We’ve come a long way in a short time. Medical staff in Wuhan reported the first cases of pneumonia caused by a mystery pathogen on December 8 last year. Chinese authorities isolated a new coronavirus (SARS-CoV-2) about a month later. Developing a new drug typically takes a least a decade. But just weeks after SARS-CoV-2’s identification more than 500 studies for COVID-19 are underway, often ‘repurposing’ drugs developed for other illnesses, based on in vitro and safety data as well as biologic plausibility.1
Meanwhile, a candidate vaccine entered a phase 1 clinical trial less than 10 weeks after the release of the genetic sequence of SARS-CoV-2.2 You can get a flavour of the approaches on clinical trial databases (eg clinicaltrials.gov/ct2/results?cond=COVID-19 in the USA). So, which are proving promising? When will a vaccine reach the clinic? And does this frenetic pace of pharmaceutical development carry risks?
New antivirals
To get new COVID-19 treatments to the clinic as soon as possible, many researchers focus on repurposing existing medicines. After all, the side effects of existing drugs are relatively well known, which lowers one of the important hurdles in drug development.
Lopinavir, for example, is a well-established HIV treatment. Like HIV, SARS-CoV-2 carries its genetic information as RNA. In vitro studies suggested that lopinavir inhibits SARS-CoV, the virus that causes severe acute respiratory syndrome (SARS). Lopinavir is usually combined with ritonavir, which increases lopinavir’s half-life (the time for plasma levels to half) and prolongs the duration of action.3
So, lopinavir–ritonavir seemed a logical choice to test as a treatment for COVID-19. In one study, 99 patients hospitalised with severe COVID-19 in Wuhan received lopinavir–ritonavir added to standard care. Another 100 patients received only standard care. Unfortunately, lopinavir–ritonavir did not significantly hasten clinical improvement, lower mortality or reduce the amount of SARS-CoV-2 shed from cells and collected in throat swabs.3
But it’s too soon to write off the combination based on one un-blinded study. Lopinavir–ritonavir is active against SARS and Middle East Respiratory Syndrome (MERS), each of which is caused by a coronavirus. Lopinavir–ritonavir has been combined with other antivirals with promising results in SARS. Further trials need to confirm whether or not there is any benefit.3
The CORIPREV-LR trial, for instance, aims to evaluate whether lopinavir–ritonavir prevents people from being infected with SARS-CoV-2. CORIPREV-LR uses ‘ring-based prevention,’ an approach that helped eradicate smallpox and was assessed during the 2013–2016 Ebola epidemic in West Africa. Researchers define ‘rings’ of people exposed to SARS-CoV-2 around an infected case. The exposed people receive lopinavir–ritonavir or usual care. Participants self-monitor symptom daily and are screened weekly.1
Other antivirals also show promise. Ivermectin, approved to treat certain parasitic infestations, shows anti-viral activity against, among other pathogens, HIV, West Nile virus, dengue virus and influenza. In microbiological investigations, ivermectin reduced SARS-CoV-2 levels about 5000-fold after 48 hours.4 Studies need to ascertain if these promising experimental findings will apply in the clinic.
The malaria treatments
The potential role of chloroquine and hydroxychloroquine, used to treat malaria and certain autoimmune rheumatic diseases, in COVID-19 has received considerable attention, including from some world leaders. Certainly, chloroquine and hydroxychloroquine seem to ‘potently block’ replication of SARS-CoV-2. However, hydroxychloroquine seems to inhibit viral replication more potently than chloroquine. Early results are promising.5
In one study, that enrolled 36 people, hydroxychloroquine produced viral clearance (no viral RNA in nasopharyngeal swabs) in 57% of patients after six days. Combining hydroxychloroquine and azithromycin increased clearance to 100%, although only six patients received both drugs. In contrast, with 13% clearance in untreated patients. Hydroxychloroquine’s benefits seemed most marked in people with symptomatic respiratory tract infections.6
Further studies assessing chloroquine and hydroxychloroquine are underway. In the COVID-19 postexposure prophylaxis trial, for instance, healthcare workers and community-dwelling adults with high-risk exposures or early symptomatic disease screen themselves electronically. A courier delivers hydroxychloroquine or placebo. Based on users’ self-reports, the study will assess whether hydroxychloroquine prevents symptomatic disease in asymptomatic people and severe disease in symptomatic patients.1
Meanwhile, researchers are determining whether experimental antivirals being developed for other infections can be diverted to tackle COVID-19. Studies performed before the current pandemic found that remdesivir, an experimental antiviral, inhibits SARS-CoV, MERS-CoV and bat CoV strains that can replicate in human airway epithelial cells.7,8 Remdesivir also seems to be effective against the deadly haemorrhagic Ebola and Marburg viruses.8 Phase 3 clinical studies are evaluating remdesivir’s safety and efficacy in adults with COVID-19.8
Targeting IL-6
Other drugs being tested do not directly target the virus, but attenuate the infection’s effects on the body. For example, blood levels of the cytokine interleukin-6 (IL-6) can increase several thousand fold in inflammatory states and potentially fatal sepsis.9 ‘Clear evidence’ suggests that peak IL-6 concentrations are associated with severity of pulmonary complications. So, several studies are assessing drugs inhibiting IL-6 for COVID-19.10
Siltuximab binds to IL-6 and is approved for some patients with multicentric Castleman disease, a rare condition affecting lymph nodes and related tissues. At the time of writing, interim results reported in a press release are available for 21 patients with serious complications of COVID-19, treated with siltuximab and followed for up to 7 days. Seven patients experienced a clinical improvement with reduced oxygen requirements. COVID-19 stabilised in nine patients. So, 16 patients were either stable or improved. Three patients worsened, one died and one experienced a cerebrovascular event.11
It’s worth noting that people with underlying cardiovascular disease are at increased risk of severe COVID-19.12,13 One study reported that 19.7% of 416 patients hospitalised in Wuhan with COVID-19 developed coronary injury. These patients were more likely than those without coronary injury to need mechanical ventilation. The proportions that needed non-invasive ventilation were 46.3% and 3.9% respectively, for example. Several complications were more common in patients with COVID-19-related coronary injury than those without, such as: acute respiratory distress syndrome (58.5% and 14.7% respectively); acute kidney injury (8.5% and 0.3% respectively); and coagulation disorders (7.3% and 1.8% respectively). Deaths rates were also markedly higher in COVID-19 patients who developed coronary injury than those who did not (51.2% and 4.5% respectively).12
The mechanism underlying COVID-19-related coronary injury is not fully understood.12 However, the inflammatory response evoked by SARS-Cov-2 superimposed on pre-existing cardiovascular disease may be responsible.12 The inflammation could rupture or erode coronary atherosclerotic plaques, which could cause cardiac injury (such as a heart attack) or cerebrovascular event.14
Hopefully, full results published in a peer-reviewed journal will confirm siltuximab’s early promise. In the mean time, studies are underway with tocilizumab and sarilumab – both of which also bind to and block IL-6 receptors (rather than the cytokine itself) and are approved for autoimmune diseases such as active rheumatoid arthritis - are now underway in COVID-19.15,16
ACE in the hole
Under an electron microscope, a ‘corona’, or halo made up of protein spikes seems to surround each coronavirus virion.17 Spike proteins on the outside of beta-coronaviruses, such as those responsible for SARS and COVID-19, anchor the coronaviruses to angiotensin converting enzyme 2 (ACE2) in the lower respiratory tract.18 ACE2 belongs to the same family of enzymes as ACE1 in the renin angiotensin system (RAS), which is targeted by ACE inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) when used to treat several cardiovascular conditions, including hypertension, heart failure and diabetic nephropathy.
The interaction between the virus and ACE2 allows SARS-CoV-2 to enter the epithelial cells lining the lung.18 SARS-CoV-2 shows a 10 to 20-fold greater affinity for ACE2 than the SARS virus. This marked affinity seems to be one reason why SARS-CoV-2 spreads so easily.14
ACE2 converts angiotensin II, a hormone, into angiotensin 1-7, a signalling molecule that is a vasodilator, natriuretic (meaning it increases sodium excretion in the urine), diuretic, anti-inflammatory and antifibrotic.19 This means that ACE2 may protect against hypertension, myocardial fibrosis and hypertrophy, arrhythmia, atherosclerosis and sodium-water retention.14
After entering the respiratory epithelium, SARS-CoV-2 seems to downregulate ACE2 expression. Some researchers speculate that the resulting imbalance increases angiotensin II activity, which could be partly responsible for organ injury in COVID-19.20 For instance, vasoconstriction, inflammation and damage from free radicals in the respiratory tree could increase the risk of acute lung injury.21
In addition to the effects on the RAS, ACE-Is and ARBs may increase ACE2 expression, which might may reduce the harmful effects associated with the high levels of angiotensin II.21 Experimental evidence suggests that losartan (an ARB) and the human ACE2 protein may protect mice from experimental models of severe acute lung injury.14 A recent paper called for studies investigating whether ACE-Is and ARBs reduce the incidence or mortality associated with acute lung injury or acute respiratory distress syndrome in COVID-19 patients with and without the usual indications for the drugs.21
The number of therapeutic leads that might yield new treatments is remarkable in such a short time. But this hectic rush to research raises the risk of duplication, competition for patients and underpowered studies (eg too few patients), which could prematurely reject promising drugs.1 More fundamentally, there’s many a slip ‘twixt experimental studies and clinical use. So, while many of these seem biologically promising, at the time of writing, few results are available. Watch this space.
Hope for a vaccine
Meanwhile, numerous vaccine candidates are being developed. The breathe of immunological approaches raises hopes that at least one will work.22 The spike protein, in particular, seems to be a promising target for a COVID-19 vaccine.2,23
One study used insights gained developing vaccines for SARS and MERS to create a candidate COVID-19 vaccine. The vaccine targets a specific subunit, which seems to evoke a stronger response than using the whole spike. An array of microneedles delivers the vaccine into the skin and seems to evoke potent and persistent immune responses against SARS-CoV-2 in experimental animals within two weeks of immunisation.
Delivery into the skin reduced the dose of vaccine needed to mount a protective immunity compared with traditional subcutaneous injection, reflecting the greater number of immune cells involved in instigating the response in the skin.23
A note of caution
It’s important, of course, that safety is not sacrificed for speed. For instance, some animals and humans who received experiment vaccines against, for instance, dengue, respiratory syncytial virus or SARS developed more severe disease when exposed to the pathogen than those who had not been vaccinated, a phenomenon called immune enhancement. Developers will be careful that immune enhancement does not emerge with the COVID-19 vaccine.22
Developing a vaccine usually takes between 5 and 7 years.24 According to the WHO and other experts, developing a COVID-19 vaccine including animal studies and clinical trials will probably take about 18 months.22 Johnson & Johnson, for example, expects to begin phase 1 clinical studies of its lead COVID-19 vaccine candidate by, at the latest, September 2020. The first batches for emergency use could reach the clinic in early 2021.24 (As an aside: I am interested to see whether immunisation against COVID-19 is influenced by and influences vaccine scepticism and the anti-vax movement more generally.)
Conclusion
In addition, making vaccines is expensive. Affluent countries may be able to afford the manufacturing costs. But studies need to determine which populations are at greatest need. And there needs to be a globally fair system to allocate any vaccine based more on clinical need than ability to pay.2 After all, if there’s one thing we’ve learnt, it’s that when it comes to a global coronavirus pandemic no country is an island.
Mark Greener is a freelance medical writer
References
1. 1. Cheng M, Lee T, Tan D, Murthy S. Generating randomized trial evidence to optimize treatment in the COVID-19 pandemic. Canadian Medical Association Journal. 2020; 192(15): E405-E407.
2. 2. Lurie N, Saville M, Hatchett R, Halton J. Developing Covid-19 Vaccines at Pandemic Speed. New England Journal of Medicine. 2020 https://doi.org.10.1056/NEJMp2005630
3. Cao B, Wang Y, Wen D, et al. (2020) A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. New England Journal of Medicine. https://doi.org.10.1056/NEJMoa2001282
4. Caly L, Druce J, Catton M, Jans D, Wagstaff K. The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Research. 2020;:104787. https://doi.org/10.1016/j.antiviral.2020.104787
5. Spinelli F, Ceccarelli F, Di Franco M, Conti F. To consider or not antimalarials as a prophylactic intervention in the SARS-CoV-2 (Covid-19) pandemic. Annals of the Rheumatic Diseases. 2020. https://doi.org.10.1136/annrheumdis-2020-217367
6. Gautret P, Lagier J, Parola P, Hoang V, Meddeb L, Mailhe M et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. 2020; 105949. https://doi.org/10.1016/j.ijantimicag.2020.105949
7. Agostini M, Andres E, Sims A, Graham R, Sheahan T, Lu X et al. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio. 2018;9(2). https://doi.org.10.1128/mBio.00221-18
8. 8. Gilead. Gilead Sciences initiates two phase 3 studies of investigational antiviral remdesivir for the treatment of COVID-19 [Internet]. 2020. Available from: http://www.gilead.com/news-and-press/press-room/press-releases/2020/2/gilead-sciences-initiates-two-phase-3-studies-of-investigational-antiviral-remdesivir-for-the-treatment-of-covid-19. Accessed 3 April 2020.
9. Rose-John S. Interleukin-6 Family Cytokines. Cold Spring Harbor Perspectives in Biology. 2017;10(2):a028415. https://doi.org.10.1101/cshperspect.a028415
10. Russell B, Moss C, George G, Santaolalla A, Cope A, Papa S et al. Associations between immune-suppressive and stimulating drugs and novel COVID-19—a systematic review of current evidence. ecancermedicalscience. 2020;14. https://doi.org.10.3332/ecancer.2020.1022
11. Ergomed. Update on siltuximab clinical study: Interim analysis data for siltuximab-treated COVID-19 Patients. 2020 Available at www.ergomedplc.com/update-on-siltuximab-clinical-s... Accessed 3 April 2020.
12. Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F et al. Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China. JAMA Cardiology. 2020. https://doi.org.10.1001/jamacardio.2020.0950
13. Guo T, Fan Y, Chen M, Wu X, Zhang L, He T et al. Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19). JAMA Cardiology. 2020. https://doi.org.10.1001/jamacardio.2020.1017
14. Yang C, Jin Z. (2020) An acute respiratory infection runs into the most common noncommunicable epidemic: COVID-19 and cardiovascular diseases. JAMA Cardiology. https://doi.org.10.1001/jamacardio.2020.0934
15. Sanofi. (2020) First patient outside U.S. treated in global Kevzara® (sarilumab) clinical trial program for patients with severe COVID-19 Available at www.sanofi.com/en/media-room/press-releases/2020/2... Accessed 3 April 2020.
16. Roche. Roche initiates phase III clinical trial of Actemra/RoActemra in hospitalised patients with severe COVID-19 pneumonia Available at www.roche.com/dam/jcr:f26cbbb1-999d-42d8-bbea-34f2... Accessed 4 April 2020.
17. Centers for Disease Control and Prevention. MERS-CoV Photos Available at https://www.cdc.gov/coronavirus/mers/photos.html Accessed February 2020.
18.Diaz J. Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19. Journal of Travel Medicine. 2020. https://doi.org.10.1093/jtm/taaa041
19. Abassi Z, Skorecki K, Heyman S, Kinaneh S, Armaly Z. Covid-19 infection and mortality - A physiologist’s perspective enlightening clinical features and plausible interventional strategies. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2020. https://doi.org.10.1152/ajplung.00097.2020
20. Vaduganathan M, Vardeny O, Michel T, McMurray J, Pfeffer M, Solomon S. Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19. New England Journal of Medicine. 2020;.https://doi.org.10.1056/NEJMsr2005760
21. Bavishi C, Maddox T, Messerli F. Coronavirus disease 2019 (COVID-19) infection and renin angiotensin system blockers. JAMA Cardiology. https://doi.org.10.1001/jamacardio.2020.1282
22. Peeples L. (2020) Avoiding pitfalls in the pursuit of a COVID-19 vaccine. Proceedings of the National Academy of Sciences. 2020. https://doi.org.10.1073/pnas.2005456117
23. Kim E, Erdos G, Huang S, et al. Microneedle array delivered recombinant coronavirus vaccines: Immunogenicity and rapid translational development. EBioMedicine. 2020. https://doi.org.10.1016/j.ebiom.2020.102743
24. Johnson & Johnson. Johnson & Johnson announces a lead vaccine candidate for COVID-19. 2020. Available at www.jnj.com/johnson-johnson-announces-a-lead-vacci... Accessed 3 April 2020.