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MORU Photo: Ellen Beer
Antibodies were the first effective treatments for COVID, but the viruses soon became resistant. During COVID major decisions on whether to deploy or withdraw these expensive antibody treatments were based on lab tests, but there was substantial uncertainty and disagreement what these lab tests meant. Since faster clearance of the virus from the mouth or throat correlates with clinical benefit, comparing the virus clearance in people with the in-vitro (laboratory) virus neutralisation tests allows researchers to calibrate these lab tests and so determine quickly if a particular antibody treatment should be used or withdrawn.
“There is a straightforward way of calibrating the therapeutic relevance of in-vitro tests for COVID-19: You can assess the antiviral effects of antibody treatments directly by measuring their effects on viral clearance in people. Viral clearance from the throat can be estimated over a period of 5 days in adults with early infections who are at low risk of progression to severe disease. The test interventions are compared with no treatment. Acceleration in viral clearance correlates with clinical benefit. These in-vivo results can be compared with the in-vitro virus neutralisation tests and the target sequences,” say the letter authors.
“Speed is essential when fighting a pandemic. How do we identify the most active antiviral treatments quickly? And how do we determine if an antibody or drug is no longer effective? This simple approach provides the answer,” said letter co-author Professor Sir Nick White, co-Head of Medical Therapeutics Unit (MTU) at the Mahidol Oxford Tropical Medicine Research Unit (MORU) in Bangkok.
“This simple methodology – which works for ‘flu, as well – allows researchers and policymakers to assess, evaluate and monitor antiviral interventions rapidly in respiratory infection epidemics and pandemics. This was a conspicuous and costly gap during the COVID-19 pandemic,” noted Prof. White.
To evaluate antiviral treatments efficiently using this approach, MORU conducts multi-country adaptive platform trials for influenza, SARS-CoV-2 (the largest such study in the world), and respiratory syncytial virus (RSV) in low-resource settings. These trials use a robust standardized virological endpoint, the rate of oropharyngeal viral clearance, to compare multiple drugs simultaneously.
Pharmacometric platform trials with frequent interim analyses allow effective and ineffective treatments to be identified early, reducing sample sizes, costs, and time to results. This approach is substantially more cost effective than current approaches to comparing and therefore choosing antiviral drugs and antibody treatments and assessing their dose-response relationships.
“This approach proved its value during COVID-19 by rapidly ruling out ineffective drugs like ivermectin and favipiravir, while supporting the use of remdesivir, molnupiravir, and the main protease inhibitors (nirmatrelvir and ensetrelvir),” said letter co-author Dr James Watson, Associate Director of the Infectious Diseases Data Observatory (IDDO) and a MORU researcher in Oxford.
“By enabling the pre-pandemic evaluation of promising therapies, this platform strengthens global preparedness – saving time, money and, potentially, lives during a future pandemic,” said Dr. Watson.
Publication
Assessing monoclonal antibodies for respiratory virus infections. White, NJ, Schilling WHK, Jittamala P, Wongnak P, Watson JA. The Lancet, Volume 406, Issue 10503, 595 - 596