Three doses of an experimental detoxified L3-derived lipooligosaccharide meningococcal vaccine offer good safety but low immunogenicity in healthy young adults

Abstract

This open, randomized phase I study evaluated the safety and reactogenicity of an experimental meningococcal serogroup B (MenB) vaccine obtained from outer membrane vesicle detoxified L3-derived lipooligosaccharide. Healthy young adults (n = 150) were randomized to receive either experimental vaccine (provided in five formulations, n = 25 in each group) or VA-Mengoc-BC (control, n = 25) administered on a 0- to 6-week/6-month schedule. Serum bactericidal assays performed against three MenB wild-type strains assessed the immune response, defined as a 4-fold increase from pre- to postvaccination. No serious adverse events related to vaccination were reported. Pain at the injection site, fatigue, and headache were the most commonly reported adverse events. Solicited adverse events graded level 3 (i.e., preventing daily activity) were pain (up to 17% of the test subjects versus 32% of the controls), fatigue (up to 12% of the test subjects versus 8% of the controls), and headache (up to 4% of any group). Swelling graded level 3 (greater than 50 mm) occurred in up to 4% of the test subjects versus 8% of the controls. The immune responses ranged from 5% to 36% across experimental vaccines for the L3 H44-76 strain (versus 27% for the control), from 0% to 11% for the L3 NZ98/124 strain (versus 23% for the control), and from 0% to 13% for the L2 760676 strain (versus 59% for the control). All geometric mean titers were below those measured with the control vaccine. The five experimental formulations were safe and well tolerated but tended to be less immunogenic than the control vaccine.

FIG. 1.

Schematic structure of the LOS of N. meningitidis. L7 and TrL3 are both truncated forms of the L3 LOS; lst and lgtB are mutations of the LOS used to prepare the L7 and TrL3 epitopes; msbB is a mutation developed to detoxify the lipid A moiety; the tetrasaccharidic chain (lacto-N-neotetraose) is in bold (Gal-GlcNAc-Gal-Glc). a, sialic acid; Gal, galactose; Glc, glucose; GlcNac, N-acetylglucosamine; Hep, heptose; KDO, 2-keto-3-deoxyoctulosonic acid; PEA, phosphoethanolamine. Modified from reference .

FIG. 2.

Study flow chart. One hundred fifty subjects were randomized among five experimental formulations and a placebo. Group TrL3-4a (n = 25), TrL3 with 4 μg LOS (∼25 μg protein), adsorbed formulation; group TrL3-8a (n = 25), TrL3 with 8 μg LOS (∼50 μg protein), adsorbed formulation; group TrL3-8n (n = 25), TrL3 with 8 μg LOS (∼50 μg protein), nonadsorbed formulation; group L7-8a (n = 25), L7 with 8 μg LOS (∼50 μg protein), adsorbed formulation; group L7-8n (n = 25), L7 with 8 μg LOS (∼50 μg protein), nonadsorbed formulation; control group VAMen (n = 25), licensed VA-Mengoc-BC. AE, adverse event; EX, excluded from the analysis; ICFW, informed consent form withdrawn; LFUC, lost to follow-up with complete vaccination; LFUI, lost to follow-up with incomplete vaccination; MV, moved; PV, protocol violation. *, one informed consent form, signed by the subject's sister instead of the mother, led to the subject's withdrawal from the study, and the subject was replaced.