AstraZeneca vaccine: pull back or push through?

(English version of post in Dutch from April 6, 2021)

Spoiler: the plunger of the syringe must be pulled back before the vaccine can be pushed through

Doctors are trained to first check that the needle has not accidentally hit a blood vessel when administering intramuscular vaccinations in the upper arm. This is done by pulling back the plunger of the syringe after inserting the needle into the arm. If there is blood in the syringe, then the injection must be reinserted with a new needle. Otherwise, the vaccine may well enter the bloodstream, whereas the vaccine is intended to end up locally in the muscle. From the muscle, at most, it then ends up in (dendritic) cells of the immune system and the regional lymph nodes. Sometimes traces of the injected material can still be found in the spleen. 

To aspirate or not to aspirate?

A number of years ago, there was a lengthy medical debate internationally about the usefulness and necessity of this procedure [1, 2]. Particularly for vaccinating children. After all, the extra step possibly causes more pain, takes (a little) longer and, when blood is found, the jab has to be made again. This has to be done with a new needle and, according to some, with a new dose of the vaccine. Annoying and a waste, so preferably not. This unintentional puncturing of a blood vessel occurs in only one out of every thousand injections. The consequence is that the vaccine may be less effective. All this together was ultimately the decisive factor in changing the worldwide recommendation for intramuscular vaccinations to: "Checking for puncture of a blood vessel prior to vaccine injection is not necessary" [3]. With this instruction, most physicians, assistants, and nurses will not simply abandon their familiar routine of aspiration (pulling back the plunger), but for the newly recruited group of vaccinators who will be injecting the large numbers of corona vaccines, this may well be the new norm. As a result, there will be sporadic cases of vaccine accidentally entering the bloodstream.       

Adenovirus vector vaccines have never been used on this scale before

BUT, the current corona vaccines have a fundamentally different composition than the classical vaccines on which this policy is based. AstraZeneca's vaccine is a so-called vector vaccine, based on an adenovirus [4]. Just like Janssen's vaccine, by the way [5]. And when an adenovirus is administered into the bloodstream all kinds of effects do occur. From the extensive experience gained with gene therapy based on adenovirus particles, it is known that, depending on the dose, concentration and injection speed, acute reactions in the bloodstream can occur. And these reactions induced by the particles are undesirable and potentially dangerous and harmful to the body. Reactions have been described such as the production of inflammatory factors (cytokines and chemokines), complement factors, coagulation problems, hemodynamic changes, liver damage and thrombocytopenia [6, 7, 8, 9, 10]. The specific receptor interaction between adenovirus particles and platelets has also been extensively described in the scientific literature [11, 12].

It is therefore at least remarkable that in the entire development process of these corona vaccines based on adenovirus vectors no attention was paid to the possible consequences of a situation that an intramuscular injection would unexpectedly (partly) enter the bloodstream. The possibility is not mentioned and does not appear to have been investigated, and in any case the results have not been published in the publicly accessible part of the registration dossier [13]. It is also remarkable and worrisome that our regulatory agencies have not missed this information and do not seem to have requested additional studies in this matter [14]. After all, we are talking about a new type of vaccine platform with which we want to inject virtually the entire world population in record time. Without having been able to build up broad experience and available user data at that scale. And then you can't rely on the simple assumption that an intramuscular injection will end up 100% local at all times. Certainly not when it was well known from the "aspirate or not aspirate" discussion that a blood vessel is hit from time to time.   

Had this possibility been foreseen and investigated, and had the results of that investigation been known, then the adjusted advice would undoubtedly have been: "Checking for puncture of a blood vessel prior to injection of the vaccine is not necessary". From the principle of caution, the advice should have been based on this anyway and should only be adjusted after thorough research that the specific vaccine does not cause any problems in the bloodstream. In England they even included a separate box on the registration form to indicate whether or not there was blood to be seen after the injection!  

Meanwhile, in practice, it has become painfully clear that there is a chance that the AstraZeneca vaccine causes a rare and serious side effect in the blood. One with coagulation problems and thrombocytopenia, in some cases even fatal [15]. Could this be due to the rare situation where the adenovirus vaccine accidentally entered the bloodstream? We don't know. Because we have not investigated it and it has not been controlled for. This has also not been reported for the lipid nanoparticles used in the Pfizer and Moderna vaccines. These types of lipid nanoparticles are also known to cause allergic reactions in the bloodstream known as complement activation-related pseudo-allergy when administered quickly and in high concentration therein [16], and also lipid nanoparticles can transfect thrombocytes [17].

As always, these effects are dose, concentration, rate and time-dependent. So if it is directly relevant and related to any specific product is to be investigated and confirmed or excluded. The models and experience to do that are all available. At the April 7 press conference, EMA said they discussed extensively on the topic. Their experts confirm the possibility of intravenous exposure, and state that they deem the volume too small to cause any effect. We can be eagerly awaiting the experimental evidence for this assumption and hopefully learn from these EMA experts what would happen to the thrombocytes that actually happen to get transfected by the lipid nanoparticles or vector vaccins through the receptor for the adenovirus expressed thereon.

Pull back or push through?

Vaccinations with the AstraZeneca vaccine have now been paused for the second time. To determine how to proceed now, the potential risks have to be weighed against the obvious benefits of being vaccinated against the coronavirus, both on an individual and a societal level. But where does that balance lie, where is the tipping point? Can there at all be risk of deadly side effects in healthy people? Or should it only be allowed in vulnerable people, who are also at risk of dying or becoming seriously ill from the coronavirus? Or should the vaccine with these side effects, if proven linked to them, be pulled back completely? Or only be used for people over 60 years old where the side effect has not (yet) been observed much? And why is that, what is the mechanism behind it? We don't know.

In the meantime, there is a lot of pressure on everyone to push the vaccine through, because the social interest in getting corona under control is obviously very high. As a society , we just need all the jabs that can be put into an arm as soon as possible. On the other hand, the chance of the mysterious (deadly) side effect is very small. So, come on, go ahead and get that shot. The vaccine is effective, it protects against corona. 

If in doubt, don't get it?

Some of the people who are now allowed or obliged to receive the shot now look at it differently. There is doubt, and doubters vote with their feet. Their confidence in the safety of the vaccine has been breached. Especially when the cause is unknown. It no longer matters that the chance of an adverse reaction is very small. Then people make the independent choice based on the simple consideration of whether or not to take the risk. Even if the experts keep explaining that it is a negligible chance. 

When there is great hope for something good or great fear of something bad, the choice consists of only two possibilities: you do it or you don't do it. Compare it to buying a lottery ticket, many people buy them, even though the chance is rationally very small that you will win the big prize. Hope takes over as it easy picturing that it is you being the one getting lucky. Just as fear of the unknown can do. Just ask the aforementioned experts if they have ever bought a lottery ticket.....the chances are that they have. We are all human.

Personally, on Good Friday I encountered a general practitioner who, because of all the AstraZeneca perils, had a whole bunch of these vaccines left over. So, in the evening I was suddenly faced with the choice of whether to get the shot. Overwhelmed and well before my time (because 52 years old, with no underlying vulnerabilities known to me), and with the above knowledge in my baggage. Since general practitioners are used to checking that no blood vessels are accidentally hit, and he would of course carefully do this for me, I confidently had the vaccination administered. Just like my wife.

Green, orange or red

So, it is and remains a personal consideration. And my confidence in being injected correctly made it so that the balance between risk and benefit gave a strong green light signal for me. Without that confidence, the balance for me would have remained at orange, and therefore perhaps the signal at red. I would then have simply waited my turn, hoping for more clarity and clarification about the cause of the perils surrounding the vaccines. And, of course, for new instructions to the vaccinators to check for the puncture of a blood vessel prior to injection. 

Until then, my advice to everyone is to first have the plunger of the syringe pulled back and only then push through the vaccine. You are free to demand that of the person who injects the vaccine into your arm.