key: cord-0818983-7p6typg4
authors: Pulvirenti, Federica; Milito, Cinzia; Cinetto, Francesco; Salinas, Ane Fernandez; Terreri, Sara; Mortari, Eva Piano; Auria, Stefania; Soccodato, Valentina; Miriam, Lichtner; Nicastri, Emanuele; Vincenzi, Laura; Carsetti, Rita; D’Offizi, Gianpiero; Quinti, Isabella
title: SARS-CoV-2 monoclonal antibody combination therapy in patients with COVID-19 and primary antibody deficiency
date: 2021-11-08
journal: J Infect Dis
DOI: 10.1093/infdis/jiab554
sha: c5b842d7fd11f896c5eb93a125d78267a936b1c3
doc_id: 818983
cord_uid: 7p6typg4

Previous reports highlighted the efficacy of SARS-CoV-2 specific monoclonal antibodies (mAbs) against COVID-19. Here we conducted a prospective study on clinical outcome and antiviral effect of mAbs added to standard of care therapy in SARS-CoV-2 infected patients with Primary Antibody Defects. Median time of SARS-CoV-2 qPCR positivity was shorter in eight patients treated with mAbs (22 days) than in ten patients treated with standard of care therapy only (37 days, p=0.026). Median time of SARS-CoV-2 qPCR positivity from mAbs administration was 10 days. SARS-CoV-2 mAbs treatment was effective and well-tolerated in patients with Primary Antibody Defects.

M a n u s c r i p t Background Due to the severely impaired immune response to immunization, Primary Antibody Deficiency (PAD) patients represent a potential at-risk group in the COVID-19 pandemic.

Early reports on cohorts of PAD patients described a low number of patients infected by SARS-CoV-2 and with a variability of clinical manifestations ranging from asymptomatic to death with the fatality rate accounting for 10% (1) (2) (3) (4) . Patients with Common Variable Immunodeficiencies (CVID) are the predominant group, showing younger age at death (3) and different risk factors predisposing to severe course in comparison to the general population (4) . CVID is the most frequent symptomatic PAD in adults and children, with a wide spectrum of clinical complications including recurrent infection, and autoimmune or inflammatory manifestations. Surveys reported a severe clinical course in some CVID patients having more severe defects in antibody responses, dysfunctional B cells, and immune dysregulation. In these patients, the defective B and T cell cellular immune responses might account for an increased risk for prolonged infections, leading to the possible emergence of dangerous vaccine-evasion mutants (5, 6) .

At present, COVID-19 directed treatments are limited, including the antiviral agent remdesivir as the first approved therapeutic option for the treatment of COVID-19. More recently, monoclonal antibodies (mAbs) have been developed with the aim to neutralize the SARS-CoV-2 spike protein, thus preventing viral binding to host cells (7) . Given the poor specific antibody responses, PAD patients may be ideal candidates for SARS-CoV-2-based MoAbs treatment.

In Italy, this new therapeutic approach has become available since March 2021 when the Italian Agency for Drugs (AIFA) approved the first SARS-CoV-2 mAb for treatment in patients >12 years old at high-risk for severe COVID-19. Treatment was approved for mild to moderate COVID-19 within 10 days of symptom onset, with the exception for those with immunodeficiency, for which mAbs administration was allowed over 10 days A c c e p t e d M a n u s c r i p t (https://www.aifa.gov.it/uso-degli-anticorpi-monoclonali). Data regarding mAbs-based therapy in the PAD population are lacking. The purpose of this study was to describe the clinical response and safety profile in SARS-CoV-2 positive PAD treated with mAbs and to compare data to SARS-CoV-2 PAD patients treated with COVID-19 standard of therapies not-including mAbs.

Patients. Adult (≥18 years old) PAD patients with SARS-CoV-2 infection routinely followed by Care Centers of Rome and Treviso were enrolled in this prospective study. 

IgG antibodies against the SARS-CoV-2 (S1) was performed on serum samples by using the (Table 2) .

Treatment with mAbs was initiated within a range of 2-15 days after the first positive nasopharyngeal swab ( Table 1) . Infusion of mAbs was well-tolerated in all patients. In 7 out of 8 participants symptoms disappeared within 2-5 days, and all but one (n. 14) remained asymptomatic thereafter. Nasopharyngeal swab SARS-CoV-2 qPCR was repeated every 7- Table 2 ). As expected, SARS-CoV-2 IgG antibodies -checked after a comparable median time from the first positive nasopharyngeal swab -were higher in mAbs-treated patients (median: 6.9 OD ratio, range: 6.4-11.7 OD ratio) than in patients receiving standard of care therapy only (median: 1.9 OD ratio, range 0.9-6.4 OD ratio, p=0.001).

Patients with primary antibody deficiencies are considered as a vulnerable population in the COVID-19 pandemic as they might be unprotected from vaccination, might have prolonged COVID-19 course and SARS-Cov-2 recurrences (3, (5) (6) (7) . Recently, we have showed that two third of PAD patients are unable to produce specific antibodies after two doses of SARS-CoV-2 vaccine and, instead of generating classical specific memory B cells, they developed atypical memory B cells, short lived plasma blasts, and variable T cell response (7) . Atypical memory B cells are mostly generated during extrafollicular reactions without the involvement of antigen selection in the germinal center reaction (8) and are considered short-lived activated memory B cells. In patients unable to mount an adequate antibody response, A c c e p t e d M a n u s c r i p t additional strategies for protection are needed. So far, prevention of SARS-CoV-2 infection could not be achieved by immunoglobulin replacement treatment, due to the lack of specific antibodies in the current lots of gamma globulins (9) . One still controversial option is the possibility to substitute the defective antibody production by convalescent plasma. The administration of convalescent plasma <72 hours after the onset of symptoms has been shown to reduce disease progression in immunocompetent patients with mild disease and at high risk for disease progression only (10) . Moreover, the low neutralizing potency of convalescent plasma therapy is difficult to be standardized. In addition, plasma and transfusion usage in patients lacking immunoglobulins and in particular, in patients without serum IgA, should be limited in that it might cause adverse reactions (11) .

Monoclonal antibody-based therapies might be a promising option for patients with antibody defects (12) . During the past year, an unprecedentedly large number of mAbs have been developed to fight COVID-19 (13) . Overall, this study confirmed the previous report (1) (2) (3) (4) showing a wide range of COVID-19 spectrum of clinical conditions in PAD patients. We showed a positive clinical and antiviral response due to treatment with mAbs added to conventional therapy. Consistent with a previous report (14) , the treatment was without severe side effects in all patients. Although the majority of our cohort continued to be COVID-19 symptom-free, two patients with severe underlying PAD-related comorbidities required hospitalization: a patient for a pre-existing severe pulmonary involvement and a patient for enteropathy.

The positive outcome in antibody deficient patients was restricted to an early time point of monoclonal administration during SARS-CoV-2 infection. We therefore suggest regular follow-ups of PAD patients by SARS-CoV-2 qPCR, and to consider an early administration of mAbs in order to avoid COVID-19 evolution and to shorten the time of SARS-CoV-2 positivity. The shift of mAbs administration from intravenous to different routes, such as intramuscular or subcutaneous (15) , is under evaluation and will possibly contribute to an easier access to these treatments for PAD. M a n u s c r i p t Tables   Table 1. Demographic and clinical characteristics of the cohort of primary antibody deficiency SARS-CoV-2 infected patients. 

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study

Clinical outcomes and features of COVID-19 in patients with primary immunodeficiencies

Clinical outcome, incidence, and SARS-CoV-2 infection-fatality rates in Italian patients with inborn errors of immunity

COVID-19 in complex common variable immunodeficiency patients affected by lung diseases

Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host

How is immunosuppressive status affecting children and adults in SARS-CoV-2 infection? A systematic review

SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: Everybody Does their Best

Potential functions of atypical memory B cells in Plasmodium-exposed individuals

Rapidly Increasing SARS-CoV-2 Neutralization by Intravenous Immunoglobulins Produced from Plasma Collected During the 2020 Pandemic

Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults

IgA Antibodies and IgA Deficiency in SARS-CoV-2 Infection

Report: Convalescent Plasma, a Targeted Therapy for Patients with CVID and Severe COVID-19

Developing therapeutic monoclonal antibodies at pandemic pace

Tackling COVID-19 with neutralizing monoclonal antibodies

Outpatient Treatment of SARS-CoV-2 Infection to Prevent COVID-19 Progression

A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t Spike specific (IgG1) IgG (OD ratio), median (range)1.9 (0.9-6.4) 6.9 (6.4-11.7) 0.001