Novel Coronavirus SARS-CoV-2, the agent responsible for coronavirus disease 2019 (COVID-19), is producing a growing public health emergency in China and elsewhere in the world.
Currently, the treatments for any coronavirus are limited. Treatments that are in the pipeline for SARS-CoV and MERS-CoV are being leveraged to determine if they may be useful against the novel coronavirus SARS-CoV-2 while more specific agents are under development.
Potential Agents Under Investigation for Activity Against SARS-CoV-2
Agents Against SARS-CoV-2
One partnership that has been examining the development of anti-viral drugs against SARS-CoV-2 is the partnership between University of Alabama (UAB) and the pharmaceutical manufacturer, Gilead. This partnership is currently conducting a placebo-controlled trial that will test the safety and effectiveness of the anti-viral drug Remdesivir. UAB is working with Gilead Sciences and nearly a dozen other universities across the U.S. as part of a five-year $37.5 million grant from the National Institute of Allergy and Infectious Diseases.1
Agents Against MERS-CoV
The combination of Regeneron’s neutralizing monoclonal antibodies, REGN3048 and REGN3051, is being studied against coronavirus infection in a first-in-human clinical trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). The safety and tolerability of the drug will be studied in 48 patients.
Both antibodies bind to S-protein of MERS-CoV. The intravenous administration of the drug in the mouse model of MERS disease resulted in the high-level neutralization of MERS-CoV in circulating blood with reduced viral loads in the lungs.2
Agents Against HIV
The use of the HIV antiretroviral (ARV) combination, lopinavir-ritonavir, has been studied in coronavirus. Lopinavir is believed to act on the intracellular processes of coronavirus replication and has demonstrated reduced mortality in non-human primate models infected with MERS-CoV.3 Lopinavir/ritonavir in combination with ribavirin showed reduced mortality rate and milder disease course during an open-label clinical trial in patients during the 2003 SARS disease outbreak4,5; however, a subsequent systematic review described these studies as inconclusive due to possible bias in selection of control group or treatment allocation.6 Another ARV manufactured by Janssen Pharmaceutical Companies, a subsidiary of Johnson & Johnson, donated its darunavir/cobicistat HIV medication for use in research activities aimed at finding a treatment for COVID-19 disease.7
The antiviral drug Galidesivir (BCX4430) has shown broad-spectrum activity against a wide range of pathogens including coronavirus. It is a nucleoside RNA polymerase inhibitor that disrupts the process of viral replication. The drug has already shown survival benefits in patients infected with deadly viruses such as Ebola, Zika, Marburg, and Yellow fever.8
Another promising therapeutic agent for COVID-19 infection that is being developed by the pharmaceutical company CytoDyn is leronlimab (PRO 140). Leronlimab is a CCR5 antagonist. The drug is already being investigated in phase 2 clinical trials as a treatment for HIV and has been awarded fast-track approval status by the United States Food and Drug Administration.9
Select coronavirus drug development programs
|Johnson & Johnson||N/A||Vaccine||Preclinical testing|
|Gilead||Chinese health authorities||Antiviral||Planning clinical study in China|
|GlaxoSmithKline||CEPI||Vaccine adjuvant||Agreement signed with Univ. of Queensland|
|Moderna||NIH, CEPI||mRNA vaccine||IND-enabling studies|
- Source: Company statements
- CEPI=Coalition for Epidemic Preparedness Innovations
Development of a Vaccine for SARS-CoV-2
The SARS-CoV-2 novel coronavirus appears to exhibit a high transmissibility rate, possibly even higher than influenza, based on recent information from Chinese expert virologists.10-12 (Also, see the “Introduction and Epidemiology” section.)
The major worry is that SARS-CoV-2 will cause a global pandemic similar to what was observed with the SARS-CoV coronavirus in 2002–2003. In that year, there were 8098 cases and 774 deaths (10% mortality), mostly in China.13 However, it also caused an epidemic in Toronto, Ontario, Canada. The SARS pandemic was a major global public health threat that prompted the World Health Organization to institute new International Health Regulations (IHR 2005).14 SARS also caused significant economic damage to China and Toronto and caused a loss in confidence in the leadership of China.
Will SARS-CoV-2 cause a similar pandemic? No one knows for sure, but there are some important differences between this virus and SARS. The good news is that COVID-19 does not seem to be as lethal as SARS, although many patients (up to one-quarter) in Wuhan are requiring respiratory support.15 Those estimates do not consider the many cases of individuals with mild symptoms who go undiagnosed. The bad news is that SARS-CoV-2 appears to be highly transmissible, possibly more so than SARS.
As the transmissibility of SARS-CoV-2 increases, the need to develop and deploy a vaccine becomes more urgent.
There are several vaccines candidates being developed after the announcement of the emergence of COVID-19. Two major biotechnology companies are developing innovative DNA and RNA vaccines, respectively. One group that is based in Oslo, Norway, is the Coalition for Epidemic Preparedness Innovations (CEPI) which develops vaccines for emerging infections. CEPI has funded four separate efforts to develop a COVID-19 vaccine: Inovio, a partnership between Moderna and the National Institute of Allergy and Infectious Diseases, CureVac, University of Queensland, in Australia and GSK.16
Over the past four years Moderna has had six positive Phase 1 clinical endpoints in its prophylactic vaccines modality and moved two additional programs into development. Moderna’s technology platform, fully integrated manufacturing site and development experience, combined with a multi-year relationship with the NIH, including exploring ways to respond to public health threats, may allow for the rapid identification and advancement of a vaccine candidate against SARS-CoV-2.
A group at the University of Hong Kong has modified an influenza vaccine to express the spike protein, while teams at the National School of Tropical Medicine and Texas Children's Hospital Center for Vaccine Development at Baylor (co-directed by Dr. Peter Hotez and Dr. Maria Elena Bottazzi), are developing a recombinant protein-based vaccine comprised of the receptor binding domain (RBD) of the spike protein. The spike protein of the coronavirus binds to receptors found deep in the host lung tissue. The RBD for SARS has already been manufactured for clinical use,17 and additional preclinical tests are being conducted to advance it into clinical trials to determine if it is safe, sufficiently protective, or cross-reactive against COVID-19. In parallel, these teams are also developing the RBD from COVID-19.
One advantage of recombinant protein-based vaccines is that they are an established, proven, well-recognized, and safe technology that led, for example, to the development of the licensed hepatitis B vaccine and the human papillomavirus vaccine..12 A second advantage is that using the selected RBD vaccine candidate appears to minimize some of the potential toxicities observed with other respiratory virus vaccines.
Once the preclinical tests for the RBD vaccine are completed, there is the possibility work may advance rapidly to human clinical trials in the Vaccine Research Center at Baylor College of Medicine.
- http://grantome.com/grant/NIH/U19-AI109680-01. (Accessed February 12, 2020.)
- Pascal KE, Coleman CM, Mujica AO, et al. Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection. Proc Natl Acad Sci U S A. 2015;112(28):8738–8743. doi:10.1073/pnas.1510830112
- Chan JF, Yao Y, Yeung ML, Deng W, Bao L, Jia L, Li F, Xiao C, Gao H, Yu P, Cai JP, Chu H, Zhou J, Chen H, Qin C, Yuen KY. CoV, Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. J Infect Dis. 2015 Dec 15;212(12):1904-13. doi: 10.1093/infdis/jiv392. Epub 2015 Jul 21.
- Chan KS, Lai ST, Chu CM, Tsui E, Tam CY, et al. (2003) Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: A multicentre retrospective matched cohort study. Hong Kong Med J 9: 399–406.
- Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, et al. Role of lopinavir/ritonavir in the treatment of SARS: Initial virological and clinical findings. Thorax. 2004;59:252–256.
- Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med. 2006;3(9):e343. doi:10.1371/journal.pmed.0030343.
- https://www.europeanpharmaceuticalreview.com/news/111977/johnson-johnson-launch-response-to-coronavirus/ (Accessed February 15, 2020.)
- Eyer L, Nougairède A, Uhlířová M, et al. An E460D Substitution in the NS5 Protein of Tick-Borne Encephalitis Virus Confers Resistance to the Inhibitor Galidesivir (BCX4430) and Also Attenuates the Virus for Mice. J Virol. 2019;93(16):e00367-19. Published 2019 Jul 30. doi:10.1128/JVI.00367-19
- https://www.thepharmaletter.com/article/cytodyn-signs-china-deal-over-coronavirus-and-cancer-candidate (Accessed February 14, 2020.)
- Li Q, Guan X, Wu P, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. 2020:1-9. doi:10.1056/NEJMoa2001316
- Zhao S, Lin Q, Ran J, et al. Preliminary estimation of the basic reproduction number of novel coronavirus (2019-nCoV) in China, from 2019 to 2020: a data-driven analysis in the early phase of the outbreak. Int J Infect Dis. 2020;243:153057. doi:10.1016/j.ijid.2020.01.050
- Boëlle PY, Ansart S, Cori A, Valleron AJ. Transmission parameters of the A/H1N1 (2009) influenza virus pandemic: a review. Influenza Other Respi Viruses. 2011;5(5):306-316. doi:10.1111/j.1750-2659.2011.00234.x
- Mahase E. China coronavirus: what do we know so far? BMJ. 2020;368(January):m308. doi:10.1136/bmj.m308
- World Health Organization. International Health Regulations (2005). https://www.who.int/ihr/publications/9789241580496/en/. Accessed February 7, 2020.
- Wang D, Bo H, Chang H et al. Clinical Characteristics of the 138 hospitalized patients with novel coronavirus-infected pneumonia in Wuhan, China. JAMA Published online Feb 7, 2020 doi:10.1001/jama.2020.1585.
- The Coalition for Epidemic Preparedness Innovation (CEPI) https://cepi.net/news/ (Accessed February 15, 2020).
- Cao Z, Liu L, Du L, Zhang C, Jiang S, Li T, He Y. Potent and persistent antibody responses against the receptor-binding domain of SARS-CoV spike protein in recovered patients. Virology J.2011;7:299.
- Van Den Ende C, Marano C et al. The immunogenicity and safety of GSK’s recombinant hepatitis B vaccine: systemic review of 20 years of experience. Expert Rev Vaccines 2017 ;16(8):8111-832