Journal of the Plague Year XII – Hope Springs Eternal

After Pfizer announced on Monday that it had successfully trialled a vaccine for Covid-19, stock markets on both sides of the Atlantic and in Asia soared. Will life really return to normal in the first half of 2021? asks Victor Hill.

“A great day for science and humanity”

So said Pfizer CEO Dr Albert Bourla. A vaccine trialled on 43,538 people in six countries stimulated immunity to Covid-19 with no safety concerns. This was the momentous joint announcement by US pharma giant Pfizer (NYSE:PFE) and the German biotech firm BioNTech (NASDAQ:BNTX) at around midday on Monday (09 November).

The British government has already ordered 40 million doses of the vaccine, of which 10 million could be available by Christmas if regulatory approval is fast-tracked. The elderly will be prioritised in the vaccination programme, along with NHS frontline staff. Then it will be offered to the over-65s and successively to under-65s with health conditions.

Sir John Bell, regius professor of medicine at the University of Oxford and a member of the government’s vaccine taskforce predicted live on the BBC that Britain would return to normal life by next spring. This was the man who pronounced in September that the virus would remain with us for a long time to come^[i].

Underlying science

The Pfizer-BioNTech vaccine, like a number of other coronavirus vaccines currently under development, is a messenger RNA-based vaccine (mRNA). RNA and DNA (which powers genetic reproduction) are both nucleic acids. Both are assembled as a chain of nucleotides; but in nature RNA is found only as a single strand while DNA has the much more complex paired double strand (“double helix”) structure.

mRNA vaccines use an entirely new medical technology which induces human cells to produce Covid-19 viral proteins in the body and thus to trigger an immune response through the production of antibodies. This is thought to be more effective than injecting Covid antibodies straight into the bloodstream. Phase 1 and 2 trials of the vaccine were promising, with the results reported in Nature magazine in early August.

mRNA vaccines have the advantage that they are theoretically relatively easy to modify should the virus mutate significantly. That is already a concern given events in Denmark, where it seems that mink which contracted Covid-19 from humans then developed a variant strain of the virus which was then transmitted to other humans. (Seventeen million of the unfortunate animals are now to be culled – though one would like to know why they were being farmed at all in an age when fur coats are no longer socially acceptable.) There was another recorded mutation originating amongst Spanish farmers which spread to the UK in July when holiday travel between Britain and the UK resumed. A constantly mutating virus represents a moving target for virologists.

Oxford University and AstraZeneca are expected to publish the trial data for their developmental vaccine shortly – possibly as soon as next week. AstraZeneca’s prospective Covid-19 vaccine uses a more conventional vaccine technology: a weakened form of a common cold virus that infects chimpanzees. It is genetically altered to carry some of the code for key proteins in the SARS-CoV-2 virus, thereby eliciting a protective immune response in humans. Importantly, this immune response consists of both antibody and T-cell production. This is important as some studies show that antibodies to Covid-19 diminish relatively quickly. This vaccine is currently in Phase 3 trials with about 30,000 people in the UK, Brazil, South Africa and the USA.

Conventional vaccine approaches have not been as effective against rapidly evolving pathogens like influenza or emerging disease threats such as Ebola or the Zika virus. RNA-based vaccines could have an impact in these areas due to their shorter manufacturing times and potentially greater effectiveness. As for the future, some clinicians think that RNA vaccines could in time be used as a therapy for cancer^[ii].

Pfizer and BioNTech will have to hand over the data relating to their trials to the Medicines and Healthcare Products Regulatory Agency before a license is granted. In practice, there will be huge political pressure on the Agency to give the green light, especially if other countries have done so already.

Market reaction

The FTSE-100 enjoyed its best day since March as shares in airlines and hospitality firms rocketed. EasyJet (LON:EZJ) was up by 36 percent and IAG (LON:IAG), the owner of British Airways, Iberia and Aer Lingus, was up 40 percent. Rolls Royce (LON:RR.), the aero engine manufacturer was up 44 percent; and SSP (LON:SSPG), the owner of the Upper Crust sandwich chain favoured by office workers and travellers, was up 52 percent. There were losers as well, however. Ocado (LON:OCDO) the online groceries giant, having powered away this year, was down 12 percent; and Kingfisher (LON:KGF), owner of the B&Q DIY chain, was down 9 percent.

Overall, the FTSE-100 was up by 4.7 percent and the FTSE-250 up 5.2 percent as retailers, pub chains and tour operators rebounded. Pub company Young’s (LON:YNGA) gained 23 percent.

European markets also surged with Paris up 7.6 percent and Frankfurt 4.9 percent. In New York, the DJIA was up 4.69 percent, the S&P by 3.52 percent and the NASDAQ by a more modest 1.43 percent. Gold fell by more than five percent; and in the currency markets the Japanese Yen was a major loser. Brent crude jumped by $10 to hit $43 a barrel.

Clearly, the markets found the news cathartic, compounding the positive sentiment unleashed by President-elect Biden’s victory: but it is worth remembering that London is still down 18 percent year-to-date and European markets are still well down. Any news of delay on the vaccine front could reverse sentiment. Global markets were more muted on Wednesday and Thursday with more negative news flow on the pandemic front.

Testing times

Also on Monday, the NHS announced that it would start testing all frontline staff twice a week. This will stop the spread of the virus by healthcare workers who are asymptomatic.

To control the spread of the virus without perennial lockdowns, a systematic testing regime must be put in place combined with effective contact tracing – and enforced quarantine of those who are found to be positive. Numerous societies in East Asia seem to have cracked this; but we in the UK are still floundering. Advances have been made on the testing side of the equation with improved diagnostics more easily available; but on the tracing and isolation side, results are dismal. Many people simply refuse to answer the 0300 number when it calls; and isolation is only very laxly enforced.

The main problem in testing in the UK has not been conducting tests but the inadequate capacity to process them. The prospect of “pregnancy-style” testing at home could be a game-changer. But would people who test positive adhere to the isolation requirements?

Reasons for caution

The momentous announcement marks, as Churchill might have put it, the end of the beginning – but it is not the beginning of the end of the coronavirus pandemic. There are three aspects of the roll-out of a vaccination programme where much could go wrong. I would characterise these as: efficacy, safety and logistics.

In terms of efficacy, we don’t know at this point – other than the 90 percent figure we have been given – how widespread immunity will be generated, even if everyone were vaccinated (which is not going to happen) nor how long such immunity will last. Interestingly, the Pfizer testing regime involved an initial shot followed by a booster. The figure suggests that one in ten people vaccinated will not develop immunity. If only two thirds of the population were vaccinated (optimistic) within the space of next year that would still mean that only six out of ten people carried immunity. It is not yet clear that that level would confer herd immunity – by which I understand the “R” value of a pathogen is sent on an ever-diminishing trajectory towards zero.

The threshold for herd or population immunity could be as low as 20 percent and as high as 80 percent – it depends on which immunological models you go with, and it obviously differs from one disease to another. Opponents of those who advocate natural herd immunity (i.e. letting the virus to its own devices) argue that herd immunity is only ever achieved by vaccination.

Moreover, that 90 percent figure may not reflect efficacy across all demographics. The vaccine might be highly effective in conferring immunity amongst the young but relatively ineffective in protecting the most vulnerable. Based on what we have been told so far, we just don’t know. This would mean that we would still have to remain vigilant in protecting care home residents, possibly indefinitely.

The safety of the vaccine will be of paramount interest. Anybody who experiences adverse side-effects as a result of being vaccinated will attract huge publicity. Virtually all vaccines do manifest side-effects in a minority of vaccinees – mostly minor, but some severe. And it may be that such side-effects only manifest themselves six or 12 months after vaccination – and therefore will not have been picked up in Pfizer’s Phase 3 trial. We just don’t know because no vaccine has ever been developed from scratch this quickly. We can be sure that any adverse publicity will only strengthen the intransigence of the anti-vaxxers – who are already saying that mRNA vaccinology interferes with the human genome in unknown ways. Any attempt at mandatory vaccination – currently mooted in Australia – would be likely to provoke deep resentment in some quarters.

Another problem is that an immune response can stop us from falling ill if we acquire the virus but does not necessarily prevent us from infecting someone else. So, we don’t yet know if even an effective vaccine will halt transmission.

The sophisticated logistics entailed in rolling out a vaccination programme on this scale at short notice will be immense – and the previous experience of rolling out a test-and-trace programme does not bode well. The Pfizer vaccine must be maintained at a super-cold temperature of around minus 70 Celsius up to about four hours before it is administered, or else it breaks down. Few GP surgeries have freezer facilities that could cope with that. Fortunately, Pfizer has designed a suitcase-sized container that will keep up to 5,000 doses at the required temperature for up to 10 days.

Capacity restraints will also come into play. For a start, the NHS in the UK does not have enough healthcare professionals to administer upwards of 50 million vaccinations – each one of which will have to take place in a socially-distanced and Covid-secure environment. That is why retired medical professionals are being called to arms to assist in the vaccination campaign. Reportedly, even doctors’ receptionists may be re-trained to administer vaccinations. (I’m not sure how I feel about that.)

On Tuesday, the UK government announced plans to set up 1,500 vaccination centres in GP surgeries and dedicated drive-through centres. These will be open 12 hours a day and will each dispense at least 1,000 jabs a week. Thus, the capacity will be (theoretically) about 1.5 million vaccinations a week. It will therefore take about three months to vaccinate 50 million people. Except that the government only has 40 million jabs on order and each person will need two jabs, 21 days apart. These will start to arrive shortly from Pfizer’s plant in Belgium – another reason why failure to agree a trade deal with the EU (to avoid “frictions” at the border) will be regarded by many as a cataclysm.

And will Pfizer-BioNTech have the production capacity to deliver all the pre-ordered product? Even if it does, the cost of rolling out this vaccine will reportedly be ten times that of the Oxford-AstraZeneca vaccine for which the UK government has placed an order for 100 million doses. The US government is paying $38 for each double shot of the Pfizer vaccine, whereas the Oxford vaccine will be sold in the EU for just £2.23 per dose.

The underlying logic of the lockdown strategy adopted with various degrees of restriction across the world was that, sooner or later, a vaccination programme would eradicate the virus. Clearly, lockdowns can contain the virus (reduce the R-rate as the politicians constantly tell us) but they can only buy time by delaying the onset of the next wave. The virus is likely to persist for some time even after the initial vaccination programme is completed. It took about 200 years of vaccinations against smallpox to eradicate that disease completely – admittedly when the science of immunity was poorly understood.

If the roll-out of a vaccination programme throughout the western world does not secure a return to normality by the end of say, June next year, then the whole argument about herd immunity and focussed protection (as per the Great Barrington Declaration) will come centre stage. That would mean that roughly one sixth of the UK population would have to isolate while the rest just get on with their lives, albeit with appropriate social distancing and hygiene protocols. People are already getting tired of lockdowns which have diminishing marginal returns. This debate is not going to go away.

Taking stock

The UK is still recording a high level of excess deaths with the figure for October 11 percent above the five-year average. 532 fatalities were reported from Covid-19 on Wednesday – the highest number since 12 May.

As of yesterday, there had been over 52.5 million cases of Covid-19 worldwide and nearly 1.3 million people have died of the virus. The USA has now recorded over 247,000 deaths while the UK has exceeded 50,000. Both countries have experienced a remarkably similar mortality rate in terms of deaths per million (746 and 740 respectively). Brazil (164,000 deaths) and Mexico (96,000) are in the same mortality rate bracket (767 and 745).

In contrast, the countries of East Asia have been astonishingly successful in repressing the virus. Covid deaths per million for Japan, Taiwan and Vietnam stand at 15, 0.3 and 13 respectively. In Europe, the outlier is Germany which has experienced 144 Covid deaths per million, though it should be noted that Germany’s death rate has spiked significantly in the second wave that first became apparent in mid-September.

The vaccine will not arrive in time to halt the second wave of the virus now underway in North America, Europe and elsewhere. A member of President-elect Biden’s new coronavirus taskforce, Dr Vivek Murthy, who was surgeon-general under President Obama, warned this week that there could be another 200,000 deaths in the USA before the vaccine and that a dark winter lay ahead.

Hope is always sustaining – even if the worst may be yet to come.

^[i] Sunday Telegraph interview with Sir John Bell, 13 September 2020

^[ii] See: https://www.phgfoundation.org/briefing/rna-vaccines?fbclid=IwAR003pHd0yefXkR1QJIyzOmqzfBdx9qHBuNdkCNisU3v9d8_wN_kgl2IShU