A Phase 4 Trial to Describe the Immunogenicity, Safety, and Tolerability of <scp>MenB</scp> ‐ <scp>fHbp</scp> in Participants &gt; 10 Years of Age With Asplenia or Complement Deficiency

Invasive meningococcal disease (IMD) is a life-threatening disease caused by Neisseria meningitidis infection [1]. Meningococcal serogroup B (MenB) is the predominant disease-causing serogroup in numerous regions, including the United States and Europe [1]. The MenB-fHbp (Trumenba [bivalent rLP2086]; Pfizer Inc., Philadelphia, PA, USA) MenB vaccine is composed of two lipidated factor H binding protein (fHbp) variants from subfamily A and subfamily B [2]. MenB-fHbp is licensed to prevent IMD due to MenB as a two- or three-dose schedule (Europe: individuals ≥ 10 years of age; United States: individuals 10–25 years of age) on the basis of clinical data from healthy individuals [2-4]. To our knowledge, no studies have evaluated MenB-fHbp immunogenicity in individuals with primary or secondary immunodeficiencies. We conducted a phase 4, open-label, single-arm study (NCT04893811) in participants ≥ 10 years of age with anatomic/functional asplenia or complement deficiency (including C5-C9, properdin, factor D, and factor H deficiencies) between August 18, 2021, and September 5, 2023, at 12 sites across the Czech Republic, Poland, and Turkey. MenB-fHbp was administered on a 0-, 6-month schedule via prefilled syringe (containing a 0.5-mL dose of 120 μg lipidated recombinant fHbp; 60 μg of each subfamily variant). Blood was collected before Dose 1 and 1 month post-Dose 2 (PD2). Comparator data from an age- and sex-matched healthy historical control group (10–25 years of age; received MenB-fHbp in a previous phase 3 study [NCT03135834]) [4]. The serum bactericidal antibody assay using human complement (hSBA) measured immune responses against 4 diverse, vaccine-heterologous MenB strains (A22, A56, B24, B44) expressing fHbp variants from both fHbp subfamilies [5, 6]. The primary immunogenicity endpoint was percentage with seroprotection at 1 month PD2; exploratory endpoints were percentage with seroresponse at 1 month PD2 and hSBA geometric mean titers (GMTs) from baseline to 1 month PD2. Safety assessments included local reactions, systemic events, use of antipyretic medication ≤ 7 days after vaccination, unsolicited adverse events (AEs), serious AEs (SAEs), and medically-attended AEs (MAEs). Further details of study endpoints, safety assessments, exclusion criteria, ethical approval, and statistical methods are presented in the Supporting Information. Fifty-three study participants were enrolled and matched to 53 historical controls (Figure S1); 51 participants had anatomic/functional asplenia, of whom 18 had sickle cell disease and two had complement deficiency (C3/C4). All participants and 51 (96%) controls received the first dose of MenB-fHbp; 47 (89%) in each group completed the vaccination phase (Dose 1 through 1 month PD2). The follow-up phase (1 month PD2 through 6 months PD2) was completed by 47 (89%) participants and 46 (87%) controls. Most study participants and historical controls were White, non-Hispanic males (Table S1). Differences in the ages of participants and controls (mean [SD], 32.5 [16.6] and 22.2 [4.3] years, respectively) were due to differing age-eligibility inclusion criteria. The percentage of individuals achieving seroprotective titers at 1 month PD2 ranged from 70.5%–90.9% (study participants) and 81.8%–100% (historical controls; Figure 1A). The hSBA GMTs increased substantially from baseline to 1 month PD2 in participants (4.1–14.3 at baseline; 17.9–97.9 PD2) and controls (5.4–12.5 and 24.9–142.9, respectively; Table 1). The percentage of individuals with seroresponse at 1 month PD2 was 53.5%–76.7% and 65.1%–90.7% (Figure 1B). Local reactions post-Dose 1 (PD1) were reported in 18.9%–86.8% of study participants versus 11.8%–80.4% of historical controls and PD2 in 20.0%–93.3% versus 4.7%–60.5%, respectively (Figure 2A); most were mild to moderate in severity. Pain at the injection site was the most common local reaction in both groups; severe pain at the injection site ≤ 7 days after any vaccination occurred in 18.9% of participants versus 2.0% of controls. One participant experienced a severe local reaction: redness > 21 caliper units 2 days PD1 lasting 3 days. Systemic events PD1 were reported in 1.9%–54.7% of participants versus 2.0%–51.0% of controls and PD2 in 2.2%–53.3% versus 0%–41.9%, respectively (Figure 2B,C); most were mild to moderate in severity, with fatigue and headache the most common in both groups. No local reaction or systemic event led to withdrawal from either study. Antipyretic medication use ≤ 7 days PD1 was reported in 34.0% of participants versus 9.8% of controls, and ≤ 7 days PD2 in 28.9% and 7.0%, respectively. Adverse events, SAEs, and MAEs were more frequent among study participants than historical controls (Table S2); AEs were reported in 26.4% of participants versus 9.8% of controls ≤ 30 days PD1 and in 12.8% of individuals in both groups PD2. The study was conducted during the COVID-19 pandemic, and the most frequent AE was COVID-19 (11.3%, n = 6); the control study preceded the pandemic, and no COVID-19 occurred. Two vaccine-related AEs occurred in study participants: vomiting ≤ 30 days PD1 in one participant and bilateral periorbital swelling 5 days PD1 in a participant with previous splenectomy (no symptoms of anaphylaxis occurred; resolved spontaneously the next day); both were MAEs. Vaccine-related AEs occurred in three controls (5.9%): hypoesthesia PD1, fatigue and injection site pain PD2, and injection site pain PD2 (n = 1 each). Serious AEs throughout the study were reported by 18.9% of study participants (sickle cell anemia with crisis, n = 4; infections, n = 3; cardiac disorders, n = 2; bone fractures, n = 2; chronic pancreatitis, n = 1; bronchiectasis, n = 1) and by 2.0% of historical controls (pneumonia, n = 1); no SAE was considered vaccine-related. MAEs were reported by 32 (60.4%) participants and 16 (31.4%) controls. Two vaccine-related MAEs were reported (described above). One study participant with a history of sickle cell disease withdrew due to an SAE and died following cardiac arrest. One newly diagnosed chronic medical condition (NDCMC; secondary hypertension, n = 1) occurred and was considered not vaccine-related. Immunocompromised individuals have increased risk of severe infection [7-10]. Many severe bacterial infections affecting immunocompromised individuals are due to encapsulated bacteria, highlighting the importance of vaccination against IMD [8, 11]. In our study, most participants developed an antibody response to MenB-fHbp; immune responses in individuals with anatomic/functional asplenia (n = 43/44 individuals in the evaluable immunogenicity population had asplenia) trended lower than in the controls. In a previous UK study, asplenic adults generated significantly lower levels of functional antibody after a single dose of meningococcal serogroup C conjugate vaccine versus controls (GMT, 157.8 vs. 1448.2; p < 0.001); however, 80% achieved the proposed protective rabbit serum bactericidal antibody assay (SBA) titer ≥ 1:8 [12]. The UK study also demonstrated that time since splenectomy influences SBA response; individuals with splenectomy < 10 years before vaccination reported lower titers. Data from children with sickle cell disease immunized with meningococcal serogroup C conjugate vaccine demonstrate a rapid decline in immunogenicity following vaccination, suggesting additional doses are needed to maintain protection [13]. A study of children/adolescents with impaired splenic function showed similar levels of functional antibodies were induced by one or two doses of MenACWY conjugate vaccine across all four serogroups in immunocompromised individuals and healthy controls [14]. A study evaluating a two-dose series of the MenB vaccine 4CMenB (Bexsero; GSK, Italy) in children with asplenia or splenic dysfunction or complement deficiency reported functional antibody titers PD1 against four MenB test strains that were similar for those with functional splenic defects and those in the healthy control group but lower in individuals with complement deficiencies [15]. Between 2010 and 2018, only 28.1% and 9.7% of eligible US patients with asplenia received MenACWY and MenB vaccines, respectively, in the 3 years following asplenia diagnosis, suggesting that increased education on vaccine recommendations among immunocompromised individuals is needed [16]. In our study, despite lower titers of functional antibodies versus controls, a high percentage of asplenic participants were seroprotected (hSBA titers ≥ lower limit of quantitation [LLOQ]) following vaccination. The only evaluable complement-deficient participant also achieved seroprotection. An hSBA titer ≥ 1:4 is the accepted surrogate of protection in healthy individuals [6, 17]. In this study, a more conservative threshold (hSBA titer ≥ 1:8 or ≥ 1:16, depending on MenB strain) was used. However, it is uncertain whether protection afforded by vaccine-induced antibodies is diminished in immunocompromised versus healthy individuals. Ultimately, real-world comparison of IMD rates in vaccinated versus unvaccinated immunocompromised individuals is needed to evaluate vaccine efficacy. Given that a predisposition to certain medical events and an increased risk of infectious complications have been established in individuals with immunocompromise, the higher rates of SAEs and MAEs observed in study participants versus historical controls were unsurprising; importantly, no SAE was considered vaccine-related. This is consistent with data following a two-dose MenACWY series in asplenic or hyposplenic children/adolescents in which 4 of 43 asplenic/hyposplenic participants and 1 of 43 controls had SAEs, none considered vaccine-related [14]. Study limitations included evaluation of a surrogate of protection (hSBA titer) and no clinical utility assessments based on disease pathology or evasion of immune response. Also, the small number of participants limited the ability to compare study participants with historical healthy controls. MenB-fHbp was well tolerated with no increased safety risk in our study population of asplenic and complement-deficient individuals. MenB-fHbp elicited functional immune responses in a high percentage of immunocompromised individuals; however, hSBA responses tended to be lower than in healthy controls. In immunocompromised individuals, it is uncertain if the vaccine-induced immune response is diminished; furthermore, the waning of immune response is not fully understood. Continued surveillance and real-world data for this population are needed. This study supports MenB-fHbp use as a two-dose series in asplenic and complement-deficient individuals ≥ 10 years of age. Y.L., A.M., R.O., J.D.M., B.M., P.P., A.S.A., and J.B. contributed to the study conception or design; L.H., P.K., I.T., E.W., J.D.M., B.M., and J.B. participated in the acquisition or generation of data; Y.L., R.O., J.D.M., B.M., and J.B. performed the analyses; I.T., Y.L., A.M., R.O., J.D.M., B.M., P.P., and J.B. contributed to interpretation of the data. All authors drafted and critically reviewed the manuscript and approved the final draft. Medical writing support was provided by John Teiber, PhD, ICON (Blue Bell, PA, USA) and was funded by Pfizer Inc. This study was sponsored by Pfizer Inc. The study protocol was reviewed and approved by an institutional review board/independent ethics committee before the study was initiated. Participants or their legally authorized representatives were informed that their participation was voluntary and signed a statement of informed consent. Lukáš Homola and Piotr Korbal declare no conflicts of interest. All other authors are employees of Pfizer Inc. and may hold stock or stock options. Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information. Table S1: Demographic characteristics of study participants and historical controls; safety population. Table S2: Study participants and historical controls reporting ≥ 1 unsolicited AE for each analysis interval; safety population. Figure S1: Disposition of study participants and historical controls. *Vaccination phase is from the date of Dose 1 through 1 month after Dose 2. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.