DENV-Mimetic Polymersome Nanoparticles Bearing Multi-Epitope Lipopeptides Antigen as the Next-Generation Dengue Vaccine

Dengue remains a severe threat to public health. The safety and efficacy of the licensed dengue vaccine is not clinically satisfactory, which necessitate the need of new approach in designing an effective dengue vaccine without eliciting adverse reaction. Herein, we have designed a lipidated multi-epitope peptide vaccine (LipoDV) that can elicit highly targeted humoral and cell-mediated immune responses. To improve its immunogenicity, LipoDV was presented on the surface of MPLA-functionalized polymersome nanoparticles (PNs-LipoDV-MPLA). The as-constructed vaccine delivery platform resembles the structural morphology of DENV owing to its spherical nanoscale particle size and surface immunostimulatory properties given by LipoDV and MPLA that emulating the functional role of DENV E and prM/M proteins respectively. A proof-of-concept study demonstrated that BALB/c mice immunized with PNs-LipoDV-MPLA induced a stronger antigen-specific antibody response with an enhanced cell-mediated immunity as characterized by the elevated IFN-γ secretion in comparison to other tested vaccine candidates which possess a lesser structural trait of DENV. The DENV-mimicking nanoparticles vaccine exhibited negligible toxicity as analyzed by hemolytic test, MTT assay, histopathological examination and abnormal toxicity test on immunized mice. Collectively, our study provides a strong foundation in designing an effective peptide-based vaccine delivery platform against DENV infection.

Efficacy of Live Attenuated Dengue Vaccines: CYD-TDV; TDV (TAK-003) and TV003/TV005

Highlight:Differences in the efficacy of CYD-TDV versus the other TAK-003 and TV003/TV005 were discussed.One licensed dengue vaccine is CYD-TDV (Dengvaxia). Abstract:Dengue fever is the most common tropical disease, but there still remains no specific therapy that can overcome it. Special attention needs to be paid to this disease, because there were large increases in incidence in the last decade. As an effective preventive strategy, finding a new vaccine for dengue fever with higher potentiation and efficacy is highly necessary to stop dengue transmission especially in the endemic area. Vaccine triggers an immune response, so that it can create a robust immune response when infected. Nowadays, there is only one licensed dengue vaccine that is CYD-TDV (Dengvaxia). However, this vaccine still has many weaknesses, namely its dependency on the serostatus of the recipient. There are also other dengue vaccines that are in ongoing clinical testing and have promising results, TDV (TAK-003) and TV003/TV005. These three vaccines are live attenuated vaccines with various results. This review discussed differences in the efficacy of CYD-TDV against the other TAK-003 and TV003/TV005; considering the known and unknown various factors.

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.

97. Tetravalent Dengue Vaccine (TAK-003) Development Program: A Bird’s Eye View

Background Dengue fever is a mosquito-borne viral disease endemic in 128 countries. An unmet clinical need remains for an effective vaccine that can be used more broadly than the vaccine presently available. A clinical development program has evaluated the long-term safety, immunogenicity, and vaccine efficacy (VE) of TAK-003, a live attenuated tetravalent dengue vaccine with a DENV-2 backbone engineered to elicit immune responses to all 4 dengue serotypes. Methods 18 clinical trials in 13 countries have involved 28,175 seropositive/seronegative participants aged from 1.5-60 years from endemic/non-endemic regions. In the ongoing pivotal phase III study, 4–16-year-old healthy children (N=20,099) were randomized 2:1 to receive two doses of TAK-003 or placebo, 3 months apart for an evaluation of VE and safety over a multi-year period stratified pre-vaccination dengue serostatus. Active surveillance throughout the trial detected symptomatic dengue. The trial will continue up to 4–4.5 years post 2nd dose, and for another 25 months after a booster dose. Data up to 3 years after the second vaccination are currently available. Results Safety and immunogenicity data from Phase I/II studies established the final formulation and dosing schedule. Overall VE in the pivotal phase III study was 80.2% [95% CI: 73.3–85.3] against virologically confirmed dengue (VCD) at 12 months post 2nd dose. At 18 months, VE was 66.2% (95% CI: 49.1–77.5) in dengue-naive and 76.1% (95% CI: 68.5–81.9) in dengue pre-exposed participants, with VE of 90.4% (95% CI: 82.6–94.7) and 85.9% (95% CI: 31.9–97.1) for prevention of hospitalized VCD and dengue hemorrhagic fever, respectively. Cumulative VE against VCD from first dose to 3 years post 2nd dose was 62.0% (95% CI: 56.6–66.7) and 83.6% (95% CI: 76.8–88.4) in prevention of hospitalized VCD. Some decline in VE was observed over time mainly driven by outpatient dengue. Two doses of TAK-003 3 months apart were well-tolerated with no important safety risks identified up to 3 years after completion of the vaccination schedule. Conclusion TAK-003 is immunogenic against all 4 dengue serotypes and continues to be efficacious, well-tolerated, and with no evidence of disease enhancement in seronegative population up to 3 years post-vaccination. Disclosures Vianney Tricou, D Phil, Takeda Pharmaceuticals International (Employee) Shibadas Biswal, MD, Takeda Vaccines, Inc (Employee) Sanjay S. Patel, PhD, Takeda Pharmaceuticals International AG (Employee) Olaf Zent, MD, Takeda Pharmaceuticals International AG (Employee) Martina Rauscher, PhD, Takeda Pharmaceuticals International AG (Employee) Gonzalo Perez, MD, Takeda group companies (Employee) Walid Kandeil, MD, Takeda Pharmaceuticals International AG (Employee) Nicolas Folschweiller, PhD, Takeda (Employee)

A Critical Observation on the Design and Development of Reported Peptide Inhibitors of DENV NS2B-NS3 Protease in the Last Two Decades

: Dengue is one of the neglected tropical diseases, which remains a reason for concern as cases seem to rise every year. The failure of the only dengue vaccine, Dengvaxia®, has made the problem more severe and humanity has no immediate respite from this global burden. Dengue virus (DENV) NS2B-NS3 protease is an attractive target partly due to its role in polyprotein processing. Also, since it is among the most conserved domains in the viral genome, it could produce a broad scope of opportunities toward antiviral drug discovery in general. This review has made a detailed analysis of each case of the design and development of peptide inhibitors against DENV NS2B-NS3 protease in the last two decades. Also, we have discussed the reasons attributed to their inhibitory activity, and wherever possible, we have highlighted the concerns raised, challenges met, and suggestions to improve the inhibitory activity. Thus, we attempt to take the readers through the designing and development of reported peptide inhibitors and gain insight from these developments, which could further contribute toward strategizing the designing and development of peptide inhibitors of DENV protease with improved properties in the coming future.

636. A Phase I Study to Evaluate the Safety, Tolerability, and Immunogenicity of a Live, Attenuated, Quadrivalent Dengue Vaccine (V181)

Background Dengue (DENV) is a mosquito-borne virus with four serotypes causing substantial morbidity in tropical and subtropical areas worldwide. A dengue vaccine that can be given to both seronegative and seropositive populations remains an important unmet medical need. V181 is an investigational live, attenuated, quadrivalent dengue vaccine. Methods In this phase 1 double-blind, placebo-controlled study, the safety, tolerability, and immunogenicity of V181 in healthy adults were evaluated in two formulations: TV003 and TV005. TV005 has a 10-fold higher DENV2 component as compared to TV003. Two-hundred participants [~ 50% baseline flavivirus-experienced (BFE) and 50% baseline flavivirus-naive (BFN)] were randomized 2:2:1 to receive TV003, TV005, or placebo on Days 1 and 180. Immunogenicity against each of the four DENV serotypes was measured using a Virus Reduction Neutralization Test (VRNT60) after each vaccination and out to 1 year after the second dose. Results There were no discontinuations due to adverse events (AEs) or vaccine-related serious AEs. The most common AEs Days 1-28 after any TV003 or TV005 vaccination were rash, headache, fatigue, and myalgia. DENV VRNT60 seropositivity to 3 or 4 serotypes (i.e. tri-or tetravalent) was demonstrated in 92.6% of BFN TV003 participants, 74.2% of BFN TV005 participants, and 100% of the BFE participants at 6 months postdose 1 (PD1). Vaccine viremia, a measure of vaccine infectivity, was transiently detected from all four DENV types after the first dose of TV003 and TV005. Tri- or tetravalent vaccine-viremia was detected in 63.9 % and 25.6 % of BFN TV003 and TV005 participants, respectively, PD1. Compared to baseline, robust increases in VRNT60 GMTs were observed after the first dose of TV003 and TV005 in both flavivirus subgroups for all DENV serotypes and minimal increases were observed PD2. GMTs in the TV003 and TV005 BFE and BFN subgroups remained above the respective baselines and placebo at 1-year PD2. Conclusion Both formulations of V181 were generally well tolerated in healthy adults. Overall, viremia and immunogenicity were higher after TV003 as compared to TV005. These data support the continued development of the V181 TV003 formulation as a single-dose vaccine for the prevention of DENV disease. Disclosures Kevin Russell, MD, MTM&H, Merck & Co., Inc. (Employee, Shareholder) Richard E. Rupp, MD, Merck & Co., Inc. (Research Grant or Support) Clemente Diaz-Perez, MD, Merck & Co., Inc. (Research Grant or Support) Charles P. Andrews, MD, Merck & Co., Inc. (Research Grant or Support) Andrew W. Lee, MD, Merck & Co., Inc. (Employee, Shareholder) Tyler S. Finn, BA, Merck & Co., Inc. (Employee, Shareholder) Kara Cox, MS, Merck & Co., Inc. (Employee, Shareholder) Amy Falk Russell, MS, Merck & Co., Inc. (Employee, Shareholder) Margaret M. Schaller, BS, Merck & Co., Inc. (Employee, Shareholder) Jason C. Martin, PhD, Merck & Co., Inc. (Employee, Shareholder) Donna M. Hyatt, BA, Merck & Co., Inc. (Employee, Shareholder) Sabrina Gozlan-Kelner, MS, Merck & Co., Inc. (Employee, Shareholder) Androniki Bili, MD, MPH, Merck & Co., Inc. (Employee, Shareholder) Beth-Ann Coller, PhD, Merck & Co., Inc. (Employee, Shareholder)

1051. Characterization of Immune Responses to a Live-Attenuated Tetravalent Dengue Vaccine

Background A safe and effective vaccine against dengue is needed to address an unmet medical need that affects a large portion of the world’s population. Takeda’s live attenuated tetravalent dengue vaccine candidate (TAK-003) has shown protection in an ongoing Phase 3 efficacy trial. TAK-003 contains an attenuated dengue type 2 virus (DENV-2), and 3 genetically modified viruses in which the structural proteins from each of the serotypes 1, 3 and 4 have been placed into the DENV-2 backbone. Exploratory immunological assessments have been a part of the TAK-003 clinical development plan to better understand the mechanisms of action of TAK-003, and to identify immune response signatures that may correlate with protection. Methods Cellular and humoral immune responses elicited by vaccination in dengue-naïve and dengue-exposed individuals were measured across several clinical trials. For the humoral response, several methods were used to measure the magnitude and characteristics of the antibodies following vaccination with TAK-003 including studies of neutralizing antibodies, antibodies that bind to the viral components of the vaccine, the affinity and complement fixing capabilities of antibodies specific to structural proteins, and additionally the level of antibodies specific to nonstructural protein 1 (NS1). Results A multifunctional cellular immune response was found following vaccination that primarily targeted nonstructural proteins in the DENV-2 backbone and was cross reactive to epitopes found in the other serotypes. The vaccine elicited neutralizing antibodies with high tetravalent seropositivity rates among participants. Further assessment of this response revealed that it consists of serotype-specific and cross-reactive neutralizing antibodies against all four serotypes. In addition, sera from vaccinated individuals neutralized genotypically diverse dengue strains. In addition to antibodies specific to structural components, antibodies to DENV-2 NS1 that were cross reactive to the NS1 proteins of the other serotypes were found. Conclusion The breadth of the cellular and humoral immune responses elicited by TAK-003 in vaccine recipients across a wide age range living in different endemicities aligns with the response profile expected of a multivalent live vaccine. Disclosures Ralph Braun, PhD, Takeda Pharmaceuticals (Employee) Mayuri Sharma, PhD, Takeda Pharmaceuticals (Employee) Christina DeMaso, n/a, Takeda Pharmaceuticals (Employee) Allan Parker, n/a, Takeda Pharmaceuticals (Employee) David Dominguez, n/a, Takeda Pharmaceuticals (Employee) Heather Watkins, n/a, Takeda Pharmaceuticals (Employee) Hansi Dean, PhD, Takeda Pharmaceuticals (Consultant) Lovkesh Karwal, n/a, Takeda Pharmaceuticals (Employee) Eduardo Nascimento, n/a, Takeda Pharmaceuticals (Employee) Nicole Messere, n/a, Takeda Pharmaceuticals (Employee) Isamu Tsuji, n/a, Takeda Pharmaceuticals (Employee) Melissa Zahralban-Steele, n/a, Takeda Pharmaceuticals (Employee) Jeffrey R. Currier, PhD, Takeda Pharmaceuticals (Scientific Research Study Investigator) Heather Friberg-Robertson, PhD, Takeda Pharmaceuticals (Scientific Research Study Investigator)

Local and Global Stability Analysis of Dengue Disease with Vaccination and Optimal Control

Dengue fever is a disease that has spread all over the world, including Thailand. Dengue is caused by a virus and there are four distinct serotypes of the virus that cause dengue DENV-1, DENV-2, DENV-3, and DENV-4. The dengue viruses are transmitted by two species of the Aedes mosquitoes, the Aedes aegypti, and the Aedes albopictus. Currently, the dengue vaccine used in Thailand is chimeric yellow tetravalent dengue (CYD-TDV). This research presents optimal control which studies the vaccination only in individuals with a documented past dengue infection (seropositive), regardless of the serotypes of infection causing the initial infection by the disease. The analysis of dengue transmission model is used to establish the local asymptotically stabilities. The property of symmetry in the Lyapunov function an import role in achieving this global asymptotically stabilities. The optimal control systems are shown in numerical solutions and conclusions. The result shows that the control resulted in a significant reduction in the number of infected humans and infected vectors.