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Summary: Background: This analysis evaluated the immune response to the two-dose, heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola virus vaccine regimen, administered 56-days apart, from multiple African sites based on results from one analytic laboratory. Methods: Immunogenicity across three trials (EBL2002, EBL2004/PREVAC, EBL3001) conducted in East and West Africa is summarised. Vaccine-induced Ebola glycoprotein-binding antibody concentrations were analysed by Q2 Solutions laboratory at baseline, 21 days (EBL2002 and EBL3001) or 28 days (EBL2004) post-dose 2 (regimen completion), and 12 months post-dose 1 using the validated Filovirus Animal Nonclinical Group Ebola glycoprotein enzyme-linked immunosorbent assay (ELISA). Responders were defined as those with a >2.5-fold increase from baseline or the lower limit of quantification (LLOQ) if

Background Reoccurring Ebola outbreaks in West and Central Africa have led to serious illness and death in thousands of adults and children. The objective of this study was to assess safety, tolerability, and immunogenicity of the heterologous 2-dose Ad26.ZEBOV, MVA-BN-Filo vaccination regimen in adolescents and children in Africa. Methods and findings In this multicentre, randomised, observer-blind, placebo-controlled Phase II study, 131 adolescents (12 to 17 years old) and 132 children (4 to 11 years old) were enrolled from Eastern and Western Africa and randomised 5:1 to receive study vaccines or placebo. Vaccine groups received intramuscular injections of Ad26.ZEBOV (5 × 1010 viral particles) and MVA-BN-Filo (1 × 108 infectious units) 28 or 56 days apart; placebo recipients received saline. Primary outcomes were safety and tolerability. Solicited adverse events (AEs) were recorded until 7 days after each vaccination and serious AEs (SAEs) throughout the study. Secondary and exploratory outcomes were humoral immune responses (binding and neutralising Ebola virus [EBOV] glycoprotein [GP]-specific antibodies), up to 1 year after the first dose. Enrolment began on February 26, 2016, and the date of last participant last visit was November 28, 2018. Of the 263 participants enrolled, 217 (109 adolescents, 108 children) received the 2-dose regimen, and 43 (20 adolescents, 23 children) received 2 placebo doses. Median age was 14.0 (range 11 to 17) and 7.0 (range 4 to 11) years for adolescents and children, respectively. Fifty-four percent of the adolescents and 51% of the children were male. All participants were Africans, and, although there was a slight male preponderance overall, the groups were well balanced. No vaccine-related SAEs were reported; solicited AEs were mostly mild/moderate. Twenty-one days post-MVA-BN-Filo vaccination, binding antibody responses against EBOV GP were observed in 100% of vaccinees (106 adolescents, 104 children). Geometric mean concentrations tended to be higher after the 56-day interval (adolescents 13,532 ELISA units [EU]/mL, children 17,388 EU/mL) than the 28-day interval (adolescents 6,993 EU/mL, children 8,007 EU/mL). Humoral responses persisted at least up to Day 365. A limitation of the study is that the follow-up period was limited to 365 days for the majority of the participants, and so it was not possible to determine whether immune responses persisted beyond this time period. Additionally, formal statistical comparisons were not preplanned but were only performed post hoc. Conclusions The heterologous 2-dose vaccination was well tolerated in African adolescents and children with no vaccine-related SAEs. All vaccinees displayed anti-EBOV GP antibodies after the 2-dose regimen, with higher responses in the 56-day interval groups. The frequency of pyrexia after vaccine or placebo was higher in children than in adolescents. These data supported the prophylactic indication against EBOV disease in a paediatric population, as licenced in the EU. Trial registration ClinicalTrials.govNCT02564523. Zacchaeus Anywaine and co-workers study safety and immunogenicity of an Ebola vaccine among children and adolescents across four African countries. Author summary Why was the study done? There have been larger and more extensive Ebola virus disease (EVD) outbreaks in Africa in the past decade with no licenced treatments available. As such, there is an unmet medical need for prophylactic Ebola vaccines. This study was performed to evaluate whether a 2-dose heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination was safe and immunogenic in healthy African children. What did the researchers do and find? In this randomised, placebo-controlled, Phase II clinical trial, the Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination regimen was administered to African participants in 2 age cohorts (12 to 17 and 4 to 11 years). No vaccine-related serious adverse events were reported, and robust immune responses were induced in both adolescents and children after receiving the active 2-dose regimen. What do these findings mean? These data support the use of the Ad26.ZEBOV, MVA-BN-Filo vaccination regimen in African adolescents and children at risk of Ebola infection. Although vaccination according to a 28-day regimen may lead to protection against EVD in a shorter time frame, vaccination according to a 56-day regimen results in higher EBOV GP binding and neutralising antibody responses. The observation that Ad26 preexisting immunity in the majority of participants does not affect the EBOV GP-specific antibody responses postvaccination augurs well for the use of this vaccine regimen even in regions with a high prevalence of preexisting Ad26 seropositivity.

Background We investigated safety, tolerability, and immunogenicity of the heterologous 2-dose Ebola vaccination regimen in healthy and HIV-infected adults with different intervals between Ebola vaccinations. Methods and findings In this randomised, observer-blind, placebo-controlled Phase II trial, 668 healthy 18- to 70-year-olds and 142 HIV-infected 18- to 50-year-olds were enrolled from 1 site in Kenya and 2 sites each in Burkina Faso, Cote d’Ivoire, and Uganda. Participants received intramuscular Ad26.ZEBOV followed by MVA-BN-Filo at 28-, 56-, or 84-day intervals, or saline. Females represented 31.4% of the healthy adult cohort in contrast to 69.7% of the HIV-infected cohort. A subset of healthy adults received booster vaccination with Ad26.ZEBOV or saline at Day 365. Following vaccinations, adverse events (AEs) were collected until 42 days post last vaccination and serious AEs (SAEs) were recorded from signing of the ICF until the end of the study. The primary endpoint was safety, and the secondary endpoint was immunogenicity. Anti-Ebola virus glycoprotein (EBOV GP) binding and neutralising antibodies were measured at baseline and at predefined time points throughout the study. The first participant was enrolled on 9 November 2015, and the date of last participant’s last visit was 12 February 2019. No vaccine-related SAEs and mainly mild-to-moderate AEs were observed among the participants. The most frequent solicited AEs were injection-site pain (local), and fatigue, headache, and myalgia (systemic), respectively. Twenty-one days post-MVA-BN-Filo vaccination, geometric mean concentrations (GMCs) with 95% confidence intervals (CIs) of EBOV GP binding antibodies in healthy adults in 28-, 56-, and 84-day interval groups were 3,085 EU/mL (2,648 to 3,594), 7,518 EU/mL (6,468 to 8,740), and 7,300 EU/mL (5,116 to 10,417), respectively. In HIV-infected adults in 28- and 56-day interval groups, GMCs were 4,207 EU/mL (3,233 to 5,474) and 5,283 EU/mL (4,094 to 6,817), respectively. Antibody responses were observed until Day 365. Ad26.ZEBOV booster vaccination after 1 year induced an anamnestic response. Study limitations include that some healthy adult participants either did not receive dose 2 or received dose 2 outside of their protocol-defined interval and that the follow-up period was limited to 365 days for most participants. Conclusions Ad26.ZEBOV, MVA-BN-Filo vaccination was well tolerated and immunogenic in healthy and HIV-infected African adults. Increasing the interval between vaccinations from 28 to 56 days improved the magnitude of humoral immune responses. Antibody levels persisted to at least 1 year, and Ad26.ZEBOV booster vaccination demonstrated the presence of vaccination-induced immune memory. These data supported the approval by the European Union for prophylaxis against EBOV disease in adults and children ≥1 year of age. Trial registration ClinicalTrials.govNCT02564523 Houreratou Barry and co-workers report on safety and immunogenicity of an Ebola vaccine in adults across four African countries. Author summary Why was this study done? With Ebola outbreaks increasing, there is an unmet medical need for a prophylactic vaccine to prevent and mitigate Ebola outbreaks. To address the urgent medical need during the 2014 to 2016 outbreak, the clinical development of the 2-dose vaccine regimen comprising of Ad26.ZEBOV and MVA-BN-Filo was accelerated. This Phase II study was part of this accelerated program, evaluating the safety and immunogenicity of the 2-dose vaccine regimen in healthy and HIV-infected African adults, with 28-, 56-, and 84-day intervals between doses. The study was amended to evaluate safety and immunogenicity of a booster vaccination with Ad26.ZEBOV, administered approximately 1 year after the first vaccination, in healthy adults. What did the researchers do and find? We conducted a randomised trial to assess the safety and the immunogenicity of the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen in 3 different vaccination intervals in healthy and HIV-infected adults. The vaccine regimen was well tolerated and induced marked immune responses; the highest humoral responses were observed after vaccination with 56-day and 84-day intervals. Anamnestic responses were observed in all healthy participants receiving Ad26.ZEBOV as booster at 1 year after the first dose. What do these findings mean? Our results demonstrate that the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen is safe and immunogenic in healthy and HIV-infected adults and induces immune memory that can rapidly be reactivated. Our findings support the prophylactic use of the 2-dose Ad26.ZEBOV, MVA-BN-Filo vaccine regimen against Ebola infection in African adult populations. The 2-dose vaccine regimen comprising of Ad26.ZEBOV and MVA-BN-Filo has received marketing authorisation under exceptional circumstances for prophylactic use against EVD in adults and children ≥1 year old within the European Union.

To assess the performance of QuantiFERON-TB Gold In-Tube (QFT-GIT) test for active tuberculosis (TB) in HIV adults, and its variation over time in patients on antiretroviral therapy (ART) and/or isoniazide preventive therapy (IPT).Transversal study and cohort nested in the Temprano ANRS 12136 randomized controlled trial assessing benefits of initiating ART earlier than currently recommended by World Health Organization, with or without a 6-month IPT. Performance of QFT-GIT for detecting active TB at baseline in the first 50% participants, and 12-month incidence of conversion/reversion in the first 25% participants were assessed. QFT-GIT threshold for positivity was 0.35 IU/ml.Among the 975 first participants (median baseline CD4 count 383/mm3, positive QFT-GIT test 35%), 2.7% had active TB at baseline. QFT-GIT sensitivity, specificity, positive and negative predictive value for active TB were 88.0%, 66.6%, 6.5% and 99.5%. For the 444 patients with a second test at 12 months, rates for conversion and reversion were 9.3% and 14%. Reversion was more frequent in patients without ART and younger patients. IPT and early ART were not associated with reversion/conversion.A negative QFT-GIT could rule out active TB in HIV-infected adults not severely immunosuppressed, thus avoiding repeated TB testing and accelerating diagnosis and care for other diseases.ClinicalTrials.gov NCT00495651.

AbstractWest African adults with warning signs of failure of antiretroviral treatment (ART) at 6 months were assessed for the probability and factors associated with success at 36 months. After 6 months on ART, patients were included if they had a bad immunologic response (BIR) (month 6 CD4 count 300 copies/ml), or both (Dual). They were followed for 30 months after inclusion. CD4 counts and HIV-1 RNA were measured every 3 months. We estimated the probability of reaching immunovirologic success (CD4 count >350/mm3and plasma HIV-1 RNA 90% between month 6 and month 36 had a likelihood of success 3.8 and 3.6 higher than other patients. The 36-month probability of success was 0.56 and 0.86 in patients with an MPR 90% and 0.59 and 0.84 in patients with and without resistance. After warning signs of failure at 6 months, a large proportion of patients reaches immunovirologic success before 36 months provided there is a high rate of adherence to medication and the absence of early resistance mutations. [ABSTRACT FROM AUTHOR]

AbstractAs antiretroviral therapy continues to scale-up in developing countries, there is concern that high levels of HIV drug resistance to antiretroviral drugs will occur. Here we describe rates of emergence of HIV-1 drug resistance and factors associated with their occurrence among adults who received antiretroviral therapy (ART) for >1 year through the Côte d'Ivoire national drug access program from 1998 to 2003. To detect genotypic drug resistance, we sequenced all 1- and 2-year specimens with detectable HIV RNA viral load. To assess factors associated with emerging drug resistance, we used log normal regression with interval censoring, including covariates in the model for self-reported drug adherence, CD4 cell count, and HIV viral load at therapy initiation, and observed changes in these measures, type of prescribed ART drugs, diagnoses of opportunistic illness, and demographic characteristics. An estimated 14.2% [95% confidence limits (CL) 11.7, 16.9] and 26.6% (95% CL 22.7, 30.8) of patients developed primary drug-resistant mutations within 1 year and 2 years after initiation of therapy, respectively. Factors associated with drug resistance included drug nonadherence, partial or lack of viral suppression, higher viral load or lower CD4 at initiation of therapy, and initiation of ART with what is now considered substandard dual combination therapy. Our results demonstrate the need to strengthen adherence and continuity in treatment programs in order to avoid interruption of ART drugs. Treatment programs should pay attention to indicators of emerging drug resistance: incomplete or lesser decreases in viral load or increases in CD4 cell counts following initiation of therapy, and the occurrence of AIDS opportunistic illnesses. [ABSTRACT FROM AUTHOR]