February 2020 ACIP Meeting – Dengue Vaccine

>> Okay, so we’ll move on to our next topic, which is dengue vaccine with talks from Dr. Atmar, Esquilin, Hombach, and Waterman So we’ll begin Dr. Atmar, please? >> Thank you, and good morning So first, want to acknowledge the members of the work group, the ACIP members, and include Dr. Bell, Ms. McNally, and Dr. Poehling Want to acknowledge our CDC co-leads, Steve Waterman, who will be speaking later in this session, and Gabriela Paz-Bailey Thanks to the ex-officio members, liaison representatives, consultants, and other CDC contributors to the efforts ongoing in this work group So this slide depicts some of the work group discussions we’ve had since our last meeting, including the dengue vaccination — a review of dengue vaccination in the Philippines, and some of the unintended consequences Review with the work group of our October ACIP presentation and the discussion that occurred during that sessions We took an informal poll that Dr. Waterman will tell you a little bit more about later in the session of work group members to address some of the needs that we need to address before we make decisions about recommendations We reviewed the CYD65, which is a followup study of Dengvaxia efficacy, looked at partnership for dengue control and pre-vaccination screening, a workshop that reviewed that with the work group, and then we reviewed Puerto Rican dengue vaccine knowledge and attitudes The presentations, then, today, Dr. Esquilin will review dengue vaccine knowledge and attitudes in Puerto Rico that I just mentioned Dr. Hombach will give us a perspective from the WHO standpoint on recommendations for dengue vaccination And then Dr. Waterman will close the session with some of the deliberations of the work group, and review of next steps So this is our anticipated schedule In June, we hope to present a CDC assessment of the laboratory tests for pre-vaccination screening, which is one of the needs, and then the possible additional cost effectiveness presentation with the idea in October we may be able to review the evidence to recommendations framework, and possible draft recommendations And I think that’s it Dr. Esquilin? Thank you >> Good morning I will be representing the dengue vaccine knowledge and attitudes data from Puerto Rico The information was obtained from three different sources — the general population, physicians which were mostly pediatricians, and from parents of children between the ages of nine to 16 years of age The general population data comes from our household survey done in — Puerto Rico The physician data was gathered from a survey sponsored by the Puerto Rico Academy of Pediatrics The opinion of parents of children between ages nine to 16 comes from focus groups conducted by the behavioral science team of the dengue branch in San Juan The general population data was obtained from a community-based cohort study implemented in 2018 known as COPA The participants were recruited from selected households in 38 cluster areas A total of 1139 adults participated in COPA When asked if they will receive the dengue vaccine for free, 73% said they will receive it for themselves, and 75% will administer it to their children when ask They also said that they will pay for the vaccine

62% said that they will pay for the vaccine for themselves, and 68% will pay for the vaccine for their children When the interest in dengue vaccine among the adult participants was explored, 59% will pay $10 per dose of the dengue vaccine, 37% will pay $20, and 12% will pay up to $50 for the vaccine When they were asked for their reasons for not wanting the vaccine, or for being unsure about it, only 1% were not worried about getting the disease There was a lack of information about the vaccine, since 22% of the participants could not state a reason, and 9% needed more information 38% of the participants were worried about the adverse reactions When they were asked about the most important feature of a dengue vaccine, most participants were concerned about the high level of protection Concern about minimal side effects was more common in participants that were unsure or not willing to receive the vaccine Now we will discuss the physician survey that was done among physicians in Puerto Rico, 102 physicians completed the survey, and 81 were either pediatricians or pediatricians with a sub-specialty In terms of the methodology, a pediatrician from the CDC dengue branch gave presentations to the local pediatric associations during the fall and winter continuing education meetings from September to February of this year Physicians were asked to complete this survey after the presentation This survey included an informational paragraph on the risk of hospitalization and severe illness in vaccinated seronegatives, and on the implications of a pre-vaccination test specificity Additional surveys were provided to pediatricians in the San Juan metropolitan area, and from the University of Puerto Rico School of Medicine The Department of Pediatrics provided with a copy of the CDC presentation, published literature on the vaccine, and on available laboratory tests for pre-vaccination screening The results were — are as follows Only 31% of physicians administer vaccines at their offices Most of the vaccines are administered at private or public administration clinics in the island, and 98% participants acknowledged that dengue is a significant public health problem in Puerto Rico Only 58% of physicians knew that there was an FDA-approved dengue vaccine Forty percent of the physicians knew that the schedule requires three doses, and 48% didn’t know Only half of the physicians answered the question on the efficacy of the vaccine, and 54% stated that they don’t know what is the approximate efficacy The answer to the question of what percent of false positive tests they were willing to accept was distributed between zero to 5% of false positive for 54% of the physicians, and 35% were not sure Assuming a laboratory tests with acceptable specificity were available, 73% of physicians will recommend the vaccine, and 21% were unsure Of those who would recommend the vaccine, 96% think that dengue is an important public health problem in Puerto Rico, and that a reasonably effective vaccine is available for seropositive persons Forty percent think that the laboratory testing reduces the

possibility of vaccinating subjects with a false positive lab result Of those unsure or not wanting to recommend the vaccine to their pediatric patients,71% had concerns about the risk of vaccinating persons with a false positive dengue lab result, and 75% needed more information For patients diagnosed with dengue, 43% of physicians have documentation of a positive lab test in the medical record for some of their patients, and only 5% for all of their patients Physicians established that the necessary steps to enable a vaccination program for children in Puerto Rico include VFC and private insurance coverage for the vaccine, and insurance coverage for the laboratory test for detection of past dengue infection A 54% of physicians would recommend the vaccine even if insurance coverage for the vaccine and the lab test were not available, but 30% were unsure If a recommended rapid test for past dengue infection were available, 66% of physicians will support changes in the Puerto Rico laboratory regulations This is to allow such a test to be performed in a medical office, so that the first dengue vaccination will not require two or more patient visits Most would favor a pilot project with phased approach of dengue vaccination before implementing a large-scale program in the island Now I will represent the data obtained from the focus groups with parents of children between nine to 16 years of age A total of 38 participants were involved in the focus groups, of which 87% were mothers The objectives of the focus groups were to assess acceptability to the vaccine, determine barriers to and motivators for a dengue vaccination program, and to identify knowledge, attitudes, and beliefs toward vaccines In terms of the methods, focus group discussions were done in three municipalities with a high dengue incidence That was in San Juan, Carolina, and Ponce The sample were parents of children between nine and 16 years, and they were recruited from the pediatrician offices, the WIC program, schools, and the Boys and Girls Club of Puerto Rico It is important to mention that 63% of those parents had at least one year of college education, and 1/3 had completed a college degree, either a bachelor degree or a master degree Previous to asking the questions, a script was read with information about the dengue vaccine, and doubts about the script were clarified to the participants In terms of general opinion about vaccines, most participants had questions about having a dengue vaccine They have positive opinions about vaccines in general, but some of them decided not to receive the flu vaccines, and were concerned about issues like that the flu vaccine changes every year, and some concerns about efficacy Also, they distrust some of the new vaccines, and others had concerns of allergic reactions and autism as a result of vaccination In terms of opinions about dengue vaccine, most participants have questions, and a few had mixed opinions about this vaccine Some will wait to see the effects of the vaccine on others’ children, and others do not find it necessary — do not find necessary to have a dengue vaccine at this moment Almost all participants did not know about the dengue vaccine

In terms of willingness to vaccinate, 38% will vaccinate, 30% answer no, and 32% were unsure The barriers to vaccine program participation identified within this group included lack or inconsistent information, high cost or lack of insurance coverage, a time-consuming lab test, side effects of the vaccine, laboratory test results that might not be 100% reliable, approval for use of this vaccine only in U.S. territories, sickness at the time of vaccination, and probable low effectiveness of the vaccine The motivators for vaccine program participation identified included provision of correct vaccine information, information about dengue and statistics in Puerto Rico, prevention of future dengue infections, support from the Puerto Rico Health Department, lab confirmation of prior dengue infection, the event of an epidemic, and educational forums Most participants will pay a deductible for the vaccine, but obviously, they would prefer it at no cost An acceptable insurance deductible for participants will be somewhere between $5 and $20, and an acceptable cost without insurance will be around $50 to $80 All participants wanted more information about Dengvaxia, and about the test to confirm past dengue infection They have multiple questions, including why the vaccine is specific for children between nine to 16 years of age Where have clinical trials have taken place, and what were the results? What does the process of approval involves, and how long does it takes? What type of vaccine is Dengvaxia, and what are the components? What is the dosage, and how many times it has to be administered? What is the percentage of effectiveness? What evidence on short-term and long-term side effects, and how to treat those side effects? Are there any possible interactions with previous medical conditions or medications? How does the vaccine reacts if people get vaccinated and later have dengue again? What countries are using the vaccine? Why it is approved for U.S. territories only, and not for the mainland? Does the Puerto Rico Health Department requires the vaccine? And finally, what dengue tests are required, and how accurate those lab tests are? Participants stated that a culturally-appropriate informed concern should include information about vaccine safety and effectiveness, specific laboratory test requirements prior to vaccination, specific consequences if vaccinated without a previous dengue infection They wanted it to include benefits and risks of vaccination, specific short-term and long-term side effects of the vaccine, results from previous clinical trial studies with number of participants in the trials, and percentage of effectiveness And they wanted that information related to the consent form to be written in a plain language, clear and concise They all recognized that the best source of information will include doctors, specifically pediatricians, nurses, the school of medicine, the Academy — the University of Puerto Rico School of Medicine at the Medical Sciences campus, and the CDC In conclusion, what did we got from all those groups? First, from the general population, we can say that adult participants demonstrated interest in the dengue vaccine for themselves and for their children The side effects and possible adverse reactions were the most

important reason for those not wanting to receive the dengue vaccine Among adult participants willing to receive the dengue vaccine, a high level of protection and minimal side effects were the most important features From the physician knowledge and attitudes survey, we can conclude that most participants were pediatricians, but only 30% administer vaccines at their offices Most vaccines are administered in public or private immunization clinics Almost all physicians recognized that dengue is a significant public health problem in Puerto Rico, but 43% were not aware that there is an approved FDA dengue vaccine Further physician education is needed regarding dengue — Dengvaxia vaccine, its schedule, efficacy, and safety Most physicians would recommend the vaccine if a laboratory test with acceptable specificity were available to document prior dengue infection Medical record documentation of past positive dengue laboratory diagnostic test for patients is limited in the island Most physicians view that the necessary steps to establish a vaccination program in Puerto Rico include VFC and private insurance company coverage for the vaccine, but also for the laboratory test And from the parental acceptability focus groups, we can conclude that most parents will agree to vaccinate their children if they have information on Dengvaxia The most important barrier for parental concern — consent to vaccinate with the vaccine is the lack of detailed information The most important motivators are having information about the vaccine effectiveness, side effects, the rationale for use in Puerto Rico, and current use in other countries, having support of the University of Puerto Rico, the Puerto Rico Health Department, and the CDC, and the disease prevention impact of the vaccine And the most important influencers will be the pediatricians and the family Thank you >> Thank you very much for that presentation, Dr. Esquilin I’ll take chairperson’s prerogative and ask the first question So since only 31% of vaccines are administered in the physician’s office, where are the other 69% administered? >> Those vaccines are administered at either private or public administration clinics in the island The vaccines that are provided by the VFC program are given to the patients in clinics that are run by the Puerto Rico Health Department, but those patients that have medical insurance can get their vaccines from private clinics established in different private hospitals in the island >> Thank you Dr. Szilagyi? >> Yeah, thanks for that information, and honestly, I think a lot of this confirms other studies of providers and patients, that there is general interest in vaccines, but that these practical feasibility issues can really either facilitate or get in the way One question I had is, what is the level of insurance coverage for the laboratory test, or for the vaccines, beyond — for the vaccines beyond VFC in Puerto Rico? >> I’m sorry, what is the interest — >> What is the cost of the laboratory, and how much insurance coverage — what percentage of children, for example, would be covered for the laboratory test? >> — we don’t have that information yet We need to have the lab test approved and then submitted to the insurance companies to see if they will approve it We still don’t know >> And do the public health clinics do the laboratory test, or would that have to be done in — >> It has to be done at a laboratory, because in Puerto Rico, we have regulations that establish that we cannot do any lab testing in the office or in a clinic It has to be done by a lab technician That is a specific regulation in the island We haven’t been able to do even HIV rapid test in the labor room

It has to be done by a lab technician, in the lab >> So may I ask the question more pointedly? So there is no point of care testing — >> No >> — in Puerto Rico? >> No, not now >> Okay, thank you Dr. Bernstein? >> It sounds like pediatricians would be a large influence on acceptance of this vaccine, and providing the important information that’s necessary Are they staffing the health centers that are administering the 69 — you know, to 69% of the children? Are there — they pediatricians, or other child health professionals? Because if the pediatricians — they’re not going to see pediatricians, it’s hard for them to be an influencer >> Well, the pediatricians are not physically at the immunization clinics We will depend and we are depending on the information provided by the nurses on-site The pediatrician will see the patients in their offices, and will recommend the vaccine, but patients still have to go to — most patients will still have to go to the immunization clinics to get the vaccine And then they will get additional information from the nurses, and the consent from the immunization clinic nurse >> So it’s an additional step in order to — >> Yeah >> — and then adding a laboratory test requirement adds additional steps >> The pediatrician will be the one recommending and ordering the lab test Then the pediatrician will have to see the result, and then approve the administration of the dengue vaccine That’s how it will work >> Dr. Atmar? >> Yeah, I mean, one of the issues that the work group is struggling with, and I think this committee has also struggled with, based on previous presentations, is the logistical nightmare of having to go through the additional step of getting the testing done Which I also understand is — so the child shows up to the pediatrician’s office, consider for vaccination Then they have to go to the laboratory to get the testing done Then someone has to evaluate the result, presumably the pediatrician, and then send to the public health clinic to get the vaccine And so, while the vaccine may be a benefit to the child, the logistics of doing that, and then the additional concern of paying for the cost of the laboratory test, which is not covered through VFC, is one of the things — and I think when Dr. Waterman gives his presentation at the end of the session, we’ll review some of these logistical considerations And one of the things that — well, that’s a major concern One of the possibilities would get a point-of-care test, but it would require a change in the law essentially to allow that point-of-care test to be done in the doctor’s office, assuming a sensitive and specific point-of-care test could even be developed, which is something else that Dr. Waterman will address >> Is there a reasonably robust electronic health record, or did the difficulties with the hurricanes or whatever kind of wipe out that option? >> Well, most — for most of the hospitals in the island and the private pediatric offices, there’s no electronic record In the main academic center in San Juan, we just implemented the electronic record three months ago So that’s a major difficulty also for getting the results of the labs available, because if we don’t have an electronic record available, patients will have to come back and bring the result And if we want to know about past dengue infection, it’s somehow a little bit difficult to get the result We have to make sure that it is filed in the paper medical record in the physician’s office >> Dr. Hunter? >> I just wanted to say, as a clinician and as a medical advisor to a local health department, this analysis is really — sets the standard, I think, for future similar analyses for the purposes of our voting on the ACIP when there is — are so complicated implementation issues I think the three groups you picked were very appropriate

I think the questions you asked were right on track of what we need to know in public health, and in clinical practice And I think that the speed in which you did it, and the size of the samples were appropriate for how fast we need to know this, and you didn’t get bogged down in the details So I just want to say you did a terrific job, and you really set the standard for what we should look at in the future >> Thank you >> Dr. Lee? >> I echo my thanks, and also two questions that either you can answer, or maybe some of our liaisons could answer One is, is there an immunization — electronic immunization registry available, and if so, is it possible to kind of amend it to enable lab testing to be part of the record? And then, I’ll ask a second question after >> That’s a very good question We do have an electronic immunization record created through Vaccines For Children, but available to all the population, even from private clinics So we do have that, and we’re going to work to change that registry to include the dengue vaccine, and probably the lab result, too So if the patient goes to a different clinic, they can find easily that that patient had the test done, and qualifies to receive a first, second, or third dose of the vaccine >> My second question — and it may be a straightforward answer — is just thinking about the vaccine injury compensation fund, and if there were any adverse effects, would these children potentially be eligible, if there were something — >> Dr. Goldman? >> Thank you, Jason Goldman, American College of Physicians Thank you for this work, and this study It really does open up a lot of possibilities, I’m thinking, in south Florida as well, because we do have a very large area of the population from Puerto Rico where I am in south Florida So it would be interesting to see, you know, expanding this kind of work, to see if there is any role for it for those who are not currently living in Puerto Rico, but who have moved to south Florida And to answer the question Dr Lee posed about the registry, Florida does have a registry, but the problem we see is, of course, the implementation, and everyone using it Because while we do have electronic records, not everyone is fully integrated with the state registry But, you know, and — as — to answer the question about point-of-care testing, I haven’t seen it, but I have tested for dengue antibodies for patients of mine who have come in and traveled, had symptoms, and have had, of course, positive, negative results So with the local labs, you know, the national labs, we can certainly do those testings, get the results, and communicate with the patients But it would be interesting to see some integration with the state shot registry, and be able to get those laboratory data That would be very helpful So it might be also interesting to expand to Florida, and see if there’s any need for it in the south Florida area as well >> Thank you >> Dr. Coyle, please? >> Hi, there I just wanted to respond to the use of an electronic immunization registry in this type of situation So it’s one thing to have an indicator indicating that you have a positive result or a negative result It’s a different issue altogether to incorporate lab results into an electronic immunization registry So I think those are the considerations that need to be put in place, and then you have to consider the interoperability between an EHR and an IIS as well So these are big shifts in the way that we’ve typically done this, and I think that is absolutely a consideration that needs to be thought about It’s not impossible It just is not typical today >> It’s difficult, but we hope we can do it >> Are there any other questions, comments? Dr. O’Leary? >> Yeah, thank you again as well for that great presentation I just wanted to ask a quick question In one of your earlier slides, you presented data among the people that didn’t get the vaccine, but it said they wouldn’t want to get the vaccine, that 17% said they didn’t believe in vaccines Is that kind of a general representation of — is that common in — that level of vaccine confidence in Puerto Rico? >> No, no We have a high percentage of vaccination in Puerto Rico for most of the vaccines What has helped us significantly is incorporating vaccines as a requisite to enter school, for school-age children

The acceptability of vaccines in the island is actually very good, but as everywhere, we have groups that are against vaccines, or are not willing to vaccinate their children >> Dr. Waterman, if you please? >> Yeah, just to clarify — that 17% is 17% of those who didn’t want to use the vaccine So in terms of the total surveyed population, it was like 3%, or something very low, much lower number >> Thank you for that clarification >> Any other comments or questions? All right, very good Thank you very much >> Thank you >> Our next presentation will come from Dr. Hombach, please >> Good morning, everybody, and thanks very much for the invitation to speak here on WHO’s position on dengue vaccination We — what I’m going to do here in the next 15 or 20 minutes is, I’ll give you the rationale on the WHO’s position on vaccination, also how it has evolved, because I think it’s important to understand this And then, obviously, what you are very interested in is to talk a little bit about implementation issues, but as you know very well, this vaccine has been only used in two very limited public programs So the experience overall is not large, but obviously we can also form experience from other vaccines So WHO’s mandate is to advise countries on the use of vaccines against diseases of public health importance, and the first-generation dengue vaccine, Dengvaxia, was licensed initially end of 2015, and then in 2016 in a number of endemic countries And so, WHO issued in 2016 its first position on dengue vaccination, but before going into this, let me just remind you again of what you probably all know — that dengue’s really a global public health priority In 2019, WHO had listed it among the 10 biggest public health threats That was certainly done with the perspective that we have an environment that is extremely favorable to further transmission and to further spread of dengue And this is combined with the situation that we have very little tools, apart from vector — environmental management and vector control, which, as we all know, is very difficult, and very difficult to scale So the need for a vaccine is really extremely important, and we are, unfortunately, still in a situation that we have a vaccine that is not very easy to implement Dengue is not a high-mortality disease if it’s well-managed It’s a morbidity disease, but it causes a lot of fear among populations It causes a lot of strain to the health system, and it can actually also have quite considerable economic cost I think the survey that you have just seen before shows that there is a high awareness around dengue I’m not going to go into detail of the first-generation vaccine, Dengvaxia, or CYD-TDV I think you have seen this before Just want to show you here in terms of the time scale of the two pivotal studies that were used for licensure of the vaccine, CYD-14 that was in Asia and CYD-15 in Latin America with overlapping age groups Asia was two to four, and Latin America was nine to 16 years of age WHO’s position in 2016 took into account data that were — that became available up to around month 48, and these were the most important original licensure data Again, I’m not going to go through those in detail, but I think it’s important to underline that the — while the efficacy against symptomatic dengue was — call it moderate, the efficacy against hospitalized dengue and severe dengue was actually very high And so, that is something that really needs to keep — be kept in mind This vaccine has been performing very well against the most severe forms of the disease The issue that, of course, occurred, which you all know, is that in the third year after the start of the trial, in the most youngest group, there was a safety signal that occurred, that there was an imbalance and increase of severe and hospitalized dengue And at that point in time, essentially, the evidence is what was causing this were not entirely conclusive, and while there was, of course, a strong suspicion

that it was tied and linked to serostatus, the way the trial was set up didn’t allow to come to a definitive conclusion on this In our first position, we actually used a lot of kind of supportive work that was done through mathematical modeling So we convened eight mathematical modeling groups that essentially assessed the impact of the vaccine in different transmission settings, and the way it’s, so to say, how these models assumed that the vaccine would work is basically shown here This is, I think, all pretty well-known It’s essentially assumed that the vaccination acts like a primary silent infection, which then brings the person, if the person was naive at the time point of vaccination — brings it into this situation where there is an increased susceptibility to disease, the secondary infection And thereafter, the person should be, so to say, in the post-secondary, low disease risk phase If the person is already — had already a single infection, the vaccination would move it, to some extent, to the second — to the post-secondary phase, and that’s where you would see protection These data fitted most — this model structure fitted most nicely, actually, the empiric data that were collected from the vaccine trial So WHO’s position in 2016 — and I’m not going to show it to you, because we modified it afterwards — was essentially a position that was informed by, obviously, the trial data, and also extensively informed by mathematical modeling And it was a position of risk minimization in populations with a highly conditional statement that basically population-based recommendation should be done only if the seroprevalence of the target population is high And the models predicted the highest effectiveness actually if you were in the range of 70% seroprevalence at nine years of age, and there was a recommendation against using the vaccine in lower seroprevalence setting So what WHO also did is — when we issued the recommendation, is we issued a very strong call for the company or the global community to gather more data on the performance of the vaccine to understand really the root causes of the safety signal And to be more specific, then, in terms of risk minimization, or risk — or avoidance of risk when using this vaccine And then, obviously, the company came about two years later with an additional retrospective analysis And I have to say, when we issued the first position, we were not — nobody actually knew that this was possible at that point in time, to do such a type of retrospective analysis, that indirectly estimated what was the serostatus at baseline before the administration of the first dose So these data came out around month 66 These were the data which we all know that created in the countries, and particularly in the Philippines, that started to use the vaccine already in 2016, a major outcry, and this study was published here in this “New England Journal.” They used three different methods to assess serostatus as baseline I am not going into detail of these methods I think important to note is particularly the serological NSN1 assay that allows to make a differentiation, to understand if the NS1 antibodies are actually derived from the vaccine, which has a yellow fever component, or from natural infection And then two statistical models were also used to — independent models were used to impute the serostatus as baseline It all gave pretty similar results So this is just a snapshot in terms of the relative risk, and what I show here, which I think is an important slide — it shows you the age group for which the vaccine was licensed, nine to 16 years of age And over the full duration of the followup of these 66 months at that point in time, and what it actually, first of all, shows, that there is a continued and reasonably robust protection against hospitalized and severe illness in seropositive individuals But that — obviously, the risk ratio, the hazard ratio looks not favorable in the seronegatives,

and if you take other figures where you also include the younger age groups, this ratio becomes less — even less favorable So that figure, while it to some extent did corroborate what our — what was in the mathematical models, also quantitatively very much fitted with the mathematical models, created a major crisis in the sense that, obviously now, we had — we were in a situation that we could essentially describe and say which individuals would not be benefiting from the vaccine, or would actually be put at risk And so, that obviously then also required that we had — for us to reconsider our position, which we swiftly did, and basically, you could think of in terms of risk minimization in seronegatives You can still think of — in principle of two approaches The one is still the population seroprevalence criteria without screening, maybe with some tweaking in terms of what seroprevalence level you would like to accept as the minimum level, and then, obviously — and, you know — and this is also the way the label has been changed — the individual pre-screening before vaccination Both have major implications Both have major — come with major problems, as we all also know There is no really validated rapid diagnostic test that the — at this time available for past infection, but as we also know, there’s a lot of work going on into this When we developed and SAGE developed the policy, they went along — they looked at a number of dimensions, the benefits and harms dimension, also the dimension of coverage And it’s actually quite interesting, because if you think of seroprevalence, and if you have to go to areas where you have very high seroprevalence, there’s actually not that many populations where you have this high prevalence And you will need to do extensive seroprevalence surveys, which are very costly also, and tedious to do There were — there are clearly ethical considerations that are very, very important in this context, and you have the issue of harm of omission versus harm of commission And there has been a lot of discussion around this Risk perception communication, extremely important — we had the Dengvaxia crisis in the Philippines going on, and then a lot of practical aspects in terms of feasibility, test limitations, cost, implementation challenges, and so forth And on balance, we — again, without going into the detail, I think on balance, there was a very clear statement that this vaccine should only be used with individual pre-screening — individual-level pre-screening prior to vaccination, even though we left the door a little bit open for seroprevalence-based use of the vaccine So the position — you probably have read it — is here It’s very clear The vaccine should only be used if there is really a risk minimization strategy that you can put in place Pre-vaccination screening is the way to proceed, according to our understanding The screening tests are — that’s, of course, quite a challenge, because you need high specificity to avoid vaccinating seronegatives, but you also need a robust and high sensitivity to assure that the seropositives are really being vaccinated And obviously, there is a lot of work to be done, and is going on in order to validate rapid diagnostic tests, and as I will say in a minute, obviously, the performance of the test depends on the epidemiological setting So it requires a very careful assessment The age group for vaccination is also relatively tricky, and I’ll show you a slide on this It depends on the transmission intensity, but it depends obviously also on operation and programmatic considerations From an epidemiological and — understanding of the vaccine performance point of view, the optimal age pool is the one where you have — where the most individuals have monotypic infection, and that would be essentially the age before you would see the peak of severe disease as a proxy And so, as I said, we left the door open for a population-wide use of the vaccine with very high seroprevalence, even though we think it’s basically not feasible And most important is a full disclosure and communication around, with this vaccine, in relation to individuals with unknown serostatus,

but also communication around the risks that come from false positives if pre-screening with rapid diagnostic test is being used There is a number of implementation considerations I think it’s very important to understand the local burden of disease, the age distribution, so that you know which group is actually best to target The rapid diagnostic test must be assessed in the context of the specific epidemiological setting We haven’t gone into affordability and cost effectiveness, but it’s clear that, besides the vaccine, you will have the cost of the test, and you will have the cost for the program operations And the program operations cost can be quite significant We know this from other vaccines We know this, for instance, from HPV delivered at school This is a relatively important cost factor that needs to be really put into the equation Implementation strategies obviously depend on the age group chosen I think that’s probably — might be a strong interest in school-based vaccination, and you need to have the necessary follow-up and record-keeping And I think we had just the discussion about electronic records, certainly something which is extremely helpful to do the follow-up And, yeah, then obviously, we have the communication issues, and overall, of course, as for any vaccine, you need to look into the local priorities in relation to other alternative investments Extremely important is to highlight that this is a vaccine that will — is partially effective, which means vector control needs to continue Clinical management needs to keep at high level, and so forth So these are all very important issues that need to be considered Just a few more details — so in relation to really the target age for vaccination mentioned is already — according to the way the vaccine works, you aim at optimizing and targeting the group where you have the highest proportion of monotypic seroprevalence And this depends on the force of infection, and so it depends on really where — you know, how the transmission intensity is If you go to higher seroprevalence settings, you will have the peak earlier, and you will have a more distinct peak And you will also have less seronegatives, so there is — even though with pre-screening approach, you have more flexibility in terms of which transmission settings do you go, it is certainly more effective and also more cost-effective if you go into settings that have pretty high burden of dengue The diagnostic tests are an area of active research, and I’m not going to go here into the details As I said already several times, you need — the positive predictive value and negative predictive value depend — depends obviously on the seroprevalence, and so, you need to look at this in — really in the context of the epidemiological setting There is a group, GDAC, that has done some surveys and interviews, both in Asia and Latin America, in terms of acceptable level of sensitivity and specificity for rapid diagnostic test So there is some information out there, but I think this is also something that needs to be brought into the equation, if you consider really implementing this vaccine I want to say two, three words around communication, and I’m sure you have all seen this This is from Heidi Larson’s vaccines confidence project, where she had surveyed the confidence into vaccines in general, vaccination in the Philippines, and then did this survey again after the Dengvaxia crisis And what you obviously see here, without going into detail, is that a strong confidence in vaccine was completely shattered with this crisis, and with now a very strong proportion of the population that has a tendency to disagree with the importance, and also with the safety of the vaccine And as you know very well, this led to a drop in vaccination coverage in general, provoked measles outbreaks, polio So the repercussions for an immunization program can be dramatic, as the Philippines situation has shown, if the communication is not properly handled

There was an attempt — I mean, this program in the Philippines was essentially abandoned after 800,000 doses had been administered And to my knowledge, there is no really follow-up evaluation being done, so you have kids who got three doses, kids who got two doses, kids who got one dose What some colleagues of mine did was essentially an estimation in terms of the proportion of — trying to understand what would be the proportion of vaccine-induced cases of dengue in relation to those that are being prevented through the use of the vaccine And this was based on the data from the clinical trial, which had — the clinical trial from Sanofi had a big sub-group in the Philippines And with the assumption you see here of the seroprevalence and the performance of the vaccine, it was estimated that, as you see here — that you avert about 18 dengue hospitalizations among seropositives for one precipitated hospitalization in dengue-naive vaccinees, and 10 to one in relation to severe disease So the overall performance of the vaccine is most likely, from our understanding, would be positive, but it hasn’t even been assessed And things have just been left in limbo, which is, I think, very unfortunately, and — both for the population, but overall, both for understanding of that vaccine So in terms of communication, I think what was presented already before is, I think, really the way to go, and what is absolutely important is that there is tailored and targeted communication And the communication must be proactive The communication must happen before the program is being put in place, and this is what our communications specialists tell us You need — once a perception has been formed on a vaccine, it’s very difficult to change it So it is very important to convey the facts and figures ahead, and so, this is something which is absolutely essential And there is many things that need to be communicated about this vaccine, because it is very complicated The risks and benefits, the rationale for the pre-screening, the issue of vaccinating seronegatives, but also the issue of sending home people who are — who are actually seropositive, but have tested negative Obviously, the issue — what we have for other vaccines as well, of partial effectiveness, the complexity the schedule, and then also, an honest discussion in terms of where we are, of duration of immunity and booster needs, which, as we know, is still something that is under investigation And all this needs to be communicated, as I said, in a proactive manner The strategy needs to be segmented to the various audiences, and last and least, communication must be both ways So there must be really opportunities for dialogue, and again, the — have seen a first attempt to understand what people need to know, and what people want to know, and what people’s wishes and perspectives are I think this concludes my presentation Again, we have a disease of very high public health priority, where we unfortunately still don’t have a perfect vaccine The current vaccine has potential, but it has significant shortcomings which come with a complex implementation challenge And again, I think what is really important is that surveillance, vector control, environmental management, and case management need to be emphasized in the dengue endemic setting, irrespective of if you go ahead with a vaccination program Thank you >> Thank you very much for that presentation Questions, comments? Yes, Dr. Poehling? >> Thank you for sharing the experience, and what you guys have learned from the Philippines That was very helpful In going back to slide 18, where you went into the estimation — I’m assuming that those estimations were for the entire population, because you hadn’t learned about the younger kids And have you split up the estimation of those prevented to those precipitated by age group, for the kids nine to 16 in particular? >> Is it this — >> Yes, that’s the one Yes >> — because I don’t see the numbers Okay. So this is really done from the randomized controlled trial

So it was age nine to 16 It’s the age group nine to 16 I think the big assumption is — here is whether the vaccine performs the same if you give one dose, two dose, or three doses, which we of course don’t know So we had to assume that it works as — for three doses >> Are there any more comments or questions? Yes, Dr. Lee? >> Always good for a comment Thank you so much for the presentation It was actually incredibly helpful to hear your experience around decision-making, and what went into your decisions It’s more of a comment than a question, but it — like, I found it really interesting, probably because I’m realizing that in a way, the way you’ve framed this is the way we think about, you know, value in healthcare in general And one of the things, in addition to considering population benefits, population risks, as well as individual benefits and risks, is that, like, the way you’re evaluating the impact of your recommendation and subsequent implementation also takes into consideration the impact on providers and patients And I was particularly struck by that vaccine confidence slide I thought that was really interesting, and a good way for us to think about the impact of our recommendations, and how we make them, and how we communicate them can really make a huge difference in our public health efforts to really help the population So thank you for that I thought that was really useful >> Thanks >> Any more comments, questions? All right, if none, then we’ll move on to our next topic, which is Dr. Waterman, please >> Okay, well, that’s my second slide, but [laughter] we’ll get started Good morning So I’m going to summarize the dengue vaccine work group’s latest considerations, and as Dr. Atmar mentioned, and as I’ll elaborate, the work group does not expect to make recommendations until an independent evaluation of the specificity of available laboratory tests for past dengue infections is available for presentation to ACIP And this contingency makes likely that the work group would not make preliminary recommendations until the October ACIP meeting at the earliest So I just want to summarize what I thought the work group considered the key points and take-homes from Dr. Esquilin’s presentation on community, pediatrician, and parent knowledge, and sentiments about Dengvaxia in Puerto Rico First, 73% of pediatricians would use Dengvaxia given an acceptable pre-vaccination screening laboratory test The majority of pediatricians would like to see a screening test with a specificity of at least 90 — of 95% at least, and preferably 99% 76% of pediatricians supported a pilot project, and I’ll talk a little bit more about that in a second Over 80% of pediatricians felt that vaccine and lab insurance coverage were necessary steps for implementation Clearly, parents and physicians need more education about the vaccine, and there’s a need to explain the rationale for vaccinating in dengue-endemic areas, such as Puerto Rico And there were relatively few negative perceptions about the vaccine in the surveys that were conducted So the dengue vaccine work group conducted an informal poll of its formal members last December, and the work group members were asked to comment on what information is needed to make a recommendation on Dengvaxia By far, the biggest and most often-mentioned concern was having an acceptably specific vaccination screening laboratory test for past dengue infection, in the sense that we do not have enough information about available tests And I think Dr. Hombach referred to that The logistical changes of pre-vaccination screening, cost, and laboratory tests were also frequently mentioned I think Dr. Hombach’s presentation echoes work group concerns about transparency — transparency with regard to communication, and the importance of clear community engagement

to avoid unintended consequences A number of work group members felt that a pilot vaccination program could be implemented in children with documentation of previous dengue infection in the medical record, and Dr. Esquilin’s presentation on Puerto Rico surveys suggests support for such an approach among Puerto Rico pediatricians A pilot vaccination program might enable logistical issues to be worked on and solved With regard to a pilot, one work group member commented that an anticipatory recommendation would allow for insurance coverage for the lab test to be put in place as testing technology improved, and argued for the advantage of having a recommendation in place in advance of possible dengue outbreaks A number of work group members expressed skepticism about a shared decision-making recommendation Comments included that shared decision-making passes off the decision-making to the clinician, and that such decision-making would be complex, and could depend on the level of education of the family So the CDC dengue branch is in the process of evaluating available and newly-developed dengue IgG laboratory tests The process involves three steps — first, the WHO and CDC landscape analysis that has been mentioned previously Fourteen laboratory tests will be evaluated as a result of this first step CDC has recently procured a number of these tests, and is in the process of procuring the others So two steps of evaluation are planned — first, evaluation on the intended use of many of these tests, which is for diagnosis of acute dengue infections, and then a second evaluation based on the performance of long-term samples for past infection All the tests will be evaluated head-to-head with a curated set of PCR-positive samples CDC has selected, and we hope to complete the process by the next ACIP meeting Cross our fingers [laughter] So before I finish, I’d like to share a slide that Dr. Perkins presented from the University of Notre Dame’s modeling of cost effectiveness of dengue vaccine Puerto Rico — last October did not get around to showing This table gives the estimated impact of Dengvaxia vaccination in Puerto Rico over a 10-year time frame for vaccinating nine-year-olds screened by a lab test with 95% specificity and 80% sensitivity at different seroprevalence levels With a 60% seroprevalence, which is what preliminary data shows for Ponce, Puerto Rico, about 3800 hospitalizations would be averted among seropositives, and 300 additional hospitalizations would be seen among vaccinated dengue naives who tested seropositive — so a ratio of over 10 to one So as always, we’d appreciate feedback with other specific data ACIP would like to see, and considerations ACIP would like the work group to cover I’d like to acknowledge again our work group members, presenters, advisors, and CDC staff supporting the work group, and that’s the presentation Thank you I do want to just comment on one of the questions that was raised about where laboratory testing would be performed in Puerto Rico Right now, there are two laboratory tests that are CLIA approved, that Sanofi has evaluated in publications, which basically show, in their evaluation, 99% specificity These are available at private laboratories There have been discussions with the health department of whether they could perform these tests or not, but that’s completely up in the air So I’m open to any questions that you may have >> Thank you very much, Dr. Waterman Before we open it up for questions, Dr. Rubin will comment on the injury compensation >> Yes. Thank you Thanks, Dr. Lee, and sorry, I didn’t have enough caffeine this morning But — so as to your question about the vaccine injury compensation program in Puerto Rico, since it’s a U.S. territory, we — I mean, if there are covered vaccines, or claims that are alleging the injuries due to the covered vaccines, those will be covered by the vaccine injury compensation program But if your question is specific to dengue, dengue vaccine is not covered at this time

>> Dr. — go ahead Dr. Wharton? >> Thank you, and I appreciate that response One thing that was just occurring to me as I was thinking about this is that if the primary side effect we’re concerned about is severe dengue, that hopefully most patients would fully recover from without sequelae, would that be a covered injury? >> For dengue vaccine, you said? At this time, dengue is not covered — >> No, I understand that, but in — if it were — if it were recommended, and the vaccine were included in the program, which I understand it’s not now I thought that the program was designed to address adverse events that had long-term sequelae, rather than something like an illness that might result in hospitalization from which the patient would recover >> Oh, okay So, I mean, in terms of — we do have a severity requirement I think that’s what you’re stating In terms of being eligible for compensation, they have to show that sequelae has to last more than six months Symptoms have to last more than six months, or there should be inpatient hospitalization and surgical intervention, or death >> Dr. Poehling? >> Following up on that question, is — if the vaccine was recommended, does it matter on the coverage if it is a shared decision-making versus is it fully recommended? >> That’s a great question Currently, right now, what’s covered in our program are the routine vaccines that the ACIP have routinely recommended for children, and I’m understanding that there’s two — two definitions for routine But it’s the ones that have immune — immunization tables, not necessarily shared clinical decision-making >> So we think it’s similar to VFC coverage in that if it’s — and the private insurance coverage in that if it’s on the immunization schedule, it will be included in the vaccine injury compensation program And it can be either a routine “all children in this age group should get it,” or a “children should get it based on shared clinical decision-making,” is in general how it’s been done Is that — >> Yes. Typically, it’s the ones that have — if they’re — for example, in the meningitis, it’s covered, but it’s only a particular age group But that’s for all age group It’s not specific populations at this time, but to be covered, the ACIP has to recommend it for routine administration to children But there also has to be an excise task before that coverage goes through >> Did you want to follow up with a question, Dr. Poehling? Okay. Dr. Lee? >> So you had asked, Dr. Waterman, what other questions we might want to be asking, and it sort of relates to this conversation, but not exactly, in that the one thing I actually want to just be mindful of is potential disparities in access, either to testing or to care that may result And so, my question really derives from the fact that I’m worried about families who may not have the ability to pay for hospitalizations out of pocket, if that were the case, and/or other sequelae So if you could do your best to try and help us with that, it’d be terrific >> Yeah, you’ve raised that question before, and I think Dr. Esquilin would be in the best position to answer that question But my impression is that access to care in Puerto Rico is quite good I mean, the large percentage of the population is covered by the indigent healthcare system, and the healthcare system has been compromised by the public debt, but that, in general, overall access is good And I don’t know if Dr. — she’s nodding her head [laughter] So I think children who have severe illness have access to hospitalization >> Dr. Szilagyi? >> Yeah, thanks This is such a difficult decision Can I just — I’m intrigued by the concept of a pilot So, often, in system improvement, or practice improvement, you do a pilot to sort of work out feasibility issues What would be really the goal here for the pilot? Would it be taking a subgroup of the population that is insured, for which there are no cost barriers? Or what — or can you talk more about what you’re thinking, in terms of a pilot? What would be learned that then would allow to be scaled

up in a meaningful way? >> Well, I think Dr Hombach and I were talking about this a little bit before the meeting started, but I think this is obviously a complex logistical process to undertake And most of the discussions around pilots have been that there is not a large population, but a significant number of persons who have already had documented dengue infection in the medical record And that you could start to vaccinate those persons, and at the same time, continue this education process, and try and solve some of the logistical and insurance issues that have been raised already So, you know, I think you could argue on the one hand that it would just be sort of a symbolic gesture It might not have much population impact, but it would get some children vaccinated, and maybe could generate momentum towards figuring out how to actually make this a programmatic process, if that was the will of the Health Department and the pediatric providers >> I see. So it wouldn’t be so much a pilot of the lab to — of this two-step or three-step process >> No, that’s not what we’ve talked about at this point, but I think eventually that part might need to be piloted as well, yeah >> Have you guys discussed about — in terms of doing a pilot, would you need an ACIP recommendation for the specific group of individuals who have previously had documented dengue before conducting a pilot, from an economic perspective? >> No, not so much from an economic perspective, because I don’t think a pilot would have — although there’s individual benefit to the vaccine, the — I — I think that probably the work group, at this point, would want to see some sort of ACIP recommendation even before commencing a pilot, though But, I mean, further discussion is needed on that, yeah >> And from a cost — >> I don’t know if Dr. Atmar wants to comment on that >> We haven’t specifically addressed that, but the discussions that have taken place have been in the context of an ACIP recommendation And part of the rationale for that is to cover the cost of the vaccine, which is a — potentially a major consideration >> Dr. Maldonaldo? >> Yeah, Steve, great presentation Thanks for that, and I think we’ve come a long way since the original set of discussions But I do want to revisit at some point this issue of a pilot, and what really that means, because it is, as you mentioned, a complex series of issues, not just scientific, but really functional, operational So building a screening test into a — into public and private sectors, settings, et cetera — I do think that would — it would be really helpful, to try to pilot that whole — because there will be a series of steps, and depending on sensitivity, specificity of the test, how do you do informed consent for that? Is it going to be separate, et cetera? Who’s going to pay? All of those things, I think a pilot would probably be helpful, because it could be complicated >> Yeah. As far as consent, I think that’s a really important issue I don’t know if it’s informed consent, like in a clinical trial, but I think that we need behavioral scientists to come up with good language that’s culturally appropriate, that — really make sure that the community understands the risks and benefits, and to sort of have that thoroughly researched ahead of time >> Yeah, and not to take too much time, but one — so for example, when we rolled out our TLD rapid testing in labor and delivery for HIV, we did a series It didn’t just roll out It took a number of, you know, on-the-ground — they weren’t really clinical trials It was really implementation demonstration projects in the U.S. We’re not talking about — we’re talking about here, in this country And that took a while to get community input, understand how that would really work, engaging OBs, and pediatricians, and nurse practitioners, et cetera It took a while to get that all in line before legislation and all that was able to do that in a really — and now, of course, it’s seamless, generally But it does take some work >> I mean, even for a pilot, we would need to have considerable education of physicians in the community So that — >> Dr. Hunter? >> So, two quick points One is, I think the main advantage of doing a pilot would be — well, not a main advantage, but one of the big advantages of it would be increasing the confidence of the general public, the pediatricians, and the parents,

that you got your act together, and you’re going to do the implementation right You’re going to listen to them The other thing I wanted to say was that I think that whether or not to do a pilot — if I were in Puerto Rico in the local health department, or the territorial health department, I would want to be the people who was deciding whether or not pilot was done I would definitely take what the CDC guidance was, but I think that pilot’s going to need to be implemented by the local folks with a lot of support But I think that they should have the authority to do that, personally >> Yeah, let me just comment that the Puerto Rico Health Department is the spokesperson for immunizations in Puerto Rico, and that would clearly happen, and would have to happen >> Dr. Atmar? >> Perhaps Dr. Esquilin is in a better position to address this, but my understanding of the way the childhood immunization program has worked in Puerto Rico, and in particular, she mentioned the high compliance because of the school requirements One of the challenges with the shared decision-making is that — and some discussion has taken place — is that — if dengue vaccine were added to the schedule, it would be handled like the other childhood vaccinations, assuming the child is seropositive And while there would be information presented to the family, whether it would be required as part of attending school to increase compliance, and to make the system work, hasn’t been fully decided But that would be the usual way to — such vaccinations would be implemented, and there was some concern in the work group that that could cause problems down the road So — but that’s my understanding of how it might be implemented, were it to be recommended as routine for persons who were seropositive >> Are there any other questions or comments? All right, very good