Altération de la réponse vaccinale contre la COVID-19 dans l'infection à VIH avancée

Introduction Les personnes vivant avec le VIH(PVVIH) ne sont pas considérées comme étant à risque de forme grave de Covid-19 toutefois leur réponse vaccinale notamment chez les patients avec taux de CD4 bas reste mal évaluée et les recommandations vaccinale chez ces patients restent les mêmes que celles de la population générale. L'objectif de cette étude était d'évaluer la réponse vaccinale chez les PVVIH et de juger de la nécessité de réalisation d'une dose supplémentaire de vaccin selon leur taux de CD4. Matériels et méthodes Il s'agit d'une étude monocentrique rétrospective. Nous avons recueilli des sérologies post-vaccination contre le SARS-COV-2 pour les PVVIH ayant terminé un schéma vaccinal avec deux doses réalisées entre le 5 mars 2021 et 17 septembre 2021. La sérologie post-vaccinale a été réalisée entre 8 et 150 jours après la seconde dose de vaccin. Ont été exclus : mineurs, greffés, PVVIH recevant une chimiothérapie ou un agent immunosuppresseur autre, PVVIH sans taux de CD4 récent, PVVIH avec antécédent d'infection par le SARS-COV-2. Les anticorps anti-Spike ont été quantifiés dans des échantillons de sérum et de plasma à l'aide du kit Architect SARS-COV-2 IgG Quant II (Abbott, North Chicago, Illinois, USA) avec une plateforme automatisée i1000SR. Facteur de normalisation BAU 0,142 : seuil de positivité 50 UA/ml = 7,1 BAU/ml ; seuil de 260 BAU/mL = 1831 UA/ml. Des comparaisons statistiques par Kruskall – Wallis, Mann – Whitney et des tests du chi-2 ont été effectués à l'aide du logiciel GraphPad6. Le seuil de significativité retenu était p = 0.05. Un comité local d'éthique a approuvé la réalisation de cette étude. Résultats Nous avons collecté les données de 105 PVVIH que nous avons divisées en trois groupes en fonction de leur taux de CD4 : CD4<200/µl (n=18), 200< CD4<500/µL (n=36) et CD4 > 500/µL (n=51). L'âge médian des patients était de 54 ans (intervalle interquartile IQR [46–60]) et 35,2 % étaient des femmes. Les patients avaient reçu deux doses de BNT162b2(75 %), mRNA-1273(8,5 %) ou ChAdOx1 nCoV-19 (16.5 %). Au moins un facteur de risque de développer une forme sévère de pneumopathie à SARS-COV-2(hypertension artérielle, diabète, IMC > 30 kg/m2 ou maladie respiratoire chronique) étaient présents chez 45,7 % des patients. 96 patients (91 %) recevaient un traitement anti-rétroviral au moment de leur vaccination. Le délai entre la seconde dose de vaccin et la réalisation de la sérologie ne différait pas significativement entre les trois groupes (p=0,14) : 51,5 jours [14.25–76] dans le groupe CD4<200/µL, 77,5 jours [32.5–97] dans le groupe 200< CD4<500/µL et 79 jours [30–103] dans le groupe CD4 > 500/ µL. Dans le groupe CD4 > 500/µL, le titre médian d'anticorps post-vaccinaux anti-SARS-COV2 était de 623,8 BAU/mL [262.2–2288] et de 334,3 BAU/mL [69.9–933.9] (p=0,003) dans le groupe CD4<500/µL. En comparant les trois groupes, le taux d'anticorps était significativement plus élevé dans le groupe CD4 > 500/µL par rapport au groupe 200< CD4<500/µL (396.5 BAU/ml [105.8–1174], p= 0,046) ; le taux d'anticorps était encore plus bas dans le groupe CD4<200/µL (247.9 BAU/ml [5.88–434.9], p=0.0017). Le taux d'anticorps protecteur établi par la HAS (260 BAU/mL) était atteint chez 44,4 % des patients avec CD4<200/µL et chez 55,6 % des patients avec 200< CD4<500/µL contre 76,5 % des patients avec CD4 > 500/µL (p= 0,01 et p=0,04 respectivement). Toutes les PVVIH avec CD4 > 500/µL avaient une sérologie post-vaccinale positive (seuil de positivité de 7,1 BAU/mL) alors que 6 des 54 patients avec CD4<500/µL (11 %, p<0,001) avaient une sérologie négative : 4 étaient dans le groupe CD4<200/µL, 2 dans le groupe 200< CD4<500/µL ; 5/6 avaient reçu le vaccin BNT162b2. Conclusion En conclusion, nous avons observé de faibles taux d'anticorps après deux doses de vaccins contre le COVID-19 chez les PVVIH avec un taux de CD4<500/µl. Les taux d'anticorps étaient les plus faibles dans le groupe de patients avec CD4<200/µL. Ces résultats devraient inciter à une attention particulière au sein de cette population qui n'est pas considérée comme « à risque » dans les politiques de santé actuelles et qui devrait donc bénéficier de stratégies vaccinales intensives impliquant une sérologie post-vaccinale et/ou un accès accéléré à des doses de vaccin supplémentaires. Une seconde partie d'étude pour analyser la réponse après une 3ème dose des patients n'ayant pas un taux d'anticorps protecteurs après deux doses est en cours, les résultats devraient être disponibles dans les mois à venir. Aucun lien d'intérêt

Humoral response to mrna vaccines BNT162B2 and mrna-1273 covid-19 in chronic lymphocytic leukemia patients

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for an ongoing global pandemic. Phase III trials have demonstrated excellent efficacies of mRNA vaccines against SARS-CoV-2 in large population studies (Baden LR, NEJM, 2021;Polack FP, NEJM, 2020). Immunosuppressed individuals such as chronic lymphocytic leukemia (CLL) patients are at risk for a suboptimal response to 2 vaccine doses (Herishanu Y, Blood, 2021). The French National Authority for Health recommends the use of a third dose in immunosuppressed patients. However, seroconversion rate after the triple-dose vaccine is not yet known. The objective of our study was to evaluate SARS-CoV-2 antibody responses after the first, second and third doses of the BNT162b2 and mRNA-1273 vaccines. Data were collected from 17 French Innovative Leukemia Organization (FILO) investigating centers and the French CLL patients' association (SILLC). SARS-CoV-2 IgG anti-Spike levels were measured at 4-6 weeks after each vaccine dose. A total of 530 patients and 14 controls were included in the study. Vaccine response was evaluated post-dose 1 for 158 CLL patients, post-dose 2, for 506 patients and post-dose 3 for 66 patients. Peripheral blood lymphocyte subsets were studied post-dose 2 by flow cytometry in 80 CLL patients and 14 controls. The median age of the patients was 71 years (range 37-93), 218 (40%) were treatment-naïve (TN), 136 (26%) had a prior CLL treatment and 176 (34%) were on therapy. Post-dose 1, the global response rate was 27% (43/158). TN patients had a response rate of 34% (23/67), similar to those who had a prior CLL treatment (33%,12/36), and higher compared to on-therapy patients (15%, 8/55, P=0.02). Post-dose 2, the global response rate was 52% (265/506). TN patients had the highest response rate of 72% (151/210) compared to previously treated patients, mostly by immunochemotherapy (60%, 78/130, P=0.02) and on-therapy patients (22%, 36/166, P<0.001) (Figure 1A). Among the 166 on-therapy patients, mostly receiving targeted agents, those receiving venetoclax monotherapy achieved a significantly higher response rate (52%, 12/23) than those treated with BTK inhibitors (BTKi) ibrutinib or acalabrutinib (22%, 23/104, P<0.001). Patients treated with venetoclax+anti-CD20 monoclonal antibodies (n=19) or venetoclax+BTKi (n=6) were all seronegative after the second dose of vaccine (Figure 1B). In multivariate analysis, the variables found to be significantly associated with seroconversion were age >65 years (OR 0.55, 95% CI 0.33-0.92, P=0.02), ongoing CLL treatment (OR 0.13, 95% CI 0.07-0.23, P<0.001) and gamma-globulins ≤6g/L (OR 0.41, 95% CI 0.19-0.88, P=0.03). Flow cytometry results suggest a differential balance of the T CD4+ cell subpopulations in Binet stage A and in patients on targeted therapy compared to healthy controls. Post-dose 2 seronegative patients were proposed a third dose and to date, 66 have been tested for the antibody response 4-6 weeks post-dose 3. The post-dose 3 response rate was 42% (28/66). TN patients and previously treated patients had a significantly higher response rate (57%, 16/28) compared to on-therapy patients (32%, 12/38, P=0.03). We further analyzed patients tested post-dose 2 with the Abbott Architect SARS-CoV-2 IgG anti-Spike assay (n=24). Those who achieved seroconversion after the third dose (n=10) had significantly higher titers post-dose 2 (median 12, IQR 3.0-40.8) compared to those who remained seronegative (n=14) (median 2.2, IQR 0.5-5.1, p<0.01), although both median values are considered below the threshold by the manufacturer. An additional cohort of 40 CLL patients who presented a SARS-CoV-2 infection prior to vaccination participated to the study and was analyzed independently. All patients achieved seroconversion after infection and a single dose of vaccine, even though 30% (n=12) had an ongoing CLL treatment. In conclusion, double-dose mRNA vaccination generated a humoral response in 52% of our CLL cohort and a third dose induced seroconversion in 42% of the patients who remained seronegat ve after the second dose. The major independent predictor of negative antibody response was ongoing treatment with BTKi. The strongest boost to immune response against the virus seems to be SARS CoV-2 infection, as a substantial increase in anti-Spike antibodies was observed in all CLL patients with prior infection, after a single dose vaccination.

Humoral response to mRNA vaccines BNT162b2 and mRNA-1273 COVID-19 in chronic lymphocytic leukemia patients

Chronic lymphocytic leukemia (CLL) patients experience both humoral and cellular immune deficiency, with a reduced number of normal B lymphocytes, and hypogammaglobulinemia. Previous large studies on vaccination efficacy are scarce but it is well-established that CLL patients have a poorer response than normal subjects to vaccination and are at increased risk of infection. Efficacy of anti-SARS-Cov-2 vaccination in CLL has been recently published by the Israeli group (Herishanu, 2021) showing that among hematological malignancies, patients who presented CLL disease are the least responsive to vaccination. We have collected the results of a large cohort of 502 French patients after vaccination by either BNT162b2 or mRNA-1273 mRNA vaccine. Patients received 2 doses at a 4-week interval. For those who received the 3rd dose, the interval was usually longer (between 6 and 8 weeks after 2nd dose). The median time to sample collection for serology was 4 weeks, and IgG anti-SARS-CoV-2 Spike antibody levels were measured by commercially available tests. We evaluated patients after the 1st and 2nd doses and collected matched samples whenever possible. Patients who had a previous COVID-19 infection were analyzed separately. We evaluated 176 patients after the 1st dose and the global seroconversion rate was only 31% (55/176). We evaluated 455 patients after the 2nd dose, and the global rate of seroconversion was 54% (246/455). Matched samples after both first and second doses were available for 118 patients. In this cohort, among the 87 patients who were seronegative after the first dose, 42 patients (48%) became positive after the second dose. Most patients who remained seronegative after two doses, received the third dose. The administration of the third dose program started recently, therefore, to date, we have the results for 31 patients only. Among these patients, 18 remained negative after this 3rd dose, while 13 (42%) seroconverted. Therefore, if we extrapolate these data, it is expected that approximately only 70-75% of CLL patients will be protected by vaccination (either by two or three doses) at the end of the vaccination program. On the other hand, 40 patients who received at least one dose of vaccine had presented a COVID-19 infection before vaccination. In this group of patients, the humoral response was evaluated in 29 patients. All of them except one, presented very high anti-Spike antibodies titer, even after one dose, and the only patient who remained seronegative after vaccination was on prolonged anti-CD20 therapy for autoimmune thrombocytopenia. We also collected cases of COVID-19 infection post-vaccination. Nineteen patients presented a COVID-19 infection after vaccination, 11/19 presented the infection after the first dose, and 8/19 after the second dose. Among those eight patients, five presented the first symptoms within the first 2 weeks after the second dose and had a more severe COVID-19 infection while the three patients with a later onset of symptoms (4-6 weeks after vaccination) had very mild symptoms. All patients tested had no antibody response before COVID infection but had highly positive anti-Spike titers after infection. Currently, the COVID- 19 pandemic has settled down and it is difficult to know if the absence of post-vaccination COVID-19 infection is related to the slowing of the pandemic or if CLL patients are protected by cell-mediated immunity, even in the absence of antibody response. In conclusion, double-dose mRNA vaccination generated a humoral response in 54% of our CLL cohort, and a third dose induced seroconversion in 40% of the patients who were seronegative after the second dose. However, the strongest boost to the immune response against the virus seems to be the COVID-19 infection, as a substantial increase in anti-Spike antibodies was observed in all CLL patients after infection, even if they were negative post-vaccination.

Strengths and limitations of a policy for handling and following up suspected pediatric cases of SARS-CoV-2 infection.

To compensate for the poor initial knowledge about pediatric SARS-CoV-2 infections and the limited access to non-urgent medical care during lockdown, a local telephone follow-up program was set up to remotely monitor children with confirmed or suspected SARS-CoV-2 infection at the pediatric emergency department of a French tertiary hospital. We retrospectively assessed 131 children. A total of 488 phone call attempts resulted in 293 (60%) teleconsultations. This telephone follow-up program was simple and appeared necessary in the first stage of the pandemic with an emergent pathogen. However, it was time-consuming and should be improved for further use.

SARS-CoV-2 was already spreading in France in late December 2019.

The COVID-19 epidemic is believed to have started in late January 2020 in France. Here we report a case of a patient hospitalised in December 2019 in an intensive care unit in a hospital in the north of Paris for haemoptysis with no aetiological diagnosis. RT-PCR was performed retrospectively on the stored respiratory sample and confirmed the diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Based on this result, it appears that the COVID-19 epidemic started much earlier in France.