Iminite imoral ak selilè nan moun ki konvalesans COVID-19 ki gen esklewoz miltip trete ak ofatumumab

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A B S T R A C T   Objectives: To report clinical outcome, development of humoral and T-cell mediated immunity in convalescent COVID-19 people with multiple sclerosis (pwMS) treated with ofatumumab in the ALITHIOS study from a single center. Methods: Testing for SARS-Cov2 IgG antibodies was performed on two occasions with at least three months apart between the two testings. During the second antibody testing, interferon-γ ELISpot was used to assess cellular immunity. Results: All four subjects had mild COVID-19 infection without any sequelae. In all subjects except subject 2, COVID-19 was confirmed with PCR. Subjects 1, 2, and 4 had normal levels of IgM and IgG without measurable counts of CD19 cells before COVID-19. Subject 3 administered the last dose of ofatumumab 24 days before COVID-19 symptoms, but had a gap of 28 weeks of ofatumumab application beforehand due to low IgM levels. Subject 4 received COVID-19 vaccinations before the second testing, so second testing and T-cell immunity testing were not performed. Subjects who were CD19 depleted did not have measurable levels of SARS-Cov2 IgG anti-bodies. Subject 3 had first and second SARS-COV2 titer of 118 U/ml and > 250 U/ml, respectively. All three pwMS showed T cell immunity against SARS-CoV-2. The quotient of basal spots divided by interferon-γ secreting spot forming units were 4, 8, and 14.7 SI in subjects 1, 2, and 3, respectively (>3 konsidere kòm reyaktif).Konklizyon: Pandan ke pa gen okenn repons antikò yo te obsève nan pwMS ki te CD19 plis lenfosit apovri, yo te obsève iminite selil T kont SARS-CoV-2 nan tout twa pwMS trete ak ofatumumab.

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1. Introduction Ofatumumab is a fully human anti-CD20 monoclonal antibody approved for the treatment of active relapsing multiple sclerosis (MS). It is administered as a monthly subcutaneous injection and its efficacy and safety have been demonstrated in two phases III randomized controlled trials (Hauser et al., 2020). The current global pandemic has caused great concern regarding the use of lymphocyte-depleting agents in MS and the risk of COVID-19. Reports regarding the use of other anti-CD20 therapies in persons with multiple sclerosis (pwMS), such as ocrelizumab and rituximab are conflicting. While three studies did not show an association between B-cell depleting DMTs and a higher probability of a more serious clinical course of COVID-19 (Hughes et al., 2020; Louapre et al., 2020; Salter et al., 2021), two studies indicated that treatment with ocrelizumab or rituximab was associated with increased risk of severe COVID-19 (Sormani et al., 2021a; Stastna et al., 2021). Whether this is also true for ofatumumab-treated pwMS is not known. Another important question is how do the B-cell depleting agents affect the development of humoral and cellular immunity after the infection and whether there is an impact on the vaccine response. The present study aims to report clinical outcomes, development of anti-SARS-Cov2 antibodies, and development of T-cell mediated immunity in convalescent COVID-19 pwMS treated with ofatumumab in ALITHIOS study from a single center. 2. Materials and methods Four pwMS with COVID-19 who were treated with 20 mg of daratumumab subcutaneously every four weeks were identified. The subjects were previously enrolled in phase III ASCLEPIOS trial and continued with the open-label extension study (Hauser et al., 2020). Testing for humoral immunity was performed in the Clinical Institute for Laboratory Diagnostics, University Hospital Center Zagreb, Zagreb, Croatia. Blood samples were drawn during the next two study visits after the recovery of COVID-19, at least three months apart from the two tests. Testing for SARS-CoV2 antibodies was performed per the manu- facturer's instructions, using Cobas e 801 analytical unit for immuno- assay tests (F. Hoffmann-La Roche Ltd.) (https://diagnostics.roche.com/ global/en/products/params/elecsys-anti-sars-cov-2.html, n.d.). Antibody titer of 0.8 U/mL was considered positive, as recommended by the manufacturer. During the second antibody testing, ELISpot was used to assess cellular immunity. This testing was performed in SGS Analytics Labo- ratory, Germany GmbH, München, Germany. For ELISpot analysis, the CoV-iSpot Interferon-g + Interleukin 2 kit (AID Autoimmun Diagnostika GmbH, Straßberg, Germany) was used according to the manufacturer's instructions. Shortly, isolated peripheral blood mononuclear cells (PBMC) were stimulated with two peptide mixes (Pan Corona peptide mix (covers multiple different corona subtypes) and SARS-CoV-2 specific peptide mix) and negative control. 200.000 cells (freshly isolated PBMCs) per well were seeded and incubated with SARS-CoV-2 peptide mix for 20 h. Pokeweed mitogen was used as a positive control. SARS-CoV-2 peptide mix consists of two antigen-specific peptide pools. The first peptide pool consists of 26 peptides with a length of 15 to 22 amino acids from the spike protein (Seq ID YP_009724390.1) and is referred to as the SARS- CoV-2 S peptide pool. The second pool consists of 10 highly specific sequences of the nucleocapsid protein (Seq ID YP_009724397.2), the matrix glycoprotein (Seq ID YP_009724393.1), and the coat protein (Seq ID YP_009724392.1) with a length of 10 to 20 amino acids, and is referred to as the SARS-CoV-2 NME peptide pool. The two pools were combined and are available as a SARS-CoV-2 peptide mix. Most of the SARS-CoV-2 specific peptides contained in the AID SARS-CoV-2 peptide mix are located in the N-terminal area of the spike protein, while that in the AID PAN-Corona conserved regions contained in the peptide mix represent the C-terminal area. Section of two cytokines was measured: interferon γ (IFNg) and interleukin-2 (IL-2). Several spots/spot forming units were counted and depending on the number of spots after stimulation compared to the basal spots, the response was classified as reactive, non-reactive, or equivocal. The thresholds for classification are as follows: if basal spots 0–1 SI: qualitative ≤5 – nonreactive, qualitative between 5 and 7 – equivocal and qualitative ≥7 – reactive; if basal spots 2–20: qualitative ≤2 – nonreactive, qualitative between 2 and ≤ 3 – equivocal and qualitative >3 - reyaktif. Pou detèmine nivo background nan tès yo itilize, yo te itilize done torik ki soti nan laboratwa a sou iminite selilè soti nan kontwòl ki an sante ak pasyan ki pa MS konvalesans.

1. Rezilta Karakteristik demografik ak klinik sijè yo ansanm ak rezilta laboratwa yo rezime nan Tablo 1. Sijè 1 te devlope lafyèv, ak doulè nan misk ak jwenti ki dire twa jou. Tès prelèvman farinj pou SARS-CoV-2 RNA viral la te pozitif. Sijè 2 a te gen yon lafyèv, anosmi, ageusia, maltèt, ak fatig ki dire pou douz jou. Yo pa t fè tès pou SARS-CoV-2, men de manm fanmi li te teste pozitif pou SARS-CoV-2 RNA viral. Sijè 3 a te fè eksperyans lafyèv ak doulè nan misk pandan douz jou epi tès pou prelèvman farinj li pou SARS-CoV-2 RNA viral la te pozitif. Sijè 4 te fè eksperyans lafyèv ak doulè nan misk ki te dire senk jou ak tès pozitif nan prelèvman farinj pou SARS-CoV-2 RNA viral. Okenn nan sijè yo pa te entène lopital akòz COVID-19. Yo te resevwa antipiretik ak analgesic jan sa nesesè, tankou asetaminofèn, ibipwofèn, ak diclofenac. Sijè 3 te resevwa twa jou 500 mg azitromisin chak jou. Tout pasyan yo te refè san sequel. Tout matyè yo te gen nivo nòmal IgM ak IgG anvan enfeksyon an. Nan sijè 1,2 ak 4, selil CD19 B yo te apovri, e sa yo te pasyan yo ki te respekte piki ofatumumab yo chak mwa. Epitou, twa sijè sa yo te teste negatif pou antikò SARS-Cov2 apre enfeksyon an nan premye tès la. Sijè 4 te resevwa vaksen kont COVID-19 anvan dezyèm tès la, kidonk, dezyèm tès ak tès iminite selil T yo pa t fèt. Sijè 3 te administre dènye dòz ofatumumab la 24 jou anvan sentòm COVID-19 men li te gen yon espas 28 semèn nan aplikasyon ofatumumab davans akòz nivo IgM ki ba. Sijè sa a te pozitif pou antikò SARS-COV-2 IgG sou tou de mezi yo, ak tit yo ogmante ak tan. Sèvi ak entèferon-ELISpot, nou te obsève ke sijè 1, 2, ak 3 te montre iminite selil T kont SARS-CoV-2 (Tablo 2). Kosyan tach fondamantal divize pa inite ki fòme tach ki sekrete entèferon yo te 4, 8, ak 14.7 SI nan matyè 1, 2, ak 3, respektivman. Done ELISpot ki soti nan kontwòl ki an sante ak pasyan ki pa MS konvalesans yo prezante nan Tablo 2.

2. Diskisyon Rapò sa a bay done klinik ak laboratwa sou COVID-19 nan pwMS ki trete ak ofatumumab. Dapre sa nou konnen, gen yon sèl rapò anvan COVID-19 ak ofatumumab. Flores-Gonzalez et al. prezante yon pasyan ki te trete ak ofatumumab ki te gen deplesyon selil B konplè ak valè nòmal IgM ak IgG nan serik (Flores-Gonzalez et al., 2021). Pasyan an te gen yon COVID asymptomatik-19 ak yon repons imoral adekwat ak prezans anti-SARS-CoV-2 IgG twa mwa apre enfeksyon an. Kontrèman, twa pasyan yo te prezante nan etid sa a ki te gen yon rediksyon selil B CD19 konplè pa t monte yon repons antikò. Nan lòt men an, pasyan 3, ki gen selil B yo refè akòz entèripsyon dòz ofatumumab, te gen antikò anti-SARS-Cov2. Konklizyon sa yo soulve plizyè pwen enpòtan. Twa nan sijè ki te rapòte yo ki te diminye nan lenfosit CD19 pa t 'devlope yon repons antikò, ki konfime rezilta nan pasyan ki te trete ocrelizumab kote terapi ak antikò monoklonal anti-CD20 te asosye anpil ak yon pwobabilite redwi pou devlope antikò apre COVID{21} } (Sormani et al., 2021b; Bigaut et al., 2021). Sa a poze kesyon si pasyan ki te refè apre COVID-19 epi ki pa t devlope yon repons antikò pral gen bon jan iminite kont enfeksyon SARS-Cov-2 ki vin apre yo. Etid sou moun ki an sante ak matyè k ap pran rituximab pou atrit rimatoyid yo montre ke repons medyatè selil T yo ka kontribye nan pwoteksyon kont SARS-CoV-2 (Sekine et al., 2020; DiPiazza et al., 2021; Bonelli et al., 2021; Bonelli et al. al., 2021; Benucci et al., 2021). SARS-CoV-2-Lenfagosit memwa espesifik yo montre karakteristik ki asosye ak fonksyon antiviral ki pisan: selil T memwa yo sekrè cytokines epi elaji lè yo rankontre antijèn ankò (Rodda et al., 2021). Petèt pi bon egzanp sou enpòtans selil T yo nan iminite imen kont SARS-CoV-2 se etid ka sou pasyan COVID-19 ki gen agammaglobulinemi. Pasyan COVID-19 ki gen agammaglobulinemi ki lye ak X oswa otosòm recesif yo te kapab retabli de enfeksyon san vantilasyon oksijèn oswa swen entansif, sa ki sigjere ke pandan ke selil B ak antikò yo enpòtan anpil pou anpeche enfeksyon oswa diminye gwosè inoculum yo, repons selil T yo kapab. ase pou netwaye enfeksyon an ak maladi minim (Soresina et al., 2020). Done sou iminite selil T nan moun ki gen MS k ap pran yon lòt terapi pou diminye selil B, Ocrelizumab ap parèt, ki mete aksan sou iminite selil T kòm yon faktè enpòtan nan pwoteksyon kont SARS-CoV-2. Premye etid la konpare repons selil B ak selil T nan longè nan 20 pwMS sou monoterapi anti-CD20 ak 10 HC apre vaksinasyon BNT162b2 oswa mRNA- 1273 mRNA. Nan etid sa a, tout yo te trete ak aCD20 terapi ki te pwodwi repons antijèn espesifik CD4 ak CD8 T selil apre vaksinasyon (Apostolidis et al., 2021). Anplis de sa, plizyè etid ki vin apre, kèk nan yo ki poko revize kanmarad yo, te konfime ke pwMS ki te trete ak ocrelizumab te pwodwi repons espesifik SARS-CoV-2-selil T ki konparab ak kontwòl ki an sante ak/oswa pwMS sou lòt MS. terapi (Brill et al., 2021; Sabatino et al., 2021; Gadani et al., 2021). Sepandan, li poko klè nan ki nivo repons selil T yo ak pou konbyen tan li ase pou pwoteje pasyan yo kont enfeksyon viris apre rekiperasyon nan COVID-19 oswa pran vaksen an. Finalman, sijè prezante a ki gen nivo lenfosit CD19 refè te gen yon repons antikò adekwat pou SARS-Cov-2. Sa gen enplikasyon non sèlman pou iminite alontèm COVID-19 men tou pou preparasyon pou vaksen COVID-19. Li te demontre ke pwMS trete ak ocrelizumab gen yon repons atenue nan vaksen (Bar-Or et al., 2020). Ofatumumab, kontrèman ak ocrelizumab, gen yon repoblasyon relativman rapid nan lenfosit CD20 apre entèripsyon tretman (Baker et al., 2020). Nan fason sa a, yo ka fè yon espas tretman anvan vaksinasyon COVID- 19 pou pèmèt yon repons antikò apwopriye. Done yo pou ocrelizumab sijere ke retade dòz la jiska nèf mwa depi anvan an asosye ak repoplasman selil B men san siy klinik aktivite MS (Barun et al., 2021). Sepandan, konbyen tan ofatumumab yo ta dwe kenbe ak ki efè ki ta kite sou posib reyaktif maladi a poko konnen.An konklizyon, nou rapòte sou kat moun ki te trete ak ofatumumab ak COVID modere -19. Pandan ke pa gen okenn repons antikò yo te obsève nan pwMS ki te apovri CD19 lenfosit, yo te obsève iminite selil T kont SARS-CoV-2 nan tout twa pwMS ki te trete ak ofatumumab. Aktyèlman gen yon etid sou COVID-19 nan jijman ALITHIOS la pou plis envestige ak verifye rezilta sa yo.

Kontribisyon otè Konsèp etid ak konsepsyon: Adamec, Habeck. Akizisyon done: Adamec, Rogi´c, Penz, Braun, Habeck. Analiz ak entèpretasyon done: Adamec, Rogi´c, Penz, Braun, Habek. Redaksyon maniskri a: Habeck. Revizyon kritik maniskri a pou kontni entelektyèl enpòtan: Adamec, Rogi´c, Penz, Braun, Habeck. Sipò administratif, teknik, ak materyèl: Adamec, Rogi´c, Penz, Braun, Habeck. Finansman etid sa a te finanse pa Novartis Pharma AG, Basel, Swis. ak/oswa frè oratè ki soti nan Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals, TG Pharmaceuticals.DR: Pa rapòte okenn konfli enterè.MH: Patisipe kòm yon envestigatè klinik ak/ oswa te resevwa frè konsiltasyon ak/oswa oratè nan men Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals, TG Pharmaceuticals.

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