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Commentary
Open Access | 
10.1172/JCI177610
Controlled human infection study underpins efficacy of the tetravalent live-attenuated dengue vaccine TV005
Annelies Wilder-Smith
Disease Control, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Address correspondence to: Annelies Wilder-Smith, London School of Hygiene and Tropical Medicine, Keppel Street, London, United Kingdom. Phone: 44.0.207.927.2164; Email: anneliesws@gmail.com.
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Published February 1, 2024 - More info
J Clin Invest. 2024;134(3):e177610. https://doi.org/10.1172/JCI177610.
© 2024 Wilder-Smith This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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Abstract
BACKGROUND Disease due to dengue viruses is a growing global health threat, causing 100–400 million cases annually. An ideal dengue vaccine should demonstrate durable protection against all 4 serotypes in phase III efficacy trials, however the lack of circulating serotypes may lead to incomplete efficacy data. Controlled human infection models help downselect vaccine candidates and supply critical data to supplement efficacy trials. We evaluated the efficacy of a leading live-attenuated tetravalent dengue vaccine candidate, TV005, against infection with a newly established dengue serotype 3 or an established serotype 2 challenge virus.METHODS Two randomized, controlled clinical trials were performed. In study 1, a total of 42 participants received TV005 or placebo (n = 21 each), and 6 months later, all were challenged with dengue 2 virus (rDEN2Δ30) at a dose of 103 PFU. In study 2, a total of 23 participants received TV005 and 20 received placebo, and 6 months later, all were challenged with 104 PFU dengue 3 virus (rDEN3Δ30). The study participants were closely monitored for safety, viremia, and immunologic responses. Infection, measured by post-challenge viremia, and the occurrence of rash and neutropenia were the primary endpoints. Secondary endpoints included safety, immunologic, and virologic profiles following vaccination with TV005 and subsequent challenge with the rDEN2Δ30 or rDEN3Δ30 strain.RESULTS TV005 was well tolerated and protected all vaccinated volunteers from viremia with DENV2 or DENV3 (none infected in either group). Placebo recipients had post-challenge viremia (100% in study 1, 85% in study 2), and all experienced rash following challenge with either serotype.CONCLUSIONS TV005 is a leading tetravalent dengue vaccine candidate that fully protected against infection with DENV2 and DENV3 in an established controlled human infection model.TRIAL REGISTRATION ClinicalTrials.gov NCT02317900 and NCT02873260.FUNDING Intramural Research Program, NIH (contract HHSN272200900010C).
Authors
Kristen K. Pierce, Anna P. Durbin, Mary-Claire R. Walsh, Marya Carmolli, Beulah P. Sabundayo, Dorothy M. Dickson, Sean A. Diehl, Stephen S. Whitehead, Beth D. Kirkpatrick
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The TV005 vaccine protects against viremia and rash
In this issue of the JCI, Pierce, Durbin, and colleagues explored a controlled human infection study conducted with attenuated DENV2 and DENV3 challenge viruses in individuals six months after vaccination with TV005 (8). The primary goal was to ascertain the efficacy of TV005, gauged by viremia levels. Secondary objectives included the evaluation of safety and analysis of immunological and virological responses. The sample size of approximately 42 individuals for both randomized, controlled trials aligns with other CHIM studies (8) (Figure 1).
Figure 1TV005 protects participants in controlled human infection studies. Six months following a single dose of TV005 or placebo, participants were challenged with attenuated dengue DENV2 or DENV3 virus. The TV005 vaccine effectively protected vaccinated individuals from viremia and rash in both challenges. All participants (100%) who received placebo and the DENV2 virus developed viremia, and 85% of participants challenged with the DENV3 virus developed viremia.
The TV005 vaccine effectively protected all vaccinated individuals from viremia and rash during challenges with DENV2 or DENV3. In contrast, 100% of individuals in the unvaccinated control group developed DENV2 viremia after a DENV2 challenge, and 85% developed DENV3 viremia following a DENV3 challenge. Most vaccinated participants developed neutralizing antibodies against multiple serotypes within 90 days of receiving TV005. Serological responses to three serotypes were observed in 100% of vaccine recipients (known as a trivalent response), and 72% of recipients showed responses to all four serotypes (known as a tetravalent response). DENV2 viremia was generally higher and lasted longer than DENV3 challenge viremia. The vaccine was generally well tolerated and safe. The majority of vaccine recipients experienced a post-vaccination short-lived mild, almost asymptomatic, rash, consistent with previous findings (8, 5).
It should be noted that the challenge strains were attenuated by the deletion of nucleotides in the untranslated region of the viral genome. Hence, no extrapolations can be drawn with regard to efficacy against severe dengue. However, one could assume that preventing infection would also translate into preventing severe dengue. Furthermore, study participants were dengue naive. Since second infections with different DENV strains manifest as more serious disease, additional studies and approaches are needed to confirm vaccine protection against wild-type dengue, both in dengue-naive and dengue-exposed persons. Furthermore, the findings do not encompass long-term safety, as the challenge occurred only six months after vaccination. Considering the experience with the first licensed tetravalent live-attenuated dengue vaccine CYD-TDV (Dengvaxia), the safety signal was observed approximately two to three years after vaccination in dengue-naive persons (9), hence, this CHIM cannot exclude long-term safety issues beyond six months. Until immune correlates for protection and risk have been established, continued real-world clinical trials that include long-term observation remain essential. Although CHIMs cannot replace phase III trials, the CHIM results from Pierce, Durbin, and co-authors (8) add valuable data on serotype-specific efficacy and safety and provide an impetus to further advance the TV005 vaccine.
The NIAID has licensed TV003 and TV005 as single-dose vaccines to various manufacturers, including those in low-to-middle income countries, ensuring future access to TV003 and TV005 once regulatory approvals are granted. The next step in the regulatory pathway is the release of the five-year phase III trial results for TV003.
Meanwhile, the WHO has endorsed the second licensed dengue vaccine, TAK-003 (Qdenga), developed by Takeda for use in high dengue burden settings (10).
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