Brazil is hoping and waiting for a new vaccine as dengue rages.

A locally produced vaccine did well in a phase 3 clinical trial but won't be available until at least 2025.

Interplay between vaccines and treatment for dengue control: An epidemic model.

Assessing public health intervention strategies is crucial for effectively managing dengue. While numerous studies have explored the impact of dengue interventions on its transmission dynamics, limited research has focused on the combined effects of implementing multiple therapeutic interventions for disease control. This study presents an epidemic model for understanding dengue transmission dynamics, incorporating two critical therapeutic measures: vaccination and treatment of infected individuals. The model is characterized by ordinary differential equations involving seven-state variables. The investigation encompasses both disease-free and endemic equilibria of the model. The findings reveal that the disease-free equilibrium (only) is globally stable when the basic reproduction number is below one. Interestingly, when the vaccine's effectiveness is low, treatment emerges as a more successful approach in reducing dengue cases than vaccination. In contrast, a highly effective vaccine alone significantly curtails dengue occurrences. Moreover, the study introduces an optimal control problem, featuring an objective function integrating two control mechanisms: vaccination and treatment. The analysis strongly suggests that implementing two control strategies outweighs the efficacy of a single approach in effectively mitigating the spread of the disease.

Live, Attenuated, Tetravalent Butantan-Dengue Vaccine in Children and Adults.

BACKGROUND: Butantan-Dengue Vaccine (Butantan-DV) is an investigational, single-dose, live, attenuated, tetravalent vaccine against dengue disease, but data on its overall efficacy are needed. METHODS: In an ongoing phase 3, double-blind trial in Brazil, we randomly assigned participants to receive Butantan-DV or placebo, with stratification according to age (2 to 6 years, 7 to 17 years, and 18 to 59 years); 5 years of follow-up is planned. The objectives of the trial were to evaluate overall vaccine efficacy against symptomatic, virologically confirmed dengue of any serotype occurring more than 28 days after vaccination (the primary efficacy end point), regardless of serostatus at baseline, and to describe safety up to day 21 (the primary safety end point). Here, vaccine efficacy was assessed on the basis of 2 years of follow-up for each participant, and safety as solicited vaccine-related adverse events reported up to day 21 after injection. Key secondary objectives were to assess vaccine efficacy among participants according to dengue serostatus at baseline and according to the dengue viral serotype; efficacy according to age was also assessed. RESULTS: Over a 3-year enrollment period, 16,235 participants received either Butantan-DV (10,259 participants) or placebo (5976 participants). The overall 2-year vaccine efficacy was 79.6% (95% confidence interval [CI], 70.0 to 86.3) - 73.6% (95% CI, 57.6 to 83.7) among participants with no evidence of previous dengue exposure and 89.2% (95% CI, 77.6 to 95.6) among those with a history of exposure. Vaccine efficacy was 80.1% (95% CI, 66.0 to 88.4) among participants 2 to 6 years of age, 77.8% (95% CI, 55.6 to 89.6) among those 7 to 17 years of age, and 90.0% (95% CI, 68.2 to 97.5) among those 18 to 59 years of age. Efficacy against DENV-1 was 89.5% (95% CI, 78.7 to 95.0) and against DENV-2 was 69.6% (95% CI, 50.8 to 81.5). DENV-3 and DENV-4 were not detected during the follow-up period. Solicited systemic vaccine- or placebo-related adverse events within 21 days after injection were more common with Butantan-DV than with placebo (58.3% of participants, vs. 45.6%). CONCLUSIONS: A single dose of Butantan-DV prevented symptomatic DENV-1 and DENV-2, regardless of dengue serostatus at baseline, through 2 years of follow-up. (Funded by Instituto Butantan and others; DEN-03-IB ClinicalTrials.gov number, NCT02406729, and WHO ICTRP number, U1111-1168-8679.).

Qdenga® - A promising dengue fever vaccine; can it be recommended to non-immune travelers?

Qdenga® has been approved by the European Medicines Agency (EMA) for individuals > 4 years of age and for use according to national recommendations. The vaccine shows high efficacy against virologically confirmed dengue and severe dengue in clinical studies on 4-16-year old's living in endemic areas. For individuals 16-60 years old only serological data exists and there is no data for individuals > 60 years. Its use as a travel vaccine is still unclear. We present the studies behind the approval and the recommendations for travelers as issued by the Swedish Society for Infectious Diseases Physicians.

Changing epidemiology of dengue fever in children in South America.

PURPOSE OF REVIEW: Dengue is the most important arthropod-borne viral disease of public health significance. Its geographic distribution includes 128 countries worldwide, affecting 390 million people every year causing significant morbidity and mortality in children and adults everywhere. RECENT FINDINGS: In the past, severe dengue affected mostly adults in the Americas; this scenario has changed and now cases of dengue, severe dengue, and dengue deaths have increased in children under 15 years in Brazil and in Colombia. Dengue and COVID-19 co-infections have been reported in South America, with increased hospitalization. A dengue vaccine for 9-year-old children and older children and adults who have serological evidence of previous dengue has been licensed in many countries; a different dengue vaccine trial for 4-16-year-old children has demonstrated decrease in clinical dengue and decrease in dengue hospitalizations. SUMMARY: There is no specific treatment of dengue, and a changing climate, insecticide resistance and urban expansion have permitted the vector's spread, making the vector control almost impossible. The hope for dengue control relies on vaccine development; there is important research on this area with one vaccine already licensed and another one showing promising results.

Dengue Vaccines: An Update.

Dengue is one of the most prevalent mosquito-borne diseases in the world, affecting an estimated 390 million people each year, according to models. For the last two decades, efforts to develop safe and effective vaccines to prevent dengue virus (DENV) infections have faced several challenges, mostly related to the complexity of conducting long-term studies to evaluate vaccine efficacy and safety to rule out the risk of vaccine-induced DHS/DSS, particularly in children. At least seven DENV vaccines have undergone different phases of clinical trials; however, only three of them (Dengvaxia®, TV003, and TAK-003) have showed promising results, and are addressed in detail in this review in terms of their molecular design, efficacy, and immunogenicity. Safety-related challenges during DENV vaccine development are also discussed.

Performance Evaluation of a Dengue IgG Rapid Diagnostic Test Designed to Determine Dengue Serostatus as Part of Prevaccination Screening.

The World Health Organization has recommended prevaccination screening for prior dengue infection as the preferred approach prior to vaccination with the dengue vaccine CYD-TDV. These screening tests need to be highly specific and sensitive, and deliverable at the point-of-care. We evaluate here the sensitivity and specificity of the newly developed OnSite Dengue IgG rapid diagnostic test (RDT). A retrospective double-blind study of the sensitivity and specificity of the OnSite Dengue IgG RDT was performed using a sample panel consisting of archived serum specimens collected during CYD-TDV clinical trials in Latin American and Asia, with the reference serostatus for each sample determined by an algorithm using measured dengue PRNT90, PRNT50, and NS1 IgG ELISA. An additional panel of dengue seronegative samples positive for other flaviviruses and infections was used to assess cross-reactivity. Samples were included from 579 participants; 346 in the specificity panel and 233 in the sensitivity panel. The OnSite dengue IgG RDT exhibited a specificity of 98.0% (95% CI = 95.9 to 99.2) and sensitivity of 95.3% (95% CI = 91.7 to 97.6). The sensitivity for samples exhibiting a multitypic immune profile (PRNT90-positive to >1 dengue serotype) was 98.8% while for monotypic immune samples (PRNT90-positive to a single dengue serotype) it was 88.1%. The OnSite dengue IgG RDT showed minimal to no cross-reactivity to related flaviviruses. These findings support the use of the OnSite dengue IgG RDT to determine dengue serostatus in CYD-TDV prevaccination screening. IMPORTANCE Dengue remains a significant public health issue, with over 5.2 million cases reported to the World Health Organization (WHO) in 2019. The tetravalent dengue vaccine (CYD-TDV) is currently licensed for use in those aged ≥9 years; however, vaccinees with no previous exposure to dengue experience an increased risk of hospitalized and severe dengue upon subsequent heterotypic infection. Consequently, WHO recommends screening for prior dengue infection before vaccination. Screening tests for previous infection need to be highly specific and sensitive, and deliverable at the point-of-care. High sensitivity ensures that the largest number of individuals with previous infection can be identified and vaccinated, while high specificity prevents the inadvertent vaccination of those without previous infection. This study of the OnSite Dengue IgG Rapid Test, which was explicitly developed to meet this need, found that it had both high specificity (98.0% [95% CI = 95.9 to 99.2]) and sensitivity (95.3% [95% CI = 91.7 to 97.6]).

Dengue: current state one year before WHO 2010-2020 goals.

BACKGROUND: Dengue is a possibly life-threatening human mosquito-borne viral infection widely spread in peridomestic (sub)tropical climates. The global incidence has expanded rapidly in the last decades, with 40% of the world's population currently at risk. To date, no anti-viral treatment other than supportive care exists. In 2015, the first and only dengue-vaccine, CYD-TDV, received marketing authorization. OBJECTIVES: To present the current understanding of dengue in terms of epidemiology, transmission, pathogenesis, disease management and prevention. To illustrate the knowledge gaps that remain to be filled in order to control dengue and achieve the WHO 2010-2020 goals. METHODS: An updated systematic review (2009-2019) was carried out. The databases Pubmed, Embase and The Cochrane Library were searched along with WHO and CDC guidelines. RESULTS: In total, 39 articles were included. Contemporary climatic and economic factors significantly contributed to the emergence of epidemic dengue. Unfortunately, CYD-TDV failed to meet safety and efficacy demands. New vaccination approaches are in the pipeline along with innovative vector-control strategies. Current anti-viral drug research focuses on repurposing drugs in addition to specific anti-dengue strategies that interfere with viral replication. CONCLUSION: The lack of understanding dengue pathogenesis and immunology has hampered the development of an effective vaccine. Recent research has provided new insights into the therapeutic and prophylactic approach. Implementation of complementary methods to control disease burden are required considering the socio-economic impact of this rapidly emerging global disease.

Updates on Dengue Vaccine and Antiviral: Where Are We Heading?

Approximately 100-400 million people from more than 100 countries in the tropical and subtropical world are affected by dengue infections. Recent scientific breakthroughs have brought new insights into novel strategies for the production of dengue antivirals and vaccines. The search for specific dengue inhibitors is expanding, and the mechanisms for evaluating the efficacy of novel drugs are currently established, allowing for expedited translation into human trials. Furthermore, in the aftermath of the only FDA-approved vaccine, Dengvaxia, a safer and more effective dengue vaccine candidate is making its way through the clinical trials. Until an effective antiviral therapy and licensed vaccine are available, disease monitoring and vector population control will be the mainstays of dengue prevention. In this article, we highlighted recent advances made in the perspectives of efforts made recently, in dengue vaccine development and dengue antiviral drug.

Targets and strategies for vaccine development against dengue viruses.

Dengue virus (DENV) is a global health threat causing about half of the worldwide population to be at risk of infection, especially the people living in tropical and subtropical area. Although the dengue disease caused by dengue virus (DENV) is asymptomatic and self-limiting in most people with first infection, increased severe dengue symptoms may be observed in people with heterotypic secondary DENV infection. Since there is a lack of specific antiviral medication, the development of dengue vaccines is critical in the prevention and control this disease. Several targets and strategies in the development of dengue vaccine have been demonstrated. Currently, Dengvaxia, a live-attenuated chimeric yellow-fever/tetravalent dengue vaccine (CYD-TDV) developed by Sanofi Pasteur, has been licensed and approved for clinical use in some countries. However, this vaccine has demonstrated low efficacy in children and dengue-naïve individuals and also increases the risk of severe dengue in young vaccinated recipients. Accordingly, many novel strategies for the dengue vaccine are under investigation and development. Here, we conducted a systemic literature review according to PRISMA guidelines to give a concise overview of various aspects of the vaccine development process against DENVs, mainly targeting five potential strategies including live attenuated vaccine, inactivated virus vaccine, recombinant subunit vaccine, viral-vector vaccine, and DNA vaccine. This study offers the comprehensive view of updated information and current progression of immunogen selection as well as strategies of vaccine development against DENVs.

Seroprevalence of Zika virus in pregnant women from central Thailand.

Zika virus (ZKV) infection in a pregnant woman, especially during the first trimester, often results in congenital anomalies. However, the pathogenic mechanism is unknown and one-third of ZKV infected pregnancies are asymptomatic. Neutralizing antibodies against ZKV has been reported in 70% of Thai adults, but the prevalence among pregnant women is unknown. Currently, vaccines and specific treatments for ZKV are under development. A better understanding of the immune status of pregnant women will increase the success of effective prevention guidelines. The prevalence of ZKV infection in pregnant women in antenatal care clinics was investigated during the rainy season from May to October 2019 at Siriraj Hospital, Bangkok, Thailand. We recruited 650 pregnant women (39.42% first, 52.26% second and 7.36% third trimester) and found that 30.77% had ZKV-specific IgG, and 39.81% had neutralizing antibodies (nAb) against ZKV (titer ≥10). Specific and neutralizing antibody levels varied by maternal age, trimester, and month. We further characterized the cross-reaction between ZKV and the four Dengue virus (DENV) serotypes by focused reduction neutralization test (FRNT) and found that cross-reactions were common. In conclusion, about 60% of pregnant women who living in central Thailand may be at risk of ZKV infection due to the absence of neutralizing antibodies against ZKV. The functions of cross-reactive antibodies between related viral genotypes require further study. These findings have implications for health care monitoring in pregnant women including determining the risk of ZKV infection, assisting the development of a flavivirus vaccine, and informing the development of preventative health policies.

Dengue virus-free defective interfering particles have potent and broad anti-dengue virus activity.

Dengue virus (DENV) is spread from human to human through the bite of the female Aedes aegypti mosquito and leads to about 100 million clinical infections yearly. Treatment options and vaccine availability for DENV are limited. Defective interfering particles (DIPs) are considered a promising antiviral approach but infectious virus contamination has limited their development. Here, a DENV-derived DIP production cell line was developed that continuously produced DENV-free DIPs. The DIPs contained and could deliver to cells a DENV serotype 2 subgenomic defective-interfering RNA, which was originally discovered in DENV infected patients. The DIPs released into cell culture supernatant were purified and could potently inhibit replication of all DENV serotypes in cells. Antiviral therapeutics are limited for many viral infection. The DIP system described could be re-purposed to make antiviral DIPs for many other RNA viruses such as SARS-CoV-2, yellow fever, West Nile and Zika viruses.

Measurement of Cellular Immune Response to Viral Infection and Vaccination.

Combined cellular and humoral host immune response determine the clinical course of a viral infection and effectiveness of vaccination, but currently the cellular immune response cannot be measured on simple blood samples. As functional activity of immune cells is determined by coordinated activity of signaling pathways, we developed mRNA-based JAK-STAT signaling pathway activity assays to quantitatively measure the cellular immune response on Affymetrix expression microarray data of various types of blood samples from virally infected patients (influenza, RSV, dengue, yellow fever, rotavirus) or vaccinated individuals, and to determine vaccine immunogenicity. JAK-STAT1/2 pathway activity was increased in blood samples of patients with viral, but not bacterial, infection and was higher in influenza compared to RSV-infected patients, reflecting known differences in immunogenicity. High JAK-STAT3 pathway activity was associated with more severe RSV infection. In contrast to inactivated influenza virus vaccine, live yellow fever vaccine did induce JAK-STAT1/2 pathway activity in blood samples, indicating superior immunogenicity. Normal (healthy) JAK-STAT1/2 pathway activity was established, enabling assay interpretation without the need for a reference sample. The JAK-STAT pathway assays enable measurement of cellular immune response for prognosis, therapy stratification, vaccine development, and clinical testing.

After the honeymoon, the divorce: Unexpected outcomes of disease control measures against endemic infections.

The lack of effective vaccines for many endemic diseases often forces policymakers to rely on non-immunizing control measures, such as vector control, to reduce the massive burden of these diseases. Controls can have well-known counterintuitive effects on endemic infections, including the honeymoon effect, in which partially effective controls cause not only a greater initial reduction in infection than expected, but also large outbreaks during control resulting from accumulation of susceptibles. Unfortunately, many control measures cannot be maintained indefinitely, and the results of cessation are poorly understood. Here, we examine the results of stopped or failed non-immunizing control measures in endemic settings. By using a mathematical model to compare the cumulative number of cases expected with and without control, we show that deployment of control can lead to a larger total number of infections, counting from the time that control started, than without any control-the divorce effect. This result is directly related to the population-level loss of immunity resulting from non-immunizing controls and is seen in a variety of models when non-immunizing controls are used against an infection that confers immunity. Finally, we examine three control plans for minimizing the magnitude of the divorce effect in seasonal infections and show that they are incapable of eliminating the divorce effect. While we do not suggest stopping control programs that rely on non-immunizing controls, our results strongly argue that the accumulation of susceptibility should be considered before deploying such controls against endemic infections when indefinite use of the control is unlikely. We highlight that our results are particularly germane to endemic mosquito-borne infections, such as dengue virus, both for routine management involving vector control and for field trials of novel control approaches, and in the context of non-pharmaceutical interventions aimed at COVID-19.

Immunogenicity and Safety of a Tetravalent Recombinant Subunit Dengue Vaccine in Adults Previously Vaccinated with a Live Attenuated Tetravalent Dengue Vaccine: Results of a Phase-I Randomized Clinical Trial.

New dengue vaccines are needed to prevent this globally expanding vector-borne disease. The V180 vaccine candidate consists of four recombinant, soluble, dengue virus envelope glycoproteins and has been previously evaluated in two clinical trials for safety and immunogenicity in Flavivirus-naive participants (NCT01477580 and NCT0093642). Here, we report on a randomized, placebo-controlled, double-blind study of the safety and immunogenicity of the V180 vaccine in subjects who have previously received the live attenuated tetravalent vaccine (LATV) developed by the National Institute of Allergy and Infectious Diseases (protocol #V180-002 [CIR-301]). The study was designed to evaluate whether this recombinant subunit vaccine could boost the neutralizing antibody responses induced by dengue LATV. Twenty participants who had previously received one or two doses of dengue LATV were randomized and received a single dose of V180 nonadjuvanted (N = 8), V180 adjuvanted with Alhydrogel™ (aluminum hydroxide gel, Brenntag Biosector, Frederikssund, Denmark) (N = 8), or placebo (N = 4). Immunogenicity was measured using a plaque reduction neutralization test at days 1, 15, 28, and 180 after vaccination. In addition, vaccine safety (solicited and unsolicited adverse events) was assessed using a vaccination report card for 28 days following vaccination, and serious adverse events were captured from the time of informed consent through the final study visit at 6 months after vaccination. The results of the study demonstrate that the V180 vaccine is generally well tolerated and immunogenic in these dengue-seropositive volunteers.

Efficacy of a tetravalent dengue vaccine in healthy children aged 4-16 years: a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: A substantial unmet need remains for safe and effective vaccines against dengue virus disease, particularly for individuals who are dengue-naive and those younger than 9 years. We aimed to assess the efficacy, safety, and immunogenicity of a live attenuated tetravalent dengue vaccine (TAK-003) in healthy children aged 4-16 years. METHODS: We present data up to 18 months post-vaccination from an ongoing phase 3, randomised, double-blind trial of TAK-003 in endemic regions of Asia and Latin America (26 medical and research centres across Brazil, Colombia, Dominican Republic, Nicaragua, Panama, Philippines, Sri Lanka, and Thailand). Healthy children aged 4-16 years were randomly assigned 2:1 (stratified by age and region) to receive two doses of TAK-003 or two doses of placebo, 3 months apart. Investigators, participants and their parents or guardians, and sponsor representatives advising on trial conduct were masked to trial group assignments. Participants presenting with febrile illness were tested for virologically confirmed dengue (VCD) by serotype-specific RT-PCR. In timeframes beginning 30 days post-second dose, the primary endpoint (overall vaccine efficacy) was assessed in the first 11 months, and the secondary endpoints (efficacy by baseline serostatus, serotype, hospitalised dengue, and severe dengue) in the first 17 months. This study is registered with ClinicalTrials.gov, NCT02747927. FINDINGS: 20 099 participants were randomly assigned and vaccinated between Sept 7, 2016, and Aug 18, 2017; 19 021 (94·6%) were included in the per protocol analysis, and 20 071 (99·9%) in the safety set. The primary endpoint was achieved with an overall vaccine efficacy of 80·2% (95% CI 73·3 to 85·3; 61 cases of VCD in the TAK-003 group vs 149 cases of VCD in the placebo group). In the secondary endpoint assessment timeframe, an overall vaccine efficacy of 73·3% (95% CI 66·5 to 78·8) was observed. Analysis of secondary endpoints showed efficacies of 76·1% (95% CI 68·5 to 81·9) in individuals who were seropositive at baseline, 66·2% (49·1 to 77·5) in individuals who were seronegative at baseline, 90·4% (82·6 to 94·7) against hospitalised dengue, and 85·9% (31·9 to 97·1) against dengue haemorrhagic fever. Efficacy varied by individual serotypes (DENV 1, 69·8% [95% CI 54·8 to 79·9]; DENV 2, 95·1% [89·9 to 97·6]; DENV 3, 48·9% [27·2 to 64·1]; DENV 4, 51·0% [-69·4 to 85·8]). Cumulative rates of serious adverse events were similar in TAK-003 (4·0%) and placebo (4·8%) recipients, and were consistent with expected medical disorders in the study population. Infection was the most frequent reason leading to serious adverse events. 20 participants (<0·1% of the safety set) were withdrawn from the trial due to 21 adverse events by the end of part two; 14 of these participants received TAK-003 and six received placebo. INTERPRETATION: TAK-003 was well tolerated and efficacious against symptomatic dengue in children regardless of serostatus before immunisation. Vaccine efficacy varied by serotype, warranting continued follow-up to assess longer-term vaccine performance. FUNDING: Takeda Vaccines.

Safety and Immunogenicity of Different Formulations of a Tetravalent Dengue Purified Inactivated Vaccine in Healthy Adults from Puerto Rico: Final Results after 3 Years of Follow-Up from a Randomized, Placebo-Controlled Phase I Study.

Four formulations of an investigational tetravalent dengue purified inactivated vaccine, administered as two doses one month (M) apart, were previously shown to be immunogenic and well-tolerated up to M13 of the phase I study NCT01702857. Here, we report results of the follow-up from M14 to year (Y) 3. One hundred healthy Puerto Rican adults, predominantly dengue virus (DENV)-primed, were randomized 1:1:1:1:1 to receive placebo or vaccine formulations: 1 µg/serotype/dose adjuvanted with aluminum, AS01E or AS03B, or aluminum-adjuvanted 4 µg/serotype/dose. No serious adverse events occurred. Two medically-attended potential immune-mediated disease cases, vaccination unrelated, were reported (groups 1 µg+Alum and 1 µg+AS03B). Of 14 instances of suspected dengue, none were laboratory confirmed. Geometric mean neutralizing antibody titers against DENV 1-4 waned from M14, but remained above pre-vaccination levels for DENV 1-3, with the highest values for group 1 µg+AS03B: 1220.1, 920.5, 819.4, and 940.5 (Y2), and 1329.3, 1169.2, 1219.8, and 718.9 (Y3). All formulations appeared to be safe and immunogenic during the 3-year follow-up.

Designing effective control of dengue with combined interventions.

Viruses transmitted by Aedes mosquitoes, such as dengue, Zika, and chikungunya, have expanding ranges and seem unabated by current vector control programs. Effective control of these pathogens likely requires integrated approaches. We evaluated dengue management options in an endemic setting that combine novel vector control and vaccination using an agent-based model for Yucatán, Mexico, fit to 37 y of data. Our intervention models are informed by targeted indoor residual spraying (TIRS) experiments; trial outcomes and World Health Organization (WHO) testing guidance for the only licensed dengue vaccine, CYD-TDV; and preliminary results for in-development vaccines. We evaluated several implementation options, including varying coverage levels; staggered introductions; and a one-time, large-scale vaccination campaign. We found that CYD-TDV and TIRS interfere: while the combination outperforms either alone, performance is lower than estimated from their separate benefits. The conventional model hypothesized for in-development vaccines, however, performs synergistically with TIRS, amplifying effectiveness well beyond their independent impacts. If the preliminary performance by either of the in-development vaccines is upheld, a one-time, large-scale campaign followed by routine vaccination alongside aggressive new vector control could enable short-term elimination, with nearly all cases avoided for a decade despite continuous dengue reintroductions. If elimination is impracticable due to resource limitations, less ambitious implementations of this combination still produce amplified, longer-lasting effectiveness over single-approach interventions.