Efficacy of a tetravalent dengue vaccine in healthy children aged 4–16 years: a randomised, placebo-controlled, phase 3 trial

Rodriguez-Arenales, Edith Johana; Concepción, Alys; Ballesteros, Ana Cecilia Villarreal; Fernando, Asvini D; Borja-Tabora, Charissa; Sirivichayakul, Chukiat; Yu, Delia; Gunasekera, Dulanie; López‐Medina, Eduardo; Rodriguez-Arenales, Edith Johanna; Moreira, Edson Duarte; Espinoza, Félix; Velásquez, Hector; Reynales, Humberto; Luz, Kléber Giovanni; Jimeno, J.; Fernando, LakKumar; Bravo, Lulu; Vargas, Luis Martinez; Rivera, Luis; Alera, Maria Theresa; Manacharoen, Onanong; López, Pío; Kosalaraksa, Pope; Wickramasinghe, V. Pujitha; Dietze, Reynaldo; Cunha, Rivaldo Venâncio da; Watanaveeradej, Veerachai; Sierra, Victor Y; Sáez-Llorens, Xavier; Biswal, Shibadas; Brose, Manja; Rauscher, Martina; Bizjajeva, Svetlana; Lefevre, Inge; Borkowski, Astrid; Wallace, Derek; Escudero, Ian; Moss, Kelley J.; Garbes, Pedro; Meyer, Seetha; Hutagalung, Yanee; Tuboi, Suely; Tricou, Vianney

doi:10.1016/s0140-6736(20)30414-1

Cited by 149 publications

(113 citation statements)

References 26 publications

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“…When dengue hospitalizations were considered, TAK-003's efficiency reached 95.4% of the tested population [42]. TAK-003 was more effective (97.7%) for the DENV-2 serotype, but also moderately effective for the other three (73.7% for DENV-1, 63.2% for DENV-3, and inconclusive results of 63% for DENV-4).…”

Section: Discussionmentioning

confidence: 93%

How super-spreader cities, highways, hospital bed availability, and dengue fever influenced the COVID-19 epidemic in Brazil

Nicolelis

Raimundo

Peixoto

et al. 2020

Preprint

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Although its international airports served as the country's main entry points for SARS-CoV-2, the factors driving the uneven geographic spread of COVID-19 cases and deaths in Brazil remain largely unknown. Here we show that four major factors likely accounted for the entire dynamics of COVID-19 in Brazil. Mathematical modeling revealed that, initially, the "super-spreading" city of São Paulo accounted for roughly 80% of the case spread in the entire country. During the first 3 months of the epidemic, by adding only 16 other spreading cities, we accounted for 98-99% of the cases reported in Brazil at the time. Moreover, 26 of the major Brazilian federal highways accounted for about 30% of SARS-CoV-2's case spread. As cases accumulated rapidly in the Brazilian countryside, the distribution of COVID-19 deaths began to correlate with a third parameter: the geographic distribution of the country's hospital intensive care unit (ICU) beds, which is highly skewed towards state capitals where the epidemic began. That meant that severely ill patients living in the countryside had to be transported to state capitals to access ICU beds where they often died, creating a "boomerang effect" that contributed to the skew of the geographic distribution of COVID-19 deaths. Finally, we discovered that the geographic distribution of dengue fever, amounting to more than 3.5 million cases from January 2019 to July 2020, was highly complementary to that of COVID-19. This was confirmed by the identification of significant negative correlations between COVID-19's incidence, infection growth rate, and mortality to the percentage of people with antibody (IgM) levels for dengue fever in each of the country's states. No such correlations were observed when IgM data for chikungunya virus, which is transmitted by the same mosquito vector as dengue, was used. Thus, states in which a large fraction of the population had contracted dengue fever in 2019-2020 reported lower COVID-19 cases and deaths, and took longer to reach exponential community transmission, due to slower SARS-CoV-2 infection growth rates. This inverse correlation between COVID-19 and dengue fever was further observed in a sample of countries around Asia and Latin America, as well as in islands in the Pacific and Indian Oceans. This striking finding raises the intriguing possibility of an immunological cross-reactivity between DENV serotypes and SARS-CoV-2. If proven correct, this hypothesis could mean that dengue infection or immunization with an efficacious and safe dengue vaccine could produce some level of immunological protection for SARS-CoV-2, before a vaccine for SARS-CoV-2 becomes available.

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Section: Discussionmentioning

confidence: 93%

How super-spreader cities, highways, hospital bed availability, and dengue fever influenced the COVID-19 epidemic in Brazil

Nicolelis

Raimundo

Peixoto

et al. 2020

Preprint

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“…Together, these results indicate that TAK-003 stimulates an independent and type-specific DENV2 NAb response in subjects who were seronegative at baseline. In contrast, most subjects developed lower levels of mainly (24,25). At 18 months, overall vaccine efficacy (VE) in individuals seronegative at baseline was 66%.…”

Section: Discussionmentioning

confidence: 99%

“…In preclinical and early clinical studies, the DENV2 component of the vaccine was observed to replicate better than the other three chimeric components (26,27) (28). In people with no pre-existing immunity DENVs, TAK-003 stimulated higher levels of neutralizing antibody to DENV2 compared to the other three serotypes (24,25).…”

Section: Introductionmentioning

confidence: 99%

“…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. This candidate, which has been shown to be safe and immunogenic in phase 1 and 2 trials, is currently being evaluated in a large multicountry phase 3 efficacy trial (24,25). In preclinical and early clinical studies, the DENV2 component of the vaccine was observed to replicate better than the other three chimeric components (26,27) (28).…”

Section: Introductionmentioning

confidence: 99%

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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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“…At present, only one dengue vaccine has been licensed although uptake has been relatively low [34]. A number of other dengue vaccines are also in development, including one that has Phase 3 overall dengue vaccine efficacy results [35,36]. Real-world regulatory experiences to date attest to the critical and almost unique complexities that (dengue) vaccine manufacturers face in relation, but not limited, to differential impacts on dengue 'sero-negatives' vs. 'seropositives' as well as varying vaccine efficacy against dengue serotypes.…”

Section: Introductionmentioning

confidence: 99%

The economic impact and cost-effectiveness of combined vector-control and dengue vaccination strategies in Thailand: results from a dynamic transmission model

2020

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Background and aims Dengue fever is a major public health problem in tropical/subtropical regions. Prior economic analyses have predominantly evaluated either vaccination or vector-control programmes in isolation and do not really consider the incremental benefits and cost-effectiveness of mixed strategies and combination control. We estimated the cost-effectiveness of single and combined approaches in Thailand. Methods The impacts of different control interventions were analysed using a previously published mathematical model of dengue epidemiology and control incorporating seasonality, age structure, consecutive infection, cross protection, immune enhancement and combined vector-host transmission. An economic model was applied to simulation results to estimate the cost-effectiveness of 4 interventions and their various combinations (6 strategies): i) routine vaccination of 1-year olds; ii) chemical vector control strategies targeting adult and larval stages separately; iii) environmental management/ public health education and awareness [EM/ PHEA]). Payer and societal perspectives were considered. The health burden of dengue fever was assessed using disability-adjusted life-years (DALYs) lost. Costs and effects were assessed for 10 years. Costs were discounted at 3% annually and updated to 2013 United States Dollars. Incremental cost-effectiveness analysis was carried out after strategies were rank-ordered by cost, with results presented in a table of incremental analysis. Sensitivity and scenario analyses were undertaken; and the impact and cost-effectiveness of Wolbachia was evaluated in exploratory scenario analyses. Results From the payer and societal perspectives, 2 combination strategies were considered optimal, as all other control strategies were dominated. Vaccination plus adulticide plus EM/ PHEA was deemed cost-effective according to multiple cost-effectiveness criteria. From the PLOS NEGLECTED TROPICAL DISEASES

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Efficacy of a tetravalent dengue vaccine in healthy children aged 4–16 years: a randomised, placebo-controlled, phase 3 trial

Cited by 149 publications

References 26 publications

How super-spreader cities, highways, hospital bed availability, and dengue fever influenced the COVID-19 epidemic in Brazil

How super-spreader cities, highways, hospital bed availability, and dengue fever influenced the COVID-19 epidemic in Brazil

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

The economic impact and cost-effectiveness of combined vector-control and dengue vaccination strategies in Thailand: results from a dynamic transmission model

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