RÉSUMÉ
Differences in innate immune 'imprinting' between vaccine adjuvants may mediate dissimilar effects on the quantity/quality of persisting adaptive responses. We compared antibody avidity maturation, antibody/memory B cell/CD4+ T cell response durability, and recall responses to non-adjuvanted fractional-dose antigen administered 1-year post-immunization (Day [D]360), between hepatitis B vaccines containing Adjuvant System (AS)01B, AS01E, AS03, AS04, or Alum (NCT00805389). Both the antibody and B cell levels ranked similarly (AS01B/E/AS03 > AS04 > Alum) at peak response, at D360, and following their increases post-antigen recall (D390). Proportions of high-avidity antibodies increased post-dose 2 across all groups and persisted at D360, but avidity maturation appeared to be more strongly promoted by AS vs. Alum. Post-antigen recall, frequencies of subjects with high-avidity antibodies increased only markedly in the AS groups. Among the AS, total antibody responses were lowest for AS04. However, proportions of high-avidity antibodies were similar between groups, suggesting that MPL in AS04 contributes to avidity maturation. Specific combinations of immunoenhancers in the AS, regardless of their individual nature, increase antibody persistence and avidity maturation.
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BACKGROUND: The 2014 Zaire Ebola virus disease epidemic accelerated vaccine development for the virus. We aimed to assess the safety, reactogenicity, and immunogenicity of one dose of monovalent, recombinant, chimpanzee adenovirus type-3 vectored Zaire Ebola glycoprotein vaccine (ChAd3-EBO-Z) in adults. METHODS: This phase 2, randomised, observer-blind, controlled trial was done in study centres in Cameroon, Mali, Nigeria, and Senegal. Healthy adults (≥18 years) were randomly assigned with a web-based system (1:1; minimisation procedure accounting for age, gender, centre) to receive ChAd3-EBO-Z (day 0), or saline placebo (day 0) and ChAd3-EBO-Z (month 6). The study was observer-blind until planned interim day 30 analysis, single-blind until month 6, and open-label after month 6 vaccination. Primary outcomes assessed in the total vaccinated cohort, which comprised all participants with at least one study dose administration documented, were serious adverse events (up to study end, month 12); and for a subcohort were solicited local or general adverse events (7 days post-vaccination), unsolicited adverse events (30 days post-vaccination), haematological or biochemical abnormalities, and clinical symptoms of thrombocytopenia (day 0-6). Secondary endpoints (subcohort; per-protocol cohort) evaluated anti-glycoprotein Ebola virus antibody titres (ELISA) pre-vaccination and 30 days post-vaccination. This study is registered with ClinicalTrials.gov, NCT02485301. FINDINGS: Between July 22, 2015, and Dec 10, 2015, 3030 adults were randomly assigned; 3013 were included in the total vaccinated cohort (1509 [50·1%] in the ChAd3-EBO-Z group and 1504 [49·9%] in the placebo/ChAd3-EBO-Z group), 17 were excluded because no vaccine was administered. The most common solicited injection site symptom was pain (356 [48%] of 748 in the ChAd3-EBO-Z group vs 57 [8%] of 751 in the placebo/ChAd3-EBO-Z group); the most common solicited general adverse event was headache (345 [46%] in the ChAd3-EBO-Z group vs 136 [18%] in the placebo/ChAd3-EBO-Z group). Unsolicited adverse events were reported by 123 (16%) of 749 in the ChAd3-EBO-Z group and 119 (16%) of 751 in the placebo/ChAd3-EBO-Z group. Serious adverse events were reported for 11 (1%) of 1509 adults in the ChAd3-EBO-Z group, and 18 (1%) of 1504 in the placebo/ChAd3-EBO-Z group; none were considered vaccination-related. No clinically meaningful thrombocytopenia was reported. At day 30, anti-glycoprotein Ebola virus antibody geometric mean concentration was 900 (95% CI 824-983) in the ChAd3-EBO-Z group. There were no treatment-related deaths. INTERPRETATION: ChAd3-EBO-Z was immunogenic and well tolerated in adults. Our findings provide a strong basis for future development steps, which should concentrate on multivalent approaches (including Sudan and Marburg strains). Additionally, prime-boost approaches should be a focus with a ChAd3-based vaccine for priming and boosted by a modified vaccinia Ankara-based vaccine. FUNDING: EU's Horizon 2020 research and innovation programme and GlaxoSmithKline Biologicals SA.
Sujet(s)
Adénovirus simiens , Vaccins contre la maladie à virus Ebola/effets indésirables , Vaccins contre la maladie à virus Ebola/immunologie , Fièvre hémorragique à virus Ebola/prévention et contrôle , Adolescent , Adulte , Animaux , Anticorps antiviraux/sang , Femelle , Vecteurs génétiques , Humains , Mâle , Adulte d'âge moyen , Pan troglodytes , Méthode en simple aveugle , Vaccins synthétiques/immunologieRÉSUMÉ
BACKGROUND: During the large 2013-16 Ebola virus outbreak caused by the Zaire Ebola virus, about 20% of cases were reported in children. This study is the first, to our knowledge, to evaluate an Ebola vaccine in children younger than 6 years. We aimed to evaluate the safety, reactogenicity, and immunogenicity of a monovalent, recombinant, chimpanzee adenovirus type-3 vectored Zaire Ebola glycoprotein vaccine (ChAd3-EBO-Z) in a paediatric population. METHODS: This phase 2, randomised, observer-blind, controlled trial was done in a vaccine centre in Mali and a university hospital centre in Senegal. Healthy children were randomly assigned through a web-based system (1:1; stratified by age group, gender, and centre) to receive ChAd3-EBO-Z (day 0) and meningococcal serogroups A,C,W-135,Y tetanus toxoid conjugate vaccine (MenACWY-TT; month 6), or MenACWY-TT (day 0) and ChAd3-EBO-Z (month 6). The study was observer-blind from study start until interim day 30 analysis and became single-blind as of interim analysis. Primary outcomes assessed were serious adverse events (up to study end, month 12), solicited local or general adverse events (7 days post-vaccination), unsolicited adverse events (30 days post-vaccination), haematological or biochemical abnormalities, and clinical symptoms of thrombocytopenia (day 0-6). As secondary endpoints, we evaluated anti-glycoprotein Zaire Ebola virus antibody titres (ELISA) pre-vaccination and 30 days post-vaccination. This study is registered with ClinicalTrials.gov, NCT02548078. FINDINGS: From Nov 11, 2015, to May 9, 2016, of 776 children screened for eligibility, 600 were randomly assigned (200 [33%] in each age strata: 1-5, 6-12, 13-17 years), 300 (50%) to the ChAd3-EBO-Z/MenACWY-TT group and 300 (50%) to the MenACWY-TT/ChAd3-EBO-Z group; all were included in the total vaccinated cohort. Post-day 0 vaccination, the most common solicited injection site symptom was pain (127 [42%] of 300 in the ChAd3-EBO-Z/MenACWY-TT group vs 60 [20%] of 300 in the MenACWY-TT/ChAd3-EBO-Z group); the most common solicited general adverse event was fever (95 [32%] of 300 in the ChAd3-EBO-Z/MenACWY-TT group vs 28 [9%] of 300 in the MenACWY-TT/ChAd3-EBO-Z group). Unsolicited adverse events post-day 0 vaccination were reported by 41 (14%) of 300 participants in the ChAd3-EBO-Z/MenACWY-TT group and 24 (8%) of 300 MenACWY-TT/ChAd3-EBO-Z recipients. Serious adverse events were reported for two (1%) of 300 children in each group; none were considered vaccination related. No clinical symptoms of thrombocytopenia were reported. At day 30, anti-glycoprotein Ebola virus antibody geometric mean concentrations (GMC) in the ChAd3-EBO-Z/MenACWY-TT group were 1564 (95% CI 1340-1826) for those aged 13-17 years, 1395 (1175-1655) for 6-12 years, and 2406 (1942-2979) for 1-5 years. Anti-glycoprotein Ebola virus IgG antibody responses persisted up to 12 months post-vaccination, with a GMC of 716 (95% CI 619-828) for those aged 13-17 years, 752 (645-876) for 6-12 years, and 1424 (1119-1814) for 1-5 years. INTERPRETATION: ChAd3-EBO-Z was immunogenic and well tolerated in children aged 1-17 years. This study provides the first ChAd3-EBO-Z data in a paediatric population. Further development should focus on multivalent approaches including Sudan and Marburg strains, and heterologous prime-boost strategies, for instance using modified vaccinia Ankara-based vaccine to boost the immune response. FUNDING: EU's Horizon 2020 research and innovation programme and GlaxoSmithKline Biologicals SA.
Sujet(s)
Adénovirus simiens , Vaccins contre la maladie à virus Ebola/effets indésirables , Vaccins contre la maladie à virus Ebola/immunologie , Fièvre hémorragique à virus Ebola/prévention et contrôle , Adolescent , Animaux , Anticorps antiviraux/sang , Enfant , Enfant d'âge préscolaire , Femelle , Vecteurs génétiques , Humains , Nourrisson , Mâle , Pan troglodytes , Méthode en simple aveugle , Vaccins synthétiques/immunologieRÉSUMÉ
[This corrects the article DOI: 10.1038/s41541-017-0027-3.].
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Combining immunostimulants in adjuvants can improve the quality of the immune response to vaccines. Here, we report a unique mechanism of molecular and cellular synergy between a TLR4 ligand, 3-O-desacyl-4'-monophosphoryl lipid A (MPL), and a saponin, QS-21, the constituents of the Adjuvant System AS01. AS01 is part of the malaria and herpes zoster vaccine candidates that have demonstrated efficacy in phase III studies. Hours after injection of AS01-adjuvanted vaccine, resident cells, such as NK cells and CD8+ T cells, release IFNγ in the lymph node draining the injection site. This effect results from MPL and QS-21 synergy and is controlled by macrophages, IL-12 and IL-18. Depletion strategies showed that this early IFNγ production was essential for the activation of dendritic cells and the development of Th1 immunity by AS01-adjuvanted vaccine. A similar activation was observed in the lymph node of AS01-injected macaques as well as in the blood of individuals receiving the malaria RTS,S vaccine. This mechanism, previously described for infections, illustrates how adjuvants trigger naturally occurring pathways to improve the efficacy of vaccines.
RÉSUMÉ
Phase IIb or III HIV-1 vaccine efficacy trials are generally large and operationally challenging. To mitigate this challenge, the HIV Vaccine Trials Network is designing a Phase IIb efficacy trial accommodating the evaluation of multiple vaccine regimens concurrently. As this efficacy trial would evaluate a limited number of vaccine regimens, there is a need to develop a framework for optimizing the strategic selection of regimens from the large number of vaccine candidates tested in Phase I/IIa trials. In this paper we describe the approaches for the selection process, including the choice of immune response endpoints and the statistical criteria and algorithms. We illustrate the selection approaches using data from HIV-1 vaccine trials.
Sujet(s)
Vaccins contre le SIDA/immunologie , Infections à VIH/prévention et contrôle , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/immunologie , Immunogénicité des vaccins , Vaccins contre le SIDA/administration et posologie , Vaccins contre le SIDA/composition chimique , Algorithmes , Essais cliniques comme sujet , Interprétation statistique de données , Infections à VIH/immunologie , Humains , Calendrier vaccinal , Efficacité du vaccinRÉSUMÉ
The impact of the investigational human immunodeficiency virus type 1 (HIV-1) F4/AS01B vaccine on HIV-1 viral load (VL) was evaluated in antiretroviral therapy (ART)-naive HIV-1 infected adults.This phase IIb, observer-blind study (NCT01218113), included ART-naive HIV-1 infected adults aged 18 to 55 years. Participants were randomized to receive 2 (F4/AS01B_2 group, Nâ=â64) or 3 (F4/AS01B_3 group, Nâ=â62) doses of F4/AS01B or placebo (control group, Nâ=â64) at weeks 0, 4, and 28. Efficacy (HIV-1 VL, CD4 T-cell count, ART initiation, and HIV-related clinical events), safety, and immunogenicity (antibody and T-cell responses) were evaluated during 48 weeks.At week 48, based on a mixed model, no statistically significant difference in HIV-1 VL change from baseline was demonstrated between F4/AS01B_2 and control group (0.073 log10âcopies/mL [97.5% confidence interval (CI): -0.088; 0.235]), or F4/AS01B_3 and control group (-0.096 log10âcopies/mL [97.5% CI: -0.257; 0.065]). No differences between groups were observed in HIV-1 VL change, CD4 T-cell count, ART initiation, or HIV-related clinical events at intermediate timepoints. Among F4/AS01B recipients, the most frequent solicited symptoms were pain at injection site (252/300 doses), fatigue (137/300 doses), myalgia (105/300 doses), and headache (90/300 doses). Twelve serious adverse events were reported in 6 participants; 1 was considered vaccine-related (F4/AS01B_2 group: angioedema). F4/AS01B induced polyfunctional F4-specific CD4 T-cells, but had no significant impact on F4-specific CD8 T-cell and anti-F4 antibody levels.F4/AS01B had a clinically acceptable safety profile, induced F4-specific CD4 T-cell responses, but did not reduce HIV-1 VL, impact CD4 T-cells count, delay ART initiation, or prevent HIV-1 related clinical events.
Sujet(s)
Vaccins contre le SIDA/immunologie , Infections à VIH/immunologie , Vaccins contre le SIDA/administration et posologie , Adolescent , Adulte , Antirétroviraux , Anticorps antiviraux , Production d'anticorps , Numération des lymphocytes CD4 , Lymphocytes T CD4+ , Femelle , Infections à VIH/sang , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/immunologie , Humains , Mâle , Méthode en simple aveugle , Jeune adulteRÉSUMÉ
BACKGROUND: Sequential 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. METHODS: In 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. RESULTS: The vaccines were generally well-tolerated, and did not cause serious adverse events. The response rate, by IFN-γ 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-α, while Ad35-GRIN induced predominantly CD8+ T-cells expressing IFN-γ +/- IL2 or TNF-α. 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. CONCLUSION: Co-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 REGISTRATION: ClinicalTrials.gov NCT01264445.
Sujet(s)
Vaccins contre le SIDA/immunologie , , Infections à VIH/prévention et contrôle , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/immunologie , Volontaires sains , Protéines du virus de l'immunodéficience humaine/immunologie , Protéines de fusion recombinantes/immunologie , Vaccins contre le SIDA/administration et posologie , Vaccins contre le SIDA/effets indésirables , Adenoviridae/génétique , Adenoviridae/immunologie , Adjuvants immunologiques , Adolescent , Adulte , Anticorps neutralisants , Anticorps antiviraux/immunologie , Femelle , Vecteurs génétiques/génétique , Vecteurs génétiques/immunologie , Anticorps anti-VIH/sang , Anticorps anti-VIH/immunologie , Infections à VIH/immunologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/génétique , Protéines du virus de l'immunodéficience humaine/génétique , Humains , Immunité cellulaire , Immunité humorale , Interféron gamma/biosynthèse , Interféron gamma/sang , Mâle , Protéines de fusion recombinantes/génétique , Sous-populations de lymphocytes T/immunologie , Sous-populations de lymphocytes T/métabolisme , Vaccination , Jeune adulteRÉSUMÉ
Intracellular cytokine staining (ICS) assay is increasingly used in vaccine clinical trials to measure antigen-specific T-cell mediated immune (CMI) responses in cryopreserved peripheral blood mononuclear cells (PBMCs) and whole blood. However, recent observations indicate that several parameters involved in blood processing can impact PBMC viability and CMI responses, especially in antiretroviral therapy (ART)-naïve HIV-1-infected individuals. In this phase I study (NCT01610427), we collected blood samples from 22 ART-naïve HIV-1-infected adults. PBMCs were isolated and processed for ICS assay. The individual and combined effects of the following parameters were investigated: time between blood collection and PBMC processing (time-to-process: 2, 7 or 24 h); time between PBMC thawing and initiation of in vitro stimulation with HIV-1 antigens (resting-time: 0, 2, 6 and 18 h); and duration of antigen-stimulation in PBMC cultures (stimulation-time: 6h or overnight). The cell recovery after thawing, cell viability after ICS and magnitude of HIV-specific CD8(+) T-cell responses were considered to determine the optimal combination of process conditions. The impact of time-to-process (2 or 4 h) on HIV-specific CD8(+) T-cell responses was also assessed in a whole blood ICS assay. A higher quality of cells in terms of recovery and viability (up to 81% and >80% respectively) was obtained with shorter time-to-process (less than 7 h) and resting-time (less than 2 h) intervals. Longer (overnight) rather than shorter (6 h) stimulation-time intervals increased the frequency of CD8(+)-specific T-cell responses using ICS in PBMCs without change of the functionality. The CD8(+) specific T-cell responses detected using fresh whole blood showed a good correlation with the responses detected using frozen PBMCs. Our results support the need of standardized procedures for the evaluation of CMI responses, especially in HIV-1-infected, ART-naïve patients.
Sujet(s)
Vaccins contre le SIDA/immunologie , Antirétroviraux/usage thérapeutique , Prélèvement d'échantillon sanguin/normes , Lymphocytes T CD8+/immunologie , Infections à VIH/thérapie , Vaccins contre le SIDA/usage thérapeutique , Adolescent , Adulte , Réaction antigène-anticorps , Lymphocytes T CD4+/immunologie , Survie cellulaire , Cryoconservation , Femelle , Cytométrie en flux/méthodes , Infections à VIH/immunologie , Séropositivité VIH/immunologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/immunologie , Tests hématologiques/méthodes , Humains , Immunité cellulaire , Techniques in vitro , Mâle , Adulte d'âge moyen , Coloration et marquage/méthodes , Facteurs temps , Charge virale , Jeune adulteRÉSUMÉ
Adjuvant System AS01 is a liposome-based vaccine adjuvant containing 3-O-desacyl-4'-monophosphoryl lipid A and the saponin QS-21. AS01 has been selected for the clinical development of several candidate vaccines including the RTS,S malaria vaccine and the subunit glycoprotein E varicella zoster vaccine (both currently in phase III). Given the known immunostimulatory properties of MPL and QS-21, the objective of this study was to describe the early immune response parameters after immunization with an AS01-adjuvanted vaccine and to identify relationships with the vaccine-specific adaptive immune response. Cytokine production and innate immune cell recruitment occurred rapidly and transiently at the muscle injection site and draining lymph node postinjection, consistent with the rapid drainage of the vaccine components to the draining lymph node. The induction of Ag-specific Ab and T cell responses was dependent on the Ag being injected at the same time or within 24 h after AS01, suggesting that the early events occurring postinjection were required for these elevated adaptive responses. In the draining lymph node, after 24 h, the numbers of activated and Ag-loaded monocytes and MHCII(high) dendritic cells were higher after the injection of the AS01-adjuvanted vaccine than after Ag alone. However, only MHCII(high) dendritic cells appeared efficient at and necessary for direct Ag presentation to T cells. These data suggest that the ability of AS01 to improve adaptive immune responses, as has been demonstrated in clinical trials, is linked to a transient stimulation of the innate immune system leading to the generation of high number of efficient Ag-presenting dendritic cells.
Sujet(s)
Immunité acquise/immunologie , Adjuvants immunologiques/administration et posologie , Cellules dendritiques/immunologie , Lipide A/analogues et dérivés , Saponines/administration et posologie , Saponines/immunologie , Vaccins/immunologie , Animaux , Présentation d'antigène/immunologie , Lymphocytes B/immunologie , Lymphocytes T CD4+/immunologie , Lymphocytes T CD8+/immunologie , Association médicamenteuse , Femelle , Antigènes d'histocompatibilité de classe II/immunologie , Humains , Lipide A/administration et posologie , Lipide A/immunologie , Activation des lymphocytes/immunologie , Souris , Souris de lignée C57BL , Monocytes/immunologie , VaccinationRÉSUMÉ
This phase II study evaluated the effect of chloroquine on the specific CD8(+) T-cell responses to and the safety of a booster dose of investigational human immunodeficiency virus type 1 (HIV-1) F4/AS01(B) vaccine containing 10 µg of recombinant fusion protein (F4) adjuvanted with the AS01(B) adjuvant system. Healthy adults aged 21 to 41 years, primed 3 years before with two F4/AS01(B) doses containing 10 or 30 µg of F4 (ClinicalTrials.gov registration number NCT00434512), were randomized (1:1) to receive the F4/AS01(B) booster administered alone or 2 days after chloroquine (300 mg). F4-specific CD8(+)/CD4(+) T-cell responses were characterized by intracellular cytokine staining and lymphoproliferation assays and anti-F4 antibodies by enzyme-linked immunosorbent assays (ELISAs). No effect of chloroquine on CD4(+)/CD8(+) T-cell and antibody responses and no vaccine effect on CD8(+) T-cell responses (cytokine secretion or proliferation) were detected following F4/AS01(B) booster administration. In vitro, chloroquine had a direct inhibitory effect on AS01(B) adjuvant properties; AS01-induced cytokine production decreased upon coincubation of cells with chloroquine. In the pooled group of participants primed with F4/AS01(B) containing 10 µg of F4, CD4(+) T-cell and antibody responses induced by primary vaccination persisted for at least 3 years. The F4/AS01(B) booster induced strong F4-specific CD4(+) T-cell responses, which persisted for at least 6 months with similar frequencies and polyfunctional phenotypes as following primary vaccination, and high anti-F4 antibody concentrations, reaching higher levels than those following primary vaccination. The F4/AS01(B) booster had a clinically acceptable safety and reactogenicity profile. An F4/AS01(B) booster dose, administered alone or after chloroquine, induced robust antibody and F4-specific CD4(+) T-cell responses but no significant CD8(+) T-cell responses (cytokine secretion or proliferation) in healthy adults. (This study has been registered at ClinicalTrials.gov under registration number NCT00972725).
Sujet(s)
Vaccins contre le SIDA/effets indésirables , Vaccins contre le SIDA/immunologie , Antipaludiques/administration et posologie , Chloroquine/administration et posologie , Infections à VIH/prévention et contrôle , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/immunologie , Rappel de vaccin/méthodes , Vaccins contre le SIDA/administration et posologie , Adjuvants immunologiques/administration et posologie , Adolescent , Adulte , Lymphocytes T CD4+/immunologie , Lymphocytes T CD8+/immunologie , Prolifération cellulaire , Cytokines/biosynthèse , Effets secondaires indésirables des médicaments/épidémiologie , Effets secondaires indésirables des médicaments/anatomopathologie , Test ELISA , Femelle , Anticorps anti-VIH/sang , Infections à VIH/immunologie , Protéines du virus de l'immunodéficience humaine/immunologie , Humains , Mâle , Jeune adulteRÉSUMÉ
The human immunodeficiency virus type-1 (HIV-1) vaccine candidate F4/AS01 has previously been shown to induce potent and persistent polyfunctional CD4(+) T-cell responses in HIV-1-seronegative volunteers. This placebo-controlled study evaluated two doses of F4/AS01 1-month apart in antiretroviral treatment (ART)-experienced and ART-naïve HIV-1-infected subjects (1:1 randomisation in each cohort). Safety, HIV-1-specific CD4(+) and CD8(+) T-cell responses, absolute CD4(+) T-cell counts and HIV-1 viral load were monitored for 12 months post-vaccination. Reactogenicity was clinically acceptable and no vaccine-related serious adverse events were reported. The frequency of HIV-1-specific CD4(+) T-cells 2 weeks post-dose 2 was significantly higher in the vaccine group than in the placebo group in both cohorts (p<0.05). Vaccine-induced HIV-1-specific CD4(+) T-cells exhibited a polyfunctional phenotype, expressing at least CD40L and IL-2. No increase in HIV-1-specific CD8(+) T-cells or change in CD8(+) T-cell activation marker expression profile was detected. Absolute CD4(+) T-cell counts were variable over time in both cohorts. Viral load remained suppressed in ART-experienced subjects. In ART-naïve subjects, a transient reduction in viral load from baseline was observed 2 weeks after the second F4/AS01 dose, which was concurrent with a higher frequency of HIV-1-specific CD4(+) T-cells expressing at least IL-2 in this cohort. In conclusion, F4/AS01 showed a clinically acceptable reactogenicity and safety profile, and induced polyfunctional HIV-1-specific CD4(+) T-cell responses in ART-experienced and ART-naïve subjects. These findings support further clinical investigation of F4/AS01 as a potential HIV-1 vaccine for therapeutic use in individuals with HIV-1 infection.
Sujet(s)
Vaccins contre le SIDA/usage thérapeutique , Lymphocytes T CD4+/immunologie , Infections à VIH/thérapie , Vaccins contre le SIDA/effets indésirables , Adjuvants immunologiques/administration et posologie , Adulte , Antirétroviraux/usage thérapeutique , Numération des lymphocytes CD4 , Lymphocytes T CD8+/immunologie , Femelle , Infections à VIH/traitement médicamenteux , VIH-1 (Virus de l'Immunodéficience Humaine de type 1) , Humains , Immunité cellulaire , Interleukine-2/immunologie , Mâle , Adulte d'âge moyen , Méthode en simple aveugle , Charge virale , Jeune adulteRÉSUMÉ
RATIONALE: Tuberculosis (TB) is a major cause of morbidity and mortality worldwide, thus there is an urgent need for novel TB vaccines. OBJECTIVES: We investigated a novel TB vaccine candidate, M72/AS01, in a phase IIa trial of bacille Calmette-Guérin-vaccinated, HIV-uninfected, and Mycobacterium tuberculosis (Mtb)-infected and -uninfected adults in South Africa. METHODS: Two doses of M72/AS01 were administered to healthy adults, with and without latent Mtb infection. Participants were monitored for 7 months after the first dose; cytokine production profiles, cell cycling, and regulatory phenotypes of vaccine-induced T cells were measured by flow cytometry. MEASUREMENTS AND MAIN RESULTS: The vaccine had a clinically acceptable safety profile, and induced robust, long-lived M72-specific T-cell and antibody responses. M72-specific CD4 T cells produced multiple combinations of Th1 cytokines. Analysis of T-cell Ki67 expression showed that most vaccination-induced T cells did not express Th1 cytokines or IL-17; these cytokine-negative Ki67(+) T cells included subsets of CD4 T cells with regulatory phenotypes. PD-1, a negative regulator of activated T cells, was transiently expressed on M72-specific CD4 T cells after vaccination. Specific T-cell subsets were present at significantly higher frequencies after vaccination of Mtb-infected versus -uninfected participants. CONCLUSIONS: M72/AS01 is clinically well tolerated in Mtb-infected and -uninfected adults, induces high frequencies of multifunctional T cells, and boosts distinct T-cell responses primed by natural Mtb infection. Moreover, these results provide important novel insights into how this immunity may be appropriately regulated after novel TB vaccination of Mtb-infected and -uninfected individuals.Clinical trial registered with www.clinicaltrials.gov (NCT 00600782).
Sujet(s)
Lymphocytes T/immunologie , Vaccins antituberculeux/immunologie , Adulte , Antigènes CD4/métabolisme , Antigènes CD8/métabolisme , Femelle , Cytométrie en flux , Humains , Immunité cellulaire/immunologie , Immunité humorale/immunologie , Interleukine-17/métabolisme , Mâle , République d'Afrique du Sud , Vaccins antituberculeux/administration et posologie , Jeune adulteRÉSUMÉ
As a new human immunodeficiency virus type 1 (HIV-1) vaccine approach, the live-attenuated measles virus (MV) Schwarz vaccine strain was genetically engineered to express the F4 antigen (MV1-F4). F4 is a fusion protein comprising HIV-1 antigens p17 and p24, reverse transcriptase and Nef. This study assessed the toxicity, biodistribution and shedding profiles of MV1-F4. Cynomolgus macaques were intramuscularly immunized one or three times with the highest dose of MV1-F4 intended for clinical use, the reference (Schwarz) measles vaccine or saline, and monitored clinically for 11 or 85 days. Toxicological parameters included local and systemic clinical signs, organ weights, haematology, clinical and gross pathology and histopathology. Both vaccines were well tolerated, with no morbidity, clinical signs or gross pathological findings observed. Mean spleen weights were increased after three doses of either vaccine, which corresponded with increased numbers and/or sizes of germinal centers. This was likely a result of the immune response to the vaccines. Either vaccine virus replicated preferentially in secondary lymphoid organs and to a lesser extent in epithelium-rich tissues (e.g., intestine, urinary bladder and trachea) and the liver. At the expected peak of viremia, viral RNA was detected in some biological fluid samples from few animals immunized with either vaccine, but none of these samples contained infectious virus. In conclusion, no shedding of infectious viral particles was identified in cynomolgus monkeys after injection of MV1-F4 or Schwarz measles vaccines. Furthermore, no toxic effect in relation to the MV vaccination was found with these vaccines in this study.
Sujet(s)
Vaccins contre le SIDA/immunologie , Antigènes du VIH/immunologie , Vaccin contre la rougeole/immunologie , Virus de la rougeole/immunologie , Vaccins contre le SIDA/pharmacocinétique , Vaccins contre le SIDA/toxicité , Animaux , Femelle , Génie génétique/méthodes , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/immunologie , Injections musculaires , Macaca fascicularis , Mâle , Vaccin contre la rougeole/pharmacocinétique , Vaccin contre la rougeole/toxicité , Taille d'organe/immunologie , ARN viral/métabolisme , Facteurs temps , Distribution tissulaire , Réplication virale , Excrétion viraleRÉSUMÉ
BACKGROUND: Induction of HIV-1-specific CD4(+) T-cell responses by therapeutic vaccination represents an attractive intervention to potentially increase immune control of HIV-1. METHODS: We performed a double-blinded, randomized, placebo-controlled clinical trial to determine the safety and immunogenicity of GlaxoSmithKline Biologicals' HIV-1 gp120/NefTat subunit protein vaccine formulated with the AS02(A) Adjuvant System in subjects with well-controlled chronic HIV-1 infection on highly active antiretroviral therapy. Ten individuals received the vaccine; whereas adjuvant alone or placebo was given to 5 subjects each. Immunogenicity was monitored by intracellular cytokine flow cytometry and carboxyfluorescein succinimidyl ester-based proliferation assays. RESULTS: The vaccine was well tolerated with no related serious adverse events. Vaccine recipients had significantly stronger gp120-specific CD4(+) T-cell responses which persisted until week 48 and greater gp120-specific CD4(+) T-cell proliferation activity as compared with controls. In the vaccine group, the number of participants who demonstrated positive responses for both gp120-specific CD4(+) T-cell interleukin-2 production and gp120-specific CD8(+) T-cell proliferation were significantly higher at week 6. CONCLUSIONS: The gp120/NefTat/AS02(A) vaccine induced strong gp120-specific CD4(+) T-cell responses and a higher number of vaccinees developed both HIV-1-specific CD4(+) T-cell responses and CD8(+) T-cell proliferation. The induction of these responses may be important in enhancing immune-mediated viral control.
Sujet(s)
Vaccins contre le SIDA/immunologie , Agents antiVIH/usage thérapeutique , Lymphocytes T CD4+/cytologie , Protéine d'enveloppe gp120 du VIH/immunologie , Infections à VIH/prévention et contrôle , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/immunologie , Adjuvants immunologiques/administration et posologie , Adolescent , Adulte , Numération des lymphocytes CD4 , Lymphocytes T CD4+/physiologie , Prolifération cellulaire , Méthode en double aveugle , Femelle , Infections à VIH/traitement médicamenteux , Humains , Mâle , Adulte d'âge moyen , Vaccins sous-unitaires/immunologie , Jeune adulte , Produits du gène nef du virus de l'immunodéficience humaine/immunologie , Produits du gène tat du virus de l'immunodéficience humaine/immunologieRÉSUMÉ
BACKGROUND: Vaccine-induced antibodies to envelope proteins frequently cause HIV seroconversion in uninfected recipients of HIV vaccine candidates and may thus have an impact on the vaccinee's ability to donate blood or acquire a life insurance policy. OBJECTIVE: To determine the occurrence of positive test results when commonly used HIV immunoassays are used to screen sera of HIV-uninfected volunteers who received an adjuvanted HIV-1 vaccine candidate containing HIV-1 antigens p24, reverse transcriptase, Nef and p17. STUDY DESIGN: Sera of 50 subjects who received this polyprotein vaccine in a single center in Belgium were tested with 6 HIV screening assays and 1 confirmation test. All samples were drawn one year after the administration of the first of two vaccine doses given with one month interval. RESULTS: Forty-five (90%) sera showed a positive test result in at least one of the 7 HIV tests used. The positivity rates were 88% in the Elecsys HIV Combi assay, 74% in the ADVIA Centaur EHIV and 48% in the PRISM HIV O Plus assay. CONCLUSIONS: Interpretation of HIV test results is becoming increasingly complex with the growing number of volunteers participating in prophylactic HIV vaccine trials worldwide and the rising number of viral antigens included in these vaccine candidates. The results of this study in recipients of a highly immunogenic adjuvanted polyprotein HIV vaccine candidate devoid of envelope proteins, illustrate the increasing need for approaches that can discriminate HIV infection-induced antibodies from those elicited by a vaccine.
Sujet(s)
Vaccins contre le SIDA/immunologie , Anticorps anti-VIH/immunologie , Séropositivité VIH/immunologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/immunologie , Vaccins contre le SIDA/administration et posologie , Vaccins contre le SIDA/effets indésirables , Belgique , Anticorps anti-VIH/biosynthèse , Anticorps anti-VIH/sang , Antigènes du VIH/immunologie , Protéine de capside p24 du VIH/immunologie , Infections à VIH/immunologie , Infections à VIH/prévention et contrôle , Transcriptase inverse du VIH/immunologie , Séropositivité VIH/sang , Humains , Vaccination , Produits du gène gag du virus de l'immunodéficience humaine/immunologie , Produits du gène nef du virus de l'immunodéficience humaine/immunologieRÉSUMÉ
BACKGROUND: This phase I/II partially blinded, randomized, dose-ranging study assessed the safety and immunogenicity of a novel human immunodeficiency virus type 1 (HIV-1) vaccine candidate consisting of a recombinant fusion protein (F4) containing 4 HIV-1 clade B antigens (Gag p24, Pol reverse transcriptase, Nef, and Gag p17) adjuvanted with AS01 in HIV-seronegative volunteers. Methods. Two doses of the recombinant F4 protein (10, 30, or 90 µg/dose), adjuvanted with AS01 or reconstituted with water for injection, were administered 1 month apart to 180 healthy volunteers aged 18-40 years. F4-specific CD4(+) T cell responses were measured using intracellular cytokine staining after in vitro stimulation by overlapping peptide pools covering the 4 individual antigens. Results. Reactogenicity was higher during the 7-day period after each vaccine dose in the adjuvanted than in the nonadjuvanted groups. In the adjuvanted groups, the overall immune response rate was high after the second vaccine dose, with highest responder rates seen in the 10-µg F4/AS01 group (100% to 3 HIV-1 antigens and 80% to all 4 HIV-1 antigens). High and long-lasting CD4(+) T cell frequencies were observed (up to a median value of 1.2% F4-specific CD4(+) T cells at day 44), with strongest responses directed against reverse transcriptase. Antigen-specific CD4(+) T cells exhibited a polyfunctional phenotype, expressing at least CD40 ligand and interleukin 2, often in combination with tumor necrosis factor α and/or interferon γ. Vaccine-induced CD4(+) T cell responses were broadly cross-reactive to all 4 antigens derived from HIV-1 clades A and C. Conclusions. These results support further clinical investigation of this HIV-1 vaccine candidate both in a prophylactic setting (alone, in conjunction with an envelope-based antigen or in combination with other vaccine approaches in a heterologous prime-boost regimen) and as a potentially disease-modifying therapeutic vaccine in HIV-1-infected subjects. CLINICAL TRIALS REGISTRATION: NCT00434512.
Sujet(s)
Vaccins contre le SIDA/immunologie , Adjuvants immunologiques/administration et posologie , Lymphocytes T CD4+/immunologie , Infections à VIH/prévention et contrôle , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/immunologie , Vaccins contre le SIDA/effets indésirables , Adjuvants immunologiques/effets indésirables , Adolescent , Adulte , Cytokines/biosynthèse , Femelle , Infections à VIH/immunologie , Séronégativité VIH/immunologie , Humains , Rappel de vaccin/méthodes , Mâle , Protéines de fusion recombinantes/immunologie , Vaccination/méthodes , Vaccins sous-unitaires/effets indésirables , Vaccins sous-unitaires/immunologie , Vaccins synthétiques/immunologie , Jeune adulteRÉSUMÉ
AS03 is an Adjuvant System (AS) containing α-tocopherol and squalene in an oil-in-water (o/w) emulsion. AS03 has been considered for the development of pandemic and seasonal influenza vaccines. Key features of AS03's mode of action were investigated in vivo in mice and ex vivo in human cells. AS03's adjuvant activity was superior to that of aluminium hydroxide and required the spatio-temporal co-localisation of AS03 with the antigen. This requirement coincided with AS03 triggering a transient production of cytokines at the injection site and in the draining lymph nodes (dLNs). The nature of the cytokines produced was consistent with the enhanced recruitment of granulocytes and of antigen-loaded monocytes in the dLNs. The presence of α-tocopherol in AS03 was required for AS03 to achieve the highest antibody response. The presence of α-tocopherol also modulated the expression of some cytokines, including CCL2, CCL3, IL-6, CSF3 and CXCL1; increased the antigen loading in monocytes; and increased the recruitment of granulocytes in the dLNs. Hence, AS03's promotion of monocytes as the principal antigen-presenting cells, and its effects on granulocytes and cytokines, may all contribute to enhancing the antigen-specific adaptive immune response.
Sujet(s)
Immunité acquise , Adjuvants immunologiques/administration et posologie , Immunité innée , Vaccins antigrippaux/immunologie , Polysorbates/administration et posologie , Squalène/administration et posologie , Tocophérols/administration et posologie , alpha-Tocophérol/administration et posologie , Animaux , Anticorps antiviraux/sang , Lignée cellulaire , Cytokines/métabolisme , Association médicamenteuse , Émulsions/administration et posologie , Femelle , Granulocytes/immunologie , Humains , Vaccins antigrippaux/administration et posologie , Lymphocytes/immunologie , Souris , Souris de lignée C57BL , Monocytes/immunologie , Muscles/immunologieRÉSUMÉ
This randomized double-blind study aimed to determine the safety and immunogenicity of a gp120/NefTat candidate human immunodeficiency virus type 1 (HIV-1) vaccine formulated with one of three different Adjuvant Systems (AS02(A), AS02(V) and AS01(B)) in healthy HIV-seronegative adults. All vaccine formulations induced strong HIV-specific CD4(+) T-cell responses characterized by high lymphoproliferative capacity and IL-2 production that were still detectable 18 months after last immunization, with strongest responses seen in the AS01(B) group. Broad coverage was demonstrated against gp120, and to a lesser extent Nef, derived from the most common circulating clades (B, C and circulating recombinant form [CRF]-01). All vaccine formulations exhibited acceptable safety and reactogenicity profiles. The demonstration of superior CD4(+) T-cell induction by AS01(B) provides important guidance for future HIV vaccine development.
Sujet(s)
Vaccins contre le SIDA/immunologie , Lymphocytes T CD4+/immunologie , Protéine d'enveloppe gp120 du VIH/immunologie , Infections à VIH/prévention et contrôle , Produits du gène nef du virus de l'immunodéficience humaine/immunologie , Produits du gène tat du virus de l'immunodéficience humaine/immunologie , Vaccins contre le SIDA/effets indésirables , Adjuvants immunologiques/pharmacologie , Adolescent , Adulte , Anticorps neutralisants/sang , Réactions croisées , Méthode en double aveugle , Femelle , Anticorps anti-VIH/sang , Infections à VIH/immunologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/immunologie , Humains , Immunité cellulaire , Interleukine-2/immunologie , Mâle , Adulte d'âge moyen , Jeune adulteRÉSUMÉ
Protection against Plasmodium falciparum sporozoite infection can be achieved by vaccination with the recombinant circumsporozoite protein-based vaccine RTS,S formulated with the AS02A Adjuvant System. Since this protection is only partial and wanes over time, we have developed a new RTS,S-based vaccine adjuvanted with AS01B. RTS,S/AS01B-induced high specific antibody titers and increased the frequency of mouse CD4(+) and CD8(+) T cells expressing IFN-gamma, and of monkey CD4(+) T cells expressing IL-2 and/or IFN-gamma and/or TNF-alpha upon stimulation with vaccine antigens. Our data provides clear evidence that combining RTS,S antigen with a potent adjuvant induces strong humoral and cellular responses in vivo.