Dengue (DEN) viruses belong to the family Flaviviridae and consist of four distinct antigenic serotypes, DEN1–4. DEN viruses are transmitted primarily by the mosquito Aedes aegypti and cause over 100 million human infections per year, which are manifested clinically by either DEN fever (DF), a self-limited febrile illness, or more severe DEN hemorrhagic fever/DEN shock syndrome (DHF/DSS) usually with a mortality that ranges from 1 to 5%. Epidemic DF/DHF has been emerging as one of the most important global public health problems in the tropical and subtropical countries at the beginning of the 21st century. It is imperative to support research on the development of new mosquito control technology and on the establishment of preventive strategies, including the development of effective and safe dengue vaccines (Liu et al., 2006).
4. Microbial Pathogenesis
During the feeding of mosquitoes on humans, DENV is presumably injected into the bloodstream, with spillover in the epidermis and dermis, resulting in infection of immature Langerhans cells (epidermal dendritic cells [DC]), and keratinocytes. Infected cells then migrate from site of infection to lymph nodes, where monocytes and macrophages are recruited, which become targets of infection. Consequently, infection is amplified and virus is disseminated through the lymphatic system. As a result of this primary viremia, several cells of the mononuclear lineage, including blood-derived monocytes, myeloid DC, and splenic and liver macrophages are infected (Martina et al., 2009).
5. Host Ranges and Animal Models
Dengue is transmitted to humans by Aedes mosquitoes, mainly Aedes aegypti. There is no animal model of disease that mimics the disease in humans (Martina et al., 2009).
6. Host Protective Immunity
In most acute virus infection models, the presence of antibodies, both neutralizing and nonneutralizing, correlates with control, elimination, and eventually protection (Martina et al., 2009).
Molecule Role Annotation :
A recombinant baculovirus encoding a dengue (DEN)-2 virus envelope glycoprotein truncated of 102 amino acids (aa) at its C-terminus (D2EA102) was constructed. Both intracellular and extracellular D2EA102 induced neutralizing antibodies in mice and were thus immunogenic. Sixty eight percent (P < 0.001) of mice vaccinated with 5 gg of extracellular D2EA102 protein were protected against lethal challenge (Delenda et al., 1994).
>NP_740316.1 membrane (M) protein [Dengue virus 4]
SVALTPHSGMGLETRAETWMSSEGAWKHAQRVESWILRNPGFALLAGFMAYMIGQTGIQRTVFFVLMMLV
APSYG
Molecule Role :
Protective antigen
Molecule Role Annotation :
A recombinant vaccinia virus that expressed the M protein of Dengue 4 virus was constructed. Mice immunized with the recombinant virus were protected against subsequent dengue 4 encephalitis challenge (Bray and Lai, 1991).
Molecule Role Annotation :
The protective efficacy and immune responses of mice intramuscularly injected with plasmid encoding DEN-2 non-structural protein 1 (NS1) was evaluated. Intravenously challenged by lethal DEN-2, mice vaccinated with NS1-DNA exhibited a delay onset of paralysis, a marked decrease of morbidity, and a significant enhancement of survival (Wu et al., 2003).
Molecule Role Annotation :
A recombinant vaccinia virus that expressed the pre-M protein of Dengue 4 virus was constructed. Mice immunized with the recombinant virus were protected against subsequent dengue 4 encephalitis challenge (Bray and Lai, 1991).
using a complex adenovirus vector, by incorporating the genes expressing premembrane (prM) and envelope (E) proteins of dengue virus types 1 and 2 (dengue-1 and -2, respectively) (CAdVax-Den12) or dengue-3 and -4 (CAdVax-Den34) (Raviprakash et al., 2008).
f. Immunization Route
Intramuscular injection (i.m.)
g.
Macaque Response
Vaccination Protocol:
Rhesus macaques were vaccinated by intramuscular inoculation of a tetravalent dengue vaccine formulated by combining the two bivalent vaccine constructs (Raviprakash et al., 2008).
Vaccine Immune Response Type:
VO_0003057
Challenge Protocol:
The ability of the vaccine to induce rapid, as well as sustained, protective immune responses was examined with two separate live-virus challenges administered at 4 and 24 weeks after the final vaccination (Raviprakash et al., 2008).
Efficacy:
For both of these virus challenge studies, significant protection from viremia was demonstrated for all four dengue virus serotypes in vaccinated animals. Viremia from dengue-1 and dengue-3 challenges was completely blocked, whereas viremia from dengue-2 and dengue-4 was significantly reduced, as well as delayed, compared to that of control-vaccinated animals (Raviprakash et al., 2008).
Vaccination Protocol:
Groups of 3–4 weeks old female C3H mice were initially immunized with 80 μg of recombinant DNA pD2NS1, or pcDNA3 as a control. Recombinant pD2NS1 in PBS, control pcDNA3 in PBS, or PBS buffer alone was intramuscularly (i.m.) injected into the mouse thighs; the mice were subsequently boosted twice using the same method at 1 week interval (Wu et al., 2003).
Challenge Protocol:
One week after the final boost, mice were i.v. challenged with 5×10^6 plaque-forming units of PL046 in 100 μl PBS. The mice after virus challenge were monitored daily for morbidity and mortality for weeks (Wu et al., 2003).
Efficacy:
Intravenously challenged by lethal DEN-2, mice vaccinated with NS1-DNA exhibited a delay onset of paralysis, a marked decrease of morbidity, and a significant enhancement of survival (Wu et al., 2003).
Vaccination Protocol:
Three-week-old female BALB/c mice were immunized by intraperitoneal injection on days 1,7, 21 and 56 with 200 gl of baculovirus infected Sf9 cell lysates (CL) or concentrated supernatant fluids (SF) supplemented with complete Freund adjuvant for the first and with incomplete Freund adjuvant for the three other injections.
Challenge Protocol:
Mice were challenged withDEN-2 virus (Delenda et al., 1994).
Efficacy:
Sixty eight percent (P < 0.001) of mice vaccinated with 5 gg of extracellular D2EA102 protein were protected against lethal challenge (Delenda et al., 1994).
4. Dengue Vaccine using Vaccinia Virus expressing M Protein
Vaccination Protocol:
BALB/c mice were immunized by i .p .inoculation of 107 p .f .u . of recombinant vaccinia virus expressing M protein (Bray and Lai, 1991).
Challenge Protocol:
The mice were challenged at age 6 weeks by intracardiac (i.c.) challenge of 100 LD50 of D4 virus, then observed 21 days for signs of encephalitis or death (Bray and Lai, 1991).
Efficacy:
Mice immunized with the recombinant virus were protected against subsequent dengue 4 encephalitis challenge (Bray and Lai, 1991).
5. Dengue Vaccine using Vaccinia Virus expressing prM Protein
Vaccination Protocol:
BALB/c mice were immunized by i .p .inoculation of 10^7 p .f .u . of recombinant vaccinia virus (Bray and Lai, 1991).
Challenge Protocol:
The mice were challenged at age 6 weeks by i .c challenge of 100 LD50 of D4 virus, then observed 21 days for signs of encephalitis or death (Bray and Lai, 1991).
Efficacy:
Mice immunized with the recombinant virus were protected against subsequent dengue 4 encephalitis challenge (Bray and Lai, 1991).
6. Dengue virus DNA vaccine 1040D2MEL encoding dengue-2 prM-E-LAMP chimeric protein
Efficacy:
When injected into mice, D2MEL elicited an enhanced antibody response compared to D2ME, which was further augmented by coimmunization with a plasmid expressing mouse granulocyte-monocyte colony stimulating factor (GM-CSF). Neutralizing antibodies are thought to be of paramount importance for protection against dengue disease (Raviprakash et al., 2001).
7. Dengue virus DNA vaccine D1ME encoding prM and E
Efficacy:
Four of the eight i.m.-inoculated monkeys were protected completely from developing viraemia when challenged 4 months after the last dose with homologous dengue virus. The other four monkeys had reduced viraemia compared with the control immunized monkeys. The i.d. -inoculated monkeys showed no reduction in viraemia when challenged with the virus (Raviprakash et al., 2000).
Vaccination Protocol:
Monkeys were divided into groups DDD, VVV, DDV, and control and immunized with D1ME-DNA or D1ME-VRP as shown in the study design. D1ME-DNA was administered intramuscularly, with 0.5 ml given in each of the two upper arms. D1ME-VRP was delivered intramuscularly, as well (Chen et al., 2007).
Vaccine Immune Response Type:
VO_0003057
Immune Response:
After the third dose of vaccine, all animals in the DDD group, VVV group, and DDV group had developed neutralizing antibodies. The dengue virus 1-specific IgG response to all vaccination regimens was predominantly of the IgG1 type, with smaller amounts of IgG2 and no measurable amounts of IgG4 (Chen et al., 2007).
Challenge Protocol:
Twenty weeks after the final immunization, animals were challenged by subcutaneous injection of 10^5 PFU of live dengue virus 1 (Western Pacific 74 strain) in a 0.5-ml volume (Chen et al., 2007).
Efficacy:
All vaccination regimens showed significant protection from viremia compared to that of the unvaccinated control group (Chen et al., 2007).
Vaccination Protocol:
Male Balb/c mice, 4–6 weeks old, were intramuscularly injected in each hind limb tibialis anterior muscle with 50 μg of the pcTPANS1 or pcDNA3 plasmids dissolved in 50 μl of PBS (100 μg/dose/mice). Mice were inoculated with two DNA doses, given two weeks apart, and bled before immunization and 4 weeks after the first DNA dose (Costa et al., 2006).
Vaccine Immune Response Type:
VO_0003057
Immune Response:
All Balb/c mice intramuscularly inoculated with the pcTPANS1 presented high levels of NS1-specifc antibodies (Costa et al., 2006).
Challenge Protocol:
Two weeks after the second DNA dose, each immunized mouse was challenged with intracerebral inoculation with 30 μL of 4.32 log10 PFU of DENV2 (Costa et al., 2006).
Efficacy:
Vaccinated animals were challenged with intracerebral DENV-2 virus inoculations and a 100% survival was observed (Costa et al., 2006).
10. Dengue Virus DNA Vaccine expressing prM/E proteins
Vaccination Protocol:
Ten 5-week-old female BALB/c mice per immunization group were inoculated three times into the quadriceps muscle with 100 μg of DENV-4-DNAv or pCI (empty vector), DENV-4 heat inactivated (1 × 10^5 PFU), or PBS. The mice were primed on day 0 and boosted 15 and 30 days after the initial inoculation (Lima et al., 2011).
Vaccine Immune Response Type:
VO_0003057
Immune Response:
The animals immunized with DENV-4-DNAv produced rising levels, after each vaccine inoculation, of specific neutralizing antibodies against dengue-4 virus (Lima et al., 2011).
Challenge Protocol:
Fifteen days after the third inoculation, the mice were challenged intracerebrally with a dose of 100LD50, prepared from a DENV-4-infected suckling mouse brain. Mouse mortality was monitored daily for 21 days (Lima et al., 2011).
Efficacy:
Immunization with DENV-4-DNAv induced significant protection against DENV-4 challenge, where 80% of the challenged mice survived (Lima et al., 2011).
11. Dengue virus DNA vaccine p1012D2ME encoding prM and E from DEN 2 New Guinea C strain
Efficacy:
In a lethal mouse intracerebral challenge model, the vaccine provided a significant level of protection. Sixty percent of the mice immunized with the DEN DNA vaccine plus pUC 19 survived the challenge compared to only 10% in the control group that received vector plus pUC (Porter et al., 1998).
12. Dengue virus DNA vaccine pcTPANS1 encoding NS1 fused to the tissue plasminogen activator signal sequence
Description:
Vector pcDNA3 expressed the secretory signal sequence derived from human tissue plasminogen activator (t-PA) fused to the full length of the DENV-2 NS1 gene (Costa et al., 2006).
Efficacy:
Vaccinated animals were challenged against DENV-2 in two murine models, based on intracerebral (i.c.) and intraperitoneal (i.p.) virus inoculations, and in both cases, pcTPANS1-immunized mice were protected (Costa et al., 2006).
13. Dengue virus DNA vaccine pE1D2 encoding E from Dengue Virus 2 strain New Guinea C
Efficacy:
All pE1D2-vaccinated mice survived challenge, while 45% of animals immunized with the pE2D2 died after infection. Furthermore, only 10% of pE1D2-immunized mice presented some clinical signs of infection after challenge, whereas most of animals inoculated with the pE2D2 showed effects of the disease with high morbidity degrees (Azevedo et al., 2011).
14. Dengue virus DNA vaccine sA encoding prM and E from Dengue Virus 4
Efficacy:
When challenged with live dengue-1 or dengue-2 virus, partial protection against dengue-1 was observed. The best protection against dengue-1 viremia was demonstrated by the mixture of shuffled vaccines (sABC) out of all the vaccines tested (Raviprakash et al., 2006).
e. Gene Engineering of
E protein from Dengue Virus 2
Type:
DNA vaccine construction
Description:
Vector pMV10.1 expressed prM and E genes in which the N-terminal 90% of E gene was shuffled.a shuffled truncated E protein (Raviprakash et al., 2006).
Description:
Vector pMV10.1 expressed prM and E genes in which the N-terminal 90% of E gene was shuffled.a shuffled truncated E protein (Raviprakash et al., 2006).
Immune Response:
Four of six animals vaccinated developed antibodies that neutralized all 4 dengue serotypes in vitro (Raviprakash et al., 2006).
Efficacy:
When challenged with live dengue-1 or dengue-2 virus, partial protection against dengue-1 was observed (Raviprakash et al., 2006).
18. Dengue Virus Vaccine TV005
a. Type:
Live, attenuated vaccine
b. Status:
Clinical trial
c. Host Species for Licensed Use:
None
d. Host Species as Laboratory Animal Model:
Human
e. Antigen
Live attenuated tetravalent dengue vaccine TV005 composed of rDEN1Δ30, rDEN2/4Δ30, rDEN3Δ30/31, and rDEN4Δ30. (Hou et al., 2022)
f. Preparation
TV005 is an admixture composed of 4 DENV strains attenuated by a 30-nucleotide deletion in the 3′ UTR (rDEN1Δ30 and rDEN4Δ30), one 30-nucleotide and one-31 nucleotide deletion in the 3′ UTR (rDEN3Δ30/31), or by replacing the prM and E of rDEN4Δ30 with those of DENV2 NGC (rDEN2/4Δ30). (Hou et al., 2022)
g. Immunization Route
Intramuscular injection (i.m.)
h. Description
Live attenuated tetravalent vaccine TV005 protects humans against DEN2Δ30 (Tonga/74) challenge. (Hou et al., 2022)
19. Dengvaxia
a. Product Name:
Dengvaxia®
b. Manufacturer:
Sanofi Pasteur
c. Type:
Recombinant vector vaccine
d. Status:
Licensed
e. Location Licensed:
immunization implementation has been limited to subnational public health programs in Brazil and the Philippines
Description:
Dengvaxia® is a live attenuated tetravalent vaccine consisting of chimeras made up of structural pre-membrane (prM) and envelope (E) genes of the four DENV types combined with the nonstructural genes of yellow fever 17D vaccine strain. (Thomas and Yoon, 2019)
(Thomas and Yoon, 2019) Only people with evidence of a past dengue infection should be vaccinated based on an antibody test, or on a documented laboratory confirmed dengue infection in the past. The vaccine should be used within the indicated age range, which in most countries is 9–45 years. The age group to target for vaccination depends on the dengue transmission intensity in a given country;
s. Description
Dengvaxia® is a live attenuated tetravalent vaccine consisting of chimeras made up of structural pre-membrane (prM) and envelope (E) genes of the four DENV types combined with the nonstructural genes of yellow fever 17D vaccine strain (chimeric yellow fever dengue – CYD) (Thomas and Yoon, 2019)
t.
Human Response
Vaccination Protocol:
Healthy children between the ages of 9 and 16 years received three injections of recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV) or placebo at months 0, 6, and 12 under blinded conditions. (Villar et al., 2015)
Immune Response:
All groups were compared to the control group, Statistically significant difference in antibodies for all serotypes for month 7 and month 13 after injection was investigated. The results showed no statistically significant difference in antibodies for all serotypes at baseline (Villar et al., 2015).
Side Effects:
Four serious adverse events were deemed to be vaccine-related by investigators and sponsors: three in the vaccine group (a moderate asthma attack 16 hours after the first injection, allergic urticaria 4 hours after the second injection, and acute peripheral polyneuropathy associated with viral meningitis 3 days after the first injection, without detectable vaccine virus in samples, unspecified seizures 18 hours after the first injection, without detectable vaccine virus in samples,). All children recovered fully without sequelae. (Villar et al., 2015)
Efficacy:
Vaccine Efficacy for 176 cases of virologically confirmed dengue in the vaccine group and 221 in the control group that were diagnosed more than 28 days after the third dose (primary outcome): Serotype 1: 50.3%, Serotype 2: 42.3% , Serotype 3: 74.0%, Serotype 4: 77.7%. Vaccine Efficacy for all children who received at least one injection from month 0 to month 25: Serotype 1: 54.8%, Serotype 2: 50.2%, Serotype 3: 74.2%, Serotype 4: 80.9% (Villar et al., 2015).
20. rMV-TDV
a. Type:
Recombinant vector vaccine
b. Status:
Research
c. Host Species for Licensed Use:
None
d. Antigen
Bivalent fusion envelope protein domain III (ED3) of DENV-1,2,3,4 (Lin et al., 2020)
rMV-TDV consists of two recombinant MV vectors carrying the genes encoding bivalent fusion envelope protein domain III (ED3) of DENV-1 and -3 or DENV-2 and -4. (Lin et al., 2020)
l.
Mouse Response
Vaccination Protocol:
Groups of 6-8-week-old AG-hCD46 mice were immunized intraperitoneally with rMV-TDV, a mixture containing 1 × 10^5 pfu of rMV-D13 and 1 × 10^5 pfu of rMV-D24, or 2 × 10^5 pfu of rMV-EGFP for the control. Mice were boosted with the same recombinant viruses and doses four weeks later. (Lin et al., 2020)
Immune Response:
A significant ED3-specific IgG response was induced after a single injection of rMV-TDV, but it was not observed in rMV-EGFP-immunized mice, and the response reached peak titers after the boost and was maintained at a high level for at least 20 weeks. A significant increase in neutralizing antibody titers (NT) to the 4 DENV serotypes was observed in rMV-TDV-immunized mice 8 weeks after vaccination compared to the rMV-EGFP controls. Only rMV-TDV- but not rMV-EGFP-immunized mice showed an obvious increase in the ED3-specific IFN-γ response dominated by DENV-3 after a single injection. Even 5 or 20 weeks later, the significantly higher level of DENV-3-specific IFN-γ responses were still maintained in rMV-TDV-immunized mice compared to the rMV-EGFP group. DENV-specific IL-4 responses were almost undetectable even after the boost. (Lin et al., 2020)
Challenge Protocol:
Mice were challenged 4 weeks after the last immunization by subcutaneously injecting 1.5 × 107 ffu of wild-type DENV-2/16681. (Lin et al., 2020)
Efficacy:
. Consistent with the higher viremia and IFN-γ increase, TNF-α but not IL-6 or IL-10 was significantly increased in the peripheral blood cells of the rMV-EGFP controls at 3 days post challenge compared to those in rMV-TDV-immunized mice, which had no increase in inflammatory cytokines (p < 0.001). (Lin et al., 2020)
Description:
YAC-CD46 mice, which carry the MV receptor-human CD46 transgene, were crossbred into AG129 mice to obtain AG-hCD46 transgenic mice (B6.129-Ifnar−/−, Ifngr−/− Tg(CD46)). (Lin et al., 2020)
(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
g. Immunization Route
Intramuscular injection (i.m.)
h.
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)
22. TV003/TV005
a. Manufacturer:
Laboratory of Infectious Diseases (LID) of the National Institute of Allergy and Infectious Diseases (NIAID)
b. Type:
Live, attenuated vaccine
c. Status:
Clinical trial
d. Host Species for Licensed Use:
None
e. 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
f. Immunization Route
Intramuscular injection (i.m.)
g.
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).
A recombinant subunit Dengue Virus vaccine that utilizes 80% of the Envelope protein of all 4 serotypes as the antigen with aluminum hydroxide adjuvant.
k.
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)
24. V180 - ISCOMATRIX™ adjuvant
a. Type:
investigational recombinant subunit vaccine
b. Status:
Clinical trial
c. Host Species for Licensed Use:
None
d. Antigen
Truncated dengue envelope proteins (DEN-80E) for all 4 serotypes (Manoff et al., 2019)
e. Immunization Route
Intramuscular injection (i.m.)
f. 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).
g.
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
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.
Truncated dengue envelope proteins (DEN-80E) for all 4 serotypes (Manoff et al., 2019)
e. Immunization Route
Intramuscular injection (i.m.)
f. 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).
g.
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.
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)
V. References
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