Vaccines are being developed and some are undergoing clinical trials to see if they might be safe and effective in preventing infection by the Coronavirus (SARS-CoV-2) that causes COVID-191-6. At the same time, many drugs are also being evaluated and undergoing clinical trials to see if they might be safe and effective in treating COVID-197-9. However, it is unlikely that we will find a single vaccine or miracle drug that will eliminate this deadly virus. If it is like the seasonal flu (influenza), people will be encouraged to get a new vaccine every year and there will be drugs that will be effective for many, but not all patients. Still, the things that support the immune system will help many people avoid infection and if infected, avoid the disease. So, not smoking, a healthy diet, physical activity, maintaining a healthy weight, minimizing alcohol consumption, getting adequate sleep, avoiding infections, having meaningful relationships and minimizing stress can help prevent COVID-19. To help understand how vaccines work and how diet can support the immune system, it’s helpful to know some basic immunology. The virus has proteins on its surface which act as antigens, which diagnostic tests look for (active infections). The antigens stimulate the immune system to produce antibodies, which indicate previous exposure to the virus in antibody tests. Antibodies bind to viral antigens, triggering an efficient immune response in most people. So, the goals of this month’s article are to describe briefly:
1) the structure and genetics of the SARS-CoV-2 virus and its pathology;
2) the ways that the innate and adaptive immune systems respond to infection;
3) vaccine and drug development.
Structure and genetics of the SARS-CoV-2 virus
The SARS-CoV-2 virus has a diameter of about 100 nm10. The genetic material inside the SARS-CoV-2 virus is a single molecule of positive-sense mRNA that contains 29891 ribonucleotides, encoding 9860 amino acids and 29 proteins8,11,12. It is surrounded by an envelope that contains lipids, as well as two proteins, a spike protein (S) and an envelope protein (E). There is also nucleocapsid protein (N) inside the virus that forms a complex with the mRNA.
The viral mRNA is used as a template for both replication and transcription13. There are 12 open reading frames (ORFs) that have the required start and stop codons. These ORFs are expressed from a nested set of nine subgenomic RNAs (sgRNA). There are also nine sequences that are used to regulate transcription. Once a host cell is infected, negative-strand RNA intermediates are produced. They are used as templates to make genomic RNA (gRNA) and subgenomic RNAs (sgRNAs). The gRNA contains untranslated regions (UTRs) and a single ORF that encodes a single polyprotein, like other beta-Coronaviruses (β-CoVs). There is a cap on the 5’end of the mRNA. There is a poly adenosine (poly A) tail on the 3’ end of the gRNA. It protects the gRNA from host enzymes (deadenylases) that could destroy it. It also binds proteins during the initiation of translation into other proteins and helps export the mature mRNA into the cytoplasm. The gRNA is packaged by the structural proteins to produce complete copies of itself. The sgRNAs encode the structural proteins and several accessory proteins. In addition, SARS-CoV-2 produces transcripts that encode previously unknown ORFs that could become translated into proteins. Surprisingly, at least 41 RNA modifications were found on viral transcripts. At the same time, transcripts with partial sequences are produced. Some of the sgRNAs may be parasites that compete for viral proteins, making them defective interfering RNAs (DI-RNAs) 10. Scientists are studying not just the genome (gRNA), but also the transcriptome (all the transcripts produced by the virus). This information will help in the development of more effective vaccines and therapies.
Even though that approach might work, it is somewhat reductionist. It might be better to use systems thinking and look at interactions between SARS-CoV-2 and human host cells8. Instead of just targeting a certain protein in the virus, target interactions between viral and human proteins. By constructing a protein interaction map, key interactions were found with human Sigma1 and Sigma2 protein receptors. The viral proteins interact with many host proteins. An international team of scientists mapped the protein-protein interactions (PPIs) between the host and virus. This map identified key drug classes with high potential to fight COVID-19. Some of them are now being tested in clinical trials: antihistimines (cloperastine and clemastine), antipsychotics (haloperidol and melperone), antimalarial (hydroxychloroquine), hormone (progesterone) and antianxiety (siramesine). Data from this and other research groups are being shared with scientists throughout the world. They also discovered that the active ingredient found in over-the-counter cough syrup (dextromethorphan) actually helped the virus infect cells better. It is used in many over-the-counter cough syrups. A dry cough is a symptom of COVID-19. So, many people are taking cough medicines. Still, the authors of the study noted that their observations in the laboratory (in vitro) should be viewed with caution until further studies are done8. Personally, I prefer using fresh ginger root as a cough drop or throat lozenge. It even keeps my mouth and throat moist when I’m doing strenuous exercises.
There are at least two notable features of the genome of SARS-CoV-2. The part that is most different from the first SARS virus (SARS-CoV) is found in the region that codes for the S protein. The S protein binds to a specific part of a protein receptor in human hosts. This part of the S protein is called the receptor-binding domain (RBD). The part of the SARS-CoV-2 genome that codes for the RBD of the spike protein is the most different from the first SARS virus. Five of the six amino acid residues in the S protein that are critical to binding to the host receptor are different in SARS-CoV-2, compared to SARS-CoV. The SARS-CoV-2 S protein has a RBD that seems to be able to bind to ACE2 in humans, ferrets, cats and other species. As described by Kristian G. Andersen and colleagues from California, New York, Louisiana, Maryland, USA, Sydney, Australia and Edinburgh, UK14:
While the analyses above suggest that SARS-CoV-2 may bind human ACE2 with high affinity, computational analyses predict that the interaction is not ideal and that the RBD sequence is different from those shown in SARS-CoV to be optimal for receptor binding. Thus, the high-affinity binding of the SARS-CoV-2 spike protein to human ACE2 is most likely the result of natural selection on a human or human-like ACE2 that permits another optimal binding solution to arise. This is strong evidence that SARS-CoV-2 is not the product of purposeful manipulation14.
The genetic data irrefutably show that SARSCoV-2 is not derived from any previously used virus backbone14.
That is, this new SARS-CoV-2 virus has a genome that no human or computer that was programmed by a human would have ever calculated. It has an S protein that doesn’t bind as well to the host receptor as the original SARS-CoV virus and a backbone structure that no human or computer could have predicted.
Sadly, fools and self-serving politicians try to find a human villain to blame. They ask, “Who started this? Who was the first person to be infected and spread the disease?” This is crazy. Human and viral reproductive biology are very different. Human genealogy can be used to try to find our common ancestors, who are always a man and a woman. We don’t replicate ourselves like viruses. We reproduce sexually. We get half of our DNA from our mothers and the other half from our fathers. Our DNA is transcribed into messenger RNA (mRNA), which is translated into proteins. In total contrast, viruses use the proteins and sub-cellular particles (like ribosomes) that are present in the host in order to replicate, or make exact copies of themselves. The only genetic material inside the SARS-CoV-2 virus is a molecule of mRNA.
So, the virus has no mother or father. Instead, it evolved from ancestors that may have been in both bats and pangolins. Some of these viruses have entered human bodies for many years, but caused no health problems. Mutations appeared and the viruses changed gradually. Moreover, viral RNA will change through recombination. That is, some parts of the mRNA from different viruses can recombine, resulting in a new viral genome, with portions of its RNA from two or more viruses. So, the base sequence (or genome) of the SARS-CoV-2 virus resembles a SARS virus in bats (96% base sequence similarity) 15. However, “some Coronaviruses from pangolins have an RBD structure that is very similar to that of SARS-CoV-2. A Coronavirus from a pangolin could possibly have been transmitted to a human, either directly or through an intermediary host, such as civets or ferrets” 16. It’s also possible that the viral mRNA from different animal sources could have recombined. The current SARS-CoV-2 viral mRNA could be a mosaic of ribonucleotides from more than one ancestor and from more than one host. That is, the metaphor of a family tree that may be appropriate for humans, animals and plants is not appropriate for viruses. Instead, the metaphor of a rhizome of life is better7. That is, the genomes of all species (especially viruses) are actually a mosaic of nucleotide sequences and genes with a variety of origins. Genomes are collections of genes with different evolutionary histories that are not well-represented by a single tree of life17.
Pathology of COVID-19
When an infected person breathes, talks, coughs or sneezes, they can expel droplets containing SARS-CoV-218. If someone else inhales them, SARS-CoV-2 enters the nose where it binds to a protein receptor on the surface of cells. This receptor is called angiotensin-converting enzyme 2, or ACE2. ACE2 is in cells throughout the body, including blood cells. It is part of the renin-angiotensin system (RAS) that helps regulate blood pressure. Once inside, the virus replicates and invades new cells. The body’s innate and adaptive immune systems usually destroy the virus before it can spread very far. Antibodies that bind the SARS-CoV-2 emerge and increase until the virus is eliminated. However, in about 5% of the infected people, the virus then proceeds down the windpipe to the lungs, where it can turn deadly. The thinner, distant branches of the lung’s respiratory tree end in alveoli (tiny air sacs). In healthy lungs, oxygen crosses the alveoli and enters the capillaries, tiny blood vessels that lie beside the air sacs. If the immune system doesn’t eliminate the virus, oxygen transfer decreases. Moreover, immune cells release inflammatory molecules called chemokines. They attract more immune cells that target and kill virus-infected cells, leaving a mixture of fluid and dead cells (pus) behind. This is the typical pathology of pneumonia. This potentially disastrous overreaction of the immune system is known as a cytokine storm in other viral infections. Cytokines are protein growth factors that are secreted by immune cells. They regulate and coordinate the immune response, while playing a role in cell proliferation and inflammation in a healthy immune response. In a cytokine storm, levels of certain proteins called cytokines (interleukins IL-6, IL-8 as well as VEGF and MCP-1) increase too much. Immune cells start to attack healthy tissues. Blood vessels leak, blood pressure drops, clots form, and catastrophic organ failure can occur18.
Cytokines are chemical signaling molecules that guide a healthy immune response; but in a cytokine storm, levels of certain cytokines soar far beyond what’s needed, and immune cells start to attack healthy tissues. Blood vessels leak, blood pressure drops, clots form, and catastrophic organ failure can ensue. Blood can clot abnormally. Blood clots can break apart and move to the lungs, blocking vital arteries, causing pulmonary embolism. Clots from arteries can also lodge in the brain, causing a stroke. COVID-19 can also damage the brain, eyes, nose, liver, kidneys, and intestines.
The CDC issued guidance on risk factors for COVID-1919.
Based on what we know now, those at high-risk for severe illness from COVID-19 are:
- People 65 years and older;
- People who live in a nursing home or long-term care facility
People of all ages with underlying medical conditions, particularly if not well controlled, including:
- People with chronic lung disease or moderate to severe asthma;
- People who have serious heart conditions;
- People who are immunocompromised:
- Many conditions can cause a person to be immunocompromised, including cancer treatment, smoking, bone marrow or organ transplantation, immune deficiencies, poorly controlled HIV or AIDS, and prolonged use of corticosteroids and other immune weakening medications.
- People with severe obesity (body mass index [BMI] of 40 or higher);
- People with diabetes;
- People with chronic kidney disease undergoing dialysis;
- People with liver disease.
However, it should be noted that the prevalence of asthma in COVID-19 patients in Wuhan, China was much lower (0.9%) than it is in the general population20. It was suggested that the immune response in COVID-19 patients “may counter the inflammation process induced by SARS-CoV-2 infection20. So, there is still much more that we need to learn about COVID-19.
Innate and Adaptive Immune Responses
We have both innate and adaptive immune responses to infections by pathogens, including viruses. The innate responses are relatively fast and relatively non-specific. The innate immune system identifies characteristic proteins and/or sugars (antigens) on pathogenic viruses, bacteria, fungi and other organisms and breaks them down. They attach the antigens to antigen-presenting cells (APCs), which present them to the adaptive immune system for destruction. The innate immune system does not have a memory and does not offer specific resistance against organisms that have entered the host in the past. The innate and acquired immune systems have opposite and complementary properties21. The innate system responds fast and causes inflammation, redness and swelling while it produces heat. It also helps activate the adaptive immune system, which responds slower and relieves inflammation. Lymphocytic B-cells originate in the bone marrow. They recognize foreign matter, microorganisms and viruses and produce antibodies that attach to foreign antigens. When a B-cell encounters an APC, it ingests the antigen. The antigen binds to T cells that are made in the thymus gland and secrete cytokines, which stimulate B-cell proliferation. Some B-cells have relatively large nuclei and make many copies of their antibodies. Other B-cells are long-lived memory cells. When a person with a healthy immune system is infected by a virus, bacteria or another pathogenic organism, some of the B cells produce antibodies that may persist for months or years, depending on how long protection against the antigen-producing pathogen is required. Next, pathogen-specific B cells persist in a resting state. They circulate in the body and can be reactivated to produce more antibodies when a person is infected again. Signals from T cells induce B cell proliferation. The B cells secrete millions of copies of the antibody that recognizes this antigen. These antibodies circulate in the bloodstream and lymph nodes. They bind to pathogenic organisms and viruses that express the antigen and mark them for destruction. When B cells and T cells are activated and undergo replication, some of their offspring become long-lived memory cells. Throughout a person’s lifetime, these memory cells can remember each specific pathogen that it encountered and will be able to mount a strong response if the pathogen is detected again. This process is called adaptive because it occurs throughout one’s lifetime as an adaptation to infection and it prepares the immune system for future challenges. Active immunity can also be induced artificially, through vaccination. The principle behind vaccination is to introduce antigens from one or more pathogenic viruses or bacteria that will stimulate the immune system. That way, the patient will develop a specific immunity without catching the disease that is associated with them.
Fortunately, researchers reported recently that the immune systems of patients who recovered from COVID-19 had a robust immune response22. The study used people who had a normal disease course and didn’t require hospitalization to learn what a healthy immune response looks like. The immune system was able to recognize SARS-CoV-2 in many ways. Their T-calls were able to target several viral antigens, especially the S protein. This should make it easier to develop new vaccines.
To understand the vaccines and drugs being developed and tested, it’s important to start with describing the life cycle of the SARS-CoV-2 virus in host cells. The life cycle begins when the S protein binds to the host ACE2 receptor. After receptor binding, there is a change in the structure of the S protein5. It helps the viral envelope fuse with the host’s cell membrane. Then viral gRNA is released into the host cell. The viral gRNA is translated into polyproteins pp1a and 1ab. These polyproteins are viral replicates. They catalyze the replication of RNA from an RNA template. The polyproteins are then broken into small products by viral proteinases. Also, the gRNA is transcribed into a series of subgenomic mRNAs. These are translated into viral proteins. Viral proteins and gRNA are then assembled into virions inside the cell then released out of the cell5.
All vaccines try to expose the body to an antigen that won’t cause a disease but will provoke an immune response that can block or kill the virus if a person becomes infected5. There are at least eight types of vaccines. They rely on different viruses or viral parts. Virus vaccines can use either inactivated or weakened viruses. Viral vector vaccines can use either replicating or non-replicating viral vectors. Nucleic acid vaccines can use either DNA or RNA. Protein-based vaccines can contain either a viral protein subunit or virus-like particles5.
Self-amplifying mRNA vaccines (SAM) use the host cell's transcription system to make target antigens that stimulate adaptive immunity. They use an engineered viral genome. They contain only the target antigen gene and cannot replicate. Moderna Therapeutics has developed a SAM based on an mRNA that encodes a stabilized version of the S protein23. The mRNA is surrounded by a novel lipid nanoparticle. The Biomedical Advanced Research and Development Authority (BARDA) in the USA has committed up to $483 million to Moderna toward accelerating the development of the mRNA vaccine candidate, mRNA-127323-24.
The conventional approach used to make flu shots (influenza vaccines) is also being used to develop a vaccine for SARS-CoV-224. They are using lab-made pieces of viral protein to build immunity. It’s called the PittCoVacc, short for Pittsburgh Coronavirus Vaccine25.
In a different approach, a weakened version of the adenovirus is used to make a vaccine, ChAdOx1 nCoV-226. Investigators at the University of Oxford, the Jenner Institute have begun testing this vaccine in a clinical trial with 1100 volunteer patients. Results may take two to six months. The first pair of volunteers were split to either receive vaccine or control (placebo) on April 23. The vaccine also contains genetic material used to make the S glycoprotein26. The UK government pledged about $25 million to the Oxford trial, and the Serum Institute of India (the world’s largest producer of vaccines) announced intentions to make 40 million doses of ChAdOx1 nCov-2 even before the trial is completed. This type of international collaboration and investment in mass production in an unproven vaccine is unprecedented. Fortunately, many scientists and government agencies are ignoring the nonsense coming from some politicians, entertainers, and charlatans. Fellow humans are not the enemy – the virus is!
Even the corporate world recognizes the need. With crucial support from Foundations, Universities and researchers, they are testing existing drugs and work with regulators to bring effective molecules to patients within a year27. For example, Moderna Therapeutics prepared a new vaccine and began a Phase 1 clinical trial. This was only possible because the Chinese scientists quickly sequenced the genome of the virus and shared the results with the world.
Vaccine candidates are entering clinical trials3. The World Health Organization says at least 70 COVID-19 vaccines are in development, while scientists at the Coalition for Epidemic Preparedness Innovations (CEPI) have counted 1153. As of 10 March, the US FDA listed more than 130 clinical trials28. Moderna was the first to begin clinical testing of a COVID-19 vaccine, just 66 days after downloading the genetic sequence of SARS-CoV-2. Most vaccine developers are pursuing a similar strategy, but are using different technologies to achieve it. Moderna’s mRNA encodes the S protein. A vaccine by CanSino Biologics, which began a clinical trial in China in March, encodes the S protein in a genetically engineered common cold virus (an adenoviral vector vaccine). Another vaccine by Inovio Pharmaceuticals, which began a clinical trial in the US in April, encodes the S protein in a circular piece of DNA. However, Inovio and Moderna have never made a commercial vaccine before. In contrast, Sanofi is developing its vaccine using conventional approaches. Its COVID-19 vaccine produces SARS-CoV-2 spike proteins in genetically engineered insect cells. This is the same process it uses for its commercial influenza vaccine, FluBlok. On April 14, GlaxoSmithKline joined arms with Sanofi and pledged to provide its vaccine adjuvant, AS03, which contains molecules that excite the immune system and boost vaccine potency. Clinical trials will start later this year, and the firms hope to have a vaccine available in the second half of 2021. It’s the first time these two companies have joined to develop a COVID-19 vaccine3.
Several clinical trials are underway in China3. Sinovac Research and Development and China National Pharmaceutical Group are testing vaccines that use inactivated SARS-CoV-2. The Shenzhen Genoimmune Medical Institute has begun clinical trials of two vaccines based on immune cells that are genetically modified to target the SARS-CoV-2 S protein. CanSino said it is gearing up for a Phase II study of its vaccine, which could provide evidence that the approach is working. In the UK, the University of Oxford is preparing to begin a clinical trial of 500 people. Johnson & Johnson is working on its own adenoviral vector vaccine a lab at Harvard and the US government, with a clinical trial planned to begin by September. At least five more mRNA vaccines are set to enter clinical testing this year. BioNTech and Pfizer started their trial. Also, Novavax plans to start clinical trials of its nanoparticle-based vaccine in Australia soon.
On April 9, the World Health Organization announced that it is planning an international study, the SOLIDARITY vaccine trial, which will test several COVID-19 vaccines3.
However, it’s important to avoid problems like disease enhancement that have occurred in previous experimental vaccines4. Since the 1960s, some vaccine candidates for diseases such as dengue, respiratory syncytial virus (RSV), and severe acute respiratory syndrome (SARS) have failed. Some test animals or people who received the vaccine and were later exposed to the virus developed more severe disease than those who had not been vaccinated.
One of the most important things we can do to save lives and eventually stop this pandemic is to educate people. Sadly, some of our political leadership has been spreading hate and lies that grab headlines. Facts backed by statistics and science don’t grab headlines, but they will guide us through this. We should avoid the potential pitfalls of fast medicine. We are not machines and neither is the virus. No manufacturer can provide a schedule that shows how much labor is needed to produce the required amount of product. This can and should be done when manufacturing masks and other personal protective equipment. It can’t be done with a vaccine that doesn’t exist.
As wise Italian scientists told me during Cortina Week 2018 and 2019, fast is always slow. In the USA we might say haste makes waste. We must not waste millions of lives by unleashing a vaccine before all the essential clinical trials are completed. If we were to recommend a new vaccine that turns out to be deadly, we could lose what little public confidence is left. It is far more important to be right than to be fast. Slow medicine is usually much better than fast medicine.
Diet and possibly even some supplements might help prevent COVID-19
The first line of defense against the SARS-CoV-2 virus and COVID-19 is our immune system. A healthy diet of fruits, vegetables, spices and whole grains can build a healthy gut microbiome, which supports the immune system29. Fruits, vegetables and spices contain not only dietary fiber but also vitamins, minerals and dietary antioxidants. Many important dietary antioxidants have anti-inflammatory activities that help maintain good health and prevent many diseases30. Examples include curcumin in turmeric, pterostilbene in blueberries, theaflavin 3,3’-digallate in ginger, glycyrrhizic acid in licorice root, hesperetin in citrus fruits, and even epigallocatechin-3-gallate (EGCG) in green tea. Recently, people have been using computer-based calculations to predict that several of these compounds can dock to potential therapeutic targets, such as the S protein and the viral protease.
One reason why the elderly are more likely to suffer and die from COVID-19 is because the thymus gland produces fewer immune cells as their immune systems weaken31. Critical populations of immune cells become depleted as the T-cell repertoire tends to collapse after the age of 63. However, it is likely that this can be prevented and the thymus gland can recover if a metabolite of vitamin B3 is elevated. This metabolite is nicotinamide adenine dinucleotide, oxidized form, or NAD+. It also tends to be depleted in the elderly32. Its concentration in the blood and the rest of the body can be elevated by taking a dietary supplement that contains another vitamin B3 metabolite – nicotinamide riboside (NAR). There are at least two dietary supplements that contain NAR: TRU NIAGEN® and Basis®. TRU NIAGEN® contains NAR, while Basis® contains not just NAR, but also the important antioxidant, pterostilbene33,34.
Perhaps the drug that has received the most publicity is hydroxychloroquine (also known as Plaquenil). The Predator in Chief of the USA threatened India with sanctions if they didn’t lift their temporary ban on exporting it. He tried to sell it as a “game-changer” in the fight against COVID-19 and says that he is taking it to prevent the disease, despite warnings from the FDA not to do so. It is used to treat malaria and lupus (systemic lupus erythematosus, or SLE). There have been reports that hydroxychloroquine did not help COVID-19 patients who received it in hospitals. These were not double-blind, placebo-controlled studies. That is, clinical trials require that neither the physician nor the patient knows whether the patient is going to receive the actual drug or a sugar pill (placebo). In either case, the patient is told that they can expect a positive outcome. The simple process of receiving assurance from a professional can lift a patient’s spirits enough that they can recover. That is, a small portion of the patients who receive the placebo do get better. This is called the placebo effect. In a proper clinical trial, statisticians will compare the percentage of patients who recover and their recovery times in both the placebo and drug groups. Statistics will tell the scientists and physicians the likelihood that the difference was due to chance. If the probability of it being due to chance is less than one in twenty (p < 0.05), most peer-reviewed journals will allow the authors to say that the drug was effective.
This can be contrasted with a trial that is not double-blind, placebo-controlled. If physicians know that they are allowed to prescribe a drug with unknown safety and possible side effects, they might be less likely to give it to patients who only have minor symptoms. Instead, it might be given preferentially to the patients who have major symptoms. So, it’s almost guaranteed that more of the patients who received the drug will die. Still, it’s possible that hydroxychloroquine is safe and effective when given to some of the patients who have COVID-19. This drug has successfully passed Phase I and II clinical trials. Phase III trials are now under way1,35. It is known to be effective in glass (in vitro) test tubes or Petri dishes in a lab. It increases the pH of acidic intracellular organelles that are essential for membrane fusion and entry of SARS-CoV-2 into host cells.
Remdesivir is another drug that has received much attention. It is a nucleoside analogue that inhibits the viral RNA polymerase and thus the replication of the virus. A clinical trial of more than a thousand people showed that people taking Remdesivir recovered in 11 days on average, compared to 15 days for those on a placebo36. So, the FDA issued an emergency use authorization for treating patients with COVID-19.
It’s also possible that inhibitors of the ACE2 signaling pathway might be effective treatments for patients who are suffering from critical, advanced and untreatable stages of the COVID-1937. It is generally thought that viral infections can increase the risk of making allergic diseases worse. However, the opposite may be true for asthma. The very small number of asthmatic patients suggests that they might be protected from SARS-CoV-2 and COVID-19. Notably, pre-existent hypertension and/or antihypertensive treatments are risk factors for SARS-CoV-2 infection. It’s possible that the many previous studies of other diseases have been misleading. That is, there is not only the membrane-bound ACE2 receptor to which the SARS-CoV-2 virus binds but also a water-soluble form that can break off from the membrane and enter the bloodstream. High blood pressure (hypertension) and heart disease can be treated in patients who have an overactive RAS signaling system due to an overactive ACE (not ACE2) enzyme. ACE and ACE2 have opposite effects on the RAS system. An overactive ACE enzyme can cause high blood pressure. By targeting the soluble ACE2 signaling system, blood pressure can decrease. So, most of the studies showed that increased ACE2 activity leads to beneficial effects. However, they were performed using models in which the ACE enzyme’s signaling pathway was upregulated, thus balancing an unbalanced situation. Most likely, this should not happen when the opposite occurs. Soluble ACE2 activation has been associated with inflammation of the gastrointestinal tract, human cirrhosis, infarction and lung injury (fibrosis). Data suggest a strong correlation between circulating soluble ACE2 activity and the predisposition to develop the most severe symptoms of COVID-19. So, the best candidate to treat patients with severe symptoms, but neither to prevent nor to treat patients with mild symptoms of COVID-19 infection, is the small synthetic molecule MLN-4760 (a specific ACE2 inhibitor, also known as C16, GL1001 or ORE 1001)37.
However, there are no sure cures for any viral infection. For most of use, our immune system can provide the cure after the first infection and prevent future infections. We can prevent and even eradicate some viruses through vaccination and herd immunity. Before this happens, only our own immune system is truly effective – but not always. Viruses are not like bacteria, which have unique features like cell walls that can be targeted with antibiotics (which should NOT be used to treat COVID-19 or any other viral disease). Viruses are not alive – even if we say that we want to kill them. They depend on the host cells to replicate and propagate. Drugs that target critical parts of the viral replication or propagation process also affect the host. However, scientists and healthcare workers are using every tool at their disposal, including new, exciting technologies. When combined with teamwork and transparency, we will save lives. Still, COVID-19 is a dynamic disease that continues to surprise us.
That is, the SARS-CoV-2 virus has been mutating38. Scientists at Duke University and Los Alamos National Laboratory in the USA, along with the University of Sheffield, UK have been tracking the evolution of SARS-CoV-2. They are using the database provided by the Global Initiative for Sharing All Influenza Data (GISIAD). GISAID is the primary COVID-19 sequence database resource. Their “intent is to complement what they provide with visualizations and summary data specifically intended to support the immunology and vaccine communities and to alert the broader community to changes in the frequency of mutations that might signal positive selection and a change in either viral phenotype or antigenicity”38. Hundreds of new ribonucleic acid (RNA) sequences of SARS-CoV-2 arrive at GISAID each day from around the globe. The team of researchers found one mutant that is rather concerning. A change from guanine (G) to adenine (A) at position 23,403 in the Wuhan reference strain changed an aspartic acid residue to glycine at position 614 in the S protein. This mutated strain (D614G) has become dominant across the world and is more infective than the original strain. The issue is so urgent that the article was published online before being peer-reviewed. Note that this is not an amino acid residue that is required for the binding to the ACE2 receptor14.
Science is the key
Scientists and healthcare professionals emphasize that the key first step in controlling the COVD-19 pandemic is testing. There are two main types of tests: viral and antibody. Viral tests tell if a person is actively infected, as evidenced by the presence of viral antigens or viral RNA. The detection of viral antibodies or RNA indicates that a person was previously exposed to the virus, but developed a healthy immune response. Most currently used tests for the virus using a reverse transcriptase-polymerase chain reaction (RT-PCR) to look for viral RNA in samples taken from a nasopharyngeal swab, which is uncomfortable and requires close contact between the patient and healthcare worker. It would be much better if saliva could be tested. The FDA recently approved Emergency Use the new test developed in the Rutgers Clinical Genomics Lab39. It uses real-time reverse transcriptase PCR to analyze saliva (as well as nasopharyngeal swabs) for viral RNA. However, the viral RNA could possibly mutate into a type whose RNA would not be detected in assays for the original SARS-CoV-2 virus. So, it might be better in the near future to look for the specific carbohydrates (sugars) that are attached to surface proteins (glycoproteins) in different viruses40. These are called glycans. Iceni Diagnostics’ at-home test kit uses host-pathogen glycan recognition (HPGR) technology. Gold nanoparticles are coated with human carbohydrates. The carbohydrates that are selected are recognized specifically by the target pathogen (SARS-CoV-2, or a human influenza virus). A duplex Coronavirus/generic flu test is also being developed to identify both viruses in one sample40.
Accuracy is essential for these tests to be useful. Inaccuracies can have deadly consequences. We must have accurate viral tests to determine who must be isolated. If a person thinks they have antibodies but don’t really, they will feel free to refrain from social distancing. They could become exposed to the virus and then expose others. So, it’s important to be patient and wait until their accuracies can be evaluated. In a recent study, 96 specimens taken from patients who had COVID-19 were tested using three different methods41. In addition, 11 negative control samples of swabs from people who tested negative for SARS-CoV-2 were included. The modified CDC assay detected SARS-CoV-2 in all 96 specimens and in none of the negative controls41.
However, there is still so much that we don’t know. If a blood test for antibodies to the original SARS-CoV-2 virus, does that mean that the person testes is safe from re-infection by the same virus or its mutant? There have been reports of sailors on the USS Theodore Roosevelt who previously had the SARS-CoV-2 virus testing positive several weeks later. Was the antibody test accurate? Is COVID-19 like the common cold in that previous exposure to a virus does not protect you from catching a cold again in just a few weeks?
Still we do know many important things. We know what types of diet and lifestyle support the immune system. We also know that the Chinese are NOT to blame for this. Chinese scientists are helping to save hundreds of millions of lives by being transparent and by sharing data rapidly and openly, in English. I haven’t seen any English speaking journals issuing Chinese translations of their articles.
I would like to add my voice to public health scientists from around the world who wrote the following in the prestigious medical journal, The Lancet42.
We sign this statement in solidarity with all scientists and health professionals in China who continue to save lives and protect global health during the challenge of the COVID-19 outbreak. We are all in this together, with our Chinese counterparts in the forefront, against this new viral threat. The rapid, open, and transparent sharing of data on this outbreak is now being threatened by rumors and misinformation around its origins. We stand together to strongly condemn conspiracy theories suggesting that COVID-19 does not have a natural origin.
Glossary of terms
Antibodies: Proteins made by immune cells that bind to antigens from a pathogen (like the spike protein in the SARS-CoV-2 virus).
Antigens: Parts of a pathogen (like the spike protein in the SARS-CoV-2 virus) that induces the production of antibodies in a host cell.
CDC: Centers for Disease Control (in the USA).
Codon. Triplet codon: Three nucleotides that code for single amino acid.
Open Reading Frame (ORF): A continuous section of codons that begins with a start codon (usually AUG) and ends at a stop codon (usually UAA, UAG or UGA).
Cytokines: Chemical signaling molecules that guide a healthy immune response.
Deoxyribonucleotide: A monomeric unit of deoxyribonucleic acid (DNA), made up of a deoxyribose sugar, a nucleic acid (Adenosine, A; Thymine, T; Guanine, G; and Cytosine, C) and a phosphoryl group.
Genome: The collection of all the genetic material in an organism or virus. The human genome is the complete sequence of deoxyribonucleic acids (DNA) in the 23 pairs of chromosomes, as well as mitochondrial DNA. In SARS-CoV-2, it is the complete sequence of ribonucleic acids (RNA) inside the virus.
Polymerase Chain Reaction (PCR): A way to amplify (make many copies) of DNA, using a reaction catalyzed by a DNA polymerase.
Proteinase: An enzyme that catalyzes the breakdown (hydrolysis) of proteins into smaller proteins and peptides.
Reverse transcription: Transcription of RNA into DNA.
Reverse transcriptase polymerase chain reaction (RT-PCR): A way to test for RNA. It combines reverse transcription of RNA into complementary DNA (cDNA), followed by amplification of specific DNA targets.
Ribonucleotide: A monomeric unit of ribonucleic acid (RNA), made up of a ribose, a nucleic acid (Adenosine, A; Uracil, U; Guanine, G; and Cytosine, C) and a phosphoryl group.
Transcription: In plant, animal and bacterial cells it is the conversion of DNA into RNA. In viruses containing RNA (like SARS-CoV-2), the genomic RNA is transcribed into other RNA molecules.
Transcriptome: The collection of all the transcripts of an organism or virus.
Translation: The conversion of mRNA into proteins or peptides.
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