Possible vaccines/treatment(s) for Coronavirus

[elbows]

Since there was rather a lot of jargon in the labelling of that table on vaccine effectiveness, here is a screenshot from this weeks Indie sage video which hopefully makes it a bit clearer what the columns are attempting to show.

 

[2hats]

Moderna interim KidCOVE immunobridging study results: two 25μg doses (4 week interval) of mRNA-1273 in (6.7k) participants 6 months to under 6 years provoked similar immunogenic response to 2x100μg dose primary series in 18-25yo adults (neutralising GMR 1.3x and 1x in 6m-2y, 2-6y v. 18-25y). Well tolerated with low reactogenicity. No severe, or worse, cases of COVID-19 were observed in the participants (omicron dominant variant). Moderna will submit a request for authorisation for this series in these age groups with the FDA, EMA, etc.

Moderna Announces its COVID-19 Vaccine Phase 2/3 Study in Children 6 Months to Under 6 Years Has Successfully Met Its Primary Endpoint

Two 25 μg doses of mRNA-1273 in participants 6 months to under 6 years met primary endpoint with robust neutralizing antibody titers similar to adults mRNA-1273 was generally well tolerated in this age group Although not a primary endpoint, statistically significant vaccine efficacy was observed...

investors.modernatx.com

 

[2hats]

(MIT/Harvard/LJI/others): Potentially interesting findings regarding subtle (perhaps not quite so subtle) differences in vaccine mRNA performance. This study (73 vaccinees, who received the standard primary series) hints to there possibly being differences in class switching: "these findings suggest that subtle variation in immune responses induced by the BNT162b2 and mRNA-1273 vaccines may confer differential protection".

Although no difference in neutralizing activity has been reported across the BNT162b2 and mRNA-1273 vaccines, differences were observed across the two platforms in this study, both in terms of isotype or subclass and in terms of Fc functions [...] elevated concentrations of IgA were noted following mRNA-1273, accompanied by higher antibody dependent neutrophil phagocytosis and antibody dependent natural killer activity.

Differences in lipid nanoparticle packaging may be a factor (though of course dosage and dose interval timing may also play roles here). mRNA-1273 appears to promote greater Fc-functional antibody response, which may not be as compromised as neutralising antibodies are when a dominant VOC is usurped by a new VOC (since Fc can target the whole surface of the spike antigen). It also appears to promote higher IgA, which as previously highlighted (#1660), potentially contributes to shutting down infection, as well as increased natural killer T-cell and phagocyte levels, which are also both key components of the innate response.

Though this work suggests maybe only a small advantage for mRNA-1273 over BNT162b2, this is perhaps indicative that there is still scope for further tuning of mRNA vaccines.
DOI: 10.1126/scitranslmed.abm2311.

(Minor footnote: Elon Musk is listed as a co-author. Apparently because "SpaceX provided in-kind contributions in support of the research such as logistical coordination and access to facilities". He's also listed as Nth co-author on several referenced papers too).

 

[2hats]

(Emory) On the importance of looking beyond the spike for better protection to both past and future variants: an intramuscular modified vaccinia Ankara (MVA) virus* recombinant viral vector vaccine, MVA/SdFCS-N, expressing SARS-CoV-2 nucleocapsid as well as spike/RBD, elicited cross-reactive antibody and CD4/CD8 T cell responses, in both systemic and mucosal compartments, protecting against heterologous SARS-CoV-2 VOC more effectively than the original solely prefusion-stabilised, spike-expressing version of the vaccine, MVA/S, in animal models.

While spike continues to accumulate mutations, the nucleocapsid (N) protein remains significantly more conserved among betacoronaviruses. It is a major structural protein and induces potent T cell responses during natural infection. For these reasons, it is an attractive target for induction of broadly-active T cells. Additionally, T cells can also provide localized protection in the respiratory mucosa so enhancing mucosal immunity could also prevent new infections by destroying incoming virions before they can replicate, reduce disease severity via local antiviral effects in the lower respiratory tract, and stop transmission by damaging virions prior to exhalation.

These results showed that improved MVA-based SARS-CoV-2 vaccine delivered intramuscularly elicits strong spike-specific antibody response with diverse functions and T-cell responses to spike and N, which contribute to protective immunity against homologous and heterologous SARS-CoV-2 variants. They also highlight the potential of MVA/dFCS-N vaccine as the initial or booster vaccine against future emerging variants.

* an attenuated vaccine of a poxvirus.
DOI:10.1126/sciimmunol.abo0226.

 

[2hats]

(UniGe) A study of both unvaccinated and vaccinated individuals measuring infectious viral loads (by in vitro culturability assay) during the first five days of symptomatic infection (early-type, delta and omicron).

Finally, we have a clear indication that number of infectious particles produced in infected persons is significantly lower in vaccinees (vaccines not only reduce risk of severe disease but also risk of transmission). Also that genome copies (PCR Ct values) are not correlated with those numbers of infectious particles.

In more detail:

Unvaccinated individuals infected with pre-VOC SARS-CoV-2 had lower infectious VL compared to Delta-infected unvaccinated individuals. Full vaccination (defined as >2weeks after reception of 2nd dose during primary vaccination series) significantly reduced infectious VL for Delta breakthrough cases compared to unvaccinated individuals. For Omicron breakthrough cases, reduced infectious VL was only observed in boosted but not in fully vaccinated individuals compared to unvaccinated subjects. In addition, infectious VL was lower in fully vaccinated Omicron- compared to fully vaccinated Delta-infected individuals, suggesting that other mechanisms than increased infectious VL contribute to the high infectiousness of SARS-CoV-2 Omicron. Our findings indicate that vaccines may lower transmission risk and therefore have a public health benefit beyond the individual protection from severe disease.

DOI:10.1038/s41591-022-01816-0.

 

[2hats]

(UPenn) A longitudinal antibody study in mRNA vaccinees (N~60; a mix of BNT162b2 and mRNA-1273 recipients) for 10 months after the primary 2-dose series and then for 3 months after a third dose booster.

Neutralising antibody titres stabilised around 6 months after primary vaccination. Memory B cells were stable for over 9 months post-vaccination and over half of them cross-reacted to omicron. It was also observed that omicron-reactive memory B cells were reactivated by a 3rd dose of current generation vaccine. Low pre-boost antibody levels correlated with a greater fold increase after boosting (which likely suggests topping-off in those with high levels of circulating antibodies, implying limited additional advantage of repeated short-interval boosting). Antibody quality (through affinity maturation) continued to improve for at least 9 months after 2-dose vaccination (as noted previously by Crotty et al in animal models).

Antibody titres post-3rd dose were similar to those observed in SARS-CoV-2 recovered individuals after 2 doses of mRNA vaccine (hybrid immunity). Breakthrough infection after 2 doses of mRNA vaccine also appeared to produce similar increases in antibodies to a 3rd vaccine dose. These boosted antibody responses subsequently declined over time but still remained significantly above pre-boost levels at 3 months post-3rd dose.
DOI:10.1016/j.cell.2022.04.009.

 

[2hats]

Valneva's whole virus, inactivated, adjuvanted vaccine, VLA2001, receives MHRA regulatory approval in the UK (as a two-dose primary series of 0.5 mL each (25 Antigen Units) given at least 28 days apart in 18-50 year olds).

Valneva COVID-19 vaccine approved by MHRA

An approval has been granted after the Valneva COVID-19 vaccine was found to meet the required safety, quality and effectiveness standards.

www.gov.uk

Valneva Covid vaccine approved for use in UK

The Valneva jab is manufactured using technology similar to how flu shots are made.

www.bbc.co.uk

 

[2hats]

Just to note that, during a press briefing yesterday, the Pfizer CEO indicated their intent to develop a multivalent vaccine targeting both omicron and previous VOCs by this autumn.

Pfizer's Bourla: COVID vaccines for new variants possible for Fall

Pfizer Chief Executive Albert Bourla said on Wednesday that the company could possibly develop a new vaccine that protects against the Omicron variant as well as older forms of COVID-19 by autumn.

www.reuters.com

 

[teuchter]

(UniGe) A study of both unvaccinated and vaccinated individuals measuring infectious viral loads (by in vitro culturability assay) during the first five days of symptomatic infection (early-type, delta and omicron).

Finally, we have a clear indication that number of infectious particles produced in infected persons is significantly lower in vaccinees (vaccines not only reduce risk of severe disease but also risk of transmission). Also that genome copies (PCR Ct values) are not correlated with those numbers of infectious particles.

In more detail:

DOI:10.1038/s41591-022-01816-0.

Am I interpreting that graph correctly if I conclude that vaccination reduces transmission significantly but not dramatically? Or does that log scale on the Y axis mean that the difference is actually quite dramatic?

 

[elbows]

Am I interpreting that graph correctly if I conclude that vaccination reduces transmission significantly but not dramatically? Or does that log scale on the Y axis mean that the difference is actually quite dramatic?

You've probably answered your own question but here are a couple of quotes from the full paper that might help. My bold:

Delta:

The decrease in infectious VL was even more pronounced in vaccinated patients (4.78 fold, 0.68 log10, p<0.0001)

Omicron:

Omicron breakthrough infections in fully vaccinated patients resulted in similar genome copies compared to Delta, but significantly lower infectious VLs (14 fold, 1.146 log10, p<0.0001)

a significantly lower infectious VL, but not RNA VL, was observed for boosted individuals (5.3 fold, 0.7280 log10, p=0.0004)

I probably didnt quote enough of those sections to fully understand what each one relates to, but hopefully the 'how many fold reduction' info is enough to get the broad idea.

There are plenty of caveats and tedious details in the study, so some caution is still required when tempted to directly equate viral loads with transmission. Other factors also influence transmission, and they saw evidence that Omicrons transmission advantage is not coming from higer viral loads. All the same, they still reached conclusions they considered to be relevant to public health.

 

[teuchter]

It's something that would be good to understand more fully. Certainly it could change my opinion on things like whether vaccination should be mandatory for healthcare workers, and so on.

 

[elbows]

Indeed. My attitude is still that health workers have a profession duty to get such vaccines. But that the limitations to what vaccines can achieve in terms of infection prevention, combined with the effects on staffing levels that forcing through a strict rule about this within the rapid timeframe first envisaged was going to cause, made the original policy counterproductive. So it made sense to back off, but I still want there to be ongoing campaigns to improve uptake in that sector, and I hope a time comes when even more effective vaccines are available which make the case simpler. In the meantime, studies like the above are important.

 

[2hats]

(Technion & others) A detailed mathematical model, calibrated to Israeli data, to understand the impact of their vaccination and booster campaign (all BNT162b2) from the individual to the population level. This throws further (epidemiological) light on the post-vaccination transmission question.

In this work, we present an in-depth analysis of the population-level impact of the different elements of the booster campaign on epidemic outcomes. We developed a transmission model that incorporates the waning of vaccine-induced immunity and its buildup after boosting. The model accounts for vaccine and booster administration per age group at a daily resolution and is calibrated using real-world data from Israel in the period from July 1st to November 25th 2021. The model was fitted to time series of polymerase chain reaction (PCR)-confirmed cases in 10-year age groups and different vaccination states. We used the calibrated model to study the impact of the booster campaign by quantifying the outcomes of counter-factual scenarios such as the application of alternative boosting campaigns in which boosting is restricted to specific age groups or in which the timing of the booster campaign is modified.

The results point to the vast benefits of vaccinating younger age groups that are not at a high risk of developing severe disease but play an important role in transmission.

This study also indicates that the timing of booster campaigns is critical during exponential phases of infection growth.
DOI: 10.1126/scitranslmed.abn9836.

 

[2hats]

(AHRI/UKwaZulu-Natal) In a small South African study (N=18) of beta/B.1.351 convalescent vaccinees a ~69x increase in omicron neutralisation was observed (live virus neutralisation assay). This compared to results from an earlier study*, by the same group, where they saw a (typically) ~20x drop in vaccinees' omicron neutralisation where prior infection was due to delta.

Obviously hybrid immunity with adequate affinity maturation will be playing some role in the overall magnitude of immunogenic responses (vaccination was 6-8 months after the original infection).

However, this may go some way to explaining why South Africa does not appear to have suffered so badly from the recent omicron wave. This could also perhaps flag up that SA hospitalisation/death figures might not be such a good guide in other regions for BA.4/BA.5 pathogenesis.

Finally, this work underlines how antigenic exposure history leads to heterogeneity in outcomes, and it might indicate that a second-generation vaccine expressing beta-spike may have utility in tackling omicron lineages.
DOI: pending; draft preprint.
* DOI: 10.1038/s41586-021-04387-1.

 

[2hats]

(AHRI/UKwaZulu-Natal) In a small South African study (N=18) of beta/B.1.351 convalescent vaccinees a ~69x increase in omicron neutralisation was observed (live virus neutralisation assay). This compared to results from an earlier study*, by the same group, where they saw a (typically) ~20x drop in vaccinees' omicron neutralisation where prior infection was due to delta.
[...]
DOI: pending

Preprint - DOI:10.1101/2022.04.15.22273711.

 

[2hats]

(Rockefeller) A small (n=18) six month study of non-convalescent recipients (23-56 years) of single-dose J&J/Janssen Ad.26.COV.2.

The single dose Ad.26.COV.2 (Janssen) vaccine elicits lower levels of neutralizing antibodies and shows more limited efficacy in protection against infection than either of the available mRNA vaccines. [...] The data help explain why boosting Ad.26.COV.2 vaccine recipients with mRNA vaccines is effective, and why the Janssen vaccine appears to have been less protective against severe disease during the Omicron surge than the mRNA vaccine.

DOI:10.1101/2022.03.31.486548

 

[2hats]

(LJI) From Crotty&Sette a small (n=27) study of recipients of a primary two-dose series of Novavax, NVX-CoV2373, which suggests potentially promising longitudinal CD4/CD8 T cell immunoresponses (ie sustained protection to serious disease due to past/present/future VOC). NVX-CoV2373 induced SARS-CoV-2-specific CD4+ and CD8+ T cells, and good antibody responses irrespective of pre-existing cross-reactivity to other endemic coronaviridae.

Together, these data support the idea that the NVX-CoV2373 vaccine induces a complex immune response consisting of robust and polyfunctional CD4+ T cells producing Th1-type cytokines as well as a rapid cTFH cell response capable of supporting a substantial neutralizing antibody response, as well as a modest CD8+ T cell response in a subset of donors. Overall, these data show that NVX-CoV2373 induces a relatively broad humoral and cellular immune response against SARS-CoV-2 in humans, and might demonstrate distinctive long-term behavior relative to mRNA vaccines.

DOI:10.1101/2022.04.08.487674.

Separately in the UK, the chair of the JCVI COVID-19 vaccination group has indicated that they will consider NVX-CoV2373 for recommendation in "due course". Probably this would mean an approval no earlier than June.

Whatever happened to the Novavax Covid vaccine?

The jab, seen as an alternative for people who are vaccine-hesitant, is widely available in the EU but still not cleared for use in the UK.

www.bbc.co.uk

 

[2hats]

(AHRI/UKwaZulu-Natal) In a small South African study (N=18) of beta/B.1.351 convalescent vaccinees a ~69x increase in omicron neutralisation was observed (live virus neutralisation assay).
[...]
Finally, this work underlines how antigenic exposure history leads to heterogeneity in outcomes, and it might indicate that a second-generation vaccine expressing beta-spike may have utility in tackling omicron lineages.
DOI: 10.1101/2022.04.15.22273711.

Interesting new results from Moderna which would appear to corroborate the above work by Sigal (AHRI) on beta/omicron antigenic history.

New clinical data for Moderna's first bivalent booster candidate, 50µg of mRNA-1273.211 (Wuhan early type plus 9 beta spike mutations), demonstrated superior neutralising titres (compared to original mRNA-1273) against all tested VOC (beta, delta and omicron). That superiority was maintained for at least six months after boosting for both the beta and omicron variants. Safety and tolerability were similar to already approved mRNA-1273.

A second bivalent booster candidate, featuring WT+omicron, mRNA-1273.214 (Wuhan early type plus 32 omicron spike mutations), is currently being evaluated in a phase 2/3 study* and may prove to be their preferred Northern Hemisphere autumn 2022 booster candidate.

Moderna Announces Clinical Update on Bivalent COVID-19 Booster Platform

Moderna's first bivalent booster vaccine candidate, mRNA-1273.211, demonstrated superior neutralizing titers compared to mRNA-1273 against all variants of concern, including Omicron; superiority was maintained for six months after booster for the Beta and Omicron variants Tolerability and safety...

investors.modernatx.com

Moderna says dual variant booster with Beta more effective vs Omicron than current shot

Moderna Inc on Tuesday said a COVID-19 booster designed to target the Beta variant as well as the original coronavirus generated a better immune response against a number of virus variants including Omicron.

www.reuters.com

e2a: That clinical trial (*) investigating bivalent mRNA-1273.214 and mRNA-1273.529 (original omicron spike only) boosters, compared to mRNA-1273, is now underway at KCH (still recruiting participants).

Pioneering multi-variant COVID booster trial opens at King's - King's College Hospital NHS Foundation Trust

www.kch.nhs.uk

 

[two sheds]

Ooh ooh ooh I'm on this one already

Asthma drug can block crucial SARS-CoV-2 protein

Montelukast, an FDA-approved drug, can bind strongly to and block the activity of a SARS-CoV-2 protein called Nsp1

www.eurekalert.org

With thanks to whoever on here recommended it - it is good for clearing airways.

 

[souljacker]

I'm a bit confused about the vaccines they are giving to kids. The NHS site says that 5-15 year olds will get the Pfizer. There is a link on their page that takes you to the information leaflet which clearly states that the Pfizer is not suitable for under 12s.

My 11yo had the Pfizer but the governments own documentation says she shouldn't. Can anyone explain? elbows 2hats

 

[Fruitloop]

Ooh ooh ooh I'm on this one already

Asthma drug can block crucial SARS-CoV-2 protein

Montelukast, an FDA-approved drug, can bind strongly to and block the activity of a SARS-CoV-2 protein called Nsp1

www.eurekalert.org

With thanks to whoever on here recommended it - it is good for clearing airways.

So is my son, and we had been wondering why Covid just seems not to be able to infect him. Most interesting.

 

[Fruitloop]

I'm a bit confused about the vaccines they are giving to kids. The NHS site says that 5-15 year olds will get the Pfizer. There is a link on their page that takes you to the information leaflet which clearly states that the Pfizer is not suitable for under 12s.

My 11yo had the Pfizer but the governments own documentation says she shouldn't. Can anyone explain? elbows 2hats

Our 5 and 10 year old had the pediatric Pfizer, which is 1/3rd of the dose of the adult one. I think that's what they're supposed to get.

 

[souljacker]

Our 5 and 10 year old had the pediatric Pfizer, which is 1/3rd of the dose of the adult one. I think that's what they're supposed to get.

I see. Still a bit odd that they state it's not suitable. It should say that the full dose isn't suitable surely.

 

[platinumsage]

5-11s Patient Information Leaflet: https://www.medicines.org.uk/emc/files/pil.13134.pdf
12+ Patient Information Leaflet: https://www.medicines.org.uk/emc/files/pil.12740.pdf

The link to the PIL on this NHS page under the title "Which COVID-19 vaccine will children get?" points to a HTML version of the 12+ leaflet on GOV.UK, whereas it should probably point to a copy of the 5-11 leaflet.

 

[elbows]

And the reason they havent updated the particular document which says its only for over 12s, and makes no mention at all of the dose size in that context, unlike both of the above leaflets, is that the document in question was for the initial emergency authorisation version, covered by regulation 174. They really shouldnt be linking to that one at all these days, since the vaccines are now authorised via a different mechanism, and the original patient info leaflet is therefore obsolete.

To quote from the MHRA website:

Initially, the COVID-19 Vaccine Pfizer/BioNTech was supplied in the UK on a temporary basis under Regulation 174 of the Human Medicine Regulations 2012, but this was always intended to be a temporary arrangement. Supply of the vaccine is now in accordance with the conditional Marketing Authorisation (CMA) with all remaining Regulation 174 stocks expiring at the end of February 2022.

From Regulatory approval of Pfizer/BioNTech vaccine for COVID-19

By the way, Spikevax (Moderna) is also licensed for children here too these days, and there is a single leaflet to cover the full range of ages for that one:

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1069393/Spikevax_PIL_140422.pdf

And here is the mid April story about Moderna being approved for kids:

MHRA approves the Moderna COVID-19 vaccine ‘Spikevax’ for use in 6 to 11-year olds

Use of the Moderna COVID-19 vaccine or ‘Spikevax’ has been approved for 6 to 11s after meeting the required safety, quality and effectiveness standards

www.gov.uk

 

[elbows]

The link to the PIL on this NHS page under the title "Which COVID-19 vaccine will children get?" points to a HTML version of the 12+ leaflet on GOV.UK, whereas it should probably point to a copy of the 5-11 leaflet.

Do you know who we could contact to get this fixed? Because as I've just said in my previous post, its actually a worse situation than them linking to the current 12+ version, they are actually linking to the old regulation 174 one which doesnt have the language about dose sizes & age.

Screenshot of where the inappropriate link is just to be clear:



From Coronavirus (COVID-19) vaccine for children aged 5 to 15

With the link currently going to Information for UK recipients on Pfizer/BioNTech COVID-19 vaccine (Regulation 174)

Im not surprised they got confused given that the 174 leaflet says it was updated on April 27th, but whatever that update was it didnt help with this detail about children, and they should probably put something at the top of that 174 leaflet pointing out that its obsolete.

 

[platinumsage]

Do you know who we could contact to get this fixed?

Presumably here

 

[elbows]

Thanks, I sent them a message.

 

[StoneRoad]

Just been entered into the phase 2/3 clinical trials for Moderna's vaccine "omicron" variant.

 

[elbows]

They fixed the issue with that NHS webpage we were talking about. They removed the obsolete link from that section and changed some wording, and there are plenty of links to the appropriate documents later in the article.

The section in question now reads:

Which COVID-19 vaccine will children get?​

Children will be given the Pfizer/BioNTech vaccine for both doses.

Children aged 5 to 11 will be given smaller doses than older children and adults.