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.

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.

A national platform for Covid-19 vaccine studies recruitment in France: Covireivac volunteer's characteristics.

During the Covid-19 pandemic, the urgent need for safe and effective vaccines has led to many vaccine trials, implying fast and extensive recruitment of volunteers. In France, until 2020, vaccine clinical research participants were usually recruited locally, through center-based pools of volunteers, and local communication plans. Covireivac is a French public online platform launched on 10/01/2020 that enables national, large-scale recruitment of volunteers for Covid-19 vaccine studies. On the Covireivac website, all adult participants registered online, gave their informed consent, and filled out two online forms with information on their identity, health status (comorbidities, treatments), and known exposure to SARS-CoV-2. Since July 2021, volunteers could mention if their children are interested in participating in a Covid-19 vaccine trial. The objective of this work is to describe Covireivac's volunteer characteristics registered from 10/01/2020 to 11/02/2022. To identify independent volunteer characteristics associated with a period of registration we performed a multivariate logistic regression. Among 54,424 registrations, 52,391 (96%) were analysed; 61% were male (n = 31,893), median age was 50 y; 13% (n = 6586) were healthcare workers. At registration, 15,879 volunteers (33%) reported at least one comorbidity, among whom 16% (n = 7349) were obese and 17% (n = 8346) had hypertension. Most volunteers registered during the first month (n = 35,876, 66%). The Covireivac platform allowed quick and large recruitment of potential volunteers for Covid-19 vaccine trials and could be used on a larger scale for vaccine trials in France. It could facilitate recruitment in vaccine trials and provide sponsors with better visibility of the recruitment capacities of clinical research centers.

[Vaccination contre le SARS-CoV-2, le Graal ?] / Anti-SARS-CoV-2 vaccination, the grail ?

ANTI-SARS-COV-2 VACCINATION, THE GRAIL? The Covid-19 pandemic, which caused an unprecedented health crisis, was partially controlled by the rapid development of effective vaccines against SARS-CoV-2. To date, 5 vaccines are approved in Europe, 10 are recognized by the World Health Organization and more than 150 vaccine candidates are in clinical development. This emerging pandemic disease context has shown the value of research and real-life data. The five vaccines used in France have been developed using different technologies with convincing Phase 3 results. Real-life data have provided additional information on the effectiveness and safety of these vaccines: they have shown the importance of a booster dose to protect against severe forms of delta and omicron variants; they have made it possible to characterize and measure the incidence of rare adverse events, such as myocardial toxicity in mRNA vaccines or the risk of thrombocytopenic thrombosis in vectorized vaccines. However, research must continue as many questions remain unanswered.

VACCINATION CONTRE LE SARS-COV-2, LE GRAAL ? La pandémie de Covid-19, responsable d'une crise sanitaire sans précédent, a pu être en partie contrôlée par le développement rapide de vaccins efficaces contre le SARS-CoV-2. À ce jour, cinq vaccins sont autorisés en Europe, dix sont reconnus par l'Organisation mondiale de la santé et plus de 150 candidats vaccins sont en développement clinique. Ce contexte de maladie pandémique émergente a montré l'intérêt de la recherche et des données en vie réelle. Le développement des cinq vaccins utilisés en France a fait appel à différentes technologies, avec des résultats d'études de phase III convaincants. Les données en vie réelle permettent de conforter les connaissances sur ces vaccins en matière d'efficacité et de sécurité : elles ont montré l'importance d'une dose de rappel pour protéger des formes graves à variants Delta et Omicron ; elles ont permis de caractériser et mesurer l'incidence d'événements indésirables rares, comme la toxicité myocardique des vaccins à ARNm ou le risque de thromboses thrombopéniques pour les vaccins vectorisés. La recherche doit cependant se poursuivre, car de nombreuses questions restent en suspens.

Immunogenicity and reactogenicity of heterologous and homologous mRNA-1273 and BNT162b2 vaccination: A multicenter non-inferiority randomized trial.

Background: Although effective mRNA vaccines for SARS-CoV-2 infection have been deployed worldwide, their interchangeability could facilitate the scale-up of vaccination programs. The objective of the trial was to assess whether the immune response induced by a heterologous SARS-CoV-2 mRNA primo vaccination is non-inferior to that of a homologous mRNA vaccination. Methods: We conducted a multicenter, randomized, open-label trial in adults 18 years of age and older who received a first dose of SARS-CoV-2 mRNA vaccine. Participants were randomly assigned in a 1:1 ratio to receive a second dose of BNT162b2 or mRNA-1273, 28 to 49 days after the first dose. Randomization was stratified on the vaccine received at the first vaccination. The primary endpoint was the anti-spike IgG antibodies titer measured 28 days after the second vaccine dose. This study is registered with ClinicalTrials.gov, Trial, NCT04900467. Findings: Of the 414 randomized participants recruited from May 28 to July 2, 2021, 390 were included in the per protocol analysis: 94 participants in group 1 (BNT162b2/BNT162b2), 96 in group 2 (BNT162b2/mRNA-1273), 97 in group 3 (mRNA-1273/mRNA-1273), and 103 in group 4 (mRNA-1273/BNT162b2). The geometric mean titers ratios of anti-spike IgG antibodies for each heterologous regimen relative to the corresponding homologous regimen were 1·37 (two-sided 95% CI, 1·10 to 1·72) in the groups 1 and 2 and 0·67 (two-sided 95% CI, 0·55 to 0·82) in the groups 3 and 4. Levels of neutralizing antibodies to the main circulating SARS-Cov-2 viral strains were higher with the vaccine regimen containing mRNA-1273. Participants who received mRNA-1273 as a second dose experienced a higher rate of local adverse reactions and general symptoms than those who received BNT162b2 (p < 0·0001). Interpretation: The two SARS-CoV-2 mRNA vaccines could be used with flexibility for the second dose of COVID-19 primo vaccination. Tolerance remains good regardless of vaccine sequence although mRNA-1273 was more reactogenic. Funding: French Ministries of Solidarity and Health and Research. BNT162b2 was provided by Pfizer/BioNTech. mRNA-1273 was provided by Moderna.

Hypogonadism: a neglected comorbidity in young and middle-aged HIV-positive men on effective combination antiretroviral therapy.

OBJECTIVE: Male hypogonadism is poorly characterized in young-to-middle-aged people with HIV (PWH). We used a reliable free testosterone assay to assess the prevalence and predictive factors for male hypogonadism in PWH on effective combined antiretroviral therapy (cART). DESIGN: A French cross-sectional study from January 2013 to June 2016. METHODS: We included HIV-1-infected men aged between 18 and 50years with HIV loads of 50 RNA copies/ml or less, on effective cART for at least 6 months. Hypogonadism was defined, according to guidelines, as a mean calculated serum free testosterone concentration less than 70pg/ml (Vermeulen equation). Sociodemographic, anthropo-metric, bone-densitometry, hormonal, immunovirological, metabolic, and therapeutic parameters were collected. The IIEF-5, HAM-D, and AMS scales, respectively, assessed erectile function, depression, and quality of life. RESULTS: Overall, 240 patients were enrolled, 231 were analyzed. Low free testosterone concentrations (<70pg/ml) were recorded in 20 patients (8.7%), and were exclusively of secondary origin. In multivariable analysis, the risk factors predictive of male hypogonadism were age more than 43 years [adjusted odds ratio (aOR) 3.17, 95% confidence interval (95% CI) 1.02-9.86; P  = 0.04], total fat percentage more than 19% (aOR3.5, 95% CI 1.18-10.37; P  = 0.02), and treatment including efavirenz (aOR3.77, 95% CI 1.29-10.98; P  = 0.02). A nadir CD4+ T-cell count more than 200 cells / µl (aOR 0.22, 95% CI 0.07-0.65;P < 0.01) were protective. CONCLUSION: Male hypogonadism remains common in young-to-middle-aged PWH with stably suppressed viral replication. Treatment including efavirenz, being over 43 years old, and having a total body fat percentage greater than 19% could be used as criteria for identifying PWH at risk. Early screening for male hypogonadism might improve care by identifying patients requiring testosterone replacement.

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).

Quantifying preferences around vaccination against frequent, mild disease with risk for vulnerable persons: A discrete choice experiment among French hospital health care workers.

The individual determinants of vaccine acceptance among health workers (HCWs) have been described in the literature, but there is little evidence regarding the impact of vaccine characteristics and contextual factors (e.g., incentives, communication) on vaccination intentions. We developed a single profile discrete choice experiment (DCE) to assess the impact of seven attributes on stated vaccination intention against an unnamed disease, described as frequent with rapid clinical evolution and epidemic potential (similar to influenza or pertussis). Attributes evaluated vaccine characteristics (effectiveness, security profile), inter-individual aspects (epidemic risk, controversy, potential for indirect protection, vaccine coverage) and incentives (e.g., badge, hierarchical injunction). A total of 1214 French hospital-based HCWs, recruited through professional organizations, completed the online DCE questionnaire. The relative impact of each attribute was estimated using random effects logit models on the whole sample and among specific subgroups. Overall, 52% of included HCWs were vaccinated against influenza during 2017-18 and the average vaccination acceptance rate across all scenarios was 58%. Aside from the management stance, all attributes' levels had significant impact on vaccination decisions. Poor vaccine safety had the most detrimental impact on stated acceptance (OR 0.04 for the level controversy around vaccine safety). The most motivating factor was protection of family (OR 2.41) and contribution to disease control (OR 2.34). Other motivating factors included improved vaccine effectiveness (OR 2.22), high uptake among colleagues (OR 1.89) and epidemic risk declared by health authorities (OR 1.76). Social incentives (e.g., a badge I'm vaccinated) were dissuasive (OR 0.47). Compared to HCWs previously vaccinated against influenza, unvaccinated HCWs who were favorable to vaccination in general were most sensitive towards improved vaccine effectiveness. Our study suggests that vaccine safety considerations dominate vaccine decision-making among French HCWs, while adapted communication on indirect protection and social conformism can contribute to increase vaccination acceptance.

Reduced bone mineral density among HIV-infected, virologically controlled young men: prevalence and associated factors.

OBJECTIVE: Reduced bone mineral density (BMD) is a frequent comorbidity observed in people living with HIV (PLHIV). We aimed to determine the prevalence of reduced BMD and its associated factors among young PLHIV men, virologically controlled by combination antiretroviral therapy (cART). DESIGN: A bicentric cross-sectional study. METHODS: We selected men, aged less than 50 years, treated by cART, with HIV-RNA less than 50 copies/ml. BMDs of lumbar spine and hip were measured by dual-energy X-ray absorptiometry (DXA). A Z-score at either site between -1.0 and -2.0 or -2 or less defined osteopenia or osteoporosis, respectively. Linear and polytomous logistic regression analyses were performed. RESULTS: Among 230 men with a median age of 43 [interquartile range (IQR), 36-47] years, BMI of 23.5 (21.3-25.3) kg/m(2) and median duration of cART of 4.2 (1.7-8.5) years, reduced BMD was diagnosed in 48.3%. In multivariate analyses, BMI decrease was associated with a risk of osteopenia [odds ratio (OR) = 1.17, P < 0.01] and osteoporosis (OR = 1.24, P < 0.01). Oestradiol levels decrease were associated with osteoporosis (OR = 1.32, P < 0.05) and lower lean mass with osteopenia (OR = 2.98, P < 0.01). There was a protective effect of the duration of cART (OR = 0.87, P < 0.01), which was even greater when the duration was more than 3 years (OR = 0.44, P = 0.02). CONCLUSION: There is a high prevalence of reduced BMD among young men, despite persistent virological control of HIV-infection. This observation raises the question of extending current recommendations for BMD assessment to PLHIV aged < 50 years for whom BMD has stabilized after cART initiation, i.e. treated for more than three years.

Clinical characteristics, risk factors, and outcome of tuberculosis in kidney transplant recipients: A multicentric case-control study in a low-endemic area.

OBJECTIVES: Tuberculosis (TB) is a rare but life-threatening infection after solid organ transplant. The present study was undertaken to assess the clinical features, risk factors, and outcome of TB after kidney transplantation in a low-prevalence area. METHODS: We conducted a retrospective study, describing all kidney transplant recipients diagnosed with TB between 2005 and 2015 in 3 French centers. For each TB case, 2 controls without TB were identified and matched by center, age, transplant date, and birth country. Risk factors associated with TB were identified and survival estimated. RESULTS: Thirty-two cases and 64 control patients were included among 3974 transplantations. The prevalence of TB was 0.83%. Median age at the time of diagnosis was 64 years; 75% were born in a high TB prevalence country, but only 3 had received isoniazid prophylaxis for latent TB infection. TB occurred at a median of 22 months after transplantation. On diagnosis, 66% had disseminated infection. Median duration of treatment was 9 months. Immunosuppressive therapy changes were necessary in all patients because of drug-drug interactions. Among cases, 5 deaths occurred during follow-up (median duration: 41 months), one directly related with TB. Survival was significantly lower in transplant recipients with TB, as compared to controls (P = .001). No predictive factors of tuberculosis after transplantation were statistically significant in univariate analysis. CONCLUSION: TB in kidney transplant recipients is a rare and late event, but is associated with significantly reduced survival. Our results emphasize the need for systematic screening for LTBI, followed by IPT in high-risk patients.

Long-term outcome and safety of prolonged bedaquiline treatment for multidrug-resistant tuberculosis.

Bedaquiline, a recently approved drug for the treatment of multidrug-resistant tuberculosis (MDR-TB), is recommended for a duration of 24 weeks. There are scarce data on patients treated with this drug outside clinical trials.All MDR-TB patients who started treatment from January 1, 2011 to December 31, 2013 and received ≥30 days of bedaquiline were included in a multicentre observational cohort.Among 45 MDR-TB patients, 53% harboured isolates resistant to both fluoroquinolones and second-line injectables, and 38% harboured isolates resistant to one of these drug classes. Median bedaquiline treatment duration was 361 days and 33 patients (73%) received prolonged (>190 days) bedaquiline treatment. Overall, 36 patients (80%) had favourable outcome, five were lost to follow-up, three died, and one failed and acquired bedaquiline resistance. No cases of recurrence were reported. Severe and serious adverse events were recorded in 60% and 18% of patients, respectively. Values of Fridericia-corrected QT interval (QTcF) >500 ms were recorded in 11% of patients, but neither arrhythmias nor symptomatic cardiac side-effects occurred. Bedaquiline was discontinued in three patients following QTcF prolongation. No significant differences in outcomes or adverse events rates were observed between patients receiving standard and prolonged bedaquiline treatment.Bedaquiline-containing regimens achieved favourable outcomes in a large proportion of patients. Prolonged bedaquiline treatment was overall well tolerated in this cohort.

HIV and hypogonadism: a new challenge for young-aged and middle-aged men on effective antiretroviral therapy.

Male hypogonadism is poorly defined in people living with HIV. Using a reliable free-testosterone assay, we examined the prevalence and risk factors of male hypogonadism among people living with HIV on effective antiretroviral therapy. Male hypogonadism was found in 12.4% of patients, twice the rate reported in the general population of the same age. Two risk thresholds, namely 5 years of antiretroviral therapy and 19% total body fat, may help to identify patients at risk.