Safety and immunogenicity of a synthetic nanoparticle-based, T cell priming peptide vaccine against dengue in healthy adults in Switzerland: a double-blind, randomized, vehicle-controlled, phase 1 study.

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 (August-September 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.

Safety and immunogenicity of a chimpanzee adenovirus-vectored Ebola vaccine in healthy adults: a randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a study.

BACKGROUND: The ongoing Ebola outbreak led to accelerated efforts to test vaccine candidates. On the basis of a request by WHO, we aimed to assess the safety and immunogenicity of the monovalent, recombinant, chimpanzee adenovirus type-3 vector-based Ebola Zaire vaccine (ChAd3-EBO-Z). METHODS: We did this randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a trial at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Participants (aged 18-65 years) were randomly assigned (2:2:1), via two computer-generated randomisation lists for individuals potentially deployed in endemic areas and those not deployed, to receive a single intramuscular dose of high-dose vaccine (5 × 10(10) viral particles), low-dose vaccine (2·5 × 10(10) viral particles), or placebo. Deployed participants were allocated to only the vaccine groups. Group allocation was concealed from non-deployed participants, investigators, and outcome assessors. The safety evaluation was not masked for potentially deployed participants, who were therefore not included in the safety analysis for comparison between the vaccine doses and placebo, but were pooled with the non-deployed group to compare immunogenicity. The main objectives were safety and immunogenicity of ChAd3-EBO-Z. We did analysis by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02289027. FINDINGS: Between Oct 24, 2014, and June 22, 2015, we randomly assigned 120 participants, of whom 18 (15%) were potentially deployed and 102 (85%) were non-deployed, to receive high-dose vaccine (n=49), low-dose vaccine (n=51), or placebo (n=20). Participants were followed up for 6 months. No vaccine-related serious adverse events were reported. We recorded local adverse events in 30 (75%) of 40 participants in the high-dose group, 33 (79%) of 42 participants in the low-dose group, and five (25%) of 20 participants in the placebo group. Fatigue or malaise was the most common systemic adverse event, reported in 25 (62%) participants in the high-dose group, 25 (60%) participants in the low-dose group, and five (25%) participants in the placebo group, followed by headache, reported in 23 (57%), 25 (60%), and three (15%) participants, respectively. Fever occurred 24 h after injection in 12 (30%) participants in the high-dose group and 11 (26%) participants in the low-dose group versus one (5%) participant in the placebo group. Geometric mean concentrations of IgG antibodies against Ebola glycoprotein peaked on day 28 at 51 µg/mL (95% CI 41·1-63·3) in the high-dose group, 44·9 µg/mL (25·8-56·3) in the low-dose group, and 5·2 µg/mL (3·5-7·6) in the placebo group, with respective response rates of 96% (95% CI 85·7-99·5), 96% (86·5-99·5), and 5% (0·1-24·9). Geometric mean concentrations decreased by day 180 to 25·5 µg/mL (95% CI 20·6-31·5) in the high-dose group, 22·1 µg/mL (19·3-28·6) in the low-dose group, and 3·2 µg/mL (2·4-4·9) in the placebo group. 28 (57%) participants given high-dose vaccine and 31 (61%) participants given low-dose vaccine developed glycoprotein-specific CD4 cell responses, and 33 (67%) and 35 (69%), respectively, developed CD8 responses. INTERPRETATION: ChAd3-EBO-Z was safe and well tolerated, although mild to moderate systemic adverse events were common. A single dose was immunogenic in almost all vaccine recipients. Antibody responses were still significantly present at 6 months. There was no significant difference between doses for safety and immunogenicity outcomes. This acceptable safety profile provides a reliable basis to proceed with phase 2 and phase 3 efficacy trials in Africa. FUNDING: Swiss State Secretariat for Education, Research and Innovation (SERI), through the EU Horizon 2020 Research and Innovation Programme.

Intravaginal and subcutaneous immunization induced vaccine specific CD8 T cells and tumor regression in the bladder.

PURPOSE: Vaccines targeting tumor associated antigens are in development for bladder cancer. Most of these cancers are nonmuscle invasive at diagnosis and confined in the mucosa and submucosa. However, to our knowledge how vaccination may induce the regression of tumors at such mucosal sites has not been examined previously. We compared different immunization routes for the ability to induce vaccine specific antitumor CD8 T cells in the bladder and bladder tumor regression in mice. MATERIALS AND METHODS: In the absence of a murine bladder tumor model expressing a tumor antigen relevant for human use we established an orthotopic model expressing the HPV-16 tumor antigen E7 as a model. We used an adjuvant E7 polypeptide to induce CD8 T cell mediated tumor regression. RESULTS: Subcutaneous and intravaginal but not intranasal vaccination induced a high number of TetE7(+)CD8(+) T cells in the bladder as well as bladder tumor regression. The entry of vaccine specific T cells in the bladder was not the only key since persistent regression of established bladder tumors by intravaginal or subcutaneous immunization was associated with tumor infiltration of total CD4 and CD8 T cells. This resulted in an increase in TetE7(+)CD8(+) T cells and a decrease in T regulatory cells, leading to an increased number of effector interferon-γ secreting vaccine specific CD8 T cells in the regressing bladder tumor. CONCLUSIONS: These data show that immunization routes should be tailored to each mucosal tumor site. Subcutaneous or intravaginal vaccination may be of additional value to treat patients with bladder cancer.