Rapid response to an emerging infectious disease - Lessons learned from development of a synthetic DNA vaccine targeting Zika virus

Abstract

Vaccines are considered one of the greatest advances in modern medicine. The global burden of numerous infectious diseases has been significantly reduced, and in some cases, effectively eradicated through the deployment of specific vaccines. However, efforts to develop effective new vaccines against infectious pathogens such as influenza, Human immunodeficiency virus (HIV), dengue virus (DENV), chikungunya virus (CHIKV), Ebola virus, and Zika virus (ZIKV) have proven challenging. Zika virus is a mosquito-vectored flavivirus responsible for periodic outbreaks of disease in Africa, Southeast Asia, and the Pacific Islands dating back over 50 years. Over this period, ZIKV infections were subclinical in most infected individuals and resulted in mild cases of fever, arthralgia, and rash in others. Concerns about ZIKV changed over the past two years, however, as outbreaks in Brazil, Central American countries, and Caribbean islands revealed novel aspects of infection including vertical and sexual transmission modes. Cases have been reported showing dramatic neurological pathologies including microcephaly and other neurodevelopmental problems in babies born to ZIKV infected mothers, as well as an increased risk of Guillain-Barre syndrome in adults. These findings prompted the World Health Organization to declare ZIKV a public health emergency in 2016, which resulted in expanded efforts to develop ZIKV vaccines and immunotherapeutics. Several ZIKV vaccine candidates that are immunogenic and effective at blocking ZIKV infection in animal models have since been developed, with some of these now being evaluated in the clinic. Additional therapeutics under investigation include anti-ZIKV monoclonal antibodies (mAbs) that have been shown to neutralize infection in vitro as well as protect against morbidity in mouse models of ZIKV infection. In this review, we summarize the current understanding of ZIKV biology and describe our efforts to rapidly develop a vaccine against ZIKV.

Keywords: Animal models; DNA vaccines; Flaviviruses; Immunity; Immunopathology; ZIKV vaccine.

Fig. 1

Conservation of ZIKV E glycoprotein sequence mapped to representative flavivirus E glycoprotein sequences. (A) A comparative model of ZIKV E glycoprotein and associated prM peptide was generated with Discovery Studio 4.5 (BIOVIA, San Diego, CA, USA). A- CLUSTAL W alignment of representative ZIKV, DENV1, DENV2, DENV3, DENV4, YFV, WNV, JEV, and TBEV E glycoprotein sequences was performed and the relative conservation of residues was mapped to the model. Blue indicates complete conservation among the sequences, shading to white and to red for the least conservation. The ZIKV E glycoprotein dimer is displayed in two orientations. Membrane orientation is behind the protein in the upper panel and below the protein in the lower panel. Conservation is evident in the fusion loop region. (B) ZIKV model as in lower panel of A with one subunit removed to display the interface between the molecules. The deleted subunit is indicated in silhouette. Conservation of the fusion loop and in the subunit interface of the EDII region.

Fig. 2

Timeline of Zika DNA vaccine development. July of 2015 marked the first reports of Zika infection in Brazil with the first association of Zika with microcephaly reported in October of 2015. Following that report, we started plasmid design and in vitro testing. In February of 2016, about the same time that the WHO declared that Zika was a “Public Health Emergency of International Concern”, we completed the first mouse studies and had begun NHP immunogenicity studies. In May, 2017, the first NHP study was completed and the IND has filed shortly after. The GLS-5700 phase 1 clinical trial started in June 2017, a short 7 months after the initial vaccine design was started (NCT02809443). All the preclinical work has since been published in September of 2016 and June of 2017, and the preliminary report of the clinical trial data was published in October 2017.