Therapy and clinical trials
The US company Inovio Pharmaceuticals launched a phase I clinical trial of INO-4800, its DNA vaccine for COVID-19. Inovio previously reported partial positive results using a similar strategy in a phase I trial of its Middle Eastern respiratory syndrome (MERS) DNA vaccine, which induced neutralizing antibodies and T-cell responses in a subset of subjects.
China’s Shenzhen Geno-Immune Medical Institute (SGIMI) has begun phase I trials of LV-SMENP-DC, a cellular vaccine made up of dendritic cells (DCs) transduced with SARS-CoV-2 spike, membrane, nucleocapsid, envelope and protease (SMENP) minigenes along with immunomodulatory genes using a lentiviral vector. People whose throat swabs tested positive for COVID-19 will receive the transduced DCs together with activated antigen-specific cytotoxic T cells subcutaneously.
SGIMI has also announced a second phase I trial testing artificial antigen-presenting cells modified with lentiviral vectors to express multiple SARS-CoV-2 minigenes as well as immunomodulatory genes.
Pfizer announced a joint effort with Germany’s BioNTechSE to bring its COVID-19 mRNA vaccine into phase I trials by the end of April.
Novartis announced plans for a phase III trial of its Janus kinase 1 (JAK1) and JAK2 inhibitor ruxolitinib in patients suffering from COVID-19-associated cytokine storms.
Gilead reported the outcomes of 53 patients who received a repurposed RNA polymerase inhibitor, remdesivir, on a compassionate basis in the New England Journal of Medicine. Thirty-six patients showed some sign of improvement, including 17 out of 30 patients on mechanical ventilation who were extubated. However, the open-label study had several limitations, including the lack of a primary endpoint, a target for patient recruitment and a control group. The study also failed to collect information on viral load, making it impossible to correlate the results with direct measures of the drug’s antiviral activity.
A phase IIb trial of 81 patients in Manaus, Brazil, treated with azithromycin in combination with high- or low-dose chloroquine, was reported in MedRxiv. The study, which has not yet been peer-reviewed, found no evidence of significant benefits of chloroquine–azithromycin and highlighted safety concerns, with the high-dose arm terminated early due to the incidence of QT interval prolongation. Also in MedRxiv, a multicenter open-label randomized control study of COVID-19 patients in China treated with hydroxychloroquine alone failed to show any effect on its primary endpoint, the negative conversion rate, but did exhibit a moderate reduction in lymphopenia and C-reactive protein levels. This study also has not yet been peer-reviewed.
A screen of Epstein-Barr virus (EBV)-immortalized memory B cells derived from a patient who recovered from SARS in 2003 identified eight monoclonal antibodies that cross-reacted with SARS-CoV-2, and one, S309, showed potent neutralizing activity. Although S309 recognizes an epitope on the SARS-CoV-2 spike glycoprotein, it does not target the receptor-binding domain and is not predicted to block angiotensin-converting enzyme 2 (ACE2) binding. The work, led by David Veesler (University of Washington, USA) and Davide Corti (Humabs Biomedical, Switzerland), was reported as a preprint and has not yet been peer-reviewed.
A modeling study led by Marc Lipsitch at Harvard’s T. H. Chan School of Public Health, published in Science, concludes that “prolonged or intermittent social distancing may be necessary into 2022”. The model assumes that immunity to SARS-CoV-2 will resemble what is observed for the related human coronaviruses OC43 and HKU1 — an assumption that remains to be tested. Based on serological samples from approximately 1,000 inhabitants of the German town of Gangelt (population of 12,529 people), an early COVID-19 epicenter, Bonn University researchers estimate an infection rate of 14% and a fatality rate of 0.37% (seven reported deaths in the town) in this non-peer reviewed report (in German). Correspondence in the New England Journal of Medicine shows results from the systematic screening of 214 mothers admitted into Columbia University Irving Medical Center’s labor and delivery unit in New York City. The letter reports a 13.7% frequency of asymptomatic carriers of SARS-CoV-2 (along with four symptomatic cases, or 1.9%).
The New England Journal of Medicine published a large-scale COVID-19 diagnostic testing effort in Iceland, which found that 43% of positive cases had reported no symptoms at the time of testing. The study also found very low rates of infection in children under 10 years of age. A Brief Communication in Nature Medicine reinforces the importance of asymptomatic carriers. The study analyzed 414 throat swabs from 94 SARS-CoV-2-positive mildly or moderately ill patients in Guangzhou Eighth People’s Hospital, China. They found the highest SARS-CoV-2 viral load in the first days after symptom onset, which gradually declined to the detection limit around day 21 after onset. The authors also analyzed publicly available data on 77 infector–infectee pairs and arrived at an estimate of 44% of pre-symptomatic transmission. The study estimates that peak infectivity occurs between days 0 and 2 of symptom onset.
A Nature study led by Haitao Yang at ShanghaiTech University, China, has solved the crystal structure of the SARS-CoV-2 main protease (Mpro). By a combination of in silico and high-throughput fluorescence resonance energy transfer screening approaches, the team identified several drugs that could specifically target Mpro, including one, the organoselenium compound ebselen, which has already been shown to have a good safety profile in humans.