Final Analysis of a Trial of M72/AS01E Vaccine to Prevent Tuberculosis.

BACKGROUND: Results of an earlier analysis of a trial of the M72/AS01E candidate vaccine against Mycobacterium tuberculosis showed that in infected adults, the vaccine provided 54.0% protection against active pulmonary tuberculosis disease, without evident safety concerns. We now report the results of the 3-year final analysis of efficacy, safety, and immunogenicity. METHODS: From August 2014 through November 2015, we enrolled adults 18 to 50 years of age with M. tuberculosis infection (defined by positive results on interferon-γ release assay) without evidence of active tuberculosis disease at centers in Kenya, South Africa, and Zambia. Participants were randomly assigned in a 1:1 ratio to receive two doses of either M72/AS01E or placebo, administered 1 month apart. The primary objective was to evaluate the efficacy of M72/AS01E to prevent active pulmonary tuberculosis disease according to the first case definition (bacteriologically confirmed pulmonary tuberculosis not associated with human immunodeficiency virus infection). Participants were followed for 3 years after the second dose. Participants with clinical suspicion of tuberculosis provided sputum samples for polymerase-chain-reaction assay, mycobacterial culture, or both. Humoral and cell-mediated immune responses were evaluated until month 36 in a subgroup of 300 participants. Safety was assessed in all participants who received at least one dose of M72/AS01E or placebo. RESULTS: A total of 3575 participants underwent randomization, of whom 3573 received at least one dose of M72/AS01E or placebo, and 3330 received both planned doses. Among the 3289 participants in the according-to-protocol efficacy cohort, 13 of the 1626 participants in the M72/AS01E group, as compared with 26 of the 1663 participants in the placebo group, had cases of tuberculosis that met the first case definition (incidence, 0.3 vs. 0.6 cases per 100 person-years). The vaccine efficacy at month 36 was 49.7% (90% confidence interval [CI], 12.1 to 71.2; 95% CI, 2.1 to 74.2). Among participants in the M72/AS01E group, the concentrations of M72-specific antibodies and the frequencies of M72-specific CD4+ T cells increased after the first dose and were sustained throughout the follow-up period. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups. CONCLUSIONS: Among adults infected with M. tuberculosis, vaccination with M72/AS01E elicited an immune response and provided protection against progression to pulmonary tuberculosis disease for at least 3 years. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598.).

Phase 2b Controlled Trial of M72/AS01E Vaccine to Prevent Tuberculosis.

BACKGROUND: A vaccine to interrupt the transmission of tuberculosis is needed. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2b trial of the M72/AS01E tuberculosis vaccine in Kenya, South Africa, and Zambia. Human immunodeficiency virus (HIV)-negative adults 18 to 50 years of age with latent M. tuberculosis infection (by interferon-γ release assay) were randomly assigned (in a 1:1 ratio) to receive two doses of either M72/AS01E or placebo intramuscularly 1 month apart. Most participants had previously received the bacille Calmette-Guérin vaccine. We assessed the safety of M72/AS01E and its efficacy against progression to bacteriologically confirmed active pulmonary tuberculosis disease. Clinical suspicion of tuberculosis was confirmed with sputum by means of a polymerase-chain-reaction test, mycobacterial culture, or both. RESULTS: We report the primary analysis (conducted after a mean of 2.3 years of follow-up) of the ongoing trial. A total of 1786 participants received M72/AS01E and 1787 received placebo, and 1623 and 1660 participants in the respective groups were included in the according-to-protocol efficacy cohort. A total of 10 participants in the M72/AS01E group met the primary case definition (bacteriologically confirmed active pulmonary tuberculosis, with confirmation before treatment), as compared with 22 participants in the placebo group (incidence, 0.3 cases vs. 0.6 cases per 100 person-years). The vaccine efficacy was 54.0% (90% confidence interval [CI], 13.9 to 75.4; 95% CI, 2.9 to 78.2; P=0.04). Results for the total vaccinated efficacy cohort were similar (vaccine efficacy, 57.0%; 90% CI, 19.9 to 76.9; 95% CI, 9.7 to 79.5; P=0.03). There were more unsolicited reports of adverse events in the M72/AS01E group (67.4%) than in the placebo group (45.4%) within 30 days after injection, with the difference attributed mainly to injection-site reactions and influenza-like symptoms. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups. CONCLUSIONS: M72/AS01E provided 54.0% protection for M. tuberculosis-infected adults against active pulmonary tuberculosis disease, without evident safety concerns. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598 .).

Factors associated with use of community-based, peer-led sexual and reproductive health services by adolescent boys and young men aged 18-24 in Lusaka, Zambia: A case control study nested in the Yathu Yathu trial.

INTRODUCTION: Adolescents and young people (AYP) aged 15-24 years have the least access to facility-based sexual and reproductive health (SRH) services, including HIV services. The Yathu-Yathu cluster-randomized trial (CRT) in Zambia tested whether a novel peer-led community-based approach increased knowledge of HIV status amongst AYP. In this nested case-control study, we aimed to identify factors associated with non-attendance to the Yathu Yathu hubs by adolescent boys and young men (ABYM) aged 18-24-years. METHODS: Yathu Yathu was a CRT conducted in two communities in Lusaka, Zambia, with 10 intervention and 10 control zones. AYP in all zones were offered prevention points cards (PPC), which incentivized and tracked service use at the hubs and health facility. In intervention zones, services were provided to AYP through community-based spaces (hubs) led by peer support workers. In these zones, cases were defined as those not having accessed any service at a hub and controls as those that accessed at least one service. Data were collected from October 2020 to January 2021 and analysed using methods appropriate for unmatched case-control studies. RESULTS: 161 cases and 160 controls consented to participate in the study. Participants aged 20-24 years (adjOR 1.99, 95%CI 1.26-3.12, p = 0.003), who were educated up to college level (adjOR 8.47,95%CI 2.08-34.53, p = 0.001) or who reported being employed in the last 12 months (adjOR 2.15, 95%CI 1.31-3.53, p = 0.002) were more likely to not attend the hubs. ABYM who had a friend with a PPC were more likely to attend the hubs (adjOR 0.18 95%CI 0.09-0.35, p<0.001). Most cases reported having their last HIV test at the local government health facility (58%) while most controls reported HIV-testing at a Yathu Yathu hub (82%). Among the controls, 84% (134/160) rated the hub experience as excellent. Among cases, 65% (104/161) stated they didn't visit the hubs "due to employment". CONCLUSIONS: Despite Yathu Yathu services being community-based and more accessible compared to health facilities, we found age, education and employment were associated with not attending hubs. Strategies are needed to reach employed young men who may not have access to SRH/HIV services during conventional working hours and to better utilise peer networks to increase service use.

High levels of vulnerability and anticipated stigma reduce the impetus for tuberculosis diagnosis in Cape Town, South Africa.

Prolonged diagnostic and treatment delays, particularly in settings experiencing concomitant human immunodeficiency virus (HIV) and tuberculosis (TB) epidemics, undermine global TB control efforts. Current TB control policy in South Africa, as organized through the National TB Control Programme (NTP), relies on the voluntary presentation of TB suspects to local clinics for diagnosis, i.e. passive case finding (PCF). In 2005 a participatory study suggested that popular interpretation and perception of TB within eight South African township sites in and around Cape Town, all carrying a high burden of HIV and undiagnosed TB, undermine PCF. Both people's association of TB with dirt and squalor, and the anticipation of HIV-related stigma, combine to impede TB diagnosis. Respondents conveyed TB as unavoidable; this perception is expressed in the context of vulnerability where so much-including dirt-is largely beyond the control of local residents. The lack of control has a disempowering effect, reducing the drive for seeking treatment. In addition, low confidence in patient confidentiality and anticipated HIV-related stigma act as direct deterrents to TB diagnosis and treatment. In conclusion, we wish to draw attention to high levels of disease stigma and vulnerability, and how these undermine PCF. Public health interventions that wish to improve case detection should aim to: (1) emphasize how early treatment improves outcome and can curb ongoing transmission; (2) combat a sense of communal vulnerability to TB; (3) address anticipated HIV-TB stigma; and (4) improve the quality of care provided at local diagnostic services, addressing low levels of patient confidentiality.

ZAMSTAR, The Zambia South Africa TB and HIV Reduction Study: design of a 2 x 2 factorial community randomized trial.

BACKGROUND: TB and HIV form a deadly synergy in much of the developing world, especially Africa. Interventions to reduce the impact of these diseases at community level are urgently needed. This paper presents the design of a community randomised trial to evaluate the impact of two complex interventions on the prevalence of tuberculosis (TB) in high HIV prevalence settings in Zambia and South Africa. METHODS: The interaction between TB and HIV is reviewed and possible interventions that could reduce the prevalence of TB in HIV-endemic populations are discussed. Two of these interventions are described in detail and the design of a 2 x 2 factorial community randomised trial to test these interventions is presented. The limitations and challenges of the design are identified and discussed. CONCLUSION: There is an urgent need to reduce the prevalence of TB in communities highly affected by HIV. Potential interventions are complex and require innovative trial designs to provide the rigorous evidence needed to inform health policy makers and to ensure that resources are used optimally. TRIAL REGISTRATION: Number: ISRCTN36729271.