COVID-19 vaccines

COVID-19 vaccines

There is no doubt that an effective vaccine against COVID-19 would be a game-changer. So it is not surprising that there are over 100 different vaccine candidates at various stages of development. It might be helpful if I review some of the ways in which vaccines can be developed, starting with the approaches that have been used historically. Whatever approach is used, the goal is to produce a protective immune response, without causing any harm to the subject.

1. Inactivated vaccine. This is conceptually the simplest approach. You grow the virus in the lab and inactivate it, e.g., by heat or chemical treatment, so that it is incapable of causing disease but is still immunogenic. The Salk polio vaccine (the one given by injection, not the ‘sugar-lump ‘one) is an example. Although conceptually simple, very few of the COVID vaccine teams are using this approach. One possible reason is that it requires the production of large amounts of active virus, which is not easy and very hazardous. It also requires meticulous testing to ensure that it is completely inactivated.

2. Live attenuated virus. This requires the virus to be genetically altered in some way so that it is unable to cause disease, but is still viable (so you can still grow it in the lab). If the virus is fully attenuated, this is a safe approach, but achieving attenuation is time-consuming – although these days, rather than trying a variety of random mutants, you can specifically knock out key genes (if you know enough about the biology of the virus). The other polio vaccine (Sabin vaccine) is an example of this type. Again, there are only a few potential COVID vaccines in this category.

3. Toxoids. The third historic approach, exemplified by tetanus and diphtheria vaccines, is to purify and inactivate the bacterial toxin responsible. This is not relevant here (I include it merely for the sake of completeness).

We then come to approaches that rely on recombinant DNA technology (‘genetic engineering’).

4. Recombinant proteins. This involves cloning one of the viral genes (typically coding for a spike protein), and putting it into a bacterial cell (or some other convenient cell) and getting that cell to make quantities of the protein (or a specific part of the protein). The host cell can be grown in large quantities and the desired protein purified for use as a vaccine. Since there is no actual virus involved, this is safe to produce and use, at least from the point of view of infection. Many of the vaccine candidates are of this type (although there may be differences in the details). Since this approach is already used for some existing vaccines, there are already large-scale production facilities available.

5. Viral vectors. In this approach, instead of expressing the protein in a bacterial cell, the gene is inserted into the genome of a harmless virus, so you use the recombinant virus as the vaccine; when it infects a human cell, the required protein will be produced. There are several well-characterised vectors available, which have been developed (and in some cases used) either for other vaccines or for gene therapy. Several of the candidate vaccines that have started clinical trials are of this type.

6. Nucleic acid vaccines. Here the vaccine consists, essentially, of just the RNA of the virus (or a DNA copy of it). The RNA or DNA is taken up by a human cell which uses the information to produce the relevant viral protein. There are also several candidate vaccines of this type in early stage clinical trials.

Testing your vaccine.

The obvious questions are Is it safe? and Does it work?

Ideally, you would start with several different lab animals to see if it is safe to use. You could test the immune response created, but that does not necessarily mean the same thing as efficacy, unless you have an animal model that mimics the human disease, so you can do challenge studies – i.e., you deliberately infect a group of vaccinated animals and see if they survive. You obviously cannot do that with humans!

You would then move, cautiously, to human studies, starting with a very limited number of healthy young volunteers (phase I), mainly to assess any possible side-effects. Again, you can monitor antibody production but you cannot assume that this equates to protection.

Phase II would consist of an extension to a larger panel of subjects, representative of the population, still mainly concerned with safety, but also possibly investigating other factors such as size of dose and route of administration.

Only in phase III would you start in earnest to get data about efficacy. This involves a much larger group of people (often thousands) in a randomised, controlled, double-blind study. They are assigned, randomly, to one of two groups. One group gets the vaccine, and the others something else (in one case, a meningitis vaccine is being used for the control group).  The subjects don’t know which group they are in, nor do those administering the vaccine or assessing the results. The key is held by an independent person who monitors the results as you go along, and may call a halt if anything is obviously going wrong, e.g., there are side effects associated with the use of the vaccine. The trial may also be halted prematurely if things are going very well; if the vaccine clearly works, it is unethical to continue giving a placebo to the control group.

That’s, more or less, the text-book description. With the COVID-19 candidate vaccines, short cuts are being used, partly because of the urgency of the situation, and partly because many of the vaccines involve the use of existing tried and tested technology. So while many vaccines are described as being in clinical trials at phase I, in practice these seem to be hybrid phase I/II trials with an element of phase III in them – e.g, using several hundred volunteers in a randomised controlled trial aimed at assessing efficacy as well as safety.

Jeremy Dale

27 April 2020




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