June 2023 ACIP Meeting - Vaccine Safety

thank you everyone and we are returning from our break uh we are happy to reconvene acip we are moving into the next session on vaccine safety and Dr Tom shim bakuro from CDC ISO will um start us off and then give us an overview of where we're headed thank you so the the topic of this session is going to be um CDC efforts to study the safety of the childhood immunization schedule next slide so I'll provide a background on the CDC immunization safety office and ISO efforts to study the safety of the childhood immunization schedule and then Dr Matthew Daly is going to talk about the childhood immunization schedule and safety and studies in the vaccine safety data link and then lastly Dr Andre Ved is going to um describe an analysis on the preliminary evaluation of aluminum content in childhood vaccines and the risk of asthma and a Danish Nationwide cohort cohort and then we'll have discussion next slide so just a some background on our office um the mission of our office is to monitor the safety of vaccines given to children and adults some of our Key activities include monitoring newly recommended vaccines and new recommendations for existing vaccines monitoring CDC priority vaccines including seasonal flu and covid vaccines conducting planned safety studies supporting the data needs of the advisory committee on immunization practices assessing individual risk factors for Adverse Events responding to vaccine safety inquiries conducting communication and Education Coordinating with State Health departments and preparing for pandemics and emergency responses next slide and these are our main monitoring programs the vaccine safety data link the clinical imun ization safety assessment project vsafe and the vaccine adverse event Reporting System next slide so in in 2013 The Institute of medicine which has um been renamed the National Academy of Medicine conducted a review of the safety of the childhood immunization schedule and The Institute of medicine in this report that you see here concluded that the available evidence supported the safety of the childhood ization schedule the identified areas that warranted further study um and concluded that randomized control trials were not suitable for studying the the schedule due to ethical concerns but identified the vaccine safety data link is a resource to conduct observational studies on the safety of the schedule next slide as a result of this report uh CDC and the vaccine safety data link um published the white paper the vssd white paper and in this paper um vssd identified plausible outcomes for study in the schedule suggested methodological approaches for studies and propose next steps next slide so I'm going to turn it over to Dr Daly here um to to to describe some vssd studies but before I do that I I want to reinforce that CDC takes vaccine safety seriously including the safety of the childhood immunization schedule and that's demonstrated by our work in the vaccine safety link data link and our continued efforts to study the safety of the schedule um hello everyone I'm Matt Dy and I'm going to present now on the childhood immunization schedule and safety studies in the vaccine safety data link link next slide um I have no conflicts of interest next slide um this is an overview of the talk that I'm I'm going to give I'm first going to review some additional aspects of the 2013 Institute of medicine report that Dr Shim Muro made reference to then I'm going to discuss feasibility work within the vaccine safety data link um specifically the white paper uh next I'm going to discuss us briefly three published vssd studies these have all been published but they haven't been presented publicly at acip they all examine various aspects of the schedule and then more long-term Health outcomes following exposure to the schedule then I'm going to touch on fut future investigations and then I'm going to try to put this into a little broader context next slide please so as Dr Shim Boro said in 2013 the I issued a report that was titled the childhood immunization schedule and safety I would highlight that this report was not done because of known problems with the schedule but was done to respond to public concern parents had said had expressed the concern the schedule seems to be too many vaccines too soon and that was what drove the to issue this report the um solicited public com com uh comment reviewed the literature for concerns and then reviewed scientific evidence around the safety of the schedule the concluded that existing evidence supported the safety of the schedule as a whole however they identified a number of evidence gaps one way to think about this is that there were no SK there were no studies that randomized children to receive the entire current schedule or no vaccines and those studies would not be ethical to conduct at this point in time however that presents certain challenges um again each new vaccine is just added to the existing schedule um in addition the highlighted several other aspects of the current evidence base such that um safety studies usually examine acute Adverse Events and there's less known about long-term Health outcomes following exposure to the schedule and this was a concern that parents had raised and then the I committee had a number of conclusions some of which we've already made reference to but that randomized controlled trials would not be appropriate in this context for ethical reasons however additional studies were needed in existing surveillance systems in particular in the vssd OR vaccine safety data link um and then the methods for these studies was going to be complex and because of that complexity additional feasibility work was needed as an aspect of complexity what does it mean to be exposed to the schedule because again it's not a question of studying a single vaccine given at two months four months and six months but somehow can you examine the entire schedule which represents multiple doses given over multiple times as an exposure in a traditional epidemiologic study and then finally The Institute of medicine um recommended Focus on long-term outcomes next slide please this led to the white paper funded by the Centers for Disease Control involved subject matter experts CDC colleagues and vssd colleagues just to explain a little bit more about the vssd it's a collaboration between the CDC and integrated Healthcare organizations and it conducts vaccine safety surveillance and research the objectives Dr Shim buur mentioned in his introductory slides but an objective was to Define measures of the schedule that could be studied with a focus on the first 24 months of life in part because this was the primary uh age at which parents were expressing concerns and then to identify plausible outcomes that could be studied in this context again with an emphasis on long-term Adverse Events not because there had been a problem that was raised but because this was the area that parents were most concerned about then there were some additional consideration about methodologic approaches and then the white paper group um looked at potential outcomes and then prioritized those outcomes based on feasibility Public Health significance public concern next slide please some additional conclusions from the white paper group included the following several high priority outcomes were identified including allergic disorders such as asthma autoimmune diseases such as type 1 diabetes melodus and neurologic disorders including epilepsy it's important to note through this entire conversation that some public concerns may have Li limited biologic plausibility that should be taken into account that wasn't a that's not necessarily a reason not to ever in investigate that hypothesis but it's a cause for caution um the white paper group had some additional conclusions that there needed to be really careful attention to bias this is true for all observational studies but in in this uh setting in particular because undervaccinated or unvaccinated children may be a different group than fully vaccinated children in a number of ways so attention to bias concern about unmeasured confounding including misclassification bias for example do kids who appear undervaccinated within the vssd are they actually undervaccinated so there was a recommendation to conduct surveys of parents this was done and for the most part confirmed that kids who appear undervaccinated in the vacine safety data link are in fact undervaccinated when you call their parents another recommendation was to use negative control outcomes this is a way to detect potential bias in a study because this is an outcome that should not be associated with the exposure um so again it's a way to detect potential bias an example would be all cause injury which shouldn't relate to any aspect of the childood immunization schedule and then there was additional caution to make sure to control for differences in healthcare utilization between these groups and then a final note of uh caution was to plan for a long and complex process there was a recommendation that any initial positive findings would need to be studied further to refute to replicate initial findings next slide please so now I'm going to transition to review three published studies the first is a VD study of antigens and non-targeted infections the public concern here was that Early Child immunization could overload the immune system um and then that that needed to be converted into a testable hypothesis the study design was a matched case control the exposure was cumulative vaccine antigen exposure estimated by summing the number of antigens in each vaccine dose birth through 23 months of age the outcome was infections but particularly infections not targeted by vaccines in emergency department and impatient settings 24 through 47 months of age so think about this in terms of the public concern this is basically saying do kids who receive the full schedule have more infectious illnesses later that aren't targeted by vaccines in this study a sample of outcomes underwent medical record review to validate those outcomes again it's a match case control so there was match matching on age sex and presence of chronic disease next next slide please here are the results of that study among children with versus without nonvaccine targeted infections from 24 to 47 months of age the match odds ratio for cumulative vaccine anent exposure was not significant with the match odds of 0.94 confidence interval that included one there were number of uh secondary analyses which were consistent with the primary findings and so the conclusion was no association between the number of antigens young children receive through vaccines in the schedule and then the likelihood of subsequent Ed or inpatient encounters for infections in other words that there was no evidence this schedule overwhelms the immune system at least overwhelms the immune system as defined by more risk of infection later next slide please so this is an additional study of the immunization schedule on type 1 diabetes here the public concern was That vaccine antigens or ingredients which would include aluminum which is used as an adimin in vaccines could interfere with immune function and as a consequence increase the risk of autoimmune disease this was a retrospective cohort study um one thing that was unique about this study was that three different exposures three different ways to measure the schedule were examined cumulative vaccine antigen exposure in the first 23 months of age cumulative vaccine Associated aluminum exposure in the first 23 months of age or average days undervaccinated this is a more complex and perhaps less intuitive exposure but what this measures is vaccines given later so it's essentially sort of a a metric of DeLay So three different exposures the outcome was type 1 diabetes melodus identified by diagnosis codes diagnosis codes and electronic health records have a high degree of accuracy for identifying incident type 1 diabetes the length of followup in this study was greater than 5 years as a mean and then analyses were adjusted for a number of factors including sex race and ethnicity and um other factors including Healthcare utilization as measured by the number of well child visits next slide please here are the results of this examination of the schedule on type 1 diabetes in the main analyses as I mentioned there were three different exposures cumulative vaccine antigen was not significant cumulative vaccine Associated aluminum was inversely Associated so a hazard less than one a hazard of 0.77 with a confidence interval that did not cross one and then average days under vaccinated was nonsignificant there were a number of sensitivity analyses including factoring bring in family history of type 1 diabetes and those were similar to the primary results so in conclusion the vaccine schedule was not associated with an increased risk of type 1 diabetes however there was this finding that there was decreased risk of type 1 diabetes at a higher vaccine aluminum exposure um but I want to highlight that we need to interpret this finding it's important to consider but interpret it with caution because there's a modest effect size here and there would be more uh study needed to either refute or replicate this finding next slide please moving on to the third published vssd study uh presented in this context of studying the schedule and then more long-term Health outcomes this was a study of vaccine Associated aluminum and risk of subsequent asthma the public concern here was That vaccine ingredients including specifically aluminum which is used in vaccines as an adant to make them more immunogenic could possibly increase the risk of allergic disorders including asthma there is some biologic plausibility excuse me to this hypothesis although I describe the biologic plausibility as uh tenuous because it's based only on animal data but there is some animal data that suggests that aluminum and vaccines could skew towards a t helper cell 2 or th2 response and it is known that th2 cells play some role in allergic asthma this study was a retrospective cohort the exposure was cumulative vaccine Associated aluminum received birth through 23 months of age and then the outcome was persistent asthma at 24 through 59 months of age that outcome was defined as one inpatient or two outpatient diagnoses of asthma plus one or more prescriptions for a long-term asthma control medication and then all of these analyses were done separately for children with or with without eczema and the reason for this is that eczema is uh condition chronic dry skin condition presents in early childhood and then is strongly associated with subsequent asthma risk so the thought there was that it could be an important uh uh confounder um um because it could also influence vaccination patterns so all analyses were done separately for children with and without eczema uh next slide please moving on to the results of this study there were more than 14,000 children in this vssd study with eczema 6.0% subsequently developed persistent asthma there were more than 312,000 children without eczema 2.1% subsequently developed persistant asthma and then the mey and vaccine Associated aluminum in these cohorts were both uh 4.18 milligrams next slide please so this slide I'm going to go through a little more slowly because there's a little bit of complexity here what this slide shows is the crude incidence rate of asthma by the quantity of vaccine Associated aluminum the Y AIS is persistent asthma per 10,000 person years and then the x- axis is vaccine Associated aluminum and milligrams I'll stop here and say what explains variability in vaccine Associated aluminum essentially two things under vaccination kids not getting all the vaccines that were recommended for them or differences in the vaccine products used the left panel is eczema before 12 months of Age Again more than 14,000 and as you can see and I said these are crude incidence rates so it's with no adjustment for co-variants and as you can see the um asthma incidence appears to increase with increasing levels of vaccine Associated aluminum the same is true for the no exema cohort it's a little less uh striking visually in part because the y- AIS is bigger because of the higher asthma risk among those with eczema in the left panel next slide please so this slide shows adjusted results primary analysis I'll walk us through this First Column is the variables including a number of co-variates second column is the adjusted Hazard ratio for the eczema cohort third column is the adjusted Hazard ratio for the no exema cohort I'll highlight that the exema cohort model is a different model than the noxema cohort as I mentioned the results are uh analysis are stratified so for the eczema cohort there's an adjusted Hazard of 1.26 with a confidence interval that does not cross one for the risk of persistent asthma for the no exema cohort the adjusted Hazard ratio is 1.19 confidence interval that also does not cross one and then there are a number of co-variates these are all chosen because they are risk known risk factors or suspected risk factors for asthma and these are all of a uh Direction and of a magnitude that we had we would expect based on the published literature and then there were additional covariates um those are included in the notes below the table next slide please so on this slide we're presenting a number of secondary analyses each row represents a different analysis First Column is the uh analysis second column is the sample size third column is the adjusted Hazard ratio for the ezema cohort fourth column is the sample size for the no exema cohort and then the last column is the hazard for the no exema cohort again each row represents a separate adjusted analysis first row is the primary analyses which I just showed on the prior slide second row if if we look at aluminum not as a continuous exposure but but as a dichotomous exposure more or less than 3 mg of aluminum um adjusted Hazard was significant for both the eczema and the no eczema cohort next row if we exclude aluminum of the extremes so if kids who got less than one milligram of aluminum from vaccines or more than five they may be very different than the rest of the cohort so if those are excluded results are significant both for the eczema and the no ezema cohort next We examined only fully vaccinated children for whom the variability in aluminum exposure was less but it would be from vaccine product and not from under vaccination the results were not significant for the eczema cohort but they were significant for the no ezema cohort that represents about 61 62% of the overall cohort if we then examined again it's a separate analysis um adjusted for breastfeeding there was only limited data from electronic health records on breastfeeding in only for about 133% of the cohort so it's a much smaller cohort size but with adjustment for breastfeeding results were not significant for the eczema cohort and not significant for the no exzema cohort although the point estimates were similar but as I mentioned the sample size was quite a bit smaller second to the last row persistent asthma at 36 to 59 months of age this was done with the thought that maybe wheezing at 24 to uh 35 months of age would would represent viral induced wheezing and not be true asthma so in that analysis looking at asthma diagnosed at a little bit older age results were significant for both the eczema cohort and the no eczema cohort and then finally the last row is a negative control outcome of all cause injury in emergency department in impatient settings 24 to 59 months of age and I as I explained there should be no association with vaccine Associated aluminum and it's a test for potential bias and here the results are uh not significant for either cohort all these analyses were adjusted for a number of covariates that are listed below next slide please so then how do we interpret these results um there was a small positive association between cumulative vaccine Associated aluminum before 24 months of age and persistent asthma 24 to 59 months of age there were positive findings for children with and without eczema we did a number of secondary analyses um there were positive associes in some but not all these analyses the study had a number of study strengths which are listed here also a number of study limitations including that there was no data on uh dietary or environmental alumin exposure um however i' put that limitation in the context that the American Academy of Pediatrics recently issued a report arguing that very little of ingested aluminum is absorbed and so it may not have too much of an immunologic effect in which case it's a little bit less of a study limitation additional limitations include that there's no data on social determinance of Health um there with all observational studies is risk of unmeasured confounding some examples there are many here because there are many asthma risk factors um but including um family history of asthma exposure to secondhand smoke um but we also need to keep in mind that they would need to be Expos associated with both the exposure and the outcome to influence findings in addition and this is an important point there could be antigen effects and what I mean by that is it could be if there's a positive Association here that it's not the aluminum within vaccines but an antigen such as acellular prusis that somehow influences immune response and subsequent allergy risk and that we're detecting it through aluminum only because aluminum is a proxy for the antigens that come along with the aluminum and as I would highlight which I've mentioned several times so far today this is the first step in a multi-step process next slide please so changing gears a little bit this is a figure that shows asthma prevalence among children less than 18 years of 18 years of age in the United States 1980 to 2020 this is based on National Health interview survey so this is parent self-report of their child's asthma and then you can see the y- axis is prevalence um in percent and then the x- axis is years and then there are additional uh tick marks for when um various vaccines were added to the schedule all of these vaccines contain aluminum with the exception of some Hib vaccines contain aluminum and some do not and as you can see from the figure asthma prevalence um was rising in the US from 1980 to 1996 again this is in all kids age less than 18 years of age then there was a gap where there was no data and then rates were stable from about 2000 to 2010 and then have been decreasing since about 2010 so this is this is entirely ecologic so we need to interpret this with all the caution that we would any ecologic data but asthma prevalence in the US did not does not appear to be rising um alongside additional aluminum containing vaccines added to the US childhood immunization schedule next slide please so I mentioned further investigations of vaccine aluminum and risk of vaccine Associated aluminum and the risk of asthma we'll hear from Dr Anders Ved who's going to present next on data from the Denmark National Database in addition there's a new study that's planned in the vssd this study will have a larger cohort and longer follow-up time although there is overlap between this cohort and the cohort in the study that I just presented um we're considering examining aluminum as a earlier exposure before 12 months of age as opposed to the study that I just presented which was 0 to 23 months of age um examining eczema as a covariant and not uh stratified by eczema and then the most important distinction between this new plan study in the vssd and the one I just presented was to examine asthma at a later age we've had a number of uh consultations with uh colleagues both at the NIH and at cesa and there's concern that I made reference to before that um asthma diagnosed earlier may represent viral induced wheezing and not true asthma and so asthma diagnosed at a later age is more likely to represent true asthma and so uh again this study would look at asthma at a later age 60 through 84 months of age is what's been proposed in addition we we have uh extensive conversations about additional considerations for other data sources which could help assess any relationship between vaccine Associated aluminum exposure and risk of subsequent asthma next slide please so uh to try to put this area of study in a broader context uh the totality of available evidence continues to support the safety of the routine childhood vaccination schedule and existing Federal safety surveillance systems are robust and responsive to concerns expressed by parents of young children and I chose that word responsive um very carefully because uh again the the safety surround systems they responded to the co pandemic pandemic and here's an example of responding specifically to a call to action from The Institute of medicine and essentially a call to action from parents to study this this area and then as you can tell from the presentation so far precipitated by the 2013 report on the schedule there's a new field of study that's being developed that's examining cumulative repeated exposures to vaccines and vaccine ingredients and as recommended by the I report examining long-term Health outcomes um so I practice uh Primary Care Pediatrics and at the time of the issuance of the ion report in 2013 if I had a parent who asked me has the safety of the entire schedule been studied in the context of long-term Health outcomes I would need to say no I would say there's a lot of supporting evidence that's supporting the safety of the schedule but it hasn't been studied in exactly that way um but now I I can say yes that it is being being studied in exactly that way um and can even communicate convey to parents um findings such as um there appears to be no evidence that antigens in the childhood immunization schedule are associated with suppl risk of infectious disease there appears to be appears to be no evidence that the schedule as a whole is associated with increased risk of autoimmune disease such as type 1 diabetes and additional study is ongoing about any relationship between vaccine associate aluminum and Asthma risk um this was an unanticipated finding and has not been replicated and then in conclusion the benefits of vaccination strongly outweigh the known and potential risks so I really appreciate the opportunity to present this to the acip today and look forward to um providing continued updates in the future I will next pass it over to Dr viid and then we'll take questions after that thank you yes good afternoon um I'll present our preliminary results from our um Danish evaluation of aluminum content in childhood vaccines and risk of asthma uh today for you uh next slide please so this is the study setting the study setup uh it's a nationwide cohort study we include all children born from 2009 to 20 2016 um we started the followup in the study in 2011 1 of January and ended it on uh the end of 2018 and similar to Dr daily study we looked at uh we had followup from two to five years of age um and it's it's important for you to understand that all our exposure and outcome data are from Nationwide registers that cover the complete ation and that we have um easily and free uh universal healthcare in Denmark and the the the studies cord size that we operate with here is 470,000 children next slide please so this is a little about the Danish childhood vaccination schedule uh it's not as expensive as many other countries in the first year of life we have uh the infant vaccines at 3 5 and 12 months uh that's a defia tus pis inactivated polio hip shot and a separate pus lot three doses then at 15 month we have MMR 1 at four years mmr2 and then a booster at five years and then HPV at 12 years and Below you can see the aluminum content in the vaccines that uh that we're using during the study period and so for the dtp shot uh for the majority of the study period uh we used a formulation here from SSI which had one microgram of aluminum hydroxide per shot this was then changed in 2019 to pentac which has only a third of that aluminum content however we did have some production and supply issues intermittently in the study period and that that's why also seeing that we've used infantri hexa and hexion um when when that was the case throughout the study period they also have an Hepatitis B part and they have a little little bit less um aluminum content than the the Shir that we used most of the time and then we've used prevenar 7 and 133 um you can see that the aluminum content for for those SC next slide please so here you can see the the cative aluminum exposure that we are talking about in our study here uh to your left we have the box plots of communative aluminum content uh received through vaccines by age2 all the numbers here are in micr Brams and from the box plots you can see that the majority of the variation in our dat dat in our study here is basically across birth cohorts it within each birth cord you don't see a lot of variation um for example in 201 11 10 11 and 12 you you can see that the percentiles overlap completely which basically means that for 50% of the at least for 50% of the of the children they had the exact same uh aluminum exposure is the same as the medium and at your right you can see the the actual numbers and if if if if to contextualize it a little bit to the US situation for the birth year 2009 the median was 4.125 micrograms of aluminum by two years of Ag and I think that's more or less the same as Dr Dy had in his uh whole study that that median value but as you can see in the later birth here U the um exposure is almost half by the end there in 2016 next slide please so how did we Define um The Asthma outcome we included similar to Dr Dailey both Hospital uh diagnoses and prescriptions um for Hospital contacts we used ib10 codes uh j45 j46 asthma and status asmatic was really severe asthma we looked at both in and out patient contacts uh for prescriptions uh we actually used the Danish validation study who who looked at the postive predictive value and sensitivity of using different um definitions of uh prescription use uh and so we try try to balance towards having a high positive predictive value and and there we used the inhal cortical steroids at least two prescription in the study period short acting beta Agonist at least three matelio cast at least two and long acting beta Agonist just one prescription and for each of these criteria that that was enough to be classified as a asthma paste in this study uh we excluded everyone who had who had prescriptions or hospitalizations before study start at the age of two and then we use survival analysis um so analyzing the time to uh the first of the above events next slide please so these are our secondary outcomes we looked at and this was sort of a datadriven approach um recognizing as I just described that we have different criterias uh for becoming an asthma case in our study and also recognizing that um these criteria of course not mutually exclusive um so an asthma case could fulfill several of these criterias and so this is just a daten cluster analysis trying to sort of make some computational phenotypes of asth or study some subcategories uh to to dig a little bit deeper into in sub analysis and we we found four four clusters the largest cluster cluster four uh was primarily defined by the inhal cortical steroids criteria and for many also um short acting beta agonists the second L largest was more L primarily defined by the short acting beta Agonist prescription criteria and then we had two smaller clusters defined by hospitalization context and montelo cast uh next slide please so these are the descriptives for the the cohort as I mentioned it was about 470,000 children uh the column to your right you can see sort of the overall uh descriptives for the cohort uh first according to birth year you can see that yeah each birth year is approximately 60,000 plus or minus in Denmark uh with respect to sex slightly more boys than girls in our cohort um with respect to MMR vaccination status by two years of age 86% had received the first MMR shot and with with respect to ethnicity uh evaluated as the birth or the country of origin of the mother um 89% um were born in Denmark of the mothers all the children in our cohort were born themselves in Denmark the other columns are categories of aluminum uh received through vaccines by the age of two um you could say sort of the main takeaway here is if you look at the topmost row the zero micrograms of aluminum these are the completely unvaccinated so having not received any of the the the scks uh shots in infancy that contains aluminum we have very few of those which is to be expected other than that you can see that the different categories of aluminum received they correlate quite quite strongly uh with the birth here and and that was sort of also what you could see when I showed you the box plots of aluminum uh exposure inner Co cohort by birth here uh next slide please and so these are our main results the primary outcome which was hospitalization contacts with Asma diagnosis or any of the different uh anti-asthma medication criteria uh we had uh 5,000 approximately 5,800 asthma cases um using uh this definition uh you can see here the hazard raos of uh getting or um fulfilling our Asma criteria throughout the followup um according to aluminum receiv received through vaccines by the age of two here the reference category is the lowest category but but among those who received aluminum containing vaccine so less than 2.25 micrograms but not completely unvaccinated these are the ones with zero micrograms and and what you can basically see is there's really no support uh for an association between aluminum receipt through the vaccines and development of asthma in this primary analysis and these results are adjusted for six year of birth maternal country of origin and mm vaccination status by H2 next slide please here it's a dose response analysis um done in each birth gear cohort the do response is per one microgram additional uh aluminum received through vaccines 5 the of two and it's the primary asthma outcome and again as you can see there is none of the uh birth cohorts is there really any strong support for an association between increasing amounts of aluminum received and development of asthma that defined using the primary outcome definition uh next slide please this is just uh then looking at the secondary outcome comes uh definitions from the data driven cluster analysis I um I showed you uh here I'm showing a comparison between the largest category of communative aluminum received which is more than 3.375 micrograms by two years of age compared to the reference category that I mentioned before we're still uh talking about Hazard ratios but now according to development of asthma defined according to the different uh criterias here again there's there's really no support for an association between aluminum received through vaccines and any of these um datadriven ways of of defining sub categories of asthma in our study next slide please the limitations yeah so limited variability in cumulative aluminum receed is is a is of course a limitation and of course the the variability that we have in our data is strongly correlated with year of which is a limitation of course as Dr Dy also mentioned we don't really know if it's true persistent asthma of if it's re uh in the youngest children next slide please but the the takeaway of these preliminary results are there's really no support B association between aluminum content uh received in vaccines and development of asthma by five years of age in Denmark next slide please there is no next slide okay that was the last one thank you thank thank you so much Professor v um so these sets of pres this set of presentations is now open for questions and discussion Dr Chen Dr Daly thank you so much for the um for walking us through all that complex information um I I do have one question comment and it might be just my naive and understanding but I and and I think I understood that you um are recognizing that Viral induced wheezing might be represent some sort of confounding and I guess what what asthma brings to mind is my medical school teaching so this might be wrong now but um you know RSV early on in life uh might be associated with increased risk of asthma we don't know why it must be a host might be a host Factor you know and so um the reason I bring that up is because uh was RSV incident medically attended visit or hospitalization looked at or is that something that you're looking at in the future because that could also represent not just the risk for asthma but also that opportunity for vaccination because they're being brought into a medical home so that that was my question yeah thanks Dr Chen so um there is a published definition of early severe bronchiolitis that is uh bronchitis resulting in hospitalization within the first 12 months of life and that is associated with subsequent risk of asthma although we don't know kind of the directionality of that meaning do kids who are asthma prone then just have that happen or does that happen and then cause them increased risk of asthma in either case We examined that in this uh study as a covariant and it was significantly associated with risk of asthma but when included as a cover it didn't change the underlying findings of the study Dr Fleming Dutra do you want to add anything um if you would like me to um so again this is Dr filing Dutra I'm the um co-lead of the maternal pediatric RSV work group and I was just going to reference kind of in um response to your second Point um there has been a more recent um observational study that was published I believe in the the Lancet um the Inspire trial that looked at the association of RSV infection in infancy and later childhood development of asthma and it was a very well done observational study that actually showed not only is bronchitis and wheezing an early childhood associated with later childhood asthma but infection even in the absence of wheezing and infancy is um related to later life uh devel or later childhood development of asthma it is um an observational study so causality cannot be established but I will also add that the two products that we're con you all are considering for prevention of RSV infection and infants um are or RSV disease and infants probably we don't think will have a large impact on infection and so if RSV infection is in that we don't know but if it's in the causal Pathway to later life asthma development the current uh products Nur s m maternal vaccination probably will not mitigate that risk but a lot is to be known and you know we don't know right now thank you Dr Long in a placebo controlled motiv ISM AB study which is a highly potent monoclonal antibod against RSV in the American Indian population that was published showed us that the prevention of RSV did not alter the likelihood of persistence and Asthma so I think that that has been put to rest except as a um unmasker if you're set up to have asthma you may be more likely to whee with RSV but RSV does not cause the proclivity for asthma I think that's where we are right now thank you Miss mcnell thank you Dr dy I assume that vssd um allows you to for any children who would have renal conditions such that they would be excluded uh Miss MN you say renal conditions yes yes any renal diseases so yes and I may need to get back to you on on details of of um sort of specific uh concerns that you have I mean I think that um you know in in this study it's it's a large cohort um however um kids with complex chronic conditions were excluded from the analyses but that's a small percentage and that's based on something called the pediatric medical complexity algorithm so um are um so uh yes we can detect it it probably wouldn't influence the study findings here um is Are there specific renal diseases that you were um inquiring about that could sort of influence whatever we observed here so just thinking about the fact that aluminum is excreted by the renal systems that was really kind of at the Crocs of my question yeah no thanks thanks for that additional context I mean I think you know we need to recognize that aluminum has been used in vaccines for more than 80 years and there are several different forms of alum aluminum hydroxide and phosphate um and that they're important immunogens they enhance the immune response they're they're there explicitly because they make vaccines work better but even so um there are things that are not known about exactly the sort of um pharmacokinetics and biologic activity of um uh of aluminum used as an adant um there are studies that show that um after vaccination serum aluminum level levels don't change hair aluminum levels don't change but then that doesn't exactly tell you sort of how that relates to how aluminum is excreted from the kidneys and there is some work that I'm not terribly familiar with around when aluminum is used in Parental parental nutrition so essentially it's IV nutrition but that's in extraordinarily high doses compared to what um is injected in vaccine so I'm not sure that's really comparable so um you know your comment is sort of just a a reason for us to also acknowledge some things that we don't know about the metabolism of aluminum um but what we do know is that probably um any sort of underlying renal disease doesn't influence the immunogenic effects of aluminum um um and so probably probably is not a not um explaining any association that we see here um that's helpful and just as a followup question you know as a parent I'm trying to think through this what what impact if any would infant formulas have in this sort of evaluation yeah thanks thanks so much for that so miss MCN what's interesting context here is that um breast milk contains aluminum and infant formula contains aluminum and so the qu one of the questions that I have in all of this is uh does the aluminum that's taken in by breast milk or by formula cause any immunologic effect and I don't have a an answer to that other than to say that the thought is that very little of that is absorbed so um we can think about it a couple different ways does it relate to the association that we saw um possible but unlikely if it's not absorbed um but do we need to know more about this um as we pursue this H hypothesis definitely yes I I might see um if Dr Buddy Cree is on and if there's anything that he would add because we've talked a little bit about this over the past couple years Dr Creech yeah this is this is buddy thanks for for that Matt um I think this level of inquiry is exactly right there are environmental exposures that may impact overall aluminum exposures um it's hard to understand how those are are are differential in some of the the the analyses that were done and then I think we have to recognize that different aluminum agits do have different pharmacokinetic and pharmacodynamic properties right so aluminum phosphate dissolves more rapidly than aluminum hydroxide so while we don't know that the immunologic effects of different Alum preps would be substantially different we do know that the pharmacokinetic and dissolution characteristics the the the charge on the surface of the molecules the shape of the molecules all of those may have an influence that's really helpful and and I just want to thank you for doing this work because I think this is so important and truly does help improve vaccine confidence thank you I'm may I ask a very specific question which is um actually looking at Professor V's uh data and and thank you very much for presenting I think it's incredibly helpful to have a complimentary data source uh and that one that has you know you have such beautiful data in Denmark you have the full cohort and all of the full information so it's really helpful to have that uh complimentary view um but one of the things I noted was the secular Trend in exposure and so that made me wonder whether or not uh there were any differences uh in the vsd data or whether the study design accounted for calendar year or any other secular or seasonal Trends yeah thanks Dr Lee so um down in the fine print on both the primary analysis slide and the secondary analysis slide um these analyses were all adjusted for um calendar year and calendar month and so you know adjusted for for example a baby born in March of 2013 it's the year plus the month and that's a fine level of adjustment but we felt like that was necessary because of risk of secular Trends including of uh viral respiratory infections that could um influence risk of asthma so um and the cohort was big enough that we could make that fine a degree of adjust adustment and that adjustment did not change the underlying Association that we observed Dr lar I'd like to Second Miss MC's comment and say thank you um as a practitioner with a large vaccine hesitant population I often get questions about the the risks and now I have more data to comment and say that they actually are studying these so I appreciate the CDC and your moving forward with these studies thank you thank you any additional questions Dr paling um I um want to Echo my thanks for your doing the study and um being very CAU uh very deliberate in the process and then also making sure that you share and explain what you do and do not understand I also very much appreciate the future directions and do um believe this this session during the acip is particularly helpful and hope that um as more information becomes available that can be included in the future thank you thank you Dr Sanchez no okay I don't see any other hands raised so I also just want to add my thanks um for uh number one pursuing this work on behalf of the public it's really important work and really hard to do um and recognize all of the challenges with the study designs and the limitations that we have but um just to say it out loud I mean the totality of the data we just reviewed is actually really reassuring um and even though we're talking about where else aluminum can come from breast milk the environment other places what I'm taking away from this is looking at both studies together that it doesn't seem like there is an association that I am concerned about in the moment um I'm also very intrigued by the findings from diabetes that it looked protective so it just it gives you a little bit of pause to say it definitely deserves further work and again really appreciate the investment and the time and the and the care that is spent um with regard to ensuring that our vaccination program is as safe as POS possible for our entire childhood population so thank you and with that I think we're going to take a five minute break and thank you um Professor Reid for um presenting from Denmark whatever time it is there we really appreciate your time and your effort um on this work as well thank you again