Safety Profile and Immunologic Responses of a Novel Vaccine Against Shigella sonnei Administered Intramuscularly, Intradermally and Intranasally: Results From Two Parallel Randomized Phase 1 Clinical Studies in Healthy Adult Volunteers in Europe

Abstract

Background: Approximately 164,000 deaths yearly are due to shigellosis, primarily in developing countries. Thus, a safe and affordable Shigella vaccine is an important public health priority. The GSK Vaccines Institute for Global Health (GVGH) developed a candidate Shigella sonnei vaccine (1790GAHB) using the Generalized Modules for Membrane Antigens (GMMA) technology. The paper reports results of 1790GAHB Phase 1 studies in healthy European adults.

Methods: To evaluate the safety and immunogenicity profiles of 1790GAHB, we performed two parallel, phase 1, observer-blind, randomized, placebo-controlled, dose escalation studies in France ("study 1") and the United Kingdom ("study 2") between February 2014 and April 2015 (ClinicalTrials.gov, number NCT02017899 and NCT02034500, respectively) in 18-45years old subjects (50 in study 1, 52 in study 2). Increasing doses of Alhydrogel adsorbed 1790, expressed by both O Antigen (OAg) and protein quantity, or placebo were given either by intramuscular route (0.059/1, 0.29/5, 1.5/25, 2.9/50, 5.9/100μg of OAg/μg of protein; study 1) or by intradermal (ID), intranasal (IN) or intramuscular (IM) route of immunization (0.0059/0.1, 0.059/1, 0.59/10μg ID, 0.29/5, 1.2/20, 4.8/80μg IN and 0.29/5μg IM, respectively; study 2). In absence of serologic correlates of protection for Shigella sonnei, vaccine induced immunogenicity was compared to anti-LPS antibody in a population naturally exposed to S. sonnei.

Findings: Vaccines were well tolerated in both studies and no death or vaccine related serious adverse events were reported. In study 1, doses ≥1.5/25μg elicited serum IgG median antibody greater than median level in convalescent subjects after the first dose. No vaccine group in study 2 achieved median antibody greater than the median convalescent antibody.

Interpretation: Intramuscularly administered Shigella sonnei GMMA vaccine is well tolerated, up to and including 5.9/100μg and induces antibody to the OAg of at least the same magnitude of those observed following natural exposure to the pathogen. Vaccine administered by ID or IN, although well tolerated, is poorly immunogenic at the doses delivered. The data support the use of the GMMA technology for the development of intramuscular multivalent Shigella vaccines.

Keywords: Clinical study; GMMA; Shigella sonnei; Vaccine.

Fig. 1

Study 1 - H03_01TP trial profile. ^aOne subject was randomized to receive placebo but he/she received 3 vaccinations of 0.29/5 μg S. sonnei vaccine. ^bOne subject received vaccine forbidden by the protocol and didn't receive third vaccination. ^cOne subject developed neutropenia after the first vaccination and he/she didn't receive the following vaccinations. FAS = full analysis set. The analysis of immunogenicity was based on modified FAS defined as: all randomized subjects who received at least one study vaccination and provided immunogenicity data at relevant time points. Subjects who received wrong vaccine at all vaccinations were analysed in the vaccine the subject actually received and blood samples collected after a vaccination visit but vaccine was not administered, were excluded from the analysis.

Fig. 2

Study 2 - H03_02TP trial profile. FAS = full analysis set. The analysis of immunogenicity was based on modified FAS defined as: all randomized subjects who received at least one study vaccination and provided immunogenicity data at relevant time points. Subjects who received wrong vaccine at all vaccinations were analysed in the vaccine the subject actually received and blood samples collected after a vaccination visit but vaccine was not administered, were excluded from the analysis.

Fig. 3

Study 1 - reported maximum local pain following each IM injection. ^aPain score 0 = No pain; Pain score 1 = Pain is present, but does not interfere with activity; Pain score 2 = Pain interferes with activity; Pain score 3 = Pain prevents daily activity. Dots represent maximum individual pain reported after each vaccination at different doses. The blue line represents the average pain score as a function of dose. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Study 1 - anti-S. sonnei LPS antibody response by vaccine dose at day 85. Dots represent individual antibody responses at different doses. The blue line represents the geometric mean ELISA units as a function of dose. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

Study 1 - reverse cumulative distribution curves of anti-S. sonnei LPS antibody for subjects receiving ≥ 1.5/25 μg by IM route. The grey line is the distribution prior to vaccination. Dots are the distribution on day 85 (i.e., 28 days post 3rd vaccination); triangles are the distribution on day 225 (i.e., 168 days post 3rd vaccination). Subjects received 1.5/25 μg (light orange), 2.9/50 μg (dark orange), or 5.9/100 μg (red). The purple line is the distribution of 87 convalescent subjects. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 6

Study 1 and Study 2 - individual antibody responses of subjects receiving vaccines by IM route. Only subjects with antibody levels available on each analysis time point are included. Panel A: Subjects with no detectable antibody at baseline. Subjects with zero detectable antibody were assigned a value of 2 ELISA units (half the detectable limit) to enable plotting. Panel B: subjects with detectable antibody at baseline. Subjects were vaccinated on day 1, 29 and 57 with 0.059/1 μg (blue), 0.29/5 μg (green), 1.5/25 μg (light orange), 2.9/50 μg (dark orange), or 5.9/100 μg (red). Solid line: subjects in Study 1. Dashed green line: subjects in Study 2. Broad pink line: median antibody in the high dose group (subjects receiving ≥ 1.5/25 μg). Broad pale blue line: median antibody in the low dose group (0.059/1 μg and 0.29/5 μg). Dotted line: median antibody (121 ELISA units) measured in convalescent sera. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)