Germany argues too little data to approve AZ vaccine for over 65’s: what are the facts?

Yesterday Germany did not recommend the use of the AstraZeneca vaccine for people aged over 65.  The EU is going to announce their ruling today (29^th January).  Given that the over 65’s are the most vulnerable, and the first target for vaccination in most countries, this is a disturbing conclusion.  

Its potential impact is all the greater as the production of AstraZeneca vaccine is planned to be the largest in the world, in part because of its low price and the fact that AstraZeneca have agreed to deliver it at cost.  In this post I consider what conclusions can be drawn on the success of the different vaccines in older people.

The challenges of the clinical trials

• All the vaccines being licensed for widespread use require proof of both safety and benefit 
• That proof is based on a comparison in large trials between the active vaccine and a placebo
• Companies doing these trials have to plan to study enough people, and to have long enough follow up to produce meaningful results
• There ae complex statistical calculations when planning a trial to ensure that enough people are recruited to provide accurate estimates of how well the vaccines work
• Given the urgency of the situation regarding the development of Covid-19 vaccines, all companies wanted to get their trials completed as quickly as possible
• All companies realised they needed to recruit across broad sections of the population but that the overall number might not be sufficient to provide accurate answers for each sub-group.
• With all these trials, the “headline result” is the outcome in all the trial participants
• Subgroup analyses are then done say by age, but accepting that within each of these subgroups there may not have been sufficient numbers recruited to answer the detailed questions 
• Even ignoring  age (see below) we can’t know from the trials for example how the vaccine works in people of different ethnicities, with different levels of obesity etc
• The aim is that once the vaccines are licensed, ‘authorities’ will be able to collect data on much larger groups of individuals in all kinds of subgroups, to provide more detailed answers
• The challenge for regulators is that they have to deal with the data they have and make assumptions about how far the data from say age subgroups is sufficient to allow a wider license  

What were the data from older age groups  in the clinical trials?

• Let me be absolutely up front and say that the numbers in older age groups recruited to the AstraZeneca trials were much lower than for the Pfizer or Moderna trials

• AstraZeneca’s initial programme was to focus on the under 55s. It was the first company to start Phase 3 trials and as is common practice, early studies on vaccines often start with recruiting younger, healthier volunteers 
• We should also note that as people age, they accumulate other health problems and it is typically only the fitter older people who are both allowed to, and actually volunteer to participating in clinical trials.
• Thus, the older people who do participate may not be representative of the general population of older people
• Nonetheless AstraZeneca had far few older people than the other companies on whom to study the effects of their vaccine 

What did the data show on the success of the vaccines in older people?

• AstraZeneca said in their publication of the trial results “vaccine efficacy could not be assessed but will be determined if sufficient data are available in the future”
• The data from Pfizer showed the following:

• Two obvious points:
  • The number of cases of Covid-19 that happened in the placebo group was very small, especially in those over 74, thus we cannot have very accurate estimates of benefit in that group  
  • On the data that do exist, the vaccine was obviously very successful in reducing cases in the over 65s
• Although the data are not repeated here, the level of protection was similar in those over 65 to the over 90% protection seen in the much larger groups of participants below that age

• The data from Moderna showed the following:

• Conclusions are very much the same as with the Pfizer vaccine.  The rate of reduction of cases (86%) was just a little lower than the 95% seen in the younger participants 

Are there other data to suggest the AstraZeneca vaccine is successful in older people?

• Before embarking on the large scale clinical trials, AstraZeneca and the other companies undertook studies on the level of immunity following vaccine 
• These were complex laboratory studies to see if the vaccine would produce the necessary  high levels of immunity in the blood samples tested
• The blood results were very reassuringly positive, which is why the companies then tested whether this would be translated into reducing the number of cases as discussed above
• I have gone back to the blood results data from the AstraZeneca vaccine early studies to see if there was any influence of age on the level of the immunity achieved.
• These are the data on the antibody response, looking only at antibodies that would ‘neutralise’ the virus
• This is what I found:

• There was no reduction in the level of the antibody response in those aged 70 and over
• I then looked at the other part of our immune response to vaccines: – the T cell response – which might be more important – and this is what I found:

• Again no evidence of a reduction in this component of our vaccine produced immunity
• Thus for the AstraZeneca vaccine the immune response was not reduced by age in the people they studied

Conclusions

• German (and may be European) regulators are right in saying that the data are too limited to say that the AstraZeneca vaccine is successful in preventing clinical infection in people over 65
• As I have shown in this blog previously, the AstraZeneca vaccine, given in 2 doses 12 weeks apart, achieves an 80% reduction in clinical cases in people under 65
• All the 3 licensed vaccines – by targeting the spike protein – are working in the same way
• The Pfizer and Moderna vaccines work equally well in preventing clinical infection in people above and below age 65, but the numbers were still too small to be confident about the accuracy of the estimates
• The AstraZeneca vaccine produces a substantially more than adequate immune response in laboratory testing which was very similar in all age groups
• Taking all this into account, I believe the UK regulator, under its emergency powers, was right to conclude that on balance the AstraZeneca vaccine was likely to be effective in those over 65
• Obviously we will get more data as the vaccines are rolled out for general use, although these data are much harder to interpret when not in a randomised trial 
• And yes, I would be happy to have the AstraZeneca vaccine (I am older than 65!)

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