High-dose immunoglobulins from convalescent donors for patients hospitalised with COVID-19

Abstract

Many initiatives have developed passive immune therapies for COVID-19 patients, including plasma from convalescent donors. Hyperimmune immunoglobulins (hIVIG), extracted from large amounts of COVID-19 convalescent plasma (CCP), as passive immune therapy, needs a longer time span to be developed than CCP, since at least 1000 kg of CCP is required.1Focosi D Tuccori M Franchini M The road towards polyclonal anti-SARS-CoV-2 immunoglobulins (hyperimmune serum) for passive immunization in COVID-19.Life. 2021; 11: 144Crossref PubMed Scopus (11) Google Scholar, 2WHOAnnex 4. Recommendations for the collection, quality control and regulation of human plasma for fractionation.WHO Tech Rep Ser. 2007; 941: 189-264Google Scholar Moreover, the required logistics and facilities to produce hIVIG make this a more expensive and less accessible alternative to CCP alone. The efficacy and safety of CCP for COVID-19 have been investigated by several studies, some of which are still ongoing.3Piechotta V Iannizzi C Chai KL et al.Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review.Cochrane Database Syst Rev. 2021; 5CD013600Google Scholar Of these, a large observational study showed that safety of CCP is reasonable.4Joyner MJ Bruno KA Klassen SA et al.Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients.Mayo Clin Pro. 2020; 95: 1888-1897Summary Full Text Full Text PDF PubMed Scopus (244) Google Scholar In December, 2021, the US Food and Drug Administration stated that high-titre anti-SARS-CoV-2 antibody-containing products, such as CCP, should only be used early in the disease course, or in patients with immunosuppressive disease or receiving immunosuppressive treatment.5US Food and Drug AdministrationConvalescent plasma EUA letter of authorization 12282021.https://www.fda.gov/media/141477/downloadDate: 2021Date accessed: January 19, 2022Google Scholar Randomised controlled trials with high-titre CCP have not shown efficacy in patients hospitalised with COVID-19 to date,3Piechotta V Iannizzi C Chai KL et al.Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review.Cochrane Database Syst Rev. 2021; 5CD013600Google Scholar, 6Abani O Abbas A Abbas F et al.Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial.Lancet. 2021; 397: 2049-2059Summary Full Text Full Text PDF PubMed Scopus (173) Google Scholar with mixed results early in the disease course.7Korley FK Durkalski-Mauldin V Yeatts SD et al.Early convalescent plasma for high-risk outpatients with COVID-19.N Engl J Med. 2021; 385: 1951-1960Crossref PubMed Scopus (62) Google Scholar, 8Libster R Pérez Marc G Wappner D et al.Early high-titer plasma therapy to prevent severe COVID-19 in older adults.N Engl J Med. 2021; 384: 610-618Crossref PubMed Scopus (421) Google Scholar This might be explained by the fact that patients had already developed antibodies themselves and adding a small dose (infusing one or two units of CCP) might not be effective.9Gharbharan A Jordans CCE GeurtsvanKessel C et al.Effects of potent neutralizing antibodies from convalescent plasma in patients hospitalized for severe SARS-CoV-2 infection.Nat Commun. 2021; 123189Crossref PubMed Scopus (66) Google Scholar Many studies investigating hIVIG for COVID-19 are ongoing. The few published studies vary substantially in their setup, such as the characteristics of the studied intervention being non-human in origin (eg, horse or swine IgG)10Lopardo G Belloso WH Nannini E et al.RBD-specific polyclonal F(ab')2 fragments of equine antibodies in patients with moderate to severe COVID-19 disease: a randomized, multicenter, double-blind, placebo-controlled, adaptive phase 2/3 clinical trial.EClinMed. 2021; 34100843Google Scholar, 11Gaborit B Dailly E Vanhove B et al.Pharmacokinetics and safety of XAV-19, a swine glyco-humanized polyclonal anti-SARS-CoV-2 antibody, for COVID-19-related moderate pneumonia: a randomized, double-blind, placebo-controlled, phase IIa study.Antimicrob Agents Chemother. 2021; 65e0123721Crossref PubMed Scopus (4) Google Scholar or human-derived hIVIG.12Parikh D Chaturvedi A Shah N Patel P Patel R Ray S Safety and efficacy of COVID-19 hyperimmune globulin (HIG) solution in the treatment of active COVID-19 infection—findings from a prospective, randomized, controlled, multi-centric trial.medRxiv. 2021; (published online July 27.) (preprint).https://doi.org/10.1101/2021.07.26.21261119Google Scholar, 13Ali S Uddin SM Shalim E et al.Hyperimmune anti-COVID-19 IVIG (C-IVIG) treatment in severe and critical COVID-19 patients: a phase I/II randomized control trial.EClinMed. 2021; 36100926Google Scholar Studies so far have been small—ranging from 18 to 245 participants—making interpretation of their results challenging. Although the studied interventions were cautiously deemed safe, there is currently not enough evidence to support the use of these passive immunisation strategies for COVID-19. The ITAC (INSIGHT 013) Study Group14The ITAC (INSIGHT 013) Study GroupHyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial.Lancet. 2022; (published online Jan 27.)https://doi.org/10.1016/S0140-6736(22)00101-5Google Scholar reports in The Lancet a multicentre, randomised, placebo-controlled clinical study with 593 patients hospitalised with COVID-19, who had been symptomatic for up to 12 days and randomly assigned to receive a high-dose single infusion of human hIVIG (400 mg/kg bodyweight or 40 g maximum) or saline as placebo, in addition to standard of care, including remdesivir. 579 patients with a median age of 59 years (IQR 49–70)—of which 250 (43%) were women, 329 (57%) were men, 325 (56%) were White, 88 (15%) were Hispanic, 87 (15%) were Black, 69 (12%) were Asian, and ten (2%) identified as other—were analysed by a modified intention-to-treat analysis, with a follow-up of 28 days. The primary outcome was a composite outcome measured by a seven-category ordinal scale ranging from no complications (pulmonary and extra-pulmonary) to death at day 7. A prespecified subgroup analysis was done to determine the role of the presence or absence of anti-spike neutralising antibodies at entry. Safety outcomes were predefined and analysed at day 7. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted odds ratio (OR) was 1·06 (95% CI 0·77–1·45; p=0·72). The authors concluded no clinical benefit of hIVIG in these patients. An unexpected difference in safety outcome between the group with neutralising antibodies compared with the neutralising antibody-negative group was found, favouring the latter group. In patients who were positive at baseline, 26·3% of patients in the hIVIG group and 16·4% of patients in the placebo group had at least one event included in the composite safety outcome (OR 2·21, 95% CI 1·14–4·29); in patients who were neutralising antibody-negative at baseline, 22·7% of patients in the hIVIG group and 34·3% in the placebo group had at least one event included in the composite safety outcome (OR 0·51, 95% CI 0·29–0·90; pinteraction=0·001). This finding might raise concerns regarding the safety aspect of hIVIG in neutralising antibody-positive patients. This study is of importance because high-dose human hIVIG (ie, four times the usual dose) has not previously been used to treat patients hospitalised with COVID-19. However, the median time from disease onset to inclusion was 8 days (IQR 6–10), which is long, suggesting that even a high dose might not be beneficial late in the disease course. It will be interesting to see the results from the same study group regarding the effectiveness in outpatients (NCT04910269). The adoption of a more universal scoring system to score disease severity, such as the WHO Clinical Progression Scale,15Marshall JC Murthy S Diaz J et al.A minimal common outcome measure set for COVID-19 clinical research.Lancet Infect Dis. 2020; 20: e192-e197Summary Full Text Full Text PDF PubMed Scopus (498) Google Scholar would be beneficial for better outcome comparison between different trials. Regarding the safety aspect, in patients with neutralising antibodies, hIVIG infusion resulted in significantly more adverse events compared with placebo than the neutralising antibody-negative group when compared with placebo, which is unexplained. Other unexplained safety questions were raised by the CONCOR-1 study group that found more adverse events in patients receiving non-high titre plasma.16Bégin P Callum J Jamula E et al.Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial.Nat Med. 2021; 27: 2012-2024Crossref PubMed Scopus (66) Google Scholar This well performed randomised controlled study is an important addition to the existing literature, unravelling the role of passive immunisation for COVID-19 patients, in particular regarding dose. However, more questions have been raised regarding the safety aspect, which needs more research for better understanding. CS-O has a consultative role as transfusion specialist, being partly employed at Sanquin Blood Bank, the Dutch national not-for-profit blood establishment that has issued convalescent plasma and provided plasma for manufacturing of hyperimmune immunoglobulins. CS-O is also partly employed at the Academic Hospital Erasmus Medical Center. SJV receives a PhD scholarship from Sanquin Sanquin Blood Supply Foundation. Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trialWhen administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. Full-Text PDF