Integrated immunogenicity analysis of a tetravalent dengue vaccine up to 4 y after vaccination

ABSTRACT

Two large pivotal phase III studies demonstrated the efficacy of the tetravalent dengue vaccine (CYD-TDV; Dengvaxia®, Sanofi Pasteur) against all dengue serotypes. Here we present an unprecedented integrated summary of the immunogenicity of CYD-TDV to identify the parameters driving the neutralizing humoral immune response and evolution over time. We summarized the immunogenicity profiles of a 3-dose schedule of CYD-TDV administered 6 months apart across 10 phase II and 6 phase III trials undertaken in dengue endemic and non-endemic countries. Dengue neutralizing antibody titers in sera were determined at centralized laboratories using the 50% plaque reduction neutralization test (PRNT₅₀) at baseline, 28 d after the third dose, and annually thereafter for up to 4 y after the third dose in some studies. CYD-TDV elicits neutralizing antibody responses against all 4 dengue serotypes; geometric mean titers (GMTs) increased from baseline to post-dose 3. GMTs were influenced by several parameters including age, baseline dengue seropositivity and region. In the 2 pivotal studies, GMTs decreased initially during the first 2 y post-dose 3 but appear to stabilize or slightly increase again in the third year. GMTs persisted 1.2–3.2-fold higher than baseline levels for up to 4 y post-dose 3 in other studies undertaken in dengue endemic countries. Our integrated analysis captures the fullness of the CYD-TDV immunogenicity profile across studies, age groups and regions; by presenting the available data in this way general trends and substantial outliers within each grouping can be easily identified. CYD-TDV elicits neutralizing antibody responses against all dengue serotypes, with differences by age and endemicity, which persist above baseline levels in endemic countries.

KEYWORDS:

• dengue
• vaccine
• flaviviruses
• immunogenicity
• antibody
• titers
• antibody persistence

Disclosure of potential conflicts of interest

All authors are employees or former employees of Sanofi Pasteur.

Acknowledgments

This integrated analysis was performed by Sanofi Pasteur.

Editorial assistance with the preparation of the manuscript was provided by Richard Glover, inScience Communications, Springer Healthcare, Chester, UK. Funding for this assistance was also provided by Sanofi Pasteur. The authors also thank Jean-Sébastien Persico for editorial assistance and manuscript coordination on behalf of Sanofi Pasteur.

We thank all the parents and participants who agreed to participate in these trials; the trial investigators and staff in the countries; and to the clinical research organization staff who contributed to the successful completion of the trials. The authors also wish to thank Stephen W. Hildreth (Sanofi Pasteur) for his contribution to the dossier writing, and the Common Technical Document task force.