Serum and Salivary IgG and IgA Response After COVID-19 Messenger RNA Vaccination.

Importance: There is still considerable controversy in the literature regarding the capacity of intramuscular messenger RNA (mRNA) vaccination to induce a mucosal immune response. Objective: To compare serum and salivary IgG and IgA levels among mRNA-vaccinated individuals with or without previous SARS-CoV-2 infection. Design, Setting, and Participants: In this cohort study, SARS-CoV-2-naive participants and those with previous infection were consecutively included in the CoviCompare P and CoviCompare M mRNA vaccination trials and followed up to day 180 after vaccination with either the BNT162b2 (Pfizer-BioNTech) vaccine or the mRNA-1273 (Moderna) vaccine at the beginning of the COVID-19 vaccination campaign (from February 19 to June 8, 2021) in France. Data were analyzed from October 25, 2022, to July 13, 2023. Main Outcomes and Measures: An ultrasensitive digital enzyme-linked immunosorbent assay was used for the comparison of SARS-CoV-2 spike-specific serum and salivary IgG and IgA levels. Spike-specific secretory IgA level was also quantified at selected times. Results: A total of 427 individuals were included in 3 groups: participants with SARS-CoV-2 prior to vaccination who received 1 single dose of BNT162b2 (Pfizer-BioNTech) (n = 120) and SARS-CoV-2-naive individuals who received 2 doses of mRNA-1273 (Moderna) (n = 172) or 2 doses of BNT162b2 (Pfizer-BioNTech) (n = 135). The median age was 68 (IQR, 39-75) years, and 228 (53.4%) were men. SARS-CoV-2 spike-specific IgG saliva levels increased after 1 or 2 vaccine injections in individuals with previous infection and SARS-CoV-2-naive individuals. After vaccination, SARS-CoV-2-specific saliva IgA levels, normalized with respect to total IgA levels, were significantly higher in participants with previous infection, as compared with the most responsive mRNA-1273 (Moderna) recipients (median normalized levels, 155 × 10-5 vs 37 × 10-5 at day 29; 107 × 10-5 vs 54 × 10-5 at day 57; and 104 × 10-5 vs 70 × 10-5 at day 180 [P < .001]). In contrast, compared with day 1, spike-specific IgA levels in the BNT162b2-vaccinated SARS-CoV-2-naive group increased only at day 57 (36 × 10-5 vs 49 × 10-5 [P = .01]). Bona fide multimeric secretory IgA levels were significantly higher in individuals with previous infection compared with SARS-CoV-2-naive individuals after 2 antigenic stimulations (median optical density, 0.36 [IQR, 0.16-0.63] vs 0.16 [IQR, 0.10-0.22]; P < .001). Conclusions and Relevance: The findings of this cohort study suggest that mRNA vaccination was associated with mucosal immunity in individuals without prior SARS-CoV-2 infection, but at much lower levels than in previously infected individuals. Further studies are needed to determine the association between specific saliva IgA levels and prevention of infection or transmission.

Incidence of COVID-19 mRNA vaccine symptomatic breakthrough infections during Omicron circulation in adults with or without infection prior to vaccination.

OBJECTIVES: COVID-19 vaccine breakthrough infections were frequently reported during circulation of the Omicron variant. The ANRS|MIE CoviCompareP study investigated these infections in adults vaccinated and boosted with BNT162b2 [Pfizer-BioNTech] and with/without SARS-CoV-2 infection before vaccination. METHODS: In the first half of 2021, healthy adults (aged 18-45, 65-74 and 75 or older) received either one dose of BNT162b2 (n = 120) if they had a documented history of SARS-CoV-2 infection at least five months previously, or two doses (n = 147) if they had no history confirmed by negative serological tests. A first booster dose was administered at least 6 months after the primary vaccination, and a second booster dose, if any, was reported in the database. Neutralizing antibodies (NAbs) against the European (D614G) strain and the Omicron BA.1 variant were assessed up to 28 days after the first booster dose. A case-control analysis was performed for the 252 participants who were followed up in 2022, during the Omicron waves. RESULTS: From January to October 2022, 78/252 (31%) had a documented symptomatic breakthrough infection after full vaccination: 21/117 (18%) in those who had been infected before vaccination vs. 57/135 (42%) in those who had not. In a multivariate logistic regression model, factors associated with a lower risk of breakthrough infection were older age, a higher number of booster doses, and higher levels of Omicron BA.1 NAb titers in adults with infection before vaccination, but not in those without prior infection. CONCLUSION: Our results highlight the need to consider immune markers of protection in association with infection and vaccination history.

Vaccine effectiveness against COVID-19 hospitalisation in adults (≥ 20 years) during Omicron-dominant circulation: I-MOVE-COVID-19 and VEBIS SARI VE networks, Europe, 2021 to 2022.

IntroductionThe I-MOVE-COVID-19 and VEBIS hospital networks have been measuring COVID-19 vaccine effectiveness (VE) in participating European countries since early 2021.AimWe aimed to measure VE against PCR-confirmed SARS-CoV-2 in patients ≥ 20 years hospitalised with severe acute respiratory infection (SARI) from December 2021 to July 2022 (Omicron-dominant period).MethodsIn both networks, 46 hospitals (13 countries) follow a similar test-negative case-control protocol. We defined complete primary series vaccination (PSV) and first booster dose vaccination as last dose of either vaccine received ≥ 14 days before symptom onset (stratifying first booster into received < 150 and ≥ 150 days after last PSV dose). We measured VE overall, by vaccine category/product, age group and time since first mRNA booster dose, adjusting by site as a fixed effect, and by swab date, age, sex, and presence/absence of at least one commonly collected chronic condition.ResultsWe included 2,779 cases and 2,362 controls. The VE of all vaccine products combined against hospitalisation for laboratory-confirmed SARS-CoV-2 was 43% (95% CI: 29-54) for complete PSV (with last dose received ≥ 150 days before onset), while it was 59% (95% CI: 51-66) after addition of one booster dose. The VE was 85% (95% CI: 78-89), 70% (95% CI: 61-77) and 36% (95% CI: 17-51) for those with onset 14-59 days, 60-119 days and 120-179 days after booster vaccination, respectively.ConclusionsOur results suggest that, during the Omicron period, observed VE against SARI hospitalisation improved with first mRNA booster dose, particularly for those having symptom onset < 120 days after first booster dose.

Neutralizing antibodies against SARS-CoV-2 variants following mRNA booster vaccination in adults older than 65 years.

Immune response induced by COVID-19 vaccine booster against delta and omicron variants was assessed in 65 adults (65-84 years old) early aftesr a first booster dose. An increase in SARS-CoV-2 neutralizing antibodies was shown in individuals not previously infected without evidence of an age-related effect, with lower increase in those infected before a single dose of primary vaccination. Of note, humoral response was observed only starting from the 5th day after the boost.

Immunoglobulin-free strategy to prevent HBV mother-to-child transmission in Cambodia (TA-PROHM): a single-arm, multicentre, phase 4 trial.

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.

Safety and immunogenicity of a measles-vectored SARS-CoV-2 vaccine candidate, V591 / TMV-083, in healthy adults: results of a randomized, placebo-controlled Phase I study.

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).

Vaccine effectiveness against COVID-19 hospitalization in adults in France: A test negative case control study.

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.

Hepatitis B e Antigen (HBeAg) Rapid Test and Alanine Aminotransferase Level-Based Algorithm to Identify Pregnant Women at Risk of HBV Mother-to-Child Transmission: The ANRS 12345 TA PROHM Study.

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.

Long-term safety and vaccine-induced seropositivity in healthy volunteers from HIV vaccine trials.

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.

Social and Behavioral Consequences of Participation in HIV Preventive Vaccine Trials in the ANRS COHVAC Cohort.

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.

Immunogenicity and safety of yellow fever vaccine in HIV-1-infected patients.

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.

Motivational interviewing training for medical students: A pilot pre-post feasibility study.

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.

Impact of early cART on HIV blood and semen compartments at the time of primary infection.

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.

Screening test for neutralizing antibodies against yellow fever virus, based on a flavivirus pseudotype.

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.

Long-term CD4(+) and CD8(+) T-cell responses induced in HIV-uninfected volunteers following intradermal or intramuscular administration of an HIV-lipopeptide vaccine (ANRS VAC16).

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.

Cytokine and gene transcription profiles of immune responses elicited by HIV lipopeptide vaccine in HIV-negative volunteers.

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.

Long-term immunogenicity of two doses of 2009 A/H1N1v vaccine with and without AS03(A) adjuvant in HIV-1-infected adults.

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.