Review of content and approval of submission: all authors

Review of content and approval of submission: all authors. suffered debilitating fatigue and malaise throughout. There was no clinical response to antiviral therapy with remdesivir or CP, and SARS-CoV-2 was consistently detected in nasopharyngeal swabs. Intrahost evolution of several spike variants of uncertain significance was identified by viral sequence analysis. Delivery of REGN-COV2, in combination with remdesivir, was associated with clinical improvement and viral clearance within 6 days, which was sustained for over 150 days despite immunotherapy for relapsed follicular lymphoma. The second case, a 68-year-old female with chronic lymphocytic leukaemia on ibrutinib, also developed persistent SARS-CoV-2 infection. Despite a lack of response to remdesivir, infection promptly cleared following REGN-COV2 in combination with remdesivir, accompanied by resolution of inflammation and full clinical recovery that has been maintained for over 290 days. == Conclusions == These cases highlight the potential benefit of REGN-COV2 as therapy for persistent SARS-CoV-2 infection in antibody deficient individuals, including after failure of CP treatment. Formal clinical studies are warranted to assess the effectiveness of REGN-COV2 in antibody-deficient patients, especially in light of the emergence of variants of concern, such as Omicron, that appear to evade REGN-COV2 neutralisation. Keywords:Antibody deficiency, Primary and secondary immunodeficiency, Chronic COVID-19, Passive immunisation, Ronapreve (REGN-COV2), B cell depleting therapy, Omicron == Background == The recognition that SARS-CoV-2 infection leads to a degree of natural immunity to reinfection [13], allied to the development of several highly effective vaccines [47], is Chaetominine cause for optimism that Chaetominine the impact of the COVID-19 pandemic might ultimately lessen. Whilst the specific immunological mechanisms underpinning immunity remain to be defined [8], SARS-CoV-2 binding and/or neutralising antibodies appear to correlate with protection against infection Chaetominine or reinfection [13,811]. It is also becoming apparent that patients with primary or secondary defects of humoral immunity exhibit suboptimal responses to natural infection and/or vaccination and are susceptible to persistent or chronic SARS-CoV-2 infection [1228], implicating antibodies in the resolution of COVID-19. Beyond the clinical importance of chronic SARS-CoV-2 infection and its associated morbidity for the individual concerned, persistently infected hosts may provide a habitat for the emergence of viral variants of concern with the capacity to transmit more efficiently and/or evade immunity, representing a potential risk to public health and infection control [29]. Treatment strategies for persistent infection are therefore needed [29] and one potential solution is immunotherapy, via the transfer of functional antibody to a seronegative recipient [30]. Options to deliver this include either convalescent plasma (CP) harvested from immunocompetent individuals following recovery from COVID-19, or specifically engineered recombinant neutralising monoclonal antibody (mAb) preparations [30]. Whilst clinical trials of CP as a treatment for patients hospitalised with COVID-19 failed to show benefit Chaetominine in a predominantly immunocompetent patient cohort [31], leading to its withdrawal from clinical use, favourable responses to CP have been CANPml reported in case reports and case series of patients with antibody deficiency (reviewed in [29]). Nevertheless, there are also reports of a lack of response to CP [15,19], with the unintended consequence of driving evolution of novel variants. Randomised trials of mAb preparations have reported efficacy in Chaetominine ambulatory patients [32] and unpublished data from the RECOVERY trial indicate efficacy in seronegative hospitalised patients. However to date, relatively few published reports describe the response to mAb therapy in antibody-deficient patients, and none to our knowledge have reported its.