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: https://twitter.com/GuptaR_lab/status/1355283902202523653?s=20

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: https://twitter.com/dgurdasani1/status/1356535486634950662?s=20

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.

https://www.biorxiv.org/content/10.1101/2021.01.27.427998v1.full.pdf

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. https://investors.modernatx.com/news-releases/news-release-details/moderna-covid-19-vaccine-retains-neutralizing-activity-against

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).