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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
  • The three vaccines were all tested in both small animals (mice) and then in macaque monkeys without problems 
  • (A few years ago I was involved in assessing the research on the safety of vaccines used on the troops in the Iraq war – given concerns about the troops exposure to infections from biological weapons – and visited the macaque monkey research unit at Porton Down – they are quite vicious!)
  • In the next stage of the development (Phase 1 and 2 trials) there were also no safety issues in human volunteers – but the numbers in these studies were small
  • There were the expected short lived local reactions
  • This applied to all vaccines’ Phase 1 and 2 trials

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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12 replies on “How can we know if the new vaccines are safe?”

Thank you as this post was easy and very clear to understand and also very reassuring regarding the safety of the vaccines.

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Have any of the vaccines been tested on children age 10-12 and upwards?
What was the ratio of men to women tested?
Very clear and easy to understand as always, thank you.

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Yes children, I think from 10 have been included in the studies but the exact numbers have not been published. Similarly we don’t know the gender split. It is possible, but I believe highly unlikely that gender will influence the success of any of the vaccines

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Thank you Alan. I agree that this is very reassuring and easy to read/understand. There seems to be a great deal of concern about as yet unknown possible longer term health risks with the vaccines (eg a la Thalidomide) due to the speed with which this has all happened. I feel this could unfortunately be a major factor in discouraging many from having a vaccine.

Also, having read your notes about the trials, do you think there would be any plan for groups previously excluded from trials to be included in any future trials, or would people with those conditions need to remain unprotected even though possibly vulnerable?

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Great questions! In my next post I will be addressing the issue of how long term side effects will be assessed and the challenges in doing so. As regards inclusion of the groups excluded from the trials, there will not be specific trials in these groups but data will be gathered from these groups as they are given the vaccines as part of the general roll out. However the underlying question is what the regulators will say when they make their decisions about issuing if a license. My guess is that they will say vaccine ok for most of these groups but to “observe special caution”- whatever that mean!!

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Could you comment as to whether you think it is worthwhile taking vitamin C and vitamin D

Supplements to help with the prevention/treatment of covid19.
Many thanks. Linda Weisgard.

Thanks

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Thanks. It is very rare for anyone these days to be deficient in Vitamin C. There was a theory many years ago that large doses of Vitamin C, ie more than you need, would protect against viruses such as the common cold. That was disproven.

Vitamin D is a different story. There are many people who are deficient in Vitamin D, without knowing about it. We know that because their blood levels are below deal. This is much more common in in winter when sun exposure is less. Whether Vitamin D actually stops you catching Covid is possible but certainly if you are D deficient, the severity of the infection can be greater. So supplements are helpful

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I don’t know whether there’ll be a choice, but if you had a preference, which of the known vaccine candidates would you personally choose, please (Oxford, Pfizer or Moderna – or maybe the Russian one)?

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In the UK and other European countries, I am sure that individuals will not have a choice! I am not sure what the situation is in the USA. At the moment, the data we are aware of are so limited that no-one can be certain which is the best. I will post next week, if I can get the data, on the issue of success in preventing infection (whether asymptomatic or not) and success in preventing clinical disease. Pfizer vaccine for sure only gave data on the latter. Oxford suggested success against the former.

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Given that long-term effects can’t ever be assessed until a long term has passed, is there usually a required minimum period of time between testing a drug and its release? If yes, what is it? And thanks for this blog!

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Was going to post today about assessment of long term effects but got sidelined by the need to put some sanity in the numbers debate! I will address the long term safety issue this week!

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