By now most people have heard that AstraZeneca, a UK pharmaceutical, working with Oxford University, are one of the major companies developing a vaccine for SARS-CoV-2, and also that they have had to pause their Phase 3 clinical trial because a subject came down with an inflammatory disorder. Let’s put this into some important context.

The basic facts are that the AstraZeneca vaccine did very well in Phase 1 and 2 preliminary trials. These are smaller trials mostly about safety, with the Phase 2 trial including some preliminary (usually open label) efficacy data. These trials are basically used to determine if it is safe and worth it to proceed to a huge Phase 3 trial. The Phase 3 trial includes 30,000 subjects. When you increase the number of subjects by orders of magnitude then you are likely to pick up increasingly rare side effects. That is one of the main points of this staged approach to research. Then, of course, a drug or vaccine might be marketed to millions of people, and still more rare side effects will crop up. There is simply no way to avoid this – it’s math. That is why so-called Phase 4 trials follow reported side effects after market.

But also, when you are studying 30,000 subjects all the things that normally happen to people will happen at the background frequency. Some of them will get sick during the trial by chance alone, having nothing to do with the study drug or vaccine. So every potential adverse effect is tracked, determined if it is biologically likely that it is related to the experimental treatment, and then statistically analyzed to see if it is above the background rate.

In this case one subject developed transverse myelitis, which is inflammation in one segment of the spinal cord. This will cause weakness and numbness at that level and below, therefore usually affecting the legs. The background incidence of transverse myelitis is about 1.3-4.6 cases per million people per year (this does not include people known to have an autoimmune disease like MS that causes transverse myelitis). If we take 4 cases per million per year, that translates to 0.033 cases per 33,000 subjects over three months. That is the probability that one of the subjects in that trial would have randomly developed transverse myelitis. That may seem really unlikely, but actually you have to consider the probability of a subject developing any disease, not just transverse myelitis. When you add it all up it’s actually pretty likely that one or several people in the trial would randomly develop a disease not related to the vaccine. In fact, this is the second person in this particular trial to develop a serious potential adverse event resulting in a pause of the trial.

Having said that, transverse myelitis is an inflammatory disease, which is what vaccine developers worry most about. Vaccine and the adjuvants they include are designed to stimulate an inflammatory response, and so inflammatory side effects are the most concerning. To some extent vaccines are a balancing act – stimulating the immune system enough to provide resistance to disease, but not so much that unacceptable adverse side effects occur. But also vaccines are designed to specifically (not generally) stimulate an immune response – against the targeted agent (more on this below).

What does all this mean for a COVID vaccine? It’s too early to tell. But this is exactly the concern – part of the severity of COVID-19 is that it provokes in some people an extreme immune reaction that causes more damage than the virus itself. Could this property translate to a vaccine against COVID-19? That is the big question, and exactly why Phase 3 trials are essential. That is also why this case of transverse myelitis is particularly concerning.

This is all part of vaccine development, and why it often takes years. Vaccines have to be tweaked and tweaked, in order to provoke a specific immune response against a vulnerable aspect of a virus, while not provoking a response harmful to the host. Sometimes researchers have difficulty finding that vulnerability, which is why we still don’t have an HIV vaccine, for example.

All of this is also why the smart money is saying that 2021 is a reasonable time-frame to expect a COVID-19 vaccine, especially for widespread distribution. Talks of getting a vaccine out in 2020 are a bit of wishful thinking – not impossible, if all the dice roll favorably, but I wouldn’t bet on it. This also informs our discussion about how to properly balance fast-tracking a vaccine while maintaining necessary safety precautions. We can certainly streamline the regulatory hurdles, and make sure the research is prioritized so it is not slowed down by limited resources. But beyond that, we cannot speed up the research itself. It takes time. You cannot, for example, know that immunity will last for six months in less than six months of follow up time (you can extrapolate, but not really know). And you cannot know what side effects are likely to crop up until you study at least tens of thousands of subjects (and as I said, even then the data is limited).

Medical professionals are used to making these risk vs benefit decisions. That is the core of medical decision-making. This is why we need to let objective scientists and doctors drive this process, and keep politics as far away from the process as possible. Of course, that is not what’s happening. Trump has already poisoned the well by suggesting a vaccine might be available by election day, by attacking the FDA for political motivation, and by disparaging his own experts and government guidelines. He then had the gall to claim that his critics were being “anti-vaccine,” while Trump is the one with a history of being actually anti-vaccine, until he thought a vaccine could help his political prospects.

But let me end with a bit of good news – vaccine technology in general continues to advance. A recent study has found a protein that helps to suppress parts of immune function, essentially decoupling some of the initial harmful inflammatory response from the long-term protective antibody response. In the preliminary study the protein reduced inflammatory side effect and actually increased antibody protection in response to the vaccine. It’s too early to tell if this specific molecule will pan out as a useful adjuvant, but it demonstrates that our knowledge of the complexities of the immune system and how to manipulate continue to advance. This is a science news story that does not get as much attention as it deserves – immune modulation is a massive win for modern medical science, and continues to advance.