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1.
Lancet Infect Dis ; 2022 May 25.
Article in English | MEDLINE | ID: mdl-35643089

ABSTRACT

BACKGROUND: Prevention of mother-to-child transmission (MTCT) of hepatitis B virus (HBV) is based on administration of vaccine and immunoglobulins (HBIg) to newborns at birth and maternal antiviral prophylaxis for those with an HBV-DNA viral load of at 5·3 log10 IU/mL or more. Many low-income and middle-income countries face difficulty in accessing HBIg and HBV-DNA quantification. The aim of this study was to evaluate the effectiveness of an HBIg-free strategy to prevent MTCT of HBV. METHODS: TA-PROHM was a single-arm, multicentre, phase 4 trial done in five maternity units in Cambodia. Pregnant women who were positive for hepatitis B surface antigen (HBsAg), aged 18 years or older were included. Women who were HCV or HIV positive, had creatinine clearance of less than 30 mL/min, severe gravid disease, and planned to give birth outside the study sites were excluded. From Oct 4, 2017, to Jan 9, 2019, HBsAg positive pregnant women who tested positive for hepatitis B e antigen (HBeAg) with a rapid diagnostic test were eligible to receive tenofovir disoproxil fumarate. From Jan 9, 2019, women who were HBeAg negative with an alanine aminotransferase concentration of ≥40 IU/L were also eligible to receive tenofovir disoproxil fumarate. Women in the tenofovir disoproxil fumarate eligible group received 300 mg of tenofovir disoproxil fumarate orally once a day from the 24th week of gestation until 6 weeks postpartum. The primary outcome was the overall proportion of infants who were HBsAg positive at 6 months of life, confirmed by positive HBV DNA quantification. For the primary outcome, the proportion (95% CI) of infants with HBsAg at 6 months was stratified according to infant's HBIg status, duration of maternal tenofovir disoproxil fumarate treatment (>4 weeks and ≤4 weeks), and study period (before and after the change in therapeutic algorithm) and was measured in a modified intention-to-treat analysis, which excluded infants lost to follow-up or who were withdrawn before 6 months. The study is registered with ClinicalTrials.gov, NCT02937779. FINDINGS: From Oct 4, 2017, to Nov 27, 2020, 21 251 pregnant women were screened for HBsAg, of whom 1194 (6%) were enrolled in the study: 338 (28%) were eligible to receive tenofovir disoproxil fumarate. For the tenofovir disoproxil fumarate eligible group, four (1% [95% CI 0·34-3·20]) of 317 infants had HBV infection at 6 months; in the subgroup of 271 children who did not receive HBIg, four (1% [0·40-3·74]) had HBV infection at 6 months. In absence of HBIg, MTCT HBV transmission occurred in none (0% [0-1·61]) of 227 women who received tenofovir disoproxil fumarate for more than 4 weeks before giving birth and three (8% [1·75-22·47]) of 36 women who received tenofovir disoproxil fumarate for less than 4 weeks. In the tenofovir disoproxil fumarate ineligible group, seven (1% [0·40-2·02]) of 712 infants had HBV infection at 6 months; in the subgroup of 567 children who did not receive HBIg, six (1% [0·39-2·30]) had HBV infection at 6 months. INTERPRETATION: An immunoglobulin-free strategy using an HBeAg rapid diagnosis test and alanine aminotransferase-based algorithm to assess eligibility for tenofovir, is effective at preventing MTCT of HBV when tenofovir was initiated at least 4 weeks before birth. FUNDING: French Agency for Research on AIDS and Viral Hepatitis and Emerging Infectious diseases. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

3.
EBioMedicine ; 75: 103810, 2022 Jan.
Article in English | MEDLINE | ID: mdl-35045362

ABSTRACT

BACKGROUND: V591 (TMV-083) is a live recombinant measles vector-based vaccine candidate expressing a pre-fusion stabilized SARS-CoV-2 spike protein. METHODS: We performed a randomized, placebo-controlled Phase I trial with an unblinded dose escalation and a double-blind treatment phase at 2 sites in France and Belgium to evaluate the safety and immunogenicity of V591. Ninety healthy SARS-CoV-2 sero-negative adults (18-55 years of age) were randomized into 3 cohorts, each comprising 24 vaccinees and 6 placebo recipients. Participants received two intramuscular injections of a low dose vaccine (1 × 105 median Tissue Culture Infectious Dose [TCID50]), one or two injections of a high dose vaccine (1 × 106 TCID50), or placebo with a 28 day interval. Safety was assessed by solicited and unsolicited adverse events. Immunogenicity was measured by SARS-CoV-2 spike protein-binding antibodies, neutralizing antibodies, spike-specific T cell responses, and anti-measles antibodies. ClinicalTrials.gov, NCT04497298. FINDINGS: Between Aug 10 and Oct 13, 2020, 148 volunteers were screened of whom 90 were randomized. V591 showed a good safety profile at both dose levels. No serious adverse events were reported. At least one treatment-related adverse event was reported by 15 (20.8%) participants receiving V591 vs. 6 (33.3%) of participants receiving placebo. Eighty-one percent of participants receiving two injections of V591 developed spike-binding antibodies after the second injection. However, neutralizing antibodies were detectable on day 56 only in 17% of participants receiving the low dose and 61% receiving the high dose (2 injections). Spike-specific T cell responses were not detected. Pre-existing anti-measles immunity had a statistically significant impact on the immune response to V591, which was in contrast to previous results with the measles vector-based chikungunya vaccine. INTERPRETATION: While V591 was generally well tolerated, the immunogenicity was not sufficient to support further development. FUNDING: Themis Bioscience GmbH, a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA; Coalition for Epidemic Preparedness Innovations (CEPI).


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/immunology , Genetic Vectors , Immunogenicity, Vaccine , Measles virus , SARS-CoV-2/immunology , Adolescent , Adult , COVID-19/genetics , COVID-19/prevention & control , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Double-Blind Method , Female , Humans , Male , Middle Aged , SARS-CoV-2/genetics
5.
Infect Dis Now ; 52(1): 40-43, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34920180

ABSTRACT

BACKGROUND: Measuring vaccine effectiveness (VE) using real-life data is critical to confirm the effectiveness of licensed vaccine, which could strengthen vaccination adherence. METHODS: We measured VE against adult COVID-19 hospitalization in five hospitals in France using a test negative design. We compared the odds of vaccinated patients hospitalized with COVID-19 with the odds of vaccinated patients hospitalized for the same symptoms with a negative test. RESULTS: A total of 853 patients (463 cases and 390 controls) were included, with a total of 170 patients vaccinated (104 with one dose, 65 with two doses, and one with three doses). There were four cases of breakthrough infections, all in immunocompromised patients. The VE was 84.0% (CI0.95=[72.6; 90.6]) for one dose and 96.2% (CI0.95=[86.8; 98.9]) for two doses. CONCLUSION: Our results confirm the high VE of COVID-19 vaccine in France to prevent hospitalizations due to the alpha variant.


Subject(s)
COVID-19 , Adult , COVID-19 Vaccines , Case-Control Studies , Hospitalization , Humans , SARS-CoV-2
6.
Clin Infect Dis ; 71(10): e587-e593, 2020 12 17.
Article in English | MEDLINE | ID: mdl-32188982

ABSTRACT

BACKGROUND: The paucity of hepatitis B virus (HBV) DNA measurement in low-/middle-income countries hinders the identification of HBV-infected pregnant women at risk of perinatal transmission. This study evaluates the validity of an algorithm selecting HBeAg-positive women and HBeAg-negative women with alanine aminotransferase (ALT) ≥40 IU/L as a predictor of high HBV DNA level. METHODS: All women with reactive samples for hepatitis B surface antigen (HBsAg) were assessed with an SD BIOLINE HBeAg rapid test and HBV DNA quantification was performed. Validities of HBeAg and of the algorithm to identify HBV DNA >2 thresholds (5.3 and 7.3 log10 IU/mL) were evaluated. RESULTS: For the 515 HBsAg-positive women, median age was 29 years, 92 (17.9%) were HBeAg positive, 47 (9.1%) were HBeAg negative with ALT ≥40 IU/L, and 144 (28.0%) had an HBV DNA >5.3 log10 IU/mL. Sensitivity and specificity of HBeAg were 61.8% and 99.2% for HBV DNA >5.3 log10 IU/mL and 81.3% and 96.7% for HBV DNA >7.3 log10 IU/mL. For the algorithm, sensitivity and specificity were 79.2% and 93.3% for HBV DNA level >5.3 log10 IU/mL and 92.7% and 88.1% for HBV DNA >7.3 log10 IU/mL. The AUCs for the algorithm (0.92 and 0.94 for HBV DNA >5.3 and 7.3, respectively) were significantly greater (P < .001) than the AUCs for HBeAg (0.81 and 0.89 for HBV DNA >5.3 and 7.3, respectively). CONCLUSIONS: An algorithm using HBeAg and ALT level could be an effective strategy to identify HBV-infected pregnant women at risk of perinatal transmission in countries where HBV DNA quantification is not routinely available.


Subject(s)
Hepatitis B, Chronic , Pregnancy Complications, Infectious , Adult , Alanine Transaminase , Algorithms , Child , DNA, Viral , Female , Hepatitis B Surface Antigens , Hepatitis B e Antigens , Hepatitis B virus/genetics , Hepatitis B, Chronic/diagnosis , Humans , Infectious Disease Transmission, Vertical , Mothers , Pregnancy , Pregnancy Complications, Infectious/diagnosis , Pregnant Women
7.
AIDS ; 33(13): 2061-2071, 2019 11 01.
Article in English | MEDLINE | ID: mdl-31306171

ABSTRACT

BACKGROUND: The ANRS COV1-COHVAC cohort was a long-term safety cohort of healthy volunteers who received preventive HIV-vaccine candidates in 17 phase I/II clinical trials. METHODS: Data collected from the first vaccine candidate administration and annually after inclusion in the cohort included grade 3/4 adverse events and all grade adverse events suggestive of neurological, ophthalmological and immune disorders, self-administered questionnaires on behaviors and HIV ELISA results. Age-and-sex-standardized mortality ratios (SMRs) were calculated with respect to the French population. The cohort was early terminated in 2016 due to the absence of safety signal. RESULTS: Of 496 volunteers, 488 were included: 355 in the 7-year prospective follow-up and 133 in the retrospective data collection only. The total follow-up after the first vaccination was 4934 person-years (median: 10 years) and 270 (76%) volunteers completed their follow-up. No relevant adverse event possibly related to the vaccine was reported. Breast cancer incidence and woman mortality did not differ from those of the French general population (standardized incidence ratio = 1.47, P = 0.45 and SMR = 0.65, P = 0.28, respectively) while man mortality was significantly lower (SMR = 0.26, P = 0.0003). At the last visit, 21/29 (72%) volunteers who received the recombinant HIV gp160 protein still showed vaccine-induced seropositivity after a median follow-up of 23 years. Only a few volunteers reported risky sexual practices (men: 20/192, women: 2/162). CONCLUSION: Volunteers showed a sustained high commitment. No long-term safety alert was identified during the postvaccine follow-up. Participating in vaccine trials did not increase risky behaviors for HIV infection. Vaccine-induced seropositivity may persist for more than 23 years after receiving rgp160.


Subject(s)
AIDS Vaccines/immunology , HIV Antibodies/blood , HIV Infections/immunology , HIV Infections/prevention & control , AIDS Vaccines/adverse effects , Adult , Clinical Trials as Topic , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Female , France , Healthy Volunteers , Humans , Male , Middle Aged , Prospective Studies , Retrospective Studies , Sexual Behavior , Social Behavior , Surveys and Questionnaires , Time
8.
J Acquir Immune Defic Syndr ; 79 Suppl 1: S37-S50, 2018 10 01.
Article in English | MEDLINE | ID: mdl-30222704

ABSTRACT

From 1992 to 2007, the ANRS (France Recherche Nord & Sud Sida-HIV Hépatites) set up a network of healthy volunteers at low risk of HIV infection and participating in preventive HIV vaccine phase I and II trials. The objectives of the ANRS COHVAC volunteer cohort include the social consequences of trial participation and their sexual behavior over time. For 488 volunteers who received a vaccine candidate, 462 selection files were collected, and from 2008 to 2016, 355 volunteers participated in the prospective cohort, including self-administered and face-to-face questionnaires administered annually. The volunteer population is relatively old, with social characteristics and engagement in society rather high. Most volunteers and people around them well accepted the trials, and participation in vaccine trials was not followed by increased risk-taking regarding HIV infection years later.


Subject(s)
AIDS Vaccines/immunology , HIV Infections/prevention & control , HIV/immunology , Adult , Cohort Studies , Female , France , Humans , Male , Middle Aged , Prospective Studies , Risk-Taking , Sexual Behavior , Social Behavior , Surveys and Questionnaires , Volunteers , Young Adult
9.
AIDS ; 32(16): 2291-2299, 2018 10 23.
Article in English | MEDLINE | ID: mdl-30096071

ABSTRACT

OBJECTIVES: The objective of this study is to investigate immunogenicity and safety of the yellow fever vaccine (YFV) in HIV-infected (HIV+) patients with high CD4 T-cell counts. DESIGN: In this prospective, comparative study of YFV-naive adults: 40 HIV+ under antiretroviral therapy (ART) with CD4 T-cell count above 350 cells/µl and plasma HIV-RNA less than 50 copies/ml for at least 6 months and 31 HIV-negative (HIV-) received one injection of the YF-17D strain vaccine. METHODS: Serologic response was assessed by using a plaque reduction neutralizing test and YFV-specific T cells by using an INFγ-Elispot assay. RESULTS: YFV was well tolerated in both groups. Most participants had asymptomatic YFV viremia at day (D) 7 after vaccination (77% of HIV- and 82% of HIV+, P = 0.58), with higher plasma level of YFV RNA in HIV+ than in HIV- (median 2.46 log10 copies/ml (range: 1.15-4.16) and 1.91 log10 copies/ml (1.15-3.19), respectively, P = 0.011). A significant but transient decrease in CD4 cell counts was seen at D7 in both groups, more pronounced in HIV- than in HIV+ patients (-261.5 versus -111.5 cells/µl, respectively, P = 0.0003), but no HIV breakthrough was observed in plasma. All participants developed protective neutralizing antibody levels from D28 and up to 1 year after injection. At D91, fewer HIV+ than HIV- participants exhibited YFV T-cell response (20 versus 54%, respectively, P = 0.037). CONCLUSION: At 1 year, YFV was immunogenic and well tolerated in HIV-infected adults under ART with CD4 T-cell counts above 350 cells/µl. However, a lower immunity of YFV T cells in HIV-infected patients was observed as compared with HIV- participants. CLINICAL TRIALS REGISTRATION: NCT01426243.


Subject(s)
HIV Infections/complications , Yellow Fever Vaccine/adverse effects , Yellow Fever Vaccine/immunology , Yellow Fever/prevention & control , Adolescent , Adult , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Enzyme-Linked Immunospot Assay , Female , Humans , Interferon-gamma/metabolism , Male , Middle Aged , Neutralization Tests , Prospective Studies , T-Lymphocytes/immunology , Yellow Fever Vaccine/administration & dosage , Young Adult
10.
Patient Educ Couns ; 101(11): 1934-1941, 2018 11.
Article in English | MEDLINE | ID: mdl-29958765

ABSTRACT

OBJECTIVE: To evaluate the impact of brief training in motivational interviewing (MI) from a non-specialist professional for medical students. METHODS: Students (n = 20) received three four-hour sessions of MI training over one week. They interviewed caregivers acting as patients in two standardised medical situations, six weeks before and three weeks after training. Global scores from the MITI-3.1.1 code, including "MI- Spirit", were attributed to the audiotaped interviews by two independent coders, blind the pre- or post-training status of the interview. Secondary outcomes were: caregivers' perception of students' empathy (CARE questionnaire), students' evaluation of self-efficacy to engage in a patient-centred relationship (SEPCQ score), and students' satisfaction with their own performance (analogue scale). RESULTS: MI-Spirit score increased significantly after training (p < 0.0001, effect size 1.5). Limited improvements in CARE score (p = 0.034, effect size 0.5) and one of the SEPCQ dimensions (sharing information and power with the patient; p = 0.047, effect size 0.5) were also noted. Students' satisfaction score was unaffected (p = 0.69). CONCLUSION: These findings suggest that brief MI training can improve communication skills in medical students. PRACTICE IMPLICATIONS: Such an intervention is feasible and could be generalised during medical studies.


Subject(s)
Clinical Competence , Communication , Motivational Interviewing/methods , Program Evaluation/methods , Students, Medical/psychology , Adult , Curriculum , Education, Medical, Undergraduate , Educational Measurement , Female , Humans , Male , Patient Simulation
11.
PLoS One ; 12(7): e0180191, 2017.
Article in English | MEDLINE | ID: mdl-28708873

ABSTRACT

BACKGROUND: HIV-infected cells in semen facilitate viral transmission. We studied the establishment of HIV reservoirs in semen and blood during PHI, along with systemic immune activation and the impact of early cART. METHODS: Patients in the ANRS-147-OPTIPRIM trial received two years of early cART. Nineteen patients of the trial were analyzed, out of which 8 had acute PHI (WB ≤1 Ab). We quantified total cell-associated (ca) HIV-DNA in blood and semen and HIV-RNA in blood and semen plasma samples, collected during PHI and at 24 months of treatment. RESULTS: At enrollment, HIV-RNA load was higher in blood than in semen (median 5.66 vs 4.22 log10 cp/mL, p<0.0001). Semen HIV-RNA load correlated strongly with blood HIV-RNA load (r = 0.81, p = 0.02, the CD4 cell count (r = -0.98, p<0.0001), and the CD4/CD8 ratio (r = -0.85, p<0.01) in acute infection but not in later stages of PHI. Median blood and seminal cellular HIV-DNA levels were 3.59 and 0.31 log10cp/106 cells, respectively. HIV-DNA load peaked in semen later than in blood and then correlated with blood IP10 level (r = 0.62, p = 0.04). HIV-RNA was undetectable in blood and semen after two years of effective cART. Semen HIV-DNA load declined similarly, except in one patient who had persistently high IP-10 and IL-6 levels and used recreational drugs. CONCLUSIONS: HIV reservoir cells are found in semen during PHI, with gradual compartmentalization. Its size was linked to the plasma IP-10 level. Early treatment purges both the virus and infected cells, reducing the high risk of transmission during PHI. CLINICAL TRIALS REGISTRATION: NCT01033760.


Subject(s)
Anti-Retroviral Agents/therapeutic use , HIV Infections/drug therapy , RNA, Viral/blood , Semen/virology , Acute Disease , Adult , CD4-CD8 Ratio , Enzyme-Linked Immunosorbent Assay , HIV-1/genetics , HIV-1/isolation & purification , Humans , Interleukin-6/analysis , Leukocytes, Mononuclear/virology , Male , Middle Aged , Principal Component Analysis , RNA, Viral/analysis , Real-Time Polymerase Chain Reaction , Time Factors , Viral Load , Young Adult
12.
PLoS One ; 12(5): e0177882, 2017.
Article in English | MEDLINE | ID: mdl-28562615

ABSTRACT

Given the possibility of yellow fever virus reintroduction in epidemiologically receptive geographic areas, the risk of vaccine supply disruption is a serious issue. New strategies to reduce the doses of injected vaccines should be evaluated very carefully in terms of immunogenicity. The plaque reduction test for the determination of neutralizing antibodies (PRNT) is particularly time-consuming and requires the use of a confinement laboratory. We have developed a new test based on the use of a non-infectious pseudovirus (WN/YF17D). The presence of a reporter gene allows sensitive determination of neutralizing antibodies by flow cytometry. This WN/YF17D test was as sensitive as PRNT for the follow-up of yellow fever vaccinees. Both tests lacked specificity with sera from patients hospitalized for acute Dengue virus infection. Conversely, both assays were strictly negative in adults never exposed to flavivirus infection or vaccination, and in patients sampled some time after acute Dengue infection. This WN/YF17D test will be particularly useful for large epidemiological studies and for screening for neutralizing antibodies against yellow fever virus.


Subject(s)
Antibodies, Neutralizing/blood , Dengue Virus/immunology , Yellow fever virus/immunology , Antibodies, Viral/blood , Dengue/immunology , HEK293 Cells , Humans , Limit of Detection , Viral Plaque Assay , Virulence
13.
Vaccine ; 31(40): 4406-15, 2013 Sep 13.
Article in English | MEDLINE | ID: mdl-23850610

ABSTRACT

BACKGROUND: We have shown that the intradermal (ID) administration of an HIV-1 lipopeptide candidate vaccine (LIPO-4) is well tolerated in healthy volunteers, with one fifth the IM dose delivered by this route inducing HIV-1-specific CD8(+) T-cell responses of a magnitude and quality similar to those achieved by IM administration. In this long-term follow-up, we aimed to investigate the sustainability and epitopic breadth of the immune responses induced. METHODS: In a prospective multicentre trial, 68 healthy volunteers were randomised to receive, at weeks 0, 4 and 12, either a 0.5 ml IM (500 µg of each lipopeptide; 35 volunteers) dose or a 0.1 ml ID (100 µg of each lipopeptide; 33 volunteers) dose of the LIPO-4 vaccine, in the deltoid region of the non-dominant arm. All 68 volunteers received the first two vaccinations, and 44 volunteers in the ID group and 22 in the IM group received the third. We describe here the long-term CD8(+) and CD4(+) T-cell immune responses, up to 48 weeks after the first immunisation. RESULTS: Response frequency was highest at week 14 for CD4(+) T cells, at 85% (28/33) for the IM group and 61% (20/33) for the ID group (p=0.027), and at week 48 for CD8(+) T cells, at 36% (12/33) for the ID group and 31% (11/35) for the IM group (p=0.67). Response rates tended to be lower for volunteers receiving the third vaccination boost, whether IM or ID. Finally, we also observed a striking change in the specificity of the CD8(+) T-cell responses induced shortly (2 weeks) or several months (48 weeks) after LIPO-4 vaccination. CONCLUSION: Lipopeptide vaccines elicited sustainable CD4(+) and CD8(+) T-cell responses, following IM or ID administration. CD8(+) T-cell responses had shifted and expanded to different epitopes after one year of follow-up. These results should facilitate the design of the next generation of prime-boost trials with repeated doses of lipopeptide vaccines.


Subject(s)
AIDS Vaccines/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Lipopeptides/immunology , AIDS Vaccines/administration & dosage , HIV Infections/immunology , HIV Infections/prevention & control , HIV-1/immunology , Healthy Volunteers , Humans , Interferon-gamma/blood , Lipopeptides/administration & dosage , Prospective Studies , Vaccination/methods
14.
AIDS ; 27(9): 1421-31, 2013 Jun 01.
Article in English | MEDLINE | ID: mdl-23759749

ABSTRACT

OBJECTIVE: To dissect the biological mechanisms involved in the cellular responses to a candidate vaccine containing 5 HIV peptides coupled to a palmytoil tail (HIV-LIPO-5) in healthy volunteers, by using extensive immunogenicity assessments with different stimulation durations. DESIGN: Immunogenicity substudy of a randomized phase II prophylactic HIV vaccine trial (ANRS VAC 18). METHODS: HIV-LIPO-5 or placebo was administered at W0, W4, W12 and W24. Peripheral blood mononuclear cells from a subset of participants at W0 and W14 were stimulated with HIV-LIPO-5, Gag peptides contained in the vaccine and control peptides. ELISpot, lymphoproliferation, intracellular cytokine staining (ICS), cytokine multiplex and transcriptomic analyses were performed. Different time points and stimulation conditions were compared, controlling for test multiplicity. RESULTS: Cultured ELISpot and lymphoproliferation responses were detected at W14. Ex-vivo ICS showed mainly interleukin (IL)-2-producing cells. Secretion of interferon (IFN)-γ, tumour necrosis factor (TNF)-α, IL-5 and IL-13 increased significantly after culture and Gag stimulation at W14 compared to W0. Metallothionein genes were consistently overexpressed after HIV-LIPO-5 stimulation at W0 and W14. At W14, significant probes increased substantially, including IFN-γ, CXCL9, IL2RA, TNFAIP6, CCL3L1 and IL-6. Canonical pathway analyses indicated a role of interferon signalling genes in response to HIV-LIPO-5. CONCLUSION: HIV-LIPO-5 vaccination elicited Th1 and Th2 memory precursor responses and a consistent modulation in gene expression. The response profile before vaccination suggests an adjuvant effect of the lipid tail of HIV-LIPO-5. Our combined immunogenicity analyses allowed to identify a specific signature profile of HIV-LIPO-5 and indicate that HIV-LIPO-5 could be further developed as a prime in heterologous prime-boost strategies.


Subject(s)
AIDS Vaccines/administration & dosage , Cytokines/genetics , Gene Expression Regulation/physiology , HIV Antibodies/immunology , HIV Seronegativity/immunology , Transcription, Genetic/immunology , AIDS Vaccines/chemistry , Adult , CD4-Positive T-Lymphocytes/immunology , Double-Blind Method , Enzyme-Linked Immunospot Assay , Female , Humans , Lipopeptides/chemistry , Lymphocyte Activation , Male , Middle Aged , Transcription, Genetic/drug effects , Vaccination
15.
AIDS ; 27(1): 87-93, 2013 Jan 02.
Article in English | MEDLINE | ID: mdl-23018437

ABSTRACT

OBJECTIVE: In immunocompromised patients, alternative schedules more immunogenic than the standard influenza vaccine regimen are necessary to enhance and prolong vaccine efficacy. We previously reported that the AS03A-adjuvanted 2009 A/H1N1v vaccine yielded a higher short-term immune response than the nonadjuvanted one in HIV-1-infected adults. This study reports the long-term persistence of the immune response. DESIGN AND METHODS: In a prospective, multicenter, randomized, patient-blinded trial, two doses of AS03A-adjuvanted H1N1v vaccine containing 3.75 µg haemagglutinin (n = 155; group A) or nonadjuvanted H1N1v vaccine containing 15 µg haemagglutinin (n = 151; group B), were administered 21 days apart. Haemagglutination inhibition and neutralizing antibodies were assessed 6 and 12 months after vaccination. RESULTS: In group A and B, the seroprotection rates were 83.7 and 59.4% at month 6, and 70.4 and 49.3 at month 12, respectively. In a multivariate analysis, persistence of seroprotection 12 months after vaccination was negatively associated with current smoking (odds ratio = 0.6, P = 0.03) and positively related with the AS03A-adjuvanted H1N1v vaccine (odds ratio = 2.7, P = 0.0002). CONCLUSION: In HIV-1-infected adults, two doses of adjuvanted influenza vaccine induce long-term persistence of immune response up to 1 year after vaccination.


Subject(s)
HIV Infections/immunology , HIV-1/immunology , Hemagglutinins/immunology , Influenza A Virus, H1N1 Subtype/immunology , Influenza Vaccines/immunology , Influenza, Human/prevention & control , Squalene/immunology , alpha-Tocopherol/immunology , Adjuvants, Immunologic/pharmacology , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/drug effects , Antibodies, Viral/blood , Antibodies, Viral/drug effects , Antibody Formation/drug effects , Drug Combinations , Female , France/epidemiology , HIV Infections/drug therapy , Hemagglutination Inhibition Tests , Humans , Influenza A Virus, H1N1 Subtype/drug effects , Influenza, Human/immunology , Male , Polysorbates , Prospective Studies , Single-Blind Method , Smoking/adverse effects , Time Factors
16.
J Infect Dis ; 204(1): 124-34, 2011 Jul 01.
Article in English | MEDLINE | ID: mdl-21628666

ABSTRACT

BACKGROUND: Human immunodeficiency virus (HIV)-infected patients have decreased immune response to vaccines. Few data are available about pandemic flu vaccination in this population. METHODS: We conducted a multicenter, patient-blinded, randomized trial in a cohort of HIV-infected adults. Patients received 2 injections 21 days apart of a AS03(A)-adjuvanted H1N1v vaccine containing 3.75 µg hemagglutinin (HA) or a nonadjuvanted H1N1v vaccine containing 15 µg HA to assess hemagglutination inhibition (HI) response and safety. RESULTS: A total of 309 patients were randomized, and 306 were vaccinated. After the first vaccine dose, HI titers ≥1:40 were observed in 93.4% of the patients in the adjuvanted group (A group) (n = 155) and in 75.5% in the nonadjuvanted group (B group) (n = 151) (P < .001); seroconversion rates were 88.8% and 71.2%, and factor increases in geometric mean titers (GMT) of 21.9 and 15.1, respectively. After 2 injections, 98.6% of patients of the A group and 92.1% of the B group demonstrated HI titers ≥1:40 (P = .018); seroconversion rates were 96.5% and 87.1%, respectively, and factor increases in GMT were 45.5 and 21.2, respectively. The majority of adverse events were mild to moderate in severity; no impact on CD4+ cell count or viral load has been detected. CONCLUSIONS: In HIV-1-infected adults, the AS03(A)-adjuvanted H1N1v vaccine yielded a higher immune response than did the nonadjuvanted one, with no impact on HIV infection.


Subject(s)
Adjuvants, Immunologic/adverse effects , HIV Infections/immunology , Influenza A Virus, H1N1 Subtype/immunology , Influenza Vaccines/adverse effects , Influenza Vaccines/immunology , Influenza, Human/prevention & control , Squalene/adverse effects , Adjuvants, Immunologic/administration & dosage , Adult , Antibodies, Viral/blood , Female , Hemagglutination Inhibition Tests , Humans , Influenza Vaccines/administration & dosage , Male , Middle Aged , Squalene/administration & dosage
17.
J Antimicrob Chemother ; 65(10): 2215-23, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20702463

ABSTRACT

OBJECTIVES: We investigated why, despite its beneficial effect on the CD4 cell count, IL-2 therapy had no clinical benefit as shown in the ESPRIT and SILCAAT trials. We focused on subgroups of patients defined according to CD4 cell counts at baseline and over time to assess the threshold above which IL-2 therapy was no longer beneficial in a large cohort of HIV-1 infected patients. METHODS: Within the French Hospital Database on HIV, a total of 953 IL-2-treated patients were compared with 27 750 IL-2-untreated patients, matched for the date of enrolment, sex, age, and the baseline CD4 cell count and plasma HIV-1 RNA level. The risk of clinical progression, defined as the occurrence of a new AIDS-defining event or death, was studied with multivariable Cox proportional hazards models and Poisson regression models. RESULTS: We found no clinical benefit in patients starting IL-2 with CD4 count ≥200 cells/mm(3) [hazard ratio (HR) =1.13; 95% confidence interval (CI), 0.81-1.57], while a benefit was observed in patients with CD4 count <200 cells/mm(3) (HR=0.64; 95% CI, 0.48-0.86). The observed benefit was due to the risk reduction in the 100-350/mm(3) stratum of updated CD4 cell counts (relative rate=0.30; 95% CI, 0.09-1.03). CONCLUSIONS: Higher CD4 cell counts at enrolment and shorter follow-up with low to intermediate CD4 cell counts may explain why IL-2 therapy had no observed clinical benefit in the SILCAAT study. Our findings suggest that the benefit of IL-2 is restricted to a narrow range of CD4 cell counts, arguing against the use of IL-2 in HIV infection to reduce the risk of clinical events.


Subject(s)
Anti-HIV Agents/therapeutic use , Antiretroviral Therapy, Highly Active/methods , CD4-Positive T-Lymphocytes/immunology , HIV Infections/drug therapy , HIV Infections/immunology , Immunologic Factors/therapeutic use , Interleukin-2/therapeutic use , Adult , CD4 Lymphocyte Count , DNA, Viral/blood , Disease Progression , Female , Follow-Up Studies , HIV Infections/mortality , HIV Infections/virology , HIV-1/isolation & purification , Humans , Male , Middle Aged , Viral Load
18.
AIDS ; 24(14): 2211-23, 2010 Sep 10.
Article in English | MEDLINE | ID: mdl-20625264

ABSTRACT

BACKGROUND: French National Agency for Research on AIDS and Viral Hepatitis's HIV-LIPO-5 vaccine includes five HIV-1 peptides, containing multiple CD8 and CD4 T-cell epitopes and coupled to a palmitoyl tail. Whether HIV-LIPO-5 immunogenicity varies with the dose is unknown. METHODS: HIV-negative volunteers were randomized to receive HIV-LIPO-5 vaccine at 50 microg/lipopeptide (N = 32), 150 microg/lipopeptide (N = 32), 500 microg/lipopeptide (N = 33) or placebo (N = 34) at weeks 0, 4, 12 and 24. HIV-1-specific CD8 (interferon-gamma ELISpot on peripheral blood mononuclear cells cultured for 12 days) and CD4 responses (peripheral blood mononuclear cell lymphoproliferation) were assessed at baseline, after each injection and at week 48. RESULTS: Local reactions were dose-dependent but no differences in systemic reactions appeared between groups. Sustained (at least on two separate occasions) CD8 response rates to at least one given HIV-1 pool were obtained in 22 of 32 (69%), 21 of 33 (64%) and 21 of 34 (62%) individuals for LIPO-5 50, 150 and 500 groups, respectively (P < or = 0.0001 for all comparisons to the placebo). Cumulative CD4 response rates were obtained in 15 of 32 (47%), 18 of 33 (55%) and 15 of 34 (44%) individuals (P < 0.0001 for all comparisons to placebo). At week 48, CD8 responses persisted in 47 of 91 (52%) HIV-LIPO-5 recipients. CONCLUSION: Doses of 50, 150 and 500 microg of French National Agency for Research on AIDS and Viral Hepatitis's HIV-LIPO-5 vaccine were able to elicit HIV-specific sustained CD8 and CD4 T-cell responses in healthy adults. Safety is good and all doses appear appropriate in further 'prime-boost' trials.


Subject(s)
AIDS Vaccines/immunology , HIV Infections/prevention & control , HIV-1/immunology , Immunity, Cellular/immunology , AIDS Vaccines/administration & dosage , Adult , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Proliferation , Double-Blind Method , Female , HIV Infections/immunology , Humans , Injections, Intramuscular , Interferon-gamma , Lipopeptides/drug effects , Lipopeptides/immunology , Male , Middle Aged
19.
J Acquir Immune Defic Syndr ; 50(2): 206-14, 2009 Feb 01.
Article in English | MEDLINE | ID: mdl-19131886

ABSTRACT

BACKGROUND: Concerns have been raised about a possible excess risk of lymphomas in HIV-infected patients exposed to interleukin 2 (IL-2) therapy. Here we compared the risks of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) in IL-2-treated and IL-2-untreated HIV-infected patients. METHODS: Patients monitored through the French Hospital Database on HIV between May 1, 1995, and December 31, 2005, were enrolled in this study. Lymphomas that occurred between the day after study entry and the end of follow-up were eligible for analysis. Poisson regression models were used in 2 separate analyses to quantify the possible relationship between IL-2 therapy and the incidence of NHL and HL. RESULTS: The IL-2-treated group consisted of 861 patients and the IL-2-untreated group of 77,605 patients. Follow-up lasted a total of 3643 and 382,720 person-years, respectively. After adjustment for sex and time-updated age, period, the CD4 cell counts, the plasma HIV RNA levels, and AIDS status, the relative rates of NHL and HL associated with IL-2 therapy were 0.64 (95% confidence interval, 0.25 to 1.65) and 0.33 (95% confidence interval, 0.04 to 2.86), respectively. CONCLUSIONS: In this large observational study, IL-2 therapy did not increase the risk of lymphoma, either NHL or HL, in HIV-infected patients.


Subject(s)
HIV Infections/drug therapy , Hodgkin Disease/epidemiology , Interleukin-1/adverse effects , Lymphoma, Non-Hodgkin/epidemiology , Adult , Aged , Cohort Studies , Databases, Factual , Female , France , HIV Infections/complications , HIV Infections/immunology , Hodgkin Disease/complications , Hospitals , Humans , Incidence , Interleukin-1/therapeutic use , Lymphoma, AIDS-Related/complications , Lymphoma, AIDS-Related/epidemiology , Lymphoma, Non-Hodgkin/complications , Male , Middle Aged , Risk Factors , Treatment Outcome
20.
AIDS ; 21(14): 1887-97, 2007 Sep 12.
Article in English | MEDLINE | ID: mdl-17721096

ABSTRACT

OBJECTIVE: Interleukin (IL)-2 therapy leads to significant CD4 cell increases in HIV-infected patients. Since phase III trials are ongoing, studies supporting the long-term feasibility of this strategy are needed. METHODS: We studied the long-term outcomes of 131 patients treated with IL-2 in two studies initiated either before (ANRS 048) or following (ANRS 079) the advent of HAART. RESULTS: At the last assessment (median follow-up 3.4 years), these patients experienced a gain of 428 cells/microl and a decrease in plasma HIV RNA to 1.70 log10 copies/ml. In both studies, high CD4 cell counts were maintained with a median of ten 5-day cycles of subcutaneous IL-2. Median time since the last cycle was 2 years. At last assessment, 59% of 048 patients maintained a non-HAART regimen. Detailed analysis at week 170 showed that median CD4 cell counts were 856 (048) and 964 (079) cells/microl. This corresponded to a gain from baseline of 515 (048) and 627 (079) cells/microl. The median viral load decreases from baseline and corresponded to 1.70 (048) and 1.88 (079) log10 copies/ml. Comparisons across the studies showed that CD4 gains and viral load changes were similar whether HAART or non-HAART was used. The frequency of cycling, but not CD4 cell counts, viral loads or antiviral regimen at baseline, was predictive of long-term CD4 gain (P = 0.03). CONCLUSION: Altogether, these observations support IL-2 as a long-term therapeutic strategy in HIV infection.


Subject(s)
HIV Infections/drug therapy , Interleukin-2/administration & dosage , Adolescent , Adult , Antiretroviral Therapy, Highly Active , CD4 Lymphocyte Count , Chronic Disease , Drug Administration Schedule , Drug Therapy, Combination , Female , Humans , Immunotherapy/methods , Long-Term Care/methods , Male , Middle Aged , RNA, Viral/blood , Reverse Transcriptase Inhibitors/therapeutic use , Treatment Outcome , Viral Load
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