ANRS0001S COV-POPART : Réponse humorale des personnes vivant avec le VIH à 12 mois d'un schéma de vaccination Covid-19

Introduction Les réponses immunitaires humorales 12 mois après la primovaccination Covid-19 par des vaccins à ARNm chez des personnes vivant avec le VIH (PVVIH) ont été comparées à celles obtenues chez des participants contrôles. Matériels et méthodes Les réponses des PVVIH et les contrôles séronégatifs inclus dans la cohorte prospective multicentrique ANRS0001S COV-POPART ont été analysées. Le pourcentage (IC 95%) de répondeurs (anticorps IgG anti-Spike positifs) et les moyennes géométriques des titres (IC 95%) des anticorps IgG anti-Spike (BAU/mL) ont été évalués à 1 mois et 6 mois après la 2ème dose du schéma de primovaccination et à 12 mois uniquement chez ceux ayant reçu une dose de rappel. Les anticorps neutralisants spécifiques (test de neutralisation in vitro contre la souche originale, Delta et Omicron BA.1) ont été mesurés dans un échantillon de participants. Les participants ayant à l'inclusion ou au cours des visites de suivi des anticorps anti-nucléocapside (NCP) positifs ont été exclus. Les tests sérologiques (ELISA Euroimmun) et la séroneutralisation ont été évalués de manière standardisée et centralisée. Résultats Au total, 858 PVVIH et 1156 contrôles ont été inclus. Les PVVIH étaient plus âgées que les contrôles: 55,2 ans (49,6-60,6) vs 46,6 ans (36,3-56,6) et plus fréquemment des hommes (75,1% vs 48,9%). Parmi les PVVIH, 97,3% étaient sous traitement antirétroviral, 95,6% avaient une charge virale indétectable et 71,8% avaient un taux de CD4 supérieur à 500 cellules/mm3. Les participants avaient principalement reçu le BNT162b2 en primovaccination (93% des PVVIH vs 84% des témoins) et 53,1% avaient reçu une dose de rappel (57,2% des PVVIH (délai médian après la 2ème dose: 6,1 mois [5,9-6,7]) et 50,1% des contrôles (délai médian 6,0 mois [5,5-6,2])). Le pourcentage de répondeurs 1 mois après la 2ème dose était élevé mais plus faible chez les PVVIH que chez les contrôles ((98,7% [97,7;99,3] vs 99,9% [99,5;99,9], p=0,0001)). Les PVVIH présentaient des niveaux significativement plus faibles d'anticorps anti-Spike à 1 mois ((1188 [650;2067] vs 1506 [950;2507] BAU/mL, p<0,0001)) et 6 mois (149 [95;235] vs 194 [124;314] BAU/mL, p=<0,0001) mais des niveaux similaires à 12 mois (520 [269;1198] vs 427 [259;1087] BAU/mL, p=0,3387) chez ceux ayant reçu une dose de rappel. Les PVVIH présentaient des anticorps neutralisants significativement plus faibles contre les souches originales, Delta et Omicron BA.1 à 1, 6 et 12 mois après la primovaccination par rapport aux contrôles. La dose de rappel a augmenté de manière significative les titres d'anticorps neutralisants contre les souches originales et Delta et, dans une moindre mesure, contre Omicron. Conclusion Les taux de répondeurs à 1 et 6 mois d'un schéma de primo-vaccination Covid-19 à ARNm étaient élevés chez les PVVIH mais leurs titres d'anticorps totaux et neutralisants étaient inférieurs à ceux des contrôles. Une dose de rappel d'ARNm a augmenté les titres d'anticorps IgG anti-Spike à des niveaux similaires à ceux des contrôles, mais l'activité neutralisante, notamment contre Omicron, est restée plus faible. Liens d'intérêts déclarés P.L. Interventions ponctuelles: Astrazeneca, GSK, Moderna, MSD, Pfizer, Sanofi

12-MONTH HUMORAL RESPONSE AFTER mRNA COVID-19 VACCINATION IN PEOPLE LIVING WITH HIV

Background: We compared the 12-month post primary vaccination humoral immune response to mRNA COVID-19 vaccines in PLHIV and controls. Method(s): PLHIV and HIV-negative healthy controls included in the French national multi-center prospective COVID 19 vaccine cohort study ANRS0001S COV-POPART were analyzed. Percentage (95% CI) of responders (positive anti- Spike SARS-CoV-2 IgG antibodies) and geometric means titers (95% CI) of anti-Spike SARS-CoV-2 IgG antibodies (BAU/mL) were assessed at 1 month and 6 months (M) after the 2nd dose of the primary vaccination and at 12 months in those who received a booster dose. Specific neutralizing antibodies (nAbs) (in vitro neutralization assay against original, Delta and Omicron BA.1 strains) were estimated in a subset of participants. Serological tests (ELISA Euroimmun) and seroneutralization were performed centrally. Result(s): Overall, 858 PLHIV and 1156 controls were included. PLHIV were older than controls: 55.2 years, (49.6-60.6) vs 46.6 years (36.3-56.6) and more frequently male (75.1% vs 48.9%). Among PLHIV at inclusion, 97.3% were under antiretroviral therapy, 95.6% had an undetectable viral load and 71.8% had CD4 counts above 500 cells/mm3. Participants had namely received BNT162b2 as the primary vaccination (93% in PLWHIV vs 84% in controls) and 53.1% had received a booster dose (57.2% in PLHIV (median time after the 2nd dose: 6.1 M [5.9-6.7]) and 50.1% in controls (median time 6.0 M [5.5-6.2])). Percentage of responders after the 2nd dose was lower in PLHIV than controls ((98.7% [97.7;99.3] vs 99.9% [99.5;99.9], p=0.0001)). PLHIV had significantly lower levels of anti-Spike antibodies at 1 M ((1188 [650;2067] vs 1506 [950;2507] BAU/mL, p< 0.0001)) and 6 M (149 [95;235] vs 194 [124;314] BAU/mL, p=< 0.0001) but similar levels at 12 M (520 [269;1198] vs 427 [259;1087] BAU/mL, p=0.3387) (Figure A). PLHIV had significantly lower nAbs against original, Delta and Omicron BA.1 strains at 1, 6 and 12 M after primary vaccination compared to controls. The booster dose significantly increased the titers of nAbs against original and Delta strains and, to a lower extent, against Omicron (Figure B). Conclusion(s): PLHIV had high response rates to mRNA COVID-19 vaccines but lower titers of antibodies and nAbs at 1 and 6 M after primary vaccination than controls. One mRNA booster dose increased SARS-CoV-2 IgG antibodies titers to similar levels to controls but neutralizing activity especially against Omicron remained lower. (Figure Presented).

COVID-19 convalescent plasma for hospitalized COVID-19 patients not requiring assisted ventilation. A randomized controlled trial

Background: The efficacy of COVID-19 convalescent plasma (CCP) as passive immunotherapy in hospitalized COVID-19 patients remains uncertain. The transfusion of a large volume of high titre CCP in recently hospitalized patients may be beneficial. Aims: To evaluate the ability CCP transfusion to improve early outcome in patients with moderate to severe COVID-19 pneumonia. Methods: The CORIPLASM study was a multicentric, open-label, Bayesian randomized, adaptive, phase 2/3 clinical trial, nested within the CORIMUNO-19 cohort, to test a superiority hypothesis. Patients 18 years or older hospitalized with COVID-19 in 14 French centers, requiring at least 3 L/min of oxygen but without mechanic ventilation assistance and a WHO Clinical progression scale [CPS, 1 to 10] of 4 or 5 were enrolled. Patients were randomly assigned (1:1) via a web-based system, according to a randomization list stratified on center, to receive usual care plus 4 units of CCP (2 units/day over 2 days) (CCP group) or usual care alone (usual care group) on day 1 and 2 post-enrollment. Primary outcomes were the proportion of patients withWHO CPS greater than 5 on the 10-point scale on day 4 and survival without ventilation or additional immunomodulatory treatment by day 14. Results: One hundred and twenty patients were recruited from April 16th 2020 and April 21th 2021 and randomly assigned to the CCP group (n = 60) and to the usual care group (n = 60) and followed up for 28 days. Immunosuppressed patients comprised 43% (26/60) and 50% (30/60) of patients in the CCP and usual care groups, respectively. Median time from symptoms onset to randomization (days) was 7.0 [interquartile range (IQR): 5.0-9.0] in the CCP group and 7.0 [IQR: 4.0- 8.5] in the usual care group. Thirteen (22%) patients in the CCP group had a WHO CPS greater than 5 at day 4 versus 8 (13%) in the usual care group (adjusted odds ratio (OR): 1.88 [95% CI: 0.71 to 5.24]. By day 14, 19 (31.6%) patients in the CCP and 20 (33.3%) patients in the usual care group had needed ventilation, additional immunomodulatory treatment or had died (adjusted HR: 1.04 [95% CI: 0.55 to 1.97]). The cumulative incidence of death was 3 (5%) in the CCP group and 8 (13%) in the usual care group at day 14 (adjusted HR: 0.40 [95% CI: 0.10 to 1.53]), and 7 (12%) in the CCP group and 12 (20%) in the usual care group at day 28 (adjusted HR: 0.51 [95% CI: 0.20 to 1.32]). Frequency of severe adverse events did not differ significantly between both treatment arms. Subgroup analysis revealed that mortality at day 28 was mostly observed in the immunosuppressed patients (15/56 vs. 4/64) and that CCP was associated with less mortality in these patients (4/26 in the CCP group vs. 11/30 in the usual care group)(HR: 0.36 [95% CI: 0.14-0.97]). Summary/Conclusions: CCP treatment did not improve early outcome in patients with moderate-to-severe COVID-19 pneumonia. CCP-associated early respiratory worsening as well as CCP-associated reduced D14 and D28 mortality were observed, while not reaching statistical significance. CCP treatment was associated with reduced D28 mortality in immunosuppressed patients.

VITAMIN C NEPHROTOXICITY IN A COVID-19 PATIENT: A CASE REPORT

BACKGROUND AND AIMS: During the time of the COVID-19 pandemic, multiple treatment options have been investigated, even though their efficacy and secondary effects remain insufficiently known. We report the case of a vitamin C induced oxalate nephropathy in a COVID-19 patient with preexisting chronic kidney disease (CKD) resulting in irreversible acute renal failure. Vitamin C, also known as ascorbic acid, has been used as an anti-inflammatory therapy for COVID-19, but review of the literature shows similar cases of acute kidney injury (AKI), raising concern. METHOD: We report the case of a 73-year-old Caucasian woman admitted for hyperthermia and digestive disorders. She had recently started a first-line chemotherapy for multiple myeloma with partial response. She also displayed preexisting stage 4 CKD (eGFR 18.50 mL/min/1.73 m2 using CKD-EPI) of unknown aetiology. She was tested positive for SARS-CoV2 by nasopharyngeal swab and soon transferred to the intensive care unit. She received intravenous corticosteroids using dexamethasone 6 g/24 h for 10 days and a piperacillin + tazobactam probabilistic antibiotherapy. She also received high doses (15 g/24 h) of vitamin C for three consecutive days. No monoclonal antibodies were prescribed due to a previous vaccination with a positive serology upon admission. Although the patient recovered from respiratory tract infection, her kidney function progressively deteriorated with serum creatinine levels rising up to 8.06 g/dL, leading to her admission in our nephrology department. The patient was initially treated with high doses of diuretics for anasarca and an abdominal CT excluded urinary tract obstruction with normal kidney size and aspect. Urinary analysis showed protein to creatinine (p/c) ratio of 1348 g/g, and presence of urinary light chains. Her monoclonal spike was measured at 2.3 g/L and her kappa/lambda fraction was 1.74. Intermittent haemodialysis was initiated, and a kidney biopsy was performed. RESULTS: Histology revealed hundreds of intratubular calcium oxalate crystals, with severe and diffuse acute tubular necrosis and interstitial edema. There was no amyloidosis, no sign of active glomerular disease and no interstitial fibrosis. Immunofluorescence (IgA, IgG, IgM, C1Q, C3, kappa and lambda) was negative. We concluded to oxalate nephropathy. After a 2-month follow-up, the patient remains dialysis dependent. Vitamin C is a precursor of oxalate and has been shown to cause secondary oxaluria, particularly with high-dose regimens in patients with altered renal function. Given the histological findings evocative of acute oxalate nephropathy, the accountability of high doses of vitamin C should be considered. No other cause of hyperoxaluria was identified in our patient beside broad spectrum antibiotic use, which could decrease intestinal bacterial oxalate degradation. In particular, there was no malabsorption The limitation of our report is the unknown cause of preexisting CKD;therefore, we cannot rule out preexisting hyperoxaluria. Also, no dosage of serum vitamin C and oxalate levels were performed during follow-up. Finally, our patient had other possible causes AKI, such as recent SARS-CoV2 infection, or linked to multiple myeloma, but these were considered unlikely given the proper haematological response to treatment and non-evocative biopsy. The rationale for vitamin C use in COVID-19 is based on in vitro studies showing its antioxidant, anti-inflammatory, anticoagulant and immune modulatory properties. There lack large clinical studies, and the literature shows conflicting results. Multiple cases of acute oxalate nephropathy were described. CONCLUSION: Vitamin C is an anti-inflammatory treatment used in COVID-19 that can lead to secondary hyperoxaluria with significant and irreversible AKI. Due to the severity of AKI in patients with preexisting CKD, we believe renal function should be considered before using high doses of vitamin C. Larger controlled trials are needed both to establish the clinical benefit of vitamin C and further describe its potential ephrotoxicity.

Étude des déterminants des réponses immunitaires humorale et cellulaire contre le SARS-CoV-2 et ses variants chez des patients atteints de lupus systémique

La vaccination s'est imposée comme le principal atout de la lutte contre la pandémie COVID. Pourtant, les patients atteints de maladies auto-immunes ont été exclus des principaux essais thérapeutiques ayant permis de valider la tolérance et l'efficacité de la vaccination contre le SARS-CoV2. Nous avons évalué l'activité de la maladie et les facteurs associés à la réponse vaccinale, au décours d'une vaccination par le vaccin BNT162b2, chez des patients atteints de lupus systémique (LS). Dans cette étude prospective, conduite entre janvier et mai 2021, l'activité clinique et biologique de 126 patients atteints de LS et les éventuels effets secondaires étaient recueillis lors de 4 consultations réalisées lors des 2 injections du vaccin espacées de 3 ou 4 semaines, et à 15 jours de chacune des injections. La réponse humorale, critère principal de jugement, était mesurée 15 jours après l'injection de rappel. Elle était déterminée par la mesure de la concentration en anticorps spécifiques dirigés contre la protéine spike, et par l'étude de la capacité de neutralisation de différents variants viraux par le sérum des patients vaccinés. Nous avons également étudié la réponse cellulaire T par des tests Interferon gamma release assay (IGRA) spécifiques du SARS-CoV2. Les résultats de l'analyse multivariée étaient exprimés par des coefficients bêta, dont la valeur mesure la taille de l'effet du facteur considéré sur la réponse vaccinale, et le degré de significativité p associé indique si cette valeur est significativement différente de 0. Parmi les 126 patients inclus, 114 (90,5 %) étaient des femmes, d'âge médian 46,6 ans (IQR 33,9–58,7). Le score SLEDAI-2 K était supérieur à 5 chez 24 (19,0 %) patients et 20 (16,7 %) patients présentaient au moins un score BILAG à B. Soixante-dix (55,6 %) patients recevaient des corticoïdes, 106 (84,1 %) de l'hydroxychloroquine et 54 (42,9 %) étaient traités par un autre immunosuppresseur, principalement le mycophénolate mofétil, le méthotrexate ou l'azathioprine. La tolérance du vaccin BNT162b2 était bonne, sans variation significative des scores BILAG et SLEDAI-2 K au décours de la vaccination, ni observation d'effets secondaires graves. La régression linéaire multivariée a permis de montrer que le mycophénolate mofétil et le méthotrexate étaient indépendamment associés à une moindre réponse humorale (Bêta = −78, p = 0,007;Bêta = −122, p < 0,001 respectivement). À l'inverse, la concentration d'immunoglobulines G (IgG) et la proportion de lymphocytes B naïfs le jour de la première injection étaient significativement associés à une concentration supérieure en anticorps anti spike (Bêta = 2;p = 0,018;Bêta = 2,5;p = 0,003 respectivement). L'hydroxychloroquine (n = 106), les corticoïdes (n = 70), le belimumab (n = 15) ne diminuaient pas significativement la réponse vaccinale. Les réponses humorale et cellulaire T étaient significativement corrélées (r = 0,46;p = 0,003). L'activité neutralisante étaient diminuée dans le cas de certains variants porteurs de la mutation E484 K mais restait détectable chez la majorité des patients (entre 76,2 et 60,3 % de sujets neutralisant les variants contre 81,7 % pour la souche initiale). Contrairement aux critères démographiques et à l'activité de la maladie lupique, le mycophénolate mofétil, le méthotrexate et le déficit lymphocytes B naïfs ou en IgG semblent indépendamment associés à une moindre réponse humorale à la vaccination par BNT162b2, devant faire discuter dans ces cas une adaptation du schéma vaccinal, par exemple en proposant une troisième injection. (French) [ FROM AUTHOR] Copyright of Revue de Médecine Interne is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

How does COVID-19 affect electoral participation? Evidence from the French municipal elections

This article investigates the effects of the COVID-19 outbreak on electoral participation. We study the French municipal elections that took place at the very beginning of the ongoing pandemic and held in over 9,000 municipalities on March 15, 2020. In addition to the simple note that turnout rates decreased to a historically low level, we establish a robust relationship between the depressed turnout rate and the disease. Using various estimation strategies and employing a large number of potential confounding factors, we find that the participation rate decreases with city proximity to COVID-19 clusters. Furthermore, the proximity has conditioned impacts according to the proportion of elderly -who are the most threatened- within the city. Cities with higher population density, where the risk of infection is higher, and cities where only one list ran at the election, which dramatically reduces competitiveness, experienced differentiated effects of distance.

Exposure-related, global alterations in innate and adaptive immunity; a consideration for re-use of non-human primates in research.

BACKGROUND: Non-human primates (NHPs) play an important role in biomedical research, where they are often being re-used in multiple research studies over the course of their life-time. Researchers employ various study-specific screening criteria to reduce potential variables associated with subsequent re-use of NHPs. However, criteria set for NHP re-assignments largely neglect the impact of previous exposures on overall biology. Since the immune system is a key determinant of overall biological outcome, an altered biological state could be predicted by monitoring global changes in the immune profile. We postulate that every different exposure or a condition can generate a unique global immune profile in NHPs. METHODS: Changes in the global immune profile were evaluated in three different groups of rhesus macaques previously enrolled in dengue or malaria vaccine studies over six months after their last exposure. Naïve animals served as the baseline. Fresh blood samples were stained with various immune cell surface markers and analyzed by multi-color flow-cytometry to study immune cell dynamics in the peripheral blood. Serum cytokine profile in the pre-exposed animals were analyzed by mesoscale assay using a customized U-PLEX NHP biomarker panel of 12 cytokines/chemokines. RESULTS: Pre-exposed macaques showed altered dynamics in circulating cytokines and certain innate and adaptive immune cell subsets such as monocytes, HLA-DR+NKT cells, B cells and T cells. Some of these changes were transient, while some lasted for more than six months. Each group seemed to develop a global immune profile unique to their particular exposure. CONCLUSION: Our data strongly suggest that re-used NHPs should be evaluated for long-term, overall immunological changes and randomly assigned to new studies to avoid study bias.

Test for Covid-19 seasonality and the risk of second waves.

Ten months into the Covid-19 pandemic it remains unclear whether transmission of SARS-CoV-2 is affected by climate factors. Using a dynamic epidemiological model with Covid-19 climate sensitivity in the likely range, we demonstrate why attempts to detect a climate signal in Covid-19 have thus far been inconclusive. Then we formulate a novel methodology based on susceptible-infected time trajectories that can be used to test for seasonal climate sensitivity in observed Covid-19 infection data. We show that if the disease does have a substantial seasonal dependence, and herd immunity is not established during the first peak season of the outbreak (or a vaccine does not become available), there is likely to be a seasonality-sensitive second wave of infections about one year after the initial outbreak. In regions where non-pharmaceutical control has contained the disease in the first year of outbreak and thus kept a large portion of the population susceptible, the second wave may be substantially larger in amplitude than the first if control measures are relaxed. This is simply because it develops under the favorable conditions of a full autumn to winter period and from a larger pool of infected individuals.

Winter Is Coming: A Southern Hemisphere Perspective of the Environmental Drivers of SARS-CoV-2 and the Potential Seasonality of COVID-19.

SARS-CoV-2 virus infections in humans were first reported in December 2019, the boreal winter. The resulting COVID-19 pandemic was declared by the WHO in March 2020. By July 2020, COVID-19 was present in 213 countries and territories, with over 12 million confirmed cases and over half a million attributed deaths. Knowledge of other viral respiratory diseases suggests that the transmission of SARS-CoV-2 could be modulated by seasonally varying environmental factors such as temperature and humidity. Many studies on the environmental sensitivity of COVID-19 are appearing online, and some have been published in peer-reviewed journals. Initially, these studies raised the hypothesis that climatic conditions would subdue the viral transmission rate in places entering the boreal summer, and that southern hemisphere countries would experience enhanced disease spread. For the latter, the COVID-19 peak would coincide with the peak of the influenza season, increasing misdiagnosis and placing an additional burden on health systems. In this review, we assess the evidence that environmental drivers are a significant factor in the trajectory of the COVID-19 pandemic, globally and regionally. We critically assessed 42 peer-reviewed and 80 preprint publications that met qualifying criteria. Since the disease has been prevalent for only half a year in the northern, and one-quarter of a year in the southern hemisphere, datasets capturing a full seasonal cycle in one locality are not yet available. Analyses based on space-for-time substitutions, i.e., using data from climatically distinct locations as a surrogate for seasonal progression, have been inconclusive. The reported studies present a strong northern bias. Socio-economic conditions peculiar to the 'Global South' have been omitted as confounding variables, thereby weakening evidence of environmental signals. We explore why research to date has failed to show convincing evidence for environmental modulation of COVID-19, and discuss directions for future research. We conclude that the evidence thus far suggests a weak modulation effect, currently overwhelmed by the scale and rate of the spread of COVID-19. Seasonally modulated transmission, if it exists, will be more evident in 2021 and subsequent years.

Test for Covid-19 seasonality and the risk of second waves (preprint)

Eight months into the Covid-19 pandemic it remains unclear whether transmission of SARS-CoV-2 is affected by climate factors. Using a dynamic epidemiological model with Covid-19 climate sensitivity in the likely range, we demonstrate why attempts to detect a climate signal in Covid-19 have thus far been inconclusive. Then we formulate a novel methodology and related criteria that can be used to test for seasonal climate sensitivity in observed Covid-19 infection data. We show that if the disease does have a substantial seasonal dependence, and herd immunity is not established during the first peak season of the outbreak (or a vaccine does not become available), there is likely to be a seasonality-sensitive second wave of infections about one year after the initial outbreak. In regions where non-pharmaceutical control has contained the disease in the first year of outbreak and thus kept a large portion of the population susceptible, the second wave may be substantially larger in amplitude than the first if control measures are relaxed. This is simply because it develops under the favorable conditions of a full autumn to winter period and from a larger pool of infected individuals.