Discussion
dengue, infections
VIRUS, DENGUE, DISEASES, INFECTIONS
In this study, NI of the immune response to YF-17D and TAK-003 was demonstrated for concurrent administration of the two vaccines compared to sequential vaccination, except against DENV-1. Some serological cross-reactivity was observed for both vaccines, prior to receipt of the second vaccine.Marginally lower GMT against DENV-1 was observed one month after the second dose of TAK-003 (Month 4) in the group that received both vaccines (Group 3) compared with the group that received only TAK-003 (Group 2) at this time point. The clinical relevance of this observation is unknown as there is no correlate of protection established for dengue. However, the immune response against DENV-1 was similar to that observed in the clinical development program, specifically the pivotal efficacy trial in subjects who were DENV seronegative prior to vaccination [As both vaccines assessed in this study were live attenuated vaccines against flaviviruses, there was the potential for immunological interferences and development of cross-reactive antibodies, leading to altered immunogenicity of one or both of the vaccines. Cross-reactivity of flavivirus antibodies has been observed following sequential natural infections [In our study, while NI of the response to the YF-17D vaccine, and to TAK-003 for DENV-2, -3, and -4 was demonstrated, DENV GMTs were numerically lower against all four serotypes 30 days after concomitant administration of the first dose of TAK-003 with YF-17D, compared with administration of TAK-003 alone. However, after the second dose of TAK-003, GMTs were mostly of similar magnitude in Groups 2 and 3, indicating that the effect was transient. The clinical implications of these observed interferences is unknown. Additionally, higher DENV GMTs following sequential vaccination (Groups 1 and 2), when compared with those following concomitant vaccination (Group 3), suggest a potential immune-enhancing effect of YF-17D (when administered prior to or after TAK-003) on TAK-003 antibody responses. Additionally, YF GMTs at Months 6 and 7 were higher in Group 1 than in Group 3 but were lower in Group 2 at Month 7 than in Groups 1 and 3 at Month 1, signaling that these immune interferences are complex, and may be influenced by the time and sequence of vaccination. As YF seroprotection rates remained near 100% at all time points post-sequential vaccination, this likely has no clinical impact for YF-17D vaccination. For TAK-003 vaccination, the clinical significance of this potential enhancing effect following sequential vaccination is currently unknown in absence of any immune correlates of protection for dengue.The short duration of follow up for immunogenicity endpoints (one month following receipt of the last vaccination) was a limitation for this particular study. While antibody persistence and long-term safety has been reported from a four-year study in children and adolescents living in endemic areas of Latin America and Asia [One of the strengths of this study was that the design allowed analysis of concomitant and sequential administration of TAK-003 and YF-17D in a large group of participants who were seronegative for both diseases. As there is already a wealth of data available for both vaccines administered separately, we also chose not to include single vaccine groups to maximize the number of participants receiving the two vaccines concomitantly or sequentially. Performing the study in a non-endemic area for either virus allowed us to assess vaccine interactions without any additional impact of flavivirus exposure, either previously or during the study, as well as adding to the safety database of TAK-003 in seronegative vaccine recipients. Both vaccines in the study were well tolerated, and the safety profile of TAK-003 was similar to that observed in previous studies across baseline seronegative and seropositive participants [In summary, no reduction in immune response to YF-17D vaccine, nor in immune responses to TAK-003 for DENV-2, -3, and -4, was observed when the 2 vaccines are co-administered. Marginally lower DENV-1 GMTs were observed. The clinical relevance of this is unknown but these titers remain similar to those observed in other trials, in particular in the pivotal efficacy trial that demonstrated the efficacy of TAK-003 against dengue cases (including those caused by DENV-1) in subjects who were DENV seronegative prior vaccination.