1. Epidemiology and Global Health
Download icon

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
Research Article
Cite this article as: eLife 2017;6:e24196 doi: 10.7554/eLife.24196
5 figures, 4 tables and 4 additional files

Figures

Figure 1 with 1 supplement
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
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) DENV-2, (C) DENV-3, (D) DENV-4.

https://doi.org/10.7554/eLife.24196.004
Figure 2 with 4 supplements
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
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 reference sequences of every known human DENV-1 genotype and a maximum likelihood phylogeny was constructed. Genotypes were assigned when sequences fell into a known genotype lineage with high bootstrap support. Bootstrap support values for nodes > 75% are indicated. Black dots at the tips indicate CYD14 sequences, grey dots indicate CYD15 sequences, and purple stars indicate the DENV CYD-TDV vaccine sequence for each serotype.

https://doi.org/10.7554/eLife.24196.010
Figure 2—figure supplement 2
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 reference sequences of every known human DENV-2 genotype and a maximum likelihood phylogeny was constructed. Genotypes were assigned when sequences fell into a known genotype lineage with high bootstrap support. Bootstrap support values for nodes > 75% are indicated. Black dots at the tips indicate CYD14 sequences, grey dots indicate CYD15 sequences, and purple stars indicate the DENV CYD-TDV vaccine sequence for each serotype.

https://doi.org/10.7554/eLife.24196.011
Figure 2—figure supplement 3
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 reference sequences of every known human DENV-3 genotype and a maximum likelihood phylogeny was constructed. Genotypes were assigned when sequences fell into a known genotype lineage with high bootstrap support. Bootstrap support values for nodes > 75% are indicated. Black dots at the tips indicate CYD14 sequences, grey dots indicate CYD15 sequences, and purple stars indicate the DENV CYD-TDV vaccine sequence for each serotype.

https://doi.org/10.7554/eLife.24196.012
Figure 2—figure supplement 4
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 reference sequences of every known human DENV-5 genotype and a maximum likelihood phylogeny was constructed. Genotypes were assigned when sequences fell into a known genotype lineage with high bootstrap support. Bootstrap support values for nodes > 75% are indicated. Black dots at the tips indicate CYD14 sequences, grey dots indicate CYD15 sequences, and purple stars indicate the DENV CYD-TDV vaccine sequence for each serotype.

https://doi.org/10.7554/eLife.24196.013
Figure 3 with 1 supplement
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; grey: CYD15, Americas. Black dots indicate the genotype of the serotype-specific CYD-TDV vaccine component.

https://doi.org/10.7554/eLife.24196.014
Figure 3—figure supplement 1
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 identities of DENV isolated in the trials compared to the CYD-TDV component. Bars on the y-axis indicate the 95% confidence intervals calculated for vaccine efficacy estimates. DENV-1 genotypes are shown in red, DENV-2 in yellow, DENV-3 in aqua, DENV-4 in blue. (A) Mean amino acid identity versus observed vaccine efficacy across all age groups. (B) Mean amino acid identity versus imputed vaccine efficacy across all age groups. (C) Mean amino acid identity versus observed vaccine efficacy in subjects ≥ 9 years of age. (D) Mean amino acid identity versus imputed vaccine efficacy in subjects ≥ 9 years of age.

https://doi.org/10.7554/eLife.24196.015
Figure 4 with 6 supplements
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 sequence (purple star); grey tips indicate publicly available sequences isolated from other studies in the countries of interest. Columns to the right indicate amino acid sites at which variation was observed in two or more CYD14/CYD15 sequences. Numbers at the top of columns indicate the amino acid site within the E gene. Bars at the top of the figures indicate the E gene domain of the site. Amino acids at variable sites in the E gene sequence of the vaccine component are shown in colour. For all other sequences, a lack of colour indicates an amino acid identical to that of the vaccine component at that site.

https://doi.org/10.7554/eLife.24196.016
Figure 4—figure supplement 1
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 publicly available sequences isolated from other studies in the countries of interest. Columns to the right indicate amino acid sites at which variation was observed in two or more CYD14 sequences. Numbers at the top of columns indicate the amino acid site within the E gene. Bars at the top of the figures indicate the E gene domain of the site. Amino acids at variable sites in the E gene sequence of the vaccine component are shown in colour. For all other sequences, a lack of colour indicates an amino acid identical to that of the vaccine component at that site.

https://doi.org/10.7554/eLife.24196.017
Figure 4—figure supplement 2
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 publicly available sequences isolated from other studies in the countries of interest. Columns to the right indicate amino acid sites at which variation was observed in two or more CYD15 sequences. Numbers at the top of columns indicate the amino acid site within the E gene. Bars at the top of the figures indicate the E gene domain of the site. Amino acids at variable sites in the E gene sequence of the vaccine component are shown in colour. For all other sequences, a lack of colour indicates an amino acid identical to that of the vaccine component at that site.

https://doi.org/10.7554/eLife.24196.018
Figure 4—figure supplement 3
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 publicly available sequences isolated from other studies in the countries of interest. Columns to the right indicate amino acid sites at which variation was observed in two or more CYD14 sequences. Numbers at the top of columns indicate the amino acid site within the E gene. Bars at the top of the figures indicate the E gene domain of the site. Amino acids at variable sites in the E gene sequence of the vaccine component are shown in colour. For all other sequences, a lack of colour indicates an amino acid identical to that of the vaccine component at that site.

https://doi.org/10.7554/eLife.24196.019
Figure 4—figure supplement 4
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 publicly available sequences isolated from other studies in the countries of interest. Columns to the right indicate amino acid sites at which variation was observed in two or more CYD15 sequences. Numbers at the top of columns indicate the amino acid site within the E gene. Bars at the top of the figures indicate the E gene domain of the site. Amino acids at variable sites in the E gene sequence of the vaccine component are shown in colour. For all other sequences, a lack of colour indicates an amino acid identical to that of the vaccine component at that site.

https://doi.org/10.7554/eLife.24196.020
Figure 4—figure supplement 5
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 publicly available sequences isolated from other studies in the countries of interest. Columns to the right indicate amino acid sites at which variation was observed in two or more CYD14 sequences. Numbers at the top of columns indicate the amino acid site within the E gene. Bars at the top of the figures indicate the E gene domain of the site. Amino acids at variable sites in the E gene sequence of the vaccine component are shown in colour. For all other sequences, a lack of colour indicates an amino acid identical to that of the vaccine component at that site.

https://doi.org/10.7554/eLife.24196.021
Figure 4—figure supplement 6
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 publicly available sequences isolated from other studies in the countries of interest. Columns to the right indicate amino acid sites at which variation was observed in two or more CYD15 sequences. Numbers at the top of columns indicate the amino acid site within the E gene. Bars at the top of the figures indicate the E gene domain of the site. Amino acids at variable sites in the E gene sequence of the vaccine component are shown in colour. For all other sequences, a lack of colour indicates an amino acid identical to that of the vaccine component at that site.

https://doi.org/10.7554/eLife.24196.022
Figure 5 with 1 supplement
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 sequences obtained within the CYD14 and CYD15 trials (middle), as well as complete E gene sequences from wild-type DENV-2 available on GenBank (bottom). Sites are indicated at the top of columns. For wild-type virus populations, the darker the block, the greater the proportion of sequences with an amino acid differing from the target amino acid at that site. When disagreement between amino acids was observed between epitope targets (as at E67 and E71), wild-type sequences were compared to 2D22 as a reference, denoted by an asterisk.

https://doi.org/10.7554/eLife.24196.023
Figure 5—figure supplement 1
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 coloured as indicated in the key (top) and compared to the vaccine sequence and wild-type sequences obtained within the CYD14 and CYD15 trials (middle), as well as complete E gene sequences from wild-type DENV available on GenBank (bottom, numbers in parentheses indicate the number of sequences used for comparison). Sites are indicated at the top of columns. For wild-type virus populations, the darker the block, the greater the proportion of sequences with an amino acid differing from the target amino acid at that site.

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

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)