A novel intramuscular bivalent norovirus virus-like particle vaccine candidate--reactogenicity, safety, and immunogenicity in a phase 1 trial in healthy adults

Abstract

Background: Noroviruses are the most important viral causes of gastroenteritis-related morbidity and mortality. A randomized, double-blind, placebo-controlled study evaluated an adjuvanted bivalent intramuscular norovirus virus-like particle (VLP) vaccine.

Methods: Forty-eight adults aged 18-49 years received either 2 doses containing genotype GI.1 VLP and a consensus GII.4 VLP or 2 doses of placebo. Doses (5 µg, 15 µg, 50 µg, or 150 µg of each VLP) were administered 4 weeks apart in the first stage. Subsequently, 54 adults, aged 18-49 (n=16), 50-64 (n=19), and 65-85 (n=19) years, received 2 doses of vaccine containing 50 µg of each VLP. Total and class-specific antibody responses, as well as histoblood group antigen (HBGA) blocking antibody responses, were measured before and after each dose.

Results: Local reactions were mainly injection site pain/tenderness, with no reported fever or vaccine-related serious adverse events. One dose of vaccine containing 50 µg of each VLP increased GI.1 geometric mean titers (GMTs) by 118-fold, 83-fold, and 24-fold and increased GII.4 GMTs by 49-fold, 25-fold, and 9-fold in subjects aged 18-49, 50-64, and 65-83 years, respectively. Serum antibody responses peaked at day 7 after the first dose, with no evidence of boosting following a second dose. Most subjects achieved HBGA-blocking antibody titers of ≥200.

Conclusions: The vaccine was well tolerated and immunogenic. Rapid immune response to a single dose may be particularly useful in military personnel and travelers and in the control of outbreaks. Clinical Trials Registration. NCT01168401.

Keywords: gastroenteritis; norovirus; vaccine; virus-like particle.

Figure 1.

Dose-related reactogenicity of the bivalent norovirus virus-like particle vaccine formulated with aluminum hydroxide and MPL (3-O-desacyl-4′-monophosphoryl lipid A; GlaxoSmithKline) in 18–49 year olds (cohort A). Frequencies of local and systemic reactogenicity events are shown by day after doses 1 and 2, with maximum severity during the observation period assessed as mild, moderate, or severe. The most common local complaints were pain and tenderness at the injection site, and the most common systemic complaint was headache. Post dosing assessment, performed 30 minutes after dosing. Abbreviation: PD, post dosing assessment.

Figure 2.

Geometric mean titers (GMTs) of enzyme-linked immunosorbent assay of total immunoglobulin (Pan-Ig) antibodies to norovirus GI.1 and GII.4 virus-like particles (VLPs) in cohort A, with dose escalation, assessed before (day 0) and 4 weeks after the first dose (day 28) and 4 weeks after the second dose (day 56). Data in parentheses show the number of subjects per group. Abbreviation: ELISA, enzyme-linked immunosorbent assay.

Figure 3.

Serum antibody responses to the vaccine containing 50 μg of norovirus GI.1 virus-like particle (VLP) and 50 μg of consensus norovirus GII.4 VLP in 18–49 year olds (cohorts A and D), 50–64 year olds (cohort B), and 65–85 year olds (cohort C). Placebo recipients are combined across all cohorts. Subjects received 2 doses of vaccine separated by 28 days (day 0 and day 28). Geometric mean titers (GMTs) of antibody are shown to GI.1 (A, C, E) and GII.4 consensus (B, D, F) VLPs as assessed by total immunoglobulin (A and B), immunoglobulin G (C and D), and immunoglobulin A (E and F) immunoassays.