December 3 & 4, 2019
Professor Heidi Larsen – Director Vaccine Confidence Project
There’s a lot of safety science that’s needed and without the good science we can’t have good communication. So, although I’m talking about all these other contextual issues and communication issues it absolutely needs the science as the backbone. You can’t repurpose the same old science to make it sound better if you don’t have the science that’s relevant to the new problem. So, we need much more investment in safety science.
Dr. Soumya Swaminathan, Chief Scientist, WHO
I think we cannot overemphasize the fact that that we really don’t have very good safety monitoring systems in many countries, and this adds to the miscommunication and the misapprehensions because we’re not able to give clear-cut answers when people ask questions about the deaths that have occurred due to a particular vaccine. And this always gets blown up in the media. One should be able to give a very factual account of what exactly happen and what the cause of that. But in most cases, there’s some obfuscation at that level and therefore there’s less and less trust then in the system.
Dr. Martin Howell WHO
Every time that there is an association, be a temporal or not temporal, the first accusation is it is the adjuvant. And yet, without adjuvants, we are not going to have the next generation of vaccines. And many of the vaccines that we do have, ranging from tetanus through to HPV, require adjuvants in order for them to work. So, the challenge that we have in front of us is how do we build confidence in this? And the confidence first of all comes from the regulatory agencies, Dr. Marion. When we add an adjuvant it’s because it is essential. We do not add adjuvants to vaccines because we want to do so. But when we add them it adds to the complexity. I give courses every year on how do you develop vaccines. How do you make vaccines. And the first lesson is, while you’re making your vaccine, if you can avoid using an adjuvant please do so. Lesson two is, if you’re going to use an adjuvant use one that has a history of safety. And lesson three is, if you’re not going to do that, think very carefully.
Stephen Evans, Professor of Pharmacoepidemiology London School of Hygiene and Tropical Medicine
It seems to me that adjuvants multiply the immunogenicity of the antigens that they are added to. And that is their intention. It seems to me they multiply the reactogenicity in many instances and therefore it seems to me that it is not too unexpected if they multiply the incidences of adverse reactions that are associated with the antigen but may not have been detected through lack of statistical power in the original studies.
Dr. Martin Howell WHO
You are correct. As we add adjuvants, especially some of the more recent adjuvants, such as the ASO1 supplement derived adjuvants, we do see increased local reactogenicity. The primary concern though usually is systemic adverse events rather than local adverse events. And we tend to get in the Phase two [and] in the phase three studies quite good data on the local reactogenicity. Those of us in this room that are beyond the age of fifty who have had the pleasure of having the recent shingles vaccine will know that this does have quite significant local reactogenicity. If you got the vaccine you know that you got the vaccine. But this is not the major health concern. The major health concern which we are seeing are accusations of long-term effects. So, to come back to this once again point to the regulators. It comes down to ensuring that we conduct the Phase two in the phase three studies with adequate size and with the appropriate measurement.
Dr. David Kaslow, VP, Essential Medicines, Drug Development Program Path
In our clinical trials where we are actually using relatively small sample sizes and when we do that we’re at risk of tyranny of small numbers. Which is you just need a single case of Wegener’s granulomatosis and your vaccine has to solve, Walt’s, how do you prove a null hypothesis? And it takes years and years to try to figure to figure that out. So, it’s a real conundrum, right. Getting the right, dealing with the tyranny of small numbers, making sure that you can really do it. And so, I think one of the things that we really need to invest in are kind of better biomarkers, better mechanistic understanding of how these things work so we can better understand adverse events as they come up.
Dr. Marion Gruber, Director, Office of Vaccine Research and Review, FDA
One of the additional issues that complicates safety evaluation is if you look at, and you struggle with, the length of follow-up that should be adequate in a, let’s say pre-licensure or even post marketing study. If that’s even possible. And again, as you mentioned pre-licensure clinical trials may not be powered enough. It’s also the subject population that you administer the adjuvant to because we’ve seen data presented to us where an adjuvant, a particular adjuvant, added to a vaccine antigen did really nothing when administered to a certain population, and usually it’s the elderly, you know compared to administering the same formulation to two younger age strata. So, so these are things which need to be considered as well and further complicate safety and effectiveness evaluation of adjuvants combined with vaccine antigens.
Dr. Bassey Okposen, Program Manager, Nigeria
I cast back my mind to our situation in Nigeria where at six weeks, 10 weeks, 14 weeks, a child is being given different antigens from different companies and these vaccines have different adjuvants, different preservatives and so on. Something crosses my mind. Is there possibility of these adjuvants, preservatives cross-reacting amongst themselves? Have there ever been a study on the possibility of cross-reactions [inaudible] that you can share the experience with us now?
Dr. Robert Chen, Scientific Director, Brighton Collaboration
Now, the only way to tease that out is if you have a large population database like the vaccine safety datalink, as well as some of the other national databases that are coming to being worthy. Actual vaccine exposure is tracked down to that level of specificity of who is the manufacturer, what is the lot number, etc etc. And there’s an initiative to try to make the vaccine label information bar-coded so that it includes that level of information. So that in the future, when we do these type of studies, we’re able to tease that out. And, in order to be – each time you subdivide them the sample size gets, becoming more and more challenging, and that’s what I said earlier today about that we’re really only in the beginning of the era of large data sets where hopefully you could start to, kind of harmonize the databases for multiple studies. And there’s actually an initiative underway, Helen may want to comment on it, to try to get more national vaccine safety data base linked together so we can start to answer these types of questions that you just raised.
Dr. Heidi Larson, Director Vaccine Confidence Project
The other thing that’s a trend and an issue is not just confidence in providers, but confidence of healthcare providers. We have a very wobbly health professional front line that is starting to question vaccines and the safety of vaccines. When the front line professionals are starting to question, or they don’t feel like they have enough confidence about the safety to stand up to it, to the person asking them the questions. I mean most medical school curriculums even nursing curriculums I mean in medical school you’re lucky if you have a half-day on vaccines, never mind keeping up to date with all this.