Many viruses (most famously HPV, but also the various hepatitis viruses that I can think off the top of my head, and maybe CMV) increase the risk of cancer in survivors.
Given that it seemingly affects so many body systems, what are the odds that SARS-CoV-2 infection will increase the probability of cancer years down the line? Obviously, we won't know the 10 year risk of even the early strains for at least another 8 years, but ....
Tomorrow's Other Viruses will explain in great detail, but, I do not think SARS-CoV-2 is likely to directly cause cancer.
Indirectly, it might cause damage that could lead to cancer.
However, for a direct cancer-causing effect to emerge, a virus generally needs to be able to cause persistent infection. So far, it doesn't look to me like SARS-CoV-2 really causes persistent infections that will last years upon years (it can cause months-long infections in immunocompromised people, however).
Some have argued that persistent infection is at the root of Long COVID, but I don't think any direct evidence has actually established this.
And persistent infection on its own is not enough. The virus also needs to have some proteins that have an oncogenic effect, something that we haven't seen SARS-CoV-2 do.
So, I really doubt it's an oncogenic virus. But...viruses do tend to surprise you.
Those intranasal vaccine results are really exciting. I hope the NIH and the Biden Administration are paying attention, and are thinking about ways they can help accelerate such research.
Regarding the Omicron booster, obviously we need to see the human data before drawing any strong conclusions. We'll likely get those data in a month or two. I wonder, though: might we expect the results to be different, whatever they ultimately are, if subjects are given, say, Novavax's (pending) Omicron-specific booster after priming with an mRNA vaccine?
Also, what exactly is the functional significance of the Moderna vaccine's higher dose? Does more mRNA mean more spike protein is produced following vaccination? Does it actually contain more than 3x more mRNA, or is it made up of proportionally more LNP? Even if not, do the different LNPs in the two mRNA vaccines have at effect on immunogenicity or reactogenicity?
I don't know what differences I'd expect with an Omicron-specific subunit vaccine as opposed to mRNA. But, there could be differences. Useful answer, I know.
My understanding of the dosage numbers on the Moderna vaccine is that it refers to the amount of mRNA supplied. It is not strictly 3x as much as in the Pfizer vaccine (and not just because 100 micrograms is not exactly 3x more than 30), because the mRNAs supplied are not the same length in each vaccine, which will impact their mass. However I would expect a roughly linear relationship between overall amount of RNA supplied and overall amount of LNP supplied.
The LNPs almost certainly have an immunogenic effect. In fact there are those who argue that the LNPs are the main source of immune response to these vaccines, because there are sensors that look for non-self lipid membranes. The RNA molecules in the vaccines are designed to be slightly less immunogenic than they could be otherwise, actually--they utilize pseudouridine instead of uridine, which tends to tamp down immune detection of RNAs.
So, yes, I think the LNPs are important to the immunogenicity, and probably also the reactogenicity, of the mRNA vaccines.
Request: at some point (I know you have lots of topics), can you write about the initial dose effect on disease severity? I've had a lot of people argue with me that infection caused by a single virion is likely to be just as bad as getting a trillion. Or, could you point me to another source if one exists? In this article, your discussion of the mouse work implicitly assumes what I sometimes call the "Initial Inoculum" effect (because I like the assonance).
Did you notice that Steve Novella also wrote about the nasal spray work you discuss? I'll duplicate my comment from Steve's blog:
There are quite a few nasal spray vaccines in development. Russia announced a trial of Sputnik 5 as a spray last year. ImmunityBio is testing one both in the US and South Africa. A Chinese firm is testing at least one (already through Phase 2). SII has one in Phase 1. There's one being tested in Iran with what seems to be a similar protocol. Cuba's testing one as well. There are more.
So, there are several nasal spray vaccines already in human trials.
Continuing with the sampling question: what do you think of the system, used among other places in Massachusetts, of sampling SARS-CoV-2 levels in sewage to get a rough idea of current incidence in the population?
Initial dose effect tends to have a very limited impact on severity of disease under real-world conditions, as I understand things. The extremely high doses used in animal experiments to guarantee fatal infection are pretty artificial compared to the range of input doses possible in a human in normal life. For many viruses, if you give a truly absurd input dose, you can manage to encourage the worst possible pathology--this is very artificial, however.
re:other nasal spray vaccines, the reason I haven't covered them is because the data aren't good. AltImmune's failed in human trials, ImmunityBio's macaque study is in my opinion uninspiring (all of the vaccinated animals there had multiple days of virus replication and no experiments they conducted looked at pathology), and it has been difficult for me to find any hard data outputs from the Russian, Chinese, Iranian, or Cuban options. We've been talking about the Cuban one for over a year now--but it doesn't seem to have moved at all. Forgive the pun, but the other inhaled vaccines I've heard about so far have left like vaporware.
This work out of Yale is the first time one of these has seemed like it might actually have legs. The reason for the difference may be their design using an injected prime followed by an IN boost.
re:sampling--Sewage levels are an approximation, and while they do help check assumptions, it's hard to correlate them with a human incidence without good random sampling data. Dr. Dean discusses this, if briefly, in her article.
Well, yes. That's exactly the issue. It can show us trends, but...don't we really want a *good* estimate of prevalence? One that uses tried and true statistical methods?
I am inviting you to speculate about something.
Many viruses (most famously HPV, but also the various hepatitis viruses that I can think off the top of my head, and maybe CMV) increase the risk of cancer in survivors.
Given that it seemingly affects so many body systems, what are the odds that SARS-CoV-2 infection will increase the probability of cancer years down the line? Obviously, we won't know the 10 year risk of even the early strains for at least another 8 years, but ....
Tomorrow's Other Viruses will explain in great detail, but, I do not think SARS-CoV-2 is likely to directly cause cancer.
Indirectly, it might cause damage that could lead to cancer.
However, for a direct cancer-causing effect to emerge, a virus generally needs to be able to cause persistent infection. So far, it doesn't look to me like SARS-CoV-2 really causes persistent infections that will last years upon years (it can cause months-long infections in immunocompromised people, however).
Some have argued that persistent infection is at the root of Long COVID, but I don't think any direct evidence has actually established this.
And persistent infection on its own is not enough. The virus also needs to have some proteins that have an oncogenic effect, something that we haven't seen SARS-CoV-2 do.
So, I really doubt it's an oncogenic virus. But...viruses do tend to surprise you.
Those intranasal vaccine results are really exciting. I hope the NIH and the Biden Administration are paying attention, and are thinking about ways they can help accelerate such research.
Regarding the Omicron booster, obviously we need to see the human data before drawing any strong conclusions. We'll likely get those data in a month or two. I wonder, though: might we expect the results to be different, whatever they ultimately are, if subjects are given, say, Novavax's (pending) Omicron-specific booster after priming with an mRNA vaccine?
Also, what exactly is the functional significance of the Moderna vaccine's higher dose? Does more mRNA mean more spike protein is produced following vaccination? Does it actually contain more than 3x more mRNA, or is it made up of proportionally more LNP? Even if not, do the different LNPs in the two mRNA vaccines have at effect on immunogenicity or reactogenicity?
I don't know what differences I'd expect with an Omicron-specific subunit vaccine as opposed to mRNA. But, there could be differences. Useful answer, I know.
My understanding of the dosage numbers on the Moderna vaccine is that it refers to the amount of mRNA supplied. It is not strictly 3x as much as in the Pfizer vaccine (and not just because 100 micrograms is not exactly 3x more than 30), because the mRNAs supplied are not the same length in each vaccine, which will impact their mass. However I would expect a roughly linear relationship between overall amount of RNA supplied and overall amount of LNP supplied.
The LNPs almost certainly have an immunogenic effect. In fact there are those who argue that the LNPs are the main source of immune response to these vaccines, because there are sensors that look for non-self lipid membranes. The RNA molecules in the vaccines are designed to be slightly less immunogenic than they could be otherwise, actually--they utilize pseudouridine instead of uridine, which tends to tamp down immune detection of RNAs.
So, yes, I think the LNPs are important to the immunogenicity, and probably also the reactogenicity, of the mRNA vaccines.
Request: at some point (I know you have lots of topics), can you write about the initial dose effect on disease severity? I've had a lot of people argue with me that infection caused by a single virion is likely to be just as bad as getting a trillion. Or, could you point me to another source if one exists? In this article, your discussion of the mouse work implicitly assumes what I sometimes call the "Initial Inoculum" effect (because I like the assonance).
Did you notice that Steve Novella also wrote about the nasal spray work you discuss? I'll duplicate my comment from Steve's blog:
There are quite a few nasal spray vaccines in development. Russia announced a trial of Sputnik 5 as a spray last year. ImmunityBio is testing one both in the US and South Africa. A Chinese firm is testing at least one (already through Phase 2). SII has one in Phase 1. There's one being tested in Iran with what seems to be a similar protocol. Cuba's testing one as well. There are more.
This is a great resource: https://www.the-scientist.com/news-opinion/track-covid-19-vaccines-advancing-through-clinical-trials-67382
So, there are several nasal spray vaccines already in human trials.
Continuing with the sampling question: what do you think of the system, used among other places in Massachusetts, of sampling SARS-CoV-2 levels in sewage to get a rough idea of current incidence in the population?
Initial dose effect tends to have a very limited impact on severity of disease under real-world conditions, as I understand things. The extremely high doses used in animal experiments to guarantee fatal infection are pretty artificial compared to the range of input doses possible in a human in normal life. For many viruses, if you give a truly absurd input dose, you can manage to encourage the worst possible pathology--this is very artificial, however.
re:other nasal spray vaccines, the reason I haven't covered them is because the data aren't good. AltImmune's failed in human trials, ImmunityBio's macaque study is in my opinion uninspiring (all of the vaccinated animals there had multiple days of virus replication and no experiments they conducted looked at pathology), and it has been difficult for me to find any hard data outputs from the Russian, Chinese, Iranian, or Cuban options. We've been talking about the Cuban one for over a year now--but it doesn't seem to have moved at all. Forgive the pun, but the other inhaled vaccines I've heard about so far have left like vaporware.
This work out of Yale is the first time one of these has seemed like it might actually have legs. The reason for the difference may be their design using an injected prime followed by an IN boost.
re:sampling--Sewage levels are an approximation, and while they do help check assumptions, it's hard to correlate them with a human incidence without good random sampling data. Dr. Dean discusses this, if briefly, in her article.
My understanding is that sewage sampling is used to show trends, rather than generate an incidence number.
Well, yes. That's exactly the issue. It can show us trends, but...don't we really want a *good* estimate of prevalence? One that uses tried and true statistical methods?