Possible vaccines/treatment(s) for Coronavirus

[2hats]

A new analysis of UK data, broadly consistent with earlier estimates from PHE (DOI: 10.1101/2021.05.22.21257658, DOI: 10.1056/NEJMc2107717), concludes that there is around a halving of the secondary attack rate in households following (at least single dose) vaccination. This approach is attempting to avoid the problem of test data missing asymptomatic infections and those where tests have not been requested.
arXiv:2107.06545.

For reference, from the latest PHE COVID-19 vaccine surveillance report, Week 28 (green=high confidence, amber=medium confidence, red=low confidence):

 

[2hats]

Further studies looking at cellular responses, and vaccine efficacy, in previously infected and uninfected individuals.

From Yale, a study examining antibody and T cell responses in previously infected and infection-naive individuals (40 healthcare workers, median age 45, 80% female) who received both doses of mRNA vaccines (80% mRNA-1273, 20% BNT162b2). While both groups retained neutralisation capacity against all variants, plasma (sampled several times up to 98 days post first dose) from previously-infected vaccinees displayed overall better neutralisation capacity across a range of VOCs, and resilience to key mutations in the RBD, than that of non-convalescents. Time since infection may play a role.

IgG levels were, as seen elsewhere, higher in convalescents after one dose, and their anti-N antibody titres (obviously not present in non-convalescents) were stable over time (unaffected by vaccination). Neutralisation assays conducted point to L452R in combination with E484K and N501Y perhaps being a more concerning combination for vaccine escape.
DOI: 10.1101/2021.07.14.21260307.

From the US (SJCRH), a small study of epitope-specific T cells elicited after natural SARS-CoV-2 infection, and (BNT162b2) vaccination of both naive and recovered individuals (19 individuals, ages roughly 40-50 years).

BNT162b2 induced a strikingly potent CD8 T cell response, comparable in functionality, magnitude, memory phenotypes, and underlying T cell receptor repertoires to infection. Vaccination after infection was able to further expand spike-specific responses. Some data might suggest that SARS-CoV-2 may reactivate cross-reactive memory CD8+ T cells from earlier episodes of particular common cold coronavirus infections. No significant difference in frequency, phenotype, or T cell receptor motifs in memory T cells generated by natural infection or vaccination was observed, suggesting that mRNA vaccines could be effective for boosting of pre-existing vaccine-induced immunity during revaccination without affecting established anti-spike T cell memory.
DOI: 10.1101/2021.07.12.21260227.

Somewhat relatedly (to the first study, at least) speculation (not a study; beware confounders) by some commentators in Israel (where 61% are fully vaccinated, 66% with at least one dose, all mRNA) that the most recent infection data might hint that recovery from previous infection is more protective against infection by delta (99% of sequenced cases; alpha 1%) than vaccination alone (9% of Israelis are convalescent yet constitute less than 1% of current cases; positivity rate for them is 0.1% compared to 1% amongst naive vaccinated).

 

[2hats]

Taiwan has approved Medigen's MVC-COV1901 prefusion stabilised, adjuvanted, protein subunit vaccine based on phase 1/2 immunogenicity data alone (the first time a covid vaccine has been approved without extensive phase 3 efficacy trials). Regulators approved the vaccine, for persons aged 20+ years, on the basis it is at least as immunogenic as AZD1222.

Taiwan clears Medigen Covid-19 vaccine for emergency use

Antibodies created by candidate proven to be ‘no worse than’ those produced by AstraZeneca shot, with no major safety concerns, health ministry says.

www.scmp.com

DOI: 10.1016/j.eclinm.2021.100989.

 

[2hats]

From Argentina, a study of Sputnik V (a recombinant adenovirus, rAd26 and rAd5, vector vaccine) in both convalescent and infection naive individuals (289 healthcare workers).

By 21 days post first dose, 94% of naive participants developed spike-specific IgG antibodies, with 90% displaying neutralising capacity to early type. A single dose elicited higher antibody levels and virus neutralising capacity in convalescents than in two-dose naive individuals. The high seroconversion rate after a single dose in naive participants suggests a benefit of delaying second dose administration to increase the number of people vaccinated. There is no evident benefit of using a second dose in previously infected individuals

DOI: 10.1016/j.xcrm.2021.100359.

 

[2hats]

From Israel, further information regarding possible immunity (see also post 1399). Reportedly based on Ministry of Health internal documents, a suggestion that waning immunity in early BNT162b2 vaccinees might be beginning to manifest. Persons vaccinated in January now appear to be 3-4 times more likely to become infected than those vaccinated in May. The effect appears to be stronger in older (60+) cohorts, but may be confounded by, for example, differing behaviour across age groups.

 

[2hats]

A test-negative case–control study led by PHE, to estimate the effectiveness of vaccination (BNT162b2 or AZD1222) against symptomatic disease caused by the delta/B.1.617.2 and alpha/B.1.1.7 variants (from over 19k cases, 22% delta).

Effectiveness after one dose of any vaccine was lower to delta, being 30.7%[95%CI:25.2-35.7], than to alpha at 48.7%[95%CI:45.5-51.7]. For two doses of BNT162b2 this effectiveness was 93.7%[95%CI:91.6-95.3] to alpha and 88.0%[95%CI:85.3-90.1] to delta. With two doses of AZD1222 the effectiveness was 74.5%[95%CI:68.4-79.4] to alpha and 67.0%[95%CI:61.3-71.8] to delta. Reductions from alpha to delta were modest.

DOI: 10.1056/NEJMoa2108891.

 

[2hats]

Further information from the Israeli Ministry of Health which both indicates a high recent efficacy of BNT162b2 to severe disease, hospitalisation and death during this (delta) wave, but also appears to suggest a reduction in efficacy to infection and symptoms.

To what degree this is perhaps waning circulating immunity, innate feature of the variant, biased by surge testing in particular areas/age groups, behaviour/testing/reporting related or, maybe, influenced by dosing interval is not yet clear.

Israel reports COVID vaccine effectiveness against infection down to 40%; data might be skewed

***

www.haaretz.com

 

[2hats]

As touched upon previously (and perhaps germane in the light of the above MoH data), intranasal SARS-CoV-2 vaccines - live attenuated for 2-49yrs, viral vector and maybe even mRNA formulations of such for others - might be a way forward for promoting longer-lived immunity, eliciting strong, enduring mucosal IgA, IgG, B and T cell responses which shut down initial upper respiratory infections early. Particularly where employed as a booster to an intramuscular prime.

A commentary piece on this: Scent of a vaccine | Science

The ideal vaccination strategy may use an intramuscular vaccine to elicit a long-lived systemic IgG response and a broad repertoire of central memory B and T cells, followed by an intranasal booster that recruits memory B and T cells to the nasal passages and further guides their differentiation toward mucosal protection, including IgA secretion and tissue-resident memory cells in the respiratory tract.

See also:

To Beat COVID, We May Need a Good Shot in the Nose

Intranasal vaccines might stop the spread of the coronavirus more effectively than needles in arms

www.scientificamerican.com

 

[elbows]

The Delta vaccines analysis from Israel sounds like it was faulty.

 

[Supine]

Sounds like the politics of vaccines is taking its toll on AZ. For what it’s worth I hope they continue. Long term the cost and shipping conditions required really make their product worthwhile.

EXCLUSIVE AstraZeneca exploring options for COVID-19 vaccine business - executive

AstraZeneca is exploring options for the future of its COVID-19 vaccine and expects greater clarity on the matter by the end of 2021, a senior executive said on Thursday, following a series of setbacks in its race to produce a shot for the world.

www.reuters.com

 

[elbows]

Politics have been a giant amplifier but arent the only factor.

 

[elbows]

The latest REACT study show that their attempts to ascertain vaccine effectiveness via this studies methods results in a declining estimate compared to the previous round. I dont think this is unexpected really, vaccines are given a greater test during times of high prevalence, with Delta firmly dominant. I also note that the underlying number of cases used is rather modest.

https://spiral.imperial.ac.uk/bitstream/10044/1/90800/2/react1_r13_final_preprint_final.pdf

At these ages, we compared swab-negatives with i) all swab-positives and ii) the subset of swab-positives who were symptomatic, that is reporting one or more classic COVID-19 symptoms in the month prior to testing (fever, loss or change of sense of smell or taste, new persistent cough). After adjusting for age, sex, region, ethnicity and index of multiple deprivation (IMD) [14], for all swab-positives, we estimated vaccine effectiveness (VE) in round 12 of 64% (11%, 85%) and 49% (22%, 67%) in round 13. For those with symptoms we estimated VE of 83% (19%, 97%) in round 12 and 59% (23%, 78%) in round 13.

In secondary analyses, for the 87% of participants aged 18 to 64 in round 13 who consented to data linkage (Methods), we estimated adjusted VE at 75% (35%, 90%) in round 12 and 62% (38%, 77%) in round 13. The apparent increase in VE for the linked participants reflected differences in odds of infection among the linked and unlinked groups (Table 5a), suggesting likely selection bias for consent to linkage. However, since the linked group had more reliable reported dates of vaccination, we examined the potential effect of a lag period of 14 days after the second vaccination and observed similar odds ratios for zero lag and 14 days lag following the second dose (Table 4).

While vaccination was associated with lower prevalence of swab-positivity, there remained potential for large numbers of fully vaccinated people to become infected. During the period of round 12, we extrapolated from our data that 29% of infections in England occurred in double-vaccinated people, rising to 44% during the period of round 13. Also, although lower than for unvaccinated individuals, nearly one in 25 double-vaccinated individuals (3.84% [2.81%, 5.21%]) tested swab-positive if they reported contact with a known COVID-19 case (Table 6).

 

[elbows]

An example of someone misjudging their personal risk and paying the ultimate price.

Fitness enthusiast, 42, who rejected vaccine, dies of Covid

John Eyers had been climbing mountains four weeks before his death in intensive care

www.theguardian.com

 

[elbows]

Latest PHE technical report on variances implies little difference in viral loads between unvaccinated and vaccinated people who catch the virus.

PCR cycle threshold (Ct) values from routinely undertaken tests in England show that Ct values (and by inference viral load) are similar between individuals who are unvaccinated and vaccinated.

In the NHS Test and Trace (NHSTT) case data, the mean and median lowest Ct values for all cases with Delta, where Ct data are available, since the 14 June 2021 are similar, with a median of 17.8 for unvaccinated and 18.0 for those with 2 vaccine doses (Figure 12). This means that whilst vaccination may reduce an individual’s overall risk of becoming infected, once they are infected there is limited difference in viral load (and Ct values) between those who are vaccinated and unvaccinated. Given they have similar Ct values, this suggests limited difference in infectiousness. To note, this analysis is undertaken on case data and are not age-stratified. Findings can be influenced by test-seeking behaviour, as well as true changes in the data, for example the age distribution of cases, which can also influence Ct values.

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1009243/Technical_Briefing_20.pdf

Since this is part of Delta analysis it was debatable whether I should put this info in the variants thread or the vaccine thread.

 

[gentlegreen]

There was a generally sensible guy on a forum this morning saying he was resisting vaccination because he was hypertensive ..

I can't find any indication that people taking ACE2 inhibitors would be adversely affected by a vaccine based on the COVID spike ... when I asked him whether he thought an actual covid infection might not be worse, he accused me of strawmanning. his argument was that if this became several shots a year and steadily tweaked spike mimicking eventually it would take its toll ...

I can't find any references beyond the early 2020 reports about ACE2 inhibitors ...

 

[ska invita]

There was a generally sensible guy on a forum this morning saying he was resisting vaccination because he was hypertensive ..

what would happen if he took it?
unless he has had a doctor saying Dont Take It it sounds like personalised imagined nonsense to me

the vaccine knocked me out both times - literally on the floor the second time - still would take it again though

 

[gentlegreen]

what would happen if he took it?
unless he has had a doctor saying Dont Take It it sounds like personalised imagined nonsense to me

the vaccine knocked me out both times - literally on the floor the second time - still would take it again though

he claims to have two doctors as parents ... he said he's holding out until he needs vaccinations to work ...

I had an interesting time with my first dose of the AZ and ditto - but I have no underlying comorbidities - except age - though my father apparently had angina at a young age according to my mother ...

 

[LDC]

There was a generally sensible guy on a forum this morning saying he was resisting vaccination because he was hypertensive ..

I can't find any indication that people taking ACE2 inhibitors would be adversely affected by a vaccine based on the COVID spike ... when I asked him whether he thought an actual covid infection might not be worse, he accused me of strawmanning. his argument was that if this became several shots a year and steadily tweaked spike mimicking eventually it would take its toll ...

I can't find any references beyond the early 2020 reports about ACE2 inhibitors ...

He's just talking shit. Hence why people with hypertension (high blood pressure) aren't being told to not have the vaccine.

 

[2hats]

First published, fully refereed Com-COV results, comparing heterologous and homologous prime-boost schedules, led by the UK Vaccine Task Force/NIHR, supporting the use of heterologous prime-boost ChAd/BNT schedules.

Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAd/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines.

DOI: 10.1016/S0140-6736(21)01694-9.

 

[2hats]

Novavax have submitted Emergency Use Authorisation filings, for their protein subunit vaccine NVX-CoV2373 (manufactured at the Serum Institute of India), with regulators in India, Indonesia and the Philippines. They will also make a submission for an Emergency Use Listing with the WHO this month (enables exports from SII to COVAX participants).

They are still planning to complete their submission to the MHRA in September, followed by their rolling submission for the EMA, then submissions to Australian, Canadian and NZ regulatory bodies. FDA submission is expected in the fourth quarter.

Separately, they report on data for a third NVX-CoV2373 booster dose at 6 months (post second dose) increasing neutralising antibodies over 4-fold for wild-type compared to the original regimen. Additionally, cross-reactive antibodies to delta/B.1.617.2 were more than 6-fold over the original regimen. Similarly, cross-reactive antibodies to other variants - alpha/B.1.1.7 and beta/B.1.351 - also increased several-fold. Notably, older recipients (60-84 years) benefited greatly.

 

[2hats]

A couple of studies involving the single dose J&J/Janssen viral vector vaccine, Ad26.COV2.S.

First the Sisonke study (470+k healthcare workers, South Africa) where it reportedly provided for around 93% protection from death and roughly 71% protection from hospitalisation due to delta/B.1.617.2, and 67% to beta/B.1.351. Protection against hospitalisation was sustained to ~65% after 4 months.

Notably the figure for delta is similar to the degree of protection a single dose of AZD1222 appears to confer. This might suggest it would not be unreasonable to offer single dose Ad26.COV2.S recipients the option of a (perhaps mRNA) booster.

Indeed a separate study (29 persons controlled for age, clinical co-morbidity, history of pre-vaccination infection, NYU), comparing convalescent, BNT162b2, mRNA-1273 and Ad26.COV2.S sera, suggests the latter elicits lower neutralising titres to beta/B.1.351, delta/B.1.617.2 and lambda/C.37, compared to mRNA vaccines. The authors suggest a second immunisation might be warranted (see also - high immune responses in earlier mixed ChAd/BNT162b2 studies, posts #1383 and #1429).

DOI: 10.1101/2021.07.19.452771.

 

[2hats]

The Israeli Health Minister has already acted on this, likely due to recent growth of delta, and has directed that adults with impaired immune systems, who had received two doses of the Pfizer vaccine, will be offered a booster shot immediately.

Israel offers third shot of Pfizer COVID-19 vaccine to adults at risk

Israel said on Sunday it will begin offering a third dose of Pfizer Inc's (PFE.N) vaccine to adults with weak immune systems but it was still weighing whether to make the booster available to the general public.

www.reuters.com

Some early data from Israel concerning a third dose booster. One should bear in mind that key confounders, such as behaviour, are not controlled for and some dispute the analysis and interpretation.

Here cases per 100k in the 60+ cohort (over 600k recipients to date) where red are unvaccinated, green fully vaccinated (2 dose), purple boosted (3 dose):

 

[2hats]

Codagenix's intranasal live attenuated COVID-19 vaccine, COVI-VAC. Here SARS-CoV-2 is attenuated by de-optimising 283 point mutation locations and deleting the furin cleavage site from the viral genome. In this animal model study the vaccine demonstrated significant immunogenic effect equivalent to convalescent immune response.
DOI: 10.1073/pnas.2102775118.

A phase 1 clinical trial is underway (48 participants) which should report on safety and immunogenicity within the next couple of months.

Intranasal COVID-19 vaccine demonstrates single-dose efficacy in preclinical studies, in parallel with achievement of Phase 1 clinical milestone

/PRNewswire/ -- Codagenix Inc., a clinical-stage synthetic biology company pioneering a novel platform for vaccines and oncolytic virus therapies, today...

www.prnewswire.com

 

[2hats]

Another mix and match study, this time from Charité Berlin. Here an assessment of reactogenicity and immunogenicity amongst (380) healthcare workers vaccinated with one of or a mix of BNT162b2 and ChAdOx1 nCov-19 (AZD1222), with assays investigating IgG antibody titres and T-cell reactivity.

The heterologous vaccination regimen presented here (10-12 week dosing interval) was well tolerated and provided for improved immunogenicity compared with homologous AZD1222 vaccination (10-12 week dosing interval) and homologous BNT162b2 vaccination (3 week dosing interval). The longer dosing interval appeared to provide for less adverse reactions than that seen in previous heterologous studies (DOI: 10.1016/S0140-6736(21)01115-6) where the dosing interval was 28 days.
DOI: 10.1016/S2213-2600(21)00357-X.

 

[2hats]

Briefly, several preprints of studies that might hint towards some degree of longitudinal waning of circulating humoral immunity, and thus efficacy to any infection (though there could be other confounders related to variant type, behaviours, etc). Note that efficacy to severe infection, hospitalisation and death holds up well. mRNA-1273 might wane slightly less gradually than BNT162b2 (though confounders: tends to have been deployed later and dosing is higher).

From Israel (Leumit Health Services) a retrospective cohort study of fully vaccinated adults (~34K, 49% female, mean age 47 years, previously infected excluded), RT-PCR tested at least 2 weeks post second dose. A higher rate of positive results were seen in those at 5+ months post second dose, particularly in the 60+ years cohort.

DOI: 10.1101/2021.08.03.21261496.

A group preprint (BioNTech, Pfizer and others) from their placebo-controlled, observer-blinded, multinational, pivotal efficacy study (46k+ participants, including 2k+ 12-15 years) of persons receiving the standard BNT162b2 regimen. Over 6 months a gradual declining trend in vaccine efficacy was observed, though the vaccine was still highly efficacious.

DOI: 10.1101/2021.07.28.21261159.

From Qatar (various) a matched test-negative, case-control study design assessing BNT162b2 and mRNA-1273 (standard dosing regimens). BNT162b2 efficacy against any delta/B.1.617.2 infection was 64.2% (95%CI:38.1-80.1%) from two weeks post first dose and before the second dose, dropping to 53.5% (95%CI:43.9-61.4%) from two weeks after the second dose (most infections serval months after full vaccination). mRNA-1273 equivalent numbers were 79.0% (95%CI:58.9-90.1%) and 84.8% (95%CI:75.9-90.8%), respectively. Importantly, effectiveness against any severe (or worse) covid due to delta, two weeks or more after second dose, was 89.7% (95%CI:61.0-98.1%) for BNT162b2 and 100.0% (95%CI:41.2-100.0%) for mRNA-1273 (100% to fatalities for both).
DOI: 10.1101/2021.08.11.21261885.

A retrospective, matched cohort study (Mayo Clinic, US) of (179+k) recipients of mRNA vaccines with unvaccinated persons, comparing efficacies in periods January-July and July alone. In the first period efficacy to infection was 86% (95%CI:81-90.6%) for mRNA-1273, and 76% (95%CI:69-81%) for BNT162b2. In comparison, in July this was measured as 76% (95%CI:58-87%) and 42% (95%CI:13-62%) respectively. For hospitalisation the numbers were 91.6% (95%CI:81-97%), 85% (95%CI:73-93%), dropping slightly to 81% (95%CI:33-96.3%), 75% (95%CI:24-93.9%).

DOI: 10.1101/2021.08.06.21261707.

 

[Monkeygrinder's Organ]

UK regulator approves ‘first of its kind’ Covid antibody treatment

Sajid Javid says green light for Ronapreve – which was used to treat Donald Trump – is ‘fantastic news’

www.theguardian.com

Sounds promising.

 

[2hats]

Even better, an antibody prophylaxis, administered by intramuscular injection, offering up to 12 months of protection, perhaps ideal for those with immune dysfunction who might seroconvert poorly after vaccination.

AZD7442, a combination of two long-acting antibodies (tixagevimab, AZD8895, and cilgavimab, AZD1061), developed from B cells from convalescent patients, was found to reduce the risk of developing symptomatic COVID-19 by 77% (95%CI:46-90) compared to placebo in this phase 3 trial. The trial accrued 25 cases of symptomatic COVID-19 at the primary analysis, with no cases of severe COVID-19 or COVID-19-related death in the AZD7442 arm, whilst there were three cases of severe COVID-19, which included two deaths, in the placebo arm.

AZD7442 PROVENT Phase III prophylaxis trial met primary endpoint in preventing COVID-19

www.astrazeneca.com

 

[elbows]

Given that when I read technical papers about variants, one of the things on their future concern radars is single antibody treatments potential to encourage escape mutants. So I'm pleased that both of the treatments mentioned above seem to involve two antibodies rather than one.

I dont know very much about the subject though, is a combination of two antibodies enough for me to be far more relaxed about this aspect, or would a combination of even more be more prudent?

 

[teuchter]

I expect there's some stuff in this article that not everyone will agree with.

Covid: What’s the best way to top up our immunity?

Now we have some protection, do we need to keep boosting or can nature take its course?

www.bbc.co.uk

 

[zahir]

Indeed. The BBC promoting disease and disability.