ABSTRACT
BackgroundPatients with primary and secondary antibody deficiency are vulnerable to COVID-19 and demonstrate diminished responses following two-dose SARS-CoV-2 vaccine schedules. Third primary vaccinations have been deployed to enhance their humoral and cellular immunity. ObjectivesTo determine the immunogenicity of the third primary SARS-CoV-2 immunisation in a heterogeneous cohort of patients with antibody deficiency. MethodsParticipants enrolled in the COV-AD study were sampled before and after their third vaccine dose. Serological and cellular responses were determined using ELISA, live-virus neutralisation and ELISPOT assays. ResultsA third primary SARS-CoV-2 vaccine significantly increased anti-spike glycoprotein antibody seroprevalence from 61.4% to 76.0%, the magnitude of the antibody response, its neutralising capacity and induced seroconversion in individuals who were seronegative after two vaccine doses. Vaccine-induced serological responses were broadly cross-reactive against the SARS-CoV-2 B.1.1.529 variant of concern, however, overall seroprevalence and antibody levels remained significantly lower than healthy controls. No differences in serological responses were observed between individuals who received the AstraZeneca ChAdOx1 nCoV-19 and Pfizer BioNTech 162b2 during their initial two-dose vaccine schedule. SARS-CoV-2 infection naive participants who had received a heterologous vaccine as a third dose were significantly more likely to have a detectable T cell responses following their third vaccine dose (61.5% vs 11.1%). ConclusionThese data support the widespread use of third primary immunisations to enhance humoral immunity against SARS-CoV-2 in individuals with antibody deficiency.
Subject(s)
COVID-19ABSTRACT
Purpose: To define the burden of morbidity and mortality arising from COVID-19 in individuals with primary (PID) and secondary immunodeficiency (SID) in the United Kingdom. Methods In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. Anonymised demographic data, pre-SARS-CoV-2 infection lymphocyte counts, co-morbidities, targeted treatments and outcomes were collected. Three groups were analysed in further detail: individuals with common variable immunodeficiency (CVID), individuals with any PID, including CVID, receiving immunoglobulin replacement therapy (IgRT) and individuals with secondary immunodeficiency. Results A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID, had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Conclusion Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count and the presence of co-morbidities are additional risk factors for poor outcome in this cohort.
Subject(s)
COVID-19 , Immunologic Deficiency Syndromes , Common Variable ImmunodeficiencyABSTRACT
Background: Elevated levels of interferon-gamma (IFNγ) have been found in COVID-19 infection, however its role in this setting remains poorly understood. Cases of non-tuberculous mycobacterium (NTM) infections due to anti-IFNγ autoantibodies (Ab) were first reported in 2004. NTM and COVID-19 co-infection in a patient with acquired IFNγ deficiency has not previously been described. The impact of anti-IFNγ Ab on the severity of COVID-19 has not been previously explored. Objective: We report a case of COVID-19 infection in a patient hospitalised with NTM infection due to acquired IFNγ deficiency caused by anti-IFNγ Ab. We also explore effects of IFNγ Ab on the severity of COVID-19 infection. Methods: : Detailed immunological investigations were performed. Bio-rad, Bio-Plex methodology was used to detect anti-IFNγ Ab, titration, IFNγ recovery assay and SARS-CoV-2 serology. Anti-IFNγ Ab were tested in patients with severe (COV-Pat) and health care workers with mild/asymptomatic COVID-19 infection (COV-Asx). Results: : Mycobacterium avium intracellulare was diagnosed following bone marrow examination and culture. High titre anti-IFNγ Ab were detected in patient’s serum. The autoantibodies neutralized both endogenously produced and exogenously administered IFNγ. SARS-COV-2 infection was identified during routine inpatient testing. Despite prolonged SARS-COV-2 infection the patient showed only minimal additional symptoms, never developed any significant inflammatory complications and eventually mounted an adequate IgG antibody response to the SARS-COV-2 trimeric S-protein. Elevated titres of anti-IFNγ Ab were detected in COV-Pat and COV-Asx, compared to non-infected healthy controls. The titres were broadly similar between COV-Pat and COV-Asx groups, but much lower compared to patients with acquired IFNγ Ab deficiency. Conclusion: IFN-γ is known to play a central role in hyperinflammatory disease states such as macrophage activation syndrome This study illustrates the potential value of inhibiting IFNγ to prevent pathological inflammatory response to COVID-19.
Subject(s)
COVID-19 , DiseaseABSTRACT
BACKGROUND COVID-19 is associated with immune dysregulation and hyperinflammation. Tocilizumab is an anti-interleukin-6 receptor antibody. METHODS Patients hospitalized with severe COVID-19 pneumonia receiving standard care were randomized (2:1) to double-blinded intravenous tocilizumab 8 mg/kg or placebo. The primary outcome measure was clinical status on a 7-category ordinal scale at day 28 (1, discharged/ready for discharge; 7, death). RESULTS Overall, 452 patients were randomized; the modified-intention-to-treat population included 294 tocilizumab-treated and 144 placebo-treated patients. Clinical status at day 28 was not statistically significantly improved for tocilizumab versus placebo (P=0.36). Median (95% CI) ordinal scale values at day 28: 1.0 (1.0 to 1.0) for tocilizumab and 2.0 (1.0 to 4.0) for placebo (odds ratio, 1.19 [0.81 to 1.76]). There was no difference in mortality at day 28 between tocilizumab (19.7%) and placebo (19.4%) (difference, 0.3% [95% CI, -7.6 to 8.2]; nominal P=0.94). Median time to hospital discharge was 8 days shorter with tocilizumab than placebo (20.0 and 28.0, respectively; nominal P=0.037; hazard ratio 1.35 [95% CI 1.02 to 1.79]). Median duration of ICU stay was 5.8 days shorter with tocilizumab than placebo (9.8 and 15.5, respectively; nominal P=0.045). In the safety population, serious adverse events occurred in 34.9% of 295 patients in the tocilizumab arm and 38.5% of 143 in the placebo arm. CONCLUSIONS In this randomized placebo-controlled trial in hospitalized COVID-19 pneumonia patients, tocilizumab did not improve clinical status or mortality. Potential benefits in time to hospital discharge and duration of ICU stay are being investigated in ongoing clinical trials.