cases among n=975 culture-confirmed TB cases were reported. The diagnostic yield of SI ranged from 35 to 95%. The pooled diagnostic yield was 74% (CI 65-81%), with significant heterogeneity (p<0.0001, I2=86%). There were no statistically significant differences in the yield between sub-groups defined by human immunodeficiency virus (HIV) prevalence or age. Univariate analysis demonstrated that the use of fiberoptic bronchoscopy (FOB) as the comparator method was associated with a 22% reduction (CI 2-42%) in the diagnostic yield of SI. However, after adjustment for confounding, the meta-regression analysis showed that FOB usage (p=0.21) and saline concentration (p=0.31) were not independently associated with the diagnostic yield. SI will detect approximately three-quarters of M. tuberculosis culture-positive cases under study conditions. Significant heterogeneity in the diagnostic yield was not explained by HIV prevalence, age, or the use of FOB as the comparator method. The use of a particular nebulized saline concentration for SI cannot be recommended on the basis of this meta-regression analysis.

Safety and tolerability of sputum induction in adolescents and adults with suspected pulmonary tuberculosis.

Sputum induction by the inhalation of hypertonic saline may increase the yield of microbiological diagnosis of pulmonary tuberculosis (TB). This is particularly relevant in paucibacillary TB, such as in children or human immunodeficiency virus (HIV)-infected patients. Sputum induction must be shown to be safe and tolerable in community settings where invasive diagnostic methods are unavailable. The objective of this study was to describe the changes in physiological parameters and adverse events occurring during sputum induction in ambulatory adult and adolescent TB suspects recruited in community clinics. Sputum induction was performed in HIV-infected (n = 35) and HIV-uninfected (n = 67) TB suspects (n = 102). Oxygen saturation (%), blood pressure (mm Hg), heart rate (/minute), respiratory rate (/minute), and adverse events were monitored at baseline, continuously during the salbutamol pre-treatment and saline nebulization phases, and for 30 min afterwards. During nebulization, there was a statistically significant increase in oxygen saturation (1%, p < 0.0001), systolic BP (7 mm Hg, p < 0.0001), and diastolic BP (2 mm Hg, p = 0.008). Post-nebulization decrease in the systolic BP occurred (4 mm Hg, p = 0.016). These changes were not considered to be clinically significant. Eight minor, transitory, self-resolving adverse events occurred (labored breathing, n = 2; chest pain, n = 2; paroxysmal coughing, n = 1; elevated heart rate, n = 1; vomiting, n = 1; hypotension, n = 1), leading to procedure termination in four participants. No serious adverse events occurred. Induced sputum is safe, tolerable, and feasible in adult and adolescent TB suspects in a community healthcare setting.

A discrete choice experiment investigating HIV testing preferences in South Africa.

BACKGROUND: South Africa (SA) has the world's highest burden of HIV infection, with an estimated 13.7% of the population living with HIV (PLWH/Persons Living With HIV). The early identification of PLWH and rapid engagement of them in HIV treatment are indispensable tools in the fight against HIV transmission. Understanding client preferences for HIV testing may help improve uptake. This study aimed to elicit client preferences for key characteristics of HIV testing options. METHODS: A discrete-choice experiment (DCE) was conducted among individuals presenting for HIV testing at two public primary healthcare facilities in Cape Town, South Africa. Participants were asked to make nine choices between two unlabeled alternatives that differed in five attributes, in line with previous DCEs conducted in Tanzania and Colombia: testing availability, distance from the testing center, method for obtaining the sample, medication availability at testing centers, and confidentiality. Data were analyzed using a random parameter logit model. RESULTS: A total of 206 participants agreed to participate in the study, of whom 199 fully completed the choice tasks. The mean age of the participants was 33.6 years, and most participants were female (83%). Confidentiality was the most important attribute, followed by distance from the testing center and the method of obtaining a sample. Patients preferred finger prick to venipuncture as a method for obtaining the sample. Medication availability at the testing site was also preferred over a referral to an HIV treatment center for a positive HIV test. There were significant variations in preferences among respondents. CONCLUSION: In addition to accentuating the importance of confidentiality, the method for obtaining the sample and the location of sites for collection of medication should be considered in the testing strategy. The variations in preferences within target populations should be considered in identifying optimal testing strategies.

Willingness to pay for primary health care at public facilities in the Western Cape Province, Cape Town, South Africa.

BACKGROUND AND OBJECTIVES: As facilities are being prepared for the implementation of National Health Insurance (NHI) in South Africa, there is a pressing need to understand how the public equates the provision of health services at Primary Health Care (PHC) centres with monetary value. Accordingly, this exploratory study was designed to ascertain the willingness to pay (WTP) for public primary healthcare services in South Africa and to identify factors that influence the WTP. METHODS: The study was conducted in Cape Town, South Africa, among 453 persons presenting at two public primary health care centres, namely Bothasig Community Day Centre (CDC) and Goodwood CDC. The study used the contingent valuation range methodology. Descriptive statistics, multiple logistic and tobit regression analyses were conducted to assess demographics, socio-economic, and health access factors that influence WTP. RESULTS: Overall, 60% of participants were willing to pay for services offered at the PHC facilities. The average willingness to pay for all participants was 49.44 ZAR, with a median of 25 ZAR. The multiple logistic regression for grouped facilities showed unemployment, public transport, and the facility attended to be significant while public transport, facility visits, and facility attended were the only significant variables in the tobit model. There was less willingness to pay for those unemployed in comparison with students, those using public transport rather than walking, those frequenting the facilities more than first-time visitors and those attending Goodwood facility in comparison with Bothasig. CONCLUSION: This study revealed factors related to the participants' WTP and to their willingness to contribute towards the health service, though at very low amounts. Understanding the economic value placed upon a service provided in a facility is essential in decision-making for quality care improvements, especially as the South African health system is making the facilities ready for NHI.

Asymptomatic COVID-19 in South Africa - implications for the control of transmission.

Asymptomatic COVID-19 may contribute significantly to the pandemic trajectory based on global biological, epidemiological and modelling evidence. A retrospective analysis was done to determine the proportion of asymptomatic COVID-19 in the workplace during the lockdown period from 27 March to 31 May 2020. We found that nearly 45% of cases were asymptomatic at the time of the first test. This high proportion of asymptomatic COVID-19 cases has implications for interventions, such as enforcing quarantine of all close contacts of COVID-19 cases regardless of symptoms.

Le COVID-19 a symptomatique pourrait contribuer significativement à la trajectoire de la pandémie en se basant sur des preuves mondiales, biologique et épidémiologiques, et en modélisant les preuves. Une analyse rétrospective a été réalisée afin de décrire la proportion d'infections asymptomatiques de SARS-CoV-2 parmi les clusters essentiels sur les lieux de travail en Afrique du Sud où des investigations de flambée ont été réalisées durant la période de confinement très restrictive du 27 mars au 31 mai 2020. Près de 45% des cas étaient asymptomatique lors du premier test. Cette proportion élevée des cas de COVID-19 asymptomatiques a des implications en ce qui concerne les interventions nonpharmaceutique comme le renforcement de la quarantaine de tous les contacts étroits des cas de SARS-CoV-2 sans tenir compte des symptômes.

Single nucleotide polymorphisms in toll-like receptor 6 are associated with altered lipopeptide- and mycobacteria-induced interleukin-6 secretion.

Toll-like receptors (TLRs) are critical mediators of the immune response to pathogens. The influence of human TLR6 polymorphisms on susceptibility to infection is only partially understood. Most microbes contain lipopeptides recognized by TLR2/1 or TLR2/6 heterodimers. Our aim was to determine whether single nucleotide polymorphisms in TLR6 are associated with altered immune responses to lipopeptides and whole mycobacteria. We sequenced the TLR6 coding region in 100 healthy South African adults to assess genetic variation and determined associations between polymorphisms and lipopeptide- and mycobacteria-induced interleukin (IL)-6 production in whole blood. We found two polymorphisms, C745T and G1083C, that were associated with altered IL-6 secretion. G1083C was associated with altered IL-6 levels in response to lipopeptides, Mycobacterium tuberculosis lysate (Mtb lysate, P=0.018) and Bacille Calmette-Guerin (BCG P=0.039). The 745T allele was also associated with lower NF-κB signaling in response to di-acylated lipopeptide, PAM2 (P=0.019) or Mtb (P=0.026) in an HEK293 cell line reconstitution assay, compared with the 745C allele. We conclude that TLR6 polymorphisms may be associated with altered lipopeptide-induced cytokine responses and recognition of Mtb. These studies provide new insight into the role of TLR6 variation and the innate immune response to human infection.

Temporal trends in the prevalence of Mycobacterium tuberculosis infection in South African adolescents.

South Africa. 1) To measure changes in the adolescent prevalence of latent tuberculous infection (LTBI) between 2005 and 2015, and 2) to evaluate medium-term impact of TB control measures on LTBI prevalence. We compared baseline data from a cohort study (2005-2007) and a vaccine trial (2014-2015) which enrolled adolescents from the same eight South African high schools. LTBI was defined based on QuantiFERON®-TB Gold In-Tube test positivity. We analysed data from 4880 adolescents between 2005 and 2007, and 1968 adolescents between 2014 and 2015, when the average LTBI prevalence was respectively 43.8% (95%CI 28.4-59.1) vs. 48.5% (95%CI 41.1-55.8). Age-specific LTBI prevalence increased between the ages 12 and 18 years by 13% only in lower socio-economic quintile schools, where the average LTBI prevalence was unchanged between the two periods (54% vs. 53%). In the highest socio-economic quintile schools, LTBI prevalence did not increase with age; however, the average LTBI prevalence increased from 20% to 38% between the two periods. Adolescent LTBI prevalence remained high and constant over a decade, suggesting that Mycobacterium tuberculosis transmission to children was not impacted in the medium term by effective TB control efforts. Trends in adolescent LTBI prevalence should be interpreted in the context of the sociodemographic factors that affect the risk of transmission before and during adolescence. .

Impact of isoniazid preventive therapy on the evaluation of long-term effectiveness of infant MVA85A vaccination.

SETTING: South Africa. OBJECTIVE: To evaluate the long-term effectiveness of infant modified vaccinia Ankara virus-expressing antigen 85A (MVA85A) vaccination against tuberculosis (TB). DESIGN: We analysed data from a double-blind randomised placebo-controlled Phase 2b MVA85A infant TB vaccine trial (2009-2012), with extended post-trial follow-up (2012-2014). Isoniazid preventive therapy (IPT) was provided by public health services according to national guidelines. The primary outcome was curative treatment for TB disease. Survival analysis and Poisson regression were used for study analysis. RESULTS: Total follow-up was 10 351 person-years of observation (pyo). Median follow-up age was 4.8 years (interquartile range 4.4-5.2). There were 328 (12%) TB cases. TB disease incidence was 3.2/100 pyo (95%CI 2.8-3.5) overall, and respectively 3.3 (95%CI 2.9-3.9) and 3.0 (95%CI 2.6-3.5)/100 pyo in the MVA85A vaccine and placebo arms. A total of 304 children (11%) received IPT, with respectively 880 and 9471 pyo among IPT and non-IPT recipients. There were 23 (7.6%) TB cases among 304 IPT recipients vs. 305 (12.9%) among 2374 non-IPT recipients (P = 0.008). IPT effectiveness was 85% (95%CI 76-91). CONCLUSION: Extended follow-up confirms no long-term effectiveness of infant MVA85A vaccination, but a six-fold reduction in TB risk can be attributed to IPT. National TB programmes in high TB burden countries should ensure optimal implementation of IPT for eligible children.

Comparison of mantoux skin test with three generations of a whole blood IFN-gamma assay for tuberculosis infection.

SETTING: A rural town in South Africa. OBJECTIVE: To compare the performance of Quanti-FERON assays with the tuberculin skin test (TST) for identifying latent tuberculosis infection (LTBI) in a high TB burden community. DESIGN: In a cross-sectional study in healthy adults, we applied the TST and took blood for the three generations of QuantiFERON assays. RESULTS: Of 358 participants whose results were analysed, 291 (81%) had a TST result of > or = 10 mm induration, and 187 (52%) > or = 15 mm. QuantiFERON-TB was positive in 215 (60%), QuantiFERON-TB Gold in 137 (38%), and QuantiFERON-TB Gold (In-Tube method) in 201 (56%). There was poor agreement between TST and QuantiFERON tests, and between the different generations of QuantiFERON tests (kappa = 0.12-0.50). Of the subset with TST indurations > or = 15 mm, 30-56% had negative QuantiFERON tests. However, positive Quanti-FERON tests were associated with males, who have a higher incidence of TB in this area. CONCLUSION: We showed poor agreement between TST and the different QuantiFERON tests in diagnosing LTBI. The surprising discordance between the Quanti-FERON TB Gold and QuantiFERON TB Gold (In-Tube method) tests needs to be investigated further.

Climate change is catchy--but when will it really hurt?

Concern and general awareness about the impacts of climate change in all sectors of the social-ecological-economic system is growing as a result of improved climate science products and information, as well as increased media coverage of the apparent manifestations of the phenomenon in our society. However, scales of climate variability and change, in space and time, are often confused and so attribution of impacts on various sectors, including the health sector, can be misunderstood and misrepresented. In this review, we assess the mechanistic links between climate and infectious diseases in particular, and consider how this relationship varies, and may vary according to different time scales, especially for aetiologically climate-linked diseases. While climate varies in the medium (inter-annual) time frame, this variability itself may be oscillating and/or trending on cyclical and long-term (climate change) scales because of regional and global scale climate phenomena such as the El-Nino southern oscillation coupled with global-warming drivers of climate change. As several studies have shown, quantifying and modelling these linkages and associations at appropriate time and space scales is both necessary and increasingly feasible with improved climate science products and better epidemiological data. The application of this approach is considered for South Africa, and the need for a more concerted effort in this regard is supported.

A double-blind, randomised, placebo-controlled, dose-finding trial of the novel tuberculosis vaccine AERAS-402, an adenovirus-vectored fusion protein, in healthy, BCG-vaccinated infants.

BACKGROUND: Several novel tuberculosis vaccines are currently in clinical trials, including AERAS-402, an adenovector encoding a fusion protein of Mycobacterium tuberculosis antigens 85A, 85B, and TB10.4. A multicentred trial of AERAS-402 safety and immunogenicity in healthy infants was conducted in three countries in sub-Saharan Africa, using an adaptive design. METHODS: In a double-blind, randomised, placebo-controlled, dose-finding trial, we enrolled BCG-vaccinated, HIV-uninfected infants aged 16-26 weeks. Infants in the safety/dose-finding phase received two doses of AERAS-402 across three dose levels, or placebo, intramuscularly on days 0 and 28. Infants in the expanded safety phase received three doses of the highest dose level, with the 3rd dose at day 280. Follow up for safety and immunogenicity was for up to two years. RESULTS: We enrolled 206 infants (52 placebo and 154 AERAS-402 recipients) into the dose-finding phase and 281 (141 placebo and 140 AERAS-402 recipients) into the expanded safety phase. Safety data were acceptable across all dose levels. No vaccine-related deaths were recorded. A single serious adverse event of tachypnoea was deemed related to study vaccine. Antibodies directed largely against Ag85A and Ag85B were detected. Low magnitude CD4+ and CD8+ polyfunctional T cell responses were observed at all dose levels. The addition of a third dose of AERAS-402 at the highest dose level did not increase frequency or magnitude of antibody or CD8+ T cell responses. CONCLUSIONS: AERAS-402 has an acceptable safety profile in infants and was well tolerated at all dose levels. Response rate was lower than previously seen in BCG vaccinated adults, and frequency and magnitude of antigen-specific T cells were not increased by a third dose of vaccine.

Block appointments in an overloaded South African health centre: quantitative and qualitative evaluation.

Long waiting times are a serious problem for patients using urban health centres in developing countries. A block appointment system was introduced and evaluated in a large South African health centre. Waiting times of all patients were measured over a one-week period before and after the implementation of appointments. Focus group and individual interviews were conducted with staff and patients. After introducing appointments, patients with acute and chronic illnesses and having appointments had significantly shorter waits than similar patients without appointments (difference in median waits: 63 and 39 minutes respectively). Appointments had no benefits for patients not seeing doctors or collecting repeat medication. There was, however, an overall increase in patients' waiting times after introducing the system, mainly due to one atypical day in the follow-up study. Focus groups and interviews revealed that staff were sceptical at baseline but at follow-up were positive about the system. Patients were enthusiastic about the appointment system at all stages. The study shows that block appointments can reduce patient waiting times for acute patients, but may not be suitable for all patients. Staff and patients had different views, which converged with experience of the new system.

Designing an adaptive phase II/III trial to evaluate efficacy, safety and immune correlates of new TB vaccines in young adults and adolescents.

This article summarises the consensus arrived at a meeting of South African and international stakeholders on specific late phase clinical trial design issues integrating the investigation of immune correlates as an integral part of a phase III protocol for a preventative TB vaccine in an adolescent/adult population. The challenge ahead is to optimize the planning for phase 3 TB vaccine preventative trials, under resource constraints, given that there are no known correlates of protection to shorten and increase the efficiencies of efficacy trials. An adaptive, multi-arm, group sequentially designed trial protocol is proposed incorporating design features that address uncertainties arising from both advances in the field and dynamic study populations and disease states. Such a design allows modifications that protect research subjects, save time, and maximize the impact of scarce financial resources. Further, the protocol underwent joint review by regulators from several African nations at a meeting of the African Vaccine Regulatory Forum (AVAREF), a regional regulatory harmonization initiative, and recommendations are included.

Analysis of time to regulatory and ethical approval of SATVI TB vaccine trials in South Africa.

BACKGROUND: Tuberculosis (TB) vaccine trials in South Africa must be approved by the Medicines Control Council (MCC) and by a human research ethics committee (HREC). Delays in regulatory and ethical approval may affect operational and budget planning and clinical development of the product. AIM: Our aim was to analyse the time to regulatory and ethical approval for TB vaccine trials conducted by the South African Tuberculosis Vaccine Initiative (SATVI) and to evaluate factors that influence time to final approval. METHOD: Sixteen new TB vaccine clinical trials conducted by SATVI between 2004 and 2012 on infants, children, and adults were included. The period between submission and final approval was determined for protocols submitted to the MCC and the University of Cape Town HREC. RESULTS: Median approval time following first submission to the MCC was 122 days (IQR 112 - 168; range 71 - 350), and for protocol amendments 103 days (interquartile range (IQR) 76 - 141; range 23 - 191; n=30). Median time following first submission for HREC approval was 60 days (IQR 33 - 81; range 18 - 125), and for amendments 6 days (IQR 4 - 13; range 1 - 37; n=30). There was no significant difference in approval time by trial phase, year of submission, revisions required, study population, sample size, or whether a clinical research organisation (CRO) was used. CONCLUSION: The time needed for regulatory and ethics approval was highly variable, but MCC approval for first submissions took twice as long as HREC approval and was the primary determinant of time to final approval. National regulatory capacity should be strengthened to facilitate the conduct of new TB vaccine trials in this country with its high burden of TB.

Vaccine trials in the developing world: operational lessons learnt from a phase IV poliomyelitis vaccine trial in South Africa.

BACKGROUND: Conducting vaccine trials in developing nations is necessary but operationally complex. We describe operational lessons learnt from a phase IV poliomyelitis vaccine trial in a semi-rural region of South Africa. METHODS: We reviewed operational data collected over the duration of the trial with respect to staff recruitment and training, participant recruitment and retention, and cold chain maintenance. RESULTS-LESSONS LEARNT: The recruitment model we used that relied on the 24h physical presence of a team member in the birthing unit was expensive and challenging to manage. Forecasting of enrolment rates was complicated by incomplete baseline data and by the linear nature of forecasts that do not take into account changing variables. We found that analyzing key operational data to monitor progress of the trial enabled us to identify problem areas timeously, and to facilitate a collegial problem-solving process by the extended trial team. Pro-actively nurturing a working relationship with the public sector health care system and the community was critical to our success. Despite the wide geographical area and lack of fixed addresses, we maintained an excellent retention rate through community assistance and the use of descriptive residential information. Training needs of team members were ongoing and dynamic and we discovered that these needs that were best met by an in-house, targeted and systemized training programme. The use of vaccine refrigerators instead of standard frost-free refrigerators is cost-effective and necessary to maintain the cold-chain. CONCLUSION: Operational challenges of a vaccine trial in developing world populations include inexperienced staff, the close liaison required between researchers and public health care services, impoverished participants that require complex recruitment and retention strategies, and challenges of distance and access. These challenges can be overcome by innovative strategies that allow for the unique characteristics of the setting, trial population, and trial team.

Tuberculosis case finding for vaccine trials in young children in high-incidence settings: a randomised trial.

SETTING: A high tuberculosis (TB) burden rural area in South Africa. OBJECTIVE: To compare TB case yield and disease profile among bacille Calmette-Guérin (BCG) vaccinated children using two case-finding strategies from birth until 2 years of age. DESIGN: BCG-vaccinated infants were enrolled within 2 weeks of birth and randomised to 3-monthly home visits for questionnaire-based TB screening plus record surveillance of TB registers, hospital admission and X-ray lists at health facilities for TB suspects and cases (Group 1), or record surveillance (as above) only (Group 2). Both groups received a close-out visit after 2 years. Participants were evaluated for suspected TB disease using standardised investigations. RESULTS: A total of 4786 infants were enrolled: 2392 were randomised to Group 1 and 2394 to Group 2. The case-finding rate was significantly greater in Group 1 (2.2/100 py) than in Group 2 (0.8/100 py), with a case-finding rate ratio of 2.6 (95%CI 1.8-4.0, P < 0.001). Although the proportion of cases with bacteriological confirmation was lower in Group 1, this difference did not reach statistical significance. There was also no significant difference in the proportions with TB symptoms and signs. CONCLUSION: Home visits combined with record surveillance detected significantly more cases than record surveillance with a single study-end visit. The TB case profile did not differ significantly between the two groups.