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Possible vaccines/treatment(s) for Coronavirus

China has approved an inhaled vaccine as a booster:

I applied to join a clinical trial for an inhaled vaccine but couldn’t make the follow up appointments work. It was a shame because they wanted people who hadn’t had a positive covid test for it & I gather this is a bit harder to find now.
 
I cant say I'm surprised that some studies seem to be suggesting that prior immune system imprinting could be an issue thats limiting the ability of updated vaccines to induce really impressive immune response against newer strains. Any thoughts 2hats ?

Our data demonstrate that both monovalent and bivalent mRNA boosters markedly increased antibody responses but did not substantially augment T cell responses. BA.5 NAb titers were comparable following monovalent and bivalent mRNA boosters, with a modest and nonsignificant trend favoring the bivalent booster by a factor of 1.3. These findings are consistent with data recently reported for a BA.1-containing bivalent mRNA booster. Our findings suggest that immune imprinting by prior antigenic exposure may pose a greater challenge than currently appreciated for inducing robust immunity to SARS-CoV-2 variants.

 
Immune system imprinting?

Also referred to by people including me as 'original antigenic sin'. The idea that the first version of a virus that our bodies encounter is imprinted rather strongly into our immune system, and that there are challenges in getting our immune system to respond as well to fight later versions of the virus that evolve. Historically this subject tended to come up when discussing new strains of influenza that arrived via pandemics, and this phenomenons role in the age profile of those most at risk from the new strain of influenza that had arrived. To give one classic example, if you were born during a period where H1N1 was the only A strain circulating in humans, and so H1N1 flu was the first influenza A your body had to deal with, your immune response to a later version of flu such as H3N2 wont be the same as someone younger whose first ever exposure to influenza involved H3N2.

The subject is bound to be more complicated than the simplistic descriptions of it that I might give, and various articles I could point to tend to focus on particular circumstances at the time. It is relevant to covid both via peoples history of which covid strains they were infected with, and via which strains their bodies were exposed to via vaccination.

In this particular case, they are looking at vaccines that have been updated to include an Omicron strain, and how well that addition is performing at 'training' your immune system to deal with these later Omicron strains. When their data indicates that protection against particular Omicron strains is not highly significantly better via the updated vaccine than it would have been via vaccination with just the original strain, they are reaching for the immune imprinting issue as an explanation.

Some example articles of past instances where issues relating to this have been looked at in this pandemic:



 
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I cant say I'm surprised that some studies seem to be suggesting that prior immune system imprinting could be an issue thats limiting the ability of updated vaccines to induce really impressive immune response against newer strains. Any thoughts 2hats ?
Already identified as a potential problem (some months ago - I've posted hints about this before).

On a quick read of that preprint: I note that the dosing intervals here seem pretty short and the pause for sampling post-last-booster very short, so inadequate time for affinity maturation could well be a factor. Also, no effort made to establish precise antigenic history (at N=18+15 it's not like the samples are that big; they could have made the effort to profile everyone). There are clearly 2-3 subjects who are always outliers at the top end of the various measured immunoresponses. What's the betting those individuals got infected in the first WT waves and then immunised 1+years later (maybe even further infected with more antigenically diverse variants), ie are possessed of strong hybrid immunity, higher affinities, broader responses? I would guess that this issue will not matter so much for immunocompetents with adequate exposure intervals (and am not yet convinced the bivalent offers any advantages to such, particularly original infection-then-vax hybrids‡).

‡ Might even be somewhat disadvantageous.
 
(Yale) A recombinant unadjuvanted sub-unit intranasal spike vaccine (P&S - featuring hexapro trimeric prefusion stabilisation of WT spike) elicits protective mucosal immunity against both SARS-CoV-2 and broader sarbecoviruses when administered as a 'booster' following completion of a primary intramuscular mRNA SARS-CoV-2 vaccine series. In an animal model this prime and spike approach induced robust B and T cell responses, IgA at the respiratory mucosa, and protected against lethal SARS-CoV-2 infection, particularly where administered with adequate delay. Immunoresponses were enhanced and broadened further where using a heterologous spike protein (P&Sx - a recombinant using prefusion stabilisation of SARS-CoV spike).
Here we describe the preclinical development of an alternative vaccine strategy, P&S [Prime and Spike], whereby [intranasl] unadjuvanted spike subunit protein elicits robust protective mucosal immunity following mRNA-LNP parenteral immunization.
Heterologous intranasal boosting with SARS-CoV-1 spike enhances pre-existing SARS-CoV-2-specific immunity and broadens reactivities to SARS-CoV.
DOI:10.1126/science.abo2523.
 
(Novavax) An extended phase 2 study of NVX-CoV2373 (original WT formulation only) as a fourth dose (second booster), each booster administered at 6 month intervals after the primary series (1283 original participants, aged 18-84 years, located in Australia and the US, all screened for previous infection via testing for anti-N; mean age of the fourth dose cohort, N=45, was 55 years). Serology conducted 14 days after the final booster dose.

The fourth dose improved neutralisation titres to BA.4/BA.5 by a ten-fold factor over the original primary series, ultimately being within 3.5x the neutralisation titres to Wuhan type largely recovering much of the immunogenicity.
Neutralising (ID50) antibody titres by dose for the ancestral (WT), BA.1, and BA.4/BA.5 variants. The dotted lines indicate correlates of protection (CoP) titres as derived for the ancestral strain with corresponding vaccine efficacy (VE). Antigenic cartography by dose for the ancestral (WT) and BA.1/BA.4/BA.5 variants. SARS-CoV-2 antigens are depicted as circles and sera are depicted as squares. Each grid square represents one antigenic unit representing a two-fold change in neutralisation titres from ancestral to variant.
A fourth dose of NVX-CoV2373 enhanced immunogenicity without increasing reactogenicity. Antigenic cartography demonstrated a more universal-like response against SARS-CoV-2 variants [BA.1/BA.4/BA.5] after a fourth dose of NVX-CoV2373, indicating that updates to the vaccine composition may not be warranted.
DOI:10.1101/2022.11.18.22282414.
 
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Not SARS-CoV-2 directly related as such but worth mentioning somewhere...

(UPenn) A universal influenza mRNA multivalent vaccine candidate (20-HA mRNA, encoding hemagglutinin antigens from all 20 known influenza A and B virus subtypes), which elicited high levels of cross-reactive and subtype-specific antibodies in animal models, indicative of a good immunoresponse to all encoded antigens.
 The 20-HA mRNA-LNP vaccine elicits long-lived antibody responses that react to all 20 HAs (mouse model).
DOI:10.1126/science.abm0271.

Commentary and news media:

 
Some new studies concerning bivalent vaccine performance and related matters...

(NHS/Moderna) A randomised trial (>3000 participants, aged 17-89) comparing omicron boosters (monovalent and bivalent) with original monovalent mRNA-1273 vaccine, given after a primary series. What is really striking here, beyond the headline conclusion, is that they actually find a relatively small difference between immunological or epidemiological outcomes for original monovalent (WT), monovalent omicron (BA.1) and bivalent (WT+BA.1) boosters (note the overlap of the CIs and bearing in mind efficacy was to any symptomatic disease; there were no COVID-19 fatalities).

Furthermore, these analyses were performed only about 1 month after administering the boosters (phase of memory B cell expansion). At 6+ months there may be next to no measurable immunological or epidemiological difference at all.
DOI:10.1101/2023.01.24.23284869.

Indeed, this (Columbia) study (41 participants, aged 24-63) suggests no significant immunological difference between monovalent (WT) and bivalent (WT+BA.5) boosters at 1 or 3 months post-dose (whilst hybrid immunity arising from subsequent BA.5 infection exhibited better immunological performance at those timepoints).
DOI: 10.1101/2023.02.13.528341.

Also of note, in the first study, immunologically they were only looking at neutralising and binding antibody titres. There were no measurements of the titres or performance of various T cell types, Fc effector functions, etc. This (LJI) study (108 participants, aged 23-73), not only confirms how vaccination primes response to subsequent infection but also provides clear evidence that CD4 and CD8 T cells are actually the fast first responders in post-vaccination SARS-CoV-2 infection episodes, kicking in in the first few days. B cells, neutralising antibodies, etc don't ramp up until the second week.
DOI:10.1101/2023.02.05.527215.

Ultimately, it appears that given sufficient dosing interval (more widely, adequate maturation), and after any initial post-dose memory B cell expansion (<<3 months), that (at least thus far) bivalents expressing more recent variant spike do not offer any significant advantage over the original (WT) spike in the immunocompetent.
 
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For completeness, to note the final outcome of a (NHS/Novavax) study of the Novavax protein subunit vaccine (Nuvaxovid) NVX-CoV2373 (WT spike based) primary series in 18-84 year olds (over 13000 participants) with no previous infection history.

At 7.5 months PCR confirmed post-vaccination efficacy was 82.7% [95%CI:73.3-88.8] whilst efficacy to asymptomatic disease was 76.3% [95%CI:57.4-86.8]. Most importantly, efficacy to severe COVID-19 was 100% with all severe episodes in the placebo arm. Data collection was predominately during the alpha/B.1.1.7 wave, with initial onset of delta/B.1.617.2 towards the end.
DOI:10.1093/cid/ciac803.
 
Some new studies concerning bivalent vaccine performance and related matters...

(NHS/Moderna) A randomised trial (>3000 participants, aged 17-89) comparing omicron boosters (monovalent and bivalent) with original monovalent mRNA-1273 vaccine, given after a primary series. What is really striking here, beyond the headline conclusion, is that they actually find a relatively small difference between immunological or epidemiological outcomes for original monovalent (WT), monovalent omicron (BA.1) and bivalent (WT+BA.1) boosters (note the overlap of the CIs and bearing in mind efficacy was to any symptomatic disease; there were no COVID-19 fatalities).

Furthermore, these analyses were performed only about 1 month after administering the boosters (phase of memory B cell expansion). At 6+ months there may be next to no measurable immunological or epidemiological difference at all.
DOI:10.1101/2023.01.24.23284869.

Indeed, this (Columbia) study (41 participants, aged 24-63) suggests no significant immunological difference between monovalent (WT) and bivalent (WT+BA.5) boosters at 1 or 3 months post-dose (whilst hybrid immunity arising from subsequent BA.5 infection exhibited better immunological performance at those timepoints).
DOI: 10.1101/2023.02.13.528341.

Also of note, in the first study, immunologically they were only looking at neutralising and binding antibody titres. There were no measurements of the titres or performance of various T cell types, Fc effector functions, etc. This (LJI) study (108 participants, aged 23-73), not only confirms how vaccination primes response to subsequent infection but also provides clear evidence that CD4 and CD8 T cells are actually the fast first responders in post-vaccination SARS-CoV-2 infection episodes, kicking in in the first few days. B cells, neutralising antibodies, etc don't ramp up until the second week.
DOI:10.1101/2023.02.05.527215.

Ultimately, it appears that given sufficient dosing interval (more widely, adequate maturation), and after any initial post-dose memory B cell expansion (<<3 months), that (at least thus far) bivalents expressing more recent variant spike do not offer any significant advantage over the original (WT) spike in the immunocompetent.


Anything on the non immunocompetent groups?
 
For completeness, let us tackle the ‘natural v vaccine acquired’ immunity paper ('Past SARS-CoV-2 infection protection against re-infection: a systematic review and meta-analysis'), which is the one highlighted by media articles (example) mentioned in another thread.

It really doesn’t tell us much new: being exposed to antigen trains and preps your immune system for future encounters with that antigen! However it is being completely misinterpreted by people who I suspect haven’t even read the paper, let alone understood it.

(UWash) A literature meta-analysis of the effectiveness of past infection by outcome (infection, symptomatic disease, and severe disease), variant, and time since infection.
DOI:10.1016/S0140-6736(22)02465-5.

There are quite a lot of flaws with it - the authors generously give you five for starters:
  1. Limited number of studies meeting the requirement of this meta-analysis, in particular running out beyond 40 weeks.
  2. Publication bias in some outcomes from some of the constituent studies.
  3. Estimation of protection not robust.
  4. Poor consistency in assessing prior infection status across the constituent studies.
  5. Inconsistency in measuring hospitalisation across constituent studies.
And then, when interviewed, one of the authors does point out the screamingly obvious fact - one has to survive infection with no consequent ill effects. Though, they completely miss the (by now well established) fact that infection plus vaccination produces results that (given everything else is equal) leave infection only or vaccine only acquired immunities in the shade (I’ve extensively covered hybrid immunity for the best part of 2 years now upthread). It is overwhelmingly advantageous for those who have been infected to then get vaccinated. Of course, they have to survive the original infection episode, avoid long covid and a range of unpleasant sequelae in order to benefit; just getting vaccinated is a far less risky way to train your immune system.

There are other shortcomings of the study that leap out at the reader:
  1. It is a meta-analysis: almost inevitably plagued by lots of poorly/inconsistently controlled variables/definitions/outcomes/etc across the independent constituent studies, many conflicting (different research groups investigating different phenomena with different tools and different techniques in different data collection environments in different healthcare systems in different countries).
  2. They intentionally screened out (tried to screen out) hybrid immunes from the get go, which would have put the rest of the study into perspective. Also - relevancy - by now the vast majority of the vaccinated population are hybrid immune (in some fashion).
  3. The vaccinees had only had their primary series (predominately short interval as per the originally approved posology); the bulk of them would have experienced insufficient time for comprehensive maturation.
  4. The longitudinal cut-off dates for the vaccinees are premature and widely varying so there is no basis on which to make sweeping comparisons after several months (and they ignored the effects of any third dose boosters, which hadn't been administered here). Figure 4 is the glaring giveaway here.
  5. Consult the supplementary data indicating post-infection efficacy - a not insignificant number of contributing studies have quite outrageous confidence intervals.
The paper is mainly concerned with making a point that, for public health and infection control purposes, recovery from infection should be treated the same as a primary course of vaccination. However this completely ignores the degree to which unvaccinated convalescents can shed infectious virus during future episodes compared to vaccinees, let alone hybrid immunes. (See eg DOI: 10.1101/2021.08.30.21262701).

PS: This research meta-study was funded by the Bill & Melinda Gates Foundation.
 
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Anything on the non immunocompetent groups?
Impending new study might be of interest:
 
Impending new study might be of interest:
That's really interesting.
Hopefully some clarity will come from their work.
 
This years spring booster plan:


The Joint Committee on Vaccination and Immunisation (JCVI) said hospital admission rates for Covid-19 in autumn 2022 showed that the risk of becoming seriously ill from coronavirus was noticeably higher in people over 75.

Anyone who lives in a care home for older adults and people aged five and over who are defined as immunosuppressed are also to be offered a booster jab.

They include people who've had organ transplants or who have blood cancer, and those undergoing chemotherapy treatment for cancer.

It's advised that the booster vaccine be given six months after someone's previous dose.

The NHS in England is expecting to offer the first spring booster doses to those eligible in April, and the campaign will last until late June. Wales has confirmed it will start on 1 April.

Four different vaccines, made by Pfizer-BioNTech, Moderna, Sanofi/GSK and Novavax could be used.
 
Interestingly it looks like, aside from Moderna and Pfizer mRNA bivalents, they will offer the protein-based Novavax monovalent and also maybe Sanofi/GSK's protein-based AS03 (squalene) adjuvanted recombinant monovalent, VidPrevtyn Beta (based on beta/B.1.351 spike).
 
The ONS have today released some vaccine effectiveness statistics for England under their 'experimental statistics' category:


The time period covered is March 2021 to March 2022 so it doesnt shed light on the most recent year, but its something.

Between 21 March 2021 and 20 March 2022, vaccine effectiveness against hospitalisation for COVID-19 was 52.2% (95% confidence interval: 51.4% to 52.9%) for a first dose, 55.7% (confidence interval: 55.2% to 56.1%) for a second dose, and 77.6% (confidence interval: 77.3% to 80.0%) for a third dose.

Vaccine effectiveness against COVID-19 mortality was 58.7% (confidence interval: 52.7% to 65.9%) for a first dose, 88.6% (confidence interval: 87.5% to 89.5%) for a second dose, and 93.2% (confidence interval: 92.9% to 93.5%) for a third dose.

Protection increases with subsequent doses and is high for the third dose or booster as has been shown in previous research, however results are slightly lower in general than previously published estimates.

Its hard to generate these estimates accurately due to lots of confounding factors and the need to make very many adjustments to account for age, health conditions, and many other factors. So the full article is rather long as they seek to explain all this.

I do note that there is a section on non-COVID-19 mortality, which includes this:

As coronavirus (COVID-19) vaccination should not provide protection against non-COVID-19 mortality, we can use non-COVID-19 mortality as a control outcome to assess the amount of confounding left in our model. The risk of death would not be expected to differ between vaccination status groups if all confounding factors were accounted for, the vaccine has no effect on non-COVID-19 mortality, and all deaths caused by COVID-19 were accurately classified as deaths involving COVID-19.

However they still found a marked reduction in the non-Covid death risk by vaccinations status. I am inclined to use this as evidence that we are woefully failing to attribute plenty of covid deaths to covid on death certificates. Its a known issue that I've also spoken about well before this pandemic when it comes to things like flu deaths, but its not one that the authorities or the media are very keen to draw attention to. The ONS at least brings this up but ultimately still suffer from a disinclination to dwell on this reality, since despite the rather interesting figures in this section they prefer to speak more vaguely of 'residual confounding'. And they say things like "The adjustments for socio-demographics, and particularly for health, act to bring the non-COVID-19 estimates closer to zero". Closer yes, but still absolutely nowhere near zero, 3 months after a third dose they still have the risk reduction at nearly 50%! And thats from a period where testing and attitudes were more likely to pick up on covid deaths as being covid than I would suggest is the case these days.
 
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(FUBerlin & others) An intranasally administered live attenuated SARS-CoV-2 virus (LAV, based on the WT sequence) vaccine, sCPD9† (with FCS deletion), which outperforms mRNA and vector SARS-CoV-2 vaccines in hamsters, both immunologically, epidemiologically, pathologically and in terms of degrees of reactogenicity. It also appears to best the other vaccines in responses/outcomes to an antigenically diverse range of challenge variants (B.1, beta, delta and omicron).
The vaccine candidate sCPD9 (blue) equals or bests the other vaccines on every metric considered.
To what degree this performance is due to the intranasal delivery route and/or down to it being a replicating attenuated vaccine is not clear (unlike the other vaccine candidates this vaccine is administered the same way the virus naturally infects, promoting URT mucosal immunological response, and also presents all the viral epitopes rather than just spike, so might prove somewhat better at reducing transmission, disease progression and response to future VOC).
DOI:10.1038/s41564-023-01352-8.

Though there is, of course, no longitudinal data here, this intranasal LAV would arguably be easier and cheaper to administer more frequently and thus perhaps be a viable candidate for 6/12 month booster regimens and in LMIC settings, so could be worth pursuing on those grounds alone. Additionally, investigations into the pathogenicity of extra-spike protein sequences probably need to be considered (conversely, some in nsp might even dampen some avenues of reactogenicity).

† sCPD9 is a codon de-optimised version of early WT lineage SARS-CoV-2 (the same amino acids, in this case in ORF1ab, are expressed via different base sequences less optimally than in the natural virus, which undermines the pathology as the host cells translate it less efficiently and the mRNA itself is less stable). Notably it has been classed as BSL-2 which should facilitate more extensive whole virion research into SARS-CoV-2 and so hopefully produce results with higher degrees of confidence (as oppose to having to use eg pseudoviruses).
Structure and recoding of the SARS-CoV-2 genome (to form various candidates): (A) The SARS-CoV-2 genome; (B) ORF 1a/1ab is directly translated and cleaved into 15 proteins of the replication-transcription complex; (C) Recoded SARS-CoV-2 regions indicated by purple boxes (green indicated non-recoded parental sequences); (D) The pink boxes indicate recoded sequences.
 
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(WUSTL) In an animal model (mice) this study demonstrates the importance of Fc effector functions in providing (here, mRNA-1273) vaccine mediated protection against infection and disease; that there is much more to such than simply neutralising antibody titres. Furthermore, this highlights the key role that Fc effector functions play in providing protection against antigenically diverse variants, including the many sub-lineages of omicron.
DOI:10.1038/s41564-023-01359-1.
 
Does anyone know whether antibodies that were present 4 months after covid vaccination would still be there. in reasonable numbers... 6 months later?
 
Does anyone know whether antibodies that were present 4 months after covid vaccination would still be there. in reasonable numbers... 6 months later?
This is a totally impossible question to answer.

But assume yes. 6 months isnt very long.


They are doing a covid vaccine trial again at my local hospital def going to sign up.
 
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Amongst a slew of new mRNA vaccines, Moderna are just embarking on a phase 1 trial of a next generation COVID-19 vaccine, mRNA-1283, that encodes for epitopes in both spike receptor binding and N-terminal domains (RBD and NTD), which should hopefully be more effective across a range of variants.

I am on a stage 3 trial of this in the UK. It's called Next Cove. 10,000 participants in various countries.

It's either Moderna 1273.222 50ug or Moderna 1283.222 10ug. 50% of participants each.

They are testing with a lower dose and also looking into how well it can be stored at fridge temperatures.

Had my jab yesterday 18 months after my third 'booster' and 5 months after having Covid again in January.
 
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It appears we bought rather a lot of Paxlovid but then restricted its use heavily, and now a huge amount of it has expired.

FT article, which covers the wider phenomenon in Europe too, although it sounds like UK had even narrower restrictions on its use: https://archive.ph/eSc45

The partial dismantling of the testing regime further reduced the ability of people to access this drug.
 
I am on a stage 3 trial of this in the UK. It's called Next Cove. 10,000 participants in various countries.

It's either Moderna 1273.222 50ug or Moderna 1283.222 10ug. 50% of participants each.

They are testing with a lower dose and also looking into how well it can be stored at fridge temperatures.

Had my jab yesterday 18 months after my third 'booster' and 5 months after having Covid again in January.
My OH and two housemates are all on this trial ...

I had a health issue that prevented me taking part when they were recruited, but I'm now on a 'flu trial instead.

just as a matter of interest, are you getting the notifications the diary entries are available for completion ?
OH's "smart" phone gets the updates but doesn't get the notification "pings" ...
 
My OH and two housemates are all on this trial ...

I had a health issue that prevented me taking part when they were recruited, but I'm now on a 'flu trial instead.

just as a matter of interest, are you getting the notifications the diary entries are available for completion ?
OH's "smart" phone gets the updates but doesn't get the notification "pings" ...

Yeah I get the alert on my phone every 2 weeks and then have to go into the app. The fact I'm being paid is probably a bit of a motivator!

I tested positive for Covid in November so I had to go to another extra apointment to have blood and PCR done. Overall the trial has been quite chill though and I wasnt very ill at all when I had covid.. I thought it was a cold. It's still had some long covid knock on effects though unsurprisingly as I already suffered with this and seem to be predisposed.

I suspect I got the low dose booster of the new unreleased vaccine due to the v minimal side effects. But who knows. I might find out this summer when it ends.
 
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