Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the betacoronavirus that has caused the ongoing global pandemic of coronavirus disease 2019 (COVID-19), is transmitted easily via respiratory droplets and has also been shown to be highly transmissible as an airborne respiratory pathogen.
SARS-CoV-2 infection leads to a systemic viral invasion and causes mild to moderate upper respiratory disease. However, in some individuals such as the elderly, immunocompromised, and obese, COVID-19 causes severe disease resulting in significant pathology and death.
The infectious dose of SARS-CoV-2 in humans is low at approximately 100 virions, which is what makes the virus a very successful transmissible pathogen. SARS-CoV-2 infection is primarily mediated through the angiotensin-converting enzyme 2 (ACE2) receptor, and ACE2 receptor-rich tissues that govern the innate susceptibility to this virus.
Using animal models for testing vaccines and drugs against SARS-CoV-2
Several animal models, including transgenic mice and Siberian hamsters, are now available for testing vaccines and drugs against SARS-CoV-2. Although these models can be used for initial testing of novel drugs, testing in non-human primate models is necessary to assess the translational potential of the drug before clinical use.
Although the rhesus macaque model of COVID-19 mimics the mild to moderate disease seen in a large proportion of humans infected by SARS-CoV-2, it does not recapitulate severe disease or mortality. However, infected macaques show quantifiable viral replication in their respiratory and gastrointestinal tracts, acute lesions in their lungs, and an increase in pro-inflammatory cytokines.
Several vaccines are becoming available with high potential to blunt the COVID-19 pandemic. Passive infusion of potent monoclonal antibodies (mAbs) that target the SARS-CoV-2 spike protein is also a powerful tool with prophylactic as well as therapeutic potential.
Determining the prophylactic potential of an mAb cocktail before respiratory challenge in rhesus macaques
Researchers from the US tested the prophylactic potential of a combination of 2 mAbs administered 3 or 75 days before respiratory challenge in rhesus macaques. They used the rhesus macaque model to test the added benefit of combinatory parenteral administration of 2 high-affinity anti-SARS-CoV-2 mAbs - C144-LS and C135-LS. These mAbs were developed to neutralize the virus and tweaked to improve their pharmacokinetics. This study has been released as a preprint on the bioRxiv* server.
The researchers write:
The rhesus macaque model of COVID-19 recapitulates the mild to moderate disease shown in a large fraction of SARS-CoV-2 infected humans but does not recapitulate the most extreme forms of the disease, including death.”
Results show that mAbs at various doses resulted in near-complete virus neutralization
The researchers demonstrated that the administration of the mAbs at various doses resulted in near-complete virus neutralization. This was evidenced by the muting of cytokine/chemokine response, no detectable titer in mucosal tissue swabs, and lack of visible pathologic sequelae.
However, inhibition of infection was dose-dependent and cohorts that received lower doses had a low-grade viral infection in many mucosal sites compared to cohorts that received a fully protective dose. A subset of animals who were challenged with infection 75 days after mAb administration still had protection from disease.
This shows that the mAbs offered protection from SARS-CoV-2 replication and disease onset even 75 days after mAb administration. These findings indicate that this combination mAb effectively inhibits COVID-19 development in the rhesus disease model and speeds up the possibility of clinical studies with this antibody combination.
Thus, rhesus macaques are a robust model for testing the efficacy of prophylactic administration of mAbs, particularly those that have shown potential in smaller animal models.”
Findings underscore the potential of mAbs to infection prevention in clinical use
Overall, the authors strongly suggest that prophylactic use of mAb combinations administered systemically can offer durable and strong protection from mucosal infection with SARS-CoV-2. The mAb cocktail used in this study is undergoing clinical trial to assess real-world efficacy. The authors believe that this approach could offer protection from disease for individuals who cannot receive a vaccine or those who work in high-risk environments and need enhanced protection from the virus.
The team concludes:
Taken together, our data strongly suggest that prophylactic use of combinations of mAbs, such as those we tested, administered systemically can provide durable and potent protection from mucosal infection with SARS-CoV-2.”
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- Beddingfield, Brandon J. and Nicholas J. Maness, Alyssa C. Fears, Jay Rappaport, Pyone Pyone Aye, Kasi Russell-Lodrigue, Lara A. Doyle-Meyers, Robert V. Blair, Ann M. Carias, Patrick J. Madden, Ramon Lorenzo Redondo, HongMei Gao, David Montefiori, Thomas J. Hope, Chad J. Roy. (2021) Effective prophylaxis of COVID-19 in rhesus macaques using a combination of two parentally-administered SARS-CoV-2 neutralizing antibodies. bioRxiv preprint server. doi: https://doi.org/10.1101/2021.05.26.445878 https://www.biorxiv.org/content/10.1101/2021.05.26.445878v1