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Given the concerns raised about the delayed vaccine dosing regimen in the UK, I'm doing another post on this. This probably won't have all the answers, but will hopefully reflect current perspectives on this among scientists, and lay out the potential benefits & risks. 1/N
Background: The UK govt recently announced that the UK would be aiming to vaccinate as many people with 1st dose of vaccines (both Oxford/Astra & Pfizer/BioNTech), and 2nd doses would be delayed for up to 12 wks to maximise the number of people who receive the 1st dose. 2/N
For clarity- the change is *not* from giving 2 doses to giving 1 dose, but rather from giving the 2nd dose later than originally planned, & outwith dosing protocol, at least for Pfizer/BioNTech, where the trial & efficacy data were based on the 2nd dose being given at 21 days.3/N
This led to Pfizer issuing a warning that efficacy could not be guaranteed if there was deviation from protocol. This has led to a lot of controversy, and concern, with different views on whether this is justifiable or not. Let's look at some of the reasons & thinking behind this
First, this is a strategy that would not have been considered were we not in a crisis situation in the UK. We are currently seeing >50,000 daily confirmed cases from COVID-19 (actual no.s likely much higher) & our hospitals are already at capacity. We are seeing >500 deaths/day
And it's unlikely the situation will get better soon. Each day the situation continues or gets worse costs hundreds of lives. With the new variant, it's very likely that even with strict restrictions cases will not come down as fast as we need them to, costing thousands of lives.
So, what is the govt strategy based on?
The thinking appears to be based on the fact that vaccine resources are limited. The thinking is that given a fixed vaccine supply, it is better to vaccinate double the population partially, rather than half this number fully.
The thinking appears to be based on the fact that vaccine resources are limited. The thinking is that given a fixed vaccine supply, it is better to vaccinate double the population partially, rather than half this number fully.
How do we evaluate whether this is justified? It depends on:
a) likely benefit
b) vaccine efficacy after 1 dose over time
c) impact of deviations from protocol - for long-term immunity and individual risk
e) impact of delayed vaccination on theoretical risk of viral adaptation
a) likely benefit
b) vaccine efficacy after 1 dose over time
c) impact of deviations from protocol - for long-term immunity and individual risk
e) impact of delayed vaccination on theoretical risk of viral adaptation
The likely benefits are of course achieving a reasonably high level of protection from COVID-19 in double the people (assuming immunity doesn't wane substantially after the 1st dose- will come to this) vs completing both doses quickly but at the cost of vaccinating fewer people.
So what do we know about vaccine efficacy after the 1st dose? This is more pertinent for Pfizer, as the original Astra/Oxford trial included longer gaps in vaccination (though not for >55 yrs of age). Pfizer efficacy in terms of reducing symptomatic COVID-19 ~ 86% after 1st dose
This is the efficacy between 10d after vaccination to 21d. The big question is whether this level holds or whether it declines after this period, as we don't have data for this, given all participants in the trial were given a booster dose at this point in time
Given, this is not my area of expertise, I'm presenting perspectives from vaccinology/immunology experts here. There is no doubt that a booster response improves immunity both quantitatively & qualitatively, as outlined by @petermbenglish here:
http://peterenglish.blogspot.com/2021/01/delaying-second-dose-of-covid-19.html
http://peterenglish.blogspot.com/2021/01/delaying-second-dose-of-covid-19.html
But most immunologists also believe that the immunity from the 1st dose won't be short lived, and is unlikely to wane significantly over 12 wks. And that efficacy in terms of preventing symptomatic disease will be high, although efficacy in preventing transmission may be lower.
The short gap in boosting for Pfizer/BioNtech was likely related to the need for quickly concluding trials & roll-out. Most vaccines have longer gaps before boosting. Many immunologists believe that a boost after a longer period may be even stronger. https://threadreaderapp.com/thread/1344949258483621888.html
Given this, many immunology experts have supported the idea of vaccinating more people, even if the response is partial (given it's still likely to be quite high), rather than vaccinating half the number fully as per protocol. Here is another expert view: https://twitter.com/VirusesImmunity/status/1345086669607890945?s=20
But of course there are uncertainties. We don't fully know the effectiveness of vaccines in reducing transmission- it's possible this effect may be lower with a single dose. However, unless it's substantially lower, vaccinating double the no.s may counteract this.
There are also concerns about the impact of less robust immune responses on viral escape and adaptation. I'm not an expert in this area, but here is one expert view on this. This is a complex area and others feel this risk is lower, but we can't be sure. https://twitter.com/florian_krammer/status/1345791187236646912?s=20
There is uncertainty around what this means for viral adaptation & different views on this. The fact is that there is a risk of vaccine escape adaptation even with full vaccination, given selection pressures. The best way to mitigate these risks is really suppress transmission.
It's important to emphasise that we are at this point needing to make these very difficult decisions because we are in a crisis. Were we in the position New Zealand, or Taiwan were in, these questions wouldn't arise, and we would be doing vaccination as per protocol.
Unfortunately, we don't have this luxury. We need to strike a balance between what is known & what may be beneficial, but with areas of uncertainty. From a purely epidemiological perspective, it makes sense to vaccine 2x the no. of people even with slightly lower efficacy.
Handling uncertainty is a key part of pandemic response, and while we can't eliminate this entirely, we can try and mitigate this, and do our best to respond in the midst of this. I don't know what the right answer is, but I'm going to make a few recommendations here.
1. I think we need *much* better communication by govt as to why these decisions are being made, with clear transparency around the benefits & risks of such an approach & scientific thinking behind it. That this is being considered because of the current crisis must be made clear
2, Contingencies need to be a part of this strategy. If we are deviating from known protocols, evaluation of these deviations need to be built in, through pragmatic trials of those being vaccinated, so we can minimise uncertainty & respond quickly to accruing data.
This is important not just within the UK, but also globally, as many countries in a similar crisis situation consider such options. This is also very important to building public trust and directly addressing vaccine hesitancy & very legitimate concerns around these approaches.
3. Many of these decisions are based on shortages of vaccine supply. We need much more focus on this & transparency around this. The govt needs to work with manufacturing & supply chain experts to get past the current bottlenecks in vaccine supply. https://twitter.com/Greg_Callus/status/1345074431492808705?s=20
4. The govt needs to work closely with GPs, HCWs & pharmacies & patients, involving them in this decision making & to understand practical challenges on the ground. And also to ensure long-term planning involves frontline considerations & isn't chaotic. A bit more on this.
Inflexibility in current govt policy on roll-out which is quite restrictive in what GP surgeries can do do is very likely to make roll-out much slower, as this hasn't considered realities on the ground. Much of vaccine roll-out has been centralised with larger GP surgeries.
While this is understandable with Pfizer, which needs specific cold chain considerations, this doesn't make sense for Astra, and asking patients from multiple surgeries to be vaccinated at one surgery will not only slow roll-out, but reduce access & put patients & staff at risk.
Previous reimbursement to GP surgeries for vaccine roll-out was based on two-dose completion, which means many surgeries will experience a substantial shortfall for vaccine roll-out. This needs to be urgently changed to payment/dose to ensure resources are available for this.
The roll-out of Astra/Oxford & BioNTech/Pfizer needs to be delinked, given the different logistics. Currently many GP surgeries can only offer either both or none. Making policy more flexible will allow much faster roll-out
Given that we are changing protocols to maximise efficiency of roll-out, it makes sense to do this at all levels, and in partnership with those who are most knowledgeable about how this can be maximised & continued supplies maintained & used without wastage.
Vaccination is not just about scientific development- it's about paying detailed attention to logistics of supply, and roll-out on the ground. Not paying attention to this can significantly impact vaccination campaigns, as outlined in this piece: https://www.nytimes.com/2020/12/31/opinion/coronavirus-vaccines-expiring.html
5. Govt communication & planning around vaccine protocols & roll-out has been chaotic & poorly planned. This is likely to undermine trust, and create vaccine hesitancy. The govt must engage with communities to address this. A piece on this @thewrittenro : https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32642-8/fulltext
6. We also need active surveillance of virus during immunisation to understand virus adaptation. We need to bring down cases as far as possible during vaccine roll-out , to minimise these risks. This means immediate & strict national lockdown, with move to remote schooling.
7. We need particular consideration of what this will mean for those who are immunocompromised, and data around what a longer period of partial immunity means particularly in terms of protection in these already vulnerable groups.
Here is a recent report from @IndependentSage that outlines important recommendations around this as well.
https://www.independentsage.org/wp-content/uploads/2021/01/IndependentSAGE-comment-on-proposal-to-reschedule-second-dose.pdf
https://www.independentsage.org/wp-content/uploads/2021/01/IndependentSAGE-comment-on-proposal-to-reschedule-second-dose.pdf
While the views expressed here are mine, I want to thank @adamhamdy @BillHanage @DebbyBogaert, and others for their valuable thoughts that has really helped refine my thinking on this over time.
