Too fast & so not safe
Sunday, 6 December 2020 18:26
Has the fast development of new COVID-19 vaccines compromised their safety?
Upon reading the claim in the title of this piece (in a tweet) I was reminded of Robert Stephenson’s problems with public perception when he unveiled the Rocket for the Liverpool and Manchester Railway in 1829. It could reach speeds of over 30 mph; speeds at which people thought that they would suffocate. Obviously, those fears evaporated as more and more people travelled on the railway … and survived.
It is my hope that a similar story will pan out with fears about COVID-19 vaccines. There is a common perception that their quick development somehow makes them less safe than a traditional vaccine. So, here are a few thoughts on how the COVID-19 vaccine has been developed and released so quickly, and why that speed has zero impact on its safety.
There are various factors that have driven the fast-paced development of the COVID-19 vaccines, including advances in molecular biology and money.
Advances in molecular biology
It took Jonas Salk seven years to develop the first polio vaccine in the 1950s. The timescale for developing vaccines had not changed very much since ... until now.
Part of that lengthy timescale was due to finding and isolating the virus. Finding viruses is a much faster process these days. Back in the early 80s, for example, it took many years to find and isolate HIV. In 2003, it took just over a month from recognising SARS as a new disease until scientists identified the virus. For COVID-19, it took a couple of weeks to identify the virus.
Another factor for the slowness of vaccine development is scientists trying to find favourable conditions to get a newly isolated virus to multiply, so that you have enough of it to do your vaccine research. However, developing RNA vaccines is incredibly quick because you do not need the actual virus; you just need to know what the genetic instructions on its genes (its RNA) say. This can be done in a matter of hours, with the results sent to every molecular biology lab in the world a few seconds later. Making these vaccines using this new RNA approach can cut out years’ worth of work because it can all be done in a lab, without the need for any of the actual virus. That also means that it's much safer for the scientists to develop.
Older style vaccines use the real viruses (either killed or in a ‘live’ form that cannot cause the disease). It takes a long time to get a virus to multiply in sufficiently large quantities for use in mass vaccination, whereas the manufacture of RNA to go into these new vaccines can be done on a fairly industrial scale in labs.
For COVID-19, scientists also had a head start because the virus was similar to the viruses that caused the SARS outbreak in 2003 and MERS in 2012. Having worked on vaccines for these viruses, they already knew the part of the virus that would be most useful for making a vaccine (the ‘spike protein’). They didn’t need to spend years looking for the virus’ weakness.
Once a vaccine has been made it then needs to be tested for effectiveness and for safety.
They start with pre-clinical tests, which are usually performed on human cells being grown in bottles in a lab or on animals. Some trials then have a Phase 0, in which a few people are injected with very small amounts of a medication to make sure that it does not cause harm.
The first full phase is Phase I, in which up to 100 healthy people are given different doses of the medication. The main aim of this phase is safety; to find out how the side effects change with different doses.
Phase II then tests the medication out on a few hundred people. This phase is designed to look at the effectiveness of a medication. For drugs designed to treat people with illnesses this is the point at which the drug is tested on those (‘non-healthy’) people.
Then Phase III usually involves 300 – 3000 participants. The new drug is compared with existing treatments and with placebos (giving some of the participants a fake that contains nothing more than sugar or salty water). More detailed data on safety and effectiveness is collected in this phase.
Phase III and COVID-19 vaccines
Phase III trials for an Ebola vaccine in 2017 had 1023 participants, a study on a Japanese encephalitis vaccine completed in April this year used 1050 participants and an ongoing Phase III trial for a dengue fever vaccine has 16 994 participants. For comparison, the Pfizer COVID-19 vaccine had just over 41 000 people in its Phase III trial. No shortcuts have been taken with the testing. All the phases have been run, and with similar numbers of people involved as would be used for any other vaccine. The trials have used the same rigorous procedures as are common to all clinical trials. So, how have these trials happened so quickly?
Trials for new drugs often last for years because the diseases that they treat develop slowly (e.g., heart disease). That is not the case with vaccines; it becomes evident fairly quickly if a vaccine is stopping people getting a disease. So, one reason for the speedy nature of the COVID-19 vaccine trials is because they are trials for a vaccine and not for a drug designed to treat people with a chronic disease.
Normally, after a phase has been completed there is a gap before the next phase, while plans are developed for how to run the next phase. The developers of the new COVID-19 vaccines have overlapped their phases and started one before the previous one has completely finished. This has further reduced the time it has taken.
However, one of the main reasons that there are usually gaps between the phases is pretty mundane – it’s money. Clinical trials are incredibly expensive to run and can cost in the region of £40 000 per patient. The gaps between trial phases for small labs are usually spent in endless, frustrating rounds of writing and applying for grants (from government agencies, from large drugs companies etc.). Many trials are never completed because money cannot be found to run the final phase. For the COVID-19 vaccines, funding has not been an issue.
Usually, the regulatory bodies are given all the data from clinical trials after the completion of Phase III. However, for the COVID-19 vaccines a change in approach has been used, in which the data from the trials has been sent straight to the regulators as it has come in. This ‘rolling review’ allows verification and approval procedures to start while trials are still ongoing. The approval process for the Pfizer vaccine in the UK has been ongoing since the start of October, and COVID-19 vaccines have been made the highest priority for the regulators with, I suspect, other work being put on the proverbial back burner.
Excitingly, now that these new approaches to vaccine-making have been shown to work, it's going to become cheap, quick and easy to make new vaccines quickly for other diseases. Many diseases that cause huge amounts of suffering around the world don't have a vaccine because it has always been so expensive to develop them; for most drug companies there just isn't a large enough market for them to justify the costs. But, these new vaccines, which can be made in a lab without a disease-causing agent having to go anywhere near the scientists, offer a new hope ... the possibility that we can now make cheap and effective vaccines to treat more diseases, which will be particularly transformative in poorer parts of this world.
It is also my hope that in as much as we appreciate that having trains that can go a lot faster than 30 mph is a ‘good thing’ today, we will soon understand that the ability to produce safe vaccines in a matter of a year or so is better than vaccine development in the past; taking up to a decade to develop a new vaccine only increases the numbers who have to suffer.
Text: Mark Levesley @marklevesley levesley.com
Photo: "Syringe and Vaccine" by NIAID is licensed under CC BY 2.0