Neisseria meningitidis factor H-binding protein fHbp: a key virulence factor and vaccine antigen

Abstract

Neisseria meningitidis is a leading cause of meningitis and sepsis worldwide. The first broad-spectrum multicomponent vaccine against serogroup B meningococcus (MenB), 4CMenB (Bexsero^®), was approved by the EMA in 2013, for prevention of MenB disease in all age groups, and by the US FDA in January 2015 for use in adolescents. A second protein-based MenB vaccine has also been approved in the USA for adolescents (rLP2086, Trumenba^®). Both vaccines contain the lipoprotein factor H-binding protein (fHbp). Preclinical studies demonstrated that fHbp elicits a robust bactericidal antibody response that correlates with the amount of fHbp expressed on the bacterial surface. fHbp is able to selectively bind human factor H, the key regulator of the alternative complement pathway, and this has important implications both for meningococcal pathogenesis and for vaccine design. Here, we review the functional and structural properties of fHbp, the strategies that led to the design of the two fHbp-based vaccines and the data generated during clinical studies.

Keywords:

• 4CMenB
• Bexsero vaccine
• factor H-binding protein
• rLP2086
• Trumenba vaccine

Financial & competing interests disclosure

V Masignani, M Scarselli and D Toneatto are currently employed by Novartis Vaccines. During the writing of this manuscript, M Comanducci and K Seib were employees of Novartis Vaccines. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Factor H-binding protein (fHbp, previously called GNA1870 or LP2086) is a Neisseria-specific lipoprotein and an important virulence determinant that is a component of two recently licensed vaccines – Bexsero^® (4CMenB, Novartis Vaccines) and Trumenba^® (rLP2086, Pfizer).

• Bexsero, a multicomponent vaccine that contains fHbp variant 1.1, neisserial adhesin A (NaDA), neisserial heparin-binding antigen (NHBA) and outer membrane vesicles (OMVs) of the New Zealand outbreak strain NZ98/254, is currently licensed in several countries for use in individuals >2 months of age and in the USA for use in adolescents. Trumenba, a bivalent vaccine containing two subvariants of recombinant lipidated fHbp (subfamily A05/subvariant 3.45 and subfamily B01/subvariant 1.55), is licensed in the USA for use in adolescents.

• Several vaccine trials have shown both vaccines to be immunogenic and able to induce bactericidal antibodies in all age groups. Although some indications are available about the potential of Bexsero on carriage, more data are needed to demonstrate a clear herd immunity effect of both vaccines on MenB carriers.

• Although Bexsero has acceptable safety and tolerability profiles, increased reactogenicity has been observed in infants upon concomitant administration of routine vaccines. In the case of Trumenba, clinical studies in infants have shown an unacceptable reactogenicity profile in this age group.

• Although fHbp is present in most meningococcal strains, a few invasive isolates have been identified which either have a frameshifted gene or express fHbp at minimal levels, suggesting that this factor is not essential for virulence and therefore the emergence of escape mutants could be possible in principle.

Notes