Matching people with the right vaccine best way to deal with side-effects

We are in a lucky situation where we can, with some logistical re-shuffling, offer alternative and effective vaccines to individuals vulnerable to side-effects

As Ireland rolls out a variety of COVID-19 vaccines in a bid to bring the pandemic under control, it has become apparent that a “one size fits all” approach may not be wholly applicable. Factors like age, gender and pre-existing conditions need to be considered to effectively deliver mass immunisation.

The phase 3 clinical trials of Pfizer, Moderna and AstraZeneca vaccines all reported increased frequency of expected symptoms including pain at injection site, fever and slight headache lasting for a few days. This is referred to as “reactogenicity”, a sign that the vaccine is doing its job; a little short-term pain for a lot of long-term gain. The frequency of these expected, on-target side-effects has been borne out in mass rollout.

However vaccines are powerful immune activators and the risk of other off-target, undesired complications , naturally exists

During the development of any drug, therapy or vaccine, scientists are obsessed with uncovering such side-effects. As a consequence only the safest candidates are brought to market.


The clinical trials for the common COVID-19 vaccines did not report an increased frequency of any serious side-effects and have been deemed both remarkably effective and safe. However, as we embark on mass global immunisation, the scale and speed of which has not been witnessed before, it becomes a numbers game and we will begin to see more reported off-target side-effects.

In these cases, we need to carefully assess if there is a causal link - if this event is indeed more common in the vaccinated population than the unvaccinated population and if it can be explained by the delivery of the vaccine.

As we approach 500 million people receiving 1 dose of various COVID-19 vaccines worldwide, we are beginning to see otherwise rare or non-apparent side effects become more frequent and thus causal links are emerging.

An early side-effect was the extreme anaphylactic response shortly after administration of the mRNA vaccines seen in some people with history of severe allergic disease. By understanding the cause of this and the sub-group of people in which it is more likely to occur, we were able to mitigate against it.

People with history of severe allergic responses can be offered a different non-mRNA-based vaccine or can be administered a mRNA vaccine under prolonged clinical supervision, such that any anaphylactic response can be immediately treated.

Now as we roll out the adenoviral vector based COVID-19 vaccines (Astra Zeneca and Johnson & Johnson), we are seeing an increase in another unexpected off-target side effect - the rare but real occurrence of severe blood clotting issues. Although unexpected, the science now suggests because these vaccines use a harmless virus - the adenovirus, acting as a Trojan Horse to deliver the COVID-19-specific instructions to the immune system - there may be an antibody-based over-reaction against the clotting system, which in a very rare sub-group of people, generally aged under 50 and predominantly female, results in thrombotic events anytime up to 3-weeks post-vaccination.

As with the anaphylactic side-effects, we can mitigate against it by firstly being aware of signs and symptoms of circulatory issues, e.g. persistent headaches, numbing in extremities and secondly, if concerned, presenting for urgent medical care.

This is where stratification of risk becomes important. The challenge is now on scientists and medical professionals to figure out which one person out of one million people are prone to this side-effect, what’s different about their immune or clotting systems that makes them respond like this and - if we can identify these people before presenting for vaccination - can we offer alternatives or mitigate risk appropriately?

Fortunately, we are in a lucky situation where we can, with some logistical re-shuffling, offer alternative and effective vaccines. But of course, this has knock-on effects to our already beleaguered national immunisation programme. Thus far, NIAC have made the decision to prioritise vaccinations based on the increased risk of death from COVID-19 infection with age and luckily this older population does not overlap with the reported age groups at risk of rare clotting events from Astra Zeneca and Johnson & Johnson vaccines.

If a true sex-bias is also observed in these responses, it means we may able to proceed with vaccinating half the younger population (males) while mitigating for others. However, all this is going to put pressure on stocks of alternative vaccines, nationally and worldwide and this decision will need to be revisited as this virus circulates in the community and as we move through the prioritised age-groups, all while global vaccine stocks fluctuate.

While we now have a wide array of vaccine tools at our disposal, the scientific and medical community is just beginning to better appreciate the variability in these biological responses. The hope is we can capitalise on our good fortune thus far and use the available vaccines in a more targeted, safe, and cumulatively effective manner.

Fred Sheedy is Assistant Professor in Trinity College Dublin’s School of Biochemistry & Immunology