EXPERT REACTION: Johnson & Johnson pauses COVID-19 vaccine trial

Stopping or pausing rules are incorporated into clinical trial protocols as an added measure to ensure volunteer safety. The way they work is that when any significant clinical event occurs, or is reported from any subject on the study, the study is automatically immediately stopped (or paused) while additional information is collected as to the nature of the event and its relatedness to the study treatment, in this case the vaccine.

Whenever dealing with a large population, such as those included in phase 3 vaccine studies, events will occur in volunteers, events that most of the time would have occurred had they been participating in the study or not. The pause allows sufficient information to be gathered and reviewed by those responsible for the conduct of the study, as well as independent experts, to ensure the event does not represent a safety concern to other volunteers on the study, and when that is confirmed the study can resume.

This is also why placebos are used in clinical trials so that we can see if events that we think are not related occur at the same rate in people on the study who have received the vaccine and those that have not and to help us determine the relatedness of significant clinical events to the vaccine.

Meeting the stopping or pausing rules on clinical trials is not uncommon and should not be perceived as indicating a safety concern with this vaccine or the other vaccines in which the same phenomenon has already been reported. While there may be a desire by many for information to be released relating to the event, the requests for transparency must be balanced with ensuring that the confidentiality of the volunteer be maintained and the integrity of the study not be compromised.

Johnson and Johnson has paused its current clinical trial of a vaccine for SARS-CoV-2 for much the same reason as AstraZeneca paused its vaccine trial a month ago. A patient in the trial has experienced an undisclosed serious adverse event requiring the trial to be halted so the event can be investigated in more detail. It does not mean the trial will not continue, and is required under ethical standards governing clinical trials. A clinical trial should only be initiated and continued if anticipated benefits justify risks and the rights, safety and wellbeing of the trial participants must prevail over all other interests. No doubt the company is also wishing to abide by its slogan 'clean and clear and under control'.

This is a blinded clinical trial with 60,000 participants and this sort of occurrence is not uncommon in a large trial. Johnson and Johnson disclosed that at this stage it was not known whether the affected participant was part of the treatment group or those given a placebo in the trial. The company has also indicated that their vaccine has produced a strong immune response against coronavirus, which is encouraging. How effective this response is in protecting an immunised individual from contracting SARS-CoV-2 is currently unknown.

It is not unusual to suspend a clinical trial if there is an adverse-reaction reported during testing. This is all part of checking that the vaccine (or drug) is safe. People can fall ill in clinical trials by chance and it may have nothing to do with the vaccine itself, this is especially likely in a large trial. Each case has to be investigated thoroughly to evaluate the cause and likelihood of it being trial related.

There was also a recent pause in the AstraZeneca SARS CoV-19 vaccine trial because of reported neurological side-effects. The Johnson &Johnson participant has not yet been identified, but it would be more worrying if it were also a neurological effect. Vaccines can sometimes cause the same virus-related problems that they are meant to prevent. Worryingly, there are now multiple reports of neuropathological effects of COVID-19 of varying presentation and severity, so if it were to be a neuro side problem that would need special attention.

It is far too early to tell if there is a generic safety problem with respect to neurological (or other organ systems) effects of any of the new SARS CoV-19 vaccines - that's what the testing is for. This is the reason that vaccine trials take a long time, to establish the safety of the treatment when given at large scale. Suspending a study due to possible side effects (connected or unconnected to the treatment) is part of normal good practise in vaccine development and shows that the study is being done properly.

There can be no rushed release of a drug, vaccine or antibody cocktail when the safety of millions of people is at stake - no matter what the political pressure. Hopefully, it will be shown that this is an effect unrelated to treatment so that the study can recommence as soon as possible. The world needs a vaccine because COVID-19 is not going away on its own.

We’re going to have to get used to hearing these sorts of reports of pauses in vaccine trials. As you vaccinate more people in these trials the chances are that there will be some illnesses in participants, and these need to be investigated. The trials pause while these investigations take place. The only difference here is that in the world that we live in right now, the progress of these trials are in the public eye, and so we are riding every bump.

It's important not to overreact until the incident is examined fully. Since these trials are double blind, we don’t even know at this stage whether the person who had the illness received the vaccine or whether they were in the placebo arm of the trial. We also don’t know the seriousness of the illness. We should all look forward to obtaining more information about this as it becomes available, but in the meantime, we should not be overly concerned.

The pausing of the J&J vaccine trial tells us the strict safety monitoring is occurring, and this should reassure people that the correct process is being followed. The J&J vaccine, like the AstraZeneca vaccine and other candidates, use an adenovirus vector -  a harmless virus that does not multiply in humans - to deliver the part of the SARS-CoV-2 virus protein that elicits antibodies. No licensed vaccines in the past have used an adenovirus vector. We do not yet know what illness the trial participant suffered, but we can assume it was a serious enough illness to pause the trial.

The key questions are:

1. Is this caused by the vaccine, or is it incidental and would have happened to this person anyway?
2. If caused by the vaccine, which component of the vaccine caused it? It could be the vector or the protein from SARS-CoV-2.

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 difference 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 antibody-dependent enhancement (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.

As more and more vaccines go through phase 3 trials, we will find some are more effective, and some are safer. Australia should diversify our options for vaccines to ensure we have enough options to choose the best ones when the time comes. If we focus only on one or two vaccines, and they end up being non-starters or have serious side effects, we could be left out in the cold. It is best to choose several different vaccine technologies - MRNA-based, vectored, subunit etc - as each technology will have unique features and may also be associated with safety.