Dengue Vodcast: Insights from Recent Infectious Disease Congresses

00:00:00: You are listening to an AIDIS Journal podcast.

00:00:06: Hello, my name is Marco Aurelio-Safati.

00:00:08: I'm a pediatric infectious disease especially associate professor at Santa Casa de Sao Paulo.

00:00:14: It's a pleasure to be here and welcome all of you To this podcast.

00:00:20: And wow the idea is too highlight in these polls in the broadcast.

00:00:26: what we will discuss today is key highlights of current dengue research from selected congresses held in two thousand twenty five.

00:00:39: so we selected three of these congresses to capture the most recent and important highlights that were presented during this Congress.

00:00:49: The first one is the World Congress of the last bit.

00:00:53: they were a society for pediatric infectious diseases, tropical medicine, then hygiene.

00:01:02: And the third and very last of the Congresses we selected was The Latin American Congress Of Pediatric Infectious Diseases, this sleepy congress that took place in Chile last year.

00:01:17: So the aim of these podcasts is really to communicate the latest scientific findings on daily research and provide insights into the clinical significance of this data.

00:01:33: So, the continuous spread of dengue due to a changing climate which is a reality... ...and also the associated increased risk-of illness highlights that clear need to protect population from disease, and particularly from complications.

00:01:52: And severe disease which is also an issue I didn't mention but associated with these six million cases we reported in Brazil in two thousand twenty four will have approximately six thousand death associated with dengue.

00:02:08: so We know the groups would higher risk protection from severe diseases.

00:02:16: So one key pillar to induce protection is vaccination, so let's now move to the vaccines presentations that were selected just briefly mentioning an overview of the available vaccines.

00:02:37: We currently have three licensed and already license set dengue vaccines, these are all live attenuated vaccines And we also had some vaccines in late stage development.

00:02:52: I will briefly mention that The first of these vaccines that were licensed years ago is CID-TDV.

00:03:01: CID TDV has a yellow fever backbone, genetically modified to express two key membrane and envelope proteins.

00:03:12: These are key elements to induce antibodies in immune responses.

00:03:18: However this vaccine proved it would be associated with increased risk of severity in persons that were vaccinated being naive to the virus, being seronegative.

00:03:31: The need to pre-screen populations, to administer the vaccine clearly jeopardizes that possibility of using this vaccine in a large scale and the vaccine is now being discontinued.

00:03:50: The schedule associated with these vaccines was three dose every six months.

00:03:56: So, the second vaccine that was licensed is TAC-Zero Zero Three.

00:04:00: TAC Zero Zero Three consists of a live attenuated Dengue II strain so we have a Dengu II strain attenuation and three other components of the vaccine are three chimeric viruses consisting of same attenuate backbone of the Dengui virus too but genetically modified to express the membrane and envelope proteins from the respective serotype one, serotype three and serotype four.

00:04:34: Two doses of vaccines are the schedule for this vaccine and these two doses should be administered a three-month apart.

00:04:43: The third vaccine license was recently licensed, it's here in Brazil.

00:04:49: It is a single-dose scheduled vaccine and this vaccine is combined formulation of three attenuated wild type dengue virus serotypes, dengue Virus I, III & IV and chimeric virus consisting of the attenuated Dengue IV backbone expressing the membrane and also pre-enveloped protein from dengue virus II.

00:05:25: In late stage development we have a very similar vaccine, it's very analogous to the Boutan III DV which is the TV zero zero three and also tv zero zero five that already in development and other vaccines that are also in the pipeline.

00:05:46: So here we see some key data that was presented, associated with these vaccines.

00:05:55: how will start with the TAC-zero zero three booster data?

00:05:59: this is very new data not yet published but what's presented in Congress so they didn't hear is the long-term.

00:06:10: and the boosted data for TACS zero, zero three was presented from two double blind placebo control phase tree studies.

00:06:21: Here we see the preliminary findings showing that TACs zero, Zero Three protected against symptomatic dengue.

00:06:31: The efficacy was sixty-one percent and also protected against dengue hospitalization, eighty four per ten vaccine efficacy.

00:06:45: These efficacy estimates were observed up to four point five years after the primary vaccination.

00:06:55: The age group of these efficacy data with children and adolescents.

00:07:02: so among children and adolescents that received previously the primary vaccination, a booster dose was given four to point five years after the primary vaccinations.

00:07:19: So what they identified in this study that was presented is continued protection against virologically confirmed dengue, as well as protection against dengue hospitalization was observed.

00:07:36: Seventy-four percent vaccine efficacy against VCD, against virologically confirmant dengue and ninety percent efficacy uh against hospitalization.

00:07:48: and these estimates were observed in a period of twenty five months after the booster so clearly showing the importance of this recent data.

00:08:05: Regarding safety, no TAC-zero zero three related serious adverse events or death were observed in these boosted data.

00:08:20: all severe dengue and dengue hemorrhagic fever cases that occur were observed in the placebo group and the safety profile was largely consistent with that scene after primary vaccination.

00:08:36: So as a summary of the findings of this booster data, dengue protection continued during the booster phase.

00:08:43: TAC-Zero Zero Three Booster was well tolerated And our opinion is not yet clear to support the need of boosted dose.

00:08:57: So here we see the evaluations from the Dane three zero trial.

00:09:08: this is a follow-up study of two phase tree trials, the Dain three one five and then Dain.

00:09:19: And here, the presenters were able to show the immunogenicity of TAC-zero-zero three against all four zero type.

00:09:30: The importance is that these data was collected in non endemic setting, although it means probably naive speculation.

00:09:41: the study was done in Mexico City which is clearly a non-endemic setting of dengue as well as parts of United States and The observations were unacceptable long term safety over up to sixty nine miles of the follow-up in adolescence, which is the Mexican data and as well as up to forty two month a follow-ups in adults.

00:10:12: Which is the US data?

00:10:16: Well let's move to my region.

00:10:19: This is real world data from Sao Paulo From Brazil during our huge twenty four outbreak this case control study this outbreak.

00:10:33: The outbreak was associated predominantly with dengue one and dengue two, and a tax zero-zero three protected against both symptomatic dengue and hospitalization due to dengue in adolescents aged ten to fourteen years.

00:10:53: This is the age group that was included initially in the vaccination program of TAX-zero, zero three here.

00:11:02: In Brazil particularly specifically showing data from Sao Paulo.

00:11:09: So following first dose as you can see here The effectiveness of vaccine against symptomatic dengue was sixty seven percent in a period of fourteen to twenty seven days.

00:11:25: so it's short-term effectiveness data and a forty nine percent after ninety days.

00:11:35: So this is preliminary data, short term vaccine effectiveness in the real world setting.

00:11:45: so these are couple of messages from other tech zero zero three studies.

00:11:54: post-marketing surveillance.

00:11:57: This is a review of safety data conducted two years after launch, although some new safety signals were identified post marketing which includes anaphylactic reactions.

00:12:12: this was seen here in Brazil on some transient vaccine viremia associated events.

00:12:19: the important message profile of TACS-zero-zero three remains positive.

00:12:28: So now we have some new general recommendations pertaining to an afilaxis that were included in the label for TACC-zero.

00:12:38: zero three vaccine, a post authorization study which is the Dane four zero one is being conducted in children and adolescents, it's ongoing to further inform on the effectiveness of the TAC-zero zero three against hospitalization due to dengue in Asia.

00:13:01: This will be key data because we'll be data collected in Asia with other stereotypes circulating, comparing to the zero types that circulated at similar periods here in Latin America.

00:13:16: A number of presentations in this Congress also analyzed immune responses to TAG-zero-zero three.

00:13:23: so in summary the TAG Zero-zero Three elicited immediate humoral and cellular immune responses in adults, regardless of whether they were naive or already exposed to dengue.

00:13:41: The humeral immune responses elicited by TAG-zero-zero three show a unique non overlapping parameters with difference being driven mainly by dengue serotype and time since vaccination.

00:13:57: This is also clearly associated with these immune responses, although the fact that human response is induced by TACS-O-O three different from those observed by natural infection, they were serotype balanced and associated with high quality immune responses.

00:14:20: Now let's share the data that was recently presented regarding the Bhutan-Thirty V vaccine.

00:14:30: this is data after five years.

00:14:33: This is a placebo control phase three trial conducted in Brazil, and the overall efficacy of five years' data from the Boutante single-dose study that included children adolescents and adults up to fifty nine years old.

00:14:56: All these age groups were included in this efficacy evaluation.

00:15:01: seventy seven Percent was the efficacy against symptomatic VCD, virologically confirmed dengue.

00:15:14: Seventy-seven percent in participants with prior exposure and fifty eight percent in those participants that were naive when included.

00:15:32: the serotypes that circulated during this study were only dengue one and dengue two.

00:15:39: So there is not yet available data against dengue three, and dengy four And the efficacy estimates again.

00:15:49: symptomatic VCD was seventy-three percent against Dengue One and fifty five percent the efficacy against dengue with warning signs and severe dengue, which was also one of the objectives.

00:16:07: It was eighty percent and a post hoc analysis then indicated hundred-percent efficacy in the prevention of hospitalization due to dengue.

00:16:19: so far no safety concerns were observed.

00:16:24: So let's move to the next topic, which is vector surveillance and control.

00:16:31: this another key pillar to prevention.

00:16:35: This clearly very important together with vaccines The control of the mosquito an improvement in surveillance methods.

00:16:45: so These are some new approaches that have been considered to improve detainee surveillance and also to improve control of the mosquito.

00:16:56: So some molecular techniques were presented, so the idea is to improve mosquito identification via this molecular technique.

00:17:10: This is a labor-and time intensive and also costly technique so reliable electronic systems vector data have also been lacking so far, but these are new techniques that are being developed.

00:17:29: Some of the approaches being considered to improve dengue surveillance also include the possibility of extraction of the virus and a vector RNA or DNA that could be performed in the field without any need for a leg.

00:17:49: Also, artificial intelligence-based identification of mosquito species.

00:17:55: The Vector Board Disease Platform for data recording and analysis And the Machine Learning Pipeline.

00:18:04: So this is...the idea's an open source pipeline supporting vector screening trying to link vector and pathogen screening data to predict disease risk factors and areas that would be in increased risks of having outbreaks of dengue.

00:18:24: And also very interesting presentations regarding vector control, so taking into account the continued expansion geographically as I mentioned previously in this presentation, approaches to improve control of the dengue vector are being evaluated to reduce transmission.

00:18:47: So mosquito traps techniques limit vector breeding so fertilization interference.

00:18:59: Stereo insects, so males sterilized using X-rays or males and females genetically modified via CRISPR to achieve functional sterility of these mosquitoes.

00:19:17: Inset sites attracting toxic sugar baits.

00:19:26: profiling of mosquitoes to identify mechanisms underlying insecticide resistance, which could be informative for public health measures.

00:19:38: And also limiting viral infections in mosquitos.

00:19:44: and one of the techniques that was presented at this Congress with the Volbacea, a bacteria infected mosquito.

00:19:54: This is a study performed in Campo Grande, here also in Brazil.

00:20:00: And this approach was shown to be very effective.

00:20:05: intervention for dengue control In an urban setting of the Brazilian city where more than one hundred million fobacca infected mosquitoes were released in the environment between December, two thousand and twenty-three.

00:20:24: And they intervention as we presented here greatly reduced the magnitude of the Dengue peaks Even with Wolbachia prevalence as low as forty percent, even in this prevalence of Wolbachian in the community of mosquitoes.

00:20:43: these significantly reduced dengue incidents.

00:20:48: In this study the incidence of dengue dropped by sixty-three per cent in fully treated areas which is a very compelling and reassuring data Long field being incorporated to really control dengue.

00:21:08: So now let's move to dengue surveillance.

00:21:12: There are some new approaches that have been considered for dengue Surveillance, dengue specific Low-cost serological Testes novel diagnostic tests.

00:21:25: there is a clear need to develop rapid and cost effective diagnosed test that can differentiate between antigenic related virus, it's important to mention that we have other arbovirus circulating in this area which sometimes can induce cross reactivity.

00:21:46: So we clearly need more accurate and rapid tests to help clinicians in the field.

00:21:57: so also broad monitoring for dengue infection, in addition to new diagnostic tests aimed at identifying infections of individual people which can be resource-intensive and challenging.

00:22:15: Also we observe techniques that more broadly monitor the presence of dengue infections across a wider cross section of our population.

00:22:27: Also, for example building on innovation made during the COVID pandemic in US they were able to monitor wastewater samples.

00:22:41: For the presence of Tengi virus.

00:22:43: this would help predict outbreaks as well to identify sequences of the virus that are circulating in different regions.

00:22:57: Also, development national surveillance systems to inform on the epidemiology of travel-related infections and also local spread.

00:23:15: Dengue prophylaxis, dengue diagnosis and dengue management.

00:23:21: We have some new approaches that are currently being considered to try.

00:23:36: study using a new antiviral in development name at Mosnod and Vir was presented.

00:23:44: And, in summary the data collected among adults between eighteen- and fifty five years show it to be promising intervention with randomized controlled human infection model with most Northern Veer prophylaxis showing that the antiviral was associated with a possibility of reduced dengue tree infection risk in naïve individuals, which were included on this trial.

00:24:25: Regarding diagnosis new dengue diagnoses as well as new management methods were presented.

00:24:34: regarding diagnosis, it's important to remind that the clinical manifestations of dengue are very similar to clinical manifestations or other arboviruses like Zika-like chikungunya which is always an issue for clinicians to be able distinguish a patient with these symptoms.

00:24:58: so improvement in diagnosis methods is clearly needed.

00:25:03: They presented some hints, in terms of clinical manifestations that may help differentiate Tengi from the other viral infections.

00:25:13: and among these clinical manifestations they highlighted That the presence of abdominal pain, leukopenia, vasophilia vomiting and nausea were all clinical manifestations more associated with dengue.

00:25:31: Also some new serological essays that could help to distinguish with accuracy a dengue for the other flavivirus, some saliva and urine-based testing which are less invasive testing based on tests regarding management for patients whose dang infection is severe associated with plasma leakage, severe bleeding in peer organ function.

00:26:10: So restoring plasma volume is the standard treatment.

00:26:16: if I could address one key message in terms of management it's the importance to decrease the complications and to decrease case fatality rate.

00:26:33: So clinicians should be able to early detection of shock, of the presence of shock in implement vigorous strategies to really manage an address this issue.

00:26:51: so DWHO currently recommends crystallite solutions for initial replacement and collides for persistent shock.

00:27:01: So adding an infusion of twenty-five percent albumin solution to a standard WHO treatment may improve survival in children with flu refractory non responder severe dengue according that was performed in India.

00:27:26: So the addition of algal mean improved survival by twenty percent and decreased, they need for other treatments.

00:27:36: low cost wearable devices that monitor ammo dynamic instability have shown promise for real time non-invasive assessment of pediatric patients with dengue shock.

00:27:53: This is also very important to predict disease progression, so being able to predict the disease progression proven also to be crucial to reduce complications and severe diseases.

00:28:10: So there are some clinical and demographic factors that may help progression to severe dengue and this includes abnormal mental activity, presence of pleural infusion, pulmonary infiltration low platelet counts.

00:28:27: Elderly in Brazil we have an experience showing that two in each three deaths associated with dengue during the were reported in elderly persons, so being elderly is clearly a risk for increased severe complications and death associated with dengue.

00:28:54: Presence of diabetes, hypertension... And obviously the presence secondary dengue infection.

00:29:03: For this context, the identification of warning signs of severe disease never forget.

00:29:10: This is also clearly important among these warning as a severe science The presence of persisting abdominal pain vomiting bleeding nose gums increased amatocrit levels fluid accumulation, liver enlargement, lethargy alternated with restlessness and also the presence of blood in vomit or spools.

00:29:38: Also notably important to mention that severe dengue has been shown in a study associated with socio-economic vulnerability.

00:29:48: Lower education, higher poverty were elements associated with increased severity of dengue.

00:29:59: and finally the point-of-care ultrasound.

00:30:03: so point of care ultrasound of the abdomen the lungs and heart may also be useful in predicting dengue severity in pediatric patients.

00:30:15: Regarding immune responses during dengue infection, we saw an overview of new findings pertaining to immune response to infections and immune-mediated enhancement.

00:30:27: So investigating immune responses to dengue helped understand the land quality for protection following infection or vaccination so whether immune responses are serotype specific which is long-term or cross reactive, and the mechanism behind this phenomenon.

00:30:53: Antibodies from a primary infection may worsen risk of having secondary infections presentation.

00:31:15: Very interestingly, this increased risk is observed only in the secondary infections but we're not observing after third or even on fourth infection.

00:31:29: so increase of severity associated with secondary infections with dengue which is the phenomenal antibody dependent enhancement a process which non-neutronizing dengue virus specific antibodies to acerotype instead of helping will facilitate viral entry into cells via FC gamma receptors.

00:31:59: This is not yet fully understood, although new research has identified potentially critical role for cells silently intermediates, such as SHP-I in this process.

00:32:16: So immune responses to dengue infection and number of presentations discussed new findings pertaining to immune response to dengue infections including the magnitude long term persistent of dengue virus antibodies characterization cross reactive antibodies and the proteomic characterization of these antibody responses to secondary infections.

00:32:46: Mathematical modeling, of this antiviral response is to help identify secondary infections.

00:32:53: they use of antibiotic responses and viremia to safely model primary, secondary and tertiary infections using attenuated dengue virus strains.

00:33:05: So these were also some new data that was presented.

00:33:10: so as a summary of this new very interesting research findings that were presented in the congresses I can highlight and expanding not only in incidents, but also in the geographic areas at risk.

00:33:33: We are seeing outbreaks of dengue in places that never reported dengue-in-the-past.

00:33:39: we have seen outbreaks of Dengue in North America... ...we have seen outbreak of dengy in Europe.

00:33:46: so denging is clearly an expanding disease.

00:33:50: Vaccination is a key pillar in the prevention, it's a key to for the prevention.

00:33:57: We have seen data with different vaccines with tax zero-zero three supporting meaningful protection and real world data in adolescence.

00:34:07: recent long term safety data showing acceptable safety upto approximately five to six years in adolescence and three or four years in adults, a booster dose was well tolerated although the totality of data is not yet sufficient.

00:34:37: We have seen very recent data with a single dose of the Bhutan-Teddy vaccine proven to be efficacious against symptomatic VCD, against virologically confirmed dengue caused by dengue one and dengue two which were the only dengue serotaps that circulated during this study regardless of dengue zero status at baseline.

00:35:01: With an acceptable safety profile upto five years after vaccination.

00:35:08: We have seen also integrated vector control measures like the Vobacca, very interesting element to help in the vector control improve its surveillance which can deliver sustained community level risk reduction and they need to optimize the outcomes.

00:35:31: this requires an integrate approach advancing diagnostics, prognostic tools to help clinicians and also the development of therapeutics that could also help better distinguish stengi from other arbovirus.

00:35:51: And really identify those at higher risk in order improve management of these patients.

00:35:58: so thank you very much for your attention.

00:36:15: You can listen to more podcasts by subscribing to ADIS Journal Podcasts with your preferred podcast provider or visiting the journal website.

00:36:25: For a full list of declarations, including funding and author disclosure statements & copyright information please visit article page on the journal web site.

00:36:36: The link to article page is found in the podcast description.