title: Safety and Immunogenicity of a Candidate Bioconjugate Vaccine against Shigella flexneri 2a Administered to Healthy Adults: a Single-Blind, Randomized Phase I Study.
abstract: Several candidate vaccines against Shigella spp. are in development, but the lack of a clear correlate of protection from challenge with the induction of adequate immune responses among the youngest age groups in the developing world has hampered Shigella vaccine development over the past several decades. Bioconjugation technology, exploited here for an Shigella flexneri 2a candidate vaccine, offers a novel and potentially cost-effective way to develop and produce vaccines against a major pathogen of global health importance. Flexyn2a, a novel S. flexneri 2a bioconjugate vaccine made of the polysaccharide component of the S. flexneri 2a O-antigen, conjugated to the exotoxin protein A of Pseudomonas aeruginosa (EPA), was evaluated for safety and immunogenicity among healthy adults in a single-blind, phase I study with a staggered randomization approach. Thirty subjects (12 receiving 10 μg Flexyn2a, 12 receiving Flexyn2a with aluminum adjuvant, and 6 receiving placebo) were administered two injections 4 weeks apart and were followed for 168 days. Flexyn2a was well-tolerated, independently of the adjuvant and number of injections. The Flexyn2a vaccine elicited statistically significant S. flexneri 2a lipopolysaccharide (LPS)-specific humoral responses at all time points postimmunization in all groups that received the vaccine. Elicited serum antibodies were functional, as evidenced by bactericidal activity against S. flexneri 2a. The bioconjugate candidate vaccine Flexyn2a has a satisfactory safety profile and elicited a robust humoral response to S. flexneri 2a LPS with or without inclusion of an adjuvant. Moreover, the bioconjugate also induced functional antibodies, showing the technology's features in producing a promising candidate vaccine. (This study has been registered at ClinicalTrials.gov under registration no. NCT02388009.).
authors: Naval Medical Research Center, Silver Spring, Maryland, USA mark.s.riddle10.mil@mail.mil veronica.gambillara@lmtbio.com.
authors: Mark S
authors: MS
authors: Riddle
authors: Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Robert W
authors: RW
authors: Kaminski
authors: LimmaTech Biologics, Schlieren, Switzerland.
authors: Claudio
authors: C
authors: Di Paolo
authors: Naval Medical Research Center, Silver Spring, Maryland, USA.
authors: Chad K
authors: CK
authors: Porter
authors: Naval Medical Research Center, Silver Spring, Maryland, USA.
authors: Ramiro L
authors: RL
authors: Gutierrez
authors: Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Kristen A
authors: KA
authors: Clarkson
authors: Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Hailey E
authors: HE
authors: Weerts
authors: Naval Medical Research Center, Silver Spring, Maryland, USA.
authors: Christopher
authors: C
authors: Duplessis
authors: Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Amy
authors: A
authors: Castellano
authors: LimmaTech Biologics, Schlieren, Switzerland.
authors: Cristina
authors: C
authors: Alaimo
authors: Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors: Kristopher
authors: K
authors: Paolino
authors: Naval Medical Research Center, Silver Spring, Maryland, USA.
authors: Robert
authors: R
authors: Gormley
authors: LimmaTech Biologics, Schlieren, Switzerland mark.s.riddle10.mil@mail.mil veronica.gambillara@lmtbio.com.
authors: Veronica
authors: V
authors: Gambillara Fonck
mesh_terms: D036002:ADP Ribose Transferases / Q000235:genetics / Q000276:immunology; D000293:Adolescent; D000328:Adult; D000907:Antibodies, Bacterial / Q000097:blood* / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology; D004405:Dysentery, Bacillary / Q000276:immunology / Q000517:prevention & control*; D005098:Exotoxins / Q000235:genetics / Q000276:immunology; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D000071497:Immunogenicity, Vaccine; D007070:Immunoglobulin A / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D008875:Middle Aged; D019081:O Antigens / Q000276:immunology; D022281:Shigella Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D012763:Shigella flexneri / Q000276:immunology*; D012764:Shigella sonnei / Q000276:immunology; D016037:Single-Blind Method; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology; D055815:Young Adult; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D005098:Exotoxins; D007070:Immunoglobulin A; D008070:Lipopolysaccharides; D019081:O Antigens; D022281:Shigella Vaccines; D018074:Vaccines, Conjugate; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A