Given so many vaccines are being tested, how will this be decided?
Vaccines are now the best hope for ending the pandemic. Yet there are well over 100 vaccines at various stages of development around the world. Why so many? Are they in unnecessary competition? Although much of the publicity in the UK and USA is around these countries’ vaccines, it is Chinese research that has been filling the scientific journals over the past month. In this post, I give a brief overview of the different approaches and how a decision on which one to use might eventually be reached
What is a vaccine?
I like the CDC’s* definition: “A vaccine stimulates your immune system to produce antibodies, exactly like it would if you were exposed to the disease. After getting vaccinated, you develop immunity to that disease, without having to get the disease first”
*The USA Centre’s for Disease Control
Historical note
- The first vaccine was created by Edward Jenner who noted that milkmaids did not get smallpox but had the disease cowpox.
- The skin blisters looked similar to smallpox, but cowpox was much milder.
- In 1796 Jenner took some fluid from the cowpox blister of a milkmaid, gave it to an 8 year old boy. He then (bravely!) inoculated the boy with fluid from a smallpox blister and thankfully the boy did not develop smallpox
- The virus that causes cowpox is the vaccinia virus, hence the now familiar term vaccine
- The vaccine research unit in Oxford is named after Jenner
Covid-19 vaccine development in China
- Not surprisingly since China had the first outbreak, and they determined the genetic code of the virus, they have been at the forefront of developing a vaccine
- Three Chinese organisations (Research Institutes in Wuhan and in Beijing and the company Sinovac) have been testing vaccines which are a mild version of the Covid-19 virus. (This has been the standard approach to producing vaccines for many diseases, such as measles)
- Another company, CanSino, has tested a vaccine using a different (and safe) virus but altered to produce the CoVid spike protein (see below). This did produce immunity but had quite substantial side effects. Nonetheless, the Chinese have said that it is now OK to use in the military
- These Chinese studies have been quite small and researchers there do not have the tradition of the network of hospitals to run large scale clinical trials
- A further problem for the West is that China does not have the same stringent government requirements to prove success and safety
How are vaccines being developed in the West?
- The aim of most of the vaccines is to deliver a safe form of the spike protein of the Covid-19 virus (the bit of the virus that causes all the problems)
- There are 3 different approaches for such a vaccine based on the spike protein (all very clever and unimaginable a few years ago)
| Approach* | How spike protein produced |
| Recombinant | Made outside the body in laboratory |
| RNA | Made by a safe virus inside body in one step |
| DNA | Made by a safe virus inside body in two steps |
*For those who are interested, more details of these approaches are at the end of this blog
In what ways are these approaches different?
- Recombinant vaccines follow a well-established technology used for other vaccines whereas the RNA approach is completely novel and thus untested in the real world
- The only widely used DNA vaccine is the one developed for Ebola
- RNA vaccines may be more resistant to any mutation in the virus
- Recombinant technology is easy to scale for mass production
- RNA vaccines can be very stable for storage and cheap to produce
What we don’t know?
- Whether these different approaches will vary in how effective they are in producing immunity and how long it lasts for
- Theoretically these approaches may vary in their safety profile
Who’s involved
- There is no shortage of major international pharma companies involved!
- Many are working with research institutes directly on development and/or clinical testing
- Others are providing the capacity, once a vaccine has been licensed, to do the necessary large scale production
- These company links are necessary. At the moment, the companies are talking about cooperation and not-for profit production – as long as there is government support for developing vaccines that are not used
- It will be interesting to see what happens when, and if, the market place opens with multiple clinically successful vaccines!
How to decide which vaccine is best?
- These different vaccines are each only being compared to an inactive vaccine and not against each other
- Although we can compare the results on both the effectiveness and safety reported from each study, such a comparison may not be a fair reflection of their relative success
- Epidemiologists would be cautious comparing between two vaccines if (say) vaccine A was tested on volunteers in Sweden and vaccine B tested on volunteers in New York
- Thus, a reasonable question is: “should we not try and prove one is better than the other(s) in a ‘head to head’ comparison?”
- That won’t happen for several reasons
- It would be impossible to have one study involving all the available vaccines so in theory we would need multiple trials comparing different pairs
- Comparing two active vaccines to see (for example) if one prevented 10% more infections than the other would need much larger numbers of volunteers than studies of an active versus an inactive vaccine
- It would thus take too much time to have a result
- There are political and industrial considerations, given all the parties involved (although these are possible to overcome)
- Hence we won’t really know which is the best vaccine (at least initially)
What will happen next?
- The West will probably ignore the results from the Chinese vaccines
- Early studies from all the approaches suggest that the different Western vaccines appear to be safe and also without major short term side effects (these two are different).
- Thus far all these approaches also produce a reasonable level of immunity. (See for example, my post on 20 July the Oxford vaccine)
- We need to await the results of the large ‘Phase 3’ studies which government regulators use to give the green light to start widespread use. (Though my post of 13 August gave the case that has been put forward by others not to wait for such results)
- With luck definitive results from these studies will be coming out from the end of this year, to say first quarter 2021.
- The pressure will then be on for different countries/companies/manufacturers to start widespread use
- Over the next 12 months independent researchers will also start undertaking sophisticated statistical analyses comparing the Phase 3 trials from the different vaccines and attempt to draw conclusions about which approach is best.
- Countries may, but probably will not, change which vaccine is used if they have already started a vaccination campaign using a safe and effective vaccine, even it is not the most effective
- In addition, all the companies/administrations will start collecting the data on what happens when the vaccines are in widespread use: what are the short, medium and long term side effects and how long do they last?
- This is a story that will run and run!
Some details about the different approaches of vaccine development
- ‘DNA Vaccine’: Made by adding into a harmless virus just that part of the Covid-19 virus gene that makes the spike protein. The spike gene in this vaccine then produces large amounts of the spike protein via a second genetic step involving RNA
- ‘RNA vaccine’: The process by which DNA produces proteins is via a second genetic process involving a messenger called RNA. RNA vaccines are the actual RNA message which deliver directly the genetic instruction to produce the spike protein
- ‘Recombinant vaccine’: Rather than relying on the vaccine to stimulate the production of the spike protein in our cells, a recombinant vaccine actually contains the spike protein which is manufactured genetically in the laboratory
Making sense of CoVid-19 with Silman 