title: Phase I study of a lipooligosaccharide-based conjugate vaccine against nontypeable Haemophilus influenzae.
abstract: Nontypeable Haemophilus influenzae (NTHi) accounts for about one-third of purulent otitis media (OM) in children and is a common cause of pulmonary infection in adults with decreased resistance. Based upon sero-epidemiological data in humans and immunochemical data in laboratory animals, a lipooligosaccharide (LOS)-tetanus toxoid (TT) conjugate was prepared and evaluated for its safety and immunogenicity in a Phase I study of 40 healthy adults. The conjugate was injected intramuscularly into all volunteers: 28 of them received a second injection 14 weeks later. Local and systemic reactions were monitored and sera, taken before and 2, 6, 14, 16, and 38 weeks after injection, were assayed for IgG, IgA, and IgM antibodies to the LOS by ELISA and for bactericidal activity. The results indicate that there were no significant local or systemic reactions after either injection. All volunteers had pre-existing IgG anti-LOS. The geometric mean (GM) level rose from 14 to 40 at 2 weeks, remained at 35 at 6 weeks (40 or 35 versus 14, P<0.01) and dropped to 27 at 14 weeks after the first injection. There was also a rise 2 weeks after the second injection (27 versus 37, P<0.05). A total of 52.5% of subjects showed serum-conversion (greater than four-fold increase) after one and two injections. At 38 weeks, the GM IgG anti-LOS was still higher than before initial injection (20 versus 14, P<0.05). A similar pattern of reactivity was observed for IgA and IgM anti-LOS. Similar to that observed in mice, but not in rabbits, the conjugate-induced antibodies did not yield significant bactericidal activity in vitro. The LOS-TT conjugate is well tolerant in adults and a Phase II evaluation of the conjugate in children is planned.
authors.affiliation: National Institute on Deafness and Other Communication Disorders, 5 Research Court, Rockville, MD 20850, USA. guxx@nidcd.nih.gov
authors.forename: Xin-Xing
authors.initials: XX
authors.lastname: Gu
authors.forename: Susan F
authors.initials: SF
authors.lastname: Rudy
authors.forename: Chiayung
authors.initials: C
authors.lastname: Chu
authors.forename: Linda
authors.initials: L
authors.lastname: McCullagh
authors.forename: Hung N
authors.initials: HN
authors.lastname: Kim
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Jianping
authors.initials: J
authors.lastname: Li
authors.forename: John B
authors.initials: JB
authors.lastname: Robbins
authors.forename: Carter
authors.initials: C
authors.lastname: Van Waes
authors.forename: James F
authors.initials: JF
authors.lastname: Battey
mesh_terms: D000328:Adult; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D000917:Antibody Formation; D002648:Child; D004797:Enzyme-Linked Immunosorbent Assay; D006192:Haemophilus Infections / Q000276:immunology*; D018073:Haemophilus Vaccines / Q000633:toxicity*; D006193:Haemophilus influenzae / Q000145:classification / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D010033:Otitis Media / Q000276:immunology / Q000382:microbiology; D012016:Reference Values; D013745:Tetanus Toxoid / Q000276:immunology; D013997:Time Factors; D018074:Vaccines, Conjugate / Q000633:toxicity*
chemical_list: D000907:Antibodies, Bacterial; D018073:Haemophilus Vaccines; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; D013745:Tetanus Toxoid; D018074:Vaccines, Conjugate; C023023:lipid-linked oligosaccharides