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Pharmacology: Pharmacodynamics: Mechanism of action: Protection against invasive meningococcal disease is mediated by serum bactericidal antibodies to bacterial surface antigens. Bactericidal antibodies act in concert with human complement to kill meningococci. This process is measured in vitro with serum bactericidal assay using human complement (hSBA) for serogroup B. A positive response in SBA is an accepted correlate of protection from meningococcal disease.
Trumenba [bivalent rLP2086] is a vaccine composed of two recombinant lipidated factor H binding proteins (fHbps) and prevents serogroup B disease by inducing broadly protective bactericidal antibody responses against epidemiologically diverse serogroup B strains. fHbp is found on the surface of meningococcal bacteria and is essential for bacteria to avoid host immune defenses. fHbps segregate into two immunologically distinct subfamilies, A and B, and >95% of serogroup B strains express fHbps from either subfamily.
Vaccination with Trumenba, which contains one fHbp each from subfamily A and B, elicits bactericidal antibodies directed against fHbp found on the surface of N. meningitidis serogroup B strains.
Clinical efficacy: The efficacy of Trumenba has not been evaluated through clinical trials. Vaccine efficacy has been inferred by demonstrating the induction of serum bactericidal antibody responses to four meningococcal serogroup B test strains (see the Immunogenicity as follows). The four test strains express fHbp variants representing the two subfamilies (A and B) and, when taken together, are representative of prevalent strains causing invasive disease. The studies assessed the proportions of subjects with a response (hSBA titer of at least 1:8 or 1:16 depending on the hSBA strain), the proportions of subjects with a 4-fold or greater increase from baseline in hSBA titer for each of the four strains and the composite response (a response for the four hSBA strains combined). The studies also assessed the proportion of subjects achieving a defined hSBA titer against a panel of 10 additional strains, each expressing a different fHbp variant. These additional hSBAs support and extend the breadth of vaccine coverage demonstrated by the 4 representative primary strains.
Immunogenicity: The immunogenicity of Trumenba described in this section is based on results from four clinical studies: Following the two-dose schedule (0 and 6 months) in subjects 10 to 25 years of age in the United States (US) and Europe (Study B1971057 [Study 1057]); Following the three-dose schedule (0, 2, and 6 months) in subjects 10 to 25 years of age globally (Studies B1971009 [Study 1009] and B1971016 [Study 1016]); Following the two-dose (0 and 6 months) and three-dose schedules (0, 1-2, and 6 months) in subjects 11 to 18 years of age in Europe (Study B1971012 [Study 1012]).
Study 1057 is a Phase 3, randomized, active-controlled, observer-blinded, multicenter trial in which subjects received Trumenba at 0 and 6 months (Trumenba was coadministered with MenACWY-CRM for the first dose) or an investigational pentavalent meningococcal vaccine at 0 and 6 months. The hSBA responses to four test strains observed after the second dose of Trumenba are presented in Table 1. (See Table 1.)
Click on icon to see table/diagram/imageThe proportion of subjects achieving a defined hSBA titer after 2 doses of Trumenba, administered on a 0- and 6-month schedule, was evaluated against a panel of 10 additional strains, each expressing a different fHbp variant (see Table 2).
Click on icon to see table/diagram/imageStudy 1009 was a Phase 3, randomized, active-controlled, observer-blinded, multicenter trial in which subjects aged 10 to 18 years received 1 of 3 lots (Groups 1, 2, and 3) of Trumenba or the active control hepatitis A virus (HAV) vaccine/saline (Group 4). The study assessed the safety, tolerability, immunogenicity, and demonstration of manufacturability of 3 lots of Trumenba administered on a 0-, 2-, and 6-month schedule. The hSBA responses to four test strains observed after the third dose in Group 1 and 4 are presented in Table 3. Results from Groups 2 and 3 are not presented, as only 2 representative strains were evaluated. Similar results were observed in Groups 2 and 3 as observed in Group 1.
Study 1016 was a Phase 3, randomized, placebo-controlled, observer-blinded, multicenter trial in which subjects 18 to 25 years of age were assigned to 2 groups in a 3:1 ratio (Group 1: Group 2). Group 1 received Trumenba at months 0, 2, and 6. Group 2 received saline at months 0, 2, and 6. The hSBA responses to four test strains observed after the third dose in Group 1 and 2 are presented in Table 3. (See Table 3.)
Click on icon to see table/diagram/imageIn Studies 1009 and 1016, the proportion of subjects achieving a defined hSBA titer after 3 doses of Trumenba, administered on a 0-, 2-, and 6-month schedule, was evaluated against a panel of 10 additional strains, each expressing a different fHbp variant (see Table 4).
Click on icon to see table/diagram/imageIn Study 1012, Trumenba was administered according to the following schedules: Group 1 (0, 1, and 6 months); Group 2 (0, 2, and 6 months); Group 3 (0 and 6 months); Group 4 (0 and 2 months); Group 5 (0 and 4 months) [see Adverse Reactions]. The hSBA responses observed after the second or third dose for Groups 1, 2 and 3 are presented in Table 5. (See Table 5.)
Click on icon to see table/diagram/imageLimited immunogenicity data is available for subjects 40 years and above.
Concomitant vaccine administration: In Study B1971010 (Study 1010) conducted in Europe, the immunogenicity of dTaP-IPV (a combined low-dose diphtheria, tetanus, acellular pertussis, and inactivated poliomyelitis virus vaccine) given concomitantly with the first dose of Trumenba was evaluated in adolescents 11 to 18 years of age. Noninferiority was demonstrated, as the lower limit of the 2-sided 95% CI for the difference in proportion of responders between the Trumenba + dTaP-IPV group (Group 1) and the dTaP-IPV-alone group (Group 2) 1 month after the dTaP-IPV dose was greater than -0.10 (-10%) for the 9 antigens in dTaP-IPV (i.e., the lowest lower bound of the 95% CI on the proportion difference was -4.7% [pertussis toxoid]).
In Study B1971011 (Study 1011) conducted in the US, the immunogenicity of concomitantly administered Trumenba and HPV4 vaccine was evaluated in adolescents 11 to 17 years of age. Immune responses were evaluated by comparisons of geometric mean titers (GMTs) for each human papillomavirus (HPV) type at 1 month after the third HPV4 vaccination and hSBA GMTs using two meningococcal serogroup B test strains [variants A22 and B24] 1 month after the third vaccination with Trumenba. The noninferiority criteria for comparisons of the GMT ratio (lower limit of the 2-sided 95% confidence interval of the GMT ratio >0.67) were met for three HPV types (6, 11, and 16) and for the meningococcal serogroup B strains. For HPV-18, the lower bound of the 95% confidence interval (CI) for the GMT ratio was 0.62 at one month after the third HPV4 vaccination. One month after Dose 3 with HPV4, ≥99% of subjects seroconverted to all 4 HPV antigens in both the saline + HPV4 and Trumenba + HPV4 groups.
In Study B1971015 (Study 1015) conducted in the US, the immunogenicity of concomitantly administered Trumenba with meningococcal polysaccharide (serogroups A, C, Y and W 135) diphtheria toxoid conjugate (MenACWY) and Tdap vaccines was evaluated in adolescents 10 to 12 years of age. Immune responses were evaluated by comparisons of GMTs for each of 10 MenACWY and Tdap antigens 1 month after the first vaccination. The criterion for the noninferiority margin of 1.5-fold was met for all MenACWY and Tdap antigens.
Persistence of immunity and response to booster vaccination: Study B1971033 (Study 1033) was an open-label, follow-up study of subjects previously enrolled in a primary study, including Study 1012. Subjects attended visits over 4 years for collection of blood samples and received a single booster dose of Trumenba approximately 4 years after receipt of a primary series of 2 or 3 doses of Trumenba.
The hSBA responses 4 years after the primary series and 26 months after the booster dose for subjects enrolled from primary Study 1012 Group 1 (0, 1, and 6 months), Group 2 (0, 2, and 6 months), and Group 3 (0 and 6 months) are presented in Tables 6 and 7. (See Tables 6 and 7.)
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Click on icon to see table/diagram/imagePharmacokinetics: Not applicable.
Toxicology: Preclinical safety data: Non-clinical data revealed no special hazard for humans based on conventional studies of repeated dose toxicity, local tolerance, and reproduction and developmental toxicity.
Reproduction studies performed in female rabbits at doses equivalent to the highest administered human dose have revealed no evidence of impaired female fertility or harm to the fetus due to Trumenba. Because animal reproductive studies are not always predictive of the human response, this vaccine should be used during pregnancy only if clearly needed. Trumenba has not been evaluated for impairment of fertility in males.
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