Safety and immunogenicity of a single dose, live-attenuated ‘tetravalent dengue vaccine’ in healthy Indian adults; a randomized, double-blind, placebo controlled phase I/II trial

Mohanty, Lalitendu; Prabhu, Madhav; Mishra, Amit Kumar; Purty, Anil J; Kanungo, Reba; Ghosh, Goutam; Kumar, R Prahan; Raj, Arjun; Bhushan, Sumit; Jangir, Manoj Kumar; Gupta, Anu; Bhakri, Anju

doi:10.1016/j.jvacx.2022.100142

Cited by 8 publications

(3 citation statements)

References 32 publications

(32 reference statements)

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“…Studies in human challenge models were carried out using a modified strain of DENV2 and the vaccine was found to provide complete protection against infection [72]. Neutralizing antibody responses for all four serotypes were seen in 48% of the subjects and phase I/ II studies carried out in India showed that 77.8% to 81.9% of individuals seroconverted to the different DENV serotypes [73,74]. Although no efficacy data are currently available for this vaccine, based on observations from human challenge models, the vaccine appears to induce a high level of protection for at least a short duration; it will be interesting to see if these findings translate to similar results in large scale clinical trials over longer periods.…”

Section: Plos Global Public Healthmentioning

confidence: 99%

Facing the escalating burden of dengue: Challenges and perspectives

Malavige,

Sjö,

Singh

et al. 2023

PLOS Glob Public Health

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Dengue is the most rapidly emerging mosquito-borne infection and, due to climate change and unplanned urbanization, it is predicted that the global burden of dengue will rise further as the infection spreads to new geographical locations. Dengue-endemic countries are often unable to cope with such increases, with health care facilities becoming overwhelmed during each dengue season. Furthermore, although dengue has been predominantly a childhood illness in the past, it currently mostly affects adults in many countries, with higher incidence of severe disease and mortality rates in pregnant women and in those with comorbidities. As there is currently no specific treatment for dengue and no early biomarker to identify those who will progress to develop vascular leakage, all individuals with dengue are closely monitored in case they need fluid management. Furthermore, diagnosing patients with acute dengue is challenging due to the similarity of clinical symptoms during early illness and poor sensitivity and specificity of point-of-care diagnostic tests. Novel vector control methods, such as the release of Wolbachia-infected mosquitoes, have shown promising results by reducing vector density and dengue incidence in clinical trial settings. A new dengue vaccine, TAK-003, had an efficacy of 61.2% against virologically confirmed dengue, 84.1% efficacy against hospitalizations and a 70% efficacy against development of dengue haemorrhagic fever (DHF) at 54 months. While vaccines and mosquito control methods are welcome, they alone are unlikely to fully reduce the burden of dengue, and a treatment for dengue is therefore essential. Several novel antiviral drugs are currently being evaluated along with drugs that inhibit host mediators, such as mast cell products. Although viral proteins such as NS1 contribute to the vascular leak observed in severe dengue, the host immune response to the viral infection also plays a significant role in progression to severe disease. There is an urgent need to discover safe and effective treatments for dengue to prevent disease progression.

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Section: Plos Global Public Healthmentioning

confidence: 99%

Facing the escalating burden of dengue: Challenges and perspectives

Malavige,

Sjö,

Singh

et al. 2023

PLOS Glob Public Health

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“…As India emerges as the epicenter of dengue disease burden, contributing nearly a third of the global dengue disease burden, and vaccine trials commence in this region, a detailed understanding of T cell responses to vaccines and natural infection in this region is important [19][20][21][22][23][24][25]. However, many knowledge gaps exist.…”

Section: Introductionmentioning

confidence: 99%

Regional Variation of the CD4 and CD8 T Cell Epitopes Conserved in Circulating Dengue Viruses and Shared with Potential Vaccine Candidates

Chawla,

Bajpai,

Saini

et al. 2024

Viruses

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As dengue expands globally and many vaccines are under trials, there is a growing recognition of the need for assessing T cell immunity in addition to assessing the functions of neutralizing antibodies during these endeavors. While several dengue-specific experimentally validated T cell epitopes are known, less is understood about which of these epitopes are conserved among circulating dengue viruses and also shared by potential vaccine candidates. As India emerges as the epicenter of the dengue disease burden and vaccine trials commence in this region, we have here aligned known dengue specific T cell epitopes, reported from other parts of the world with published polyprotein sequences of 107 dengue virus isolates available from India. Of the 1305 CD4 and 584 CD8 epitopes, we found that 24% and 41%, respectively, were conserved universally, whereas 27% and 13% were absent in any viral isolates. With these data, we catalogued epitopes conserved in circulating dengue viruses from India and matched them with each of the six vaccine candidates under consideration (TV003, TDEN, DPIV, CYD-TDV, DENVax and TVDV). Similar analyses with viruses from Thailand, Brazil and Mexico revealed regional overlaps and variations in these patterns. Thus, our study provides detailed and nuanced insights into regional variation that should be considered for itemization of T cell responses during dengue natural infection and vaccine design, testing and evaluation.

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“…Compared to its parent strain, rDEN3Δ30/31-7164 has restricted replication in juvenile rhesus monkeys, a model of severe combined immunodeficiency (SCID) mice, and mosquitos [ 26 ]. rDEN3Δ30/31-7164 has been evaluated in one phase 1 clinical trial, and TV003 has been evaluated in multiple phase 1 and 2 trials [ 9 – 11 , 28 , 37 , 38 ], with full phase 3 trial data pending (NCT02406729). Although rDEN3Δ30/31-7164 monovalent vaccination has never been tested in flavivirus exposed individuals, the virus has been administered to immune individuals as part of several tetravalent formulations with excellent safety profiles.…”

Section: Introductionmentioning

confidence: 99%

Phase 1 trial to model primary, secondary, and tertiary dengue using a monovalent vaccine

Odio,

Lowman,

Law

et al. 2023

BMC Infect Dis

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Background The four co-circulating and immunologically interactive dengue virus serotypes (DENV1-4) pose a unique challenge to vaccine design because sub-protective immunity can increase the risk of severe dengue disease. Existing dengue vaccines have lower efficacy in DENV seronegative individuals but higher efficacy in DENV exposed individuals. There is an urgent need to identify immunological measures that are strongly associated with protection against viral replication and disease following sequential exposure to distinct serotypes. Methods/Design This is a phase 1 trial wherein healthy adults with neutralizing antibodies to zero (seronegative), one non-DENV3 (heterotypic), or more than one (polytypic) DENV serotype will be vaccinated with the live attenuated DENV3 monovalent vaccine rDEN3Δ30/31-7164. We will examine how pre-vaccine host immunity influences the safety and immunogenicity of DENV3 vaccination in a non-endemic population. We hypothesize that the vaccine will be safe and well tolerated, and all groups will have a significant increase in the DENV1-4 neutralizing antibody geometric mean titer between days 0 and 28. Compared to the seronegative group, the polytypic group will have lower mean peak vaccine viremia, due to protection conferred by prior DENV exposure, while the heterotypic group will have higher mean peak viremia, due to mild enhancement. Secondary and exploratory endpoints include characterizing serological, innate, and adaptive cell responses; evaluating proviral or antiviral contributions of DENV-infected cells; and immunologically profiling the transcriptome, surface proteins, and B and T cell receptor sequences and affinities of single cells in both peripheral blood and draining lymph nodes sampled via serial image-guided fine needle aspiration. Discussion This trial will compare the immune responses after primary, secondary, and tertiary DENV exposure in naturally infected humans living in non-endemic areas. By evaluating dengue vaccines in a new population and modeling the induction of cross-serotypic immunity, this work may inform vaccine evaluation and broaden potential target populations. Trial Registration NCT05691530 registered on January 20, 2023.

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Safety and immunogenicity of a single dose, live-attenuated ‘tetravalent dengue vaccine’ in healthy Indian adults; a randomized, double-blind, placebo controlled phase I/II trial

Cited by 8 publications

References 32 publications

Facing the escalating burden of dengue: Challenges and perspectives

Facing the escalating burden of dengue: Challenges and perspectives

Regional Variation of the CD4 and CD8 T Cell Epitopes Conserved in Circulating Dengue Viruses and Shared with Potential Vaccine Candidates

Phase 1 trial to model primary, secondary, and tertiary dengue using a monovalent vaccine

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