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Dengue Vaccine Booster in Healthy Adolescents and Adults in Latin America

Evaluation 4–5 Years After a Primary 3-Dose Schedule

Coronel, Diana, MD*; García-Rivera, Enid J., MD; Rivera, Maribel, MD; Arredondo-García, José Luis, MD§; Dietze, Reynaldo, MD; Perroud, Ana Paula, MD; Cortés, Margarita, MD**; Bonaparte, Matthew, PhD††; Zhao, Jessie, MSc‡‡; Tila, Mihaela, MD§§; Jackson, Nick, PhD§§; Zambrano, Betzana, MD¶¶; Noriega, Fernando, MD††

The Pediatric Infectious Disease Journal: May 2019 - Volume 38 - Issue 5 - p e90–e95
doi: 10.1097/INF.0000000000002286
Vaccine Reports
Free
SDC

Background: The tetravalent dengue vaccine (CYD-TDV, Dengvaxia, Sanofi Pasteur) demonstrated efficacy in 2 previous phase III trials conducted in endemic countries. Neutralizing antibodies (NAbs) elicited by 3 doses of this vaccine have been associated with efficacy. Long-term follow-up data has shown that NAb immune responses tend to wane over time, after the third dose. This study compared the immune response elicited by a booster (4th) dose of CYD-TDV with the immune responses from the same participants obtained post-dose 3 of the primary series administered 4–5 years earlier.

Methods: This multicenter, observer-blind, randomized, placebo-controlled, phase II noninferiority trial was conducted in healthy adolescents and adults in dengue endemic countries of Latin America (Colombia, Honduras, Brazil, Mexico and Puerto Rico). All participants had been immunized with 3 doses of CYD-TDV in phase II studies conducted 4–5 years earlier. NAb levels against each dengue virus serotype 28 days postbooster or placebo injection were reported.

Results: A total of 187 participants received CYD-TDV and 64 received placebo. Prospectively defined noninferiority criteria for dengue NAbs after the booster dose compared with postdose 3 were met for all 4 serotypes. Prospectively defined superiority criteria were met for 3 of the 4 serotypes.

Conclusions: Antidengue NAb levels can be boosted to levels at least as high as, or higher than those observed after completion of the primary 3-dose series, with an additional dose of CYD-TDV 4–5 years after the standard 3-dose vaccination schedule.

From the *Clinical Sciences Sanofi Pasteur, Mexico City, Mexico

School of Medicine, Hospital UPR Carolina, University of Puerto Rico, Puerto Rico

Inversiones en Investigación Médica S.A. INVERIME S.A, Tegucigalpa, Honduras

§Instituto Nacional de Pediatría Clinical Research Unit, Mexico City, Mexico

Universidade Federal do Espirito Santo, Núcleo de Doenças Infecciosas/CBM/UFES, Vitoria, Brazil

Clinical Sciences Sanofi Pasteur, Sao Paulo, Brazil

**Clinical Sciences Sanofi Pasteur, Bogota, Colombia

††Clinical Sciences Sanofi Pasteur, Swiftwater, PA

‡‡Clinical Sciences Sanofi Pasteur, Beijing, China

§§Sanofi, Paris, France

¶¶Clinical Sciences Sanofi Pasteur, Montevideo, Uruguay.

Accepted for publication December 18, 2018.

Sanofi Pasteur sponsored this trial totally.

D.C., A.P.P., M.C., M.B., N.J., B.Z. and F.N. work for Sanofi Pasteur. J.Z. worked for Sanofi Pasteur during the development of the trial. M.T. currently works for Sanofi, Paris, France. E.J.G.-R., M.R., J.L.A.-G. and R.D. were fully sponsored by Sanofi Pasteur for the execution of this trial.

This trial was registered on ClinicalTrials.Gov: NCT02623725.

Address for correspondence: Diana Coronel, MD, Sanofi Pasteur, Av. Universidad 1738, Colonia Coyoacán, Ciudad de México 04000, Mexico. E-mail: dianaLeticia.coronel@sanofi.com.

Dengue disease continues to be a major public health concern. The World Health Organization estimates that 3.9 billion people in 128 countries are at risk of infection with dengue viruses and that there may be 50–100 million dengue infections worldwide every year.1–3 An estimated 500,000 people with severe dengue require hospitalization, a large proportion of whom are children, and about 2.5% of those affected die.1 Vaccination may contribute to control the disease in areas with high burden of disease.4

Until December 2015, the only preventive measures against dengue infection were to rely on mosquito control and personal protection.1 As of April 2018, the CYD dengue vaccine (CYD-TDV, Dengvaxia, Sanofi Pasteur) has been granted marketing authorization in 19 countries in Latin America and Asia. The World Health Organization recently updated the recommendations for implementing immunization with Dengvaxia.5 The efficacy of Sanofi Pasteur’s dengue vaccine was demonstrated in participants 2–16 years of age in 2 long-term phase III studies.6,7 This efficacy was shown to be correlated with post-dose 3 neutralizing antibody (NAb) titers, with high antibody levels being associated with high vaccine efficacy (VE) for all serotypes.8 Long-term follow-up showed a predictable decrease of NAbs against all 4 serotypes 1 year after the third injection, regardless of the age group, which was followed by a trend to stabilization during the subsequent years. However, long-term GMTs for each serotype remained higher than GMT values before vaccination.9 A recent analysis showed that VE was higher among baseline seropositive participants (76%) than in the baseline seronegative ones (39%).10

The aim of this study was to assess the immunogenicity and safety of the CYD-TDV administered as a booster in healthy adolescents and adults who received 3 doses of the vaccine 4–5 years earlier in 2 trials conducted in Colombia, Honduras, Mexico, Puerto Rico and Brazil.11,12 This study specifically assessed the noninferiority of the NAb responses 28 days postbooster vaccination compared with the VE-associated responses 28 days post-third dose of the primary vaccination.

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MATERIALS AND METHODS

Study Design

This was a multicenter, observer-blind, randomized, placebo-controlled, phase II noninferiority trial conducted in healthy adolescents and adults in Brazil, Colombia, Honduras, Mexico and Puerto Rico between April 14, 2016, and November 23, 2016. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation guidelines for good clinical practice,13 as well as with all local and/or national regulations and directives. In addition, each study site’s Institutional Review Board and Independent Ethics Committee approved the study protocol. No protocol amendments occurred. All participants and/or participants’ parents/guardians provided written informed consent before study entry.

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Participants

A total of 251 healthy adolescents and adults (sex ratio male/female 1.15) 15.3–23.8 years of age signed informed consent forms to participate in this trial, out of a total of 372 eligible subjects who had received 3 doses of CYD-TDV (6 months apart) 4–5 years earlier in 2 previous immunogenicity and safety phase II trials in healthy children and adolescents 9 to 16 years of age.11,12 Of these, 98% were dengue seropositive before receiving the booster dose.

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Exclusion Criteria

The exclusion criteria were as follows: (1) previous vaccination against dengue that was not part of the previous mentioned trials; (2) pregnant, lactating or childbearing potential women (to be considered of nonchildbearing potential, a female must be premenarche, surgically sterile or using an effective method of contraception or abstinence from at least 4 weeks before the first vaccination until at least 4 weeks after the last vaccination); (3) participation at any time of study enrollment in another trial; (4) receipt of any vaccine in the 4 weeks preceding the trial vaccination or planned to receive any vaccine in the 4 week following the trial vaccination; (5) use of immune globulins, blood or blood-derived products in the past 3 months; (6) known or suspected congenital or acquired immunodeficiency; (7) use of any immunosuppressive therapy; (8) known systemic hypersensitivity to any of the vaccine components or history of a life-threatening reaction to the vaccines used in the trial or to a vaccine containing any of the same substances; (9) chronic illness that, in the opinion of the Investigator, could interfere with trial conduct or completion; deprivation of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily; current alcohol abuse or drug addiction; moderate or severe acute illness/infection on the day of vaccination or febrile illness (temperature ≥38.0°C); identified as an investigator or employee of the investigator or study center with direct involvement in the proposed study, or any identified immediate family member.

The major exclusion criteria were as follows: previous vaccination against dengue that was not part of the previously mentioned trials; women who were pregnant, lactating or of childbearing potential; participation at any time of study enrollment in another trial; receipt of any vaccine in the 4 weeks preceding the trial vaccination or planned to receive any vaccine in the 4 weeks following the trial vaccination.

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Randomization and Blinding

Participants were randomly assigned to 1 of the 2 study groups (group 1 or group 2) via an interactive voice response system or interactive web response system according to a 3:1 ratio (for every 3 participants included in the dengue vaccine group, another participant was included in the placebo group). A double randomization system was used, where treatment allocation was separated from doses dispensed. Participant numbers were not reassigned for any reason.

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Vaccines

CYD-TDV was presented as a powder and saline solvent (NaCl 0.9%) for reconstitution immediately before use in 0.5 mL volumes containing 4.5–6 log10 cell-culture infectious dose 50% (CCID50) of each live, attenuated, recombinant dengue serotype 1, 2, 3, 4 virus. CYD-TDV was administered subcutaneously in the upper arm. Placebo was presented as NaCl 0.9% solution and administered subcutaneously in the upper arm in 0.5 mL volumes. All participants in group 1 received CYD-TDV, and all those in group 2 received placebo injection at enrollment (day 0).

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Immunogenicity Assessments

All participants provided blood samples at pre-injection to assess baseline dengue serostatus and at 28 days postinjection to assess immunogenicity. NAbs against each of the 4 parental dengue virus strains were measured by 50% plaque reduction neutralization assay (PRNT50)14 in samples obtained 28 days postdose 3 of CYD-TDV, immediately before the booster injection and 28 days postbooster injection. In addition, specific postbooster/prebooster geometric mean titers ratios (GMTRs) for each of the 4 parental dengue virus strains of the CYD-TDV were estimated 28 days postbooster or placebo injection. For immunogenicity, 2-sample t tests on the log10 transformed titers were used for 95% confidence intervals (CI) for the ratio of geometric mean titers (GMTs; difference between GMTs on log scale). Assuming that log10 transformation of the titers/titers ratio followed a normal distribution, the mean and 95% CIs were first calculated on log10 (titers/titers ratio) using the usual calculation for normal distribution, then antilog transformations were applied to the results of calculations, to compute GMTs/GMTRs and their 95% CIs. Seroconversion rates 28 days postbooster, for each of the 4 parental dengue virus strain of CYD-TDV, were defined as the percentage of participants with either a prebooster titer <10 (1/dil) and a postbooster titer ≥40 (1/dil), or a prebooster titer ≥10 (1/dil) and a ≥4-fold increase in postbooster titer as determined by PRNT50.

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Safety and Reactogenicity

Participants were observed for 30 minutes postbooster injection to assess any immediate injection site or systemic adverse events (AEs). Participants or parents/legally acceptable representatives recorded in diary cards information on solicited injection site reactions (pain, erythema and swelling) from day 0 to day 7 postinjection, solicited systemic reactions (fever, headache, malaise, myalgia and asthenia) from day 0 to day 14 postinjection; and unsolicited AEs from day 0 to day 28 postinjection. The intensity of unsolicited AEs was graded using a 3-point scale (grade 1: no interference with activity; grade 2: some interference with activity and grade 3: significant; prevents daily activity) and the action taken for each event, if any (eg, medication, contact healthcare provider and hospitalization). Information on serious and nonserious AEs of special interest was collected in defined time windows according to the type of AEs of special interest [serious hypersensitivity/allergic reactions (within 7 days postvaccination), serious viscerotropic disease and serious neurotropic disease (within 30 days postvaccination) and serious dengue disease requiring hospitalization (at any time of the trial)]. Information on serious AEs (SAEs) was collected throughout the trial. The investigators assessed the causal relationship of each unsolicited systematic AE and all SAEs up to 6 months after the last vaccination and assigned them as either related or unrelated to vaccination.

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Statistical Analysis

With 273 evaluable participants in the CYD-TDV group (group 1), the overall power using paired t test to reject the 4 individual null hypotheses simultaneously was expected to be 88.3%. The calculation assumed a noninferiority margin (delta) = 2, one-sided type I error = 0.025 and correlation between the responses postdose 3 and postbooster dose of the same serotype in the same subject = 0.5. The analysis was performed using the Sponsor’s Biostatistics platform with SAS software, version 9.4 or higher (SAS Institute, Cary, NC). For each serotype, noninferiority was demonstrated if the lower limit of the 2-sided 95% CI was >1/2. After noninferiority was demonstrated, superiority was demonstrated if the lower limit of the 2-sided 95% CI was >1. Analyses for other objectives were descriptive; no hypotheses were tested. For immunogenicity, 2-sample t test on the log10-transformed titers were used for 95% CI for GMTRs (difference between GMTs on log scale). The 95% CIs for percentages were calculated using the exact binomial distribution (Clopper-Pearson method). Assuming that log10 transformation of the titers/titers ratio followed a normal distribution, the mean and 95% CIs were calculated on log10 (titers/ titers ratio) using the usual calculation for normal distribution, then antilog transformations were applied to the results of calculations, to compute GMTs/GMTRs and 95% CIs.

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RESULTS

Of the 372 potentially eligible participants, 251 were contacted and eligible to participate from the previous studies.11,12 After randomization, 187 participants were allocated to the CYD-TDV group (group 1) and 64 participants to the placebo group (group 2). The per-protocol analysis set included 177 participants, and the full analysis set included 185 participants in group 1. Mean age of the participants was 19.1 years (15–23 years). The overall distribution of randomized participants by country and treatment group is summarized in Table 1.

TABLE 1

TABLE 1

Overall, at 28 days postbooster injection, 250 (99.6%) participants remained in the study (ie, one subject from the CYD-TDV group was discontinued for noncompliance), and 249 (99.2%) participants provided a blood sample (ie, 2 participants from the CYD-TDV group did not provide a sample).

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Noninferiority of CYD-TDV Booster Compared With the Third CYD-TDV Dose in Previous Trials

Noninferiority of dengue NAb after CYD-TDV booster dose compared with postdose 3 of CYD-TDV, in terms of dengue PRNT50, was demonstrated for the 4 serotypes (lower limit of 2-sided 95% CI >1/2; Table 2).

TABLE 2

TABLE 2

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Superiority of CYD-TDV Booster Compared With the Third CYD-TDV Dose in Previous Trials

As the overall noninferiority of the CYD-TDV booster was demonstrated, a superiority analysis of the booster dose compared with postdose 3 was performed for each serotype using GMTRs. The superiority of the booster dose was demonstrated for serotypes 1, 2 and 4. The superiority of the booster dose could not be demonstrated for serotype 3 as the lower limit of the 2-sided 95% CI of the GMTR was <1 (Table 3).

TABLE 3

TABLE 3

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Immune Response 28 Days Postbooster Injection

GMTs were similar between treatment groups prebooster. These GMTs for serotypes 1, 2 and 3 tended to be within a similar range, but those for serotype 4 tended to be lower than for other serotypes. After the CYD-TDV booster injection all GMTs increased compared with prebooster injection levels. There was little or no change in GMTs for all serotypes from pre- to postplacebo injection (Table 4).

TABLE 4

TABLE 4

The seroconversion rate 28 days postbooster injection for serotype 1 was 16.9% (95% CI: 11.7%–23.3%) in CYD-TDV group and 3.1% (95% CI: 0.4%–10.8%) in the placebo group; 19.2% (95% CI: 13.7%–25.8%) and 17.2% (95% CI: 8.9%–28.7%) for serotype 2; 20.3% (95% CI: 14.7%–27.0%) and 4.7% (95% CI: 1.0%–13.1%) for serotype 3; 19.8% (95% CI: 14.2%–26.4%) and 6.3% (95% CI: 1.7%–15.2%) for serotype 4, respectively.

A covariance analysis of postbooster titers against each of the 4 serotypes between 2 treatment groups was completed to control for baseline NAb levels, this analysis confirmed that the CYD dengue vaccine increased NAb levels for each serotype, regardless of prebooster titers in each treatment group. Adjusting for baseline serostatus, the CYD-TDV booster achieved a balanced antibody response to all 4 dengue serotypes. The CYD-TDV/placebo GMTRs and associated 95% CIs for each serotype were as follows: serotype 1, ratio 2.04 (95% CI: 1.50–2.78); serotype 2, ratio 1.74 (95% CI: 1.28–2.38); serotype 3, ratio 1.85 (95% CI: 1.37–2.50); and serotype 4, ratio 2.19 (95% CI: 1.53–3.13; Table 5).

TABLE 5

TABLE 5

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Dengue Serostatus at Baseline

The immune response to CYD-TDV booster injection was analyzed according to the serostatus of participants at baseline (prevaccination) in the previous studies.11,12 Among the 177 participants enrolled in the CYD-TDV group, 136 (77%) participants were dengue seropositive at baseline and 41 (23%) were seronegative. In the placebo group, there were 46 (72%) participants dengue-seropositive at baseline and 18 (28%) seronegative. Overall, NAb titers against each serotype postdose 3, prebooster injection and 28 days postbooster injection were higher in participants dengue seropositive at baseline. In group 1, prebooster GMTs (1/dil) ranged from 224 (serotype 4) to 668 (serotype 1) in dengue-seropositive participants and from 29.6 (serotype 1) to 54.9 (serotype 4) in those seronegative. At 28 days postbooster injection, GMTs ranged from 343 (serotype 4) to 940 (serotype 1) in dengue-seropositive participants and from 100 (serotype 1) to 347 (serotype 4) in those seronegative. The D28 (day 28) postbooster/PD3 (postdose 3) GMTRs ranged from 0.817 (serotype 3) to 1.5 (serotype 2) in dengue-seropositive participants. In dengue-seronegative participants, the GMTRs were notably higher, ranging from 2.24 (serotype 3) to 3.45 (serotype 2). The difference (CYD-TDV versus placebo) in the seroconversion rate against each serotype was influenced by baseline dengue serostatus, with higher seroconversion rate differences in dengue-seronegative participants (Table 6).

TABLE 6

TABLE 6

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Safety Evaluations

An overview of the frequency of adverse events following booster with CYD-TDV or placebo is provided in Table 7. Overall, 61.0% of participants in the CYD-TDV group and 48.4% in the placebo group experienced at least one solicited reaction after the booster injection. Among these participants, 8.0% of participants in the CYD-TDV group and 6.3% in the placebo group reported at least one grade 3 solicited reaction; mostly systemic reactions. The 2 treatment groups were comparable in terms of number, intensity, time of onset and duration of solicited reactions. The most frequently reported solicited injection site reaction in both groups was injection site pain (24.6% and 18.8% in the CYD-TDV and placebo groups, respectively). The most frequently reported solicited systemic reaction in both groups was headache [87 (46.5%) and 22 (34.4%) participants in the two groups, respectively]. One SAE was reported and considered not related to vaccination. No AEs or SAEs leading to discontinuation were reported, and no dengue cases were reported. No deaths were reported within 28 days postbooster injection.

TABLE 7

TABLE 7

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DISCUSSION

For each serotype, the postbooster injection/postdose 3 GMTRs in the CYD-TDV group were >1 with corresponding 95% CIs above 0.5 for each serotype, thus fulfilling the overall prespecified noninferiority criteria for the booster. The superiority of the CYD-TDV booster compared with the third CYD-TDV injection was assessed in the full analysis set and was demonstrated for serotypes 1, 2 and 4. According to data from 2 previous pivotal efficacy studies (CYD14 and CYD15) in children and adolescents (2–16 years of age), postimmunization GMT levels against all 4 serotypes tend to naturally decrease during the first 1–2 years postdose 3 compared with levels 28 days postdose 3 but appear to stabilize above baseline or slightly increase in the third year.9 In this study, the prebooster GMTs for serotype 1 and serotype 2 were similar to those achieved postdose 3. Nonetheless, in light of the trend toward decreasing GMT levels, the demonstration that an additional (boosting) dose is able to reestablish antibody levels, at least as high or better than those associated with efficacy against dengue of any severity, is reassuring.8 In the context of the recent findings concerning CYD-TDV efficacy, which is driven by baseline serostatus (higher in baseline seropositive and lower in baseline seronegative),10 and also considering the recent SAGE recommendations published in April 2018,5,15 the use of a booster dose may be of value in subjects that were already exposed to dengue in countries where this vaccine is used, given the correlation of rising NAb titers with efficacy.8

It is also important to highlight that the proportion of participants who were seropositive at baseline (D0 in the previous selected trials)11,12 was comparable between study groups. Participants who were dengue seronegative at baseline (pre-dose 1) had lower GMTs prebooster injection than those dengue seropositive at baseline. This concurs with observations from other CYD-TDV studies.6,7 The difference between dengue-seronegative and dengue-seropositive participants at baseline carries over to their NAb levels 28 days postbooster injection. Indeed, in the CYD-TDV group, GMTs postbooster injection tended to be lower in those dengue seronegative compared with those who were dengue seropositive at baseline. However, it is notable that in participants who were dengue seronegative at baseline, the booster dose provided a much greater increase in the D28 (day 28)/PD3 (postdose 3) GMTRs across all 4 serotypes than in those who were seropositive.

The reactogenicity of the booster injection administered 4–5 years after the 3-dose primary schedule produces similar responses, than in the selected previous trials.11,12

Limitations of this trial included the sample size limited to the participants of the 2 previous trials; the lack of immunologic assays to assess B memory cells and possibility of natural exposure to dengue virus between the last dose of the primary series and the booster dose, which may have an effect on the boosting results observed. Another important limitation is that this study was not designed to evaluate clinical outcomes, so that it is not possible to fully understand the implications of the immunogenicity observations. These results are presented while waiting for follow-up study data and the results from a similar study conducted in Asia, as well as another study that is currently evaluating more proximal boosting. Long-term follow-up efficacy data in the large efficacy studies would be needed to better inform the potential role of booster injections with the CYD-TDV vaccine.

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ACKNOWLEDGMENTS

A special acknowledgment for Luis Ángel Villar, MD, who conducted and provided the data for the CYD64 trial from the site Centro de Atención y Diagnóstico de Enfermedades Infecciosas, CDI, Barranquilla, Colombia.

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REFERENCES

1. World Health Organization. Dengue and severe dengue fact sheet. Updated April 2017. Available at: http://wwwwhoint/mediacentre/factsheets/fs117/en/. Accessed May 29, 2018.
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3. Jentes ES, Lash RR, Johansson MA, et al. Evidence-based risk assessment and communication: a new global dengue-risk map for travellers and clinicians. J Travel Med 2016; 23:taw062.
4. World Health Organization. Guidelines on the quality, safety and efficacy of dengue tetravalent vaccines (live, attenuated). WHO Expert Committee on Biological Standardization. WHO Technical Report Series No. 979, 2013. Annex 2. Available at: http://www.who.int/biologicals/areas/vaccines/TRS_979_Annex_2.pdf. Accessed May 29, 2018.
5. World Health Organization. Revised SAGE recommendation on use of dengue vaccine. Available at: http://www.who.int/immunization/diseases/dengue/revised_SAGE_recommendations_dengue_vaccines_apr2018/en/. Accessed May 29, 2018.
6. Capeding MR, Tran NH, Hadinegoro SR, et al; CYD14 Study Group. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet. 2014;384:1358–1365.
7. Villar L, Dayan GH, Arredondo-García JL, et al; CYD15 Study Group. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med. 2015;372:113–123.
8. Moodie Z, Juraska M, Huang Y, et al. Neutralizing antibody correlates analysis of tetravalent dengue vaccine efficacy trials in Asia and Latin America. J Infect Dis. 2018;217:742–753.
9. Vigne C, Dupuy M, Richetin A, et al. Integrated immunogenicity analysis of a tetravalent dengue vaccine up to 4 y after vaccination. Hum Vaccin Immunother. 2017;13:2004–2016.
10. Sridhar S, Luedtke A, Langevin E, et al. Effect of dengue serostatus on dengue vaccine safety and efficacy. N Engl J Med. 2018;379:327–340.
11. Dayan GH, Garbes P, Noriega F, et al. Immunogenicity and safety of a recombinant tetravalent dengue vaccine in children and adolescents ages 9-16 years in Brazil. Am J Trop Med Hyg. 2013;89:1058–1065.
12. Villar LÁ, Rivera-Medina DM, Arredondo-García JL, et al. Safety and immunogenicity of a recombinant tetravalent dengue vaccine in 9-16 year olds: a randomized, controlled, phase II trial in Latin America. Pediatr Infect Dis J. 2013;32:1102–1109.
13. International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceutical for Human Use. ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R1). Available at: https://wwwichorg/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guidelinepdf. Accessed May 29, 2018.
14. Timiryasova TM, Bonaparte MI, Luo P, et al. Optimization and validation of a plaque reduction neutralization test for the detection of neutralizing antibodies to four serotypes of dengue virus used in support of dengue vaccine development. Am J Trop Med Hyg. 2013;88:962–970.
15. World Health Organization. Dengue vaccine: WHO position paper – September 2018. Wkly Epidemiol Rec. 2018:93; 457–476.
Keywords:

dengue; vaccine; booster; neutralizing antibodies; immunogenicity

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