Archive for the ‘monoclonal antibodies’ Category
stuff on covid19 and immunology
Canto: Well it’s a great time to be living in quiet South Australia, with a global pandemic raging in many places elsewhere..
Jacinta: Particularly the US, which we’ve long been focussing on, maybe in a schadenfreude kind of way.
Canto: Yes or maybe in a lazy way, because we’re so inundated by American media, social media, cable news, the NYT, the WaPo, the Atlantic, Politico, the Medcram lecture series, it just seems easier to plug into US info these days. Which makes me wonder…
Jacinta: And all hell’s breaking loose with Trump having come down with covid19 and the misinformation machine starting to overheat. Currently – October 5 – according to the Worldometer figures, which we’ve been using since the start of the pandemic – the USA has suffered 214,611 deaths, more than a fifth of the world’s deaths by that database’s figures.
Canto: Yes, we’ve noticed that the US media always has figures a little below ours – I presume because they’re using the Johns Hopkins figures, which seem to have a time lag. We can’t say which is more reliable of course. Complete reliability for all sources is unlikely.
Jacinta: In any case the USA has spectacularly failed to get on top of this virus, and is still experiencing high case-rates and death-rates, though the variations between states are constantly changing, and tell their own complex story. Overall, though, unless something drastic happens, the US is on track to have suffered 250,000 to 300,000 deaths by the end of the year – and I haven’t accounted for the winter season.
Canto: Yes and that’s no outlier prediction, that’s just a very simple forward projection.
Jacinta: I’m half-wondering when the Trump administration will try to throw cold water – or bleach perhaps – at the covid figures, as they’ve tried to misinform with everything else to do with the virus, including Trump’s condition and the timeline of his infection. But I want to look at what we’re hearing from the Walter Reed medicos about his treatment, and more generally about immunology and the virus’ progress. From the figures, it doesn’t seem as if anything is working very effectively, but Trump will be getting treatment that isn’t widely available to anyone else in that country, and we’re getting no clear answers as to how he’s faring.
Canto: The treatment everyone’s reporting on currently is the ‘antibody cocktail’ produced by the drug company Regeneron. This was made available through an emergency use authorisation, and unsurprisingly there’s now demand pressure on the product. He’s also on the antiviral remdesivir, and the steroid dexamethasone, and it seems he’s been given oxygen, though medical and other experts have had to read between the lines of public announcements to work out what exactly is going on.
Jacinta: Yes, many experts suspect he’s been sicker than he’s been prepared to admit, and of course the Democrats and health officials are all wishing him well and ‘praying for him’ in their American way. Frankly, I hope he dies, for the simple reason that his death will likely save thousands of lives, as it will stem the flow of misinformation, and scare even his dumbest followers into wearing masks, physically distancing and generally starting to act sensibly and humanely. It will have been the best thing he’s ever done with his life. But enough controversy, let’s look at immunology and treatment. According to the NYT, Trump has also been taking Vitamin D, zinc, the hormone melatonin, and famotidine, an anti-heartburn medication.
Canto: So he’s fit as a fiddle, then?
Jacinta: Hmm. As we know, Dr Seheult on Medcram has spoken of the benefits of zinc and vitamin D, as well as remdesivir and dexamethasone, but none of these treatments have been subjected to rigorous clinical trials in relation to SARS-CoV2 as yet. It’s my guess that Trump himself is pushing the envelope to be treated with these drugs, though it could also be that he’s actually quite sick, as I’ve said. And unless he actually dies, it could be that we’ll never know.
Canto: He won’t die. Anyway, what about Regeneron, and these monoclonal antibodies?
Jacinta: Well we’ve talked about them before, but they’ve been mostly used in the past against cancer cells. In fact they’re finding uses in many medical fields but they’re tricky to manufacture, and would be expensive to roll out…
Canto: Actually I’ve heard some reports that it’s polyclonal antibodies they’re giving him. Is there a difference? I thought maybe because they were giving him a ‘cocktail’ of monoclonal antibodies, this amounted to polyclonal…?
Jacinta: Well, who knows what they’re actually giving him, but according to my reading, researchers have engineered (cloned) immune cells that produce specific antibodies – antibodies to a specific antigen, or more accurately, to the epitope, or binding site, of that antigen. That’s monoclonal antibodies. Polyclonal antibodies can bind to multiple epitopes, which sounds better but maybe they’re harder to manufacture in an effective form.
Canto: So these monoclonal or polyclonal antibodies are proteins, synthesised versions of proteins produced by the immune system. Is it that, due to the virus, the body is prevented from producing these antibody proteins naturally, or can’t produce enough of them, or what?
Jacinta: What I gather is that the response to the virus varies – some are producing antibodies, some aren’t. A report came out last week about Regeneron’s treatment, this ‘cocktail of two monoclonal antibodies’:
The company showed slides with detailed data from 275 infected people in a placebo-controlled trial that ultimately plans to enrol 2100 individuals who are asymptomatic or, at worst, moderately ill. The analysis divides patients into two groups: those who had detectable antibodies against SARS-CoV-2 at the trial’s start and those who did not, a so-called seronegative group. The monoclonal cocktail showed little effect on people who already had antibodies against the virus. But it appeared to help the seronegative patients, powerfully reducing the amount of virus found in nasopharyngeal swabs and alleviating symptoms more quickly.
So it appears to boost the immune system of those who haven’t, or haven’t yet produced antibodies to the virus. So, useful for those in the earliest phase of having contracted covid19. But all of this has to be more thoroughly tested – for example, would the treatment work as a general preventive?
Canto: There’s another company, Eli Lilly, which has been trialling a single monoclonal antibody treatment, with slightly different results – both companies have given low-dose and high-dose treatments, and Regeneron found no statistically significant difference, whereas Lilly found the high dose ineffective – which is good news as the lower dose will presumably be cheaper to manufacture, with fewer adverse effects, if any. The two companies have a slightly different approach to using their medications – though this might change in such a fluid situation. Regeneron is thinking of developing diagnostic tools to identify those most in need of the treatment, e.g those with the highest viral load, and those with low antibody levels (serology). Lily, on the other hand, are thinking that any covid19-positive people at higher risk – diabetics, overweight, or simply elderly – should be given the treatment, if possible.
Jacinta: In the meantime, the dangers of this virus are constantly being underplayed by this administration under pressure, clearly, from the Boy-King, while a large cluster of people who’ve had contact with him, either at the White House or on any of his jaunts around the country. Exactly who set off the cluster will probably never be known, because it sounds like they’re refusing, again under the orders of a clearly incompetent wee boy, to engage in contact tracing!
Canto: It’s a SNAFU to be sure. Apparently one of this number – 34 at last count – is gravely ill in hospital. It’s like we’re watching an episode of ‘Horrible Histories’ in real time. It’s good to see that the polls are predicting a landslide. That means if the actual numbers come in and it’s close, it may be to do with the dirty business Trump and the Republican ‘leadership’ appear to be trying on vis-à-vis voter suppression. And then all hell will break loose.
Jacinta: Hell will break loose no matter what happens. This next month or two will be a cracker for us non-Americans. We’re certainly living in interesting times. But seriously, my condolences to the American people.
References
https://www.sciencemag.org/news/2020/09/provocative-results-boost-hopes-antibody-treatment-covid-19
https://www.worldometers.info/coronavirus/country/us/
Coronavirus Pandemic Update 97: Vitamin D & COVID-19 Immunity, The Endothelium, & Deficiencies
Coronavirus Pandemic Update 77: Remdesivir Update; COVID-19 in Mexico
Coronavirus Pandemic Update 88: Dexamethasone History & Mortality Benefit Data Released from UK
covid19: monoclonal antibodies, symptomatic v asymptomatic, corticosteroids, comorbidities
covid19: monoclonal antibodies, symptomatic v asymptomatic, corticosteroids, comorbidities
keeping it simple, for now
Jacinta: Let’s look at monoclonal antibodies briefly before we continue with those medcram updates. Francis Collins, the somewhat controversial but scientifically reliable directer of the NIH in the USA, recently described ‘monoclonals derived from people who’ve survived covid19’ as the best hope for treatment in the absence of a vaccine. So what are these monoclonals? There are lots of useful videos on youtube that provide detail. I’m picking one from the JAMA network. The technology for producing these types of antibodies was developed in the mid-seventies. It was called ‘murine hybridoma’ technology, murine meaning ‘mice’. I remember first reading about monoclonal antibodies in a Scientific American article in the early eighties. It went straight over my head of course, but now it’s time to get a grip on them. So mice were injected with an antigen, which in general terms is a pathogen that induces an immune response. In more specific terms an antigen is a molecule or structure, part of a larger pathogenic molecule, that can be bound to by an ‘antigen-specific antibody’ or B cell receptor. B cells are lymphocytes that secrete antibodies. So the researchers induced this response, then isolated B cells from the spleen of the mice, which they fused with myelomas (cancerous plasma cells). Cancer cells are notoriously long-lived – see ‘the Immortal Life of Henrietta Lacks’ – so these fused cells, called ‘hybridomas’, act like B cells in producing antibodies, and like tumour cells in their ability to replicate. So these hybridomas can be grown in culture and each one can produce a single antibody type, which targets a single antigen type. Hence monoclonal. They can clone themselves for a specific antigen. So, once you know your antigen, you can create a ‘monoclonal’ specifically for it, or two or three to choose from. And now, with covid19 and with technological development, we can isolate monoclonal antibodies not from mice but from recovered covid19 patients. So that’s a somewhat over-simplified account – for more detailed info on monoclonal antibodies, this zero to finals video is excellent, and there are doubtless others. The target for this work is generally the S-protein of the SARS-CoV2 virus, with various particular sites being looked at, and a number of teams working on the research. Some are pretty well ready to go, with specific antibodies or sets of antibodies. The argument is that they could be used for high-risk groups such as ICU workers and nursing home clients, as a kind of temporary vaccine.
Canto: Okay, something else to keep track of. So update 93 discusses an article published in Nature Medicine – all the authors appear to be Chinese – which looks at 37 asymptomatic covid19-infected subjects and their antibodies, compared to those of 37 symptomatic subjects.
Jacinta: So they looked at their immunoglubulin G (IgG) levels. These are the most common types of antibody, created and released by plasma B cells. They graphed the IgG during the acute and convalescent phases, and they defined the acute phase as that in which the viral RNA was detectable in a respiratory specimen, and the convalescent phase as from eight weeks post-release from hospital. What the graph shows is that the IgG levels decreased from acute to convalescent in both symptomatic and asymptomatic cases, but more in the symptomatic cases. They also looked at ‘neutralisation rates’, which presumably refers to the effect of antibody activity. A positive effect means more neutralising antibodies are produced. These seemed about the same between the phases for both groups, but another graphic shows that in the convalescent phase, the symptomatic group have substantially more neutralising antibodies. It seems from this admittedly small study that asymptomatic subjects are at risk of reinfection, after a period of time.
Canto: And even symptomatic subjects after recovery, as we have obviously no longitudinal studies on anti-viral IgG levels, as the study points out.
Jacinta: Well that takes us to the next study, from Spain, which managed to round up almost 52000 participants. The study tells us between late April and mid-May the estimated seroprevalence (the percentage of inhabitants that had the virus) for the whole country was around 5%, depending on different test types and results, and with great variation between regions. Findings were that prevalence increased with increasing age. Looking at different jobs, those working in healthcare were clearly more at risk, and to a lesser but still significant degree, those working in nursing homes…
Canto: Which is still largely healthcare, but less trained, and often less prepared for this onslaught…
Jacinta: Point taken. And those living in the larger municipalities were more often infected than those in less densely populated regions. Interestingly, they found that the rapid (and cheap) fingerpoint test, which provides results within ten minutes, was pretty close to being as effective as an immunological assay, which is important as the delay in test results has been a major issue.
Canto: Amazing. Why aren’t they using this all the time? Everywhere?
Jacinta: That’s another issue – maybe later. Anyway, much of this study confirms the many smaller studies that have been conducted. They found that healthcare workers comprised 24% of all confirmed cases. This may be partly because they had more access to testing. There is so much to glean from this study, I can only skim. But here are some very interesting remarks in their conclusion:
One in three infections seems to be asymptomatic, while a substantial number of symptomatic cases remained untested. Despite the high impact of covid19 in Spain, prevalence estimates remain low, and are clearly insufficient to provide herd immunity. This cannot be achieved without accepting the collateral damage of many deaths in the susceptible population and overburdening of health systems. In this situation, social distance methods and efforts to identify and isolate new cases are imperative for future epidemic control.
Canto: So there are no easy solutions, and even a vaccine is not necessarily going to be the magic bullet everyone’s hoping for. The proof of the pudding will be in the eating, and we haven’t eaten any vaccines yet. They won’t be on the menu for a while, and it’ll be a lot longer before we can gauge their nutritional value.
Jacinta: Yes, what you’re saying is, we don’t know how long antibodies to this virus will last. We’re still in unexplored terrain with respect to this very unusual and deadly virus. An article published on the Jama Network quite a while ago is still relevant now in its conclusions, as nothing we’ve so far found disconfirms it:
… the immune response to covid19 is not yet fully understood and definitive data on post-infection immunity are lacking. Amidst the uncertainty of this public health crisis, thoughtful and rigorous science will be essential to inform public health policy, planning and practice.
Canto: Frustrating to many. So with update 94 we’re getting towards mid-July and they’re noting that things are hotting up, as the weather is cooling down, in Australia, though of course it bears no comparison to the US tragedy. They were talking about things getting worse in their autumn, but summer hasn’t given them any sort of break.
Jacinta: So update 94 first looks at inhaled corticosteroids, one of many medications being considered and perhaps used by health professionals, others being ivermectin (a broad-spectrum anti-parasitic drug) and nitric oxide, all without solid RCT-type evidence. Even so, case reports and other low-level studies show promise, and these are arguably desperate times. A study presented by Dr Seheult suggested that some corticosteroids showed positive immunological effects in case reports and in vitro. Interestingly, asthmatics have been prescribed corticosteroids quite regularly…
Canto: As have I, from time to time. At least I think it was corticosteroid…
Jacinta: Well, that’s interesting, I know you’re not asthmatic but with bronchiectasis you have asthma-like symptoms at times. And the good news for you, and generally interesting news for us all, is that ‘asthma patients with covid19 do not appear to have a higher rate of hospitalisation or mortality compared with other covid19 patients’. Indeed it may be the opposite, as data from Wuhan indicates that less than 1% of their hospitalised patients had asthma, compared to 5% in the general population. In New York, too, asthma wasn’t even in the top ten comorbidities, which is pretty striking for a virus that hits the lungs first. Similarly, COPD, which your ailment is surely associated with, comes in below diabetes, renal disease and a whole range of cardiovascular issues as a comorbidity factor. A possible reason for this is that the kind of chronic inflammation produced by asthma and COPD is associated with reduced ACE2 expression, meaning fewer receptors for the virus. So these conditions could actually be protective. And they might also be on corticosteroid inhalers, which may also be protective.
Canto: That sounds great. Let’s leave it there before I hear any bad news…
References
Coronavirus Pandemic Update 93: Antibodies, Immunity, & Prevalence of COVID-19 – New Data from Spain
Coronavirus Pandemic Update 94: Inhaled Steroids COVID-19 Treatment; New Pneumonia in Kazakhstan?
How do monoclonal antibodies work? Rituximab, infliximab, adalimumab and others
Coronavirus Treatment and Prevention with Monoclonal Antibodies