The universal threat posed by SARS-CoV-2 has quickly mobilised international research. Since December 2019, over 1,700 scientific articles have been listed in the PubMed database. The FDA's Clinical Trial Registry contains 220 registered trials and the WHO's larger registry contains almost 700 clinical studies. Preliminary approaches have already emerged and are based on the knowledge gained from work previously conducted on existing coronaviruses (SARS, MERS) and other RNA viruses (influenza, HCV, Ebola...). Rapidly performed genome sequencing and modelling of structural viral proteins have also made it possible to establish a list of potentially effective and already-available molecules (drug repurposing).
Ongoing clinical research around the world
The WHO international clinical trials registry platform now lists a total of 381 interventionalstudies on SARS-CoV-2, including eight phase I studies, three phase I/II studies, 23 phase II studies, nine phase II/III studies and 15 phase III studies. In Europe, 160 randomised clinical trials have been identified as of March 20, 56 of which are controlled clinical trials (CCTs) evaluating targeted treatments. According to a CRESS analysis (Centre for Research in Epidemiology and Statistics), the molecules or combinations of molecules most frequently evaluated in these CCTs are oseltamivir alone or in combination with ritonavir, lopinavir-ritonavir, remdesivir, baloxavir marboxil, tocilizumab and umifenovir.
In France, dedicated research has been rapidly launched, mostly through the REACTing consortium (REsearch and ACTion targeting emerging infectious diseases), coordinated by Inserm (the national institute for health and medical research) and created in 2014 to provide timely responses to emerging infectious diseases. On March 12, the consortium selected 20 research projects, including three epidemiology research projects, seven fundamental research projects and four research projects in the field of human and social sciences. The five other trials are aimed at better understanding the links between viral shedding and biological and clinical response, developing serological tests and identifying therapeutic approaches (vaccines and drug repurposing). The most recently selected project is the Discovery trial, which compares the efficacy of remdesivir, lopinavir-ritonavir alone or in combination with β interferon and hydroxychloroquine in standard care, compared to standard care alone in severe COVID-19 cases. It will eventually include 800 French patients and a total of 3,200 European patients, thus constituting the European counterpart of the "mega-trial" launched by WHO on these same molecules.
From viral targets...
Genome sequencing has revealed a 79% homology between the SARS-CoV-2 and SARS-CoV-1 with several important elements that are structurally very similar between the two coronaviruses. The latter include the RNA-dependant RNA polymerase (RdRp); the viral C3CLpro and PLpro proteases, which mediate viral replication; or the spike S glycoprotein, which allows viral entry into cells. Hence, several approaches are being considered:
- Inhibition of viral entry into cells:
The spike S protein, present on the surface of the virus, binds to the cell's ACE2 receptors with the help of the cellular protease TMPRSS211. SARS-CoV-2 then enters the cell through endocytosis.
Several molecules counteract this first step: choloroquine, hydroxychloroquine and baricitinib have been reported to inhibit endocytosis and camostat, registered in Japan for the treatment of chronic pancreatitis, is an antagonist of the TMPRSS211 protein.
Umifenovir (Arbidol®), an antiviral treatment for influenza infection used in Russia and China, is also the subject of several clinical studies; although preliminary results do not appear conclusive. More recently, CD147 has been identified as a transmembrane receptor involved in cell entry and an anti-CD147 monoclonal antibody, meplazumab, is undergoing clinical trials in China with promising preliminary data.
- Inhibition of RNA polymerase, an essential component for viral replication:
Several antivirals target this mechanism: remdesivir (a nucleotide analogue), which has been studied in the treatment of SARS and MERS-CoV-related diseases, the Ebola virus, and different betacoronaviruses, is the logical candidate of several clinical studies. Favipiravir (organofluorine pyrazine), originally registered in Japan for the treatment of influenza, has been found to have a broad-spectrum antiviral activity against RNA viruses. Initial data from an open, non-randomised Chinese study suggest a higher efficacy profile for this molecule compared to that of the lopinavir-ritonavir combination. This has led to the registration of favipiravir in China as the first COVID-19 specific drug. Other antiretrovirals such as ribavirin (a nucleoside analogue) are also under investigation.
- Inhibition of the proteases, another component necessary for viral replication:
The anti-HIV proteases combination, lopinavir-ritonavir, is still being considered even though disappointing results were recently obtained. Other anti-HIV molecules under investigation are the combination treatments darunavir-cobicistat, atazanavir-ritonavir or danoprevir.
Finally, through drug repurposing, the drugs for seasonal influenza oseltamivir and baloxavir marboxil, and IgG1 MHAA4549A are also being investigated in clinical trials.
... to inflammatory mechanisms
COVID-19 is associated with increased levels of certain cytokines and chemokines, such as IL-1, IL-2, IL-4, IL-7, IL-10, IL-12, IL-13, IL-17, GCSF, IFNg and TNFα. Severe forms of COVID-19 have been shown to be associated with elevated release of IL-6, IL10, TNFα or IP-10. These inflammatory responses contribute to the severity of the disease. Consequently, such findings quickly prompted the evaluation of monoclonal antibodies such as tocilizumab or sarilumab (anti-IL-6), adalimumab (anti-TNFα), ixekizumab (anti-IL-17), in both severe and non-severe forms of the disease. Similarly, interferons, known for their ability to interfere with the replication mechanism of viruses, are interesting candidates and several of them are currently being evaluated (IFNα1b, IFNα2b, IFNβ1b). In Canada, a clinical trial using colchicine is aimed at decreasing the cytokine storm associated with severe forms of COVID-19. Baricitinib (anti-JAK) may have an effect on the production of cytokines and the entry of the virus into the cell. Finally, checkpoint inhibitor therapies (camrelizumab, CD24Fc) and immunosuppressants (pirfenidone, fingolimod) are also being studied in various clinical trials.
The drug repurposing trend is far from over. According to a recent publication, 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds could be candidates. In the meantime, international R&D bodies are working on the development of antiviral compounds with anti-protease or RNA polymerase blocking mechanisms. Other, more experimental approaches, are also being pursued such as interfering RNAs that interact with a specific messenger RNA to reduce translation into protein (antisense RNA or oligonucleotides, ribozymes, etc.)
What prospects exist on the vaccination front?
The surface spike S protein is the key inducer of host immune response in SARS-CoV-1 studies and is therefore the main target of vaccine research. Three vaccines have already entered clinical trials:
- The mRNA-1273 vaccine is one of the first vaccines to reach the clinical evaluation stage in the United States. This messenger RNA encodes the spike S protein, whose translation will trigger immunity. The phase I trial began at the end of February and is expected to compare safety and immunogenicity in 45 patients receiving one of the three designated doses, with the end of the study scheduled for June 2021. The developing company has reported that it is unlikely to have a vaccine available before 12 to 18 months, however, it has indicated that it may be considered for use in some individuals, including healthcare professionals, as early as fall 2020.
- In the United Kingdom, a phase I/II study conducted by Oxford University is evaluating the safety and efficacy of a vaccine in which a recombinant adenovirus contains the SARS-CoV-2 S-glycoprotein gene. It is recruiting 510 adult patients randomised into five groups (3 active, 2 placebo) with a planned follow-up at 12 months. A second vaccine, using the same vector and the same target, has also reached phase I and has already started recruitment in China, with safety and immunogenicity monitoring over six months post-injection.
In parallel, a Chinese research institute is currently evaluating two therapeutic vaccination approaches aimed at activating the production of SARS-CoV-2-specific T lymphocytes. The first one is based on artificial antigen presenting cells and the second on an efficient lentiviral vector system to deliver viral genes.
Other candidates expected to reach clinical stages in the next few weeks include the INO-4800 DNA vaccine, the BNT162 mRNA vaccine (to be tested as early as the end of April), and a subunit vaccine (by May). According to WHO, around 40 other vaccines are in the pre-clinical phase.
The plasma transfusion option
Passive immunotherapy trials are underway in China and the United States where infected patients are receiving convalescent plasma and the FDA has authorised the use of transfusions for severe and critical cases. The promising results obtained in the uncontrolled case series of five critically ill Chinese patients with acute respiratory distress syndrome must now be confirmed by randomised controlled studies.
-Translated and adapted by Sarah Issa from Caroline Guignot's COVID-19 : la recherche clinique internationale connaît un dynamisme inédit