EXPERT REACTION: Pause of AstraZeneca's COVID-19 vaccine trial
Opinion piece/editorial: This work is based on the opinions of the author(s)/institution.
Following news yesterday that AstraZeneca has paused their Phase 3 Covid-19 vaccine trials due to a suspected adverse reaction, more information has been released about the participant that led to the global shutdown. There are ongoing media reports that the patient experienced neurological symptoms consistent with a rare but serious spinal inflammatory disorder called transverse myelitis, however the company told the ABC earlier there was no final diagnosis and earlier reports were incorrect. Below Australian experts respond.
Organisation/s: Australian Science Media Centre, Murdoch University, The University of New South Wales, CSL Innovation Pty Ltd, CSIRO, Australian Catholic University, University of Sydney, Griffith University, University of Auckland
These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.
The Astra Zeneca vaccine, like some other candidates, use an adenovirus vector - a harmless virus - to deliver the SARS-CoV-2 spike protein (which is a small component of the virus, not the whole virus). The spike protein is the most commonly used protein from the virus in the different vaccines. No licensed vaccines in the past have used an adenovirus vector. A person in the phase 3 trials allegedly developed transverse myelitis (although AZ is now saying it is not transverse myelitis). Transverse myelitis is a condition of the spinal cord, usually caused by immune-mediated damage to the myelin in the spinal cord.
The key questions when an adverse event occurs in a clinical trial are:
- Is this caused by the vaccine, or is it incidental and would have happened to this person anyway?
- If caused by the vaccine, which component of the vaccine caused it?
The adenovirus vector has not been used in vaccines that have been licensed before. We do know that transverse myelitis has been reported very rarely after adenovirus infection, although with a different adenovirus. The one in the vaccine is a chimpanzee adenovirus. There are other virus vectors, like modified vaccinia Ankara, which have been widely used for vaccines and shown to be safe.
Could it have been the spike protein? The virus SARS-CoV-2 does cause immune-mediated illness in some people - such as a rare inflammation of blood vessels seen in children; as well as other immunological reactions. One is called Antibody Dependent Enhancement (ADE), which was seen with SARS and MERS CoV vaccines. In these cases, if someone has already got immunity to the virus (because they have been exposed before, or in some cases because they have antibodies to the common-cold causing coronaviruses), they can develop a much more severe, immune mediated illness after they are vaccinated. From what we know about coronaviruses, and past research on MERS and SARS vaccine, the ADE is not associated with the spike protein, but with one of the other proteins, which is not contained in this vaccine. In addition, ADE generally does not present with myelitis. However, myelitis can be caused by viral infections, so it remains possible that this is a vaccine adverse event.
We determine if a vaccine adverse event is causal or coincidental by looking at the rates of the event in vaccinated and unvaccinated people in the clinical trial. If there is no different in the two groups, that is reassuring. If however, the rate of the adverse event is statistically significantly higher in the vaccinated group, that indicates it is likely caused by the vaccine. All trials have safety committees that carefully evaluate the evidence and decide on whether the vaccine caused the event. In some cases, vaccine adverse events are so rare that they will not be detected in standard clinical trials. This happened with the dengue vaccine, which showed no safety issue in clinical trials, but ADE occurred when it was used in a large scale vaccination program in the Philippines with far higher numbers of people vaccinated than in the clinical trials. The same occurred with the very first rotavirus vaccine - a very rare side effect, a bowel disorder in children, was not seen in the clinical trials, but became apparent when the US began vaccinating infants with it in the 1990s. That vaccine was withdrawn and the subsequent, newer rotavirus vaccines had to undergo massive scale clinical trials (>60,000 people) to prove they did not cause that same problem. So a clinical trial is not the end of the story.
This is why we do safety monitoring post-licensure of vaccines. Our old vaccines are tried and tested in this way, and extremely safe. A new vaccine has to be rigorously tested to ensure safety.
The lesson for Australia is to diversify our options for vaccines - of all the candidates, some will be more effective than others; and some will be safer than others. We must diversify to ensure we have enough options to choose the best ones when the time comes.
The decision by AstraZeneca to pause a phase 3 clinical trial of a vaccine for SARS-CoV-2 following a serious adverse reaction experienced by one of the trial participants is expected. A clinical trial should only be initiated and continued if anticipated benefits justify risks and the rights, safety and well-being of the trial subjects must prevail over all other interests. This is a requirement of independent ethical approval before the trial commenced.
The trial participant affected will require careful investigation to determine if the adverse reaction was caused by an undiagnosed autoimmune disorder, a viral pathogen (e.g. Influenza, Hepatitis B, Herpes virus) and/or stimulation via the vaccine itself. Unwillingness by the pharmaceutical company to comment immediately is most likely a reflection of the time required to carefully dissect these possibilities via diagnostic tests to identify the possible cause(s) and likely occurrence in other trial participants.
The formulation of the AstraZeneca vaccine involves a platform not previously used in an approved vaccine, so caution is required to interpret if an unexpected immune stimulation gave rise to the inflammatory spinal disorder experienced by the trial participant. Information on specific inclusion and exclusion parameters of trial participants would provide further insight.
The pause of the phase 3 AstraZeneca COVID-19 clinical trial is a good example of the robust safety precautions in clinical trials such as this. Most clinical trials include stopping/pausing or halting rules so that as a result of a significant medical event, the trial is halted automatically until the nature of the event, its relatedness to the vaccine being given in the clinical trial, and the implications for the safety of the other volunteers in the trial, can be fully understood. It is also not uncommon in large later phase trials to see significant medical events simply based on the incidence of these events in the population and the large numbers of volunteers included in the study.
Clinical trials are designed not only to ensure volunteer safety is maintained throughout but also so that incidents such as this can be assessed and managed appropriately. This is why stopping rules are included and placebo controls are used so that relatedness to the investigational product can more easily be determined. It is also why a board is assembled to asses these events, often referred to as the data safety monitoring board or DSMB. The key focus now is to ensure the volunteer in question is receiving optimal care to manage the medical event and for all of the available information relating to this event to be collated and assessed by the investigators and the DSMB to determine if or more likely when the trial can resume.
Although this adverse reaction has been a big headline, and one can understand this given we are in a pandemic and all hoping for a vaccine to take us out of this, it is important not to overreact. There are perhaps a few important things to note.
Firstly, the recording of an adverse reaction does not necessarily mean that this was caused by the coronavirus vaccine being tested. One possibility is that the person who had the reaction may not have even received the vaccine and could have been in the placebo arm of the trial. In this trial those not receiving the coronavirus vaccine being tested were injected with a different vaccine as a control. As this is a double blind trial, where both the investigators and the participants are blinded to what they are administering/receiving, it will not be immediately obvious what the person who reacted adversely had received.
Also, the presence of an adverse reaction does not necessarily mean it was caused by the vaccine. This is a classic problem in these types of trials where one has to try work out whether a one-off adverse reaction is likely to have caused this response. This is not always easy.
Finally, the halting of the trial should reassure us that the proper processes and safety precautions are being followed, despite the urgency to find an effective vaccine to respond to this pandemic. The investigators need to go through the process of trying to work out what may have happened in this situation before progressing with this trial. Adverse reactions in these sorts of trials do occur and this does not necessarily mean that there is a major problem with the vaccine. The world will no doubt be watching this very closely over the coming days and weeks.
Associate Professor Helen Petousis-Harris is a vaccinologist at the University of Auckland
Halting during a clinical trial is not uncommon and pausing to investigate a possible safety signal shows that this vaccine is not being rushed and that safety is being carefully assessed.
A vaccine is a biological product that triggers an immune response so there is always the theoretical possibility of immune-mediated adverse events. Many conditions that are inflammatory or appear to be autoimmune in nature are often preceded by a natural infection, such as influenza, or herpes virus, and the SARS-CoV-2. However, vaccines are not usually a cause of such events. While this event could be vaccine-associated, it is more likely that it is not. It is also possible that the cause of this event may not be able to be determined. It is important to allow the investigation to conclude, and also to be prepared for other COVID-19 vaccine trials to experience haltings during their journey, as safety is taken very seriously.
Serious adverse events do appear from time to time in clinical trials. The fact that the serious adverse event occurred in the treatment arm - that is to say the person who got the serious adverse event, actually got the vaccine and not placebo - is of concern. However it is now for the study coordinators to independently investigate if the serious adverse event can be attributed to the vaccine or is likely to be something completely independent. This is the very reason why we put all new compounds through such strenuous processes and is also the reason why it takes time.
In clinical trials, unexpected events, side effects or adverse events happen. Due to the nature of this trial, which is being so heavily scrutinised, if these things do happen then AstraZeneca is probably obliged to temporarily stop the trial to see if there is any connectedness between the vaccine and the unexpected event. It is important that all of the safety measures are followed scrupulously, as they would be with any other Phase 3 clinical trial.
Scientists by their nature are incredibly cautious, so before we have something such as a vaccine or a drug, we try very hard to ensure the data we have is incredibly robust. For this reason, it’s premature to say we have a vaccine in hand. There are 165 or more vaccine candidates around the world, but we are still some way off having a vaccine available to the general public.
The main challenge in vaccine construction is to ensure safety - both short and long term. Underdeveloped vaccines can sometimes cause signs of the disease they are designed to fight in certain susceptible people. Sometimes this can be refined out by careful control of the size and frequency of dose.
Acute disseminated encephalomyelitis has been recently detected as a rare side-effect in COVID-19 patients by UK researchers. This is a worrying complication of COVID-19 that causes brain and spinal inflammation. There are multiple known neurological effects of SARS CoV-2 infections, which vary from simple “pins and needles”, to neurological and brain damage, right through to stroke. Several mechanisms are likely be involved including direct attack, embolism and autoimmune, but the mechanistic picture is still unclear.
That a SARS CoV-2 vaccine in development could cause such effects is not impossible, but in the case of the AstraZeneca vaccine trial there is only one case so far and that is not proven to be connected to the treatment. Assuming that they recommence the Vaccine trial soon (and I think it is highly likely that they will) I am sure that the trialists will be carefully monitoring any possible neurological problems very closely. But the disease causes multiple systemic effects outside the lung, so all possible manifestations of the infection will have to be followed carefully. This is why vaccine development takes a long time. Efficacy is often relatively easy to test, but safety assessment takes a lot of studies with a large number of participants. There can be no short cuts when the plan is to administer a treatment to hundreds of millions of people; it’s got to be proven safe and I am confident that the major vaccine suppliers will ensure this irrespective of political pressure.
The halting of the Astra- Oxford COVID vaccine trial is not unexpected and is a good sign that the investigation team is proceeding cautiously and not cutting corners. All trial protocols have safety monitoring built into them and usually independent data safety monitoring committees and the Astra trial is no exception.
It is a good sign and reassuring for the community. It has most likely made headlines as the eyes of the world are on COVID vaccine development at the moment and is possible in other future trials, so we may see it again.
Details are currently not available from AstraZeneca.
However, 'pausing’ is completely normal part of process in therapeutic evaluation ensuring safety to public - this is a good thing.
As many of our scientific colleagues would say and I quote - ’this could be (i) trivial; (ii) serious; (iii) unrelated to vaccine; or (iv) related to vaccine.’
The system is working, and also highlights importance of adhering to rigorous evaluation procedure of clinical trial. It is important to not rush things simply because the public would like to hear good news.
People need to understand hope is important, but hype is bad.
Pausing a trial shows that due care is being taken to ensure the vaccine is safe and well understood. It’s exactly how trials are designed to work and it’s not uncommon. All clinical trials have built-in checks and balances to ensure that a robust data set is developed to show whether a medicine or vaccine is safe and effective in the majority of people. The researchers will now investigate whether this adverse event was caused by something other than the trial vaccine – consistent with the fact that medical events statistically occur in all large groups of people – or whether it was a reaction to the vaccine. This understanding will determine a path forward.
Developing a safe and effective vaccine is a highly complex process. The world has rallied around creating a COVID-19 vaccine, with more than 170 vaccine candidates at varying stages of development around the globe.
Late-stage or large-scale human trials for the Oxford-AstraZeneca vaccine are being undertaken across multiple countries, involving tens of thousands of people. The purpose of these trials are to examine the safety and efficacy of the vaccine candidate.
We understand that the trials have been voluntarily paused to independently review an unexplained illness in one of the trial participants. We understand this is a single event and at this stage the cause of the illness is unknown.
Events like this are not uncommon in clinical trials, and are a standard part of the scientific process.
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