# The Impact of Serotype Cross-Protection on Vaccine Trials: DENVax as a Case Study

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## Abstract

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## 1. Introduction

## 2. Results

## 3. Discussion

## 4. Materials and Methods

#### 4.1. Linear Infection Model

#### 4.2. Modeling Vaccine Trials with the Linear Infection Model

## 5. Bayesian Analysis

## Author Contributions

## Funding

## Acknowledgments

## Conflicts of Interest

## References

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**Figure 1.**Bayesian estimate of DENVax vaccine efficacies (VE) against virologically confirmed dengue for the first 12-month surveillance (part 1). In (

**a**) DEN3 serotype-specific vaccine efficacy by serostatus. Red and blue curves show our estimates for the seronegative and seropositive individuals, respectively. In (

**b**) serotype-specific VE estimations. The raw data used to estimate the distribution by dengue serotype for individuals aged 4–16 years old was obtained in [9] and are shown in Table 1. High vaccine efficacy for dengue serotype 2 and intermediate to low vaccine efficacy for the other serotypes are observed.

**Figure 2.**Bayesian estimates comparison of DENVax vaccine efficacies (VE) against virologically confirmed dengue cases. Yellow and light blue curves show the estimates for the first 12 months (part 1) and the 18 months (part 2) surveillance, respectively. In (

**a**) overall VE estimations for all serotypes, in (

**b**) VE estimation for seronegative individuals and in (

**c**) VE estimations for seropositive individuals. Data from Table 1 and Table 2, in good agreement with results reported in [9,10], are used to estimate the distribution by dengue serotype and serostatus for individuals aged 4–16 years old. Vaccine efficacy is decreasing over time.

**Figure 3.**Bayesian estimate of vaccine efficacies (VE) against virologically confirmed dengue. In (

**a**) serotype-specific VE for Dengvaxia, Sanofi Pasteur. The raw data used for VE estimation by dengue serotype for individuals aged 9 years and older was obtained in [8]. In (

**b**) serotype-specific VE for DENVax, Takeda. The raw data used to estimate the VE by dengue serotype for individuals aged 4–16 years old was obtained in [10] and are shown in Table 2.

**Table 1.**Compilation of vaccine efficacies estimation for Takeda’s DENVax vaccine phase 3 trial post-vaccination surveillance period part 1 (12 months). Section A shows the vaccine efficacies by serostatus and serotype, and Section B shows the overall vaccine efficacy by serotype. Highlighting problems observed for serotypes 3 (blue) and 4 (grey) are indicated. The raw data used for the Bayesian analysis are available in [9].

Part 1 Efficacy Data of the TAK-003 Phase 3 Trial | |||||||||
---|---|---|---|---|---|---|---|---|---|

section A | section B | ||||||||

Seropositive at baseline (82.2%) | Seronegative at baseline (74.9%) | Overall (seropositive and seronegative) | |||||||

vaccine efficacy | |||||||||

Dengue Serotype | Vaccinated | Control | Estimated vaccine | Vaccinated | Control | Estimated Vaccine | Vaccinated | Control | Estimated vaccine |

($n=9167$) | ($n=4589$) | efficacy and 95% | ($n=3531$) | ($n=1726$) | efficacy and 95% | ($n=$ 12,700) | ($n=6316$) | efficacy and 95% | |

Dengue cases | Dengue cases | Confidence Interval | Dengue cases | Dengue cases | Confidence Interval | Dengue cases | Dengue cases | Confidence Interval | |

ALL | 41 | 110 | $81.4\%$ | 20 | 39 | $74.8\%$ | 61 | 149 | $79.7\%$ |

[$73.6\%,87.1\%$] | [$57.4\%,85.4\%$] | [$72.8\%,85.1\%$] | |||||||

$DEN1$ | 7 | 17 | $78.9\%$ | 9 | 13 | $65.9\%$ | 16 | 30 | $73.2\%$ |

[$51.8\%,91.4\%$] | [$22.2\%,85.8\%$] | [$52.2\%,85.4\%$] | |||||||

$DEN2$ | 3 | 42 | $96.2\%$ | 0 | 22 | $100\%$ | 3 | 64 | $97.5\%$ |

[$89.9\%,98.8\%$] | [$93.6\%,99.3\%$] | ||||||||

$DEN3$ | 28 | 47 | $70.0\%$ | 11 | 4 | $\mathbf{-}\mathbf{31.2}\mathbf{\%}$ | 39 | 51 | $61.9\%$ |

[$52.6\%,81.4\%$] | [$\mathbf{-}\mathbf{353.2}\mathbf{\%}\mathbf{,}\mathbf{53.8}\mathbf{\%}$] | [$42.4\%,75.8\%$] | |||||||

$DEN4$ | 3 | 4 | $\mathbf{61.9}\mathbf{\%}$ | 0 | 0 | inconclusive | 3 | 4 | $\mathbf{61.9}\mathbf{\%}$ |

[$\mathbf{-}\mathbf{63.2}\mathbf{\%}\mathbf{,}\mathbf{91.9}\mathbf{\%}$] | [$\mathbf{-}\mathbf{62.4}\mathbf{\%}\mathbf{,}\mathbf{91}.\mathbf{9}\mathbf{\%}$] |

**Table 2.**Compilation of vaccine efficacies estimation for Takeda’s DENVax vaccine phase 3 trial post-vaccination surveillance period part 2 (18 months). Section A shows the vaccine efficacies by serostatus and serotype, and Section B shows the overall vaccine efficacy by serotype. Highlighting problems observed for serotypes 3 (blue) and 4 (grey) are indicated. The raw data used for the Bayesian analysis are available in [10].

Part 2 Efficacy Data of the TAK-003 Phase 3 Trial | |||||||||
---|---|---|---|---|---|---|---|---|---|

section A | section B | ||||||||

Seropositive at baseline (82.2%) | Seronegative at baseline (74.9%) | Overall (seropositive and seronegative) | |||||||

vaccine efficacy | |||||||||

Dengue Serotype | Vaccinated | Control | Estimated vaccine | Vaccinated | Control | Estimated Vaccine | Vaccinated | Control | Estimated vaccine |

($n=9167$) | ($n=4589$) | efficacy and 95% | ($n=3531$) | ($n=1726$) | efficacy and 95% | ($n=$ 12,700) | ($n=6316$) | efficacy and 95% | |

Dengue cases | Dengue cases | Confidence Interval | Dengue cases | Dengue cases | Confidence Interval | Dengue cases | Dengue cases | Confidence Interval | |

ALL | 75 | 150 | $75.8\%$ | 39 | 56 | $66.1\%$ | 114 | 206 | $72.5\%$ |

[$67.2\%,81.0\%$] | [$48.9\%,77.3\%$] | [$65.6\%,78.1\%$] | |||||||

$DEN1$ | 21 | 37 | $71.2\%$ | 17 | 25 | $66.7\%$ | 38 | 62 | $69.4\%$ |

[$51.8\%,83.3\%$] | [$39.2\%,82.1\%$] | [$54.6\%,79.7\%$] | |||||||

$DEN2$ | 7 | 54 | $93.2\%$ | 1 | 26 | $97.7\%$ | 8 | 80 | $94.6\%$ |

[$91.1\%,97.1\%$] | [$90.7\%,99.7\%$] | [$90.3\%,97.7\%$] | |||||||

$DEN3$ | 43 | 54 | $60.3\%$ | 20 | 6 | $\mathbf{-}\mathbf{59.9}\mathbf{\%}$ | 63 | 60 | $47.7\%$ |

[$40.6\%,73.2\%$] | [$\mathbf{-}\mathbf{328.5}\mathbf{\%}\mathbf{,}\mathbf{31.1}\mathbf{\%}$] | [$25.4\%,63.1\%$] | |||||||

$DEN4$ | 4 | 5 | $\mathbf{59.5}\mathbf{\%}$ | 1 | 0 | inconclusive | 5 | 5 | $\mathbf{50.1}\mathbf{\%}$ |

[$\mathbf{-}\mathbf{47.2}\mathbf{\%}\mathbf{,}\mathbf{89.4}\mathbf{\%}$] | [$\mathbf{-}\mathbf{72.5}\mathbf{\%}\mathbf{,}\mathbf{85.4}\mathbf{\%}$] |

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**MDPI and ACS Style**

Aguiar, M.; Stollenwerk, N.
The Impact of Serotype Cross-Protection on Vaccine Trials: DENVax as a Case Study. *Vaccines* **2020**, *8*, 674.
https://doi.org/10.3390/vaccines8040674

**AMA Style**

Aguiar M, Stollenwerk N.
The Impact of Serotype Cross-Protection on Vaccine Trials: DENVax as a Case Study. *Vaccines*. 2020; 8(4):674.
https://doi.org/10.3390/vaccines8040674

**Chicago/Turabian Style**

Aguiar, Maíra, and Nico Stollenwerk.
2020. "The Impact of Serotype Cross-Protection on Vaccine Trials: DENVax as a Case Study" *Vaccines* 8, no. 4: 674.
https://doi.org/10.3390/vaccines8040674