Sex, Age, and Race Effects on Immunogenicity of MenB-FHbp, A Bivalent Meningococcal B Vaccine: Pooled Evaluation of Clinical Trial Data

Invasive meningococcal disease (IMD) is a rare but life-threatening condition caused by Neisseria meningitidis and is most commonly diagnosed in children aged < 1 year, adolescents, and young adults [1]. Disease typically manifests as meningitis or bacteremia, with case fatality rates from 10% to 20% and debilitating long-term sequelae in up to 20% of survivors [1]. In several regions worldwide, meningococcal serogroup B (MenB) accounts for more cases of IMD than any other serogroup, causing 38% of cases in the USA and 51% of cases in the European Union in 2017 [2, 3]. Vaccination is the most effective method for large-scale prevention of IMD [4].

MenB-FHbp (Trumenba^®, bivalent rLP2086; Pfizer Inc, Philadelphia, PA, USA), which consists of two recombinant factor H binding protein (FHbp) variants from each subfamily [subfamily A (variant A05) and subfamily B (variant B01)], is one of two vaccines licensed to prevent MenB disease [5, 6]. Because individual MenB strains generally express a single subfamily variant [7, 8], the MenB-FHbp formulation is predicted to broadly protect against diverse MenB disease-causing strains [7]. An extensive clinical development program has been completed for MenB-FHbp [9], but the impact of sex, age, and race on MenB-FHbp immunogenicity has not been systematically assessed.

Variability in vaccine responses based on age [10‐14], sex [15‐19], and race [20‐23] has been observed for other vaccines. Therefore, it is important for public health authorities and medical practitioners to understand whether differences in vaccine efficacy occur in various populations in order to maximize vaccine benefit [15, 16, 18, 24]. Moreover, understanding the challenges to effective vaccination in specific populations can inform vaccine clinical trial design and vaccine uptake after licensure [18, 20].

MenB-FHbp was shown to elicit robust immune responses and to have an acceptable safety profile during an extensive clinical development program, including studies enrolling 20,803 adolescents and adults [9]. Although data analyzed by demographic subsets have not been published, differences in point estimates of immunogenicity end points based on sex and race were observed in some of the individual studies [8]. However, there were too few participants within each study to provide a comprehensive assessment of the impact of demographics on immunogenicity. Therefore, the current analysis pooled data from studies across the MenB-FHbp clinical development program to generate a larger sample size for evaluating whether sex, age, or race affected MenB-FHbp immunogenicity.

Robust immunogenicity of MenB-FHbp has been individually shown in each of the 11 clinical studies collectively enrolling > 20,000 adolescents and adults [9]. A pooled analysis from seven of these clinical studies, which included > 8000 subjects from the clinical development program, was conducted to detect any emergent effects of demographic factors on MenB-FHbp immunogenicity. In this subgroup analysis, immunogenicity was similar across sex, ages assessed, and race (predominantly white and black). Some variation in hSBA responses was observed between individual test strains across all groups analyzed; this is expected based on differences in FHbp sequences and cell surface expression levels across MenB strains [33, 34]. Moreover, although minor differences by sex were observed among percentages of subjects with ≥ 4-fold rise in titers from baseline, percentages of subjects with titers ≥ LLOQ, and GMTs, the percentages of subjects with titers ≥ 1:4 against each test strain were highly consistent. Because an hSBA titer of 1:4 is the accepted correlate of protection from meningococcal disease [31, 32], the slight differences in immunogenicity end points reported here are unlikely to be clinically meaningful and do not impact current MenB-FHbp vaccination recommendations [5]. Although the current analysis was focused on immunogenicity only, it should be noted that a previous analysis identified no safety concerns among data pooled from adolescents and adults in the MenB-FHbp clinical development program (unpublished data).

Sex, age, and race were selected as factors to include in this analysis because these characteristics have previously been associated with variable immunogenicity of numerous vaccines [10‐12, 15‐23]. These demographic influences also interact with one another, illustrated in part by fluctuations in sex-dependent immune responses at different times throughout the lifespan [15, 19, 24]. A commonly observed influential variable is age, which is typically associated with decreased immunogenicity in infants and adults aged ≥ 65 years [10, 11]. As an example, clinical trials with live-attenuated and inactivated influenza vaccines are of interest to highlight differences in vaccine efficacy by age group. In a study of children aged 6–59 months, there were 54.9% fewer cases of culture-confirmed influenza among study children who received the live-attenuated vaccine compared with the group who received the inactivated vaccine [35]. In contrast, in a study of adults aged 18–49 years, the inactivated vaccine provided a 50% reduction in confirmed influenza compared with those given the live-attenuated vaccine [36]. Among children, adolescents, and young adults, aging may either increase or decrease immune responses depending on the vaccine [37‐40]. Variable vaccine efficacy among the above-listed age groups has also been shown specifically for some strain-specific MenB outer membrane vesicle (OMV) vaccines. For example, a case-control study of an OMV antigen-based vaccine developed in Cuba found that protective efficacy was greater among Brazilian adults aged 24–47 years compared with those aged < 24 years [39]. In a review of OMV antigen-based MenB vaccines with vaccine efficacy or hSBA data published before 2015, several studies showed variability across age groups in both vaccine effectiveness and hSBA responses [40]. Additionally, there is evidence to suggest immune responses to vaccines can vary even within the specific age range included in this study. Two studies investigating the immunogenicity of a bivalent human papillomavirus vaccine among female subjects aged 10–25 years found that antibody responses following vaccination were higher in subjects aged 10–14 years compared with those aged 15–25 years [13, 14]. However, in the study presented here, the small differences observed in immune responses between different age groups were not considered clinically meaningful.

Sex differences in vaccine response have also been reported for some vaccines [15‐19]. Although the reasons for these differences are not fully understood [15], underlying mechanisms may include sex-based differences in innate and adaptive immunity [17, 18], modulations of immune cell function by sex hormones [15‐17, 24], genetic influences [15, 17, 24], and sex-specific features of the diet or microbiome [15]. Most vaccines elicit stronger immune responses in women than in men [15, 17], and this trend persists throughout the lifespan from infancy into late adulthood [19, 24]. An example of this observation is the seasonal trivalent inactivated influenza vaccine, which produces significantly higher GMTs in women compared with men, regardless of dose amount or age [41].

Additionally, some vaccines are associated with variable immune responses based on race or geographic location of the vaccinated subject [20‐23, 42, 43]. For example, compared with infants from other countries, those from the Philippines showed lower seroprotection rates and geometric mean concentrations against hepatitis B after vaccination with the combined diphtheria, tetanus, and whole cell pertussis–hepatitis B virus and Haemophilus influenzae type b conjugate vaccine with oral live attenuated poliovirus vaccine (DTPw-HBV/Hib-TT + OPV) coadministered with either a 7- or 10-valent pneumococcal conjugate vaccine [43]. These and other variable responses could result from genetic or environmental factors, although the precise contributions of each are unclear [20‐23]. Because the predominant disease-causing vaccine serotypes may differ across global regions [44, 45], responses to vaccinations may also differ geographically.

The effects of sex, age, and race have not been comprehensively reported for licensed, broad-spectrum MenB vaccines. Controlled studies that investigate the possible influence of demographics on vaccine immunogenicity are important for informing vaccine recommendations [15, 16, 19, 24]. The main strength of this subgroup analysis was its large sample size of > 8000 subjects from the pooled evaluable immunogenicity population across seven randomized clinical studies conducted with similar methodology. Limitations include the relatively restricted age range of subjects (10–25 years), although forthcoming data could potentially address subgroup differences in immunogenicity among younger cohorts. Moreover, generalizability of age and race results is limited by the age groups and races included in this study, as most of the evaluable population was aged 10–18 years (80.7%) and white (87.0%). Additionally, most of the racial diversity from this analysis came from only a small number of studies; most of the subjects included were white or black, with Asians and other races representing 0.8% and 3% of the total evaluable immunogenicity population, respectively. As such, studies including a greater number of Asians and other races are needed to reach meaningful conclusions regarding immune responses to MenB-FHbp in these groups. Furthermore, this study focuses on the three-dose MenB-FHbp vaccination schedule; the effects of sex, age, and race on immune responses following a two-dose (0-, 6-month) schedule, which is also approved [5], were not evaluated. Despite these considerations, it is notable that these analyses suggested no clinically meaningful differences in immunogenicity between groups based on sex, ages assessed, or races evaluated, which indicates that no changes in the clinical management of these subpopulations are warranted regarding vaccination with MenB-FHbp. Additional insight could be provided by long-term follow-up from studies further evaluating the impact of demographics on immunogenicity.

The immunogenicity profile of the MenB-FHbp vaccine suggested that there were no clinically meaningful differences by sex, age groups assessed or race (predominantly white and black) across three-dose data pooled from the clinical development program. The robust immune responses and lack of clinically significant differences across demographic groups support the continued use of MenB-FHbp for prevention of MenB disease in these populations, as is currently recommended by health authorities.