Temper your excitement about the Covid vaccine

Ever since Giacomo Pylarini, a physician working in the Ottoman Empire, sent a report to the Royal Society in 1701 that Turkish women believed pus from a smallpox survivor could induce immunity in a healthy person – and was dismissed as a dangerous quack – inoculation has been as much an art as a science. But it has proven to be the greatest life-saver of all time, eliminating smallpox and suppressing many other diseases. In Pylarini’s prescient words, it is 'an operation invented not by persons conversant in philosophy or skilled in physic, but by a vulgar, illiterate people; an operation in the highest degree beneficial to the human race.'

It looks like a vaccine is probably going to work against Covid. That was never guaranteed: it’s been decades since scientists started seeking a vaccine for malaria and HIV, with no luck so far, and flu vaccines only last for a limited time before the virus mutates. But the announcement last week that the German firm BioNTech’s vaccine, developed in partnership with Pfizer, seems to prevent Covid infection is encouraging news. Kudos to Kate Bingham for spotting it early.

Temper your excitement though. The sample size is small, the safety of the vaccine not yet proven, its effectiveness in the elderly uncertain, the duration of immunity unknown and it needs to be stored at -70C, which requires some pretty James Bond style logistics. Then there’s the challenge of immunising 67 million people in a short space of time.

The reason the vaccine prefers such a cold temperature is that it’s made of a fatty bubble containing messenger RNA, an unstable compound, never before used to make a vaccine. This is a critter whose purpose was first spotted, legend has it, at a seminar on Good Friday in 1961. The talk was being held in a private room in King's College, Cambridge, because the laboratories were closed for the holiday. The speaker was the French resistance hero and molecular biologist Francois Jacob who was describing an experiment.

The host of the seminar, Sydney Brenner, suddenly let out a 'yelp'. The scientists had got stuck with a wrong idea about how genes told cells what proteins to make. Jacob’s experiment broke the logjam, Brenner saw: genes must produce short-lived, working-copy read-outs of their messages that go out and get translated into protein by special little machines.

They soon retired to Francis Crick’s house for a party. It was, said Jacob, 'a very British evening with the cream of Cambridge, an abundance of pretty girls, various kinds of drink, and pop music. Sydney and I, however, were much too busy and excited to take an active part in the festivities…A euphoric Sydney covered entire pages with calculations and diagrams. Sometimes Francis would stick his head in for a moment to explain what we had to do.'

When a virus infects you, its genes are transcribed into messenger RNAs by your own cell machinery, and these are then translated into the proteins that build more viruses. Eventually your immune system wakes up to what is happening and suffocates those proteins. So if you can inject specific messengers to be translated into copies of just part of the virus’s 'spike' protein, you will alert the immune system without causing disease. That’s what Ozlem Tureci and Ugur Sahin, the founders of BioNTech, did. It worked in the lab.

They approached Pfizer, whose chief executive Albert Bourla decided to take a punt on the project with the firm’s own cash, refusing government grants. Back in September, he explained why: 'I wanted to liberate our scientists from any bureaucracy. When you get money from someone that always comes with strings. They want to see how we are going to progress, what types of moves you are going to do. They want reports. I didn’t want to have any of that.' Seems to have worked.

To get results from phase 3 clinical trials for a vaccine this fast is unprecedented and suggests the messenger approach may be the future for vaccines. It is inherently safer than using attenuated or inactivated viruses as vaccines, which worked for polio but not before one of the manufacturers, Cutter Laboratories, in 1955 paralysed more than 200 people with polio through an inadequately inactivated virus. Later polio viruses were contaminated with a virus called SV40 that luckily proved harmless. That kind of thing no longer happens but side effects do. Trials of other covid vaccines have been paused to investigate adverse reactions, including this week the Chinese company Sinovac’s inactivated coronavac vaccine in Brazil.

The Oxford-Astrazeneca team uses a harmless virus into which a coronavirus gene has been inserted. Results from that vaccine’s trials are expected soon. Imperial College is using a DNA version of the messenger method.

There are eleven vaccines in phase 3 trials. The chances that some of them are both safe and effective must be fairly high. But everything about vaccine development is uncertain. Will the vehicle deliver the vaccine to the right place? Will you get an immune response? Will it be strong and long-lasting? Will there be side effects? Will the virus mutate too fast? We don’t know the answers yet.