Arline Lyons Profile picture
Mar 31 50 tweets 26 min read
Day 2 of The Royal Society event on COVID-19! #royalsociety #COVID19
Dr Nathalie McDermott - contracted COVID-19 2 years ago, spine affected, needs minicab to get to work, and mobility scooter to do her clinical work. Significant cost to employer, disability funding from government. #royalsociety #COVID19
Dr Nathalie McDermott - problems with defining long COVID, distinguishing it from other conditions, tracking it. Also affects children through multi-system inflammatory syndrome, symptoms can persist for months, affects schooling. #royalsociety #COVID19
Dr Nathalie McDermott - vaccination protects against long COVID but can still occur in those vaccinated and boosted. Long COVID not talked about, considered when changing public health guidance. #royalsociety #COVID19
Dr Nathalie McDermott - long COVID will have an ongoing, cumulative and significant effect on the UK economy. #royalsociety #COVID19
Dr Nathalie McDermott - different phenotypes of long COVID, some overlap with ME/chronic fatigue syndrome, research into long COVID will benefit the other two. #royalsociety #COVID19
Prof Ling-Pei Ho - immune pathogenesis and therapeutics. Part of a respiratory translational research collaboration that was developing treatments, switched to COVID. #royalsociety #COVID19
Prof Ling-Pei Ho - initially relied on data from intensivists in China and Italy. ICU admissions had a number of similarities in gender, weight, pre-existing illnesses, immune response. Pattern of lung damage meant prone positioning was effective. #royalsociety #COVID19
Prof Ling-Pei Ho - tried to understand the underlying immune response, looking at immune profiles of hospital patients (CIRCO), deep phenotyping. Found clear difference in hospital patients who went on develop severe disease. #royalsociety #COVID19
Prof Ling-Pei Ho - type of neutrophils, not number, was significant. T cell and neutrophil numbers returned to normal in mild and moderate disease, but not in severe. Significant abnormalities in monocytes also seen on admission. #royalsociety #COVID19
Prof Ling-Pei Ho - dynamic immune response, CIRCO gave picture of early signals of dysregulated immune response, fast recruitment of patients to RECOVERY trial. #royalsociety #COVID19
Prof Ling-Pei Ho - COMBAT study created multi-omics blood atlas for different severity of disease. Wanted to find predictive biomarkers for disease severity. Bulk RNA sequencing of whole blood showed genes associated with different outcomes. #royalsociety #COVID19
Prof Ling-Pei Ho - unusual cells seen more in severe disease. More immature neutrophils, neutrophil progenitors in severe COVID. Severe disease associated with certain aspects of immune response. #royalsociety #COVID19
Prof Ling-Pei Ho - analysis revealed 11 proteins had significant effect on progression to severe disease. Need for further clinical trials. Results of CIRCO and COMBAT suggest infection-driven emergency myelopoiesis. #royalsociety #COVID19
Prof Ling-Pei Ho - results confirmed in phase 2/3 clinical trials. Need to maintain the collaboration seen in COVID response. Integrate phase 2 and 3 trials, simplify phase 2, let it be run by experts. #royalsociety #COVID19
Prof Ling-Pei Ho - preventing severe disease is key, identify effective treatments and timing, monocytic pathway under-utilised. #royalsociety #COVID19
Prof Ling-Pei Ho - immuno-modulation may have a role in flu treatment, has not been tested. Apart from clotting in COVID, lung damage similar to flu. #royalsociety #COVID19
Prof Ling-Pei Ho - biomarkers for severe disease, only researched on hospitalised patients, needs to be investigated in the community, in early stages of disease. #royalsociety #COVID19
Dr Jay Grobler - Merck, speaking about molnupiravir. Looked for potentially effective treatment that could be developed quickly, to have an impact on the pandemic. #royalsociety #COVID19
Dr Jay Grobler - N-hydroxycytidine, molecule similar to molnupiravir, has been researched for over 50 years, poor bioavailability until a prodrug form was developed. #royalsociety #COVID19
Dr Jay Grobler - drug is substrate for viral RNA polymerase, incorporated into template strand, introduces errors. Like assembling flat-pack furniture in the wrong way. #royalsociety #COVID19
Dr Jay Grobler - variants differ primarily in the spike protein, not replication machinery, so molnupiravir equally effective against all variants. Resistance possible but not yet observed. Errors in replication significantly decreases infectivity. #royalsociety #COVID19
Dr Jay Grobler - issue that drugs for flu need to be taken very soon after infection. Phase 2 trial in people within 7 days of positive test, different doses, number of errors in viral replication shown to increase with dose, plateaus at 400-800 mg #royalsociety #COVID19
Dr Jay Grobler - errors randomly distributed, not concentrated at any specific genes. Treatment with molnupiravir reduced positive viral culture from patients. Possible that treatment reduces infectivity, can break cycles of transmission. #royalsociety #COVID19
Dr Jay Grobler - phase 3 trial in high risk outpatients, not vaccinated, variants identified, mostly delta, mu, gamma at that time. Drug found to significantly reduce risk of hospitalisation and death, early termination of study due to strong results. #royalsociety #COVID19
Dr Jay Grobler - sustained improvement in symptoms, reduced progression to severe disease, drug well tolerated compared to placebo. Molnupiravir also active against many RNA viruses, including pathogens designated by WHO as potential future pandemics. #royalsociety #COVID19
Dr Jay Grobler - risk of driving viral mutation/driving variants as drug is a mutagen? Extremely unlikely, so many errors introduced that virus is rendered unfit. Also investigated mutations in spike protein and saw nothing unusual. #royalsociety #COVID19
Dr Jay Grobler - risk to reproductive health? Studies have been done in different areas of reproductive health, recommended to use contraception while using the drug, as a precaution. #royalsociety #COVID19
Dr Jay Grobler - practical use of molnupiravir in the clinic? Indicated for those at high risk of progression to severe disease, e.g. elderly, underlying conditions. #royalsociety #COVID19
Dr Davide Corti - broadly neutralising antibodies, monoclonal antibodies against SARS-CoV-2. His lab also developed antibodies against Ebola virus. Method to effectively isolate antibodies developed in 2004, used for SARS. #royalsociety #COVID19
Dr Davide Corti - already working on antibodies against coronaviruses when SARS-CoV-2 emerged. Used memory B cells against SARS-CoV-1, blood sample taken in 2013 from person infected in 2003. Antibodies recognise receptor binding domain in SARS-CoV-2. #royalsociety #COVID19
Dr Davide Corti - receptor binding domain is highly conserved across coronaviruses. Possible to inhibit receptor binding through stearic hindrance, although not seen in vitro. #royalsociety #COVID19
Dr Davide Corti - Futher mutations in the therapeutic antibodies may allow them to activate T cells. Trials were accelerated during the pandemic, development usually takes 18 months. #royalsociety #COVID19
Dr Davide Corti - variants, each one lasted about 4 months, evolution driven by increased transmission at first, then immune evasion, possibly inter-species transmission. Omicron evades many therapeutic antibodies. #royalsociety #COVID19
Dr Davide Corti - broadly neutralising antibodies can overcome antigenic shift, unlike antibodies effective against early variants that lose activity against later variants. Possible for antibodies to regain activity against later variants. #royalsociety #COVID19
Dr Davide Corti - preclinical studies show lack of correlation between in vitro and in vivo results in some cases, need to test both. Also role for Fc-effector function, which seems to be retained across variants. #royalsociety #COVID19
Dr Davide Corti - AstraZeneca antibodies engineered to not have effector function, so loss of neutralising activity equals total loss of activity. #royalsociety #COVID19
Dr Davide Corti - development of resistance, need for combined treatment? Unclear what mutations seen with antibody use indicate, if they are fit mutations or not. #royalsociety #COVID19
Prof Sir Peter Horby - revolutions and revelations. Immuno-modulation initially not advised, then dexamethasone seen to be effective in certain stages. Corticosteroids + tocilizimab also shown to be effective, use of multiple immuno-modulators. #royalsociety #COVID19
Prof Sir Peter Horby - triple therapy now used, how far can we go, targeting, optimisation, accessibility, learnings for other diseases e.g. community acquired pneumonia. #royalsociety #COVID19
Prof Sir Peter Horby - 3D structure of virus used for drug design and selection. Effect of seropositivity/seronegativity on outcome, use to predict progression. New focus on identifying aspects of host (patient) and virus to select treatment. #royalsociety #COVID19
Prof Sir Peter Horby - revolutions in clinical trial design, large scale platform trials, inclusive young and old, pregnant women. Data linkage, online data, need to bring regulators up to speed, agree on certainty of data. #royalsociety #COVID19
Prof Sir Peter Horby - embedding trials in clinical care. Takes average 8 minutes to enter patient in RECOVERY trial and have drug allocated. More inclusion of minorities, include more drugs, combinations. #royalsociety #COVID19
Prof Sir Peter Horby - poor enrollment of patients in 2009 flu pandemic, trial procedures too complex, took too long, pandemic had passed, no actionable results. Reverse result for COVID, high enrollment, many actionable results. #royalsociety #COVID19
Prof Sir Peter Horby - FDA found only 5% of COVID trials were adequately powered. RECOVERY started fast, delivered results fast, much lower cost per patient, much more effective. Need smarter trial design, more clinical integration, investment in platforms #royalsociety #COVID19
Prof Sir Peter Horby - need more appropriate regulation, recognise role of public-private partnership. #royalsociety #COVID19
Prof Sir Peter Horby - arm of RECOVERY for long COVID? If there are enough people with a condition, can set up large platform trial. Need to be clear about risk to patients, then start. #royalsociety #COVID19
Prof Sir Peter Horby - implications for research ethics committees? MHRA very receptive to idea of large, open-ended platform trials. Internationally, ethics committees in lower income countries more conservative. Trials have changed, regulators slower. #royalsociety #COVID19
Prof Sir Peter Horby - how to keep using the data gathered in RECOVERY, keep it running, investigate long COVID? Would be a shame to stop! Have already added influenza, but need investment, changes in regulation. #royalsociety #COVID19
Break time! Will start a new thread for the next set of talks.

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More from @arlinelyons

Mar 30
Settling in to watch the @royalsociety 2-day event on COVID-19. Dame Linda Partridge starts with thanks to everyone involved in fighting the pandemic and scientific advances. #royalsociety #COVID19
"We can always do better" - Prof David Navarro on integrating context during the pandemic. "We need a story to make groups everywhere to appreciate what this pandemic means and their place in it." And that story is not easy to find. #royalsociety #COVID19
Prof David Navarro: the virus is the problem, people are the solution. Longer term illness is a huge potential threat, no-one should take infection lightly. The poorer you are the worse the impact of illness. #royalsociety #COVID19
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