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A traditional phase 3 clinical efficacy study for a Zika vaccine may be unfeasible because of the current low transmission of Zika virus (ZIKV). An alternative clinical development approach to evaluate Zika vaccine efficacy (VE) is therefore required, delineated in the US FDA's Accelerated Approval Program for licensure, which utilizes an anti-Zika neutralizing antibody (Zika NAb) titer correlated with non-human primate (NHP) protection as a surrogate endpoint. In this accelerated approval approach, the estimation of VE would be inferred from the percentage of phase 3 trial participants achieving the established surrogate endpoint. We provide a statistical framework to predict the probability of protection for human participants vaccinated with a purified inactivated ZIKV vaccine (TAK-426), in the absence of VE measurements, using NHP data under a single-correlate model. Based on a logistic regression (LR) with bias-reduction model, a probability of 90% protection in humans is expected with a ZIKV NAb geometric mean titer (GMT) ≥ 3.38 log 10 half-maximal effective concentration (EC 50 ). The predicted probability of protection of TAK-426 against ZIKV infection was determined using the two-parameter LR model that fit the calculated VE in rhesus macaques and the flavivirus-naïve phase 1 trial participants' ZIKV NAb GMTs log 10 EC 50 , measured by a ZIKV reporter virus particle assay, at 1 month post dose 2. The TAK-426 10 µg dose predicted a probability of protection from infection of 98% among flavivirus-naïve phase 1 trial participants.

Background: We report 2-year persistence of immune response to Takeda's prophylactic purified formalin-inactivated whole Zika virus vaccine candidate (TAK-426) compared with that observed after natural infection., Methods: A randomized, observer-blind, placebo-controlled, dose-selection, phase 1 trial was conducted in 18-49-year-old adults at 9 centers (7 in the United States, 2 in Puerto Rico) from 13 November 2017 to 24 November 2020. Primary objectives were safety, tolerability, and immunogenicity of 3 increasing doses of TAK-426 administered as 2 doses 28 days apart to flavivirus (FV)-naive and FV-primed adults. Here, we report on safety and persistence of immunity up to 2 years after primary vaccination with 10-μg TAK-426, the highest dose, and compare neutralizing antibody responses with those observed after natural infection., Results: TAK-426 at 10-μg had an acceptable safety profile in FV-naive and FV-primed adults up to 24 months after dose 2. Seropositivity for neutralizing antibodies was 100% at 1 year, and 93.8% and 76.2% at 2 years in FV-naive and FV-primed groups, respectively. TAK-426 responses were comparable in magnitude and kinetics with those elicited by natural Zika virus infection., Conclusions: These results support the further clinical development of TAK-426 for both FV-naive and FV-primed populations., Clinical Trials Registration: NCT03343626., Competing Interests: Potential conflicts of interest. C. J. A., F. N., K. J. M., K. B., P. K., M. L., E. W., T. D. P., W. R. B., J. S., and G. D. are employees of Takeda and hold stock/stock options in Takeda. H. H. H., H. P., F. P., and V. M. were employees of Takeda when the study was conducted and may hold stock/stock options in Takeda. E. J. A. reports consultancy for Janssen, Medscape, Pfizer, Sanofi Pasteur, GlaxoSmithKline, and Moderna; safety monitoring boards for Kentucky BioProcessing, Sanofi Pasteur, and WCG and ACI Clinical; institutional clinical research funding from GlaxoSmithKline, Janssen, MedImmune, Merck Sharp & Dohme, Micron, PaxVax, Pfizer, Regeneron, and Sanofi Pasteur; and institutional funding from the National Institutes of Health for clinical research on Moderna and Janssen vaccines. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The development of a safe and effective Zika virus (ZIKV) vaccine has become a global health priority since the widespread epidemic in 2015-2016. Based on previous experience in using the well-characterized and clinically proven dengue virus serotype-2 (DENV-2) PDK-53 vaccine backbone for live-attenuated chimeric flavivirus vaccine development, we developed chimeric DENV-2/ZIKV vaccine candidates optimized for growth and genetic stability in Vero cells. These vaccine candidates retain all previously characterized attenuation phenotypes of the PDK-53 vaccine virus, including attenuation of neurovirulence for 1-day-old CD-1 mice, absence of virulence in interferon receptor-deficient mice, and lack of transmissibility in the main mosquito vectors. A single DENV-2/ZIKV dose provides protection against ZIKV challenge in mice and rhesus macaques. Overall, these data indicate that the ZIKV live-attenuated vaccine candidates are safe, immunogenic and effective at preventing ZIKV infection in multiple animal models, warranting continued development., (© 2021. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)