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Possible vaccines/treatment(s) for Coronavirus

Moderna have greenlit an omicron/B.1.1.529 vaccine candidate, mRNA-1273.529. They expect to have it ready for clinical testing within 60-90 days.

Novavax have also already started work on an omicron targeted version of their vaccine and expect to have that ready for testing and potential manufacture within a few weeks.
 
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Pfizer too.

If this is the case, Pfizer and BioNTech expects "to be able to develop and produce a tailor-made vaccine against that variant in approximately 100 days, subject to regulatory approval".

 
Pfizer, like AstraZeneca, are currently only evaluating their present vaccines efficacy to omicron (are their official statements thus far).
 
Further steps towards correlates of protection (against infection), here a published study from Fred Hutch/Duke/Emory/Moderna/others for mRNA-1273.

From a sample of standard two-dose regimen individuals vaccine efficacies for given neutralisation titres were determined (note not third-dose boosted, which as previous work (eg Crotty et al) has indicated, looks like it generates a better quality of response).

Post-vaccination 50% neutralisation titres 10, 100, and 1000 had corresponding estimated vaccine efficacies of 78% (95%CI:54-89), 91% (95%CI:87-94), and 96% (95%CI:94-98). (Important note: neutralising antibodies, not binding antibodies).
ID50 level as a correlate of risk and as a correlate of protection by day 57. (A) cumulative incidence of COVID-19 by 100 days post day 57, (B) cumulative incidence of COVID-19 by 100 days post day 57 by day 57 ID50 level, (C) Vaccine efficacy by day 57 ID50 level.
These results are useful for performing immunogenic comparisons (immunobridging studies) between vaccines (particularly now that placebo controlled trials are unethical and/or there is insufficient sustained prevalence to conduct timely trials), rather than determining individual immunity/vaccination need (since they don't factor in individual medical history, risk, or cellular immunity response). The authors point out that a similar approach is regularly used for determining Influenza vaccine efficacy and selecting them for a given strain in a given season.
DOI: 10.1126/science.abm3425.

TL;DR said:
Some correlates of protection from infection for Moderna's COVID-19 vaccine have been determined. They could be used going forward to evaluate the potential of other vaccines and redesigned/multivalent vaccines targeting new variants of concern.
 
Moderna have greenlit an omicron/B.1.1.529 vaccine candidate, mRNA-1273.529. They expect to have it ready for clinical testing within 60-90 days.

Novavax have also already started work on an omicron targeted version of their vaccine and expect to have that ready for testing and potential manufacture within a few weeks.

Ah, lovely. That will be a “we have a couple of new projects with super-aggressive timelines” email on Monday morning, them…

<not complaining ;) >
 
From the Netherlands (RIVM) a study of variation in post-vaccination infection risk by variant of concern.

Risk of infection was determined from analysis of 28+K sequenced samples collected March-August 2021 from individuals with known immune status:
We find evidence for an increased risk of infection by the Beta (B.1.351), Gamma (P.1), or Delta (B.1.617.2) variants compared to the Alpha (B.1.1.7) variant after vaccination. No clear differences were found between vaccines. However, the effect was larger in the first 14-59 days after complete vaccination compared to 60 days and longer.
Odds ratio (likelihood of getting infected compared to alpha) for given immune status and VOC (adjusted for week of sampling, gender and age). Error bars indicate 95% confidence intervals.
Note the sizeable confidence intervals.

The infection-mediated versus vaccine-mediated odds ratios might suggest there are some protective immune responses to other epitopes (eg nucleocapsid, membrane, indeed other expressions of spike) and underscore maturation timing.
DOI: 10.1101/2021.11.24.21266735.

TL;DR said:
This study confirms a lower vaccine effectiveness against infection by delta, beta and gamma variants, compared to alpha. This effect was largest early after complete vaccination (difference in risk was less significant beyond 59 days post-dose-two). It may suggest advantages in mixing vaccinations and choosing optimal timing intervals of doses.
 
Moderna have greenlit an omicron/B.1.1.529 vaccine candidate, mRNA-1273.529. They expect to have it ready for clinical testing within 60-90 days.
However the Moderna CEO thinks it will take "months" to start shipping a new variant vaccine.
 
However the Moderna CEO thinks it will take "months" to start shipping a new variant vaccine.

Yep, scaling up always takes a while. They're gonna need a lot of the stuff.

It will def come out fast enough for the anti-vaxxers to go ape shit about it being "completely untested", though.
 
From Germany (Erlangen and others), a study that (again) points to intranasal boosters, particularly as part of a mixed vaccination series, as potentially being the way forward.

Here a heterologous mRNA prime (actually low-dose BNT162b2) followed by an intranasal (Ad5) viral-vector boost in an animal model was found to promote very high levels of mucosal SARS-CoV-2 IgA protection. Likely this upper respiratory tract tissue immunity will greatly reduce the chances of infection and thus development of disease. It will also probably significantly reduce transmission too.
Mucosal, spike-specific IgA responses.
The regimen also induced high levels of lung-resident memory T cells and IgG antibodies, with broad neutralisation to a range of VOCs.
DOI: 10.1038/s41467-021-27063-4.
 
Under-dosing mutagenic antivirals, such as molnupiravir (for example - due to missed doses, incomplete courses, or low initial drug penetrance at the site of action), may lead to sublethal mutagenesis and so accelerate within-host evolution of the virus, potentiating new variants of concern that enhance transmissibility or immune escape.

Details: 'Mutagenic antivirals: the evolutionary risk of low doses'

See also:
 
I wonder if thats what Whitty was referring to when he said on Saturday that they needed to review how they would use those drugs. And then of course Javid used such drugs as part of his 'reassuring' lets not shield the vulnerable comments in yesterdays press conference.
 
Under-dosing mutagenic antivirals, such as molnupiravir (for example - due to missed doses, incomplete courses, or low initial drug penetrance at the site of action), may lead to sublethal mutagenesis and so accelerate within-host evolution of the virus, potentiating new variants of concern that enhance transmissibility or immune escape.

Details: 'Mutagenic antivirals: the evolutionary risk of low doses'

See also:
More commentary on this and thoughts on the limitations of use (ie prescribe only to high risk patients and mitigate risk for female patients who might be pregnant).
Rethinking Molnupiravir
 
Novavax has initiated development of an Omicron-specific construct of its SARS-CoV-2 Spike protein (rS) antigen, currently in use in NVX-CoV2373. The initial steps required to manufacture an Omicron-specific spike are underway and GMP manufacturing in a commercial facility is anticipated in January 2022. Lab-based assessment of a new strain-matched nanoparticle vaccine will begin within a few weeks.

Meanwhile EMA rolling review of Valneva's inactivated whole virus vaccine, VLA2001, begins.
 
Phase 2 trial COV-BOOST results for mixing third dose boosters have been published. Individuals who had had the standard two-dose regimens of either AstraZeneca AZD1222 or Pfizer/BioNTech BNT162b2 were third dose boosted with one of Novavax NVX-CoV2373, Valneva VLA2001, J&J/Janssen Ad26.COV2.S, Moderna mRNA1273 or CureVac CVnCov, at 10-12 weeks after dose 2 (<<6 months).

All vaccine boosters raised antibody and neutralising immune responses in original two-dose AZD1222 recipients. All vaccine boosters except VLA2001 raised antibody and neutralising immune responses in original two-dose BNT162b2 recipients. NVX-CoV2373 appeared to induce a T cell response comparable to that of BNT162b2. Unfortunately immunogenicity data are only available for up to one month after dose 3, so far.
DOI: 10.1016/S0140-6736(21)02717-3.

Summary thread from the study lead.


It would be interesting to re-examine the neutralising activity of sera from these individuals after 3 and 6 months.
 
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From KCL a study of (delta/B.1.617.2) breakthrough infection (BTI) immunoresponses in vaccinees, comparing them to (delta) infections in the unvaccinated, so adding to the 'other side' of the hybrid immunity picture.
Differences in neutralising antibody response between (A) delta infected individuals and (B) COVID-19 vaccinated individuals experiencing breakthrough infection. Fold decrease in geometric mean titre relative to delta are indicated.

Post-infection vaccinee sera were far better able to neutralise all VOCs (even beta/B.1.351) than the unvaccinated whose sera neutralised delta less well and the other VOCs relatively poorly.
Rapid production of Spike-reactive IgG was observed in the vaccinated group providing evidence of effective vaccine priming. Overall, potent cross-neutralizing activity against current SARS–CoV–2 variants of concern was observed in the BTI group compared to the infection group.
This research underlines how hybrid immunity significantly enhances immunoresponse affinity/avidity/breadth.
DOI: 10.1101/2021.12.01.21266982.
 
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From Imperial (and others) a study, based on UK healthcare worker data, that highlights how the type and pattern of exposure to different VOC, antigenic imprinting, in vaccinees modulates the subsequent immunoresponse to a range of VOCs.

For example, here infection with alpha/B.1.1.7 then vaccination was found to induce reduced neutralising titres compared to infection with early-type WT then vaccination.
T cell and B cell immunity and neutralisation hierarchy following heterologous exposure through infection with the B.1.1.7 VOC during the second UK wave and in the context of single and two dose vaccination.
Neutralization potency against VOCs changed with heterologous virus encounter and number of antigen exposures. Neutralization potency fell differentially depending on targeted VOCs over 5-months from the second vaccine dose. Heterologous combinations of spike encountered during infection and vaccination shape subsequent cross-protection against VOC, with implications for future-proof next-generation vaccines.

The indication is that the phenomenon of enhanced vaccine responses by infection, which has been reproducibly described by us and others, is less effective if the infection involves heterologous spike from a VOC.
This research points to the potential complications of "over specialising" forthcoming vaccines, ie tuning them to one particularly troublesome VOC at the expensive of VOCs as yet unseen; degrees of original antigenic sin. A universal coronavirus vaccine needs to very carefully select antigens to optimise for cross-reactivity.
DOI: 10.1126/science.abm0811.

(Cf previously noted work on mapping the antigenic distance between VOCs and implications for [spike] antigen selection for future vaccines.)

'Mainstream' press (TL;DR):
 
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(And not entirely unrelated to the previous post... another step towards a universal coronavirus vaccine.)

An announcement of phase I trials of DIOSynVax's pan-sarbeco coronavirus DNA plasmid vaccine candidate, pEVAC-PS.

It aims to target all coronaviruses through focusing on expressing modified non-spike antigens common to all coronaviridae, selecting carefully to avoid triggering unintentional hyper-inflammatory responses. It has already demonstrated good cross-reactive promise to a number of sarbecoviruses in animal models.

This DNA vaccine comes in freeze-dried powder form, so can be stored at room temperature and administered intradermally by a needle-free 'jet'.


 
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Phase 2 trial COV-BOOST results ... All vaccine boosters except VLA2001 raised antibody and neutralising immune responses...

It would be interesting to re-examine the neutralising activity of sera from these individuals after 3 and 6 months.
Comment from Valneva:
The setting in this study leads us to believe that COV-Boost does not allow any conclusions to be reached regarding the use of VLA2001 as a booster in a real-life setting.

Valneva believes it is likely that the short interval between the second shot and booster shot could have adversely impacted the results for VLA2001, given that a longer interval is generally required for inactivated vaccines.

Additionally, Valneva's own press release states that they expect homologous booster data in 1Q2022 and that they are co-ordinating a separate heterologous booster trial with a dose 2-3 interval of at least six months.
 
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(DFTK, Tübingen) A small (n=36, ages 18-80 years) phase I trial of a peptide-based T cell vaccine, CoVac-1.

No adverse reactogenic events were observed. SARS-CoV-2-specific T cell responses (T-helper CD4+ and CD8+) targeting multiple vaccine peptides were induced in all study participants and interferon-γ T cell responses persisted in the follow-up analyses, exceeding both post-infection and approved vaccine responses.
CoVac-1-induced T-cell responses. CoVac-1-induced long-term T-cell responses. Intensities of CoVac-1-induced IFN-γ T-cell responses compared to spike-specific T-cell responses in healthy immunised donors after second vaccination with approved mRNA vaccines.
Further (phase II) trials are anticipated to evaluate this vaccine candidate for patients with B cell/antibody deficiency.
DOI: 10.1038/s41586-021-04232-5.

Some background:

See also previously post #1555 for another T cell vaccine candidate.
 
Further results from the Com-COV2 study. Here a non-inferiority randomised controlled trial examining safety, reactogenicity, and immunogenicity of heterologous vaccine regimens namely mRNA-1273 and NVX-CoV2373 as second-dose vaccines for people (50+ years, n~1000) who received a first dose of AZD1222 or BNT162b2 8-12 weeks prior, as well as comparing them to the approved homologous two-dose regimens.

Reactogenicity in heterologous schedules of viral vector then mRNA vaccine increased compared to the standard homologous schedules, but not where NVX-CoV2373 was the second dose.

Kinetics of immunogenicity by vaccine schedule: (A) anti-spike IgG and (B) T cell response.
All immunogenic outcomes are from samples taken at 28 days post second dose. mRNA-1273 as a heterologous boost after AZD1222 or BNT162b2 prime induced a higher binding and neutralising antibody response than either standard homologous schedule. NVX-CoV2373 after AZD1222 prime was superior to the standard homologous AZD1222 regimen (for both humoral and cellular immunity). NVX-CoV2373 after BNT162b2 did not induce higher binding antibody titres compared to standard homologous BNT162b2; however those titres still exceeded those produced by standard homologous AZD1222. Drops in neutralising antibody responses to beta/B.1.351 and delta/B.1.617.2 VOC were seen across all schedules, whereas T cell responses were not affected. Notably, the greatest T cell response was seen in the AZD1222/NVX-CoV2373 schedule.
DOI: https://doi.org/10.1016/S0140-6736(21)02718-5.
 
Statement from Pfizer/BioNTech on omicron/B.1.1.529 and their initial neutralisation study results (note: pseudovirus).
  • Preliminary laboratory studies demonstrate that three doses of the Pfizer-BioNTech COVID-19 Vaccine neutralize the Omicron variant (B.1.1.529 lineage) while two doses show significantly reduced neutralization titers
  • Data indicate that a third dose of BNT162b2 increases the neutralizing antibody titers by 25-fold compared to two doses against the Omicron variant; titers after the booster dose are comparable to titers observed after two doses against the wild-type virus which are associated with high levels of protection
  • As 80% of epitopes in the spike protein recognized by CD8+ T cells are not affected by the mutations in the Omicron variant, two doses may still induce protection against severe disease
  • The companies continue to advance the development of a variant-specific vaccine for Omicron and expect to have it available by March in the event that an adaption is needed to further increase the level and duration of protection – with no change expected to the companies’ four billion dose capacity for 2022
Neutralising titres to omicron induced by BNT162b2 at one month after third-dose booster are similar to those to early-type 21 days after the original two-dose series.
25 of 31 key BNT162b2 induced CD8+ T cell epitopes are unaffected by omicron.
 
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Following on from Pfizer/BioNTech (post #1585), a summary of three other small omicron vaccine neutralisation studies announced in the past ~24 hours.

Live omicron virus neutralisation assay results (AHRI/KZN, Durban) performed with BNT162b2 vaccine induced sera. The apparent raw neutralisation reduction is around 40-fold compared to earlier type D614G. This new VOC appears to still be using the ACE2 receptor. Omicron does not escape from hybrid immunity (previous infection plus vaccination, in that order), which may not be surprising as this a not untypical fold-advantage hybrid immunity exhibits over non-convalesecent two-dose vaccine induced immunity, in otherwise healthy individuals. This may suggest that a three-dose vaccination regimen could provide sufficient antibody protection. No T cell analysis.
Neutralisation reduction for BNT162b2 sera versus omicron/B.1.1.529 relative to early-type D614G.
DOI: 10.1101/2021.12.08.21267417.

Omicron lentiviral pseudovirus neutralisation assay results (Karolinska, Sweden). Up to a 25-fold reduction in neutralisation titres was observed across cohorts of blood donors and healthcare workers. They also found that a WHO neutralisation standard, used to standardise their assays, exhibited a 40-fold loss of neutralisation to omicron relative to early type. This preliminary report did not clarify which donors were convalsecent only, vaccinee only or hybrid.
Pseudovirus neutralisation titres for blood donors (BD) and hospital workers (HW) versus early-type (WT), delta/B.1.617.2 and omicron/B.1.1.529 variants.

A more comprehensive live omicron virus neutralisation study (Goethe, Germany) examining various vaccine induced sera, from both two-dose and three-dose regimens (each cohort of 10-20 individuals, variously ages 20-93 years).

Poor neutralisation against delta/B.1.617.2 and no efficacy against omicron/B.1.1.529 were observed using sera from heterologous two-dose AZD1222/BNT162b2 vaccinated individuals. BNT162b2-boosted individuals showed a significant increase of neutralising antibody titres but a ~27-fold reduction (relative to delta) in neutralisation against omicron (2 weeks post third dose). Neutralisation of omicron by double BNT162b2 convalescent vaccinees exhibited a ~33-fold reduction; though note that the median age of this particular convalescent vaccinee cohort was 88 years (range 68-93 years) and the majority were infected after vaccination (hybrid response unlikely to be as strong as for younger convalescent cohorts who were infected well in advance of vaccination). The most effective vaccination regimen was two-dose mRNA-1273 boosted by BNT162b2, with a ~23-fold reduction (relative to delta) in neutralisation against omicron (note: measured at only 2 weeks post third dose).
Antibody-mediated neutralisation efficacy against authentic SARS-CoV-2 variants delta and omicron: (A,B,C) neutralisation assays for various vaccination regimens; (D) neutralisation efficacy of monoclonal antibodies imdevimab and casirivimab. The percentages indicate the relative number of sera that achieved a measurable titre. (delta=red, grey=omicron)
Additionally, whilst the monoclonal antibodies imdevimab and casirivimab efficiently prevented delta infection, they failed to neutralise omicron. This study did not analyse T cell responses.
DOI: 10.1101/2021.12.07.21267432.
 
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Very preliminary data from a further neutralisation study (Medizinische Universität, Innsbruck). Details a little lacking right now but apparently live virus neutralisation assays.

All two-dose homologous schedules and convalescent immunity performed poorly at neutralising omicron/B.1.1.529. The best performing two-dose vaccination schedule was heterologous AZD1222/BNT162b2.

It would appear these results point to hybrid immunity ("super immune") apparently yielding the best neutralising results with infection-then-vaccination superior to vaccination-then-infection (seemingly consistent with Crotty's earlier speculations). Note that some of the results may (as in other small numbers studies mentioned in the last couple of posts) be confounded to degrees by age(/immunocompetence) of some study participants.
Neutralisation titres to alpha, beta, delta, omicron, for sera from various standard homologous vaccination regimens (a,b,d), heterologous AZ1222/BNT162b2, convalescents (e,f,g), and hybrid immunity (h).

No preprint yet.

e2a: Lead author confirms that BNT162b2 vaccinees were sampled 1 month after second dose, whereas mRNA-1273 vaccinees were sampled 4-5 months after second dose (likely has a bearing on the former seemingly outperforming the latter, contrary to almost every previous study observation).
 
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From the UKHSA 'SARS-CoV-2 variants of concern and variants under investigation in England, Technical briefing 31, 10 December 2021'.
The Variant Technical Group reviewed the available neutralisation data from published international and internal UK studies (UK Health Security Agency, University of Oxford). UK data will be published as soon as possible and cited here when available. Across 5 preliminary live virus studies (3 international and 2 UK), there was a 20- to 40-fold reduction in neutralising activity by Pfizer 2-dose vaccinee sera for Omicron compared to early pandemic viruses. There was at least 10 fold loss of activity when compared to Delta; in both UK studies this was over 20 fold. A greater reduction in activity was seen for AZ 2-dose sera, and for a high proportion of such sera, neutralising activity fell below the limit of quantification in the assay. An mRNA booster dose resulted in an increase in neutralising activity irrespective of primary vaccination type, including an increase in the proportion of samples that were above the limit of quantification. This is true regardless of which vaccine was used for the primary course. These data are from the early period after the booster and data are urgently required on the durability of neutralising activity.
(Very early) estimates of vaccine effectiveness against symptomatic COVID-19 due to the omicron/B.1.1.529 variant were made using a test negative case control study and compared to that due to delta/B.1.617.2, ie a real world epidemiological estimate, rather than a lab based neutralisation study. The final analysis included 56,439 delta and 581 omicron cases.

Original two-dose homologous AZD1222 regimen exhibits zero percent vaccine effectiveness to symptomatic infection by omicron. Original two-dose homologous BNT162b2 regimen exhibits ~30 percent vaccine effectiveness to symptomatic infection by omicron. A third dose of BNT162b2 raises vaccine effectiveness to symptomatic infection by omicron to around 70-75%.
Vaccine effectiveness against symptomatic diseases by period after dose 1 and dose 2 for delta (black squares) and omicron (grey circles) for (A) recipients of 2 doses of AZD1222 vaccine as the primary course and BNT162b2 as a booster and (B) recipients of 2 doses of BNT162b2 vaccine as the primary course and BNT162b2 as a booster (third dose booster is last data point in each case).
Note: small study participant numbers lead to wide confidence intervals (and particularly the ~0% estimate for AZD1222).

e2a: Part of the data and analysis (for delta) available in this UKHSA/NIHR preprint.

2e2a: Omicron neutralisation data (Oxford) provided in this brief preprint - DOI: 10.1101/2021.12.10.21267534.
Neutralisation assays of SARS-CoV-2 Victoria early-type, beta, delta and omicron using (A) AZD1222 serum (ChAd) and (B) BNT162b2 (BNT) serum.
 
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