International COVID-19 trial to restart with focus on immune responses

Ledford, Heidi

doi:10.1038/d41586-021-01090-z

Cited by 11 publications

(8 citation statements)

References 3 publications

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“…A possible good sense solution encompasses the identification of cohorts to be prioritized for testing, e.g., those at higher risk of being infected by VOCs, or those in whom vaccine immunogenicity appears lower and/or shorter, such as older men, subjects with a high body mass index or undergoing immunosuppressive treatments, and patients with cancer or severe impairment of renal function, who are also at higher risk of developing more severe forms of COVID-19 illness (Table 2) [66]. Notably, the recent claim made by the WHO stating that international COVID-19 trials shall be restarted with more focus on immune response provides significant support to targeted anti-SARS-CoV-2 antibodies testing for assessing the effectiveness of existing treatments, thus including vaccinations [67].…”

Section: Discussionmentioning

confidence: 99%

Anti-SARS-CoV-2 Antibodies Testing in Recipients of COVID-19 Vaccination: Why, When, and How?

2021

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Although universal vaccination is one of the most important healthcare strategies for limiting SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) circulation and averting the huge number of hospitalizations and deaths due to coronavirus disease 2019 (COVID-19), significant inter-individual variability of COVID-19 vaccines’ efficacies has been described, mostly due to heterogeneous immune response in recipients. This opinion paper hence aims to discuss aspects related to the opportunity of monitoring anti-SARS-CoV-2 antibodies before and after COVID-19 vaccination, highlighting the pros and cons of this strategy. In summary, the advantages of anti-SARS-CoV-2 antibodies’ testing in recipients of COVID-19 vaccination encompass an assessment of baseline seroprevalence of SARS-CoV-2 infection in non-vaccinated individuals; early identification of low or non-responders to COVID-19 vaccination; and timely detection of faster decay of anti-SARS-CoV-2 antibody levels. In contrast, potential drawbacks to date include an unproven equivalence between anti-SARS-CoV-2 antibody titer, neutralizing activity, and vaccine efficiency; the lack of cost-effective analyses of different testing strategies; the enormous volume of blood drawings and increase of laboratory workload that would be needed to support universal anti-SARS-CoV-2 antibodies testing. A potential solution entails the identification of cohorts to be prioritized for testing, including those at higher risk of being infected by variants of concern, those at higher risk of unfavorable disease progression, and subjects in whom vaccine immunogenicity may be expectedly lower and/or shorter.

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Section: Discussionmentioning

confidence: 99%

Anti-SARS-CoV-2 Antibodies Testing in Recipients of COVID-19 Vaccination: Why, When, and How?

2021

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“…Much of the work presented in this paper formed the basis of a proposal to the World Health Organisation (WHO) for the use of artesunate as a therapy for patients seriously ill with Covid-19. This idea is now in clinical trials as part of the 'SOLIDARITY' initiative [44][45][46] . Neutrophils migrated up gradient of 10nM 2 O 2 over 1mm (see Methods).…”

Section: Discussionmentioning

confidence: 99%

Artemisinin inhibits innate immune cell chemotaxis, cytokine production and NET release

Morad

Luqman

Pinto

et al. 2022

Preprint

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Immune cell chemotaxis to the sites of pathogen invasion is critical for fighting infection, but in life-threatening conditions such as sepsis and Covid-19, excess activation of the innate immune system is thought to cause a damaging invasion of immune cells into tissues and a consequent excessive release of cytokines. In these circumstances, tempering excessive activation of the innate immune system may, paradoxically, promote recovery. Here we identify the antimalarial compound artemisinin as a potent and selective inhibitor of neutrophil and macrophage chemotaxis induced by many chemotactic agents. Artemisinin released calcium from intracellular stores in a similar way to thapsigargin, a known inhibitor of the Sarco/Endoplasmic Reticulum Calcium ATPase pump (SERCA), but unlike thapsigargin, artemisinin blocks only the SERCA3 isoform. Inhibition of SERCA3 by artemisinin was irreversible and was inhibited by iron chelation, suggesting iron-catalysed alkylation of a specific cysteine residue in SERCA3 as the mechanism by which artemisinin inhibits immune cell motility. In murine infection models, artemisinin potently suppressed immune cell invasion into both peritoneum and lung in vivo and inhibited the release of cytokines/chemokines and neutrophil extracellular traps (NETs). This work suggests that artemisinin may have value as a therapy in conditions such as sepsis and Covid-19 in which over-activation of the innate immune system causes tissue injury that can lead to death.

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“… 5 Following these results, four new multicenter trials with imatinib are currently recruiting; p.o. imatinib in Solidarity by the World Health Organization (WHO) and the REMAP‐CAP study 51 ; and i.v. imatinib in the INVENT‐COVID and IMPRESS studies.…”

Section: Discussionmentioning

confidence: 99%

Elevated acute phase proteins affect pharmacokinetics in COVID‐19 trials: Lessons from the CounterCOVID ‐ imatinib study

Bartelink

Bet

Widmer

et al. 2021

CPT Pharmacom & Syst Pharma

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This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID‐19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID‐19 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (C max ) and trough concentration (C trough ) were 2.32‐fold (95% confidence interval [CI] 1.34–3.29), 2.31‐fold (95% CI 1.33–3.29), and 2.32‐fold (95% CI 1.11–3.53) lower, respectivelwy, for patients with CML/GIST compared with patients with COVID‐19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1‐acid glycoprotein (AAG) concentrations measured in patients with COVID‐19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG‐PK‐Model) gave an estimated mean (SD) prediction error (PE) of −20% (31%) for total and −7.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID‐19 compared to CML/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID‐19.

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International COVID-19 trial to restart with focus on immune responses

Cited by 11 publications

References 3 publications

Anti-SARS-CoV-2 Antibodies Testing in Recipients of COVID-19 Vaccination: Why, When, and How?

Anti-SARS-CoV-2 Antibodies Testing in Recipients of COVID-19 Vaccination: Why, When, and How?

Artemisinin inhibits innate immune cell chemotaxis, cytokine production and NET release

Elevated acute phase proteins affect pharmacokinetics in COVID‐19 trials: Lessons from the CounterCOVID ‐ imatinib study

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