A multi-component meningococcal serogroup B vaccine (4CMenB): the clinical development program

Abstract

Recently approved in Europe and Australia, the multi-component meningococcal B vaccine, 4CMenB (Bexsero®, Novartis Vaccines and Diagnostics), contains three surface-exposed recombinant proteins (fHbp, NadA, and NHBA) and New Zealand strain outer membrane vesicles (NZ OMV) with PorA 1.4 antigenicity. This comprehensive review of the 4CMenB clinical development program covers pivotal phase I/IIb/III studies in over 7,000 adults, adolescents, and infants. The immunological correlate for clinical protection used was human complement-mediated serum bactericidal activity titers ≥4 or 5 against indicator strains for individual antigens. Based on achievement of protective titers, a four-dose schedule (three primary doses and one booster dose) for infants and a two-dose schedule for adolescents provided the best results. Observed increases in injection site pain/tenderness and fever in infants, and injection site pain, malaise, and headache in adolescents compared with routine vaccines, were mostly mild to moderate; frequencies of rare events (Kawasaki disease, juvenile arthritis) were not significantly different from non-vaccinated individuals. 4CMenB is conservatively estimated to provide 66-91 % coverage against meningococcal serogroup B strains worldwide.

Figures

Fig. 1

Representation of the antigenic components of 4CMenB. 4CMenB contains three recombinant antigens, fHbp, NadA, and NHBA, combined with OMV from MenB strain NZ 98/254. fHbp factor H-binding protein, NadA Neisserial adhesin A, NHBA Neisseria heparin-binding antigen, OMV outer membrane vesicles, PorA-OMV NZ Porin A as part of the New Zealand strain OMV

Fig. 2

Immunogenicity in response to four doses of 4CMenB in infants. a Percentages of participants with hSBA titer ≥5. b Geometric mean titers. Error bars represent 95 % confidence intervals. Target antigens are indicated on the x axis. Immunogenicity was assessed 1 month after receipt of the third of three doses at 2, 4, and 6 months of age co-administered with routine vaccines, at 12 months of age (pre-boost) before administration of the fourth (booster) dose co-administered with the measles-mumps-rubella vaccine, and 1 month (post-boost) after the booster vaccination. fHbp factor H-binding protein, hSBA human serum bactericidal assay, NadA Neisseria adhesin A, NHBA Neisseria heparin-binding antigen, PorA-OMV NZ porin A as part of the New Zealand strain outer membrane vesicles

Fig. 3

Immunogenicity in response to two doses of 4CMenB given 1 month apart in adolescents. a Percentage of participants with hSBA titer ≥4 at 1 month after each of two doses of 4CMenB administered 1 month apart to adolescents aged 11–17 years. b Geometric mean titers. Error bars represent 95 % confidence intervals. Target antigens are indicated on the x axis. fHbp factor H-binding protein, hSBA human serum bactericidal assay, NA not available, NadA Neisseria adhesin A, NHBA Neisseria heparin-binding antigen, PorA-OMV NZ porin A as part of the New Zealand strain outer membrane vesicles

Fig. 4

4CMenB tolerability in infants. a Solicited local reactions after dose 1. Injection site data are provided for 624 infants given 4CMenB, PCV7, and DTaP-HBV-IPV/Hib concomitantly. Erythema, swelling, and induration were characterized as severe if local reaction was >50 mm. Tenderness was categorized as severe if subject cried when injected limb was moved. b Solicited general reactions after dose 1. Reactogenicity rates are given for infants who received 4CMenB and routine vaccines separately, 4CMenB at 2, 4, 6 months and routines at 3, 5, 7 months. Data are shown for the first dose of 4CMenB and routines (at 2 and 3 months, respectively). Reactions were categorized as severe if subject was unable to perform normal daily activities; fever was severe if temperature was ≥40 °C. Routine vaccines were DTaP-HBV-IPV/Hib (combined diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated polio, and Haemophilus influenzae type b vaccine) and PCV7 (7-valent pneumococcal glycoconjugate vaccine)

Fig. 5

Fever rates for 4CMenB with concomitant routine vaccines vs. routine vaccines alone by dose in infants. Fever rates are given for infants who received 4CMenB, routine vaccines, or routines + MenC. Numbers in parentheses indicate the months in which the infant received the vaccine. For study V72P12, axillary temperatures were measured in 63–64 % of subjects and rectal temperatures in 35–37 % of subjects. For study V72P13, fever was measured rectally in almost all subjects. R routine vaccines, namely DTaP-HBV-IPV/Hib (combined diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated polio, and Haemophilus influenzae type b vaccine) and PCV7 (7-valent pneumococcal glycoconjugate vaccine)

Fig. 6

Predicted capsular group B strain coverage of 4CMenB globally. The color code indicates the level of predicted coverage (no color indicates no MATS data available). MATS meningococcal antigen typing system