How can we know if the new vaccines are safe?

The recent euphoria over the success of new vaccines against Covid-19 has, not surprisingly, raised questions about both their short- and long-term safety.  In the press releases the companies and researchers have emphasised that there were no safety issues in the trials thus far.  Regulators on both sides of the Atlantic though will be looking very carefully at the available data from the trials reported this month.  In this post I consider what do we know to date and what questions remain to be answered.

Role of regulators

The regulators around the world have the sole responsibility for issuing a license for any vaccine for public use. Without this approval widespread use cannot happen

• Over the next few weeks, drug regulators will be pouring in detail over the safety data from the clinical trials before issuing a license 
• Their prime focus will be assessment of safety
• They also have a duty to weigh up the size of any risks against the benefits
• Despite the political and commercial pressures to grant licenses rapidly for widespread use of the vaccines, they will not deviate from their safety role
• (For the record I sat on the UK’s drug safety review committee for 10 years!)
• Thus, the issuing of a license is a badge of safety but for sure (see below) they will demand further surveillance of safety following the introduction of any of the vaccines

What are the safety questions?

No surprises here – the key questions are:

• What are the possible adverse health problems that can result from the use of the vaccine?
• How severe are they?
• How common are they?
• Are there specific subgroups of the population who are more at risk, for example by age, or women who are pregnant etc?

What are the possible adverse health problems?

• It is useful to distinguish between:
  • Health problems that are plausible adverse consequences based on what we know
  • An increased risk of other health problems that were not anticipated
• As regards the former, these include:
  • Reactions at the injection site eg some local inflammation etc
  • Mild viral symptoms eg fever, aches etc
  • Allergic response immediately or very shortly after a vaccine dose, which could be mild or severe
• As regards the latter, these include
  • Evidence of toxicity based on planned frequent testing for testing for abnormalities in blood counts, plus liver or kidney function (these are standard questions for any new vaccine or drug)
  • Occurrence of an unexpected illness or disease ranging from mild disorders such as a widespread rash to something more severe which could also range from:
    •  the exceptionally rare – such as the case of transverse myelitis (inflammation of the spinal cord-see below) 
    • To an increased risk of something more common, but equally serious, such as major infection and septicaemia*

*I give these only as examples of  adverse events which any vaccine trial (including those for influenza) would need to collect data on 

How do trials collect data on the above risks?

Again, no surprises here.  The table below shows what safety data was collected from the participants in the Oxford Trial.  I assume that the other vaccine trials collected similar data 

What do we know about the occurrence of the above?

• Detailed data from the recent (‘Phase 3’) trials have not been made public
• All the companies have reported though that there are indeed some local reactions and mild viral-type symptoms these are self-limiting and also worse after the first dose of the vaccine than the second 
• The only significant other health problem was the two cases of spinal cord inflammation as I previously commented on (https://makingsenseofcovid19withs.com/2020/09/09/astrazeneca-vaccine-pause-why-and-what-now/ )
• Data from the blood tests and reports of any other unexpected illnesses will be available to the regulators but were not included in the press releases for any of the vaccines 
• We can be confident that if there had been any concerns, the independent data monitoring committees for all these trials would have issued warnings 

Are there other sources of data on safety?

I am an epidemiologist who only works in numbers from studying humans but:

• It is reasonable to accept  that given what we know about the design of these vaccines, there are no specific health problems that we might have expected apart from the self-limiting local reactions and minor symptoms described above
• Useful here to compare this situation with treatments for cancer where the drug developers are aware that a new drug will carry significant known risks but given the target disease, that may be a price worth paying

Clinical trials versus real world evidence 

• One key issue, that is relevant to any similar clinical trial, is that the participants in a trial are normally healthier compared to the rest of the general population 
• Indeed, in these trials, which are in a real sense experiments, they would only get ethical approval if they excluded people who might be at risk of any adverse consequence – and opting for the greatest possible caution
• As an example, the list below gives the exclusions for the Oxford trial.  

• The Oxford trial also excluded

• Further, all these trials are of volunteers who put themselves forward 
• Thus, even though the Oxford trial which would allow older people to participate if they for example had asthma, it is perhaps less likely that such people would not choose to volunteer
• I do need to emphasise that this selection of the more healthy is inevitably the case for all such trials.   Hence following the issuing of a license, regulators will insist on all companies undertaking surveillance to identify if ‘in vaccine use in the real world’ the vaccines are similarly safe
• Such surveillance activities are referred to as ‘Phase 4’ ie post licensing studies.  I will discuss the issues that they involve in my next post on this blog!  

Conclusions

• At this stage in their development, based on what has been released and published thus far, there do not appear to be any suggestions of a safety problem at least in the first couple of months after vaccination
• This conclusion would not be unexpected given what we know about how the vaccines work
• We cannot know and totally exclude any significant risks to the more vulnerable people nor whether there are risks beyond this initial 2 months 
• We also should not forget that those who are possibly more vulnerable to risks from the vaccine are definitely more vulnerable to the risks from the infection
• And in case you are asking- would I have any of the 3 vaccines if they were licensed tomorrow – the answer is yes! 

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