Developing the Covid-19 vaccine

[shpalman]

Dear NHS staff, we expect you to deal with all the extra covid cases caused by our decision to let families see each other over Christmas for which our vaccination strategy won't make any difference but we're still not going to give you the vaccine (although maybe try volunteering for a trial) KTHXBYE

[shpalman]

Can't believe it didn't occur to me to adapt ice cream vans for delivery of the vaccine in the community.

[bob sterman]

I'm not an proper expert in this either, but the vaccine should reduce your ability to spread a virus, otherwise the concept of herd immunity doesn't work.

Certainly it should - if herd immunity is the objective of the vaccination programme. But vaccination can also be valuable to simply stop people who become infected from getting seriously ill - without impacting the reservoir of potential infection sources (e.g. tetanus vaccine).

[Martin Y]

Can't believe it didn't occur to me to adapt ice cream vans for delivery of the vaccine in the community.

Buy me and stop one.

[sTeamTraen]

Can't believe it didn't occur to me to adapt ice cream vans for delivery of the vaccine in the community.

Buy me and stop one.

My Dad says these don't work.

[sTeamTraen]

I'm not an proper expert in this either, but the vaccine should reduce your ability to spread a virus, otherwise the concept of herd immunity doesn't work.

Well, that seems a bit like begging the question (although it may not be; that particular topic makes my head spin).

Presumably we have herd immunity (R < 1) with, say, the measles vaccine, because (a) many people are vaccinated and (b) that particular vaccine reduces the amount of virus being shed, either in the asymptomatic or symptomatic phases of the disease. My point is that while this seems to be intuitively likely, it isn't necessarily the case; or rather, the coefficients may not be especially favourably. For example, perhaps the measles vaccine reduces symptom severity (on whatever scale that's measured) by 60%, but reduces viral shedding by 90%. For a COVID vaccine, that might be the inverse. We would then see numbers not unlike what we have seen from the trials (where the key outcome is, I guess, "number of people needing hospital treatment", and a secondary outcome might be "days off work"), but I wonder if there is any record of, say, number of close family members being infected.

I can imagine that you might have a disease/vaccine combo where you can't stop people passing it on. For example, you might have a variant of the common cold that, in one person in 100, goes to their liver and f.cks it up, but otherwise they just get a sniffle. It seems like a vaccine for that might raise the defensive potential of whatever protects the liver, but not reduce the amount of the virus in circulation (and, hence, being sneezed out over everybody you encounter) at all.

I'm not raising this as a big worry --- it's more out of intellectual curiosity.

[headshot]

Can't believe it didn't occur to me to adapt ice cream vans for delivery of the vaccine in the community.

An ice cream van just came past our house playing it music at 5pm on 5th December when it's 4c outside. Maybe they're already trialling it.

[Bird on a Fire]

Can't believe it didn't occur to me to adapt ice cream vans for delivery of the vaccine in the community.

An ice cream van just came past our house playing it music at 5pm on 5th December when it's 4c outside. Maybe they're already trialling it.

Those ones have to be selling drugs of some sort.

[Sciolus]

The concern is that you could have a large number of vaccinated people walking around who, while not going to get (bad) symptoms themselves, would be potential spreaders to the unvaccinated, of whom there will be many, if only because the whole operation takes time. And since getting vaccinated is being sold as a way to get back to normal, it's going to be hard to get those people to continue to wear masks or not attend large sex parties in Brussels. So you could have the ironic effect of making the effective R rate go up rather than down.

The priority groups are not particularly significant spreaders, being either elderly, vulnerable or medical (who hopefully will continue to exercise infection control discipline regardless of vax status). Hopefully by the time we get to under-70s --- several months off --- we'll have a better idea of the answer.

I'm not raising this as a big worry --- it's more out of intellectual curiosity.

As mentioned upthread (mainly by me banging on about it, frankly, here I go again), it's not just intellectual curiosity, but key to the proper prioritisation of the vax programme.

* - of course depending on whether it can be distributed, and how much actually arrives, because I keep hearing contradictory things i.e. it can stay in a fridge for a week vs. an entire batch of 975 has to be used within 6 hours of opening it and can't be moved more than once or something. So health care workers have been de-prioritized but it's still not clear to me if it can actually be delivered to care homes. Except in Scotland where they interpreted the cold-chain rules differently. Or maybe it's just because it's colder up there.

If I understand Tom's posts correctly (apologies if not), it's technically possible to be more flexible but not allowed by the current licence because of raisins (need for specialist protocols?).

An ice cream van just came past our house playing it music at 5pm on 5th December when it's 4c outside. Maybe they're already trialling it.

Drug dealers, innit. (Damn, ninjaed)

[TimW]

That'll be Mr Trippy.

[Bird on a Fire]

I've got 99 problems

[jdc]

I'm not an proper expert in this either, but the vaccine should reduce your ability to spread a virus, otherwise the concept of herd immunity doesn't work.

The big thing you want from a vaccine *for infectivity* is to generate a strong T-cell response. These are the part of the immune response that recognise and kill off infected cells. Infected cells are the "factories" for producing more virus, so shutting them down quickly is key to stopping viral replication. So that will reduce the amount of virus you're producing and therefore able to breathe out and pass on. Whether that's enough to eliminate transmission to others, I don't know, but it will definitely reduce the chances.

(Antibodies also matter but are more about blocking the virus from infecting more cells. People talk about them more because they are much easier to measure from a blood sample.)

I'm no kind of expert at all, but I'm not going to let that stop me.

I think it might be a strong B-cell response. Or possibly both, depending on the infection in question.

https://pubmed.ncbi.nlm.nih.gov/15297622/

The current experiments use the Friend retrovirus model to demonstrate that vaccine-primed B cells are essential for sterilizing immunity, and the results indicate that the requisite function of these cells is the production of virus-neutralizing antibodies rather than priming or reactivation of T cells.

[...] These results emphasize the importance of inducing both T cell responses and virus-neutralizing antibody responses for effective retroviral vaccine protection.

https://www.nature.com/articles/d41586-020-02400-7

Long-term immunity can vary by type and also by degree of response. Vaccine developers often hope to elicit what’s known as sterilizing immunity, a response, typically mediated by antibodies, that can rapidly prevent a returning virus from gaining ground in the body. But not all vaccines or infections elicit the neutralizing antibodies required for sterilizing immunity. HIV, for example, rarely induces neutralizing antibodies2, a fact that has complicated efforts to develop vaccines against it.

https://thehill.com/changing-america/we ... we-need-it

Sterilizing immunity means that the immune system is able to stop a pathogen, including viruses, from replicating within your body.

This typically happens when immune cells in the body are able to bind to the pathogen in places that prevent it from being able to enter a cell where it can start making copies of itself. Some of these immune cells may produce sterilizing antibodies, which are proteins that recognize specific proteins and structures on the surfaces of pathogens.

To achieve sterilizing immunity, your body needs to produce enough neutralizing antibodies and it needs to be able to do so in the long term. Ideally, it leads to life-long immunity.

Here's something on the coronavaccines and sterilizing immunity:

https://theprint.in/world/vaccines-can- ... us/548194/

Preclinical studies have also shown that some of the vaccines in development achieved complete viral suppression in monkeys. Johnson & Johnson, Novavax and Pfizer-BioNTech were all able to virtually eradicate the virus from animal respiratory tracts. (Vaccines in development by AstraZeneca Plc and Moderna didn’t quite manage this.) But these are not human trials, of course.

Unfortunately, it’s not yet possible to find out whether vaccines are able to produce a sterilizing immunity based on current clinical trials as they have not been set up to provide that information. If participants had been asked for weekly nasal swabs, scientists could compare viral loads in vaccinated subjects and unvaccinated ones who developed Covid-19. But the Pfizer-BioNTech and Moderna trials required nasal swabs only on vaccination days and then again if subjects reported symptoms.

At this point, the only way to find out whether vaccines confer sterilizing immunity is by doing another trial. Given the stakes involved, this might be warranted. Meanwhile, companies that are about to start a late-stage trial, such as Novavax, have the time and opportunity to include weekly swab tests in their protocols. It’s something they should consider.

[tom p]

Participants in a trial travel to the investigation sites. They will be reasonably centralised, but then the participants get paid 'expenses' for attending. That sort of money is loose change for a company like Pfizer. For an NHS which is overstretched and under-resourced and in a country about to hit the deepest recession for >300 years, it's impossible.
The logistics are totally different.

The Pfizer/Biontech vaccine study that had 43998 participants has registered 155 study locations which include 39 U.S. states, including Hawaii, as well as Argentina, Brazil, Germany, South Africa, and Turkey. There must have been a lot learned about the logistics to achieve that.

The NHS is not expected to pay for this from its usual budget. I don't know how it can have escaped your attention, but the country is already spending hundreds of billions of pounds as a result of this coronavirus, so money will be found - especially as it's such a highly visisble expense.

Arrogant ignoramuses should keep their worthless opinions to themselves.

And you could do with toning down that superciliousness.

Not when I'm right and I know what I'm talking about and you're completely wrong.
You could do with shushing and reflecting and learning. Then you might make yourself look like less of a c.nt.
ETA: vaccine (and other medicine) trials have been going on a long time, and the manufacturers have always done them as quickly as possible.
Your 'they must be able to learn from this' shows the depth of your ignorance.

[Herainestold]

Can't believe it didn't occur to me to adapt ice cream vans for delivery of the vaccine in the community.

An ice cream van just came past our house playing it music at 5pm on 5th December when it's 4c outside. Maybe they're already trialling it.

Those ones have to be selling drugs of some sort.

Ice cream is a drug.

[AMS]

I'm not an proper expert in this either, but the vaccine should reduce your ability to spread a virus, otherwise the concept of herd immunity doesn't work.

The big thing you want from a vaccine *for infectivity* is to generate a strong T-cell response. These are the part of the immune response that recognise and kill off infected cells. Infected cells are the "factories" for producing more virus, so shutting them down quickly is key to stopping viral replication. So that will reduce the amount of virus you're producing and therefore able to breathe out and pass on. Whether that's enough to eliminate transmission to others, I don't know, but it will definitely reduce the chances.

(Antibodies also matter but are more about blocking the virus from infecting more cells. People talk about them more because they are much easier to measure from a blood sample.)

I'm no kind of expert at all, but I'm not going to let that stop me.

I think it might be a strong B-cell response. Or possibly both, depending on the infection in question.

I think (and again, not 100% sure here), the question of sterilising immunity is more about the ability of your antibodies to prevent the virus infecting more of your own cells, i.e your immune system protecting you. But we were more talking about ability to infect others, which for covid will be about the amount of live virus you're sending out in respiratory droplets and aerosols. It's not quite the same question as whether you, as vaccinee, are protected. This is going to get tricky as it's probably straying into the world of secretory IgA, which I'm much less familiar with than IgG, but I think is more involved in what's going on in mucosal surfaces. (Immunology is complicated, plus I'm not an immunologist, plus this is heading into the bits of immunology where things are less well understood anyway, as you can't do the basic research using cells pulled out of blood samples.)

I suspect the bit about needing both a T-cell and a B-cell response is probably correct though.

[Martin_B]

Can't believe it didn't occur to me to adapt ice cream vans for delivery of the vaccine in the community.

An ice cream van just came past our house playing it music at 5pm on 5th December when it's 4c outside. Maybe they're already trialling it.

[Off topic] As someone who worked as an ice cream van driver, you sell more in the evenings going round residential areas (especially housing estates) than you do during the main part of the day. And because you are then selling to people who are going back to their houses to eat it, the temperature outside doesn't matter, so your sales only drop off by a bit.

In fact, when the outside temperature is low, it's more bearable inside the van which is, essentially, a mobile greenhouse containing 3-4 freezers chucking out heat, in which you have to stay for ~12 hours a day during summer. Not a job for those with a weak bladder!
[/Off topic]

[headshot]

Can't believe it didn't occur to me to adapt ice cream vans for delivery of the vaccine in the community.

An ice cream van just came past our house playing it music at 5pm on 5th December when it's 4c outside. Maybe they're already trialling it.

[Off topic] As someone who worked as an ice cream van driver, you sell more in the evenings going round residential areas (especially housing estates) than you do during the main part of the day. And because you are then selling to people who are going back to their houses to eat it, the temperature outside doesn't matter, so your sales only drop off by a bit.

In fact, when the outside temperature is low, it's more bearable inside the van which is, essentially, a mobile greenhouse containing 3-4 freezers chucking out heat, in which you have to stay for ~12 hours a day during summer. Not a job for those with a weak bladder!
[/Off topic]

I have learned something today!

[sTeamTraen]

I'm not raising this as a big worry --- it's more out of intellectual curiosity.

As mentioned upthread (mainly by me banging on about it, frankly, here I go again), it's not just intellectual curiosity, but key to the proper prioritisation of the vax programme.

Oh. Well, glad I asked then.

[jdc]

I'm not an proper expert in this either, but the vaccine should reduce your ability to spread a virus, otherwise the concept of herd immunity doesn't work.

The big thing you want from a vaccine *for infectivity* is to generate a strong T-cell response. These are the part of the immune response that recognise and kill off infected cells. Infected cells are the "factories" for producing more virus, so shutting them down quickly is key to stopping viral replication. So that will reduce the amount of virus you're producing and therefore able to breathe out and pass on. Whether that's enough to eliminate transmission to others, I don't know, but it will definitely reduce the chances.

(Antibodies also matter but are more about blocking the virus from infecting more cells. People talk about them more because they are much easier to measure from a blood sample.)

I'm no kind of expert at all, but I'm not going to let that stop me.

I think it might be a strong B-cell response. Or possibly both, depending on the infection in question.

I think (and again, not 100% sure here), the question of sterilising immunity is more about the ability of your antibodies to prevent the virus infecting more of your own cells, i.e your immune system protecting you. But we were more talking about ability to infect others, which for covid will be about the amount of live virus you're sending out in respiratory droplets and aerosols. It's not quite the same question as whether you, as vaccinee, are protected. This is going to get tricky as it's probably straying into the world of secretory IgA, which I'm much less familiar with than IgG, but I think is more involved in what's going on in mucosal surfaces. (Immunology is complicated, plus I'm not an immunologist, plus this is heading into the bits of immunology where things are less well understood anyway, as you can't do the basic research using cells pulled out of blood samples.)

I suspect the bit about needing both a T-cell and a B-cell response is probably correct though.

No, sterilizing immunity is what you need to prevent you infecting others.

https://en.wikipedia.org/wiki/Neutralizing_antibody

A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralisation renders the particle no longer infectious or pathogenic.

Immunity due to neutralizing antibodies is also known as sterilizing immunity, as the immune system eliminates the infectious particle before any infection takes place.

https://www.sciencedirect.com/topics/ag ... g-immunity

The ideal vaccine would prevent infection through complete sterilizing immunity (complete protection without detectable HIV virus at any time or any transmission to others).

https://www.nature.com/articles/d41586-020-02400-7

Sterilizing immunity for COVID-19 would be ideal, because it would reduce the risk of people with minimal symptoms spreading the infection widely.

[Bird on a Fire]

Can't believe it didn't occur to me to adapt ice cream vans for delivery of the vaccine in the community.

An ice cream van just came past our house playing it music at 5pm on 5th December when it's 4c outside. Maybe they're already trialling it.

[Off topic] As someone who worked as an ice cream van driver, you sell more in the evenings going round residential areas (especially housing estates) than you do during the main part of the day. And because you are then selling to people who are going back to their houses to eat it, the temperature outside doesn't matter, so your sales only drop off by a bit.

In fact, when the outside temperature is low, it's more bearable inside the van which is, essentially, a mobile greenhouse containing 3-4 freezers chucking out heat, in which you have to stay for ~12 hours a day during summer. Not a job for those with a weak bladder!
[/Off topic]

I've wondered about this for a long time. Thanks Martin!

[Trinucleus]

Just received an email inviting ne for an appointment for the trial of another vaccine that is under development.

Very happy to support our world class medical and scientific establishment in their meticulously planned testing programme.

Unfortunately the attachment wouldn't open.

[raven]

This is a great thread, all very interesting thanks the knowledgable folks posting in it.

A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralisation renders the particle no longer infectious or pathogenic.

I'm guessing that's why vaccines are targeting the spike protein, then? If it's the spike protein that latches onto the cell and allows the virus to enter, antibodies that stick onto the spike will interfere at that point, no virus into the cells, no replication, no infection, etc. Does that make sense or is it a case of it's more complicated than that?

I'm somewhat confident that the NHS can cope with the logististics of doling a vaccine out, even if it has to be kept at -70 and you have to organise a second dose 3 weeks later. Our GPs have certainly been very efficient with the flu vaccine: Saturday morning clinics in all the village halls, turn up, queue for a bit, in and out with no fuss. (They did clinics for the usual at risk groups back in Oct/Nov, and are onto the 50-64 yr olds now so we just got ours done.) I'm more concerned about whether enough people will come forward to have a vaccine. I know friends who haven't gone for their flu shot because they're WFH, hardly going anywhere, and think that going to get a shot would just be increasing their risk of catching flu anyway.

[sTeamTraen]

I know friends who haven't gone for their flu shot because they're WFH, hardly going anywhere, and think that going to get a shot would just be increasing their risk of catching flu anyway.

I had a flu shot although I'm mostly isolating. I just think it would be stupid to get COVID and then die of some combination of that and the flu.

[raven]

I've never had a flu shot before, but it's tried & tested, I figured the village hall was no more risky than the supermarket, maybe less so as it wasn't chilled, and so it seemed like a good idea to me.

Also, as the doctor who jabbed me said, better to get the flu shot now because you don't want to get it at the same time as the Covid one.

[jdc]

A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralisation renders the particle no longer infectious or pathogenic.

I'm guessing that's why vaccines are targeting the spike protein, then? If it's the spike protein that latches onto the cell and allows the virus to enter, antibodies that stick onto the spike will interfere at that point, no virus into the cells, no replication, no infection, etc. Does that make sense or is it a case of it's more complicated than that?

As far I understand it, that the spike protein allows entry to the cell is one of the main reasons they targeted it.

https://translational-medicine.biomedce ... 20-02392-y

Spoiler:

An early study on recombinant vectors expressing the S protein of SARS-CoV found this protein to be highly immunogenic and protective against SARS-CoV challenge in hamster, while in contrast, the N, M, and E proteins did not significantly contribute to a neutralizing antibody response or protective immunity [1].

Evidence of the key role played by the S protein in counteracting coronavirus infection came from studies on human-neutralizing antibodies from rare memory B cells of individuals infected with SARS-CoV [2] or MERS-CoV [3]. In such studies, antibodies directed against the S protein of SARS-CoV were found effective in inhibiting virus entry into the host cells. More recently, it has been found that SARS-CoV S elicited polyclonal antibody responses, and vigorously neutralized SARS-CoV-2 S-mediated entry into cells, thus further encouraging the use of this molecular target for vaccination and immunotherapies [4].

Structural studies of antibodies in complex with SARS-CoV S and MERS-CoV S have provided information about the mechanism of competitive inhibition to the host receptor. The receptor-binding domain (RBD) in SARS-CoV-2 S protein was identified and found to bind strongly to ACE2 receptors [5]. SARS-CoV RBD-specific antibodies cross-react with SARS-CoV-2 RBD protein, and SARS-CoV RBD-induced antisera neutralized SARS-CoV-2, providing additional evidence that targeting this domain of the S protein of SARS-CoV-2 with a vaccine could be effective in preventive COVID-19 [5].

Given the above and that the coronavirus S glycoprotein is surface-exposed and mediates entry into host cells by interacting with angiotensin-converting enzyme 2 (ACE2), it rapidly became the main target of neutralizing antibodies and the focus of therapeutic and vaccine design.