Mutations are errors that arise as genes are copied. They occur frequently with RNA viruses such as SARS-CoV2. Most cripple the virus, making them evolutionary dead ends. Occasionally, though, one confers advantage and the mutant’s progeny proliferate. It may even become the dominant virus type, locally or internationally.
For respiratory viruses, evolution favours mutants that disseminate more efficiently but are less lethal. Their victims remain active, spreading the virus, whereas patients with a variant that gives severe disease retire to bed, infecting fewer secondary cases. Evolution also favours mutants that evade immunity arising from prior infection or vaccination. In 1984, Sylvia Reed of the MRC Common Cold Unit found it difficult to infect volunteers with the common cold coronavirus 229E, to which 89% already had antibodies, but it was much easier with an 229E variant to which their antibodies gave incomplete protection.
We’re entering the same game with SARS-CoV2.
The B.1.1.7 UK variant gained traction during Lockdown 2.0, with rising cases in south-east England despite restrictions on shopping and socialising. Perhaps lockdown disproportionately suppressed its less spreadable progenitor?
B.1.1.7 has multiple mutations, one of which gives an N501Y substitution in the spike protein targeted by vaccines. This increases transmissibility but doesn’t undermine antibody binding and vaccine efficacy. Two further variants – the South African and the Brazilian – have additional mutations, giving a more concerning E484K (glutamate to lysine) replacement in the spike protein. This flips a negative charge to positive and reduces binding of the antibodies raised by the various vaccines. Clinically, it was associated with failure of the AZ vaccine in a small (2,000 patient) trial in South Africa and reduced efficacy of the yet-to-be licensed NovaVax product from 89% to 60%.
Fear of importing these variants lies behind the Government’s imposition of quarantine for travellers entering the UK from southern Africa and South America, as well as Portugal, Panama and the UAE. Will such regulations, and threatened 10-year prison sentences for those who flout them, protect us?
The answer to that is ‘no’. Firstly because the South African variant is already circulating in the UK and is doubtless under-detected. Secondly, because they will continue to be imported from elsewhere in the world and, as a trading nation, we cannot isolate ourselves. And, above all, because E484K mutations have emerged independently here, notably around Bristol, and will continue to do so. Currently the Zoe app suggests 230,000 people are infected with Covid-19 in the UK. Each of these will be carrying and producing billions of virus particles. With these numbers, domestic generation of mutants will outweigh import.
This does not mean that vaccination itself is a forlorn hope. It is reducing case numbers here and in Israel and should reduce disease severity even when it fails to prevent infection. But it does mean that we should be realistic in our expectations. Vaccines will improve matters but won’t bring us to the unreachable mirage of Zero Covid. We have only ever eradicated one virus, smallpox, and it was far less clever and adaptable than SARS-CoV2.
As Matt Hancock said last week, our expectation should be to live with Covid-19, as with influenza, which causes 10,000-30,000 UK deaths annually. We will likely need to tweak vaccines to address circulating variants, perhaps annually. This will be easier than for influenza because coronaviruses are not so prone to sudden massive recombination events and because mRNA vaccines – a real breakthrough – can be chemically manufactured and adapted, whereas flu vaccines begin with the tedious task of growing the virus in eggs.
There is one final point to make, stemming from the fact that immunity, like muscles, improves with work, not idleness.
As vulnerable groups are vaccinated – and second shots should be accelerated – lockdown should be swiftly released, allowing circulation of virus in the low-risk population. Those who have been vaccinated will thereby be exposed at a time when their antibody levels are high and best able to fend off weakly-covered variants. The result will be to boost and widen immunity. The touted alternative of a very cautious re-opening, sounds safer, but it isn’t. It hazards delivering a population with waning immunity as we enter the next winter virus season.
Professor David Livermore is a Professor of Medical Microbiology at UEA and a member of HART, the Health Advisory & Recovery Team.