A Phase I, double-blind, randomized, vehicle-controlled, dose-finding, safety study of a synthetic nanoparticle-based, T cell priming peptide vaccine against Dengue virus in healthy adults in Switzerland

Background
Vaccines that minimize the risk of vaccine-induced antibody-dependent enhancement and severe dengue are needed to address the global health threat posed by dengue. This study assessed the safety and immunogenicity of a gold nanoparticle (GNP)-based, multi-valent, synthetic peptide dengue vaccine candidate (PepGNP-Dengue), designed to provide protective CD8+ T cell immunity, without inducing antibodies.
Methods
In this randomized, double-blind, vehicle-controlled, phase 1 trial (NCT04935801), healthy naïve individuals aged 18-45 years recruited at the Centre for primary care and public health, Lausanne, Switzerland, were randomly assigned to receive PepGNP-Dengue or comparator (GNP without peptides [vehicle-GNP]). Randomization was stratified into four groups (low dose [LD] and high dose [HD]), allocation was double-blind from participants and investigators. Two doses were administered by intradermal microneedle injection 21 days apart. Primary outcome was safety, secondary outcome immunogenicity. Analysis was by intention-to-treat for safety, intention-to-treat and per protocol for immunogenicity.
Findings
26 participants were enrolled (Aug-Sep 2021) to receive PepGNP-Dengue (LD or HD, n=10 each) or vehicle-GNP (LD or HD, n=3 each). No vaccine-related serious adverse events occurred. Most (90%) related adverse events were mild; injection site pain and transient discoloration were most frequently reported. Injection site erythema occurred in 58% of participants. As expected, PepGNP-Dengue did not elicit anti-DENV antibodies of significance. Significant increases were observed in specific CD8+ T cells and dengue dextramer+ memory cell subsets in the LD PepGNP-Dengue but not in the HD PepGNP-Dengue or Vehicle-GNP groups, specifically PepGNP-activated CD137+CD69+CD8+ T cells (day 90, +0·0318%, 95% CI: 0·0088-0·1723, p= 0·046), differentiated effector memory (TemRA) and central memory (Tcm) CD8+ T cells (day 35, +0·8 /105 CD8+, 95% CI: 0·19-5·13, p= 0·014 and +1·34 /105 CD8+, 95% CI: 0·1-7·34, p= 0·024, respectively).
Interpretation
Results provide proof of concept that a synthetic nanoparticle-based peptide vaccine can successfully induce virus-specific CD8+ T cells. The favourable safety profile and cellular responses observed support further development of PepGNP-Dengue.
Funding
Emergex Vaccines Holding Limited.