Therapy and clinical trials
One of the oldest forms of immunotherapy is being pressed into action again. A study in JAMA follows the transfer of serum from five donors who had recovered from the respiratory disease COVID-19 and had high titers of immunoglobulin G antibodies to the causative coronavirus SARS-CoV-2 to five patients on mechanical ventilation. Three of the five recipients were weaned from assisted ventilation and were subsequently discharged. The study has many limitations beyond the small number of patients, including the lack of a placebo group and the diverse set of treatments, including antivirals, that each patient was receiving. An earlier preprint in medRxiv described the outcomes of ten patients treated with such convalescent plasma. Three of the patients were on mechanical ventilation, and two were successfully weaned.
Diagnostic and serology
A detailed analysis of nine mild cases of COVID-19 in Germany showed detectable SARS-CoV-2 in oro- and naso-pharyngeal swabs that peaked at day 5 of symptoms. Live replicating SARS-CoV-2 was found in the throat, in contrast to what has been described for SARS-CoV. Both viral RNA and live virus were detected in sputum, which may lead to simplified sample-collection protocols. Although high viral RNA concentrations were found in stool, the authors were not able to isolate live virus from this source. All urine and blood samples tested negative for viral RNA.
Ju et al. used labeled SARS-CoV-2 spike protein receptor-binding domain (RBD) as a probe to sort antigen-specific B cells from eight infected patients in Shenzhen, China. From these sorted B cells, the authors produced 206 monoclonal antibodies with confirmed RBD binding. The capacity of monoclonal antibodies to compete with the receptor ACE2 for RBD binding was the best predictor of their neutralizing activity. Interestingly, the study found both germline clones and somatically mutated clones with high virus-neutralizing capacity.
Establishing animal models of COVID-19 is a critical step toward understanding its pathophysiology and developing novel therapies. In Cell Host & Microbe, ferrets were shown to mimic important aspects of human SARS-CoV-2 infection, including viral replication, fever and ferret-to-ferret transmission (although no fatalities were observed). Like humans, infected ferrets shed virus in nasal washes, saliva, urine and feces. A preprint in bioRxiv also shows that ferrets are susceptible to SARS-CoV-2 infection, and reports viral replication and transmission in domestic cats, but not in dogs, pigs, chickens or ducks.
Modelling work by Ferretti et al. suggests that digitizing contact tracing through a mobile-phone app may achieve sustainable epidemic suppression. The app would build “a memory of proximity contacts” and eliminate the delay in notifying contacts of infected people. The authors caution that their models rely on a basic reproduction number (R0) derived using data from China, which may not be accurate for the fast-spreading European epidemic.
Viral origin and structure
A pair of papers in Nature report additional crystal structures for the SARS-Cov-2 RBD bound to ACE2. Lan et al. infer convergent evolution of SARS-CoV and SARS-CoV-2 RBDs, indicative of selection in the passage to humans. Shang et al. use surface plasmon resonance to show that the RBD from SARS-CoV-2 binds more strongly to human ACE2 than does the RBD from SARS-Co-V. Interestingly, Shang et al. propose that a related bat coronavirus, RaTG13, may also use ACE2 to enter human cells―a finding with worrying implications for the ability of bat coronaviruses to directly invade human hosts. In a third report in Nature, two separate sub-lineages of coronaviruses closely related to SARS-CoV-2 were identified in the suspected intermediate host, the Malayan pangolin.