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Possible vaccines/treatment(s) for Coronavirus

Phase 3 immunobridging trial (>4000 18+ yr old participants) of SK Bioscience's second generation, AS03-adjuvanted, self-assembling protein nanoparticle COVID-19 vaccine candidate, GB510/AS03 ('SKYCovione') reports promising results. A refrigerator stable vaccine, administered as two 25µg doses, 4 weeks apart, it was found to be immunogenically non-inferior to AZD1222 (with 2.93 times the neutralising antibody response). Low reactogenicity noted.

SK Bioscience are aiming for regulatory approval in ROK soon, licensing it royalty-free throughout the pandemic, and intend to make it available to COVAX.
 
(Berlin) sCPD9, a live attenuated intranasal COVID-19 vaccine booster (created by codon pair de-optimisation, CPD, aka synthetic attenuation virus engineering, which here reduced virulence, replication rate, some 100-fold lower than the parent type). This delivered very encouraging results in a hamster model challenge trial, performing better than intramuscular mRNA or viral vector vaccines, particularly against recent VOC including delta and omicron. Notably, importantly, much higher nasal mucosa IgA were observed.
Serum neutralisation titres of hamsters having received prime-boost vaccination prior (0 days post-challenge, dpc) and at 2- and 5-days post-challenge with live SARS-CoV-2 virus, for key variants. (Ad2=adenovirus vector vaccine candidate; mock=control, mock vaccination with sterile cell culture) ELISA (optical density reads, OD) detecting anti-spike IgA levels in nasal washes of prime vaccinated hamsters at indicated time points, days post-challenge (dpc).
We find that specifically this live attenuated vaccine elicits superior protection from SARS-CoV-2 infection especially at mucosal sites of virus entry.

An important and frequently discussed issue with live attenuated vaccines is their potential susceptibility to previously established immunity, which would restrict vaccine virus replication and potentially limit their use as booster vaccines after initial immunization by vaccination or natural infection. Our results indicate however, that sCPD9 does effectively boost immune responses and greatly improves protection.
DOI: 10.1101/2022.05.16.492138.

Human phase 2/3 trials of a CPD live attenuated intranasal vaccine, Codagenix's CoviLiv (was COVI-VAC, earlier results mentioned in posts #1433 and #1501), are already underway in the UK and have produced some encouraging interim results - blocking nasal replication and producing a robust cellular immunity response capable of responding to omicron VOC (inducing such an immunoresponse even prior to the recent omicron waves), perhaps with the potential to provide protection for a wide range of past and future variants.
 
Interesting. A study of 30,000 health workers in Qatar showed that the flu vaccination also gave protection against COVID19. Was in late 2020 though and protection might not be that long lasting.
Influenza vaccines have a surprising health benefit: they might also prevent COVID-19, particularly in its most severe forms1.

A study of more than 30,000 health-care workers in Qatar found that those who got a flu jab were nearly 90% less likely to develop severe COVID-19 over the next few months, compared with those who hadn’t been recently vaccinated against flu.

The study, which was conducted in late 2020, before the roll-out of COVID-19 vaccines, is in line with previous work suggesting that ramping up the immune system using influenza vaccines and other jabs could help the body to fend off the coronavirus SARS-CoV-2.
 
Novavax phase 3 trial of their (BA.1) omicron-specific protein subunit booster, NVX-CoV2515, and a bivalent (original WT NVX-CoV2373 plus NVX-CoV2515) now underway in Australia.
 
Interim data (phase 2/3 trial with 437 participants) for Moderna's mRNA-1273.214 (50µg bivalent WT+omicron spike) indicate that it induced superior neutralising antibody response against the omicron variant one month after administration (relative to original mRNA-1273). Binding antibody titres were also significantly higher against all other variants of concern (alpha, beta, gamma, delta, omicron) compared to the original formulation.
 
Interim data (phase 2/3 trial with 437 participants) for Moderna's mRNA-1273.214 (50µg bivalent WT+omicron spike) indicate that it induced superior neutralising antibody response against the omicron variant one month after administration (relative to original mRNA-1273). Binding antibody titres were also significantly higher against all other variants of concern (alpha, beta, gamma, delta, omicron) compared to the original formulation.
ooh, that's good news. [I'm on the uk's version of that trial !]
I wonder how long that superiority in response will last ?

e2a - changed as I'm on the UK's version ...
 
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Note: those results are from the US phase 2/3 booster study, not the UK (NIHR) one. The full results won't be available until following analysis after 3 months post-vaccination. Moderna are releasing these preliminary results so the regulators can begin to factor them into decisions about potential boosters this coming (northern hemisphere) winter.
 
Note: those results are from the US phase 2/3 booster study, not the UK (NIHR) one. The full results won't be available until following analysis after 3 months post-vaccination. Moderna are releasing these preliminary results so the regulators can begin to factor them into decisions about potential boosters this coming (northern hemisphere) winter.
Ah, OK.

But I'm still pleased at those results ...
 
(LJI) An immunological evaluation of the four approved US vaccines - Moderna mRNA-1273, Pfizer/BioNTech BNT162b2, Janssen Ad26.COV2.S and Novavax NVX-CoV2373 - examined longitudinally for 6 months, and a comparison with convalescent immunoresponse.
Summary of immunoresponses to Moderna mRNA-1273, Pfizer/BioNTech BNT162b2, Janssen Ad26.COV2.S and Novavax NVX-CoV2373 vaccines and comparison with that of convalescents (Binding and neutralising antibodies, CD4/CD8/cTfh T cells, and memory B cells.

In summary:
  • 100% of mRNA or NVX-CoV2373 vaccinees make spike memory CD4+ T cells.
  • mRNA vaccines and Ad26.COV2.S induce similar frequencies of spike memory CD8+ T cells (though NVX-CoV2373 CD8s sufficient).
  • Infection or Ad26.COV2.S immunisation increase frequency of spike CXCR3+ memory B cells.
  • Antibody wanes in response to mRNA vaccines, but memory T and B cells are comparatively stable.
  • NVX-CoV2373 antibody titres were comparable to those induced by mRNA at 6 months.
Across the antigen-specific immune metrics assessed, mRNA vaccines were consistently the most immunogenic, with levels higher than or equal to that of Ad26.COV2.S and NVX-CoV2373 vaccines for each immune response. NVX-CoV2373 elicited CD4+ T cell memory and neutralizing antibody titers comparably to the mRNA vaccines. The responses induced by the Ad26.COV2.S were generally lower but relatively stable. The mRNA vaccine platforms were associated with substantial declines in neutralizing antibody titers over 6 months, while memory CD4+ T cells, memory CD8+ T cells, and memory B cells exhibited small reductions (T cells) or increases (B cells). These observations appear to be consistent with the relatively high degree of protection maintained against hospitalizations with COVID-19 after these vaccines over 6 months, and the differential VE reported between mRNA COVID-19 vaccines and Ad26.COV2.S.
DOI: 10.1016/j.cell.2022.05.022.

Commentary:
 
(MIT/Harvard/UCLA/LJI) A comprehensive study into the difference between (mRNA mediated) hybrid (infected-then-vaccinated) and naïve vaccinee immunity, which finds that hybrid immunity offers a qualitatively improved antibody response able to better leverage Fc-effector functions against conserved regions of the virus, possibly driving more robust phagocytosis.

This study found clear differences in SARS-CoV-2 specific serum antibodies, following vaccination, between previously infected and naïve individuals, with antibody responses of greater magnitude and epitope specificity in individuals vaccinated after prior infection. Although antibody levels were similar after a second dose, several important differences persisted in Fc-receptor responses and shifts in coordination of the immune response. Previously-infected individuals had lower RBD-IgG3 levels, hinting at enhanced class-switching, and enhanced Fc-receptor binding marking the generation of potentially functionally optimised antibodies particularly targeting the highly conserved S2-domain of the spike protein.
For each of  naïve infected and previously infected individuals after 1st and 2nd vaccine doses: (B) Isotype titres for subclasses specific for S1, RBD, S2, and NTD; (C) Fc-receptor binding titres for those same spike regions.
In convalescent vaccinees, enhanced Fc-receptor binding was skewed towards preserved sub-classes that are known to drive rapid and robust phagocytosis, perhaps enabling individuals with hybrid immunity to clear viruses and kill infected cells more aggressively, providing an advantage even in the face of the emergence of VOCs that evade neutralisation.

Whilst naïve vaccinees exhibited a S1-dominated response, likely due to the stabilisation of the spike immunogen which reduces visibility of the S2 subunit, hybrids demonstrated S2-specific Fc-receptor binding capacity expansion (which, as seen for all betacoronaviridae, has been strongly conserved across all VOCs, with only 6 substitutions in omicron).
Given our emerging appreciation for the disease attenuating, rather than blocking, functions of S2-specific antibodies that are mediated largely via Fc-effector functions, these data argue that hybrid immune induction of potentially cross-reactive, functional antibodies to the S2 [spike subunit] may contribute to more robust protection against VOCs.
These findings may point to potential avenues of development for next generation vaccines to take.
DOI: 10.1101/2022.06.10.495727.
 
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(Imperial/Barts/UKHSA/others) As highlighted several times before, it is apparent that your antigenic exposure history, or immune imprinting, can have an influence on your immunoresponse and outcome of infection. Here a two year study of such in healthcare workers explored their B and T cell responses to omicron/BA.1 infection.

Hybrid vaccinees (originally infected with early type) appear to have a minimal S1 immunoresponse to omicron infection (little beneficial subsequent immunity gain in this respect from an omicron infection). Prior exposure to alpha/B.1.1.7 in particular resulted in less durable S1 binding antibodies against omicron/B.1.1.529. Meanwhile, previously uninfected vaccinees, subsequently infected by omicron, developed better responses to earlier VOC but not omicron sub-lineages; their T cell recognition of omicron spike was, unexpectedly, also reduced. (Though contrast with the findings of hybrid immunoresponses and outcomes with beta/B.1.351 imprinting and note the Fc-receptor/S2 investigation highlighted above).
In summary, these studies have shown that the high global prevalence of B.1.1.529 (Omicron) infections and reinfections likely reflects considerable subversion of immune recognition at both the B, T cell, antibody binding and neutralising antibody level, although with considerable differential modulation through immune imprinting. Some imprinted combinations, such as infection during the Wuhan Hu-1 and Omicron waves, confer particularly impaired responses.
The findings could underline why it may not be possible for a significant number of persons to build any sort of herd immunity to omicron lineage virus through [breakthrough] infection.
DOI: 10.1126/science.abq1841.

Overview and some commentary:
 
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Are there any studies where people werent previously exposed to a previous strain or vaccinated that we can compare to that study? ie where for some subjects the very first Covid imprinted in the immune system in any way was an Omicron strain?
 
That study includes some (eg see figure 6). Apparent shortcomings of the study are the preoccupation with the S1 subunit and no detailed investigation of sub-classes, Fc, etc (see eg the MIT/etc study in the preceding post), so it would appear the full hybrid picture, but the poor cross-reactivity in omicron lineage is the main takeaway (also observed by Kimura/Sato and other groups at Imperial).

Separately there is a recent study from BioNTech that compared double and triple vaccinated omicron-naïves with omicron-convalescents; the outcomes are not inconsistent with any of the above but still the main takeaway is the gradual ablation of the remaining [what were] conserved RBD epitopes (again, focused in S1) and thus evasion of immunity in omicron sub-lineage development, particularly in the infection naïve. (Findings relative to naïve vaccinees: induction of broadly neutralising antibodies in omicron BA.1-convalescent vaccinees, bias towards RBD-specific B cell responses in those same individuals, elevated evasion of immunity in BA.1-convalescent vaccinees, and omicron BA.1-convalescent double-vaccinated individuals having higher frequencies of both B cells and neutralising antibody titres against previous VOCs).
DOI: 10.1126/sciimmunol.abq2427.
 
That study includes some (eg see figure 6).
I couldnt see anything in figure 6 which showed people who remained both unvaccinated and uninfected until they caught Omicron. But maybe I didnt make it clear that this is what I was after, or maybe I have misinterpreted something in figure 6. Anyway please dont spend any more time trying to answer my query, cheers for your thoughts as always.
 
I could imagine it might be an uphill task to assemble a sample of unvaccinated persons who first got infected by SARS-CoV-2 during the recent omicron waves, outside of newborns, those with immunodysfunction and autoimmune diseases. Circumstances which would almost certainly preclude their involvement in studies seeking insights into outcomes for the general population. You would largely be left with those objecting to vaccination who (i) would likely not be so amenable to engaging with such a study and (ii) would have tended to have been prone to (re-)infection anyway.
 
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Yes. I was interested in theory because this pandemic has given us the opportunity to get beyond overly simplistic concepts such as original antigenic sin, and explore the complex realities of immune imprinting in more suitable detail instead. And obviously we are still able to explore this subject, but widespread vaccination means certain combinations are hard to find and study by this stage. Never mind.
 
I could imagine it might be an uphill task to assemble a sample of unvaccinated persons who first got infected by SARS-CoV-2 during the recent omicron waves, outside of newborns, those with immunodysfunction and autoimmune diseases. Circumstances which would almost certainly preclude their involvement in studies seeking insights into outcomes for the general population. You would largely be left with those objecting to vaccination who (i) would likely not be so amenable to engaging with such a study and (b) would tended to have been prone to (re-)infection anyway.

In the UK perhaps, but not in many other countries.
 
True. The challenge then is to find one of those countries that is then also a good candidate for actually bothering to do that sort of research with the right level of detail. The UK is reasonably good at doing such studies, especially when they can use health care workers whose history of infection and vaccination is well recorded.

So Im not sure I really expect to get useful answers to the sort of question I was poising, ie 'how will immunity to future strains differ in practice for people that didnt have contact with the original generation of vaccines or any of the pre-omicron strains?'. And I have no idea whether answers to that question will actually be interesting. I just remain broadly interested in the subject of what sort of differences we might see for people whose first immune impression of the virus is quite different to those were infected in previous waves and/or had the first gen vaccines.
 
I suppose countries like China and Australia have far more people who wont have been exposed to the virus pre-Omicron, but then the challenge is to find enough of those that both havent been vaccinated and are in young enough age groups that age-related factors dont muddy the waters in terms of measurable immune system things.
 
Plausibility of Claimed Covid-19 Vaccine Efficacies by Age: A Simulation Study
The distribution of alleged vaccine efficacies of the Sputnik vaccine by age in the phase-III trial is very unlikely to occur in genuine experimental data, even if the number of patients recruited, vaccine efficacy, and overall infection rate are true and there is no underlying difference in vaccine efficacy by age.
DOI: 10.1097/MJT.0000000000001528.

Author overview:
 
More results from Moderna's trial of their bivalent mRNA-1273.214 (WT+omicron/BA.1 spike) autumn vaccine booster candidate.
One month after administration in previously vaccinated and boosted participants, a 50µg booster dose of mRNA-1273.214 elicited potent neutralizing antibody responses against the Omicron subvariants BA.4 and BA.5 in all participants regardless of prior infection. Based on this and prior data, the Company is working to complete regulatory submissions in the coming weeks requesting to update the composition of the booster vaccine to mRNA-1273.214.
At one month post-administration mRNA-1273.214 boosted neutralising titres against BA.4/BA.5 by 5.4-fold (95%CI:5.0-5.9) above baseline in all study participants regardless of prior infection history, and by 6.3-fold (95%CI:5.7-6.9) in seronegative participants.

Their CEO hopes they will be ready to ship mRNA-1273.214 in August.

Moderna also announced plans to establish an mRNA Innovation and Technology Center in the UK, including a state-of-the-art mRNA vaccine manufacturing facility.
 
Valneva's whole virus, inactivated, adjuvanted vaccine candidate, VLA2001, now one step away from EMA regulatory approval.
 
Pfizer/BioNTech results for their omicron-spike tuned autumn vaccine booster candidates, BNT162b2 OMI (monovalent BA.1 spike based) and bivalent (BNT162b2 + BNT162b2 OMI, ie WT+BA.1).

They were found to be well tolerated, with good immunogenic responses measured for both (note: neutralising titres only). Unsurprisingly the monovalent performed better against BA.1.
One month after administration, a booster dose of the Omicron-adapted monovalent candidates (30 µg and 60 µg) increased neutralizing geometric mean titers (GMT) against Omicron BA.1 13.5 and 19.6-fold above pre-booster dose levels, while a booster dose of the Omicron-adapted bivalent candidates conferred a 9.1 and 10.9-fold increase in neutralizing GMTs against Omicron BA.1. Both Omicron-adapted vaccine candidates were well-tolerated in participants who received one or the other Omicron-adapted vaccine.

In a SARS-CoV-2 live virus neutralization assay tested on sera from participants over 56 years of age and older, sera efficiently neutralized BA.4/BA.5 with titers approximately 3-fold lower than BA.1.

This coming week the FDA will discuss options, considering Pfizer, Moderna and Novavax omicron-spike tuned candidates, with a view to recommending which variant(s) should be in an autumn booster.
 
Valneva's whole virus, inactivated, adjuvanted vaccine candidate, VLA2001, now one step away from EMA regulatory approval.
VLA2001 now approved for use throughout the EU.
 
Interim data (phase 2/3 trial with 437 participants) for Moderna's mRNA-1273.214 (50µg bivalent WT+omicron spike) indicate that it induced superior neutralising antibody response against the omicron variant one month after administration (relative to original mRNA-1273) ...
Preprint for the full results of this Moderna mRNA-1273.214 bivalent (WT/B.1.1.529 spikes) 50µg booster candidate study now available.
In conclusion, the omicron-containing bivalent vaccine mRNA-1273.214 had a safety and reactogenicity profile similar to that of the current booster vaccine mRNA-1273 when administered at the 50-μg dose. mRNA-1273.214 elicited a superior neutralizing antibody response against omicron, compared to mRNA-1273, and potent neutralizing antibody responses against the BA.4 and BA.5 omicron subvariants 28 days after immunization. Antibody responses were also higher against the ancestral SARS-CoV-2 (D614G) and multiple additional variants [alpha, beta, gamma, delta]. These results are consistent with the evaluation of our first, beta-containing, bivalent vaccine which induced enhanced and durable antibody responses against multiple SARS-CoV-2 variants and bivalent vaccines can be a new tool as we respond to emerging variants.
DOI:10.1101/2022.06.24.22276703.
 
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