Safety, immunogenicity, and tolerability of meningococcal serogroup B bivalent recombinant lipoprotein 2086 vaccine in healthy adolescents: a randomised, single-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Neisseria meningitidis serogroup B is a major cause of invasive meningococcal disease, but a broadly protective vaccine is not currently licensed. A bivalent recombinant factor H-binding protein vaccine (recombinant lipoprotein 2086) has been developed to provide broad coverage against diverse invasive meningococcus serogroup B strains. Our aim was to test the immune response of this vaccine.

METHODS: This randomised, placebo-controlled trial enrolled healthy adolescents from 25 sites in Australia, Poland, and Spain. Exclusion criteria were previous invasive meningococcal disease or serogroup B vaccination, previous adverse reaction or known hypersensitivity to the vaccine, any significant comorbidities, and immunosuppressive therapy or receipt of blood products in the past 6 months. Participants were randomly assigned with a computerised block randomisation scheme to receive ascending doses of vaccine (60, 120, or 200 μg) or placebo at 0, 2, and 6 months. Principal investigators, participants and their guardians, and laboratory personnel were masked to the allocation; dispensing staff were not. Immunogenicity was measured by serum bactericidal assays using human complement (hSBA) against eight diverse meningococcus serogroup B strains. The co-primary endpoints were seroconversion for the two indicator strains (PMB1745 and PMB17) analysed by the Clopper-Pearson method. Local and systemic reactions and adverse events were recorded. The study is registered at ClinicalTrials.gov, number NCT00808028.

FINDINGS: 539 participants were enrolled and 511 received all three study vaccinations--116 in the placebo group, 21 in the 60 μg group, 191 in the 120 μg group, and 183 in the 200 μg group. The proportion of participants responding with an hSBA titre equal to or greater than the lower limit of quantitation of the hSBA assays (reciprcocal titres of 7 to 18, depending on test strain) was similar for the two largest doses and ranged from 75·6 to 100·0% for the 120 μg dose and 67·9 to 99·0% for the 200 μg dose. Seroconversion for the PMB1745 reference strain was 17 of 19 (89·5%) participants for the 60 μg dose, 103 of 111 (92·8%) participants for the 120 μg dose, 94 of 100 (94·0%) participants for the 200 μg dose, and four of 73 (5·5%) participants for placebo. For the PMB17 reference strain seroconversion was 17 of 21 (81·0%) participants for the 60 μg dose, 97 of 112 (86·6%) participants for the 120 μg dose, 89 of 105 (84·8%) participants for the 200 μg dose, and one of 79 (1·3%) participants for placebo. The hSBA response was robust as shown by the high proportion of responders at hSBA titres up to 16. Mild-to-moderate injection site pain was the most common local reaction (50 occurrences with the 60 μg dose, 437 with the 120 μg dose, 464 with the 200 μg dose, and 54 with placebo). Systemic events, including fatigue and headache, were generally mild to moderate. Overall, adverse events were reported by 18 participants (81·8%) in the 60 μg group, 77 (38·9%) in the 120 μg group, 92 (47·2%) in the 200 μg group, and 54 (44·6%) in the placebo group. Fevers were rare and generally mild (one in the 60 μg group, 24 in the 120 μg group, 35 in the 200 μg group, and five in the placebo group; range, 0-6·3% after each dose). Incidence and severity of fever did not increase with subsequent vaccine dose within groups. One related serious adverse event that resolved without sequelae occurred after the third dose (200 μg).

INTERPRETATION: The bivalent recombinant lipoprotein 2086 vaccine is immunogenic and induces robust hSBA activity against diverse invasive meningococcus serogroup B disease strains and the vaccine is well tolerated. Recombinant lipoprotein 2086 vaccine is a promising candidate for broad protection against invasive meningococcus serogroup B disease.

FUNDING: Wyeth, Pfizer.