While political leaders across the globe have been closing their borders, scientists have been transcending theirs, creating an unprecedented global collaboration. Never have so many experts in so many countries focused simultaneously on a single topic and with such urgency. Nearly all other research has come to a grinding halt. Usual imperatives like academic credit have taken a backseat. Online repositories are making studies available months ahead of journals. Researchers have identified and shared hundreds of genome sequences of the viral pathogen. More than 200 clinical trials have been launched, amassing global endeavours. It is thought that the closest comparison to this moment might be the height of the AIDS epidemic in the 1990s, when scientists and doctors locked arms to combat the disease. But the two can hardly be compared considering today’s technology and pace of information-sharing three decades later. This openness is very much reflected on the servers of medRxiv and bioRxiv, two online archives that share academic research before it is reviewed and published in journals. They have been flooded with coronavirus research from across the globe. And, despite the nationalistic tone set by the Chinese government, even Chinese researchers have contributed a sizeable portion of the coronavirus research available in the archives. So, nearly five months into the pandemic, with over 1.5 lakh people already dead and no signs of slowing of the spread, let us look at the round-up on some of the vital aspects of COVID-19 research.
• The combination of lopinavir-ritonavir features prominently in the SOLIDARITY trial launched by the World Health Organization (WHO), both alone and in combination with interferon-β.
• To date, over 380 trials for COVID-19 have been posted on ClinicalTrials.gov, ranging from repurposed antiviral drugs to novel diagnostic imaging techniques.
• Antibody- and convalescent plasma-based approaches have dominated the news. The FDA just approved a plasma therapy trial at Johns Hopkins University. Takeda has announced a polyclonal hyperimmune antigen-purified antibody concentrate. The process used to recover antibodies from patients, already approved for the treatment of other infectious diseases, could lead to fast-track approval. Regeneron is pursuing a monoclonal antibody strategy using its humanized mouse antibody screening platform to produce an antibody cocktail for both therapy and prophylaxis.
• Although hopes for antibody-based immunity are high, currently, there is hardly any data available on whether human populations develop immunity to SARS-CoV-2. The WHO has announced a large-scale effort (named SOLIDARITY II) to collate serological data from different countries and post results from the initiative within the next few months.
• Some studies have found a correlation between the serum levels of interleukin-6 (IL-6) and severity of COVID-19 symptoms. Additionally, a preprint suggests that treatment of 20 severe or critical COVID-19 patients with the anti-IL-6 receptor drug tocilizumab could have been effective. Roche announced the launch of a trial of tocilizumab, recruiting 330 participants with severe COVID-19. Preliminary results are expected in the summer. Sanofi and Regeneron have expanded the testing in an existing clinical trial of their own anti-IL-6 receptor monoclonal antibody in rheumatoid arthritis to include severe or critically ill COVID-19 patients.
• 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 patients who received a repurposed RNA polymerase inhibitor, remdesivir, on a compassionate basis in the New England Journal of Medicine. 36 out of 53 patients showed some sign of improvement, including 17 out of 30 patients on mechanical ventilation who were extubated. However, several limitations include the lack of a primary endpoint, a target for patient recruitment and a control group. The study also did not 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-chloroquine, was reported in MedRxiv. The study found no significant benefits of chloroquine–azithromycin and highlighted some safety concerns, with the high-dose arm terminated early due to the incidence of QT interval prolongation. A Chinese multicenter open-label randomized control study of COVID-19 patients treated with hydroxychloroquine alone, also in MedRxiv, found no effect on its primary endpoint, the negative conversion rate, but did exhibit a moderate reduction in lymphopenia and C-reactive protein levels.
• No vaccines are expected to reach the market within the next year. Currently, the WHO is curating a list of potential vaccines, of which two are currently under clinical evaluation: an adenoviral vector-based approach by CanSino Biological Inc. and the Beijing Institute of Biotechnology, and an RNA product by Moderna Inc. and the National Institute of Allergy and Infectious Diseases.
• Inovio Pharmaceuticals launched a phase I clinical trial of INO-4800, its DNA vaccine for COVID-19. Previously Inovio had reportedpartial positive results using a similar strategy in a phase I trial of its Middle Eastern respiratory syndrome (MERS) DNA vaccine.
• 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. SGIMI also announced a second phase I trial testing artificial antigen-presenting cells modified with lentiviral vectors to express multiple SARS-CoV-2 minigenes and immunomodulatory genes.
• Pfizer announced jointly with BioNTechSE from Germany to bring its COVID-19 mRNA vaccine into phase I trials by the end of April.
Diagnostics and Serology
• A detailed analysis of 9 mild cases of COVID-19 in Germany detected SARS-CoV-2 in oro- and naso-pharyngeal samples that peaked at day 5 of symptoms. Live replicating SARS-CoV-2 was found in the throat, unlike that described for SARS-CoV. Both the viral RNA and the live virus were detected in the sputum, which may lead to simpler sample-collection protocols. Although high viral RNA concentrations were found in the stool, the authors were not able to isolate live virus from it. No urine or blood samples had 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, they 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.
• A study surveying levels of neutralizing antibodies (NAbs) to the SARS-CoV-2 spike protein in the plasma of 175 patients who had recovered from COVID-19 in one health centers in Shanghai, China, published in medRxiv, shed light on the development of natural immunity to the virus. Although patients in this study were classified as mild cases, antibody levels correlated positively with C-reactive protein and inversely with lymphocyte counts (NAb levels also tended to be higher in older subjects). A troublesome aspect of the study was that approximately 30% of recovered patients showed low NAb titers, including 10 patients with NAbs below the detection limit of the assay.
• A screen of Epstein-Barr virus-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. Though 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.
As the number of confirmed cases surges past 2.2 million globally, clinicians are uncovering new information about the spread of this disease in the body of an individual every day. The fast-evolving understanding of how the virus attacks cells around the body could be a crucial help for the doctors on the front lines providing treatment.
Establishing animal models of COVID-19 is a critical step toward understanding its pathophysiology and developing novel therapies.
• In Cell Host & Microbe, ferrets have been shown to mimic important aspects of human SARS-CoV-2 infection, including viral replication, fever and ferret-to-ferret transmission (although there were no fatalities). Infected ferrets also shed virus in nasal washes, saliva, urine and feces like humans.
• A preprint in bioRxiv also reported viral replication and transmission in domestic cats, but not in dogs, pigs, chickens or ducks.
• Also, a tiger in the Bronx zoo, USA has tested positive for SARS-CoV-2.
• Modelling work by Ferretti et al. suggests that digitizing contact tracing through a mobile phone app may be able to suppress the epidemic sustainably. The app would help build “a memory of proximity contacts” and eliminate the delay in notifying contacts of infected people. The authors, however, caution that their models rely on a basic reproduction number (R0) derived using the Chinese data, which may not be accurate for the fast-spreading European epidemic.
• An analysis of 1,591 patients in 72 regional hospitals in Lombardy, Italy, published in JAMA, reports that mortality in the intensive care unit was 26%. Among the patients studied, the majority were male (82%) and had extensive comorbidities, confirming previous reports that these factors may play a part in the severity of the disease. The most frequent comorbidity was hypertension (49% overall and 62% of deaths).
• Among those patients whose files had respiratory support data, 88% were put on mechanical ventilation.
• A brief communication, published in Nature Microbiology, reports evidence of community spread of SARS-CoV-2 within the city of Wuhan, China. The researchers re-analysed 640 throat swabs collected for influenza-like illness in Wuhan between October 2019 and January 2020. Nine of the swabs tested positive for SARS-CoV-2; the first positive sample was collected in the first week of 2020.
• 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% (44 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.
Viral Origin and Structure
• Andersen et al. presented a detailed analysis of the origin of SARS-CoV-2. A couple of papers report additional crystal structures for the SARS-CoV-2 RBD bound to ACE2. Lan et al. inferred convergent evolution of SARS-CoV and SARS-CoV-2 RBDs, indicative of selection in the passage to humans. Shang et al. used surface plasmon resonance to show that the RBD from SARS-CoV-2 bound more strongly to human ACE2 than did the RBD from SARS-Co-V. Interestingly, Shang et al. proposed that a related bat coronavirus, RaTG13, might also use ACE2 to enter human cells – a finding with worrying implications for the ability of bat coronaviruses to directly invade human hosts. In another report, a probable link to pangolin was identified with respect to the origin of SARS-CoV-2.
• A Nature study led by Haitao Yang at Shanghai Tech University, China, has solved the crystal structure of the SARS-CoV-2 main protease (Mpro).
Here’s looking forward to many more such discoveries lighting up our gloomy hearts in the upcoming days!