The race to find a cure: the guide on potential COVID-19 vaccines and treatments
As of June 2020, there were over 6mln COVID-19 cases all over the world, and the number continues to grow. It is hard to find the most significant occasion that would blow our minds and social media. Scientists are making efforts to develop vaccines and drugs to slow the pandemic and reduce the disease's damage. Some of these treatments will likely be drugs that are already approved and used for other health conditions or have been tested on other viruses.
"Summit", the world's fastest supercomputer has identified 77 potential COVID-19 treatments. The research, detailed in a paper published on the preprint server ChemRxiv, may help researchers create a drug to treat the deadly virus, and that is one of many critical first steps. Let's see what other potential vaccines and medications may give some hope but first start with some basics.
What is the immune system and its functions?
The immune system is an inner army that helps our bodies to fight infections and viruses. It includes:
- White blood cells - they move throughout your body, searching for bacteria, viruses, parasites and launching an immune attack.
- Antibodies - help the body to fight microbes and the toxins they produce.
- Lymphatic system - manage the body fluid levels and harmful cell products, absorb some fats and many more functions.
- Complement system - consists of proteins that complement antibodies functions.
- Spleen - removes microbes and breaks damaged or old red blood cells
- Thymus - filters and regulates blood content, produces the white blood cells known as T-lymphocytes.
- Bone marrow - produces the red blood cells for oxygen delivery, the white blood cells to fight infection, and the platelets so our blood could clot.
White blood cells are the most important players in your immune system. There are two different types of them: phagocytes and lymphocytes. Phagocytes move through your blood vessels and tissues to ingest or absorb pathogens and toxins that may cause disease. When a phagocyte absorbs a pathogen, it starts to release a chemical so lymphocytes can identify the type of pathogen.
Lymphocytes consist mostly of:
- Macrophages. They digest germs, dead or dying cells. The macrophages leave behind antigens, parts of invaders. As soon as the body identifies antigens, it starts to stimulate antibodies to attack them.
- B-lymphocytes are defensive white blood cells that produce antibodies to attack the antigens.
- T-lymphocytes are also defensive white blood cells that attack infected cells in the body.
In a healthy state, the immune system is finely-tuned and doesn't require extra support. However, when it isn't functioning properly, the body becomes more susceptible to illness. For example, if a person becomes immunocompromised, it means that the immune system is weaker than expected, and there is a higher risk to get an infection and become sick. This condition may arise due to chronic medical conditions, autoimmune diseases, malnutrition, and many other reasons. On the other hand, viruses may trigger an excessive immune reaction named 'cytokine storm.' In such a case, the body attacks its own cells and tissues rather than fighting off the virus.
Endocannabinoid vs Immune system
The endocannabinoid system (ECS) is a body's complex cell-signalling system that consists of endocannabinoids, receptors, and enzymes. ECS is responsible for keeping the internal balance and helping to regulate many processes from mood and sleep to chronic pain and immune system responses.
Your body naturally produces endocannabinoids to keep internal functions running smoothly. Endocannabinoid receptors are found throughout your body. Endocannabinoids can bind to them to indicate that the ECS needs to take action. CB1 receptors are located in the central nervous system, while CB2 receptors are mostly found in the peripheral nervous system, especially immune cells. CB2 receptors in the immune cells may signal that your body's experiencing inflammation. Therefore, ECS and the immune system are closely related.
What can be the treatment for COVID-19?
There are three approaches to coronavirus management:
- keep the virus from entering the cells;
- prevent the virus from replicating;
- lower the potential damage to the body.
The main goal of antivirals is to alleviate symptoms, reduce infectivity, and shorten the duration of illness. These drugs can stop the replication cycle of the virus at various stages. Antiviral therapy can be effective for a limited number of infections. Unlike antimicrobial medications, antivirals don't deactivate or break the virus but inhibit viral replication. In such a way, the antiviral medications do not let the disease begin or progress, allowing the innate immunity to neutralise the virus. At a time when over 70 drugs and experimental treatments are examined to treat the COVID-19, the World Health Organisation (WHO) has begun a global trial called 'Solidarity' to find out if any of drug candidates can treat infections with the new coronavirus.
Here are the main AntiCovid candidates:
Lopinavir/ritonavir combination, sold as Kaletra, is used with other antiretroviral drugs for the treatment of human immunodeficiency virus (HIV). AbbVie, its manufacturer, is collaborating with health authorities and institutions to evaluate its antiviral activity, efficacy and safety against COVID-19. Two randomised clinical trials assessing the LPVr in treating COVID-19 haven't shown benefits or clinical improvement from LPVr treatment. There was some evidence that the drug may have reduced mortality, and shortened time to discharge and ICU admissions. However, the study published in The Lancet has found that a combination of lopinavir/ritonavir, ribavirin and interferon beta-1b shortened the time to get rid of the virus.
It is a broad-spectrum antiviral developed by the biopharmaceutical company Gilead Sciences to inhibit Ebola virus. Later, Gilead Sciences discovered that remdesivir had antiviral activity against other viruses, including coronaviruses. As for MERS, this antiviral has proven to be effective in blocking the virus from replicating. Preliminary results from a placebo-controlled double-blind, randomised controlled trial by the US National Institutes of Health, have shown that remdesivir reduced the recovery time from 15 to 11 days in people with COVID‑19 and lowered a mortality rate or the group receiving remdesivir. However, a study in The Lancet showed that participants in a clinical trial who took remdesivir had no benefits compared to people who took a placebo.
Despite the conflicting results, remdesivir has been authorised for emergency use in India, the US, and approved for use in Japan for people with severe COVID-19 symptoms. In May 2020, Remdesivir was approved for COVID-19 treatment in the UK due to limited supply for patients with specific clinical criteria.
Favipiravir, also known as Avigan, is an antiviral medication used to treat influenza. An Open-Label Control Study has shown that people treated with Favipiravir had faster viral clearance and better chest imaging change than those treated with Lopinavir/ritonavir.
Some reports from China have suggested the medication might be effective as a treatment for COVID-19. Patients who were taking medicine in Shenzhen turned negative for the novel coronavirus in four days after becoming positive. Fujifilm Toyama Chemical, the manufacturer of the drug, has declined to make any comments on the claims. Interim results of the clinical trial in Japan on COVID-19 patients did not show its effectiveness in slowing down the disease progression. Japan expects to finish the clinical trials by the end of May 2020 and get the approval for the drug. So far, it sends the drug to other countries for clinical trial testing in people with mild or moderate symptoms of COVID-19.
Umifenovir, sold as Arbidol, is an antiviral medication by Pharmstandard for influenza infection used in China and Russia. Preliminary tests by experts of the National Health Commission of China claimed that Arbidol, together with darunavir, could inhibit replication of the novel virus. There is also evidence that Arbidol can block the trimerisation of spike glycoprotein, which prevents the virus from entering the cell and results in the formation of unmatured or naked virus that is less infectious. When tested along with the lopinavir/ritonavir as a potential treatment for COVID-19, the drugs haven't shown effectiveness against mild-to-moderate COVID-19 in adults. Considering different results, further studies are required.
Drugs approved for other indications
Chloroquine and Hydroxychloroquine
Chloroquine and hydroxychloroquine are effective drugs against malaria, rheumatoid arthritis, and lupus, but its use against COVID-19 is doubted. The use of these drugs in COVID-19 is based on broad publicity of small and uncontrolled studies, showing that the combination of hydroxychloroquine and macrolide azithromycin could suppress viral replication. A lot of the evidence suggesting its benefits also comes from the news and publications on social media on people getting better after drug consumption. In March 2020, the FDA allowed the use of these drugs for emergency use if clinical trial access was unavailable. Some countries, such as China, have issued guidelines on its COVID-19 application and began stockpiling the drugs. However, more extensive studies such as large-scale, international, real-world analysis support the lack of a clinical benefit of chloroquine and hydroxychloroquine and show its potential dangers in patients with COVID-19. In April 2020, the FDA provided a warning against the use of both drugs outside of the medical setting due to their potentially dangerous side effects, such as cardiovascular toxicity.
Tocilizumab, sold as Actemra, is an immunosuppressive drug for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis, severe arthritis in children. Studies in China have suggested that tocilizumab may effectively treat patients with severe symptoms of COVID-19. COVID-BioB Study conducted in Italy has shown that patients who received tocilizumab instead of the standard of care had better clinical outcomes and lower mortality rate, but neither study result was statistically significant. Roche Holding AG, the drug's manufacturer, has launched a randomised, controlled Phase 3 trial to assess tocilizumab's effectiveness in severe cases of COVID-19.
The drug, sold under the name Kevzara, is a human monoclonal antibody against the interleukin-6 receptor. Sanofi and Regeneron Pharmaceuticals developed the drug for the treatment of rheumatoid arthritis. Sarilumab is being evaluated for its potential ability to reduce the inflammatory response in the lungs in patients with COVID-19 who have acute respiratory distress syndrome (ARDS). Preliminary data from an Italian paper has shown that Sarilumab may become a promising treatment for COVID-19, but parallel administration of other drugs could also contribute to the result. Phase 2 results of the Regeneron trial has shown that Sarilumab was not effective in treating severe or critical cases of COVID-19. However, Regeneron plans to continue the trial with the critical cases and the higher-doses of the drug.
The drug also sold under brand names Stromectol and Soolantra cream, is a medication for the treatment of parasite infestations, such as intestinal strongyloidiasis, onchocerciasis, lice and rosacea. The drug is FDA-approved for parasitic infections, so has potential for repurposing. Ivermectin has shown to cause broad-spectrum antiviral activity in vitro. The paper published in Antiviral Research suggested its ability to inhibit SARS-CoV-2 with a ~5000-fold reduction in virus within 48 h in cell culture. Japan plans to evaluate Ivermectin against COVID-19 in a clinical trial, according to Prime Minister Shinzo Abe’s claim published in Pharma Japan.
The drug by Novartis, known as Ilaris, is a monoclonal antibody that targets interleukin (IL)-1β. Canakinumab is approved for the treatment of cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated, hyperimmunoglobulin D syndrome/mevalonate kinase deficiency, periodic syndrome, familial mediterranean fever. The studies published in The Lancet have shown that patients with COVID-19, taking Canakinumab, had increased levels of IL-1β and other cytokines at the time of cytokine storm syndrome. Novartis has launched Phase 3 of CAN-COVID trial to evaluate Canakinumab's ability to treat cytokine storm syndrome in patients with COVID-19 and expects results from the trial by mid-summer 2020.
Research has shown that convalescent plasma could be applied as passive immunotherapy in MERS and in SARS-CoV-2 to neutralise the virus. Convalescent plasma can be applied to treat patients with early symptoms and prevent nurses and physicians from the disease. Preliminary findings have shown that convalescent plasma may be beneficial for patients with COVID-19, such as improving the clinical status of patients with COVID-19 and acute respiratory distress syndrome. There is more evidence, proving that convalescent plasma might be effective in treating people with COVID-19 patients. The trial on 5,000 hospitalised adults suggested convalescent plasma was safe for use.
In March 2020, the FDA approved the use of convalescent plasma taken from people recovered from COVID-19 for severe or immediately life-threatening cases under an emergency investigational new drug application. Healthcare company Grifols along with BARDA plans to develop a COVID-19 treatment on convalescent plasma basis.
Stem cells may cause a potent immunomodulatory and anti-inflammatory effect. Due to this ability, they may potentially improve the immune system functions, altered by COVID-19. There are 10 projects registered in the official international registry for clinical trials, suggesting the use of mesenchymal stem cells for coronavirus pneumonia or moderate to severe acute respiratory distress syndrome (ARDS). Some trials have entered a phase II/III clinical trial.
What is cannabis & CBD potential for COVID-19?
Cannabis and CBD products are well-known for their health benefits. CBD (Cannabidiol) is derived from Cannabis Sativa and Cannabis Indica plants. It is the main ingredient of all CBD supplements, from the most popular CBD tinctures and CBD oils to exotic CBD edibles and CBD-infused products. Cannabidiol and cannabis may be helpful in numerous conditions from stress and anxiety to chronic pain and neurological disorders. As for the novel coronavirus, cannabis is not a cure for the COVID-19. However, it has many benefits, useful during pandemic times, such as:
Raising the number of natural killer cells
Studies on autoimmune health in animal models have shown that CBD may suppress the activity of B cells, T cells, T helper and T cytotoxic lymphocyte subsets. Such an effect helps to balance the immune system. Outside of an autoimmune sphere, CBD may support the activity of natural killer cells (NK), a type of lymphocyte or a white blood cell and an essential part of the innate immune system. NK cells contribute to the body's response to viral infections.
Support a potent inflammatory response
CBD can help keep a healthy inflammatory response. Studies on animals have shown that CBD may support a strong inflammatory response in the lungs. During the studies, it improved lung function in mice that were exposed to a lung irritant.
Studies have suggested that CBD could benefit the lungs: lowered total lung resistance and elastance, myeloperoxidase activity in the lung tissue, pro-inflammatory cytokine/chemokine production, leukocyte migration into the lungs, protein concentration and also support of healthy levels of TNF and IL-6 cytokines and MCP-1 and MIP-2 chemokines. These effects could potentially improve respiratory function. In a study with asthma models, CBD significantly decreased TNF-α, IL-6, IL-4, IL-13, IL-10, and IL-5 cytokines. Such an effect may be useful for relieving the cytokine storm, an excessive reaction of the immune system.
Stress relief and calming effect
Chronic stress, inevitable during pandemic times, can be damaging for the immune system. CBD helps to support healthy stress response and improve sleep quality. Cannabidiol can activate the 5-HT1A serotonin receptor that influences aggression and anxiety. Stress-relieving properties of CBD are associated with its ability to regulate cerebral blood flow in brain regions linked to anxiety. Human trials have shown that CBD could also reduce mild stress in people giving a public speech.
Prevention of the infection
The latest research of Canadian scientists has suggested that certain cannabis strains may increase resistance to the coronavirus.
The idea that lies in research is to prevent the virus from entering the body. The novel coronavirus requires a "receptor", known as "angiotensin-converting enzyme II" or ACE2, to enter a human body. ACE2 can be found in oral and nasal mucus, lung tissue, testes, the kidneys, and gastrointestinal tracts. Adjusting of ACE2 levels in those areas may potentially reduce our susceptibility, or vulnerability, to the novel virus and lower the risk of infection. The study is yet to be peer-reviewed and verified.
As stated previously, endocannabinoid and immunity systems are closely related. CBD doesn't directly trigger endocannabinoid receptors but adjusts their ability to bind to cannabinoids. ECS receptors are also engaged in many different aspects of your health, such as nervous and immune systems functions. CBD may also influence other types of receptors while occupying certain enzymes and enhancing the natural levels of endocannabinoids. Cannabidiol may also prevent endocannabinoids from being broken down.
What are potential COVID-19 vaccines?
Vaccines can imitate the infection, helping to develop immunity. This kind of infection makes the immune system produce antibodies and T-lymphocytes. In some cases, getting a vaccine can cause minor symptoms, while the body develops immunity. Once the imitation infection goes away, the body keeps T-lymphocytes and B-lymphocytes that will remember how to fight against that disease in the future. Usually, it takes a few weeks for the body to produce such lymphocytes after vaccination.
CEPI experts consider three major technology platforms for an effective vaccine against the novel coronavirus:
- viral vector
- nucleic acid (such as DNA and RNA)
- a virus-like particle used for DNA replication
The good thing is that vaccines can protect both the person who's vaccinated and people around him. Viruses don't infect vaccinated people, which means they can't pass the virus to others. That is known as herd immunity. Many companies are elaborating potential vaccines for SARS-CoV-2. Some of them are supported by the nonprofit Coalition for Epidemic Preparedness Innovations (CEPI).
Here are some projects:
Moderna Therapeutics (USA)
The company has experience in creating mRNA-based vaccines and has developed a candidate for the prevention and treatment COVID-19. First phases of the clinical trial have shown that the vaccine has produced antibodies in respondents. Earlier studies showed that their vaccine platform was safe. The company plans to enter a phase III clinical trial in July 2020. If clinical trials prove to be effective, an early version of the vaccine may be available by fall 2020 for vulnerable groups such as healthcare workers.
Inovio Pharmaceuticals Inc. (USA)
Innovio developed a DNA vaccine candidate made of optimised DNA plasmids, small circles of synthesised or reorganised double-stranded DNA. The vaccine named INO-4800 is designed to induce a potent immune response by providing monoclonal antibodies. Preclinical studies on the vaccine have shown promising immune responses in multiple animal models. In April 2020, Inovio started the Phase I of clinical trials with an enrollment of 40 volunteers getting intradermal vaccine injection and electroporation through the CELLECTRA® 2000 device. The open-label trial will assess the safety, tolerability, and immunological profile of the vaccine. The company expects to make up to one million doses of the vaccine available by the end of 2020 for emergency use and additional trials.
The Oxford team already had an experience with developing a vaccine against MERS, another type of coronavirus and got promising results in clinical trials.
In cooperation with the Jenner Institute, the Oxford team has developed the vaccine candidate. ChAdOx1 vaccine contains a weakened and safe version of an adenovirus. Human trials on ChAdOx1 began in March 2020 in Oxford. A phase I/II of the placebo-controlled trial on 510 healthy adult volunteers aims to study the safety, immunogenicity, and efficacy of the vaccine. In May, the team reported that the vaccine was effective against COVID-19 in animal studies. The company expects to launch a late-stage clinical trial with an enrollment of 5,000 volunteers with no age limit by the mid of 2020.
BioNTech (Germany) & Pfizer (USA)
German biotech company BioNTech along with US pharmaceutical giant Pfizer has joined the race of vaccine development. The mRNA-based vaccine candidates are a part of "Lightspeed" project by BioNTech. Two potential vaccines include a nucleoside modified mRNA (modRNA), one contains uridine containing mRNA (uRNA), and the fourth candidate is a self-amplifying mRNA (saRNA). The Paul-Ehrlich-Institut, German regulatory body, has allowed starting the Phase 1/2 of clinical trials. The clinical trial of a BNT162 vaccine will begin in Germany and then in the US once there is regulatory approval. The trials will also evaluate the effects of repeated immunisation for uRNA or modRNA candidates.
University of Queensland (Australia)
The team of the University of Queensland has developed a vaccine candidate based on molecular clamp technology that locks the S protein into a shape which helps the immune system to indicate and neutralise the virus. The University collaborated with Viroclinics Xplore, a Dutch leading diagnostic and clinical trial operation service company, to begin preclinical studies. The vaccine by the University of Queensland will be tested on the live coronavirus to assess its effectiveness against infection. If it is successful, the vaccine will be tested on humans in Q3 2020.
CanSino Biologics Inc. (China)
CanSino Biologics Inc. has developed Ad5-nCoV, a genetically engineered vaccine with the replication-defective adenovirus type 5 as the vector for spike protein (S protein) expression. The Ad5-nCoV entered clinical trials after positive results of preclinical animal studies such as a potent immune response and a good safety profile.
CanSino planned to conduct Phase II enrolling 500 healthy participants with the Institute of Biotechnology, Academy of Military Medical Sciences. CanSino expects to detect COVID-19 antibodies in patients in 28 days after the vaccination.
Johnson & Johnson (USA)
Johnson & Johnson has also announced a collaboration with BARDA, the Biomedical Advanced Research and Development Authority, on vaccine development. They plan to use the same technologies as in the development of an investigational Ebola vaccine. Johnson & Johnson cooperates with global partners to consider the library of antiviral molecules, support the development of potential treatments for COVID-19 and help people all over the world.
Sanofi Pasteur (France)
Sanofi Pasteur plans to cooperate with BARDA and develop a vaccine, using the company's recombinant DNA platform. Earlier Sanofi was involved in developing a vaccine for SARS. The company's researchers expect to develop a vaccine candidate for testing within six months and plan to evaluate the vaccine effectiveness in people within a year to up to 18 months.
Scientists and experts from pharmaceutical companies all over the world are working on potential medications, treatments and vaccines that may fight the novel coronavirus. Some companies are developing antiviral drugs, while others evaluate the medications approved for other conditions for their potential against COVID-19. Some of those drugs are aimed at blocking the virus, while others may help relieve excessive immune responses that harm the lungs and other organs. Other pharmaceutical companies are developing vaccines that might prevent the disease. DNA and mRNA-based vaccines are considered the most promising as they can induce stronger immune responses. Just like medications and treatments, potential vaccines need to go through the strict clinical trial stages and tested for effectiveness and safety, which is especially important during a pandemic. Getting the vaccine done, finishing clinical trials and mass production will take time. Even with accelerated timelines for the vaccines, health care workers and high-risk groups are the first ones to be vaccinated, while the general public is likely to wait a year or more.