A thread discussing recent evidence on longer gap dosing with Astra/Oxford, Pfizer, current gaps in our understanding of impacts, as well as the possible impact of new variants on vaccine effectiveness. Thread.
First, I want to say that this although thread may highlight uncertainties & gaps in current evidence I fully advocate taking the vaccine, as this will offer protection. But I also firmly believe that discussing uncertainties in evidence & transparency around data is important.
Astra/Oxford published data yesterday, suggesting that longer gaps between the 1st and 2nd dose may be associated with higher efficacy. Vaccine efficacy between 3-12 wks after a single dose was reported to be 76% with protection being similar throughout this period.
The efficacy post-2nd dose is also reported to be higher with the longer duration gap - >6wks vs <6wks efficacy reported as 82% vs 55%. Immunogenecity data on antibody binding responses also supported a 2x increase in response after the longer gap vs the shorter gap in 18-55 yr s
Let's look at some of the caveats around this now. The original published trial did not report of vaccine efficacy over 55s due to sparse data. There are still no efficacy data presented for the longer or shorter gap for the elderly, as far as I can see.
The MHRA approval for the elderly was based on immunogenicity data which showed high levels of response among the elderly. But the current data does not seem to include immunogenicity on those >55 yrs after 8 wks after the 1st dose, either.
So, we don't seem to have data on longer gaps in this group. Why is this important?
While it's likely that the efficacy will extend to older age groups, immune responses in older people can be less potent and less durable. Here's a relevant example from recent data on Pfizer.
Recent work by the @GuptaR_lab lab has rather concerningly shown that while sera from people <80yrs effectively neutralised virus among all post 1st dose, neutralisation was only achieved in <1/2 after the 1st dose among >80s. All achieved good neutralisation after the 2nd dose.
The second dose in the study was given at 3 weeks. These data suggest that for Pfizer longer gaps may potentially leave the most vulnerable to severe disease less protected for longer. Data and discussion can be found here:

Given these are the groups that are being vaccinated now, and most at risk of death from COVID-19, this needs urgent consideration. It may be that policies are different for the elderly, where there is more uncertainty around this, and where less protection can be very risky.
The new variants now circulating in the UK - including the B117 (UK variant) with the E484K mutation, and the B1351 (South Africa variant) both have shown high levels of escape from antibodies from people infected prior to the emergence of these variants, in the laboratory.
Worryingly, recent trials from vaccines that had participants in South Africa and other countries showed lower effectiveness in the SA arms of the trial, suggesting potentially lower effectiveness against these variants:
Pfizer examined neutralisation of an engineered virus virus carrying three mutations that are found on the SA variant, including E484K - by post-vaccination sera. They found slightly lower neutralisation against this virus compared to the regular virus.

biorxiv.org/content/10.110…
They concluded that this was unlikely to result in reduced vaccine efficacy.
Caveats:
1. The characteristics of the people who contributed the sera are unclear- particularly age groups. No sub-analysis presented by age.
2. All mutations in the variant were not studied
Moderna also claimed that vaccine efficacy was unlikely to be impacted despite an 8 fold reduction in neutralisation B.1.351 among 8 people between 18-55 yrs. There was no data reported on the elderly.

investors.modernatx.com/news-releases/…
Important to note that antibody assays may not correlate directly with vaccine efficacy for many reasons. But there are legitimate reasons for concern. Importantly, even vaccines trialled against the SA variant retained a high level of effectiveness, even though this was reduced
So what does this mean?
While it is very encouraging that data for Astra/Oxford suggest that longer gaps may improve vaccine efficacy, we still need data for the elderly, where this vaccine is now being extensively used.
While the efficacy may extend similarly to other age groups, we cannot assume this without more data.

For Pfizer, the laboratory data are concerning, and we need re-assurance around what deviations from protocol mean for vaccine efficacy among the elderly.
It's also worth remembering the efficacy pyramid-
Severe disease
Symptomatic disease
Transmissibility
Infection

Reduced efficacy may have less impact at the top (we may see similar efficacy with severe disease), but lower tiers (e.g. transmissibility) may be impacted.
Vaccines are not all the same, and it's possible that a dosing regimen that works for one may not be best for the other. Given the people we are vaccinating now, we need to really be collecting data in real-time to ensure that the most elderly are protected to a high level
We need to ensure that our vaccine policies are not putting those most vulnerable at risk. We also need to better understand how longer gaps in dosing & overall vaccine effectiveness may interact with new variants circulating within the UK.
While these variants are not dominant or potentially at high frequency now, we need to consider the impact of vaccination selection pressure on the spread of these variants, and potentially emergence of new variants capable of escape.
We also need a focus on reporting on the elderly in all trial efficacy and laboratory neutralisation data. It's clear these responses can be different, and results from younger age groups may not always directly translate to those most at risk.
Sorry, just wanted to highlight that in the earlier tweet I meant that potentially policy could be different among the elderly, and for different vaccines (specifically in this group).

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More from @dgurdasani1

3 Feb
I believe that claims that scientists make need to stand up to scrutiny, especially in the midst of a pandemic, where scientists have an ethical duty to inform accurately. Calling out false claims is not the same as trolling & harassing someone because they disagree with you.
During the past many weeks, I've engaged with scientists when I felt they made claims that were not in line with current evidence. I usually do this by first contacting the scientist directly & discussing why evidence cited may be flawed, &/or providing direct evidence against.
In my experience, this approach has not worked. Inevitably, it has led to people claiming personal attacks, which means they don't have to engage on the evidence. So evidence-based discussions don't happen, and discussions get shut down.
Read 18 tweets
3 Feb
It's being widely reported that 1 dose of the Astra/Oxford vaccine reduces transmission by 67%. My understanding is that this is not what the paper shows, or what the authors have claimed. I'm happy to be corrected if I've got this wrong. Short thread.

theguardian.com/society/2021/f…
The Astra/Oxford trial asked people enrolled to self-swab every week and send in swabs for testing. They also asked them to reach out and get tested if they had symptoms. So all tests carried out are a combination of:
1. asymptomatic testing
2. testing sought due to symptoms
When we break down efficacy by these categories, the trial reports an efficacy of 76% in preventing *disease* (or symptomatic infection) and ~16% efficacy (with a lot of uncertainty due to small numbers) for asymptomatic infection. The combined efficacy for PCR +ves is 67% Image
Read 8 tweets
2 Feb
Concerning data from PHE today suggesting that sequencing shows that there are 11 cases of the UK variant (B117) identified that also have the E484K mutation (the one found in the so-called South Africa and Manaus variants). This is important and concerning for many reasons. 🧵
To recap the B117 ('UK variant') is defined by a number of mutations, including the 501Y mutation thought to be associated with increased transmissibility, which is also shared by the so-called South Africa (B1351) and Manaus (P1) variants.
In addition, both B1351 (SA) & P1 (Manaus) variants also have the E484K mutation. This mutation has been associated with a high level of escape of neutralising antibodies directed at previous variants in the laboratory, raising concerns about vaccine efficacy.
Read 24 tweets
1 Feb
I've recently come across a disinformation around evidence relating to school closures and community transmission that's been platformed prominently. This arises from flawed understanding of the data that underlies this evidence, and the methodologies used in these studies.
Let's look at the paper being cited here. This study published in Nature Human Behaviour examined >50,000 interventions (at fine scale) across >200 countries. The number of countries examined allowed examination of these in depth.

nature.com/articles/s4156…
As the authors state, the key strength of the study is that examination across so many different contexts allowed a disentanglement of interventions. The authors used four approaches, including a case-control analysis to specifically deal with this issue.
Read 13 tweets
30 Jan
These studies are heavily flawed, and are don't include any of the larger, and less biased studies that contradict this view. There are ample studies with larger sample sizes, including from the ONS, that show primary school children play an important role in transmission.
And completely misses the direct impact on children from Long COVID. 12% of primary school children have symptoms lasting > 5 wks. We need to look at this based on the breadth of evidence, and the design of these studies- which unfortunately even many scientists haven't done.
The ECDC paper is extremely flawed, and quotes largely studies from symptom based testing designs, which we know hugely underestimate the impact of children on transmission. And from periods when either community tranmission was low, or school attendance was low in many regions.
Read 8 tweets
26 Jan
On @BBCOS today discussing the tragedy of exceeding 100,000 COVID-19 deaths in the UK, and what led to this.

19:03 for a bit and then 19:23 onwards:
bbc.co.uk/iplayer/live/b…

Also, a few thoughts in a thread below:
The PM said during the briefing today, that the govt did the best they could. He was 'deeply sorry' for every single death.

If every single death is a tragedy, then why didn't we treat every death as preventable?

Why did we repeatedly talk about 'tolerable deaths'?
How on earth can he say he did his best, when UK policy was almost never evidence based - and the govt invited proponents of the ideology of naturally acquired herd immunity to brief him on policy- at a point in time we urgently needed to act to prevent thousands of deaths?
Read 16 tweets

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