Is two months long enough to monitor for vaccine safety concerns?

News of Moderna’s mRNA candidate achieving 94.5% efficacy is the latest in a string of promising coronavirus vaccine-related announcements.
 
However, like Pfizer/BioNTech’s 90% effective candidate, the positive news comes with a key disclaimer: it is not yet known whether the vaccine has any unwanted side effects or safety concerns.
 
Barring any unforeseen events, both vaccine developers are likely to seek – and receive – emergency use authorisation (EUA) from the US Food and Drug Administration (FDA) within the coming weeks, once they have complete a median follow-up duration of at least two months after the conclusion of the full vaccination regimen.
 
The inherent need for an effective vaccine against COVID-19 – which in less than 12 months has infected nearly 55 million people and resulted in at least 1.3 million deaths – means this follow-up period is much shorter than the minimum of six months typically required to gain approval.
 
But while a vaccine is likely required for humanity to reach a post-COVID normal, the rush to get there comes with its own safety risks.
 
‘We have to balance the safety we get upfront with the need to try to save lives with a vaccine that’s helping to prevent a virus that’s killing 1000 or more people a day in the United States,’ Dr Peter Marks, director of the FDA division that approves vaccines, said last month.
 
‘We picked two months as something that was reasonably aggressive, yet also somewhat, kind of in the middle.
 
‘Not too aggressive, not too conservative – in the middle.’
 
Professor Dale Godfrey, Immunology Theme Leader at the Doherty Institute, told newsGP the idea of whether two months represents an adequate period is ‘not a straightforward answer’, but things are more likely to ‘go wrong’ earlier in the monitoring phase than towards the end.
 
‘Ordinarily, two months is way shorter than it would normally take to assess phase 3 trial results,’ he said.
 
‘But no one’s going to be happy if we say, “Yeah, we’ll get a vaccine to you in five years”. So it’s a risk–benefit analysis.
 
‘If you don’t issue a vaccine, outside of the normal three-, five-, 10-year timeframe, you’ll certainly lose a lot of lives and have a lot of people who get extremely ill from COVID.’
 
One aspect that separates the current trials from previous vaccine efforts, and which may make them more likely to pick up potential side effects that might otherwise have been missed within such a short period of time, is the high number of people that have been enrolled in trials.
 
‘They can establish with a larger number of people in a phase 3 trial much more quickly how effective the vaccine is; but at the same time you’ve got a higher chance of establishing earlier what, if anything, might go wrong,’ Professor Godfrey said.
 
‘Now, of course, none of this will tell you if there’s going to be a problem that might crop up a year later, and there’s no way around that other than wait for a year or two years or five years or however long any longer term potential problems might take.
 
‘[But given the toll of COVID] it’s not like waiting the normal amount of time is the much safer and lower risk approach. So it’s weighing up those important factors.’
 
According to Dr Marks, safety is what ‘keeps [him] up at night’.
 
‘The way we’re going to get over COVID-19 is if we get a vaccine that has 70% or 80% efficacy and we can deploy that to 70 or 80% of the population,’ he said.
 
‘[That way] we actually have a chance of having herd immunity, and we can be back in restaurants and in banks ... and doing what we normally do.
 
‘[But] it’s only going to happen if people have confidence enough to go get vaccinated, and we do have a crisis in vaccine confidence.’


One aspect that separates the current trials from previous vaccine efforts is the high number of people that have been enrolled in trials.

While Oxford University/AstraZeneca and Johnson & Johnson have both had to ‘pause’ clinical trials due to a ‘potentially unexplained illness’, neither of the mRNA vaccines have experienced similar setbacks.
 
Some recipients of the Pfizer/BioNtech candidate have reported feeling ‘hungover’ for up to five days post-injection, while Modern’s main side effects have been fatigue, muscle aches and injection-site pain after the vaccine’s second dose, characterised as more common than with flu shots but on par with others such as shingles vaccine.
 
University of Sydney vaccine expert Professor Robert Booy told newsGP ‘past experience’ suggests a vaccine candidate is unlikely to produce a serious side effect beyond about two months.
 
However, the fact mRNA vaccines have never previously been used on humans means the safety profile is not as well known as other candidates, such as those that rely on viral vectors.
 
‘These vaccines that have only been monitored two months [following second dose] should have built in surveillance for between three and six months, where people are contacted, preferably by email, and then they have a contact point to report anything that they’re worried about,’ he said.
 
Professor Booy said he is not ‘massively concerned’ about the safety of the two mRNA candidates, but does still hold some reservations.
 
‘I’m still a bit nervous about mRNA because it’s so new – and it’s so new that we can’t even speculate what it’s going to cause,’ he said.
 
‘That’s why I suggest the best quality phase 4 post-marketing surveillance, with follow-up at three months after vaccination and six months. Then you’ll have the kind of quality reassurance to go on with the program.’
 
Another issue, according to Professor Booy, is that previous studies conducted on other coronaviruses that presently only cause a common cold show that there is a risk of secondary infection within a few months.
 
‘The risk can be anywhere between about 5% and 25%, so that’s not insignificant, and whether it will be less severe would also be determined [by that surveillance],’ he said.
 
‘It could be built in safety-wise to check for secondary infection, as well as known serious neurological side effects. It sounds a bit “researchy”, but given the lack of knowledge, it’s a worthwhile investment in longer term follow up.’
 
Regardless of the potential for side effects, Professor Godfrey and Professor Booy both said they would still choose to receive a vaccine if given the opportunity.
 
‘There’s nothing inherently distressing about this new vaccine formulation,’ Professor Godfrey said. ‘Yes it’s mRNA, and so that could see people say, “Well , we don’t know what effect they’ll have on in the long run”, and that’s understandable.
 
‘But there’s no particular reason to think they’re likely to cause serious problems in the long run, either.’
 
Professoy Booy said the health implications of getting infected with COVID are likely more of a risk than the chance of unwanted side effects from a coronavirus vaccine – even a rushed one.
 
‘Frankly, I don’t want to get COVID. So if the opportunity comes within my professional working life for me to get a vaccine, I’ll put my hand up,’ he said.
 
‘I think the benefit would outweigh the risk. There are the acute effects on the lung, and also on the heart and sometimes on the brain [with COVID].
 
‘There are chronic effects as well, in a minority of people, and again, it can affect the heart, the lungs, the brain and the kidneys in a chronic way.
 
‘I don’t want either of those downsides.’
 
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