It was the 11th November as I sat down to write. I was listening to the Remembrance Day evensong from Ely Cathedral, having just read Barbara Millar's
moving account of the journey of the Unknown Warrior. Reminders of that awful combination of war and pandemic has the effect of bringing tears to my eyes every year; this year it is particularly poignant as so many people are reliving the experience that so many families suffered in 1918/19 and the years leading to Armistice.
My wife's grandfather died on the Somme and his wife died in the pandemic, leaving five orphans under the age of 15. My own grandmother died at the same time, also leaving five young children. Although mercifully the present pandemic has mostly killed people of my age, it has not left younger ones untouched and again very many families are mourning loss or suffering prolonged symptoms. Little wonder we are so optimistic on hearing the news of a vaccine; is this the way out? Will we get back to normal?
We are becoming used to hearing of potential medical breakthroughs in terms that give hope. In an era of hype, downright lies and metaphors, when we are told of oven-ready deals it seems sensible to look critically at such claims – to take these uncooked dishes with a pinch of salt, even when they are conveyed by the most reputable of media. To a sceptic, the premature announcement of a 90% effective vaccine does ring some alarm bells, especially when the whole world is desperate for such good news. Let's look at them critically.
The story of vaccines is well known, from the 18th-century introduction of variolation from Turkey by Lady Mary Wortley Montague and vaccination with cowpox by Jenner, through Pasteur's 19th-century experiments with rabies, and the introduction one by one of smallpox, measles, mumps, tetanus, German measles and poliomyelitis immunisation, leading to worldwide eradication by WHO of smallpox and hope that polio will follow. It is a long story of slow but recently accelerating scientific progress. Now we can also be protected from hepatitis and even cervical cancer (a viral disease) and, if we wish to travel abroad, from any number of more exotic diseases. And, of course, we also have available influenza vaccines that are modified annually to deal with the regular variation in that virus.
Most of those in Europe under the age of 65 take their protection from all these potentially fatal diseases for granted; the resulting extraordinary rise in longevity of our population is barely noticed save by the managers of care homes. We have become complacent about the single greatest achievement of medicine, immunisation, and some misguided folk even regard it as harmful. As a witty friend recently remarked to me, the trouble with preventive medicine is that there are no grateful patients!
Since we first heard of the outbreak of COVID-19 in Wuhan, we have been hoping for a vaccine and some may not realise how extraordinary an achievement is the production of several possible vaccines within a year of discovery of the virus, a process that has previously taken many years. It has been a triumph of modern science.
First, Chinese scientists worked out and published the genetics and structure of the virus, then its means of infecting human lung cells was discovered – the spikes on its surface are molecular keys that latch onto an enzyme receptor on the cell surface and allow the virus to enter. Our bodies' defences can recognise the proteins in these spikes, and not only produce antibodies to them but also mobilise other so-called T-cells to attack the virus. This is part of the inflammatory reaction that may make you feel ill and sometimes leads to severe illness, but in most cases leads to cure. The trick for the scientists was to find a way of producing this defensive reaction artificially without the risk of causing illness, a method based since Pasteur's time on using an attenuated or killed virus.
In the case of this virus, SARS-CoV-2, some new and revolutionary methods have depended on advances in molecular biology. In one, the basic genetic molecule (mRNA) that codes for the spike protein is synthesised, a process doggedly pioneered over many years by a remarkable Hungarian-American scientist, Katerin Karikó. This chemical is wrapped in a fatty coat as a nanoparticle (the same size as a virus, a few thousand millionths of a metre in diameter) and put in a suspension that can be injected. Others have tried a different method, such as inserting the viral spike mRNA in a different harmless virus; these technologies depend on recent discoveries in basic science and, at least to me, are mind-blowing.
The method of using mRNA in a nanoparticle is a revolutionary way of producing vaccines, which traditionally have used whole viruses grown in cultures (often in eggs) and then administered either alive but in an attenuated form or killed. The technique therefore does not carry the risk of infection nor of allergy to, say, egg protein given with it. It seems that a problem may be distribution, since the molecule of mRNA is unstable and deteriorates at room temperature; indeed, the current leading vaccine in the race to be authorised for use needs to be kept at -80˚C. This is achievable by storing it in so-called dry ice, the solid form of carbon dioxide which is used, for example, in making fogs for theatrical performances and is relatively easily manufactured. Once removed from this refrigeration, it only remains active for a few days in a normal freezer.
Effectiveness and safety
While the production of these vaccines depends on this extraordinary science, their application in populations depends on two well-established methodologies: testing and distribution. Testing depends on national regulation but must be meticulous in looking for effectiveness and safety. Effectiveness means that it is able to produce the desired immune response, that it does reduce the risk of the disease in the vaccinated subject, and also is likely to prevent the subject from passing it to others. Safety means that it does not cause allergic or toxic effects in animals and then in human volunteers.
In the case of COVID-19, large numbers of volunteers have been given two doses of vaccine (or placebo) and are being followed up carefully to record any symptoms and the development of the disease in many trials worldwide. It is said that vaccines are close to being used in China, India and Russia, and now we have at least five promising ones in the late stages of testing in Europe and USA, from Pfizer/BioNTech and Moderna, using the mRNA nanoparticle, and Astra Zeneca/Oxford, Johnson and Johnson, and Janssen, using recombinant virus carrying the mRNA. Many other vaccines using these or more traditional methods are undergoing trial, and this encourages the belief that more than one will prove effective.
The scientists involved will be popular subjects for television and radio interviews; remember that their fame and, often through investments, their fortune may depend on success, so they will not understate the chances of their vaccine being the answer to the world's problem. Early trial results can be misleading though the Pfizer report that 90% of the first volunteers to get COVID-19 were in the placebo group is certainly encouraging. However, the trial protocol requires them to wait until almost double the number that have been reported have caught the disease before drawing conclusions on efficacy. Of course, we have heard little yet about safety, but one assumes no significant problems have occurred so far.
Post-licensing surveillance should reveal any problems, but the most important issue is the duration of any immunity conferred. It may take years before we can be assured that this is both strong and of long duration. It may be neither, but we are informed that both antibody and T-cell responses to the Pfizer vaccine occur and that the T-cell response is expected to be longer lasting. Thus far, we have no way of knowing. This is my first pinch of salt; we need to wait several months before we can be reasonably sure of the first few vaccines' immediate efficacy, but it is reasonable to be optimistic.
Distribution and usage
The next problems will be in distribution and equity in their initial use while supplies of the successful vaccines are built up. The most encouraging thing to me is that there is hope of several vaccines becoming available. Another is that the mRNA model used in all of those mentioned above is reported to be pretty adaptable and can be used to take account of variants in the viral genome as they occur, as with the mink virus.
Once supplies are available, the obvious UK strategy will be the same as now – to protect the NHS so that it can deal with its usual load, and to protect the economy. The former requires those most at risk of falling seriously ill to be immunised first and should be guided by our knowledge of who are most susceptible and who are most highly exposed; the over-70 generation, those with chronic illness and severe obesity, those working with patients or potential patients in the NHS and care sector, and school and further education teachers. Thereafter, administration can be guided by age.
If, by spring, we are in the happy position of having more than one vaccine available, there may be conflicts in choosing one in terms of cost and estimated efficacy. It would be very optimistic to suppose all will be 90% effective, and a lesser degree is still acceptable. Cost/availability to these independent islands with a wrecked economy are likely to be political issues. Equally important will be the strategy developed – should we aim to eradicate the infection worldwide through WHO or get enough to minimise its effects in our islands? The ethical and biologically sensible answer is the former and there is already a measure of international agreement on that, something that will be facilitated by a change of President in the USA.
As supplies of any vaccine are likely to be limited for worldwide distribution initially, we must look carefully at how we should adapt to the period of getting the infection under control, since it will be impracticable to immunise the whole population initially, and this leads to my second pinch of salt.
Back to normal?
There is a great yearning to 'get back to normal', but it is unlikely that we can ever do that. Not only is it likely that this virus will be a threat to mankind and animals in spite of vaccines for many years but also it has the potential to mutate. And even if it were eradicated, this is only one of a series of pandemics over millennia and others need to be prepared for. We in Britain and the USA have already made a series of mistakes in this one; we were hopelessly unprepared by concentrating on austerity and running down our public infrastructure; we have voted for an economic model that created great riches for some and a seriously deprived underclass almost mimicking that in Victorian times in its potential susceptibility to epidemics; our greed for energy has led to the even greater threat of disastrous climate change; and now we have come out of lockdown far too incautiously and precipitated a huge second wave.
I believe that there is a new normal ahead and we shall reach it by treading a cautious path even after the disease has come under control. This path involves restricting indoor gatherings save in large well-ventilated areas, continued social distancing, widespread use of face coverings and meticulous hand hygiene. Schools, colleges, many workplaces, restaurants, shops and places of worship are learning how to manage these restrictions and must expect to continue them at least until most of the more susceptible and the NHS/social care workforces are vaccinated. Combine this with a further surge in unemployment and probable political unrest among those disappointed at the outcome of voting for Brexit and a government of millionaires, and I suspect that the new normal will resemble the 1950s.
Three weeks ago, I suggested that by now we should know whether the restrictions imposed on us have succeeded in suppressing the virus (28 October
). It is apparent that they did not, with the daily numbers in hospital and on ventilators in Scotland rising steadily. Only now, with increased control are they perhaps starting to stabilise, but I believe even tighter restrictions are necessary to get numbers down. If anything, England is in an even worse situation. I am sorry to feel obliged to stress again the need for an effective test, trace and isolate system based locally, since neither government has yet shown itself capable of organising one. I sincerely hope our governments will not repeat their other mistake of opening the economy rapidly, especially in response to demands for a normal Christmas.
Our Hindu and Sikh friends have enjoyed a more self-restrained Diwali and I hope we Christians, Jews, Muslims and pagans can accept similar restrictions on our usual winter celebrations if these are necessary to protect our families and our neighbours. I recall that it is but a few decades since a Scottish Christmas was a byword for sobriety; now this may need to include Hogmanay.
Anthony Seaton is Emeritus Professor of Environmental and Occupational Medicine at Aberdeen University and Senior Consultant to the Edinburgh Institute of Occupational Medicine. The views expressed are his own