Safety and immunogenicity of two heterologous HIV vaccine regimens in healthy, HIV-uninfected adults (TRAVERSE): a randomised, parallel-group, placebo-controlled, double-blind, phase 1/2a study.
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SUBMITTER: Baden LR
PROVIDER: S-EPMC7529856 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
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Safety and immunogenicity of two heterologous HIV vaccine regimens in healthy, HIV-uninfected adults (TRAVERSE): a randomised, parallel-group, placebo-controlled, double-blind, phase 1/2a study.
Baden Lindsey R LR Stieh Daniel J DJ Sarnecki Michal M Walsh Stephen R SR Tomaras Georgia D GD Kublin James G JG McElrath M Juliana MJ Alter Galit G Ferrari Guido G Montefiori David D Mann Philipp P Nijs Steven S Callewaert Katleen K Goepfert Paul P Edupuganti Srilatha S Karita Etienne E Langedijk Johannes P JP Wegmann Frank F Corey Lawrence L Pau Maria G MG Barouch Dan H DH Schuitemaker Hanneke H Tomaka Frank F
The lancet. HIV 20201001 10
<h4>Background</h4>Bioinformatically designed mosaic antigens increase the breadth of HIV vaccine-elicited immunity. This study compared the safety, tolerability, and immunogenicity of a newly developed, tetravalent Ad26 vaccine with the previously tested trivalent formulation.<h4>Methods</h4>This randomised, parallel-group, placebo-controlled, double-blind, phase 1/2a study (TRAVERSE) was done at 11 centres in the USA and one centre in Rwanda. Eligible participants were adults aged 18 to 50 yea ...[more]
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Project description:BackgroundDeveloping a cross-clade, globally effective HIV vaccine remains crucial for eliminating HIV.MethodsThis placebo-controlled, double-blind, phase 1/2a study enrolled healthy HIV-uninfected adults at low risk for HIV infection. They were randomized (1:4:1) to receive 4 doses of an adenovirus 26-based HIV-1 vaccine encoding 2 mosaic Gag and Pol, and 2 mosaic Env proteins plus adjuvanted clade C gp140 (referred to here as clade C regimen), bivalent protein regimen (clade C regimen plus mosaic gp140), or placebo. Primary end points were safety and antibody responses.ResultsIn total 152/155 participants (clade C, n = 26; bivalent protein, n = 103; placebo, n = 26) received ≥1 injection. The highest adverse event (AE) severity was grade 3 (local pain/tenderness, 12%, 2%, and 0% of the respective groups; solicited systemic AEs, 19%, 15%, 0%). HIV-1 mosaic gp140-binding antibody titers were 79 595 ELISA units (EU)/mL and 137 520 EU/mL in the clade C and bivalent protein groups (P < .001) after dose 4 and 16 862 EU/mL and 25 162 EU/mL 6 months later. Antibody response breadth against clade C gp140 and clade C/non-clade C gp120 was highest in the bivalent protein group.ConclusionsAdding mosaic gp140 to the clade C regimen increased and broadened the elicited immune response without compromising safety or clade C responses. Clinical Trials Registration. NCT02935686.
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Project description:Adjunctive dexamethasone reduces mortality from tuberculous meningitis (TBM) but not disability, which is associated with brain infarction. We hypothesised that aspirin prevents TBM-related brain infarction through its anti-thrombotic, anti-inflammatory, and pro-resolution properties. We conducted a randomised controlled trial in HIV-uninfected adults with TBM of daily aspirin 81 mg or 1000 mg, or placebo, added to the first 60 days of anti-tuberculosis drugs and dexamethasone (NCT02237365). The primary safety endpoint was gastro-intestinal or cerebral bleeding by 60 days; the primary efficacy endpoint was new brain infarction confirmed by magnetic resonance imaging or death by 60 days. Secondary endpoints included 8-month survival and neuro-disability; the number of grade 3 and 4 and serious adverse events; and cerebrospinal fluid (CSF) inflammatory lipid mediator profiles. 41 participants were randomised to placebo, 39 to aspirin 81 mg/day, and 40 to aspirin 1000 mg/day between October 2014 and May 2016. TBM was proven microbiologically in 92/120 (76.7%) and baseline brain imaging revealed ?1 infarct in 40/114 (35.1%) participants. The primary safety outcome occurred in 5/36 (13.9%) given placebo, and in 8/35 (22.9%) and 8/40 (20.0%) given 81 mg and 1000 mg aspirin, respectively (p=0.59). The primary efficacy outcome occurred in 11/38 (28.9%) given placebo, 8/36 (22.2%) given aspirin 81 mg, and 6/38 (15.8%) given 1000 mg aspirin (p=0.40). Planned subgroup analysis showed a significant interaction between aspirin treatment effect and diagnostic category (Pheterogeneity = 0.01) and suggested a potential reduction in new infarcts and deaths by day 60 in the aspirin treated participants with microbiologically confirmed TBM (11/32 (34.4%) events in placebo vs. 4/27 (14.8%) in aspirin 81 mg vs. 3/28 (10.7%) in aspirin 1000 mg; p=0.06). CSF analysis demonstrated aspirin dose-dependent inhibition of thromboxane A2 and upregulation of pro-resolving CSF protectins. The addition of aspirin to dexamethasone may improve outcomes from TBM and warrants investigation in a large phase 3 trial.
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Project description:BackgroundAd26.RSV.preF is an adenovirus serotype 26 vector-based respiratory syncytial virus (RSV) vaccine encoding a prefusion conformation-stabilized RSV fusion protein (preF) that demonstrated robust humoral and cellular immunogenicity and showed promising efficacy in a human challenge study in younger adults. Addition of recombinant RSV preF protein might enhance RSV-specific humoral immune responses, especially in older populations.MethodsThis randomized, double-blind, placebo-controlled, phase 1/2a study compared the safety and immunogenicity of Ad26.RSV.preF alone and varying doses of Ad26.RSV.preF-RSV preF protein combinations in adults aged ≥60 years. This report includes data from cohort 1 (initial safety, n = 64) and cohort 2 (regimen selection, n = 288). Primary immunogenicity and safety analyses were performed 28 days postvaccination (cohort 2) for regimen selection.ResultsAll vaccine regimens were well tolerated, with similar reactogenicity profiles among them. Combination regimens induced greater humoral immune responses (virus-neutralizing and preF-specific binding antibodies) and similar cellular ones (RSV-F-specific T cells) as compared with Ad26.RSV.preF alone. Vaccine-induced immune responses remained above baseline up to 1.5 years postvaccination.ConclusionsAll Ad26.RSV.preF-based regimens were well tolerated. A combination regimen comprising Ad26.RSV.preF, which elicits strong humoral and cellular responses, and RSV preF protein, which increases humoral responses, was selected for further development. Clinical Trials Registration. NCT03502707.
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Project description:BackgroundVaccination is the most important preventive strategy against influenza, however post-vaccination antibody responses are often inadequate especially among HIV-infected persons. Vitamin D deficiency has been suggested to adversely influence immune responses and is highly prevalent among HIV-infected adults. Therefore, we evaluated the association between 25-hydroxyvitamin D [25(OH)D] levels and post-influenza vaccination responses.MethodsWe conducted a prospective cohort study evaluating the immunogenicity of monovalent influenza A (H1N1) vaccination among both HIV-infected and HIV-uninfected adults (18-50years of age) during the 2009-2010 influenza season. Antibody titers were evaluated at baseline, day 28, and 6months post-vaccination using hemagluttination inhibition assays. Serum 25(OH)D levels were measured at day 28. Univariate and multivariate regression analyses examined the association between 25(OH)D levels [categorized as <20ng/ml (deficiency) vs. ⩾20ng/ml] with the primary outcome of seroconversion. Secondary outcomes included seroprotection; a ⩾4-fold increase in titers; and geometric mean titers post-vaccination. Analyses were repeated using 25(OH)D levels as a continuous variable.ResultsA total of 128 adults [64 HIV-infected (median CD4 count 580cells/mm(3)) and 64 HIV-uninfected] were included. Seroconversion at day 28 post-vaccination was achieved in fewer HIV-infected participants compared with HIV-uninfected participants (56% vs. 74%, p=0.03). Vitamin D deficiency was more prevalent among HIV-infected persons vs. HIV-uninfected persons (25% vs. 17%), although not significantly different (p=0.39). There were no associations found between lower 25(OH)D levels and poorer antibody responses at day 28 or 6months for any of the study outcomes among either HIV-infected or HIV-uninfected adults.ConclusionVitamin D deficiency was common among both HIV-infected and HIV-uninfected adults, but lower levels did not predict antibody responses after H1N1 (2009) influenza vaccination. Low 25(OH)D levels do not explain poorer post-vaccination responses among HIV-infected persons.
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Project description:BackgroundAnti-amyloid vaccines may offer a convenient, affordable, and accessible means of preventing and treating Alzheimer's disease. UB-311 is an anti-amyloid-β active immunotherapeutic vaccine shown to be well-tolerated and to have a durable antibody response in a phase 1 trial. This phase 2a study assessed the safety, immunogenicity, and preliminary efficacy of UB-311 in participants with mild Alzheimer's disease.MethodsA 78-week, randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 2a study was conducted in Taiwan. Participants were randomised in a 1:1:1 ratio to receive seven intramuscular injections of UB-311 (Q3M arm), or five doses of U311 with two doses of placebo (Q6M arm), or seven doses of placebo (placebo arm). The primary endpoints were safety, tolerability, and immunogenicity of UB-311. Safety was assessed in all participants who received at least one dose of investigational product. This study was registered at ClinicalTrials.gov (NCT02551809).FindingsBetween 7 December 2015 and 28 August 2018, 43 participants were randomised. UB-311 was safe, well-tolerated, and generated a robust immune response. The three treatment-emergent adverse events (TEAEs) with the highest incidence were injection-site pain (14 TEAEs in seven [16%] participants), amyloid-related imaging abnormality with microhaemorrhages and haemosiderin deposits (12 TEAEs in six [14%] participants), and diarrhoea (five TEAEs in five [12%] participants). A 97% antibody response rate was observed and maintained at 93% by the end of the study across both UB-311 arms.InterpretationThese results support the continued development of UB-311.FundingVaxxinity, Inc. (Formerly United Neuroscience Ltd.).
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Project description:BackgroundSequential prime-boost or co-administration of HIV vaccine candidates based on an adjuvanted clade B p24, RT, Nef, p17 fusion protein (F4/AS01) plus a non-replicating adenovirus 35 expressing clade A Gag, RT, Int and Nef (Ad35-GRIN) may lead to a unique immune profile, inducing both strong T-cell and antibody responses.MethodsIn a phase 1, double-blind, placebo-controlled trial, 146 healthy adult volunteers were randomized to one of four regimens: heterologous prime-boost with two doses of F4/AS01E or F4/AS01B followed by Ad35-GRIN; Ad35-GRIN followed by two doses of F4/AS01B; or three co-administrations of Ad35-GRIN and F4/AS01B. T cell and antibody responses were measured.ResultsThe vaccines were generally well-tolerated, and did not cause serious adverse events. The response rate, by IFN-? ELISPOT, was greater when Ad35-GRIN was the priming vaccine and in the co-administration groups. F4/AS01 induced CD4+ T-cells expressing primarily CD40L and IL2 +/- TNF-?, while Ad35-GRIN induced predominantly CD8+ T-cells expressing IFN-? +/- IL2 or TNF-?. Viral inhibition was induced after Ad35-GRIN vaccination, regardless of the regimen. Strong F4-specific antibody responses were induced. Immune responses persisted at least a year after the last vaccination. The complementary response profiles, characteristic of each vaccine, were both expressed after co-administration.ConclusionCo-administration of an adjuvanted protein and an adenovirus vector showed an acceptable safety and reactogenicity profile and resulted in strong, multifunctional and complementary HIV-specific immune responses.Trial registrationClinicalTrials.gov NCT01264445.
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Project description:BackgroundWe conducted a phase I, randomized, double-blind, placebo-controlled trial to assess the safety and immunogenicity of escalating doses of two recombinant replication defective adenovirus serotype 35 (Ad35) vectors containing gag, reverse transcriptase, integrase and nef (Ad35-GRIN) and env (Ad35-ENV), both derived from HIV-1 subtype A isolates. The trial enrolled 56 healthy HIV-uninfected adults.MethodsAd35-GRIN/ENV (Ad35-GRIN and Ad35-ENV mixed in the same vial in equal proportions) or Ad35-GRIN was administered intramuscularly at 0 and 6 months. Participants were randomized to receive either vaccine or placebo (10/4 per group, respectively) within one of four dosage groups: Ad35-GRIN/ENV 2×10(9) (A), 2×10(10) (B), 2×10(11) (C), or Ad35-GRIN 1×10(10) (D) viral particles.ResultsNo vaccine-related serious adverse event was reported. Reactogenicity events reported were dose-dependent, mostly mild or moderate, some severe in Group C volunteers, all transient and resolving spontaneously. IFN-γ ELISPOT responses to any vaccine antigen were detected in 50, 56, 70 and 90% after the first vaccination, and in 75, 100, 88 and 86% of Groups A-D vaccine recipients after the second vaccination, respectively. The median spot forming cells (SFC) per 10(6) PBMC to any antigen was 78-139 across Groups A-C and 158-174 in Group D, after each of the vaccinations with a maximum of 2991 SFC. Four to five HIV proteins were commonly recognized across all the groups and over multiple timepoints. CD4+ and CD8+ T-cell responses were polyfunctional. Env antibodies were detected in all Group A-C vaccinees and Gag antibodies in most vaccinees after the second immunization. Ad35 neutralizing titers remained low after the second vaccination.Conclusion/significanceAd35-GRIN/ENV reactogenicity was dose-related. HIV-specific cellular and humoral responses were seen in the majority of volunteers immunized with Ad35-GRIN/ENV or Ad35-GRIN and increased after the second vaccination. T-cell responses were broad and polyfunctional.Trial registrationClinicalTrials.gov NCT00851383.
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Project description:BackgroundHuman immunodeficiency virus (HIV)-infected individuals are at increased risk of herpes zoster (HZ), even in the antiretroviral therapy (ART) era. Because concerns exist about the use of live-attenuated vaccines in immunocompromised individuals, a subunit vaccine may be an appropriate alternative.MethodsThis phase 1/2, randomized, placebo-controlled study evaluated the immunogenicity and safety of an investigational HZ subunit vaccine (HZ/su). Three cohorts of HIV-infected adults aged ≥18 years were enrolled: 94 ART recipients with a CD4(+) T-cell count of ≥200 cells/mm(3), 14 ART recipients with a CD4(+) T-cell count of 50-199 cells/mm(3), and 15 ART-naive adults with a CD4(+) T-cell count of ≥500 cells/mm(3). Subjects received 3 doses of HZ/su (50 µg varicella-zoster virus glycoprotein E [gE] combined with AS01B adjuvant) or 3 doses of saline at months 0, 2, and 6.ResultsOne month after dose 3, serum anti-gE antibody concentrations and frequencies of gE-specific CD4(+) T cells were higher following HZ/su vaccination than after receipt of saline (P < .0001). Median cell-mediated immune responses peaked after dose 2. Humoral and cell-mediated immune responses persisted until the end of the study (month 18). No vaccination-related serious adverse events were reported. No sustained impact on HIV load or CD4(+) T-cell count was noted following vaccinations.ConclusionsHZ/su was immunogenic and had a clinically acceptable safety profile in HIV-infected adults.Clinical trials registrationNCT01165203.
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Project description:BackgroundCo-trimoxazole prophylaxis reduces mortality among HIV-infected children, but efficacy in HIV-exposed but uninfected (HEU) children in a non-malarial, low-breastfeeding setting with a low risk of mother-to-child transmission of HIV is unclear.MethodsHEU children in Botswana were randomly assigned to receive co-trimoxazole (100 mg/20 mg once daily until age 6 months and 200 mg/40 mg once daily thereafter) or placebo from age 14-34 days to age 15 months. Mothers chose whether to breastfeed or formula feed their children. Breastfed children were randomly assigned to breastfeeding for 6 months (Botswana guidelines) or 12 months (WHO guidelines). The primary outcome, analysed by a modified intention-to-treat approach, was cumulative child mortality from treatment assignment to age 18 months. We also assessed HIV-free survival by duration of breastfeeding. This trial is registered with ClinicalTrials.gov, number NCT01229761.FindingsFrom June 7, 2011, to April 2, 2015, 2848 HEU children were randomly assigned to receive co-trimoxazole (n=1423) or placebo (n=1425). The data and safety monitoring board stopped the study early because of a low likelihood of benefit with co-trimoxazole. Only 153 (5%) children were lost to follow-up (76 in the co-trimoxazole group and 77 in the placebo group), and 2053 (72%) received treatment continuously to age 15 months, death, or study closure. Mortality after the start of study treatment was similar in the two study groups: 30 children died in the co-trimoxazole group, compared with 34 in the placebo group (estimated mortality at 18 months 2·4% vs 2·6%; difference -0·2%, 95% CI -1·5 to 1·0, p=0·70). We saw no difference in hospital admissions between groups (12·5% in the co-trimoxazole group vs 17·4% in the placebo group, p=0·19) or grade 3-4 clinical adverse events (16·5% vs 18·4%, p=0·18). Grade 3-4 anaemia did not differ between groups (8·1% vs 8·3%, p=0·93), but grade 3-4 neutropenia was more frequent in the co-trimoxazole group than in the placebo group (8·1% vs 5·8%, p=0·03). More co-trimoxazole resistance in commensal Escherichia coli isolated from stool samples was seen in children aged 3 or 6 months in the co-trimoxazole group than in the placebo group (p=0·001 and p=0·01, respectively). 572 (20%) children were breastfed. HIV infection and mortality did not differ significantly by duration of breastfeeding (3·9% for 6 months vs 1·9% for 12 months, p=0·21).InterpretationProphylactic co-trimoxazole seems to offer no survival benefit among HEU children in non-malarial, low-breastfeeding areas with a low risk of mother-to-child transmission of HIV.FundingUS National Institutes of Health.
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