Improvement of the Dengue Virus (DENV) Nonhuman Primate Model via a Reverse Translational Approach Based on Dengue Vaccine Clinical Efficacy Data against DENV-2 and -4

Barban, V.; Mantel, Nathalie; Montfort, Aymeric de; Pagnon, Anke; Pradezynski, Fabrine; Lang, Jean; Boudet, Florence

doi:10.1128/jvi.00440-18

Cited by 17 publications

(16 citation statements)

References 59 publications

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“…Macaques challenged with DENV-2 by the intradermal (ID) route seroconverted more rapidly than those challenged by the SC route [27], and macaques challenged with DENV-2 by the IV route exhibited higher peak RNAemia titers compared to those challenged ID or SC. [28] Small groups of macaques infected with DENV-3 by the SC, ID, or IV routes exhibited some differences in the tissue distribution of virus, but all groups exhibited only transient (1-4 days) and low level viremia. [29] The effect of prior DENV exposure or immunity on subsequent DENV infection has also been explored in macaques.…”

Section: Introductionmentioning

confidence: 92%

Route of inoculation and mosquito vector exposure modulate dengue virus replication kinetics and immune responses in rhesus macaques

et al. 2020

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Dengue virus (DENV) is transmitted by infectious mosquitoes during blood-feeding via saliva containing biologically-active proteins. Here, we examined the effect of varying DENV infection modality in rhesus macaques in order to improve the DENV nonhuman primate (NHP) challenge model. NHPs were exposed to DENV-1 via subcutaneous or intradermal inoculation of virus only, intradermal inoculation of virus and salivary gland extract, or infectious mosquito feeding. The infectious mosquito feeding group exhibited delayed onset of viremia, greater viral loads, and altered clinical and immune responses compared to other groups. After 15 months, NHPs in the subcutaneous and infectious mosquito feeding groups were re-exposed to either DENV-1 or DENV-2. Viral replication and neutralizing antibody following homologous challenge were suggestive of sterilizing immunity, whereas heterologous challenge resulted in productive, yet reduced, DENV-2 replication and boosted neutralizing antibody. These results show that a more transmission-relevant exposure modality resulted in viral replication closer to that observed in humans.

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Section: Introductionmentioning

confidence: 92%

Route of inoculation and mosquito vector exposure modulate dengue virus replication kinetics and immune responses in rhesus macaques

et al. 2020

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“…In children with no immunity to DENVs, Dengvaxia was poorly efficacious and the vaccine increased the risk of severe dengue disease upon exposure to wild type DENV infections. The poor performance of Dengvaxia in dengue-naïve children is mainly due to unbalanced replication of vaccine components, where the DENV4 component is replication-and immune-dominant compared to the other three serotypes (19)(20)(21)(22)(23). Takeda is based on an attenuated DENV2 strain and 3 additional chimeras of the attenuated DENV2 strain expressing the envelope proteins of DENV1, 3 and 4.…”

Section: Introductionmentioning

confidence: 99%

Defining levels of dengue virus serotype-specific neutralizing antibodies induced by a live attenuated tetravalent dengue vaccine (TAK-003)

White

Young

Stoops

et al. 2020

Preprint

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The four dengue virus serotypes (DENV1-4) infect several hundred million people each year living in tropical and sub-tropical regions. Clinical development of DENV vaccines is difficult because immunity to a single serotype increases risk of severe disease during a second infection with a new serotype. Leading vaccines are based on tetravalent formulations to induce simultaneous and balanced protective immunity to all 4 serotypes. TAK-003 is a tetravalent live attenuated dengue vaccine candidate developed by Takeda Vaccines Inc, which is currently being evaluated in phase 3 efficacy trials. Here, we use antibody depletion methods and chimeric, epitope transplant DENVs to characterize the specificity of neutralizing antibodies in dengue-naïve adults and non-human primates immunized with TAK-003. Our results demonstrate that TAK-003 induced high levels of DENV2 neutralizing antibodies that recognized unique (type-specific) epitopes on DENV2. In contrast, most vaccinated subjects developed lower levels of DENV1, DENV3 and DENV4 neutralizing antibodies that mainly targeted epitopes that were conserved (cross-reactive) between serotypes. We conclude that the DENV2 component in the vaccine is immunodominant because of the high levels of serum neutralizing antibodies targeting type-specific epitopes. We also conclude that DENV1, 3 and 4 vaccine components are less immunogenic because most study subjects did not develop type-specific serum neutralizing antibodies to these serotypes. While DENV vaccine development has been guided by the presence of neutralizing antibodies to each serotype as a benchmark, our results indicate that the presence of neutralizing antibodies alone are not a reliable indicator of the immunogenicity of each vaccine component.Author summaryThe development of tetravalent dengue vaccines has been guided by neutralizing antibodies to each serotype as a correlate of safe and effective vaccine induced immunity. However, the absolute levels of neutralizing antibodies to each serotype has proven to be an unreliable correlate of protection. Levels of antibodies to epitopes that are unique to each serotype, which are measures of immunity independently stimulated by each vaccine component, rather than total quantity of neutralizing antibodies, are likely to be better correlates of protection. Here, we mapped the specificity of antibodies induced by the Takeda tetravalent dengue vaccine TAK-003 in monkeys and humans with no prior immunity to dengue. The TAK-003 vaccine induces high levels of serotype 2 specific neutralizing antibodies that map to known protective epitopes. In contrast, the serotype 1, 3 and 4 neutralizing antibody responses are lower and mainly consist of cross-reactive antibodies binding to epitopes conserved between serotypes. These heterotypic antibodies, which are most likely derived from the serotype 2 component, may not provide long term protection in vivo.

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“…Although improvements following non-human primate assessments of CYD-TDV and DPIV+AS03 B have been noted, the studies also suggest a risk of enhanced viremia and disease many months following vaccination. 11,12 Two DPIV+AS03 B doses administered 1 M apart were well tolerated and induced robust neutralizing antibody (Nab) titers against all four DENV types in dengue-seronegative 13 and dengue-seropositive adults. 14 Although antibody titers waned considerably within 6 M after vaccination in seronegative participants, 13 they remained high in seropositive participants.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Safety and Immunogenicity of an AS03B-Adjuvanted Inactivated Tetravalent Dengue Virus Vaccine Administered on Varying Schedules to Healthy U.S. Adults: A Phase 1/2 Randomized Study

Lin

Lyke

Koren

et al. 2020

The American Journal of Tropical Medicine and Hygiene

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Dengue disease and its causative agents, the dengue viruses (DENV-1-4), cause high morbidity in tropical and subtropical regions. We evaluated three dosing regimens of the investigational tetravalent AS03 B-adjuvanted dengue-purified inactivated vaccine (DPIV+AS03 B). In this phase 1/2, observer-blind, placebo-controlled study (NCT02421367), 140 healthy adults were randomized 1:1:2 to receive DPIV+AS03 B according to the following regimens: 0-1 month (M), 0-1-6 M, or 0-3 M. Participants received DPIV+AS03 B or placebo at M0, M1, M3, and M6 according to their dosing schedule. Primary objectives were 1) to evaluate the safety of DPIV+AS03 B for 28 days (D) after each dose; 2) to demonstrate the added value of a booster dose (0-1-6 M versus 0-1 M) based on neutralizing antibody titers to each DENV type (DENV-1-4) at 28 D after the last dose; and, if this objective was met, 3) to demonstrate the benefit of a longer interval between the first and second doses (0-1 M versus 0-3 M). Adverse events (AEs) within 7 D after vaccination tended to be more frequent after DPIV+AS03 B doses than placebo; the number of grade 3 AEs was low (£ 4.5% after DPIV+AS03 B ; £ 2.9% after placebo), with no obvious differences across groups. Within 28 D following each dose, the frequency of unsolicited AEs after DPIV+AS03 B appeared higher for three-dose (0-1-6 M) than two-dose (0-1 M and 0-3 M) regimens. No serious AEs were considered related to vaccination, and no potential immune-mediated diseases were reported during the study. All three schedules were well tolerated. Both primary immunogenicity objectives were demonstrated. The 0-3 M and 0-1-6 M regimens were more immunogenic than the 0-1 M regimen.

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Improvement of the Dengue Virus (DENV) Nonhuman Primate Model via a Reverse Translational Approach Based on Dengue Vaccine Clinical Efficacy Data against DENV-2 and -4

Cited by 17 publications

References 59 publications

Route of inoculation and mosquito vector exposure modulate dengue virus replication kinetics and immune responses in rhesus macaques

Route of inoculation and mosquito vector exposure modulate dengue virus replication kinetics and immune responses in rhesus macaques

Defining levels of dengue virus serotype-specific neutralizing antibodies induced by a live attenuated tetravalent dengue vaccine (TAK-003)

Safety and Immunogenicity of an AS03B-Adjuvanted Inactivated Tetravalent Dengue Virus Vaccine Administered on Varying Schedules to Healthy U.S. Adults: A Phase 1/2 Randomized Study

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