A video recording of this week’s Grand Rounds presentation on the Approach to Monoclonal Antibodies in Ebola and now COVID is now available: http://bit.ly/Sept16MGR

Questions and answers can be found here: https://stanford.io/2VSkoGb

And here’s a summary from Joy Wu, MD, PhD, associate professor of endocrinology:

Inpatient updates (Neera Ahuja, MD)

• world hotspots - Israel, Spain, Argentina
• cases in US, Bay Area, and SHC consistently declining
• 430 hospitalized at SHC from Mar 1 to Sep 13: stable ICU and death rates, gender and age distribution
• pediatric inpts: 87% Hispanic, 55% male, 38% previously healthy, 66% asymptomatic (admitted for other diagnoses)

• SARS-CoV-2 = (+) strand single-stranded RNA virus, genetically similar to SARS and bat coronaviruses
• single glycoprotein on surface (Spike) required for interaction with host receptor (ACE2), fusion and entry into cells
• advantages of fully human monoclonal Abs as rapid response
  • rarely have off target toxicity
  • unlike vaccines, will provide immediate protection that may last >1 mo
  • newest technologies allow isolation of fully human mAbs will low immunogenicity potential
  • straightforward to identify multiple mAbs that bind different epitopes on the pathogen -> multiple mAbs can be used in combo to prevent mutational escape
  • new innovations have bypassed traditional bottlenecks in development and dramatically shortened timelines
• preferably “cocktail” of 2 non-competing Abs to allow for high neutralization potency while protecting against mutant escape, to be used for prophylaxis and/or treatment of COVID-19
• epitope domain relatively small, cannot find 3 Abs that bind without neutralizing each other (unlike Ebola)
• all Abs must meet criteria: block replicating virus, bind to and neutralize infected cells, at sub-nanomolar concentrations
• Baum, Science 2020: Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies (https://science.sciencemag.org/content/369/6506/1014)
• Baum BioRxiv 2020: REGN-COV2 can protect rhesus macaques from infection, and increase clearance in infected rhesus macaques
• 4 ongoing trials
  • hospitalized (IV): no O2, low flow O2, high flow O2, mechanical ventilation
  • outpatient (IV): symptomatic vs asymptomatic
  • household contacts prophylaxis (SQ): PCR+ vs PCR- at baseline
  • normal human volunteer multidose PK/safety
• immune modulation by IL-6R blockade with sarilumab may have modest effect in critical COVID-19 but studies not large enough to definitely answer
• baseline viral titers are higher in patients requiring more ventilatory support, and among intubated patients higher viral titers associated with worse outcomes
• hospitalized patients may have mixed cause of O2 requirements: partially due to overactive immune system, partially due to continued live viral replication
• single-arm experiments in this disease can be misleading, need well-designed control experiments