Archive for the ‘antivirals’ Category
stuff on the immune system and that recent pandemic: 1 – how to get lost in a single cell
got that?
Canto: So, looking way back to the Covid-19 year or two, which we survived (and I’m wondering if the virus has too), have we retained what we’ve learned from all those Medcram videos we watched, and from the various ‘vaccine hesitant’ characters we encountered…
Jacinta: One of whom was a nurse as I recall, but I must say, mind like a sieve, I don’t feel I’ve retained much, so we’re reading Nobel Prize-winning immunologist Peter Doherty’s An insider’s plague year, to help us set down some info and promote our lifelong learning.
Canto: So what’s the difference between a drug and a vaccine, Doherty asks, noting that even experienced journalists confuse the two. Drug of course is a broad term, for anything chemical used to treat people, by pill, injection, bottle, patch or suppository. At the beginning of his ‘plague journal’ Doherty mentions two drugs I recall from our Medcram viewings, hydroxychloraquine, an anti-malarial, and remdesivir, ‘an experimental anti-Ebola drug’.
Jacinta: Yes, hydroxychloraquine was touted early on in the year (2020) as being of some use. A USA site, Drugbank online, said this:
Chloroquine and hydroxychloroquine are both being investigated for the treatment of SARS-CoV-2
followed by this:
The FDA emergency use authorization for hydroxychloroquine and chloroquine in the treatment of COVID-19 was revoked on 15 June 2020.
Remdesivir seems to have been somewhat more effective in reducing symptoms, as was seen earlier in treating MERS-CoV sufferers. It received the FDA’s authorisation just a few weeks before the other drug’s authorisation was revoked.
Canto: The word drug features in the USA’s FDA (Food and Drug Administration), while in Australia we have the TGA (Therapeutic Goods Administration), and therapeutic is simply medicalese for drug. The first of these tended to be natural remedies such as quinine, a useful anti-malarial extracted from Cinchona tree bark. Tonic water has quinine in it, hence the name. Another natural anti-malarial is artemisinin, from sweet wormwood. These ingredients, extracted and purified, have been extremely important in combatting the biggest killer disease in the global south.
Jacinta: In treating SARS-CoV2, remdesivir was the only effective antiviral in the first 12 months, apart from – monoclonal antibodies. I’ve heard of them, now I’m going to try and explain them. I’ll start with this quote from the Mayo Clinic:
Monoclonal antibodies are laboratory-produced molecules engineered to serve as substitute antibodies that can restore, enhance, modify or mimic the immune system’s attack on cells that aren’t wanted, such as cancer cells.
Antibodies (aka immunoglobulin, of which there are 5 types) are Y-shaped proteins that can bind to specific antigens (the foreign nasties) via a lock-and-key mechanism. Monoclonal antibodies, as mentioned above, have been particularly effective in some cancer treatments.
Canto: Well, only this month our TGA has posted an update on the decreased effectiveness of monoclonal antibodies against emerging SARS-CoV2 variants:
emerging data show that anti-spike protein monoclonal antibodies demonstrate a significant decrease in their in-vitro neutralising activities against many newer circulating SARS-CoV-2 variants, particularly Omicron and its subvariants.
Jacinta: Mmm. So let’s go on with our very basic training in immunology. So it’s the organs of the lymphatic system – the lymph nodes, the thymus, the spleen and the bone marrow – that produce or harbour and further develop our immune cells. Now, these immune cells come in different types with different names, such as phagocytes, which are a type of white blood cell (WBC)…
Canto: Yes, this immune system stuff might require dozens or hundreds of posts. Phagocytes can be ‘professional’ or non-professional’ depending on effectiveness. The professionals include neutrophils, macrophages, mast cells, dendritic cells and monocytes – all WBCs. They’re all more or less good at detecting antigens. And I believe these WBCs form what’s called the innate, rather than adaptive, immune system.
Jacinta: So getting back to the SARS-CoV2 Betacoronavirus – we’ll be jumping around a lot in these posts, methinks – it has this thing called a spike protein on its outer coat, and this protein has a receptor-binding domain (RBD) with binds to the angiotensin-converting enzyme (ACE) receptor, or ACE2 receptor. ACE2 receptors exist throughout the body but the principal pathway for this virus involves the epithelial cells at the base of the lungs and in the blood vessels. So I’m reading a Nature article, referenced below, entitled ‘Mechanisms of SARS-CoV-2 entry into cells’, and I want to frame this stuff in my own words to understand it. Apparently ACE2 is the receptor for other Betacoronaviruses and Alphacoronaviruses, so immunologists and virologists are pretty familiar with it.
Canto: Yes, and there’s all this terminology – for example a virion is the whole viral particle – not just the DNA or RNA core and its proteins but the external envelope – everything that allows it to exist extra-cellularly. So a coronavirus virion is made up of nucleocapsid and other proteins, including the spike proteins that facilitate entry into potential host cells via the ACE2 receptors.
Jacinta: So let’s focus for now on the nucleocapsid (N) protein. Another Nature article, with multiple authors, has this title: ‘The SARS-CoV-2 nucleocapsid protein is dynamic, disordered, and phase separates with RNA’, which sounds ominous. And the article starts with a problem:
The SARS-CoV-2 nucleocapsid (N) protein is an abundant RNA-binding protein critical for viral genome packaging, yet the molecular details that underlie this process are poorly understood.
Yes, especially by me. I get that these N proteins bind and ‘package’ the RNA, but I don’t get ‘phase separation’…
Canto: Phase separation is a key biological concept, it seems, but complex, and probably something that requires lab work to fully comprehend. Here’s a quote from ScienceDirect that might help:
Many biological macromolecules, such as proteins and nucleic acids, exert their biological functions by forming phase-separated condensates, and phase separation is closely related to various human diseases. Gene transcriptional regulation is an indispensable part of gene expression and normal function in cells. Its abnormal regulation often causes the occurrence of different diseases. In recent years, the occurrence of phase separation during transcriptional regulation has become an area of intense research.
It sounds like problems with phase separation may lead to irregular transcription, or vice versa, resulting in variants, mutations and such, but I’m guessing.
Jacinta: So reading further into the ScienceDirect article, you’re right, it’s near impossible to understand this stuff just through reading – you surely need to see it happening in cells. And cells, such as our own, are effing complex. Here’s another (long) quote to prove it:
In cells, which are the basic unit of the structure and function of organisms, the need for various components to perform their corresponding functions at the correct time and space is a problem that cells continuously need to solve. To this end, cells have evolved a set of organelles, including membrane-encapsulated organelles (such as mitochondria, nuclei, lysosomes, the Golgi apparatus, and endoplasmic reticulum) and membrane-less organelles (such as nucleoli, Cajal bodies, stress granules, P bodies, U bodies, and signaling bodies) …. Membrane-encapsulated organelles enclose specific proteins, nucleic acids and other substances to perform their functions within a particular space. Still, how other types of membrane-less organelles form and exert their biological functions has eluded investigators for many years. In recent years, it has been discovered that different intracellular biological macromolecules assemble and separate from each other to form liquid-like structures called “biomolecular condensates”….
and it goes on. It’s dauntingly complex, but I must say I wish I was 40 years younger and working in this fascinating field. To work out more precisely the processes involved and then to be able to manipulate them…
Canto: Homo deus indeed.
Jacinta: Femo deus if you don’t mind, and that’s not even a recognised term. I just can’t wait for the 31st century.
Canto: Well let’s just stay in the shallows and say a few words about these membraned and unmembraned intracellular organelles. Mitochondria we know a bit about, the ATP-yielding (making?) organelles that existed separately eons ago as prokaryotes…
Jacinta: Thank the indefatigable iconoclast Lynn Margulis for presenting this argument, and endosymbiosis in general, against vociferous mostly male opposition…
Canto: Lysosomes are the ‘digestive system’ of the cell, containing enzymes that break down the polymeric structures of proteins, lipids, nucleic acids and carbohydrates. They vary greatly in size depending on the digestive tasks they work on. The Golgi apparatus or complex is, unsurprisingly, a complex organelle that packages proteins to be sent out into the intracellular or intercellular world – nuff said. The endoplasmic reticulum has two sub-units, rough and smooth. They’re kind of attached to the nuclear membrane of the cell, the smooth further out than the rough. It’s involved in transportation and protein folding, let’s say no more.
Jacinta: So now to the membrane-less organelles – but it looks like phase transition as a subject for analysis is about how these organelles transition from dormant to active states or how they transition from one task to another. Anyway, just a few words to introduce these organelles. Nucleoli are defined briefly as ‘small dense spherical structures in the nucleus of a cell during interphase’. They also appear to segregate in unexpected ways as cells divide – again something about phase transition. Cajal bodies are often associated with nucleoli and are involved in the processing of some RNA molecules. They appear to have other roles that aren’t yet fully understood. Stress granules are these changeable, dynamic, liquid-solid entities made from RNP (ribonucleoprotein). P bodies are somewhat similar, as are U bodies, named for being ‘uridine-rich’, whatever that may mean. In any case P and U bodies appear to act co-operatively. Signalling bodies, according to Khan Academy:
A signaling molecule is released by one cell, then travels through the bloodstream to bind to receptors on a distant target cell elsewhere in the body.
Canto: Okay, that’s enough terminology, and we won’t do all the references as nobody reads this stuff anyway.
Jacinta: Fine, we’re having fun, though it may take till doomsday to get our heads around this stuff. Wish I could afford a lab, and all its equipment….
References
Peter Doherty, An insider’s plague year, 2021
https://go.drugbank.com/drugs/DB01611
https://www.nejm.org/doi/full/10.1056/nejmoa2007764
https://www.tga.gov.au/news/news/update-effectiveness-monoclonal-antibodies-against-covid-variants
covid19: corticosteroids, male susceptibility, evaluating health, remdesivir, coagulation factors
from The Lancet, ‘the four horsemen of a viral apocalpse’
Canto: So short-course use of some steroids was being advocated in the medcram update 88, though without thorough RCT evidence.
Jacinta: Well, data was presented from the Oxford RCT on those on oxygen or on ventilators showing a statistically significant reduction of mortality from short-course (up to 10 days) low dosage of dexamethasone, a freely-available steroid medication. The study involved some 2000 patients, but only those severely afflicted were helped by the medication.
Canto: An interesting aside to the data is that in the study males outnumbered females by almost 2 to 1, and that accords with the overall ratio of male to female covid19 patients Dr Seheult is finding, which rather shocked me. Why would more males be coming down with the disease? Presumably that’s not the infection rate, but the rate at which they need to be hospitalised.
Jacinta: Yes, you’re right, according to this Australian site (unfortunately undated):
Reports continue to emerge that men are significantly more vulnerable to COVID-19 than women. The commonly held perception that more men smoke and this makes them more susceptible along with other lifestyle factors does not tell the whole picture. White House COVID-19 Task Force director Dr Deborah Birx highlighted a “concerning trend” that men in all age brackets were becoming seriously ill from the virus at a higher rate than women, including younger males.
They’re suggesting more research needs to be done on this gender difference, for health issues in general. Some are claiming that estrogen makes a difference. In any case I think cardiovascular problems are more common in males – but maybe not so much in younger males.
Canto: So update 89 is fairly short, and deals with US data about cases and deaths, most of it out of date now, and more on corticosteroids and the dangers of unsupervised use. Update 90 introduces us to a tool I’ve never heard of called ‘Discern’. Very useful for we autodidacts in helping us, for example, to enlighten our doctors as to our condition. Discern is a tool for evaluating internet health info, such as medcram’s updates on youtube, or anything else on youtube. The instrument asks you to evaluate the material according to 16 different criteria. Interestingly, this tool has been tested on covid19 material by a study out of Poland done in March. The results weren’t so good, especially for news channels.
Jacinta: Yes, physicians’ information did best – but of course we don’t go to news channels for health information, and we’d advise against anyone else doing so. The study evaluated the Discern tool itself and found it excellent, then used the tool to evaluate health information, specifically on youtube. Of course know that there’s ‘viral misinformation’ from various news outlets that gets posted on youtube. And good to see that the medcram updates were some of the most highly rated using the Discern tool.
Canto: So we’re now into reporting from early July with update 91. It starts by looking at a ‘covid risk calculator’ in which you can type in your age, gender, BMI, underlying conditions, waist circumference, and other data which you might need a full medical checkup to find out about (and that’s overdue for me), including, for example, %FMD, a measure I’ve never heard of, but which has to do with endothelial function.
Jacinta: FMD stands for fibromuscular dysplasia. The Johns Hopkins medicine site describes it as a rare blood vessel disease in which the cells of some arteries become more stiff and fibrous and less flexible. This leads to weakness and damage. Not sure how it relates to covid19 but surely any pre-existing blood vessel damage is a danger for those contracting the virus.
Canto: Right, so it’s unlikely anyone will know offhand their percentage of FMD. I don’t even know my HDL and LDL levels, never mind my HbA1c or lipids. I’d love to be able to take measures of all these myself, without visiting a doctor.
Jacinta: Typical male control freak. So all of this is to measure your risk of covid19 hospitalisation, ICU admission or mortality. Fun times. So next the update looks at Gilead, the makers of the antiviral remdesivir, who donated all their supplies of the drug to the USA in early May. But of course they kept manufacturing the drug and have to recoup the money they spent researching, developing and trialling it etc. The Wall Street Journal reports that a typical course of the drug will cost over $3000 per patient. Interestingly the Trump administration is wanting the drug to stay in the USA as much as possible, rather than be available overseas, and is spending money to that effect.
Canto: Hmm. Is that protectionism?
Jacinta: Yes I suppose. It’s not surprising that a country wants to look after its own first, especially via a product produced within its own borders. But I suspect this government would’t be interested in helping any other country – unless there was a quid pro quo. And there’s another antiviral, favipiravir, currently being trialled in Japan and the USA (I mean as of early July), and a vaccine, developed in China, is being used on the Chinese military in what seems a rather rushed and somewhat secretive fashion – we don’t know if they got the soldiers’ permission on this seemingly untried vaccine. At least at the phase 3 level.
Canto: Very CCP.
Jacinta: So onto update 92, and we revisit the electron transport chain, with four successive electron transfers converting molecular oxygen into water. Problems within this chain can produce reactive oxygen species (ROS) such as superoxide, hydrogen peroxide and hydroxy radicals, which are destructive in excess. We also look, yet again, at covid19’s impact on angiotensin and particularly the production of superoxide, which in turn causes endothelial dysfunction, increased von Willebrand factor activity, which leads to thrombosis. People were presenting as ‘happy hypoxics’, looking and feeling fine but with very low oxygen levels, and autopsies revealed ‘microthrombi in the interalveolar septa’ of victims’ lungs. All this leading to a paper published in The Lancet which looked at factors in this process of coagulation and thrombosis:
We assessed markers of endothelial cell and platelet activation, including VWF antigen, soluble thrombomodulin [a marker of endothelial cell activation], soluble P-selectin [a marker of endothelial cell and platelet activation], and soluble CD40 ligand [a marker of platelet and T-cell activation], as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes.
So this was about getting to the bottom of the increased clotting. And the results were hardly surprising, but the final discussion section is worth quoting at length, as it seems to capture much that we know about covid19’s effects (at least short-term effects) at the moment:
We therefore propose that COVID-19-associated coagulopathy is an endotheliopathy that results in augmented VWF release, platelet activation, and hypercoagulability, leading to the clinical prothrombotic manifestations of COVID-19-associated coagulopathy, which can include venous, arterial, and microvascular thrombosis. The factors responsible for this endotheliopathy and platelet activation are uncertain but could include direct viral infection of endothelial cells, collateral damage to the tissue as a result of immune infiltration and activation, complement activation, or any number of inflammatory cytokines believed to play a role in COVID-19 disease.
They suggest anti-platelet therapy and endothelial cell modification treatments as well as anticoagulation treatments, and they suggest some agents ‘which might have therapeutic potential’.
Canto: Potential? You’d think they’d be onto all this by now.
Jacinta: Well there’s also potential for untried medications – at least untried in this context – to go terribly wrong. And it’s also likely that some hospitals are already onto using the safer forms of treatment. Dr Seheult speaks of the antioxidant N-acetylcysteine (NAC) in this context, as it has been shown to be a thrombolytic when used intravenously. There are studies pending on the effects of NAC in treating covid19 patients.
Canto: Now, I’ve just been watching something on monoclonal antibodies as perhaps the most promising treatment yet, short of a vaccine. Can you explain….
Jacinta: Yes I’ll try, maybe next time.
References
Coronavirus Pandemic Update 88: Dexamethasone History & Mortality Benefit Data Released From UK
Coronavirus Pandemic Update 89: COVID 19 Infections Rising in Many States; Dexamethasone Cautions
Coronavirus Pandemic Update 90: Assess The Quality of COVID-19 Info With A Validated Research Tool
Coronavirus Pandemic Update 91: Remdesivir Pricing & Disparities in Drug Availability
Coronavirus Pandemic Update 92: Blood Clots & COVID-19 – New Research & Potential Role of NAC
amhf.org.au/covid_19
https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(20)30216-7/fulltext
Covid 19: some stuff on remdesivir
Canto: So there’s this promising new antiviral drug that researchers are working on. Remdesivir. Terrible name. Why not something more hard-hitting like rambovir or rockyvir?
Jacinta: Well I’m not sure it’s an American drug, and I don’t think it’s new. It’s new for Covid-19. Everything’s new for Covid-19. And here we should repeat the standard caveat: ‘No specific agent has yet been demonstrated to be clinically effective in the management of Covid-19’.
Canto: Well done. So I’m reading this online article from a week or so ago – and a week’s a long time in Covid-19 – on the website of the Medical Journal of Australia, and it tells me that the antimicrobial remdesivir is ‘an investigational nucleotide prodrug’ – glad it’s not one of them antidrugs – and was used on the first diagnosed Covid-19 sufferer in the US. So maybe it is American. The article doesn’t say anything about its effect on the patient, but apparently it was first developed as a potential therapy for Ebola, and there’s some laboratory evidence that it can inhibit the replication of SARS-CoV-2.
Jacinta: That’s right, so four clinical trials have already begun in the US to test the effects of remdesivir, and another two are registered in China.
Canto: Well according to this media release only yesterday (April 17) from the National Institutes of Health (NIH) in the USA, they’ve already been testing the drug on poor old rhesus macaques…
Jacinta: They infected em? Bastards.
Canto: History is written by the victors my friend. And also by those who can actually write. Anyway, they responded very well to early treatment with reduced clinical signs and lung damage in a study designed to simulate treatment procedures for human patients in a hospital setting…
Jacinta: That’s nice. They got to sleep in real beds, like middle-class macaques.
Canto: Maybe. Of course, none of this has been peer-reviewed yet, but it’s very promising. But let me give you the total lowdown. You know that there have to be control groups, right?
Jacinta: Uhhh – uh-o. So… Let me see, they were all infected with the virus, but only some got the remdesivir, right?
Canto: Well of course they had to make the comparison. So they had two groups of six rhesus macaques, and they infected both groups with SARS-CoV-2. Then 12 hours later the treatment group received an injection of remdesivir. Sorry about the other group. After that the treatment group received a booster injection every day for the next six days. The initial treatment was timed to more or less coincide with the animals’ highest projected viral load. They first examined the animals 12 hours after initial treatment, and the treatment seemed pretty effective, only one still showed some mild symptoms, while in the control group they all displayed ‘rapid and difficult breathing’ …
Jacinta: Called dyspnoea in medical lingo.
Canto: Thank you. So the study continued for seven days, and over that time the treated monkeys were found to have significantly less virus in, and damage to, their lungs than the untreated.
Jacinta: So what happened to the untreated monkeys after that?
Canto: I might say ‘don’t ask, don’t tell’, but I think it’s reasonable to assume that after seven days they were treated with remdesivir and recovered. And that they chose a short, seven-day testing period so as not to endanger any monkey lives?
Jacinta: Hmmm. I don’t know too much about monkey business… Anyway, this remdesivir is obviouly promising and we must watch out for the results of other trials. But what is this remdesivir? What exactly is an antiviral, or a ‘nucleotide prodrug’, and do they all act in the same way? I know they’re not vaccines, they don’t induce antibodies, so how do they suppress the infection?
Canto: Okay, so our first stop on our info crawl is Wikipedia. Think of antivirals as a counterpart to antibiotics, aimed at viruses rather than bacterial pathogens, except that, unlike most antibiotics, their aim is to suppress rather than to kill the pathogen.
Jacinta: Really? Why not aim to kill the virus?
Canto: I don’t know, perhaps that’s not so easy with viruses. Anyway, while most antivirals target specific viruses, some are broad-spectrum, and I suppose remdesivir is one of those, since it was also successful against MERS, another coronavirus, and was first developed to combat Ebola virus, which isn’t a coronavirus as far as I know.
Jacinta: Remdesivir was earlier described as a nucleotide prodrug. A nucleotide is the basic structural unit of a nucleic acid such as RNA. A prodrug is by definition an inactive biological or pharmacological compound that can be converted within the body to have active drug properties. So the field of antiviral drug research has developed a lot, especially as a result of the HIV epidemic, and those that followed. All of this has expanded our knowledge of how viruses enter hosts and proliferate. SARS-CoV-2 is a set of RNA nucleotides surrounded by a protein capsid, or capsule, over which is a lipid envelope. It enters the host via the spike protein, and through this membrane fusion it infects host T lymphocytes – white blood cells that form a part of our immune system.
Canto: Yes, and trying to describe it all in lay terms – so that we understand it – is damn difficult. We know remdesivir has been somewhat effective for a broad spectrum of action against RNA viruses, and I note in this abstract that it’s ‘a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps)’ My guess is this means it acts like a nucleotide, inhibiting these RDRps. An RNA polymerase, I’m learning, is an enzyme (a type of protein) that’s ‘responsible for copying a DNA sequence into an RNA sequence, during the process of transcription’. But maybe an RNA-dependent RNA polymerase works on RNA, in the absence of DNA. So presumably remdesivir inhibits this essential enzyme from carrying out the transcription process that replicates the virus.
Jacinta: Maybe. By the way, as we travel the net on our info crawl, we’ve discovered some amazing stuff, such as this Covid-19 pandemic series of ongoing videos from a source called MedCram that began in late January and traces the spread, and the drama. The series begins with these words: ‘one of the things that’s in the news and hopefully goes away real soon is the coronavirus epidemic from 2019…’ That, to me, was more compelling than any advertising hook I’ve ever read.
Canto: Yes I’m keen to watch the whole series. Anyway, I believe remdesivir, also called RDV, has been used in an unauthorised way on human subjects already, and news from this Chemical and Engineering News website is that, understandably, interest in the drug and in scaling up production is reaching fever pitch, with a lot of pressure on Gilead, the company that presumably has a patent on RDV.
Jacinta: Of course, as we’ve already pointed out, this is exactly not the time for one private company to get precious about its rights to profit. Scaling up, assuming the drug’s effectiveness can be confirmed, should involve multiple labs in multiple countries. Having said that, producing a drug like RDV, described as a ‘medium complexity project’ compared to an apparently simpler drug such as the antimalarial drug hydrochloroquine, already involves a chain of companies and suppliers in a multi-step process. Every step in the process would need to be efficient, to prevent bottlenecks. Scaling-up also raises questions – remember Tamiflu? Our government stockpiled it in vast amounts in spite of damning analyses by the Cochrane Collaboration and others about its limited effectiveness and problematic side-effects. We don’t yet have proper analysis of RDV’s effectiveness, and we don’t know how much of it might be required, because nobody can predict the eventual course of this pandemic.
Canto: All true, but right now people are dying, and this is clearly the worst pandemic in more than a century. There are of course candidates other than RDV, it would be unwise to focus on just one, but public and private resources should be combined to bring any possible effective treatment to fruition. That’s what I reckon.
References
https://www.mja.com.au/journal/2020/clinical-presentation-and-management-covid-19
https://en.wikipedia.org/wiki/Antiviral_drug
https://ama.com.au/ausmed/govt-stands-tamiflu-despite-damning-findings
Covid 19: hopes, failures, solutions
Covid-19 continues to be devastating, especially in the USA, where there are vastly more cases than anywhere else, and vastly more deaths, though the picture there is complex. The hardest-hit region, the New York area, is seeing devastation in poorer districts such as Queens, where the Elmhurst public hospital is inundated with uninsured, critically ill patients. New York has suffered almost half of US deaths. Some other states and regions, especially physical outliers such as Alaska, Hawaii and the Virgin Islands, have very low numbers, and it would be hard to explain why the spread of cases across the mainland has been so uneven. Of course it’s obvious that there has been no federal leadership on the pandemic.
Here in Australia, where the numbers seem to be improving (we’re 33rd on the list of total cases, down from 18th when I first started paying attention to the list about three weeks ago, and 52nd on the list of total deaths), our conservative federal government is keen to open up the country again, and has released modelling to the effect that the virus will be eliminated from the mainland if we maintain current physical distancing measures, though it’s likely to take weeks rather than months:
The model suggests that every 10 people infected currently spread the virus to five more people, on average. At that level, the virus would eventually be unable to circulate and would die out within Australia.
Sydney Morning Herald, ‘Australia in course to eliminate Covid-19, modelling shows’
Australia’s current reproduction number (R0) is just a little over .5. A maintained R0 of 1 or less will eventually eliminate the virus. Of course, there will be fluctuations in that number, so it will be difficult to project a time when things are ‘all clear’. Another difficulty with modelling is that the number of infected but asymptomatic people is unknown and difficult to estimate. For example, recent Covid-19 testing of the entire crew of the aircraft carrier Theodore Roosevelt found that a substantial majority of those who tested positive were asymptomatic, casting doubt on previous estimates (already worrying for transmission) of one in four cases being asymptomatic.
The asymptomatic/presymptomatic transmission issue was addressed by Bill Gates in this article back in February. It’s what makes SARS-CoV-2 a much more serious threat than the previous SARS and MERS viruses. Gates, in this very important article, also provides an outline of what needs to be done globally to fight this pandemic and to prepare for inevitable future ones. If only…
It’s worth comparing Gates’ call for national and global co-ordination, and more expenditure, in the fields of epidemiology and disease prevention, with another more recent article, also published in the New England Journal of Medicine, which tells a tale of Britain and its NHS, gutted by years, in fact decades of ‘reforms’ and budget cuts:
Thanks to government “reforms” of the NHS, it has become highly decentralized, with over 200 commissioning groups in England that can make independent decisions about staffing and procurement of equipment — far from the monolithic “socialist” health care system it is often assumed to be. The devolved governments in Wales, Scotland, and Northern Ireland have substantial health system autonomy. At a time when central management of staff and resources might be most helpful, the decentralized decision-making structure leads to competition for resources and inconsistent policies.
One can hope that the travesty of this virus, especially in places like the US and the UK, will lead to a rethinking of the importance of a well-funded, centralised, co-ordinating and interventionist government in modern states, with particular emphasis on the healthcare system. But I suspect that, in the USA at least, things will go the other way, and the government-hating and government-blaming will only intensify. I’d love to leave this topic and look at solutions – that’s to say I’d love to focus more on the science, but I’m barely equipped to do so. Still, I like to have a go. A very technical and comprehensive review review of pharmacological treatments has been posted recently on the JAMA website, which includes an account of how SARS-CoV-2 enters host cells and utilises those cells for reproduction.
The review claims that currently the most promising therapy is the antiviral drug remdesivir. So what is it and how does it work? I’ll try to answer that question next time.
References
https://www.nejm.org/doi/full/10.1056/NEJMp2005755?query=recirc_artType_railA_article
the science of Covid-19: global collaboration and broad-spectrum antivirals
An interesting article in the New Yorker has introduced me to David Ho, whose work on AIDS in the eighties and nineties led Time magazine to name him its person of the year in 1996. Almost forty years on from reporting the first AIDS cases in 1981, Ho continues to fight the disease, which still kills a million people a year. That might shock some people, but out of sight, out of mind, it’s not happening here. Covid-19 has killed about 100,000 in a few months, all over the world, and the global curve is no cause for complacency, to put it mildly. And you can catch it just by breathing. And many researchers have said this is just a rehearsal for the big one. Well, let’s just deal with this one first, and learn from it. People like David Ho are on the front line, desperately seeking new, comprehensive antiviral solutions.
Drug companies, however, have tended to invest in chronic viral infections, such as AIDS and hepatitis B, rather than acute ones which do deadly damage then disappear, as did SARS and MERS. Both these infections were gone before a vaccine was fully developed, so there would have been no return on investment. Many researchers are pointing out that it’s therefore not a task suited to private enterprise, which tends to be competitive rather than collaborative, as well as having other priorities. This article linked to the Johns Hopkins website focuses on some of the problems related to lack of co-ordination regarding messaging and possible treatments. The pandemic is global, it obviously disregards boundaries, so we need to be less nationalistic and proprietorial and more humanistic in response. To quote the article,
As a first step, the biomedical community needs to insist on consistent use of central registries of clinical studies and on early sharing of complete details of both successful and failed studies, and not withhold important scientific evidence as proprietary information.
If adequate testing shows promising results, that information needs to be shared immediately, in a way that can be analysed and the testing replicated. This of course includes methods of analysing and tracking the virus and its proteins. Developing treatments at the moment is tricky due to the apparently huge variation in the responses to infection – from being completely asymptomatic to the other extreme. Drugs may have to vary in toxicity to treat these varying symptoms. With effective collaboration, rigorous testing of treatments doesn’t have to be a slow process – at least it can can be much quicker than it has been before.
Meanwhile, not all health authorities are on the same page regarding physical distancing measures. The USA’s Centers for Disease Control and Prevention (CDC), a federal government agency, has sparked controversy by allowing asymptomatic ‘critical infrastructure’ workers who’ve been exposed to SARS-CoV-2 to return to work under strict guidelines. It’s noteworthy that the US federal government has been pushing a rapid return-to-work scenario for some weeks, though it has often been inconsistent in its messaging. Asymptomatic carriers of the virus are officially estimated at about 25%, though some experts argue that the figure could be as high as 50%. Individuals can also be presymptomatic rather than asymptomatic, and this is difficult to identify due to the variability of the onset of symptoms. In any case there is still the possibility of spread from either group. The lack of precise evidence about asymptomatic transmission tends to make most experts err on the side of reducing the risk. Also, according to this paper, distancing measures have likely reduced the spread of seasonal influenza (particularly virulent this season), especially in countries such as Japan, where there was an early awareness of Covid-19 prevention measures.
Not surprisingly, the advent of this virus, which has brought with it a return of all the unheeded warnings of the past decade or more, has inspired and spurred a lot of interesting new research and approaches to dealing with viruses – long regarded as the most potentially dangerous pathogens out there. The New Yorker article relates some of the history, from the first antiviral drug to be marketed in the early sixties, ‘a repurposed anti-cancer drug put to use as a topical treatment for a herpes infection that attacked the cornea’, to drugs such as ribavirin and acyclovir in the seventies, and then on to breakthroughs in the eighties in the battle against HIV/AIDS. There will be more breakthroughs with this new pandemic, but the point is that the threat of new viral outbreaks has been touted for years, but antiviral research gets limited funding and all but shuts down when there’s no clear and present danger. The current pandemic may or may not convince us that work on broad-spectrum antivirals needs to be ongoing and cannot be subject to private market fluctuations or whims.
Lest I lead people into thinking I have much of a clue as to what broad-spectrum antivirals are, let me assure you… but there’s something of a clue in the name. It should be about finding some common factor in the invasive behaviour of viruses, and what they do to replicate once inside, and using that knowledge to develop or activate agents that will shut down or act against such behaviour. A website called Creative Biolabs has a bit more to say on its front page:
By inhibiting virus replication/reproduction in infected cells or improving cellular defense system, these broad-spectrum antiviral drugs are effective in the clinical treatment of viral infection, as well as for SARS-CoV-2 infection. Mechanisms drugs with broad-spectrum SARS-CoV-2 antiviral activities mainly involve:
– Inhibiting or killing the virus directly
– Interference with virus attachment/membrane fusion
– Preventing the virus from penetrating into cells
– Inhibiting the biosynthesis of the virus
– Inhibiting the assembly and release of the virus
– Enhancing the antiviral ability of the host
From what I can gather, Creative Biolabs is a bonafide life-science company servicing various private pharmaceutical companies as well as government agencies. So hopefully I can learn, from their website and many others, more about broad-spectrum antivirals and any other possible treatments and ventures that might reduce the threat of viral epidemics.
References
https://www.newyorker.com/magazine/2020/04/13/the-quest-for-a-pandemic-pill
https://jamanetwork.com/journals/jama/fullarticle/2764657
https://en.wikipedia.org/wiki/Ribavirin