Is Dengvaxia a useful vaccine for dengue endemic areas?

Gubler, Duane J.; Halstead, Scott B.

doi:10.1136/bmj.l5710

Cited by 24 publications

(13 citation statements)

References 21 publications

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“… 40 Thus, determining the recipient’s serostatus before administration of the vaccine remains a high priority. 41 , 42 In addition, the vaccine has variable efficacy against the four dengue serotypes (lower for serotypes 1 and 2 than for serotypes 3 and 4), 43 – 45 with an overall efficacy of 76% against symptomatic, virologically confirmed dengue up to 25 months after the first vaccination in those with evidence of prior dengue infection(s) aged ≥ 9 years. 40 Nonetheless, the overall number of infections would likely be unaffected because only seropositives would be targeted for vaccination.…”

Section: Discussionmentioning

confidence: 99%

Mortality among Hospitalized Dengue Patients with Comorbidities in Mexico, Brazil, and Colombia

Macías

Werneck

Castro

et al. 2021

The American Journal of Tropical Medicine and Hygiene

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Dengue patients with comorbidities may be at higher risk of death. In this cross-sectional study, healthcare databases from Mexico (2008–2014), Brazil (2008–2015), and Colombia (2009–2017) were used to identify hospitalized dengue cases and their comorbidities. Case fatality rates (CFRs), relative risk, and odds ratios (OR) for in-hospital mortality were determined. Overall, 678,836 hospitalized dengue cases were identified: 68,194 from Mexico, 532,821 from Brazil, and 77,821 from Colombia. Of these, 35%, 5%, and 18% were severe dengue, respectively. Severe dengue and age ≥ 46 years were associated with increased risk of in-hospital mortality. Comorbidities were identified in 8%, 1%, and 4% of cases in Mexico, Brazil, and Colombia, respectively. Comorbidities increased hospitalized dengue CFRs 3- to 17-fold; CFRs were higher with comorbidities regardless of dengue severity or age. The odds of in-hospital mortality were significantly higher in those with pulmonary disorders (11.6 [95% CI 7.4–18.2], 12.7 [95% CI 9.3–17.5], and 8.0 [95% CI 4.9–13.1] in Mexico, Brazil, and Colombia, respectively), ischemic heart disease (23.0 [95% CI 6.6–79.6], 5.9 [95% CI 1.4–24.6], and 7.0 [95% CI 1.9–25.5]), and renal disease/failure (8.3 [95% CI 4.8–14.2], 8.0 [95% CI 4.5–14.4], and 9.3 [95% CI 3.1–28.0]) across the three countries; the odds of in-hospital mortality from dengue with comorbidities was at least equivalent or higher than severe dengue alone (4.5 [95% CI 3.4–6.1], 9.6 [95% CI 8.6–10.6], and 9.0 [95% CI 6.8–12.0). In conclusion, the risk of death because of dengue increases with comorbidities independently of age and/or disease severity.

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Section: Discussionmentioning

confidence: 99%

Mortality among Hospitalized Dengue Patients with Comorbidities in Mexico, Brazil, and Colombia

Macías

Werneck

Castro

et al. 2021

The American Journal of Tropical Medicine and Hygiene

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“…More pressing, in spite of the moderate and acceptable levels of efficacy shown, some safety concerns were raised, including that children, which were likely a surrogate for flavivirus-naïve individuals since the vaccine was tested in hyperendemic regions, were more likely to require hospitalization (77). Since then, it has been surmised that an ADE-like response may be occurring in certain vaccinated individuals having breakthrough cases, which is induced by the antibodies to the vaccine (78). It is also possible that the mismatch of the virus non-structural proteins to DENV is a contributing factor to the development of breakthrough cases in vaccinated individuals (10).…”

Section: Implications For Rational Flavivirus Vaccine Designmentioning

confidence: 99%

Cross-Reactive Immunity Among Flaviviruses

2020

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Flaviviruses consist of significant human pathogens responsible for hundreds of millions of infections each year. Their antigenic relationships generate immune responses that are cross-reactive to multiple flaviviruses and their widespread and overlapping geographical distributions, coupled with increases in vaccination coverage, increase the likelihood of exposure to multiple flaviviruses. Depending on the antigenic properties of the viruses to which a person is exposed, flavivirus cross-reactivity can be beneficial or could promote immune pathologies. In this review we describe our knowledge of the functional immune outcomes that arise from varied flaviviral immune statuses. The cross-reactive antibody and T cell immune responses that are protective versus pathological are also addressed.

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“…Vaccines for JEV and YFV, but not for WNV or ZIKV (24), are currently licensed for use in humans and are based on live attenuated vaccine (LAV) or inactivated platforms. A DENV LAV, based on a chimeric DENV/YFV, was recently licensed, but significant controversy remains over its safety and efficacy (25,26). While all licensed vaccines rely on serological markers as immune correlates measured with validated assays (3), the potential role of T cell-mediated immunity is not yet fully understood.…”

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confidence: 99%

T Cell Responses Induced by Attenuated Flavivirus Vaccination Are Specific and Show Limited Cross-Reactivity with Other Flavivirus Species

Grifoni

Voic

Dhanda

et al. 2020

J Virol

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Members of the flavivirus genus share a high level of sequence similarity and often circulate in the same geographical regions. However, whether T cells induced by one viral species cross-react with other related flaviviruses has not been globally addressed. In this study, we tested pools of epitopes derived from dengue (DENV), Zika (ZIKV), Japanese encephalitis (JEV), West Nile (WNV), and yellow fever (YFV) viruses by intracellular cytokine staining (ICS) using peripheral blood mononuclear cells (PBMCs) of individuals naturally exposed to DENV or immunized with DENV (TV005) or YF17D vaccine. CD8 T cell responses recognized epitopes from multiple flaviviruses; however, the magnitude of cross-reactive responses was consistently severalfold lower than those to the autologous epitope pools and was associated with lower expression of activation markers such as CD40L, CD69, and CD137. Next, we characterized the antigen sensitivity of short-term T cell lines (TCL) representing 29 different individual epitope/donor combinations. TCL derived from DENV monovalent vaccinees induced CD8 and CD4 T cells that cross-reacted within the DENV serocomplex but were consistently associated with >100-fold-lower antigen sensitivity for most other flaviviruses, with no cross-recognition of YFV-derived peptides. CD8 and CD4 TCL from YF17D vaccinees were associated with very limited cross-reactivity with any other flaviviruses and in five out of eight cases >1,000-fold-lower antigen sensitivity. Overall, our data suggest limited cross-reactivity for both CD4 and CD8 T cell responses between flaviviruses and have implications for understanding immunity elicited by natural infection and strategies to develop live attenuated vaccines against flaviviral species. IMPORTANCE The envelope (E) protein is the dominant target of neutralizing antibodies for dengue virus (DENV) and yellow fever virus (YFV). Accordingly, several DENV vaccine constructs use the E protein in a live attenuated vaccine format, utilizing a backbone derived from a heterologous flavivirus (such as YF) as a delivery vector. This backbone comprises the nonstructural (NS) and capsid (C) antigens, which are dominant targets of T cell responses. Here, we demonstrate that cross-reactivity at the level of T cell responses among different flaviviruses is very limited, despite high levels of sequence homology. Thus, the use of heterologous flavivirus species as a live attenuated vaccine vector is not likely to generate optimal T cell responses and might thus impair vaccine performance.

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Is Dengvaxia a useful vaccine for dengue endemic areas?

Abstract: An effective dengue vaccine that provides balanced protection is still elusive, and Duane J Gubler argues that some partially effective vaccines offer overall benefit—but Scott B Halstead says that this would need a completely new serotesting regimen to avert serious harm

Cited by 24 publications

References 21 publications

Mortality among Hospitalized Dengue Patients with Comorbidities in Mexico, Brazil, and Colombia

Mortality among Hospitalized Dengue Patients with Comorbidities in Mexico, Brazil, and Colombia

Cross-Reactive Immunity Among Flaviviruses

T Cell Responses Induced by Attenuated Flavivirus Vaccination Are Specific and Show Limited Cross-Reactivity with Other Flavivirus Species

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