Great Barrington Declaration (2)

Sorry folks, more COVID-19, more anger. Again a screen shot from part way down this page here, published by the UK government.

https://coronavirus.data.gov.uk/details/deaths?areaType=region&areaName=London

It looks like this:

That dark blue, slightly wavering, rising line is the deaths of the over 60s with a positive PCR. Some really will be COVID-19. They should never have been exposed to the virus. Should they have wished to, they should have been allowed to stay shielding and they should have been helped financially and practically to do so. Anyone, of any age, who became seropositive in the first wave could safely be in close contact with them today, no need for loneliness this winter. This course should have been offered as an option.

It wasn't.

The lower, paler blue line is the deaths of the under 60s. This line runs along the x axis. Very, very few people in London under 60 years of age have died with a positive PCR this Winter. Not many in the Spring for that matter either.

Shutting down much of the country, including London, in to Tier 4 lockdown (welcome to my world) has done nothing to protect the vulnerable over 60s and wasn't needed for the under 60s.

This is exactly why I signed the Great Barrington Declaration, to avoid this. Focused protection for those who need/want it, lots of it. Throw money at them. Let the rest of us get on with life.

Boris Johnson and Matt Hancock are politicians. I expect nothing from them, they're not exactly bright. But Whitty and Valance have no excuse. They must know what the above graph looks like. They know. Both of them were taught immunology once upon a time (implausible though that seems nowadays).

The lockdowns have done nothing to protect Norfolk from our Winter catch-up. We have no focused protection for the elderly. It's wrong.

Sorry for the rant.

Happy New Year.

Peter

IgG IgA and sniffing a virus which stinks

Just a quick post, possibly the last for a while as I have quite a lot going on off-blog at the moment and time will be scarce over the next couple of months.

I have downloaded this graph from the UK government website which can be accessed at

https://coronavirus.data.gov.uk/details/deaths?areaType=region&areaName=London

Obviously it will be out of date within 24h but, unless you are Whitty or Vallance, you will not be expecting the line to suddenly spike upwards to give (sarcasm warning) 4000 deaths per day for the whole of the UK next week.

These are the figures for London:

London is at herd immunity. Even with the second wave.

I'd like to perform a thought experiment. Let's imagine Fred. Fred lived in Lewisham and was a typical victim of the lipid hypothesis, but had not progressed to frank diabetes or significant metabolic syndrome. He contracted SARS-CoV-2 in mid February, coughed for three days and recovered. He wasn't tested, didn't go to A and E and was not a Spring peak statistic. He has 1) T cell mediated immunity 2) mucosal surface IgA immunity and 3) possibly some antibodies, neutralising, though these may not be at a level detectable in routine serology. He is, absolutely, not on the graph for the April peak in deaths.

Here comes the sad bit.

Fred has had recurrent stomach pain throughout the Summer. He keeps taking the Gaviscon and it does a bit of good but not much. The pain is never quite bad enough to go to A and E, certainly not in the face of the then current viral pandemic.

Fred's problems continue on and off until early November at which point he collapses with incapacitating stomach pain and profuse vomiting. He is still immune to SARS-CoV-2.

He is admitted to hospital and worked up for acute pancreatitis. It is difficult to describe how appalling this is as a medical emergency, and yes, it is triggered by polyunsaturated fatty acids, thank your cardiologist. After a day or so on a medical ward he is transferred to the ITU, just after his SARS-CoV-2 PCR result comes back positive.

Fred is immune to SARS-CoV-2. His respiratory system is covered in IgA. Any SARS-CoV-2 he picks up in the hospital will simply stay there, bound and unable to invade.

But if you take a swab from his throat/nasopharynx, especially in a hospital area with even minor exposure to SARS-CoV-2, the fact that that some viral particles are bound by IgA in a fully immune person makes no difference to a PCR machine running at 40 amplification cycles. He will come up positive.

Pancreatitis comes with a significant death rate. Fred dies (he's imaginary, no need to be sad, for Fred anyway) on the 28th of November 2020. What did he die of? Obviously he is in the stats for COVID-19, second wave, London. At the right hand end of the graph at the top of the post.

Here in the UK deaths at home have been running at 1000/week above normal levels since the lockdowns started in March and this has not diminished. Over 75% of these do not get COVID-19 mentioned on their death certificate. Fred made it to hospital, bound a few stray SARS-CoV-2 particles to his IgA and so died with COVID-19 by PCR amplification, which does get mentioned on his death certificate.

The chances of London not having reached herd immunity in the Spring seems vanishingly small. Certain pockets appear to have been missed and are catching up at the moment, the virus is, absolutely, still around and, absolutely, still making some people very, very ill.

But I think Fred is also common.

It is easy for anyone with a smattering of immunology and basic knowledge about PCR technology to access the data for London, which make this clear.

I'm loathe to attribute motive but SAGE has been after an extended full lockdown ever since before lockdown 2 started and they needed more than genuine infection figures, or even deaths, to get it.

I got three rapid sequential texts at 11pm on Saturday night explaining about the "new, 70% more contagious" strain of virus spreading in the South East and the essentially total shutdown of the area, just to the south of us here on the Norfolk/Suffolk border, which was going to happen at midnight.

I couldn't get back to sleep.

I was angry.

I'm well aware of the state of COVID-19 around the UK and how areas spared in the Spring are catching up now. Norfolk will be one of these. This is not trivial.

But those late night texts about a massive change in policy based around a mutation and what I guess is garbage modelling (you think that the 70% increase in transmission rate comes from some sort of data? Haha. I would bet Ferguson modelled this. It will be as good as his previous models. And then it won't be a prediction, just a "scenario", when it turns out to be bogus) are frank psychological manipulation using fear. Bullying on a national scale.

I'm left wondering if those people who control the Prime Minister and used this "tweak" to force the lockdown they so desperately wanted were actually expecting the channel crossings to be immediately closed?

They should have been, given that we are living through times of a global pandemic of stupidity. But then, they are part of the problem.

Peter

IgG IgA and sniffing a virus

Basic immunology 101, ignoring T memory cells and cell mediated immunity..

If you contract a respiratory virus it colonises your nose/throat/windpipe. If you are unlucky it will also colonise your lungs and you might well be headed for a week or two in the ITU.

If it doesn't, you get better.

If you are re exposed to the same virus a month later you will not become ill unless you have something very, very wrong with your immune system. But might you transmit the virus still?

You can track the response of your immune system to the virus by tracking serum antibody production. The immediate effect is to generate IgM antibodies. These fade after a few weeks and are used clinically as a marker for recent infection. After a week or so you make IgG antibodies. These are present for a few months or even for life, depending on which virus we are talking about and whether there is continued exposure. If they are "neutralising" antibodies they will actually stop the virus invading cells by attaching to the cell-invasion protein of the virus. They are protective against illness.

There is another class of "poor relation" antibodies, the IgAs. These are mucosal cell surface produced antibodies. They are produced on the membranes of your nose, throat, trachea and possibly lungs if the virus gets that far and you survive.

IgA largely stops the virus becoming re-established in your nose on re-exposure. Neither IgM nor IgG, even if it is a virus neutralising IgG antibody, is going to do this.

Just to avoid controversy (and because the paper is handy) let's look at mice vaccinated against influenza using an adenovirus vector vaccine. The group used exactly the same vaccine in two groups of mice, in one they gave it intranasally, in the other intramuscularly.

Reduction of influenza virus transmission from mice immunized against conserved viral antigens is influenced by route of immunization and choice of vaccine antigen

"Here we demonstrate that transmission reduction is more effective when mice are immunized against A/NP and M2 intranasally than via the intramuscular route"

The intranasal route stimulated marked IgA production. The intramuscular route produced a minimal IgA response. Once vaccinated the group then challenged the vaccinated mice with field virus and assessed the ability of those vaccinated mice to transmit the field virus to non protected mice.

Intranasal, IgA generating, vaccination reduced transmission by 88.2%.

There is nothing surprising about this.

I fully expected the same vaccine given intramuscularly to do nothing at all to reduce transmission but it did, oddly enough, reduce transmission potential by 47%. Of course the question to be asked is whether this 47% transmission rate reduction would allow a vaccinated care worker to safely nurse your granny during an influenza pandemic.

You also still have to ask whether an 88.2% reduction in transmission might make a care worker safe to nurse an elderly person.

An adenovirus vector vaccine will induced an immune response to the protein coded for in the mRNA built in to that vaccine. If injected in to a muscle it should induce IgG in the bloodstream to that protein which, if neutralising, should protect against illness. That's good, but limited.

Contrast that to a genuine field virus infection. It starts in your nose, spreads to your throat and then down your windpipe to give you a marked production of membrane based IgA throughout the airway. It is going to induce IgA production to a whole host of viral proteins, not just the one or two forms of IgGs generated by a vaccine (even if given intranasally to generate some IgA). Some field antibodies will be very useful, some less so.

It seems to me that the probability of reducing or even eliminating viral transmission might be much better from a field virus infection than from a limited antibody response generated by an vaccine, even if given intranasally.

Quite what might happen if you combined intranasal and intramuscular administration, or even gave two doses of intranasal vaccine a few weeks apart are open questions for mice in influenza models. Yes, a model is only a model.

How much of this might be generic to respiratory viruses in general I don't know but I would be amazed if it wasn't.

As always there are a slew of questions which follow on from this concept but I'll stop here with my fondness of IgA inducing vaccines and particularly of asymptomatic infections. Having said that, I would qualify it as a vet. Anyone who has had the pleasure of administering an intranasal vaccine to a 40kg aggressive dog who is voting against said intranasal vaccination with his teeth is another matter. Luckily you can get it in through a muzzle on a good day. 

Peter

FIP vaccines etc

This post is just some random musings about coronavirus vaccines, most clearly in cats. The rest is speculation.  As an introduction here is the abstract-like entry for a book chapter pulled up by Duckduck from 'tinternet. It sums up pretty much what I recall from back in the days when I was a clinician dealing with the horrible disease of Feline Infectious Peritonitis (FIP), derived from complications of Feline Enteric Coronavirus infection. No author is stated but if I was an editor looking to have a chapter written about FIP I would, without any doubt, send the request to Niels Pedersen, who authored this (very long and involved) review:

A review of feline infectious peritonitis virus infection: 1963–2008

The chapter abstract summarises the interesting bits of the Pedersen's review nicely:

Coronaviridae

In Fenner's Veterinary Virology (Fifth Edition), 2017

Immunity, Prevention, and Control

Feline infectious peritonitis is not controlled easily; control requires the elimination of the virus from the local environment, whether this is the household or the cattery. This requires a high level of hygiene, strict quarantine, and immunoprophylactic measures. Because kittens acquire the infection from their queens, early weaning programs have also been used in attempts to interrupt virus transmission.

The development of a safe and highly effective vaccine remains elusive, even with the availability of bioengineering approaches. The only commercially available feline infectious peritonitis vaccine contains a temperature-sensitive mutant virus, based on a serotype II virus. The vaccine is applied to the nasal mucosa to reduce virus replication and antibody formation. Under these conditions, a cellular immune response is favored, and some protection putatively is achieved. Vaccination of infected, seropositive adult cats is not effective. In addition, experimental challenge of vaccinated cats has resulted in “early death” due to feline infectious peritonitis in some cases.

A broad spectrum coronavirus protease inhibitor drug has recently shown considerable therapeutic efficacy for treatment of cats with feline infectious peritonitis, a finding that suggests the disease might in the future be treated with antiviral drugs.

What is clear from FIP vaccination is that antibody production (or the administration of hyperimmune serum or pure IgG antibodies) in the absence of a cell mediated immune response, is lethal on challenge of kittens with a field strain of FIP virus. The serum is harmless, the IgG is harmless, the vaccine is harmless. What matters is how the disease progresses when field virus meets the antibody replete host. The effect of a vaccinia virus vector vaccine was described here (you only really need to read the title, it says it all):

Early Death after Feline Infectious Peritonitis Virus Challenge due to Recombinant Vaccinia Virus Immunization

which could reasonably be described as a bit of a booboo.

To summarise: Vaccines which stimulate antibody production without stimulating cell mediated immunity are a problem. This is Antibody Derived Enhancement. It's real. It has plagued (no pun intended) certain vaccines, obvious for FIP but Dengue Fever vaccine is a similar but non-related example in humans.

I'll leave FIP alone now except for adding that work with the reagent GS-441524 suggests that FIP is no longer the invariable death sentence which it was two or three years ago. People who have worked clinically with FIP, or lost cats to FIP, will understand the awe that this drug inspires. I hope it gets used sensibly.

Anyhoo.

I was listening to Radio 4's The Life Scientific which featured an interview with Prof Sarah Gilbert from Oxford, heavily involved in the development of an adenovirus delivered vaccine for protection of humans against SARS-CoV-2.

Apart from how genuine and extremely bright she is the main thing I recall is her comment that she was very pleased that the vaccine she was developing produced a robust cell mediated immune response in additions to stimulating antibody production.

This is excellent and is all that you could ask of a vaccine where antibodies are frequently high and ineffective well before admission of patients destined to die of COVID-19 complications in the ITU.

It looks like cell mediated immunity is what matters. That antibodies are non protective is also suggested by the extremely poor results using antibody rich serum from recovered patients to treat unwell patients with COVID-19. There is no suggestion that serum treatment did direct harm, just it didn't do much good.

So the major question this poses is how much good the vaccine might do in patients who are going to become ill with COVID-19 in the future. It is not an unbelievable stretch of fantasy to suggest that the defining characteristic of people who are going to go on to become seriously unwell after exposure to SARS-CoV-2 might just be those are the ones who are unable to mount an effective cell mediated immune response.

How well might the T cells of an 80 year old, morbidly obese diabetic respond to the vaccine, assuming they are not very likely to respond to the field virus?

We can but hope that if they do fail to develop cell mediated immunity then at least their antibody response (which will still happen) does no harm. And we can hope that cell mediated immunity response has been carefully assessed in the population to which to a COVID-19 vaccine is being rolled out as of today in the UK... 

Otherwise it's a bit of an experiment on many, many people's grannies.

Peter