While September seems like an age ago, we at the Cleveland Clinic are still recovering from a whirlwind week that including our institution holding the presidential debate, and unless you have completely avoided TV, intranet, and social media you have heard that POTUS tested positive for COVID-19 2 days after leaving our facility, where he roamed mask-less. And while Len and I continue to be puzzled by scenes of him taking an excursion from Walter Reed wearing only a cloth mask, and then removing his mask once returning home, this reminds us how important it is to continue to upkeep social distancing and masking and to educate our patients to do the same. Daily rapid COVID testing is not a replacement for mask-wearing and social distancing. These tests can have up to 30% false-negative rates and this makes no sense to us.
What we know about Monoclonal antibodies and COVID-19
We are all aware the president received as part of aggressive therapy for his COVID-19 (in addition to the antiviral remdesiver and dexamethasone reserved for patients with hypoxia) a ‘cocktail’ of two monoclonal antibodies produced by Regeneron. We have been in contact with George Martin, a really smart dermatologist who serves on the National Psoriasis Foundation COVID-19 Task Force with Cassie, and he has shared the following narrative and references and the link to the public data. It should be noted that many monoclonals are now in clinical trials for COVID-19 including an advanced trial by Lilly who has released press statements (https://investor.lilly.com/news-releases/news-release-details/lilly-announces-proof-concept-data-neutralizing-antibody-ly) about their experience and is investigating it in combination with other agents as well, including remdesivir (a double anti-viral approach). It should be noted that the Lilly antibodies, unlike the Regeneron antibodies, failed to show a dose-effect at higher concentrations which is disturbing to us. As we always say “the data are the data”.
Excerpted from Dr Martins highly informative Maui Derm web site: (https://mailchi.mp/mauiderm/covid-19-articles-and-commentary-from-maui-derm-faculty-9545220)
Regeneron used two separate approaches to develop neutralizing antibodies against SARS-CoV-2: one from genetically-humanized mice and the other from B cells from convalescent patients. This strategy yielded a very large collection of antibodies with diverse sequences, three-dimensional structure, binding properties, neutralization and antiviral activity against the SARS-CoV-2 spike protein. Pairs of highly potent antibodies that bind to the receptor-binding domain of the spike protein were selected in order to minimize the risk for “viral escape” of mutated virus that has been observed in response to selective pressure from a single antibody treatment (1). In a trial of 275 patients with early pauci-symptomatic disease the antibodies were effective at reducing viral load and shortening illness.
References including the details of the study are below.
1. A. Baum et al., Science 10.1126/science.abd0831 (2020)).
Non-human primate studies in pre-clinical setting showed that this antibody cocktail was successful in preventing infection and clearing the SARS-CoV-2 virus in animals already infected (2)
(2) bioRxiv preprint doi: https://doi.org/10.1101/2020.08.02.233320. In addition to the Phase 1 study (2067) in which symptomatic outpatients received IV therapy, additional studies currently recruiting or underway include:
· Study 2066 involving 4 cohorts (N=390/cohort) of hospitalized patients to receive IV antibody cocktail who (1) require no O2, (2) low flow O2, (3) High flow O2 (4) mechanical ventilation.
· Study 2067 Household contacts prophylaxis (SQ injection)
· Study 2093 Normal human volunteer multi-dose SQ injections (PK/Safety)
· UK/NHS RECOVERY Phase 3 Hospitalized Study (IV)
A detailed summary of the Phase 1 results and the entire program overview can be found in the link below: https://investor.regeneron.com/static-files/a596a85e-e72d-4529-8eb5-d52d87a99070 Topline summary from the Phase 1 study:
· The REGN-COV2 antibody cocktail reduces viral loads and symptoms vs. placebo in non- hospitalized patients who are infected with SARS-CoV-2
· Greatest improvements were observed in patients who had not mounted their own effective immune response prior to treatment (antibody seronegative and/or high viral loads at baseline)
We await more detailed reporting.
What about MIS-A?
In other COVID-19 news, just last week an MMWR report was released by the CDC on COVID-19 related multisystem inflammatory syndrome in Adults (MIS-A), a rare but severe complication of COVID-19 and essentially the adult version of MIS-C (https://www.cdc.gov/mmwr/volumes/69/wr/mm6932e2.htm), which we had been hearing about for several months now. The report is written by Bamrah and colleagues, and Len and I feel privileged to have been acknowledged as consultants to CDC in the process of developing this preliminary case definition. (https://www.cdc.gov/mmwr/volumes/69/wr/mm6940e1.htm). So, what do we know about MIS-A? The criteria for this entity are as follows: 1) severe illness requiring hospitalization in a person aged ≥ 21 years, 2) a positive test for SARS-CoV-2 (nucleic acid, antigen or antibody) during current admission or in the previous 12 weeks, 3) severe dysfunction of one or more extrapulmonary organ systems, 4) laboratory evidence of severe inflammation and 5) absence of severe respiratory illness. Bamrah and her group describe 16 patients with MIS-A including 9 cases reported to CDC as well as 7 published case reports. Ten patients had positive SARS-CoV-2 PCR at the time of presentation with MIS-A, 7 of these also had positive antibodies on
presentation. Six patients had negative PCR on presentation and of these 4 had positive antibodies. Two patients had positive PCR 14 and 37 days prior to admission with negative PCR at the time of admission, and 3 patients had remote positive PCR (25-41 days prior) with persistent positive PCR on admission. Clinically, all 16 patients had evidence of cardiac effects ranging from ECG abnormalities to LV dysfunction on echocardiogram. Other systems involved included GI, derm, and mucous membranes. Inflammatory markers were markedly elevated with CRP ranging from 84-580 mg/L, Ferritins 196 to >100,000ng/mL, and elevated D-dimer. Seven patients received IVIG, 10 received steroids, and 2 anti-IL therapy. The majority required ICU care and vasopressors, 2 patients died. It cannot be underscored enough that excluding patients with ARDS is critical in increasing our understanding of COVID-19 inflammatory states since ARDS itself can be the source of ongoing inflammatory drivers (i.e. damage associated membrane patterns, DAMPS) which confound most studies thus far. The pathophysiology of MIS-A is currently unknown (same for MIS-C) and numerous mechanisms have been proposed including a post-infectious process, an autoinflammatory process, or even autoimmune as at times there appears to be a delay between acute COVID-19 infection and onset of MIS-A, but not always. Interestingly, no patients in the CDC series, and only one patient in the case reports was Caucasian. Add this to the list of the many things we need to learn more about
Shout out with any questions or comments, or anything you’d like to read about in future issues of COVID-19 Corner
Shout out with any questions or comments