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Immunogenicity and Safety of Yellow Fever Vaccine (Stamaril) When Administered Concomitantly With a Tetravalent Dengue Vaccine Candidate in Healthy Toddlers at 12–13 Months of Age in Colombia and Peru

A Randomized Trial

López, Pio MD; Lanata, Claudio F. MD; Zambrano, Betzana MD; Cortés, Margarita MD; Andrade, Teresa MD; Amemiya, Isabel MD; Terrones, Cynthia MD; Gil, Ana I. MSc; Verastegui, Hector; Marquez, Viviana; Crevat, Denis MD; Jezorwski, John MS; Noriega, Fernando MD

Author Information
The Pediatric Infectious Disease Journal: October 2016 - Volume 35 - Issue 10 - p 1140-1147
doi: 10.1097/INF.0000000000001250


Dengue and yellow fever (YF) viruses are closely related members of the Flaviviridae family. Both these viruses co-circulate in a number of countries in Latin America.1 There are 4 dengue serotypes (serotypes 1–4) and all are known to circulate in the region.2 Moreover, dengue in Latin America is generally transmitted by Aedes aegypti mosquitoes3 and the same vector is also responsible for the transmission of “urban” YF along with Haemagogus spp for “sylvan” or “jungle” YF and to lesser extent Sabethes chloropterus and possibly Aedes fulvus.4 The global burden of illness associated with YF is estimated at 200,000 cases annually, resulting in some 30,000 deaths.5 Of these estimated number of YF cases, about 10% occurred in Latin America, and although endemic in several countries, the vast majority (95%) were mainly reported in only 4 countries: Peru, Bolivia, Brazil and Colombia. In 1995, Peru experienced the largest outbreak of YF in South America in 40 years with 449 cases reported.6,7 Resurgence of the disease in Brazil during the late 1990s and emergence in the early 2000s in areas previously not considered at risk, prompted mass vaccination campaigns.8 In comparison, dengue is an escalating public health concern in Latin America with over 2.3 million cases of dengue and an estimated 1280 associated deaths reported in the World Health Organization Americas region alone in 2013.2

YF vaccines are available and are included as part of the routine childhood vaccination schedule (from 9 to 15 months of age) in Latin American countries with YF endemicity.7 A recombinant, live, attenuated, tetravalent (serotypes 1–4) dengue vaccine (CYD-TDV) candidate has already undergone extensive clinical assessment,9–16 and has also been assessed in 2 phase III studies.17,18 Longer term follow-up of participants in these 2 latter studies is currently on going to better define vaccine efficacy and safety.19 Introducing any new vaccine into the childhood national immunization schedules, particularly during the first 2 years of life, can be challenging given the number of vaccines already scheduled. As there is the potential for any vaccine to interfere with another vaccine when administered together, given the inherent similarities between the YF vaccine and CYD-TDV,15 cross-reactive immune responses could occur and possibly affect the immunogenicity and safety of either vaccine.

This trial was conducted to demonstrate the noninferiority of the immune response against the YF vaccine in Flavivirus (FV) seronegative toddlers when administered concomitantly with CYD-TDV compared with those receiving the YF vaccine concomitantly with placebo, and to assess the antibody response to both vaccines, as well as to describe their safety profiles.


Study Design and Participants

This was a randomized, observer-blind, controlled, multicenter, phase III trial conducted in 792 toddlers in Colombia and Peru between September 7, 2011 and September 2, 2013. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and the International Conference on the Harmonization-Good Clinical Practice. The study was approved by each study site’s independent ethics committee, and written informed consent was obtained from all participants’ parents/guardians before study entry. The trial was registered at (identifier NCT01436396).

Eligible participants were toddlers aged 12 months (or up to the first day of the 13th month after birth) in good health and who were born at full term (≥37 weeks pregnancy) with a birth weight ≥2.5 kg. The toddlers had to have received all vaccinations in the national immunization schedule, with the exception of the seasonal influenza vaccine. Participants were excluded if they had previous history of YF or dengue infection or if they had previous vaccinations against YF (including previous maternal vaccination against YF), measles, mumps, rubella and hepatitis A. Other exclusion criteria included: known or suspected congenital or acquired immunodeficiency; receipt of blood or blood-derived products in the past 3 months, which might interfere with assessment of the immune response; receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding 6 weeks, or long-term systemic corticosteroid therapy (for more than 2 consecutive weeks within the previous 3 months); seropositivity to human immunodeficiency virus; history of central nervous system disorder or disease, including seizures; thrombocytopenia, bleeding disorders or receipt of anticoagulants in the 3 weeks preceding inclusion; and known systemic hypersensitivity to any of the components of the vaccines.

To allow for a cautious, stepwise approach to vaccine administration, a blinded early safety data review was performed, after the first vaccination of the first 40 participants (20 participants in each group). Study recruitment was paused while safety data were summarized and reviewed by the Sponsor. The decision taken by the Sponsor to continue the vaccinations was communicated to the Investigators and was sent to the institutional review board and local ethics committee. Hospitalized dengue cases were reviewed by an Independent Data Monitoring Committee for severity assessment.

Random Assignment and Blinding

An interactive voice recognition system or interactive web response system (IVRS/IWRS) was used to assign participants an enrollment number and for random allocation in a 1:1 ratio to 2 study groups using permuted block randomization (blocks of 4) stratified by center. Both treatment allocation and dose numbers were randomized, thereby ensuring that dose numbers could not be used to distinguish between treatment groups. A designated, unblinded staff member at each site not involved in data collection or safety assessments (ie, observer blind) used the centralized interactive voice recognition system or interactive web response system to obtain the product code assigned, reconstituted the vaccine, and administered the assigned vaccine or placebo.

Vaccination and Vaccines

YF vaccine (Stamaril; Sanofi Pasteur S.A., France) was supplied as powder and solvent for suspension for injection. Each 0.5 mL injection of reconstituted vaccine contained 1000 LD50 units of the virus. The solvent consisted of NaCl 0.4%. CYD-TDV (Sanofi Pasteur S.A., France) was supplied as powder and solvent for suspension for injection. Each 0.5 mL injection of reconstituted vaccine contained 5 ± 1 log10 cell-culture infectious dose 50% of each attenuated, recombinant dengue serotypes 1, 2, 3 and 4 viruses. The solvent consisted of NaCl 0.4%. The placebo was 0.5 mL injection of NaCl 0.9%.

Group 1 received the YF vaccine and the first CYD-TDV injection at enrollment (M0), followed by the second and third CYD-TDV injections after 6 (M6) and 12 (M12) months (ie, at 18 and 24 months of age). Group 2 received the YF vaccine and a placebo at enrollment (M0), followed by the first and second CYD-TDV injection at M6 and M12, respectively.

The YF vaccine, CYD-TDV and placebo vaccines were administered as subcutaneous injections in the deltoid region of the upper arm; at M0 the vaccine(s) or placebo were administered in opposite arms. Toddlers also received the Measles, Mumps, and Rubella (MMR) vaccine and pneumococcal conjugated vaccine in their national immunization schedule 1 month after the first set of study injections (M1, at 13 to 14 months of age). Because there were slight differences in the official vaccination calendars for other vaccines between the 2 countries, to offer an equal benefit to all participants in the trial, the following vaccines were also offered to all participants: hepatitis A vaccine 1 month after the first set of study injections (M1); a pentavalent vaccine for diphtheria, tetanus, acellular pertussis, polio and Haemophilus influenzae type b (DTaP-inactivated poliovirus vaccine//Hib) 1 month after the second study injections (M7, at 19 to 20 months of age); and a hepatitis A vaccine 1 month after the third study injections (M13, at 25 to 26 months of age). No safety or immunogenicity was recorded for the MMR, pneumococcal conjugated, hepatitis A or DTaP-inactivated poliovirus vaccine//Hib vaccines.


All participants provided 1 blood sample (3 mL) before the first vaccination for assessment of baseline FV immune status (YF and dengue) and 1 blood sample (3 mL) 28 days after the first set of study injections for assessment of YF neutralizing antibodies titers. In participants who received CYD-TDV injections, blood samples (3 mL) were also obtained 28 days after the second and third set of study injections for assessment of dengue neutralizing antibody titers. YF and dengue neutralizing antibody titers were determined using a 50% plaque reduction neutralization test (PRNT50) with constant challenge doses of YF virus and parental dengue virus strains of CYD-TDV constructs, respectively, as described elsewhere.14 Both assays had a lower limit of quantitation titer of 10 (1/dil). A threshold titer of 10 (1/dil) was used to assess the immunogenic response to both vaccines; for YF, titers above this threshold were considered as seroconverted.

Safety and Reactogenicity

Participants were kept under observation for 30 min after each trial vaccination to assess the occurrence of any immediate adverse events/reactions. Parents/guardians were provided with rulers, digital thermometers, and diary cards to record daily temperature and any solicited local injection site reactions (tenderness, redness and swelling) during the 7-day period after each study vaccination, and systemic symptoms (fever, vomiting, abnormal crying, drowsiness, loss of appetite and irritability) for 14 days. Parents/guardians also recorded the use of medication to alleviate symptoms or action taken (eg, contact with health-care provider for prescription or hospitalization). Parents/guardians also graded the intensity of subjective solicited reactions and unsolicited adverse reactions using a 3-point grading scale of increasing severity (grades 1–3) previously described.20 Measurable adverse reactions of erythema, swelling and fever were also graded using the same scale of increasing severity during statistical analysis as previously described.21 Occurrence of unsolicited (ie, spontaneously reported) nonserious adverse events were recorded for up to 28 days after each injection. The study investigators assessed the causal relationship of each unsolicited systematic adverse event to vaccination as either unrelated or related. Serious adverse events were recorded throughout the trial and up to 6 months after the last vaccination, and assessed for causal relationship to vaccination by the study investigators.

Adverse events of special interest monitored were hypersensitivity/allergic reactions within 7 days of injection, viscerotropic or neurotropic disease reported as a serious adverse event within 30 days after the injection, and suspected serious dengue disease at any time during the study. Suspected serious dengue disease was defined as an acute febrile illness (temperature ≥38°C) on at least 2 consecutive days and with sign(s) of severity requiring hospitalization. In such cases, 2 blood samples were collected: an acute sample (0–5 days after fever onset) and a convalescent sample (7–14 days after the acute sample). Virological confirmation of dengue was defined as detection of wild type dengue virus by NS1 antigen enzyme-linked immunosorbent assay and/or amplified genomic sequences by reverse transcription polymerase chain reaction.

Sample Size Determination and Statistical Analyses

The primary objective of this study was to test the noninferiority of the antibody response (in terms of seroconversion rates) against YF in toddlers receiving 1 injection of YF vaccine administered concomitantly with the first injection of CYD-TDV compared with those receiving the YF vaccine administered concomitantly with placebo, assuming a noninferiority delta margin (clinically significant difference) of 10%. Based on simulations using the Wilson score method (without continuity correction) and, assuming a 15% drop out rate, an alpha = 2.5% (1 sided), a seroconversion rate of 80%22 and a 90% power, then a total of 792 participants (396 per group) would need to be enrolled (336 per group evaluable).

A noninferiority test was performed using the 95% 2-sided confidence interval of the difference in the YF seroconversion rates 28 days after vaccination between the 2 groups in participants who were FV seronegative at baseline. The 95% CI was calculated based on the Wilson score method without continuity correction as described by Newcombe and colleagues.23 Noninferiority was demonstrated if the lower limit of the 2-sided 95% CI was greater than −10%.

The primary immunogenicity analyses were performed on the per-protocol set defined as those participants who met all protocol-specified inclusion criteria and without any protocol-specified exclusion criteria, received the YF vaccine injection and the first CYD-TDV or placebo injection, provided a pre- and postinjection serum sample within the specified times and with valid test results, and who were FV seronegative at baseline. The intent-to-treat set (defined as participants who received the YF vaccine injection along with CYD-TDV or placebo injection, provided postinjection blood sample with valid test results) was used for the secondary YF immunogenicity analyses. For the dengue immunogenicity analyses, in a subset of 250 subjects, the full analysis set was defined as participants who received at least one CYD-TDV injection, and provided a postinjection blood sample with valid test results. The safety analysis set consisted of all participants who received at least one injection of YF vaccine, CYD-TDV or placebo, analyzed according to the treatment received at the first injection. The incidences of adverse events were calculated along with the 95% CIs by allocated group.



A total of 792 participants were enrolled and randomized; 472 (59.6%) in Colombia and 320 (40.4%) in Peru. The flow of participants through the study is shown in Figure 1. Six (0.8%) participants did not meet at least one inclusion criterion or had at least one exclusion criterion. Four participants, 1 in group 1 and 3 in group 2, did not complete their vaccination schedule according to the official immunization calendar for Colombia or Peru. One participant from group 1 had a history of central nervous system disorder or disease, including seizure and a second participant in group 1 had received 1 vaccine in the 4 weeks preceding the first trial vaccination.

Participant disposition flow chart. An additional visit (visit 2) was scheduled approximately 15 days after visit 1 for the first 40 participants only for assessment of injection site reactions and systemic events.

The 2 groups were well balanced in terms of baseline characteristics (Table 1).

Table 1
Table 1:
Baseline Characteristics of the Participants (Intent-to-treat Set)


Yellow Fever Vaccine Immune Response

YF seroconversion rates 28 days after the first study injections in the per-protocol analysis are summarized (Table 2)—administration of the YF vaccine concomitantly with CYD-TDV was noninferior to the immune response after concomitant administration of YF and placebo in FV seronegative toddlers. The difference in seroconversion rates (PRNT50 ≥ 1:10) between the 2 groups was 0.33% (95% CI: 0.98; 1.87). A similar result was also observed in the intent-to-treat cohort (Table 2).

Table 2
Table 2:
Noninferiority of Yellow Fever Seroconversion Rate at 28 Days Post First Injections

Log10 YF antibody titers before and 28 days after the first study injections are illustrated in box plots for both groups in the intent-to-treat set (Fig. 2).

Box plots for yellow fever log10 antibody titers before and 28 days after administration of the yellow fever vaccine concomitantly with a dengue vaccine candidate (group 1) or concomitantly with a placebo (group 2) (intent-to-treat set).

CYD-TDV Immune Response

The proportion of dengue immune subjects at baseline was low and similar in both groups, with 23 subjects (6.0%) in group 1 and 22 subjects (5.8%) in group 2. Geometric mean titers of the antibodies against the 4 dengue serotypes preinjection and after the second and third set of study injections for the intent-to-treat set (dengue immunogenicity) are summarized in Figure 3. For dengue serotype 1, participants who received 3 CYD-TDV injections (group 1) had a higher GMT than those who received only 2 injections (group 2; P < 0.001). GMTs for dengue serotype 2, 3 and 4 were similar in participants in group 1 who received 3 dengue injections and group 2 following only 2 dengue injections (P > 0.05). After 2 CYD-TDV injections, participants previously primed with YF vaccine (group 2) had higher GMTs, than participants who received the first CYD-TDV concomitantly with YF vaccine (group 1) for serotype 2 (P = 0.0003) and serotype 3 (P = 0.004), but not for the other 2 serotypes (P > 0.05).

GMTs for dengue serotypes 1, 2, 3 and 4, 30 days after the second dengue vaccination (groups 1 and 2) and third dengue vaccination (group 1), (intent-to-treat set—dengue immunogenicity). Statistical comparison shown following 2 doses of CYD-TDV. #Group 1 received the yellow fever vaccine and the first CYD-TDV injection at enrollment (month 0), followed by the second and third CYD-TDV injections at month 6 and month 12, respectively. Group 2 received the yellow fever vaccine and a placebo at enrollment (month 0), followed by the first and second CYD-TDV injection at month 6 and month 12, respectively. The statistical comparisons shown are for comparisons between the 2 groups following the second CYD-TDV injection (ie, postinjection 2 in group 1 and postinjection 3 in group 2; Wilcoxon rank sum test).

After the second CYD-TDV injection, the percentage of participants with dengue titers above 10 (1/dil) were 91.2%–100% and 97.2%–100% across the 4 serotypes in groups 1 and 2, respectively. After the third CYD-TDV injection in group 1, the percentage of participants with dengue titers above 10 (1/dil) were 97.3%–100% across the 4 serotypes.


There were no immediate unsolicited adverse events or reactions. A summary of the safety overview is presented in Figure 4. There were no safety concerns after concomitant administration of YF vaccine with CYD-TDV during the study period, however, fever was more frequent following concomitant administration of YF vaccine with CYD-TDV compared with YF vaccine and placebo (26.7% vs. 16.5%; P < 0.001). Most solicited reactions were of grade 1 intensity occurring within 3 days after any injection. Details of injection site and systemic reactions are summarized in Table, Supplemental Digital Content 1,

Safety overview. Group 1. 1st injection: yellow fever vaccine + CYD-TDV injection at enrollment (month 0). 2nd injection: CYD-TDV injection at month 6. 3rd injection: CYD-TDV injection at month 12. Group 2. 1st injection: yellow fever vaccine + placebo at enrollment (month 0). 2nd injection: CYD-TDV injection at month 6. 3rd injection: CYD-TDV injection at month 12. AEs indicates adverse events; SAEs, serious adverse events.

A total of 8 participants experienced adverse events that led to study discontinuation: 3 in group 1 and 5 in group 2. Overall, 73 participants experienced 83 serious adverse events at any time during the study with no differences between study groups: 35 (8.9%) in group 1 and 38 (9.7%) in group 2 reported 41 and 42 serious adverse events, respectively. All serious adverse events (except one, see below) were considered as not-related to the study treatments by both the study investigators and sponsor. Of these serious adverse events, 5 led to study discontinuation: 2 in group 1 (both febrile seizures with 1 occurring 1 day after the first study injections, which was considered possibly related to study injections by the study sponsor, and the other occurred 84 days after the first study injections); and 3 in group 2 [viral meningitis (diagnosis based on clinical features and cerebrospinal fluid leak characteristics) 27 days after the first study injection, febrile convulsion episode 97 days after the first CYD-TDV injection, and a traumatic brain injury caused by a fall 23 days after the second CYD-TDV injection].

There were a total of 11 episodes of febrile seizures: 6 participants/7 episodes in group 1 and 4 participants/4 episodes in group 2. Most of these cases occurred >40 days after vaccination. All but one of them had underlying conditions (respiratory and gastrointestinal). In 10 of these 11 cases, the participants presented concomitant infections (mainly upper respiratory tract infections) at the moment of seizure episodes that could have explained the occurrence of fever.

Few participants reported nonserious adverse events of special interest: 11 (2.8%) in group 1 and 7 (1.8%) in group 2. All but one of these adverse events of special interest (1 episode of urticaria in group 1 that started on the day of injection, lasted for 6 days and spontaneously resolved) were considered as not related to the study injections. There was 1 virologically confirmed (NS1 antigen and reverse transcription polymerase chain reaction screening both positive) hospitalized dengue case (serotype not identified) reported in group 2 during the study (20 days after the third study injection). This case was assessed by the Independent Data Monitoring Committee as nonsevere and the participant fully recovered.


The CYD-TDV candidate shares the same genes as those encoding the nonstructural and capsid proteins in the attenuated YF-17D vaccine.15 As there is the potential for any vaccine to interfere with another vaccine when coadministered, given the similarities between the 2 vaccines it has been queried whether the YF vaccine and CYD-TDV could be safely given together, and whether CYD-TDV could interfere with the response to the licensed YF vaccine. This study conducted in Colombia and Peru, was the first study to assess whether administration of YF vaccine concomitantly with CYD-TDV could affect the immunogenicity and safety of the YF vaccine in toddlers. Concomitant administration of YF vaccine with CYD-TDV resulted in a good YF antibody response fulfilling the prospective statistical criteria of noninferiority and with no clinically relevant impact on the safety profile of the YF vaccine in toddlers.

In a prior study conducted in 2- to 11-year-old Peruvian children with a history of YF vaccination, CYD-TDV was shown to have a good safety profile and to elicit robust, well-balanced antibody responses against the 4 serotypes in both dengue naïve, and previously exposed individuals.14 In addition, CYD-TDV appeared to restimulate existing YF immunity to some extent, which may have occurred as a response to shared YF-17D nonstructural antigens.14

Studies have suggested that participants with previous YF exposure (including vaccines) may have a better response to CYD-TDV.11,24 An age de-escalation phase I study in 2- to 45-year-old participants, in which 1 group was immunized with YF vaccine followed by 2 doses of CYD-TDV and another with 3 doses of CYD-TDV, showed that 2 doses of CYD-TDV in YF vaccine recipients were generally as immunogenic as 3 doses given to YF vaccine-naive individuals.11 Therefore, it could be hypothesized that only 2 doses of CYD-TDV may be sufficient instead of the usual 3 doses in YF vaccine-primed individuals. However, this earlier study and the present study were not designed to assess whether 2- or 3-dose CYD-TDV schedules were equivalent.11 It should also be noted that there is currently no recognized neutralizing antibody seroprotection threshold measured by PRNT for dengue.10 As such the correlation between antibody levels determined by PRNT and clinical protection against dengue disease or infection remains to be established. On-going phase III efficacy trials are expected to provide information on this.

An outbreak of dengue (serotype 1) occurred in Lima during the first semester of 2012. This outbreak did not appear to have influenced the immunological response to serotype 1 in this study as there were no marked differences in serotype 1 GMTs between the Cali and Lima sites. In addition, no clinical or hospitalized dengue cases were reported among the trial participants from the Lima study site. It should be noted that the current study was not designed to determine CYD-TDV efficacy.

There were no safety concerns with concomitant administration of YF vaccine with CYD-TDV, and the safety profile observed in our study appears comparable to other studies with these vaccines in older children, adolescents and adults during the observation period.11,14,24 Fever was more frequent after concomitant administration of YF vaccine with the first injection of CYD-TDV compared with administration of YF vaccine with placebo (26.7% vs. 16.5%; P < 0.001), however, most cases were mild or moderate and resolved within a few days following medication. An increased incidence of fever has previously been reported in 12-month-old children following coadministered of YF-vaccine with an MMR vaccine relative to sequential administration of the vaccines (16.6% vs. 11.8%).25 This increase in fever cases was also observed following coadministration of CYD-TDV and MMR vaccine relative to sequential administration of the vaccines (28.8% vs. 11.7%), in 12-month-old children.21 However, it cannot be precluded that coadministration of 2 FV vaccines may increase the reactogenicity, particularly in terms of fever. Serious adverse events occurred at a similar rate in both study groups; only 1 serious adverse event of febrile seizure was considered as related to study injection, but this condition is frequent for this age and the child recovered the same day. Very few participants (about 1%) discontinued the study because of adverse events.

In conclusion, the concomitant administration of YF vaccine with CYD-TDV results in a good YF antibody response, with no clinically relevant impact on the immunogenicity or safety profile of the YF vaccine. Both vaccines may therefore be administered to children at the same visit, offering benefits to public health whilst minimizing health-care resources. A previous completed phase III study, performed in children aged 2 to 14 years old, found that vaccine efficacy tended to increase with age, probably reflecting increasing exposure to FV/dengue with age.17 Based on these findings, it is possible that toddlers may not be included in the final target group.


The authors thank all the children and their parents/guardian’s for their participation in this research. In addition, we thank Luis Fernando Mejia for his contributions to the study conduct in the site of Cali and Edda Franco for the management of study documentation for the site in Peru. In addition, thanks are due to the following people within Sanofi Pasteur at the time the study was conducted: Mark Boaz at the Global Clinical Immunology Department for conducting the immunological assays; Anna Skipetrova and Mihaela Tila for vaccine safety assessment; Marcela Cangrejo for study management and logistics; Pascale Chermette and Lizbeth Carmona for program management, and Jo-Ann West, Jean-Sébastien Persico and Grenville Marsh for coordinating the preparation of this report.


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vaccine; safety; immunogenicity; yellow fever; dengue

Supplemental Digital Content

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