Adjuvanted intranasal Norwalk virus-like particle vaccine elicits antibodies and antibody-secreting cells that express homing receptors for mucosal and peripheral lymphoid tissues

Abstract

Background: Noroviruses cause significant morbidity and mortality from acute gastroenteritis in all age groups worldwide.

Methods: We conducted 2 phase 1 double-blind, controlled studies of a virus-like particle (VLP) vaccine derived from norovirus GI.1 genotype adjuvanted with monophosphoryl lipid A (MPL) and the mucoadherent chitosan. Healthy subjects 18-49 years of age were randomized to 2 doses of intranasal Norwalk VLP vaccine or controls 21 days apart. Study 1 evaluated 5-, 15-, and 50-μg dosages of Norwalk antigen, and study 2 evaluated 50- and 100-μg dosages. Volunteers recorded symptoms for 7 days after dosing, and safety was followed up for 180 days. Blood samples were collected for serological profile, antibody secreting cells (ASCs), and analysis of ASC homing receptors.

Results: The most common symptoms were nasal stuffiness, discharge, and sneezing. No vaccine-related serious adverse events occurred. Norwalk VLP-specific immunoglobulin G and immunoglobulin A antibodies increased 4.8- and 9.1-fold, respectively, for the 100-μg dosage level. All subjects tested who received the 50- or 100-μg vaccine dose developed immunoglobulin A ASCs. These cells expressed molecules associated with homing to mucosal and peripheral lymphoid tissues.

Conclusions: The intranasal monovalent adjuvanted Norwalk VLP vaccine was well tolerated and highly immunogenic and is a candidate for additional study.

Trial registration: ClinicalTrials.gov NCT00806962.

Conflict of interest statement

Potential conflicts of interest: S.S.E.-K. and M.F.P. have each been reimbursed for travel to one scientific meeting by LigoCyte Pharmaceuticals. P.M.M., R.S., C.R., and R.B. are employed by LigoCyte Pharmaceuticals.

Figures

Table 1.

Frequency of Solicited Adverse Events Reported during the First 7 Days after Administration of Vaccine or Placebo in Study 2, by Group

Table 2.

Response Rates of Norwalk Virus-Like Particle-Specific Immunoglobulin A (IgA) Antibody Secreting Cells (ASCs) and ASC Geometric Mean (GM), by Group

Table 3.

Norwalk Virus-Like Particle-Specific Immunoglobulin G (IgG) and Immunoglobulin A (IgA) Antibody Seroresponse Rates (percent of subjects with ⩾4-fold rise) and Geometric Mean of Fold Rise (GMFR), by Group by Study at Day 56 (35 days after Vaccination 2) Compared with Prevaccination

Table 4.

Norwalk Virus-Like Particle-Specific Hemagglutination Inhibition Antibody Geometric Mean Titers (GMTs), Geometric Mean of Fold Rises (GMFR), and Seroresponse Rates by Group in Study 2

Table 5

Norwalk Virus-Like Particle-Specific Immunoglobulin G (IgA) and Immunoglobulin G (IgG) Cell Surface Receptor Homing Molecules in Study 2

Figure 1.

Norwalk virus-like particle (VLP)-specific immunoglobulin G (IgG) and immunoglobulin A (IgA) geometric mean antibody titers, by group in studies 1 and 2. In study 1, 28 adult subjects were randomized sequentially by group to receive 2 doses of (1) 5 μg of Norwalk VLP vaccine (5 subjects, squares) or adjuvant control (2 subjects, diamonds), (2) 15 μg of Norwalk VLP vaccine (5 subjects, triangles) or adjuvant control (2 subjects, diamonds), or (3) 50 μg of Norwalk VLP vaccine (10 subjects, circles) or adjuvant control (4 subjects, diamonds). A, Serum IgG geometric mean titers from study 1. B, Serum IgA geometric mean titers from study 1. In study 2, 61 healthy adult subjects were enrolled at 4 sites and randomized 2:2: 1:1, respectively, to receive either 2 doses of (1) 50 μg of Norwalk VLP vaccine (20 subjects, circles), (2) 100 μg of Norwalk VLP vaccine (20 subjects, triangles); (3) adjuvant control (10 subjects, filled diamonds), or (4) true placebo (11 subjects, open diamonds) consisting of a puff of air (no dry powder). C, Serum IgG geometric mean titers from study 2. D, Serum IgA geometric mean titers from study 2. All doses were delivered intranasally, and the 2-dose regimen was separated by 21 days.

Figure 2.

Norwalk virus-like particle (VLP)-specific hemagglutination inhibition antibody geometric mean titers, by group in study 2. Sixty-one healthy adult subjects were enrolled at 4 sites and randomized 2:2:1:1, respectively, to receive either 2 doses of (1) 50 μg of Norwalk VLP vaccine (20 subjects, circles), (2) 100 μg of Norwalk VLP vaccine (20 subjects, triangles), (3) adjuvant control (10 subjects, filled diamonds), or (4) true placebo (11 subjects, open diamonds) consisting of a puff of air (no dry powder). All doses were delivered intranasally, and the 2-dose regimen was separated by 21 days.