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>> Now we’re going to finish up with the ACIP Dengue Vaccines Work Group This is a new work group that was convened back in October of last year in response to the Sanofi resubmission of BLA to the FDA for Dengvaxia, that we heard earlier today was approved last month There had been a previous dengue vaccine discussions that took place in 2016 and 2017 as part of the ACIP Flavivirus Vaccine Work Group and there were actually presentations on dengue and dengue vaccines in February and June of 2017. And then there was this gap between then and when we restarted in October 2018 So dengue vaccine discussions were put on hold until 2018 As was mentioned, again, earlier today, VERPACK reviewed in March 2019 and the approval of Dengvaxia occurred in May 2019 So, here are the terms of reference for the work group The objective is to develop recommendation for the use of safe and effective dengue vaccines in the U.S and U.S. territories among children and adults, including those living in dengue endemic areas and for persons traveling from non-endemic to endemic areas The terms of reference were developed– or the objective was developed before the vaccine was approved and, in fact it’s only currently approved for children and so the adults no longer really apply Under dengue vaccines then we’re going to review the safety, immunogenicity and efficacy data from clinical trials and long-term follow-up of studies for dengue vaccines submitted for licensure in the U.S., develop evidence based recommendations for implementation of vaccination in public and private sectors with dengue vaccines that are licensed in the U.S. for use, and identify areas where additional data are needed, i.e. user directions to improve control of dengue through safe and cost effective vaccination So, here’s our work group Chip Walter is the other ACIP member and he will be rotating off so we’ll be looking for an additional member I have to thank the ex officio members, our liais– liaison representatives, consultants, CDC contributors and particularly Steve Waterman and Gabriela Paz-Bailey for their work and we’ll hear from both of them a little bit later this afternoon Next slide please So, this is what we’re going to do today We’re going to start off with a presentation on dengue epidemiology in the United States by Gabriela Paz-Bailey and then we’re going to hear about Dengvaxia phase three clinical trial results and long-term follow-up form Gustavo Dayan from Sanofi And then finish up with Dengue Vaccine Work Group considerations and what our planned next steps are from Steve Waterman And next slide I think– and then what we anticipate will happen in October at the next ACIP meeting, we’ll present a great analysis and preliminary recommendations and we hope to have a vote with– on our final recommendations in February 2020 And I think that’s it Yeah. So, Gabriela Paz-Bailey, then we’ll present on dengue epidemiology >> Thank you, Dr. Atmar >> Thank you for the opportunity to present to ACIP today So I’m going to talk about Dengue global epidemiology I’m also going to talk just a few slides on dengue laboratory testing considerations as this vaccine requires screening before vaccinating And then I’m going to review the dengue epidemiology in the U.S and its territories to consider where dengue vaccine could be beneficial So, what is the global dengue burden and why is it such a big public health problem? So, dengue virus is transmitted by Aedes species, mosquitos primarily, Aedes aegypti and Aedes albopictus and is the most important virus transmitted by mosquitos worldwide

There is an increasing and substantial global burden and annually there are about 390 million infections, 100 clinical infections, half a million hospitalizations and about 20,000 deaths And the epidemics typically have a cyclical pattern over years with seasonal incidents correlated with the higher temperature months and with the rainfall months It is a problem throughout the tropics and the sub-tropics and it’s endemic in about 128 countries So its endemic in Asia, Latin America, including the Caribbean, Africa and the Pacific And now, with increasing travel, with increasing connectivity and rising world temperatures there are more areas that are becoming at risk of dengue Next slide Infections can occur with any of the four distinct dengue virus serotypes, natural infection resulting lifelong protection for that serotype But, in theory, a person can be infected with dengue four times in his or her lifetime About a third of infections are symptomatic and the typical classic symptoms include abrupt onset of fever, headache, retroorbital pain, muscle and bone pain, and this is why it’s called break bone fever, and often there is also rash And, of those symptomatic, between 10 to 20% are hospitalized and one to five percent of clinical cases result in severe dengue And hospitalizations rates vary based on early recognition, appropriate management and the local clinical practices Next slide The detection of four virus serotypes has expanded worldwide, together with growing hyperendemicity, hyperendemicity meaning that more than one serotype is circulating, and of course diagnostic availability has changed over time But until the 1980s the majority of areas had only one reported or two reported dengue virus serotypes circulating And more recently all four virus serotypes frequently co-circulate An example of this, next slide, is Puerto Rico, which has monitored serotype distribution for over four– for over three decades And, in addition to co-circulation of the multiple serotypes that you can see in this graph, the proportion of each of the four circulating serotypes varies over time Next slide This slide is to emphasize that dengue transmission is dynamic, that it’s constantly changing and that seroprevalence measured 10 years ago does not necessarily reflect seroprevalence today The data come from [inaudible] study in a particular Managua district in Nicaragua and it shows that seroprevalence by age group has changed substantially between 2004 and 2015 In the Y axis you can see the proportions here are positive, and in the X axis you can see age And I want to highlight the difference between the yellow line that is 2004 and the dark blue line that is 2015 So, while 50% of children were seropositive at age four and a half in 2004, 50% seroprevalence is reached by age 11 years in 2015 Next slide Of the estimated eight point nine billion global financial burden of dengue, most of it, five billion, results from patients who are hospitalized or that die from dengue Age, co-morbidities, host genetics, virus strain are risk factors for severe dengue, but heterotypic secondary infection is the greatest risk factor for dengue hemorrhagic fever and for dengue shock syndrome Next slide How secondary dengue infections increase your risk of severe dengue has been explained by antibody-dependent enhancement, or ADE And the mechanism for this is that at a certain concentration, heterotypic antibodies bind but do not neutralize variants of the subsequent infecting dengue type and these will lead to higher [inaudible] loads to an imbalance inflammatory response and, ultimately, will result in vascular leakage and severe dengue or shock The graph is from a longitudinal analysis of the risk of hazard of severe dengue disease by pre-existing dengue antibody titers for the pediatric cohort in Managua, Nicaragua

For dengue hemorrhagic fever and dengue shock syndrome they showed accumulative hazard of 11– 11% for intermediate antibody titers, compared to one point six percent among dengue [inaudible] children and one point five percent for children with high titers So, having no antibody titers or having high antibody titers is better than just having some antibody titers Next slide This table shows modeling results, results from mathematical modeling that were fit to the phase three Dengvaxia trials and they were produced by Sam Clifford and Stephen Flash from the London School And the table shows what proportion of first and secondary infections progresses to a given disease outcome that include symptomatic biologically confirmed dengue after two years, hospitalizations after five years, or severe dengue after five years And the model estimates that 19% of primary infections result in symptomatic dengue, three percent in hospitalizations and point three percent in severe dengue And after a secondary infection, 35% result in symptomatic dengue, 11% in hospitalization and two percent in severe dengue So, this shows that the majority but not all hospitalizations and severe dengue occur after secondary infections in this model Next slide So, the current dengue vaccine requires screening for dengue serostatus before vaccination and IGD testing will likely be used to determine previous serostatus There are currently no FDA IDG approved tests in the U.S and performance may be affected by the recent Zika epidemic because of cross reactivity with the different flaviviruses High specificity would be needed to avoid vaccinating true seronegatives that falsely test positive Next slide However, when thinking about test performance, sensitivity and specificity are not the only target metrics for SA development Tests with a given sens– sensitivity and specificity are more likely to misclassify truly seronegative individuals in low transmission settings compared to high transmission settings, because the pretest probabilities– probabilities of testing positive are lower In this example, of the 20% seroprevalence with a test specificity of 90% and sensitivity of 70%, 36% of persons testing positive would be false positives or actually negative for past dengue infection Next slide In a higher prevalence setting of 80% seroprevalence, the positive predictive value is higher, 97%, and then only three percent of persons testing positive would be false positives the problem here would be the imperfect sensitivity, since more than half of those testing negative would be true seropositive who could actually benefit from the vaccine Next slide I will now talk about dengue in the United States and its territories Next slide In collaboration with [inaudible] economists and modeler have proposed levels of risk based on seroprevalence to identify areas that would benefit from vaccination and where the risk of false positives would be low Areas with 10% seroprevalence at the target age group to start vaccination are considered very low risk, 30% low risk, 50% moderate risk, 70% high risk, and 90% very high risk Next slide So, ideally, we would have seroprevalence data available to us as risk But as for the rest of the world, there is limited seroprevalence data available in the United States and its territories We have proposed to use the dengue risk definition of the CDC Yellow Book that provides advice to travelers And since dengue epidemics in many regions typically occur every three to five years the Yellow Book assumes that endemic areas would be the most likely to report more than 10 cases in at least three distinct years over the most recent 10-year period These areas are classified as frequent or continuous risk The Yellow Book classifies areas with at least some or sporadic risk as defined as any area with at least one reported locally acquired case in the previous 10 years And then, as no risk, areas where there are no reports of dengue transmission

Next slide This criteria then define endemic areas as including the U.S territories of Samoa, Puerto Rico and the U.S. Virgin Islands and the U.S. Free Associated States of the Federated States of Micronesia and Palau Next slide So I’m going to describe now the U.S. territories that would fall into frequent continuous risk Next slide So, let me start with Puerto Rico Next slide This slide compares dengue incident rates in the black line in Puerto Rico to countries in Latin America And it’s just to show you that the rates in Puerto Rico are very similar to rates in Mexico, El Salvador, Peru and Columbia For Brazil their rates are 10 times higher than in all the other countries, so the scale percentage is different And, of course, reporting practices and under reporting varies by country Next slide This graph shows a number of suspec– suspected cases for the most recent years in Puerto Rico Passive surveillance data shows that the highest number of cases were in 2010 and in 2013 In 2014 there was a large chikungunya outbreak and in 2016 a Zika outbreak, and there has been some but little circulation of dengue since 2014 Next slide The map shows the number of cases in Puerto Rico by municipality Dengue transmission occurs throughout the island but there is a lot of heterogeneity and areas with higher population density have more cases, such as the San Juan metropolitan area and then the Ponsa municipality in the south coast Next slide This graph presents a number of cases and rates for the most recent years when there was transmission, so note that is data from 2010 to 2013 Passage surveillance data for Puerto Rico for this year shows that the highest number and the highest rates of confirmed and probable cases are in the 10 to 14 age group and the 15 to 19 age group The number of cases in older age group drops likely because by age 20 most people have already had a secondary infection We have documented a high degree of underreporting in Puerto Rico and a recent study suggested that for every case that is reported there are about 100 symptomatic cases that are not reported, and for every hospitalized case there are between five to nine hospitalized cases not reported Next slide This graph presents dengue associated deaths and the case rate fatality has varied by year But I show you the number of this by age group So, in contrast to the higher number of cases in children and in adolescents only six of the 64 lab confirmed deaths in this period were in children and there was only one in the 15 to 19-year-old age group So, 90% of lab positive deaths were in adults from 2010 to 2013 Next slide One of the few seroprevelant surveys that is available for Puerto Rico was done in 2007 in Patillas, that is the southeast of the island, and the seroprevalence among 10 to 11-year old’s was 43% and by 16 to 18, 60% were seropositive Next slide I would also like to provide you with some information on how dengue test results are processed in Puerto Rico persons who are symptomatic and seek care will visit their private providers office or go to an emergency room If the provider suspects dengue, a dengue test is ordered Testing is centralized at the public health laboratory, where PCR and IDM tests are done, and these results are sent back to the name in the form that appears as the provider, which could be the clinical lab that ordered the test, or the hospital, or the private physician So we’re unsure how many of these test results make it back to the patient record, but anecdotally we have heard that many really don’t make it back to the patient record Dengue is a notifiable disease and all results are kept in an– in the arbovirus surveillance system that is managed by the Puerto Rico Department of Health Next slide There is an immunization registry in Puerto Rico There are about 220 providers for the vaccine for children program and that covers about 60% of the vaccines that are administered

And there are also 300 private providers, including vaccination centers, and– and those provide about 40% of the vaccines that are administered in Puerto Rico The immunization registry covers both children and adults and it’s really complete They have 70% coverage of private providers and 100% of providers in– VFC Next slide So, I’m moving now to the U.S. Virgin Islands In the past 25 years there have been several periods of increased dengue virus transmission in the U.S. Virgin Islands, the most recent in 2012-2013 During the last outbreak there was a sero incident study that was conducted at the schools in St. Croix in 2012, and they found that 20% of school aged children and adolescents and 17% of teachers were recently infected with dengue; so that was IGM testing Unfortunately, they did not do IGG testing as part of this survey Next slide In 2012 and 2013 there were 310 cases reported, and you can see the age distribution and the incidence rate in this graph The highest number and rate was in the 10 to 14-year age group Next slide The U.S. Pacific territories and affiliated independent states include American Samoa, Guam, Northern Mariana Islands, Palau, the Marshall Islands and the Federated States of Micronesia And there are periodic outbreaks that have been detected among the pacific islands since 1958, usually with only one dengue serotype at a time We don’t really know whether continuous endemic transmission occurs in any of the islands, it’s– it’s really unclear However, there was this 2010 sero survey in American Samoa among adults that found 96% of the sample population was dengue IGG seropositive In 2016 and 2018 Americans Samoa saw a large dengue outbreak with over 1000 lab confirm cases Next slide So, these are the number of cases and the hospitalizations similar to the graphs that I showed you for Puerto Rico and the USBI with the highest numbers and the highest rates among the 10 to 14 and 15 to 19 age groups Next slide So now, talking a little bit about the areas with sporadic and uncertain transmission, next slide, there have been large dengue outbreaks, historically, in Hawaii More recently in 2015 and 2016 there were 264 cases reported due to dengue one The outbreak strain was a dengue one strain that was different from previous transmission in– in 2001, so likely due to a new importation of the virus A sero survey in a small rural community in 2001 in the Island of Maui show that 14% had evidence of recent infection and 17% had evidence of past infection Next slide Several counties in Southern and Central Florida have reported locally acquired cases in 2009 and 2010; nearly 90% cases were reported There was a sero survey in 2013 in Martin County that found that two percent of those surveyed had evidence of recent infection and a separate survey in Key West show that four percent had evidence of recent infection and seven percent had evidence of past infection, so really low seroprevalence Next slide Since 1980, Texas has detected a number of outbreaks with a few locally acquired dengue cases in border cities that are usually associated with large outbreaks in the Mexico cities In 2013 there were 24 locally acquired cases that– that were reported Next slide There was a sero survey that was conducted in 2005 at the end of a dengue two outbreak that showed large differences in seropositivity on the Mexico side of the border compared to the U.S. side Overall, IGM positivity that measures recent infections was 32% in Matamoros, Mexico and only four percent in Brownsville IGG seroprevalence was high in Matamoros, 77% for all age groups and 39% overall on the U.S. side Next slide There are about 800 cases among travelers per year, on average, and the most common travel destination overall has been the Caribbean, but it does vary from year to year

Next slide So, in summary, dengue is a public health problem throughout the tropics and subtropics, including the Americas Seroprevalence data are unfortunately limited Seroprevalence affects assay performance and the U.S. territories with frequent or continuous risk include Puerto Rico, USVI and American Samoa and potentially some affiliated Pacific Islands The cases and incidence rates in Puerto Rico, SUVI and American Samoa are the highest in the 10 to 19 age group, but there are also many cases occurring among adults Next slide And I just want to acknowledge the work group chair, Dr. Steve Waterman and the other members of the dengue branch that contributed to this presentation Thank you >> Thank you, Dr. Paz-Bailey We’ll open it up to questions, if anybody has any; I have two regarding the dengue test– test flow in Puerto Rico What’s the average turnaround time for that test once it reaches the– the center? >> The average turnaround time, I mean, I think it depends on the volume of testing that is going on, but it’s about two weeks >> Okay, so that would also add probably to the lack of transmission back to the patient itself Alright, and then the other question is the immunization rest– registry in Puerto Rico Given the recent climactic challenges that that country has suffered, how much disruption of this– of this registry exists and if it is disrupted do we have an idea when it will be back to its previous state of affairs? >> Yes. I mean the– probably, it was disrupted in the immediate days after Hurricane Maria, but we have had conversations with the Health Department and its fully operational right now >> Thank you Any other questions, comments? Very good Thank you very much So, next we’ll move on to presentation by Dr. Gustavo Dayan on Dengvaxia phase three clinical trials and long-term follow-up from Sanofi Pasteur >> Good afternoon everybody and thank you for the opportunity of presenting here at the ACIP meeting So, in the next few minutes I’m going to discuss the results of our phase three clinical trials, in terms of efficacy, safety, and long-term follow-up So, Dengvaxia is a Tetravalent live attenuated viral vaccine and the development of this vaccine has taken more than 20 years of research Dengvaxia combines two different viruses, so the Yellow Fever vaccine virus where the capsid and the non-structural proteins act as the backbone of the vaccine and also the dengue viruses So, the precursor membrane and envelope genes were isolated from each of the four dengue serotypes and were inserted into that backbone As a result, we obtain a chimeric vaccine, which is a combination of the two viruses and produces or reduces protection against the four dengue serotypes Next. Oh, there you are So, the development program started in 2002 It comprises 26 clinical trial studies and these involved 41,000 subjects enrolled in 16 countries More than 28,000 subjects received Dengvaxia in in clinical trials and most of them were aged nine to 45 years of age Dengvaxia is now licensed in 20 countries, including the U.S and also in the European Union As we have discussed before, the indication in the U.S. is nine to 16 years in seropositive subjects, and we’ll discuss a little bit the basis of this indication So, let’s start with the efficacy results So, we have two phase three clinical trials in the program So both of them were randomized of observer-blind placebo control studies One study CYD-14 was conducted in children aged two to 14 years of age in 11 centers, in five countries in Asia Pacific The other study, CYD-15, was conducted in children

and adolescents age nine to 16 years of age in 22 centers in five countries in Latin America Study CYD-14 enrolled about 10,000 subjects who were randomized two to one to receive either Dengvaxia or placebo and study CYD-15, approximately 20,000 subjects were randomized to receive Dengvaxia or placebo The studies also include baseline samples in a subset So the subset is the immunogenicity and reactogenicity subset and these will stand this way following the WHR recommendations for the development of vaccines, of dengue vaccines So, this is just to describe a little bit the design of both studies Both studies were identical in design, so they included three different doses separated by six months each and then a long-term follow-up period of five years after the last injection The study was divided in two different phases; the active phase and the hospital phase The active phase started with the first injection and then it– it ended at month 25, and the main purpose of this phase was to asses efficacy So, we had an active surveillance system to be able to detect any suspected dengue case So, efficacy was assessed one month after the third injection, and this was the primary endpoints of the primary endpoint of the studies and also from the moment of the first injection until month 25 The study also had this hospital phase The hospital phase started at month 25 and finished at the end of the studies Here we were only detecting hospitalized cases, so the surveillance system was assigned to detect only hospitalized cases and the main purpose of this phase was the long-term safety follow-up So, in summary, safety for hospitalized and severe dengue was started from the very beginning the– of the studies and was continued until the end of both studies And these are the first results that we got with both studies So here you have the efficacy from month zero to month 25, so both studies met their primary endpoint, and, as you can see, we obtained efficacy was approximately 55 and 65 in CYD-14 and 15 respectively We also were able to show efficacy against hospitalized dengue, have the percentages there, and also unimportantly to severe dengue cases So, as I mentioned before, we had a long-term follow-up, and during that long-term follow-up we started to see an increased risk of hospitalized dengue approximately in year four in one of the studies, in study CYD-14, which was the study conducted in the younger children So, our product goals included some pre-specified analysis by ICH age groups and we were able to see that this was particularly focused in children two to five years of age So, next. Next Okay. So, these safety signal detection prompted us to conduct some additional analysis using different age groups and we were able to show that the relative risk for hospitalization and for severe dengue was lower in subjects that were more than nine years of age That is what prompted us to use nine years as the cutoff for the initial indication in endemic countries However, we knew that the age was closely related to the baseline studies, so this is the prior dengue infection The problem– next The problem is that we didn’t have baseline specimens on all the subjects, because, as you may remember, we only collected baseline samples in a subset of patients So, we had, by design of the studies, one sample in almost all subjects at month 13 So that– this is one month after the third injection But again, we face another problem; we had the blood samples but we didn’t have the assay, because the assay that we used was a PRNT assay that was specifically designed to assess the response to the vaccine But here we wanted to assess the response to then So, we had to leverage another assay, the NS1 antibody assay

to be able to infer the baseline serostatus from those specimens collected at month 13 And these are the first results of these NS1 supplemental analysis In the upper part you have the results in the seropositive subjects, those who have previously been exposed to dengue, and in the lower part you have the seronegative subjects So, with the round symbols you see the estimates and with the whiskers where the [inaudible]– the 95% confidence intervals We also include the vertical dotted line, which is the null value So, as you can see, we see a very different response in those who are seropositive, where all the estimates I tow– are towards the left of the null value, indicating protection, compared to the seronegative subjects, where the estimates are towards the right of the null value, indicating an increased risk So, here, I wanted to show you the risk reaction of hospitalization; these are hospitalized patients but by serotype So this in seropositive subjects, aged nine to 16, which is an indication in the U.S. So, as you can see, the risk is increased for all the four serotypes, and importantly the upper bound of the 95% confidence intervals spare the null value Okay. We also looked at the time to dengue hospitalization So, in this figure, we described the communitive incidences for hospitalized dengue cases for both Dengvaxia, described in blue, and the control group, described in grey As you can see, there is a clear separation of both occurs from the moment of the first injection until the end of the surveillance period We did a similar exercise for the severe dengue cases and this is again seropositive subjects, age nine to 16 years of age, and you can see clearly same pattern, so clear separation of both occurs Dengvaxia and control at the beginning from the first dose and until the end of the surveillance period We also looked at the vaccine efficacy This is the traditional vaccine efficacy against any symptomatic dengue disease And this is again seropositive subjects nine to 16, and as you can see, the efficacy was consistent in both studies and it was approximately 75% We also looked at the efficacy– efficacy in seropositives in this age group by serotype, and as you can see in this graph, we can see that there is efficacy for each of the four serotypes And the lower bound of the confidence intervals also spared the null value Next. There you are So, we also looked at the population level effects and for that we looked at the cumulative incidents over a five-year period So basically, we looked at the differences, or the attributable risk, which is the difference of the incidence in the vaccinated and unvaccinated children And we observed that the attributable risk for both hos– we looked at both hospitalized and severe dengue and the attributable risk for hospitalized was minus 15, and for severe dengue was minus four So, next. Yeah So, in summary, just to conclude on the efficacy data, we observed, as you saw a different profile by serostatus, which was favorable for seropositive subjects and unfavorable for those seronegative And in seropositive subjects, aged nine to 16 years of age, we saw protection against symptomatic hospitalized and severe dengue The evidence of efficacy was consistent in both phase three clinical trials and we saw protection against the four serotypes And then in terms of population effects we saw that a vaccination of 1000 seropositive subjects would prevent 15 hospitalized cases and four severe cases in the conditions of these clinical trials So, let’s take a quick look at safety And here I put the overall safety profile of the vaccine in study CYV-15 and here I am including both seropositives

and seronegatives and this is a study that has the biggest population and has the age of the indication in the United States In the upper part of this table we have the reactogenicity data, and as you can see the percentages are a little higher for the vaccine group compared to the placebo This is particularly true for the injection site reactions, mainly In terms of safety, so, we saw that in terms of serious adverse events the percentages were pretty similar in both Dengvaxia and the placebo group Those that were post any dose and then those that were six months post any dose So, what we see here, and I wanted to also clarify is that we also looked at the viscerotropic and neurotropic disease because this vaccine has the backbone of the Yellow Fever vaccine virus so there was a concern that vaccination with the backset could cause viscerotropic or neurotropic disease and we didn’t see any case In terms of deaths– next There you are So, we– the percentages were pretty similar in both Dengvaxia and placebo groups and we didn’t see any deaths related to the vaccine Next. So, this is– these are the solicited injection site reactions that we included in both trials So, we looked at pain, erythema, and swelling, and as you can see, the percentage of pain mainly and a little bit swelling were higher in subjects receiving the vaccine compared to those who received the placebo Most of the injection site reactions were grade one or grade two and they were short duration and started normally within three days after vaccination We also looked at solicited systemic reactions and we looked at fever, headache, malaise, myalgia and asthenia And, as you can see here, the percentages were pretty similar, so no clinical significant differences from Dengvaxia, described in blue and the placebo in grey Again, most reactions were mild or moderate in intensity or short duration We also looked at the unsolicited adverse events or unsolicited adverse reactions and again, really nothing very different when we compare the vaccine to the placebo group And again, most of them were mild or moderate We also have data from post-marketing because the vaccine has been used So we have approximately three million doses or two point nine million doses distributed, mainly in the Philippines and in Brazil, where they organize vaccination campaigns And we got approximately 3000 spontaneous case reports and that included 553 serious adverse events Most frequently adverse events were consistent with a clinical development plan, but we also– next We also detected some allergic and anaphylactic reactions that were rare but had not been detected in the pre-licensure process, but were detected in the post-licensure experience So the frequencies less than point zero one We had 134 potential allerg– allergic reactions within the first seven days and three cases of anaphylactic reactions So that May that’s include the allergic and anaphylactic reactions in the prescribing information So, in summary, we have the rate of sums solicited adverse reactions, particularly the injection site reactions were higher in the vaccine group compared to the placebo Low rates of grade three adverse events in general The majority of the reactions were mild to moderate in intensity The rates of SAEs were low and similar in the control group We didn’t see any cluster of events, no cases of viscerotropic and neurotropic disease No related deaths were reported and we detected allergic and anaphylactive reactions in the post-marketing surveillance So I just wanted to bring the indication as a summary So, as it was mentioned before, Dengvaxia was approved for the use in the U.S. to prevent dengue disease caused by any of the four serotypes, in individuals nine to 16 years of age with evidence of laboratory confirmed previous dengue infection

and also living in endemic areas And previous dengue infection can be assessed through medical history with previous lab confirmation or current serotesting prior to vaccination Next So the vaccine is to be administered subcutaneously In 3 dose schedule zero, six and 12 month Next And since the vaccine is linked to serotesting we started to explore different possibilities to execute serotesting globally and particularly in Puerto Rico So here I included the two tests that are under clear approval in Puerto Rico and they are available So one of them is an IgG ELISA test and the other one is RDT, a rapid diagnostic test, and important to see that this is our internal evaluation, the specificity of this test was very high And this was very important because, of course, we want to avoid the possibility of any false positive result So, in summary, so, assessing more than 25,000 subjects, Dengvaxia has demonstrated a favoring– a favorable safety profile efficacy against symptomatic, hospitalized and severe dengue, against each of the first serotypes when used in seropositive subjects aged nine to 16 years of age So, next. So, thank you and I’m open to any questions you might have >> Thank you, Dayan– Dr. Dayan, excuse me Are there any questions from the group? Dr. Moore >> Thanks Gustavo I had a question about the rates of viscerotropic and neurotropic disease You mentioned that in reference to the clinical trial Was that also looked for in the post-marketing surveillance? >> Yes >> Because obviously the clinical trials numbers were too small to have– >> Yes >> Detected something like that >> Yes. That applies to both the pre-clinical and the– the clinical trials and also the post-licensure experience Yeah, we didn’t see any– any issue >> Okay. Okay >> Yeah, and by the way, we had protocol– a specific protocol to assess AVD and AND in the clinical trials because this was considered as an adverse event of special interest, so we had specific protocol to assess any potential AVD or AND case >> Okay. Thanks >> AJ >> Yeah, I have two questions Thank you for this presentation The– when you said there was no deaths and you are including post-marketing due with the anaphylaxis that there were also no deaths that were recorded in that group And this is interesting the way you say it, I’m just curious, how– because you had to test people for dengue before they actually meet the requirement for the vaccine, right? >> No. In these– in these companies when the vaccine was used in the field, we didn’t have this information so the vaccine started to be used without these restrictions on the seropositive subjects, so everybody was vaccinated So then when we found these new results, we started to incorporate this new recommendation in seropositive subjects >> So, the requirement now after your post-marketing experience is to have it tested and have a positive dengue before they qualify for that >> Correct Correct. And this was what we incorporated for the submission to the FDA and what was approved for the– for the use in the United States >> Just curious, do you have the cost for the testing? >> The cost of the testing? >> Yes >> So, I don’t know I don’t think it is very expensive I don’t know Maybe my colleagues in Puerto Rico from the CDC can say what the cost would be, but– for the testing, but I don’t think it is a very expensive test Normally, it’s– especially the RDTs are not very expensive tests I wouldn’t be able to tell you a price on dollars though >> Anybody else? Dr. Maldonado first >> Thank you I actually did get a copy of the– I don’t have it with me now but there is a copy of the table with the test and the costs for them There’s about, I don’t know, four or five of them maybe, I can’t remember >> Oh >> But I have two questions for you Thank you for that presentation The first question I have is regarding the earlier studies around Dengvaxia, the WHO website still has data from 2017; they haven’t updated it and this data didn’t– I didn’t see a citation, so I assume it’s not published But their pool data efficacy was much different So, their efficacy against serotype three was 71.6 and four was 76.9 and four serotypes one and two was 54.7 and 43.0, so I’m just wondering is this new data and is this–

>> Yeah >> But there– this is pooled, because this is pooled data from several countries? >> Yeah. So, what– what you have is data that combines studies but they are not taking into account the seropositivity or the serostatus at baseline So these came afterwards because the analysis that we did we had to, first of all, get to the test, to the NS1 assay and then conduct all this analysis So you have data that are combined and that were published also in the New England Medicine where we have all the results, but without taking into account the baseline serostatus, and then you have also these data who are also published in the New England Journal where you have more recently, that was published last year, when you have this analysis by serostatus with the NS1 in it >> Cases. Okay, I have a second question also Thank– so, regarding the use of Dengvaxia in the Philippines, you didn’t mention the 14 deaths that were supposedly associated with the vaccine and I don’t know that that data has ever been confirmed but could you talk a little bit about that? >> Yeah So the situation in the Philippines, in the Philippines the vaccine was approved for use in 2015 According to the– they followed also WHO recommendations because that was approved for use and their own regulatory agencies and they conducted different vaccination campaigns, in total 800,000 subjects approximately Then when we gave this information to– we made public this information that took some time because we had to develop the assay and then produce the analysis, they r– so they really took the license back; there was a suspension of the license for a while, and then finally they just withdrew it completely So the– the issue with the deaths is that they report some deaths that were they say that they are associated to the vaccine, but it’s very difficult really to get a clear association with the vaccine, and most of the deaths are not even virologically confirmed dengue, because they report the cases but they don’t have sometimes virological confirmation And also, it’s difficult to establish and we don’t have a lot of data either to assess the cases completely >> Well but one– let me just interrupt for a second because I was– and I worked with the Philippine Pediatric Society around this issue because they had a huge anti-vaccine– >> Yes >> Response because of this and whether it was true or not, these kids actually have– each of them had a code number and they were being followed by the government So, I think these kids clearly got vaccine or placebo, that part’s really for sure, they knew that And I guess the question is what happened? When I talked to the Ministry of Health and WHO they were all try– had different stories about how they were investigating the deaths, so I’m just wondering what the company was– ? >> Yeah >> How the company was– ? >> So, yeah These– these children actually received the vaccine because they were vaccinated in the vaccination campaign and they– the problem was to really identify if it was or it was not related to the vaccine and there was a special committee, a WHO committee, that looked into the cases and they couldn’t get to a really final conclusion, so this is the Advisory Committee on Safety, the WHO Advisory Committee, and they were not able to conclude Of course, you know, any deaths is a problem and we feel very sad about that, exactly, only one Yeah >> But you didn’t mention them at all and I guess the other question, I’m sorry to belabor this, but 14 deaths is a pretty big deal >> Yeah >> Those children were kids who got the vaccine, you could have calculated a comparison with kids who didn’t get the vaccine who were in– >> No. No, because they were children who were vaccinated in vaccination companies, yeah >> So that wasn’t done >> Dr. Moldano I think you’re recommending and maybe perhaps you should just say this that the ACIP Work Group look at that original data, is that what you would ask? >> Yeah. There’s two really good papers I think he cited them, and then the last set of data as well, and I think then you just– if you want to go back to the WHO website you can find more information about what happened in the Philippines >> Thank you We’ll take that under advisement Dr. Stephens >> This is probably a naive question, but can you give us the immunological thinking of why this vaccine is protected and those that are prior have had prior disease versus the younger group, because I think that would be helpful to at least me on the committee? >> Yeah. So, what happens is as Dr. Paz-Bailey explained, secondary infections are more related to more severe disease So, and this is, as she explained, based on different theories, it’s not clearly, but clearly but mainly the U2ADE, so basically what you have is an increase of antibody titers after the first infection that are protective to that serotype

But then there is also cross-reactive protection against other serotypes that is short duration So, when these serotypes, these heterotypic response starts to decrease then that increases the risk of a more severe disease for different mechanisms So, it may increase the entrance of the viruses into the cells and trigger an immune response that may con– use basically this plasma leakage So this is the immunological pathogenesis So what we think is that when we are giving the vaccine to seronegative subjects, we are infecting the subjects for the first time, creating a primary infection So when they have a secondary infection they would be at more risk for severe disease, whereas, when you have– when you vaccinate a person who had been previously infected, so this would be a secondary infection and this would increase the– or decrease the risk of hospitalization and also induce efficacy to protect against future infections >> Dr. Cone >> Can I ask a question about the population that was studied? So, in the pooled data of over 25,000 children, what proportion– what– what number of those were actually from Puerto Rico versus other countries and how app– how generalizable do you think this data actually is to kids living in Puerto Rico where which would be the primary population that we’re thinking about? >> So, we had approximately 1300 subjects who were recruited in Puerto Rico In Puerto Rico we had two different sites; one was in San Juan and the other one was in the southern part of the island in Guayama And these– we looked at the demographic charac– characteristics I don’t have the slide here but it’s pretty similar And we were even able to look at the efficacy of the vaccine We don’t have many cases, but we have some and the efficacy was even I think it was around 94% The confidence intervals were higher, were a little wider because of course we don’t have many cases, but it’s very comparable We didn’t have enough hospitalized cases to assess the risk, but I think, in general, in terms of demographics and in terms of vaccine efficacy they are very comparable >> Dr. Messonnier >> Yeah. Thank you I know this is really complicated so I appreciate you taking us through it slowly One thing I just want to make sure I understand is while there are other countries that have the vaccine licensed, no country is currently routinely using it? And also, the– the language specifically under the FDA licensure hasn’t– we have no– any country or location that’s actually implemented it specifically the way that FDA recommended it; is that operationally true and therefore ACIP will have to make its recommendations based on the available data, there’s nothing else coming? >> Yeah. So, what happened is that at the meeting when we had the first indication was in children Most of the coun– different countries have different indications So they can have nine to 16, nine to 45, nine to 60, depending on– on what– what the situation is So, at the beginning they had this indication for the whole population When we realized that we had this safety signal and this problem with the seronegatives, so we informed, of course, all the regulatory authorities and they started to update their recommendations So now they have updated recommendations and most of them included this clause of having seropositive– seropositivity to be able to be vaccinated >> But none of them have operationalized it yet in a large way? >> Yeah. They– well, the vaccination now is mainly in the private market in the– in the cases where the vaccine is– is recommended We don’t have, at this point, any vaccination campaign ongoing, but if the vaccination was updated in the country, so the indication was updated in the country they have to follow the new indication >> Dr. Hunter >> So, if we were to operationalize this in Puerto Rico, and we had a test that sensitivity gave us false negatives and false positives with a turnaround time of two weeks and it had never done– been done anywhere else, you’re asking us to vote on something like that eventually That’s not very reassuring for me as a voting member >> Yeah. So, what we are– we are– at this point, what we are doing is trying to discuss what would be the potential ways to use the vaccine in– in a setting like Puerto Rico So we have been in discussions with the working group and also

with regulatory authorities in Puerto Rico to see how this could be implemented because they have some laboratory testing that could be used with the system that Dr. Paz-Bailey explained We acknowledge it’s– it’s difficult to implement We have– we have also some materials that we– we have and that can be put in place in case the vaccine is used by healthcare practitioner guidelines because we want this to be very clear to the healthcare practitioners who will be administering the vaccine And also, we have an online training program that could potentially be used for to train the healthcare workers that would be using the vaccine And of course, you know, our idea is to make the new information available to everybody as soon as we have it because we have some additional data we are analyzing after the NS1 analysis >> I just want to say it would be much more reassuring to have something that had actually been tried before, before we actually vote on it >> So I just want to addre– respond to that and I mean I think you’ve hit the key issue that the work group has already begun to struggle with and will continue to assess over the coming months and that we will end up presenting to you the results of our struggles with this question and, ultimately, I think will strongly influence the assessments that the committee has on the utility or potential utility of the vaccine We don’t have the answers right now and we’ll see whether they become available in the coming months >> Sure >> Yes, go ahead >> So my last comment is I’m– I’m coming from a perspective of working at a local health department where the– or at a state level health department where the CDC can’t come in and help us out unless we ask them to help us out, okay So, if Puerto Rico– Puerto Ricans in some fashion asked for we’re demanding this, that would change my opinion quite a bit So, if there was a really strong demand and they were willing to– to take the risks because they felt that it would benefit them personally, you know, or collectively, that would change my opinion a lot >> So, the ETR is extremely important in this, right, I mean that’s what you’re saying is that DTR– >> Maybe we should Steve go ahead because I think that’s his presentation >> I think– I think it’s important to let the voting members air their questions because this is going to be something that’s going to be a very difficult vote and that they should be aired now and we should add to the body of questions as they have So we’re going to let Echez go and then I will let Dr. Moore go and I think Dr. Alt needs questions too >> I was just asking for clarification, so I– so when an individual who is negative for dengue get this vaccine does it make them at increased risk for getting an infection or at increased risk for side effects? >> So, what we observed is that when the seronegative subjects get the vaccine, they have increased risk of hospitalization and then also to have more severe disease So that– that’s what we described And severe disease was classified, we had an IDMC, so an independent data monitoring committee that classified the cases as severe So, this is what there is an increased risk of hospitalization and severe dengue in those who are seronegative >> So, still confusing So, increased severe disease when they have the infection or with the vaccine? Because when you give the vaccine to someone that is seronegative, you actually mean they don’t have the infection So, you would get increased hospitalization, so I would consider that a side effect Then you are also saying they are also increased risk that if they do get the disease that they will have more severe infection >> Yeah. So, the– the vaccine efficacy also was– was not– was not good for the seronegative, so in the seronegative subjects, for example, that were more than nine years of age, the vaccine efficacy was around 38-39%, but the confidence interval was– were very very wide If you look at the vaccine efficacy, those who were less than nine years of age, that was lower and those cases,

so you can see the vaccine in that particular group in the seronegatives was not very efficacious And then on top of that we had that increased risk So, when they got the disease because they were not protected by the vaccine, they had a higher risk to have a more severe disease or, two, they were more likely to be hospitalized if they had dengue >> Dr. Moore >> Yes, I just was wanting a little more information about the allergic reactions, not the anaphylactic ones, but the other allergic reactions that were noticed in the part– post-marketing surveillance Could you tell us a little bit more about those, what sort of allergic reactions they were? >> Yeah. So, the reactions were typically associated with what we use and S and Q, so this is a standardized measure query to group all these reactions that– that could be, and they were– I don’t have the list here but they were more related to, for example, rash or they have, for example, I think they were, for example, reactions in the skin or [inaudible], so different– and we have a protocol to follow the map So these– these were– they were considered potential allergic reactions based on these, but none of them was an anaphylactic reaction So this was done during the pre-clinical, within the clinical studies, and also, we detected that in the post-marketing experience So, using this algorithm we were able to classify these potential allergic reactions, but during the clinical trials we didn’t see any real anaphylactic reaction and in the post-marketing we did see those cases that I described, and that’s why we included them into the– into the indication >> So I’m going to ask Dr. Ault to go next And then I’m not cutting the questions off but I want to move forward to have Dr. Waterman present And then if we need to circle back around and have Dr– Dr. Dayan come to the podium we’ll do so So, Dr. Ault, your question and then Dr. Waterman his presentation Go >> My question is more of a long-term question Is VAERS friendly to Spanish speakers? Is that a– if we’re thinking about doing that >> So, the website and guidance and instructions for reporting is in Spanish The actual report form is in English and there’s– there’s multiple reasons why that is and difficulties with med coding and such, but– but their– the instructions, the website and also if a person wants to call in to the 1-800 number they can get to a Spanish speaking person, so we think there’s plenty of opportunities to take a report from somebody who– who speaks Spanish as their first language >> Thank you for that So, thank you Dr. Dayan What we’re going to do now is have then Dr. Waterman proceed with the work group considerations and next steps please >> Okay, good afternoon Get through the– get though the end of this So, I– I’d like to summarize the work groups recommendations, considerations today and the next steps toward making recommendations regarding Dengvaxia We good? So, the– the FDA approved indication recommended by the VERPACK and announced in May for Dengvaxia is for children nine to 16 years of age who have a laboratory confirmed previous dengue infection and live in endemic areas, such as the U.S. territories of American Samoa, Guam, or excuse me, Puerto Rico, and the U.S. Virgin Islands Next slide The Dengue Vaccines Work Group has drafted this policy question to guide the evidence to recommendations framework and the grade assessment Should three doses of CYTDB be administered routinely to persons nine to 16 years of age with laboratory confirmed previous dengue infection and living in endemic areas to prevent virologically confirmed dengue hospitalizations and severe dengue? As you’ve heard from dr. Paz-Bailey,

dengue viruses have caused steadily increasing morbidity and mortality worldwide over the last 60 years In the U.S. territories of Puerto Rico, the U.S. Virgin Islands and American Samoa, dengue viruses circulate at endemic or virtually endemic levels The situation that also applies to two U.S. affiliated Pacific nations, Palau and the Federated States of Micronesia Age specific seroprevalence data are scarce in most of the world, including the U.S. Higher population prevalence of dengue antibody reduces the likelihood of false positive pre-vaccination screening tests Based on modeling of Dengvaxia impact with Sanofi trial data, WHO Sage recommends that countries could consider vaccinating without screening of serop– at seroprevalence levels in nine-year old’s of at least 80% Severe dengue can occur in infants, children and adults In the Sanofi trial, severe dengue occurred in about four percent of unvaccinated children overall Severe dengue often manifests as a leaky capillary syndrome, which can lead to shock and death untreated Shock from dengue can almost always successfully be managed if monitored for and treated appropriately with fluid replacement Severe illness can sometimes manifest with GI hemorrhage, liver failure and or meningoencephalitis Higher risk of leaky capillary syndrome is associated with secondary dengue infections The proposed pathogenetic mechanism is known as antibody dependent enhancement, or ADE– ADE Dr. Paz-Bailey showed this slide of the prospective study in Nicaraguan children that demonstrates higher risk of this syndrome when heterotypic or cross-reactive dengue antibody levels fall to moderate levels consistent with the ADE mechanism Dr. Dayan has summarized the long-term phase three trial data for Dengvaxia In seropositive children, nine to 16 years, the vaccine is about 75% efficacious against philologically confirmed symptomatically dengue with higher levels of protection for hospitalization and severe illness The vaccine is effective against all four serotypes in seropositives The highest efficacy is for the dengue four virus serotype Depletion antibody studies by Dr. Silva at the University of North Carolina show that Dengvaxia produces high levels of homotypic antibody for dengue four compared to the other serotypes However, in seronegatives, the risk of hospitalization is higher in vaccinated children with a hazard ratio of one point four one and a hazard ratio for severe dengue of two point four four Apart from this risk in seronegatives the clinical trial safety profile data is comparable in vaccines and controls And I’ll just make the– the comment that in the work group so far I think the– the view of the quality of these clinical trials is that they’re first rate clinical trials and the efficacy data was– was conducted to the highest standards As mentioned by Dr. Atmar, the dengue vaccine’s work group convened last October after about a year’s hiatus in dengue related discussions as part of the flavivirus work group This slide showed the topics covered during the work group meetings the last eight months We’ve had three work group meetings on IgG tests that might be used for pre-vaccination screening Dr. Robert Luo presented on a systematic review of 10 published evaluations of four rapid diagnostic tests These tests are not FDA cleared tests but available in various parts of the world and could be performed in the U.S. under clearer regulations The sensitivities range between 30 and 60% The specificity– specificities range between 65 and 100% with wide confidence intervals The CDC dengue branch has also conducted a preliminary landscape analysis, so over 30 rapid diagnostic tests and IgG ELISA tests Both the Luo paper for WHO and the CDC assessment point out that these tests were designed for detecting acute infection and not past infection

The composition of the panels to evaluate these tests does not have information on infections with other flaviviruses or flavivirus vaccinations Such samples are needed to evaluate cross-reactivity and specificity Sanofi has identified three tests, as Dr. Dayan pointed out, two rapid diagnostic tests and one IgG test, ELISA test, that are available in Puerto Rico and American Samoa One of the RDTs was included in the Luo study Sanofi evaluated the sensitivity and specificity of these tests with a well characterized set of samples including Yellow Fever and Japanese Encephalitis neutralization test positives, 400 samples This evaluation found specificities of greater than 90– 99% for all three tests When the three tests were evaluated with– with Zika microneutralization test positive samples cross-reactivity was three to 13% The initial 99% figure was not involving Zika positive samples The manuscript on these results is in preparation Sanofi’s developing with bi– devel– co-developing with the biotech company in San Diego an RDT IgG test that could be used for pre-vaccination screening, which they plan to submit for FDA clearance WHO Is also working on a target product profile project The opt able pre-vaccination screening test would be a low cost, rapid diagnostic test that could be performed on whole blood from a finger stick sample The minimum sensitivity and specificity would be greater than 90% The optimal reference panel would include curated specimens that are positive for dengue, other flaviviruses and dengue plus previous flavivirus samples at varying timepoints after infection, as well as a variety of flavivirus vaccine recipients The work group will be completing the ETR framework and grade assessment analysis– grade analysis over the next few months in order to make recommendations to ACIP The topics in cover– covered will include a CYDTV cost effectiveness studies, acceptability, and the implementation issues or feasibility issues as well as any update– as well as an update of any information available on laboratory tests In formulating recommendations, the work group will need to consider overall cost effectiveness given the unusual requirement of pre-vaccination screening, and best information on the sensitivity and specificity of available tests Hopefully an independent evaluation of available IgG laboratory tests using close to optimum serum panels can be conducted in the near future The co– the confidence in cost effectiveness and predictive value estimates will improve with updated population representatives seroprevalence data CYD will clearly need to be explained to the population through immunization program outreach and implement it with carefully vetted informed consent language We need to find out what are the feasible logistics of pre-vaccinating– pre-vaccination screening in the U.S. territories Is there a strong program, territorial program for vaccinating school aged children? With better seroprevalence data the optimal age for vaccination might need to be adjusted It also seems worth considering identifying subject populations living in the U.S. from endemic areas who frequently return to endemic areas to visit friends and relatives For example, Puerto Ricans in Florida and New York or Latino populations living on highly mobile U.S. Mexico border So many thanks and I’d like to acknowledge our chair, Dr. Atmar and our hard-working work group members and presenters >> Thank you, Dr. Waterman Open for questions, comments, etc. Dr. Hunter >> I just want to say that your summary of what you’re addressing and what you think the important issues are are very very reassuring to me and that, you know, the goal of getting the greater than 90% sensitivity and specificity I think is key; that’s going to be quite a challenge and it’d be very nice to have some pretty hard data on whether that really actually works in an implementable way >> So, I would like to ask a question So the informed consent process that you brought up, will this require a higher level of informed consent than we have

in the– obtained in the past? What will be the impact of this on patient physician interaction in getting approval for use of this vaccine by an individual? Things to consider >> That was a question for me? >> That was more of a statement than a question [laughter] Rhetorical but– but it is something to consider I mean, I think Dr.– Dr. Messonnier >> Yeah, I just want to maybe ask– go back and ask a question, which is is the local AAP chapter involved in these discussions because clearly a huge amount of the issue here is the feasibility of implementation of this in Puerto Rico and using all of the appropriate channels to answer that question seems quite important, so I just wondered of AAP’s, you know, engaged in that way and can help with these questions that Dr. Romero is asking? >> David >> We– I think it’s a fantastic suggestion, Dr. Messonnier I– I– we have not begun those conversations yet This– this presentation gives us the opportunity to at the fall COID meeting We also have a [inaudible] liaison to with the Latin American equivalent of the Pediatric Infectious Disease Society to the COID as well and I think [inaudible] could be another good– or actually the representative is currently Puerto Rican, so– so it works well in that regard, but I think getting more people’s input that live in the areas that would be impacted by recommendations is a fantastic recommendation >> Any further question– questions or comments? Dr. Talbot >> I think it would be very helpful for the committee to have someone review what happened in the Philippines Not by Sanofi who’s been dealing with this but someone who’s been doing some of the investigating I think it would be very helpful just to answer a lot of the questions and input some of the concerns to rest >> So again, following up on what Dr. Maldonado suggested, is [inaudible] Any other comments, questions, for Dr. Waterman? Does– does the group or anyone else have any questions for Dr. Dayan? Okay, then I have only to thank you for the presentation Is there any other business? Then we have concluded our session today and the June meeting of the ACIP Thank you very very much for a lot of hard work both pr– before the meeting and during Thank you [banging sound]

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