1. Epidemiology and Global Health

Genetic epidemiology of dengue viruses in phase III trials of the CYD tetravalent dengue vaccine and implications for efficacy

  1. Maia A Rabaa  Is a corresponding author
  2. Yves Girerd-Chambaz
  3. Kien Duong Thi Hue
  4. Trung Vu Tuan
  5. Bridget Wills
  6. Matthew Bonaparte
  7. Diane van der Vliet
  8. Edith Langevin
  9. Margarita Cortes
  10. Betzana Zambrano
  11. Corinne Dunod
  12. Anh Wartel-Tram
  13. Nicholas Jackson
  14. Cameron P Simmons  Is a corresponding author
  1. Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Vietnam
  2. University of Oxford, United Kingdom
  3. Sanofi Pasteur, France
  4. Sanofi Pasteur, United States
  5. Sanofi Pasteur, Colombia
  6. Sanofi Pasteur, Uruguay
  7. Sanofi Pasteur, Singapore
  8. Peter Doherty Institute, University of Melbourne, Australia
https://doi.org/10.7554/eLife.24196
Share this article
Cite this article
  1. Maia A Rabaa
  2. Yves Girerd-Chambaz
  3. Kien Duong Thi Hue
  4. Trung Vu Tuan
  5. Bridget Wills
  6. Matthew Bonaparte
  7. Diane van der Vliet
  8. Edith Langevin
  9. Margarita Cortes
  10. Betzana Zambrano
  11. Corinne Dunod
  12. Anh Wartel-Tram
  13. Nicholas Jackson
  14. Cameron P Simmons
(2017)
Genetic epidemiology of dengue viruses in phase III trials of the CYD tetravalent dengue vaccine and implications for efficacy
eLife 6:e24196.
https://doi.org/10.7554/eLife.24196
  2. Download BibTeX
  3. Download .RIS
5 figures, 4 tables and 4 additional files

Figures

Figure 1 with 1 supplement
Download asset Open asset
Sequencing flow chart for samples obtained in CYD-TDV trials.

(A) CYD14, (B) CYD15.

https://doi.org/10.7554/eLife.24196.003
Figure 1—source data 1

Sequence alignment of DENV-1 prM and E genes from CYD-TDV trials.

https://doi.org/10.7554/eLife.24196.005
Figure 1—source data 2

Sequence alignment of DENV-2 prM and E genes from CYD-TDV trials.

https://doi.org/10.7554/eLife.24196.006
Figure 1—source data 3

Sequence alignment of DENV-3 prM and E genes from CYD-TDV trials.

https://doi.org/10.7554/eLife.24196.007
Figure 1—source data 4

Sequence alignment of DENV-4 prM and E genes from CYD-TDV trials.

https://doi.org/10.7554/eLife.24196.008
Figure 1—figure supplement 1
Download asset Open asset
Probability of sequencing success versus viremia.

White boxes show the range and IQR of viremia levels from successful sequencing attempts, grey boxes show the range and IQR of viremia levels from unsuccessful sequencing attempts. (A) DENV-1, (B) …

https://doi.org/10.7554/eLife.24196.004
Figure 2 with 4 supplements
Download asset Open asset
Distribution of DENV serotypes and genotypes sequenced in CYD14 and CYD15 vaccine trials by country.

Numbers in parentheses indicate the total number of samples of each genotype for which complete or partial E gene sequences were obtained.

https://doi.org/10.7554/eLife.24196.009
Figure 2—figure supplement 1
Download asset Open asset
Genotype assignment of DENV-1 E gene sequences obtained from VCD samples in CYD14 and CYD15.

Phylogenetic trees showing the distribution of DENV-1 genotypes for which E genes were sequenced in CYD14 and CYD15 vaccine trials. E gene sequences were aligned with up to five publically available …

https://doi.org/10.7554/eLife.24196.010
Figure 2—figure supplement 2
Download asset Open asset
Genotype assignment of DENV-2 E gene sequences obtained from VCD samples in CYD14 and CYD15.

Phylogenetic trees showing the distribution of DENV-2 genotypes for which E genes were sequenced in CYD14 and CYD15 vaccine trials. E gene sequences were aligned with up to five publically available …

https://doi.org/10.7554/eLife.24196.011
Figure 2—figure supplement 3
Download asset Open asset
Genotype assignment of DENV-3 E gene sequences obtained from VCD samples in CYD14 and CYD15.

Phylogenetic trees showing the distribution of DENV-3 genotypes for which E genes were sequenced in CYD14 and CYD15 vaccine trials. E gene sequences were aligned with up to five publically available …

https://doi.org/10.7554/eLife.24196.012
Figure 2—figure supplement 4
Download asset Open asset
Genotype assignment of DENV-4 E gene sequences obtained from VCD samples in CYD14 and CYD15.

Phylogenetic trees showing the distribution of DENV-4 genotypes for which E genes were sequenced in CYD14 and CYD15 vaccine trials. E gene sequences were aligned with up to five publically available …

https://doi.org/10.7554/eLife.24196.013
Figure 3 with 1 supplement
Download asset Open asset
Average genotype-specific amino acid identity of DENV isolated in CYD-TDV trials compared to the vaccine strain of the corresponding DENV serotype.

Black bars indicate the IQR of the full sample set. Coloured dots show the geographic regions from which each genotype was collected – red: CYD14, maritime SE Asia; blue: CYD14, mainland SE Asia; …

https://doi.org/10.7554/eLife.24196.014
Figure 3—figure supplement 1
Download asset Open asset
Genotype-specific amino acid identity of DENV isolated in CYD-TDV trials compared to the vaccine strain of the corresponding DENV serotype versus vaccine efficacy.

Symbols indicate the intersection of mean amino acid identity to CYD-TDV components and mean genotype-specific vaccine efficacy. Bars on the x-axis indicate the range of pairwise amino acid …

https://doi.org/10.7554/eLife.24196.015
Figure 4 with 6 supplements
Download asset Open asset
Amino acid differences between the DENV-2 E gene vaccine sequence, DENV-2 viruses isolated in CYD14 and CYD15 vaccine trials, and representative subsets of publically available DENV-2 sequences from the vaccine trial sites.

(A) CYD14 DENV-2 phylogeny, (B) CYD15 DENV-2 phylogeny. Coloured tips on the trees show sequences isolated in the CYD-TDV trials (country of origin coloured as indicated in the key) and the vaccine …

https://doi.org/10.7554/eLife.24196.016
Figure 4—figure supplement 1
Download asset Open asset
Amino acid differences between DENV-1 E gene vaccine sequences, DENV-1 viruses isolated in CYD14 vaccine trials, and representative subsets of publically available DENV-1 sequences from the vaccine trial sites.

Coloured tips on the trees show sequences isolated in the CYD14 trial (country of origin coloured as indicated in the key) and the respective vaccine sequence (purple star); grey tips indicate …

https://doi.org/10.7554/eLife.24196.017
Figure 4—figure supplement 2
Download asset Open asset
Amino acid differences between DENV-1 E gene vaccine sequences, DENV-1 viruses isolated in CYD15 vaccine trials, and representative subsets of publically available DENV-1 sequences from the vaccine trial sites.

Coloured tips on the trees show sequences isolated in the CYD15 trial (country of origin coloured as indicated in the key) and the respective vaccine sequence (purple star); grey tips indicate …

https://doi.org/10.7554/eLife.24196.018
Figure 4—figure supplement 3
Download asset Open asset
Amino acid differences between DENV-3 E gene vaccine sequences, DENV-3 viruses isolated in CYD14 vaccine trials, and representative subsets of publically available DENV-3 sequences from the vaccine trial sites.

Coloured tips on the trees show sequences isolated in the CYD14 trial (country of origin coloured as indicated in the key) and the respective vaccine sequence (purple star); grey tips indicate …

https://doi.org/10.7554/eLife.24196.019
Figure 4—figure supplement 4
Download asset Open asset
Amino acid differences between DENV-3 E gene vaccine sequences, DENV-3 viruses isolated in CYD15 vaccine trials, and representative subsets of publically available DENV-3 sequences from the vaccine trial sites.

Coloured tips on the trees show sequences isolated in the CYD15 trial (country of origin coloured as indicated in the key) and the respective vaccine sequence (purple star); grey tips indicate …

https://doi.org/10.7554/eLife.24196.020
Figure 4—figure supplement 5
Download asset Open asset
Amino acid differences between DENV-4 E gene vaccine sequences, DENV-4 viruses isolated in CYD14 vaccine trials, and representative subsets of publically available DENV-4 sequences from the vaccine trial sites.

Coloured tips on the trees show sequences isolated in the CYD14 trial (country of origin coloured as indicated in the key) and the respective vaccine sequence (purple star); grey tips indicate …

https://doi.org/10.7554/eLife.24196.021
Figure 4—figure supplement 6
Download asset Open asset
Amino acid differences between DENV-4 E gene vaccine sequences, DENV-4 viruses isolated in CYD15 vaccine trials, and representative subsets of publically available DENV-4 sequences from the vaccine trial sites.

Coloured tips on the trees show sequences isolated in the CYD15 trial (country of origin coloured as indicated in the key) and the respective vaccine sequence (purple star); grey tips indicate …

https://doi.org/10.7554/eLife.24196.022
Figure 5 with 1 supplement
Download asset Open asset
Sequence conservation between the DENV-2 vaccine component and wild-type DENV-2 viruses at epitope locations targeted by virus neutralising human mAbs.

Amino acid targets for five neutralising human mAbs (Fibriansah et al., 2015b; Rouvinski et al., 2015) are coloured as indicated in the key (top) and compared to the vaccine sequence and wild-type …

https://doi.org/10.7554/eLife.24196.023
Figure 5—figure supplement 1
Download asset Open asset
Sequence conservation between DENV vaccine components and wild-type DENV viruses at epitope locations targeted by virus neutralising human mAbs.

Amino acid targets for neutralising human mAbs (Fibriansah et al., 2014; Cockburn et al., 2012a; Fibriansah et al., 2015a, 2015b; Teoh et al., 2012; Rouvinski et al., 2015; Costin et al., 2013) are …

https://doi.org/10.7554/eLife.24196.024

Tables

Table 1
Observed and imputed efficacy of CYD-TDV in all participants who received ≥1 injection (intention to treat) by serotype and genotype.
https://doi.org/10.7554/eLife.24196.025

CYD dengue vaccine groupControl groupVaccine efficacy
Observed		Vaccine Efficacy with imputation for missing genotype data
CasesPerson-years at riskDensity incidence (95% CI)CasesPerson-years at riskDensity incidence (95% CI)%(95% CI)%(95% CI)
Serotype 163.1(52.7; 71.2)54.7(45.4; 62.3)
Genotype I CYD14CYD15137420.1 (0.1; 0.2)1867960.3 (0.2; 0.4)58.8(18.3; 79.5)57.4(29.7; 74.2)
Genotype IV CYD1440137420.3 (0.2; 0.4)5167960.8 (0.6; 1.0)61.3(41.5; 74.5)53.3(37.2; 65.3)
Genotype V CYD1553270160.2 (0.1; 0.3)76134340.6 (0.4; 0.7)65.3(50.9; 75.7)54.9(40.7; 65.6)
p-value*0.86140.9912
Serotype 239.1(18.9; 54.3)43.0(29.4; 53.9)
American/Asian CYD1548270350.2 (0.1; 0.2)50134610.4 (0.3; 0.5)52.2(28.9; 67.9)50.2(32.6; 63.2)
Asian I CYD14CYD28137660.2 (0.1; 0.3)1468560.2 (0.1; 0.3)0.3(−94.9; 46.6)19.8(−30.0; 49.6)
Cosmopolitan CYD1428137660.2 (0.1; 0.3)2168560.3 (0.2; 0.5)33.8(−18.0; 62.2)43.8(16.1; 62.2)
p-value*0.14690.2493
Serotype 375.1(62.9; 83.3)71.6(63.0; 78.3)
Genotype I CYD14913835<0.1 (0.0; 0.1)1468950.2 (0.1; 0.3)67.9(26.9; 86.6)58.1(25.2; 76.8)
Genotype II CYD14CYD0138350.0 (0.0; 0.0)46895<0.1 (0.0; 0.1)100.0(69.3; 100.0)85.8(41.1; 97.9)
Genotype III CYD14413835<0.1 (0.0; 0.1)768950.1 (0.0; 0.2)71.6(6.1; 92.6)68.4(19.8; 88.4)
Genotype III CYD152327060<0.1 (0.1; 0.1)47134590.3 (0.3; 0.5)75.7(60.5; 85.5)74.2(64.3; 81.4)
Genotype III CYD14 + CYD152740896<0.1 (0.0; 0.1)54203540.3 (0.2; 0.3)75.2(61.0; 84.6)73.7(64.3; 80.8)
p-value*0.37510.2561
Serotype 474.1(61.7; 82.5)76.9(69.5; 82.6)
Genotype I CYD1419138260.1 (0.1; 0.2)1868740.3 (0.2; 0.4)47.4(−0.9; 72.5)58.3(29.9; 75.2)
Genotype II CYD14CYD813826<0.1 (0.0; 0.1)2468740.3 (0.2; 0.5)83.5(64.8; 93.1)83.8(69.3; 91.5)
Genotype II CYD15CYD1127063<0.1 (0.0; 0.1)31134420.2 (0.2; 0.3)82.4(66.0; 91.5)80.8(71.2; 87.3)
Genotype II CYD14 + CYD15CYD1940890<0.1 (0.0; 0.1)55203160.3 (0.2; 0.4)82.9(71.7; 90.1)81.8(74.3; 87.1)
p-value*0.00720.0086

  1. Cases: number of subjects with at least one sequenced symptomatic virologically-confirmed dengue episode during the active phase of follow-up.

    Density incidence: data indicate cases per 100 person-years at risk.

  2. *The p-value was obtained by testing the heterogeneity of genotype distribution between groups (within each serotype) using a Chi2 (or Fisher’s exact test).

    CYD Genotype of the serotype-specific CYD-TDV vaccine component.

Table 2
Observed and imputed efficacy of CYD-TDV for subjects 9 years and older who received ≥1 injection (intention to treat) by serotype and genotype
https://doi.org/10.7554/eLife.24196.026

CYD dengue vaccine groupControl groupVaccine efficacy
Observed		Vaccine Efficacy with imputation for missing genotype data
CasesPerson-years at riskDensity incidence (95% CI)CasesPerson-years at riskDensity incidence (95% CI)%(95% CI)%(95% CI)
Serotype 167.7(56.1; 76.3)58.4(47.7; 66.9)
Genotype I CYD14CYD66683<0.1 (0.0; 0.2)833060.2 (0.1; 0.5)62.8(−6.8; 87.8)69.0(33.8; 85.5)
Genotype IV CYD14866830.1 (0.1; 0.2)1933060.6 (0.3; 0.9)79.2(54.1; 91.4)64.0(39.7; 78.5)
Genotype V CYD1553270160.2 (0.1; 0.3)76134340.6 (0.4; 0.7)65.3(50.9; 75.7)54.9(40.7; 65.6)
p-value*0.52130.5400
Serotype 248.6(27.4; 63.7)47.1(31.3; 59.2)
American/Asian CYD1548270350.2 (0.1; 0.2)50134610.4 (0.3; 0.5)52.2(28.9; 67.9)50.2(32.6; 63.2)
Asian I CYD14CYD1266870.2 (0.1; 0.3)933300.3 (0.1; 0.5)33.6(−62.7; 71.9)34.6(−27.4; 65.7)
Cosmopolitan CYD1456687<0.1 (0.0; 0.2)433300.1 (0.0; 0.3)37.8(−151; 83.5)40.3(−41.4; 74.3)
p-value*0.77360.7253
Serotype 376.0(62.3; 84.7)73.6(64.4; 80.4)
Genotype I CYD1446715<0.1 (0.0; 0.2)633470.2 (0.1; 0.4)66.8(−16.3; 91.5)61.2(−4.1; 86.1)
Genotype II CYD14CYD067150.0 (0.0; 0.1)33347<0.1 (0.0; 0.3)100.0(55.4; 100.0)80.1(7.6; 97.1)
Genotype III CYD1416715<0.1 (0.0; 0.1)23347<0.1 (0.0; 0.2)75.1(−160; 98.8)75.1(−27.4; 96.6)
Genotype III CYD152327060<0.1 (0.1; 0.1)47134590.3 (0.3; 0.5)75.7(60.5; 85.5)74.2(64.3; 81.4)
Genotype III CYD14 + CYD152433775<0.1 (0.0; 0.1)49168060.3 (0.2; 0.4)75.7(60.8; 85.3)74.3(64.7; 81.4)
p-value*0.59280.6985
Serotype 485.2(74.6; 91.4)83.2(76.2; 88.2)
Genotype I CYD1436716<0.1 (0.0; 0.1)1233270.4 (0.2; 0.6)87.6(60.9; 97.2)86.2(63.6; 94.8)
Genotype II CYD14CYD36716<0.1 (0.0; 0.1)1433270.4 (0.2; 0.7)89.4(67.7; 97.6)89.6(70.5; 96.3)
Genotype II CYD15CYD1127063<0.1 (0.0; 0.1)31134420.2 (0.2; 0.3)82.4(66.0; 91.5)80.8(71.2; 87.3)
Genotype II CYD14 + CYD15CYD1433779<0.1 (0.0; 0.1)45167690.3 (0.2; 0.4)84.6(72.6; 91.8)82.6(74.7; 88.1)
p-value*1.00000.6678

  1. Cases: number of subjects with at least one sequenced symptomatic virologically-confirmed dengue episode during the active phase of follow-up.

    Density incidence: data indicate cases per 100 person-years at risk.

  2. *The p-value was obtained by testing the heterogeneity of genotype distribution between groups (within each serotype) using a Chi2 (or Fisher’s exact test).

    CYD Genotype of the serotype-specific CYD-TDV vaccine component.

Table 3
Estimation of the interaction between genotype and vaccine group for symptomatic VCD detected during the active phase of follow-up by serotype in all participants who received >= 1 injection (intention to treat) (CYD14/CYD15).

The estimate of the interaction term between genotype and vaccine group is derived from Cox proportional hazards regression models including the vaccine group, the genotype and the interaction.

https://doi.org/10.7554/eLife.24196.027
Estimated interaction with observed vaccine efficacyEstimated interaction with vaccine efficacy with imputation
SerotypeParameterParameter estimate95%Parameter estimate95%
 Serotype 1Genotype IV vs Genotype I−0.058[−0.858; 0.743]0.095[−0.475; 0.665]
Genotype V vs Genotype I−0.167[−0.936; 0.603]0.067[−0.492; 0.625]
 Serotype 2American/Asian vs Asian I−0.732[−1.486; 0.022]−0.471[−1.032; 0.089]
Cosmopolitan vs Asian I−0.404[−1.259; 0.451]−0.344[−0.966; 0.267]
 Serotype 3Genotype II vs Genotype I−12.748[−729.203; 703.707]−1.079[−2.754; 0.596]
Genotype III vs Genotype I−0.251[−1.208; 0.705]−0.459[−1.116; 0.198]
 Serotype 4Genotype II vs Genotype I−1.114[−1.943; −0.285]−0.8184[−1.434; −0.203]
Table 4
Estimation of the interaction between genotype and vaccine group for symptomatic VCD detected during the active phase of follow-up by serotype in subjects older than 9 years of age who received >= 1 injection (intention to treat) (CYD14/CYD15).

The estimate of the interaction term between genotype and vaccine group is derived from Cox proportional hazards regression models including the vaccine group, the genotype and the interaction.

https://doi.org/10.7554/eLife.24196.028
Estimated interaction with observed vaccine efficacyEstimated interaction with vaccine efficacy with imputation
SerotypeParameterParameter estimate95%Parameter estimate95%
 Serotype 1Genotype IV vs Genotype I−0.574[−1.917; 0.768]0.153[−0.760; 1.066]
Genotype V vs Genotype I−0.061[−1.177; 1.054]0.385[−0.416; 1.186]
 Serotype 2American/Asian vs Asian I−0.327[−1.277; 0.624]−0.270[−0.987; 0.448]
Cosmopolitan vs Asian I−0.064[−1.637; 1.510]−0.089[−1.151; 0.972]
 Serotype 3Genotype II vs Genotype I−13.019[−943.634; 917.597]−0.664[−2.578; 1.250]
Genotype III vs Genotype I−0.309[−1.665; 1.047]−0.405[−1.443; 0.633]
 Serotype 4Genotype II vs Genotype I0.226[−1.174; 1.626]0.244[−0.789; 1.277]

Additional files

Supplementary file 1

(a) Sequencing success rates in samples from virologically confirmed dengue cases in vaccine and control groups from the CYD-TDV trials.

(b) Mean percent identity between E gene amino acid sequences of the relevant serotype-specific CYD-TDV vaccine strain and virus populations sampled in CYD14/15. (c) Number of E gene sequences per genotype per country in CYD-TDV trials versus publicly available sequences on GenBank. I. CYD14, II. CYD15. (1d) Variation in the number of cases, imputed versus observed.

https://doi.org/10.7554/eLife.24196.029
Supplementary file 2

Observed and imputed efficacy of CYD-TDV for subjects less than 9 years of age who received ≥1 injection (intention to treat) by serotype and genotype.

https://doi.org/10.7554/eLife.24196.030
Supplementary file 3

Phred scores indicating sequence quality for all CYD14/15 DENV prM/E sequences.

https://doi.org/10.7554/eLife.24196.031
Transparent reporting form
https://doi.org/10.7554/eLife.24196.032

Download links