• Product Name: DENVax
• Type: Live, attenuated vaccine
• Status: Clinical trial
• Host Species for Licensed Use: None
• Antigen: whole virus (DENV2) and prM/E (serotypes 1 - 4) (Torres-Flores et al., 2022)
• Preparation: (Torres-Flores et al., 2022)Tak-003/DENVax is based on a live-attenuated DENV-2 strain (PDK-53-V) in which the pre-membrane (prM) and envelope (E) genes of YFV have been replaced by the homologous genes from each one of the four DENV serotypes
• Immunization Route: Intramuscular injection (i.m.)

• Manufacturer: Laboratory of Infectious Diseases (LID) of the National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Live, attenuated vaccine
• Status: Clinical trial
• Host Species for Licensed Use: None
• Preparation: (Torres-Flores et al., 2022)TV003/TV005 was constructed by a deletion of 30 nucleotides (172–143) in the TL2 stem-loop of the 3′-UTR of DENV-4 and DENV-1 (rDEN4∆30 and rDEN1∆30), DENV-2 and DENV-3 components were constructed from the rDEN4∆30 backbone
• Immunization Route: Intramuscular injection (i.m.)

• Type: Subunit vaccine
• Status: Clinical trial
• Host Species for Licensed Use: None
• Antigen: Truncated dengue envelope proteins (DEN-80E) for all 4 serotypes (Manoff et al., 2019)
• E from Dengue virus 1 gene engineering:
  • Type: Recombinant protein preparation
  • Description: Truncated versions of E consisting of the N-terminal portion of E (DEN-80E) for all 4 serotypes. (Manoff et al., 2019)
  • Detailed Gene Information: Click Here.
• E protein from Dengue Virus 2 gene engineering:
  • Type: Recombinant protein preparation
  • Description: Truncated versions of E consisting of the N-terminal portion of E (DEN-80E) for all 4 serotypes. (Manoff et al., 2019)
  • Detailed Gene Information: Click Here.
• E from Dengue virus 3 gene engineering:
  • Type: Recombinant protein preparation
  • Description: Truncated versions of E consisting of the N-terminal portion of E (DEN-80E) for all 4 serotypes. (Manoff et al., 2019)
  • Detailed Gene Information: Click Here.
• E from Dengue virus 4 gene engineering:
  • Type: Recombinant protein preparation
  • Description: Truncated versions of E consisting of the N-terminal portion of E (DEN-80E) for all 4 serotypes. (Manoff et al., 2019)
  • Detailed Gene Information: Click Here.
• Immunization Route: Intramuscular injection (i.m.)
• Description: A recombinant subunit Dengue Virus vaccine that utilizes 80% of the Envelope protein of all 4 serotypes as the antigen with aluminum hydroxide adjuvant.

• Type: investigational recombinant subunit vaccine
• Status: Clinical trial
• Host Species for Licensed Use: None
• Antigen: Truncated dengue envelope proteins (DEN-80E) for all 4 serotypes (Manoff et al., 2019)
• Immunization Route: Intramuscular injection (i.m.)
• Description: A recombinant subunit Dengue Virus vaccine that utilizes 80% of the Envelope protein of all 4 serotypes as the antigen with ISCOMATRIX™ adjuvant (Manoff et al., 2019).

• Type: investigational recombinant subunit vaccine
• Status: Clinical trial
• Host Species for Licensed Use: None
• Antigen: Truncated dengue envelope proteins (DEN-80E) for all 4 serotypes (Manoff et al., 2019)
• Immunization Route: Intramuscular injection (i.m.)
• Description: A recombinant subunit Dengue Virus vaccine that utilizes 80% of the Envelope protein of all 4 serotypes as the antigen (Manoff et al., 2019).

Human Response

• Vaccination Protocol: Healthy children and adolescents 4 to 16 years of age in regions of Asia and Latin America were randomly assigned in a 2:1 ratio (stratified according to age category and region) to receive two doses of vaccine or placebo 3 months apart. (Biswal et al., 2019)
• Immune Response: Of the 20,071 participants who were given at least one dose of vaccine or placebo (safety population), 19,021 (94.8%) received both injections and were included in the per-protocol analysis. The overall vaccine efficacy in the safety population was 80.9% (95% confidence interval [CI], 75.2 to 85.3; 78 cases per 13,380 [0.5 per 100 person-years] in the vaccine group vs. 199 cases per 6687 [2.5 per 100 person-years] in the placebo group). In the per-protocol analyses, vaccine efficacy was 80.2% (95% CI, 73.3 to 85.3; 61 cases of virologically confirmed dengue in the vaccine group vs. 149 cases in the placebo group), with 95.4% efficacy against dengue leading to hospitalization (95% CI, 88.4 to 98.2; 5 hospitalizations in the vaccine group vs. 53 hospitalizations in the placebo group). Planned exploratory analyses involving the 27.7% of the per-protocol population that was seronegative at baseline showed vaccine efficacy of 74.9% (95% CI, 57.0 to 85.4; 20 cases of virologically confirmed dengue in the vaccine group vs. 39 cases in the placebo group). (Biswal et al., 2019)
• Side Effects: The incidence of serious adverse events was similar in the vaccine group and placebo group (3.1% and 3.8%, respectively) (Biswal et al., 2019)

Human Response

• Vaccination Protocol: The lyophilized vaccine formulation was reconstituted before administration. One 0.5-ml dose of TAK-003 contained approximately 3.6, 4.0, 4.6, and 5.1 log10 plaque-forming units of TDV-1, TDV-2, TDV-3, and TDV-4, respectively. The placebo was a 0.5-ml injection of saline. Vaccine and placebo were administered subcutaneously into the upper arm (Biswal et al., 2019).
• Immune Response: Against any serotype, efficacy was 80.2% in the per-protocol population (95% confidence interval [CI], 73.3 to 85.3; P<0.001; 61 cases of virologically confirmed dengue in the vaccine group and 149 in the placebo group).
  For specific serotypes; efficacious for DENV-2,3, and 1. 97.7% efficacy against DENV-2, 73.7% efficacy against DENV-1, and 62.6% efficacy against DENV-3; Inconclusive against DENV-4.
  
  The overall vaccine efficacy in the safety population was 80.9% (95% confidence interval [CI], 75.2 to 85.3; 78 cases per 13,380 [0.5 per 100 person-years] in the vaccine group vs. 199 cases per 6687 [2.5 per 100 person-years] in the placebo group) (Biswal et al., 2019).

Human Response

• Vaccination Protocol: Among the 98 adults who were randomized into the trial, 57 (58%) were female, 92 (94%) were white, and the mean age was 27 years (range, 18 to 48 years). The gender, race/ethnicity, and age distributions were generally consistent across the treatment groups.The first, second, and third injections of trial product were received by 98 (100%), 94 (96%), and 90 (92%) of randomized participants, respectively. Overall, 83 (85%) participants completed the trial. (Manoff et al., 2019)
• Immune Response: The medium-dose V180 formulation with Alhydrogel™ did not meet the pre-specified definition of a positive immune response, but showed limited evidence of immunogenicity for all 4 serotypes: SCRs ranged from 14.3 to 62.5%, while GMTs ranged from <10 to 20. For the medium-dose V180 formulation with Alhydrogel™, GMTs for some serotypes increased by Month 3, and then returned to baseline by Month 8 (6 Months Postdose 3).Tetravalent or ≥trivalent responses were exhibited by lower proportions of recipients of medium-dose V180 with Alhydrogel. (Manoff et al., 2019)
• Side Effects: For all 4 treatment types, pain/tenderness was the most frequent injection-site AE, followed by erythema and swelling. Fever (temperature ≥38.0°C [100.4°F]) was reported in 0 (0%) Alhydrogel™ recipients. (Manoff et al., 2019)

Human Response

• Vaccination Protocol: Among the 98 adults who were randomized into the trial, 57 (58%) were female, 92 (94%) were white, and the mean age was 27 years (range, 18 to 48 years). The gender, race/ethnicity, and age distributions were generally consistent across the treatment groups (data not shown).The first, second, and third injections of trial product were received by 98 (100%), 94 (96%), and 90 (92%) of randomized participants, respectively (Figure 1). Overall, 83 (85%) participants completed the trial. (Manoff et al., 2019)
• Immune Response: Virus Neutralizing Antibody:
  
  Each of the 6 V180 formulations containing ISCOMATRIX™ adjuvant met the pre-specified definition of a positive immune response, with seroconversion rates of ≥85.7% for all 4 dengue serotypes; GMTs ranged from 73 to 1344. Within each V180 dose level, GMTs were slightly higher (within 2-fold) for formulations with 60 ISCO™ units than formulations with 30 ISCO™ units. In contrast, for a given dose level of ISCOMATRIX™ adjuvant, GMTs did not increase with increasing doses of V180 antigen.
  
  All 6 V180 formulations with ISCOMATRIX™ adjuvant had similar profiles: GMTs increased by Month 2 (28 Days Postdose 2), increased further by Month 3 (28 Days Postdose 3), and then declined over time through Month 14 (1 Year Postdose 3), remaining generally above baseline for DENV1, DENV2, and DENV3, and generally returning to baseline for DENV4. During long-term follow-up, GMTs generally remained higher in the 60 ISCO™ unit group than the 30 ISCO™ unit group for the low-dose V180 cohort, but tended to converge in the medium-dose and high-dose V180 cohorts.
  
  Memory B-Cell Responses:
  
  Induction of B-cell memory to each of the four DENV serotypes was observed in peripheral blood mononuclear cells among all participants who received 3 injections of high-dose V180 with ISCOMATRIX™ adjuvant (30 or 60 ISCO™ units) at 28 Days Postdose 3, the mean number of dengue-specific memory B cells in these recipients had increased in frequency by 1 to 2 logs over the pre-vaccination baseline
  
  (Manoff et al., 2019)
• Side Effects: V180 with ISCOMATRIX™ adjuvant was associated with a higher frequency of injection-site AEs (adverse effects) overall, injection-site AEs of erythema or swelling that were ≥5 cm or ≥10 cm, and a higher frequency of injection-site pain/tenderness that participants assessed as severe (defined in the protocol as the inability to do work or usual activities). V180 with ISCOMATRIX™ adjuvant was also associated with higher frequencies of systemic AEs overall, and those assessed by the investigator as related to study product. Fever (temperature ≥38.0°C [100.4°F]) was reported in 5 (9%) ISCOMATRIX™ adjuvant recipients.
  
  (Manoff et al., 2019)

Human Response

• Vaccination Protocol: Among the 98 adults who were randomized into the trial, 57 (58%) were female, 92 (94%) were white, and the mean age was 27 years (range, 18 to 48 years). The gender, race/ethnicity, and age distributions were generally consistent across the treatment groups. The first, second, and third injections of trial product were received by 98 (100%), 94 (96%), and 90 (92%) of randomized participants, respectively. Overall, 83 (85%) participants completed the trial. (Manoff et al., 2019)
• Immune Response: Virus-Neutralizing Antibody:
  
  The unadjuvanted high-dose V180 formulation did not meet the pre-specified definition of a positive immune response, but showed limited evidence of immunogenicity for all 4 serotypes: SCRs ranged from 14.3 to 62.5%, while GMTs ranged from <10 to 20. There was no detectable immune response in the unadjuvanted medium-dose V180 group or the placebo group. For the unadjuvanted high-dose V180 formulation, GMTs for some serotypes increased by Month 3, and then returned to baseline by Month 8 (6 Months Postdose 3). Tetravalent or ≥trivalent responses were exhibited by lower proportions of recipients of high-dose unadjuvanted V180, and by no recipients of medium-dose unadjuvanted V180. In the majority of instances when participants had FRNT50 titers ≥10 for only 3 seotypes, DENV4 was the serotype with a titer <10.
  
  Memory B-Cell Responses:
  
  The mean change ranged from a 0.4-log decrease to 1-log increase among recipients of unadjuvanted high-dose V180, and generally increased <1 log among placebo recipients.
  
  (Manoff et al., 2019)
• Side Effects: For all 4 treatment types, pain/tenderness was the most frequent injection-site AE, followed by erythema and swelling. Fever (temperature ≥38.0°C [100.4°F]) was reported in 0 (0%) unadujuvanted recipients. (Manoff et al., 2019)