Vaccines’ Progress: Paul Major Interview

Paul Major, fund manager, BB Healthcare Trust shares his thoughts on the rollout of vaccines in the UK and what new data is telling us about the future of COVID-19.

Please explain the efficacy of the UK’s dosing approach: prioritising the maximisation of first doses administered and thus delaying the second dose of the Pfizer and AstraZeneca vaccines in use beyond the recommended 21 days for Pfizer and at the upper end of the 4-12 weeks allowed for the Astra/Oxford vaccine under its UK approval. As you noted in your monthly review the controversy around this was heightened in January by data from Israel suggesting real-world efficacy from a single dose of the Pfizer vaccine may be lower than expected and also some stories in the German media suggesting the EU Medicines Agency might have an issue with the apparent effectiveness of the Astra/Oxford vaccine in the elderly (i.e. the people the UK is giving it to at this time). Attacking a virus in a weak manner, so it is able to mutate its way out of trouble is the route to more strains and potentially the emergence of one that could evade current vaccinations entirely. This is a point that has been made by Pfizer and Dr Fauci. Which vaccine would you choose?

It is very easy to fall into the trap of criticising the UK Government’s pandemic response, given our death toll and the various policy U-turns etc. It is undeniable that the government took a calculated risk with this dosing strategy, and that the evidence supporting it at the time was not that strong. However, there is the simple realpolitik that there are limited vaccine supplies and one must decide how to allocate them in the best way possible.

We had guaranteed access to the AZ/Oxford vaccine in significant quantities, so this is what we used. The AZ/Oxford vaccine was approved based on an interim (i.e. incomplete) clinical dataset and it is fair to say that data around some groups (e.g. the elderly) is rather scant and that the overall data quality, in terms of error bars and confidence intervals etc., is not as robust as that for the other two UK-approved vaccines.

Does efficacy look as good as the Pfizer or Moderna products?

No, and certainly not versus the newer variants. However, it is still pretty darn good and the original trials did support dose intervals of up to 12 weeks. Personally, I would prefer to have the other vaccines and prefer they were given as intended dosing-wise, but I would also like world peace, plastic-free oceans and a winning lottery ticket. We have to live in the real world.

Although Fauci’s points around accelerated emergence of so-called escape mutations are technically valid, we think they are largely moot when one can argue for 80%+ efficacy from single doses of all of these vaccines (note: it is very difficult to settle on a definitive efficacy value; there are many ways to measure these things that will give different answers). The emergence of new variants is inevitable and, thanks to our world-leading role in pathogen sequencing, we are going to find a lot of them first in the UK (and probably get blamed for them by the EU as well!).

Mutation is random and then environmental factors decide which mutations persist and become prevalent. However you can “drive” natural selection in a certain direction with external forces. In the first wave of SARS-CoV-2, the virus was new to us all and thus it could reproduce easily. The mutations that propagated were those that helped it spread (so called virulence traits). One year on, we have maybe 10%+ of the population that have natural immunity from prior exposure and a growing proportion who have been vaccinated. It logically follows that the selection pressure/drive will be in favour of those strains that allow the virus to evade the antibodies created by vaccination or prior exposure. The “E484K” mutation present in the Manaus, South African and now Liverpool/Manchester variant is an example. Natural selection has favoured the same spontaneous mutation in three different regions of the world at three timepoints. We have identified a number of point mutations that may allow the virus to evade antibodies and it’s probably just a matter of time before all of these arise in new strains

How does a vaccine program impact transmission? What the significance of the Clalit Israeli data?

Transmissibility is a very important question. Vaccines are designed to protect the vaccinated and any additional societal benefit is a bonus. We are in a pandemic and, until you have compelling data that vaccination has an impact on transmission, you need to be very careful about rolling back the spatial and temporal restrictions that have sadly become part of our everyday lives and interactions. Not everyone has been vaccinated and vaccine efficacy is not 100% (although no-one given a vaccine so far has been hospitalised or died of COVID-19 as far as we are aware, suggesting 100% efficacy against serious morbidity and mortality), so you are still going to get cases and you are still going to see deaths and hospitalisations. The variants increase this risk by decreasing vaccine efficacy.

Although we have seen some preliminary data from the Astra/Oxford group on reduced transmissibility (based on PCR testing of the active and placebo groups), this data suggests much lower efficacy on transmission than on serious infection prevention and the Clalit data from Israel may also suggest some degree of lower level cases in the vaccinated population. What this means is that we have some evidence that transmission may be reduced to some extent but that is all we can say. If you were to simply end all restrictions tomorrow, it is certain that case numbers would increase. This may not lead to another bolus of hospitalisations etc. but the public perception of COVID risk now seems so distorted that to do so would be political suicide. For this reason alone, the path out of lockdown is likely to be gradual and would probably be slowed in the event that the “R value” spikes up again.

Generally are we correct to assume viruses becomes more transmissible (virulent) and less lethal over time? Is the falling hospital fatality rate supporting this?

An evolutionary biologist would say yes. Killing your transmission vector (humans) is bad for business, you want them walking around coughing and sneezing over everyone to maximise the chances of reproduction. All other factors being equal then, evolution will over time favour more virulent but less lethal strains. I think we can be very confident that SARS-CoV-2 will become like the common cold over millennia, but mutations are random and in the meantime, it could persist as is for a very long time yet. Coronaviruses have error correction in their reproductive arsenal, so they evolve relatively slowly.

The falling hospitalisation rate versus infections is probably another example of the “denominator problem”, in that we are now over counting infections (due to setting cycle time thresholds on PCR tests too high) versus under-testing at the beginning due to a lack of testing capacity. As such, it would appear that the probability of an infectious person going into hospital has gone down, when actually it is very similar to before. The mortality rate has definitely decreased; we can measure this by looking at the proportion of people sick enough to be hospitalised that then go on to die. This is testament to the tremendous progress made in collaborative research and we should all be proud that the UK has been a leader in this with the REACT studies and so forth.

Why then the alarm, led by politicians, about new strains, Kent, South Africa etc? Surely the industry will learn to deal with these quicker each time?

I would agree this issue has been handled poorly by all concerned, but arguably the media is as much to blame as the government by intentionally withholding contextual information. There have been thousands of strains of SARS-CoV-2 identified for many months now. Most of the changes that define something as a variant make no difference to the virus in terms of virulence or morbidity risk and so go unremarked. To then pick on one and call it a “mutant” is a bit ridiculous and to focus on it being the dominant strain without pointing out that it need only account for a small percentage of total cases to be the dominant strain is negligent. We also think the government has been incredibly premature to talk about any evidence that the “Kent” variant has higher mortality. The error bars around this are very very wide.

If you look at how flu vaccination works, we try to predict the dominant strain of flu one year ahead and make a vaccine against this. Most of the time we do a good job, sometimes less so and we see more illness and mortality. We need to go this route with SARS-CoV-2, producing polyvalent (i.e. effective against multiple strains) vaccines based around the mutations that are most likely to allow the virus to “dodge” existing immunity. I think we will get there in the next year or two but until we do, there will be concern about vaccines being rendered ineffective.

Given the innate caution inherent in UK govt scientific advice (repeated ‘warnings’ in recent days of conflating vaccination with transmissibility, e.g.) where does this leave the UK’s re-opening calendar?

Our view on this topic has been boringly consistent for many months now: this is going to take longer than the media or the government would like you to believe. Quite why anyone wasn’t honest about this from the beginning is beyond us; false hope is as bad as no hope and the Government must have realised that when you say we can “start getting back to normal by Easter”, the media will hear “back to normal by Easter” and the public will imagine a late spring bonfire of PPE and hand sanitizer. Sadly, it will not be so distinct and these restrictions will fade away gradually over time. We said we hope that Christmas 2021 will not feature too many restrictions and that remains our default view. Foreign holidays are still a distant dream I think. As for the NHS clearing its waiting lists, I think that will take a long time indeed and the real human cost of this pandemic is yet to be fully appreciated.

This interview was initially published in Primary Access & Research.