Vaccine Profile
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Neisseria meningitidis serogroup B bivalent factor H binding protein vaccine Expert Rev. Vaccines 14(4), 493–503 (2015)
Nathan James Brendish1 and Robert Charles Read*2 1 NIHR Wellcome Trust Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Mailpoint 218, West Wing, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK 2 Academic Unit of Clinical and Experimental Sciences and Institute for Life Sciences, University Hospital Southampton NHS Foundation Trust, University of Southampton, and NIHR Respiratory Biomedical Research Unit, Mailpoint 814, South Academic Block, Southampton General Hospital, Southampton, SO16 6YD, UK *Author for correspondence: Tel.: +44 023 8120 4404 [email protected]
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With the successful development of meningococcal vaccines against other serogroups, disease caused by Neisseria meningitidis serogroup B now accounts for a disproportionate frequency compared with other serogroups, particularly in the US and Europe. Infants and adolescents bear the highest incidence of disease, which typically manifests as meningitis and septicemia. This vaccine profile article examines a bivalent factor H binding protein (fHbp; also known as LP2086) vaccine that has now been approved by the US FDA for use in 10- to 25-year olds. The manufacturer has shelved plans for further investigation of its use in infants because of high rates of fever in Phase I and II trials in that age group. KEYWORDS: fHbp . MenB vaccine . meningococcal vaccine . rLP2086 . Trumenba
With the successful development of meningococcal vaccines against other serogroups, disease caused by Neisseria meningitidis serogroup B (MenB) now accounts for 87% of all microbiologically proven cases of meningococcal disease in England, and among infants, 94% [1]. In the USA, MenB disease accounted for over 40% of all meningococcal cases in 2012 [2]. The disease is sinister and carries an overall case fatality rate in Europe of 8% [3]. In one English study of invasive meningococcal disease, the case-fatality rate was 11%, with septicemia being a prominently poor prognostic feature [4]. There are broadly two peaks of incidence of meningococcal disease. In one large US report, children under 5 years old had the highest annual incidence, and most significantly at risk were infants aged less than 1 year (5.38 per 100,000). The second peak of incidence occurred in 18- to 24-year olds (0.76 per 100,000). Serogroup B disease followed the same age-distribution pattern (infants 83% sequence homology within the two identified subfamilies, denoted by A and B, and is present in all strains included in a database of 1837 invasive MenB isolates [18]. Clinical efficacy & safety Phase I & combined Phase I & II studies
Currently, there are five published Phase I studies relating to the bivalent fHbp vaccine, of which two are dual Phase I and II, and these studies encompassed infants (from 42 days old), toddlers (18–36 months), children and adolescents (8–14 years), young adults (18–25 years) and adults (18–40 years; summary in TABLE 1). There are two other Phase II trials, one in adolescents (11–18 years) and one in adults (18–40 years old). The Phase I and II study involving infants was terminated early due to a significant frequency of fever in those receiving the initial low doses. Sixty-four percent of infants who received a 20 mg dose of bfHbp and 90% who received the 60 mg dose became pyrexial (‡38 C), compared with 29% of controls. The study was a randomized, multi-center, single-blinded trial conducted in Spain, with test subjects receiving a dose of bfHbp alongside routine childhood vaccinations and controls receiving routine childhood vaccinations only. The trial originally planned to test 120 and 200 mg doses as well but was terminated before this, and no blood had been taken to test for immunogenicity by the time of termination. In total, from 46 participants randomized out of a planned 744, 32 infants had received a dose of bfHbp, of which 22 received 20 mg and 10 received 60 mg and no participant had received more than one dose. One subject developed aseptic meningitis after receiving a 60 mg dose along with routine vaccinations and the treating physician considered that this case was not vaccine related. However, the safety data review by a project-independent safety committee that was prompted by this case revealed the significant frequency of fever, which prompted the sponsor, Pfizer, to terminate the study [38]. The study authors note that a similar incidence of fever in a comparable infant population was noted in a large trial for rival informahealthcare.com
Vaccine Profile
vaccine 4CMenB, without significant concerns raised. For infants receiving 4CMenB along with routine childhood vaccinations, albeit in a much larger and Phase II study, fever recorded after any vaccine dose was 76 or 80% of infants depending on the protocol, however, at any single dose were 26 to 62% [39]. Another paper on infants looking at 4CMenB measured temperature differently, but found that 65.3% of infants receiving 4CMenB developed a temperature ‡38.5 C within 6 h of vaccination [40]. In a Phase I observer-blind, ascending-dose, randomized, multi-center study in Australian toddlers, three same-dose inoculations of bfHbp were administered at 20, 60 or 200 mg, depending on study arm, at 0, 1 and 6 months after enrollment. Controls were given a hepatitis A vaccine (VAQTA, CSL Biotherapies/Merck & Co.; with the middle dose of three being a saline placebo instead). A total of 99 toddlers were enrolled, with 67 toddlers receiving at least one of the planned three bfHbp doses, and the others, the control. One participant experienced urticaria nearly 24 h after first 60 mg study dose, which resolved with antihistamine and paracetamol treatment and this was judged to possibly be vaccine-related. One participant randomized to receive 20 mg received 200 mg in error, and was included in the 200 mg analysis regarding safety, but otherwise excluded from the study. There were three cases of severe erythema (>7 cm diameter) that did not interfere with limb movement in the 200 mg dose cohort. Fever occurred in 0–40.9% of bfHbp inoculations compared with 9.7–18.8% of control doses. At 60 mg of bfHbp, the peak incidence of fever occurred at the third dose at 31.6%, whereas at the 200 mg dose, the peak incidence of fever occurred at the first dose at 40.9%. Fever in toddlers given a comparable dose was notably lower compared with infants in the paper discussed above, although the studies were of different design. In terms of bactericidal activity, the authors conceded that the limited number of toddlers and test strains in this Phase I study, which was not powered to look for vaccine efficacy, make generalization to the wider toddler population difficult. However, whereas seroconversion rates from pre- to postvaccination after the third dose were 61.1–83.3% (rate depending on dose cohort) against a vaccine-antigen homologous strain, seroconversion rates for vaccine-antigen heterologous strains were 11.1–44.4% post-dose three at the 200 mg dose [41]. A combined Phase I and II, multi-center, randomizedcontrolled trial was done in children and adolescents in Australia. This involved 127 participants, of which 106 received at least one of three planned same-dose bfHbp vaccines (20, 60 or 200 mg), and 21 controls were given a hepatitis A and B vaccine (Twinrix, GlaxoSmithKline, Brentford, United Kingdom). The trial was halted earlier than planned originally as there was a decision to change the formulation of the vaccine for future studies, with little comment on this except that it was to ‘improve stability.’ Although adverse local events reported were higher than the controls, most were mild or moderate. Pain was the most 495
496
Randomizedcontrolled, multi-center, single blinded, open-label
I and II
I
I and II
I
MartinonTorres et al. (2014)
Marshall et al. (2012)
Nissen et al. (2013)
Richmond et al. (2012)
Key results including safety Terminated early due to unacceptable fever rates
Notable three cases of severe erythema at highest dose. Fever frequency less than in infants. Seroconversion rates dependent on fHbp variant tested
Formulation change after study to ‘improve stability’. Injection site pain a notably frequent adverse event. Seroconversion rates appear higher than in toddlers but still variable depending on fHbp variant tested First-in-human study. No significant safety concerns. Immunogenicity shown
Vaccination Schedules (number of subjects) Cohort 1: one 20 mg dose bivalent fHbp plus routine childhood vaccinations (22); Cohort 2: one 60 mg dose plus routine childhood vaccinations (10); Controls: routine childhood vaccinations only (14). Originally planned 4 doses of each study dose at 2,4,6 and 12 months age Cohort 1: three doses of 20 mg at 0, 1 and 6 months (22) vs controls (10). Cohort 2: three doses of 60 mg at 0, 1 and 6 months (23) vs controls (10). Cohort 3: three doses of 200 mg at 0, 1 and 6 months (22) vs controls (12). Controls received hepatitis A vaccine with saline placebo instead at second of three doses, over the same schedule Cohort 1: three doses of 20 mg at 0, 1 and 6 months (16). Cohort 2: three doses of 60 mg at 0, 1 and 6 months (45). Cohort 3: three doses of 200 mg at 0, 1 and 6 months (45). Controls (21) received hepatitis A and B vaccine (Twinrix, GlaxoSmithKline) over the same schedule Cohort 1: three doses of 20 mg at 0, 1 and 6 months (21). Cohort 2: three doses of 60 mg at 0, 1 and 6 months (23). Cohort 3: three does of 200 mg at 0, 1 and 6 months (24). Each cohort was against controls (total 35)
Key inclusion (I)/exclusion (E) criteria I: Infants (42–90 days old), healthy, male or female, guardian consent. E: any previous vaccination, vaccine-component anaphylaxis, significant chronic disease, confirmed Neisseria meningitidis or N. gonorrhoeae infection, blood products receipt, impaired immunity, contraindication to vaccination
I: Toddlers (18–36 months), healthy, male or female, guardian consent. E: previous MenB or control vaccination, severe reaction or anaphylaxis to vaccination, vaccine component hypersensitivity, significant chronic disease, N. meningitidis infection, impaired immunity, immunosuppressive therapy or blood products receipt in last 6 months
I: Children and Adolescents (8–14 years), healthy, male or female. E: pregnancy; previous meningococcal disease; any previous MenB vaccine; received a full schedule of hepatitis A or B vaccination; blood products recipient, another investigational study involvement, immunodeficiency disorder, bleeding disorder, hypersensitivity to vaccines, direct descendant of study site personnel
I: Young adults (18–25), healthy, hematological and serum biochemistry/hepatic profile in range. E: previous meningococcal disease or MenB vaccine, recent receipt of blood products, immunization with any live-attenuated vaccine or other meningococcal vaccine 30 days or any inactivated vaccine 14 days before administration of study vaccine. Reliable contraception required for females
All funded by Wyeth, or Pfizer, after acquisition of Wyeth. fHbp: Factor H binding protein; MenB: Neisseria meningitidis serogroup B; SBA: Serum bactericidal activity.
Randomized, placebocontrolled, multi-center, double-blind, ascending dose level
Randomized, activecontrolled, multi-center, observer-blind, parallel-group
Randomized, activecomparator/ placebocontrolled, multi-center, observer-blind, ascending-dose
Type
Phase
Study (year)
Table 1. Summary of published Phase I and II trials for bivalent fHbp vaccine.
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[43]
[42]
[41]
[38]
Ref.
Vaccine Profile Brendish & Read
Expert Rev. Vaccines 14(4), (2015)
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I
II
II
Sheldon et al. (2012)
Richmond et al. (2012)
Marshall et al. (2013)
Open-label, multi-center
Randomized, placebocontrolled, multi-center, single-blind
Randomized, open-label, active/placebocontrolled, laboratory-blindonly
Type
Overall lower rates of localized and systemic reactions compared with Phase I in adults. No serious AE related to vaccine. >94% of participants developed seroprotective SBA titers to 4 of 5 strains of MenB, 81% of remaining strain
Three doses of 120 mg at 0, 1 and 6 months (60). No controls
[46]
[45]
One possible anaphylaxis was the only serious adverse event related to vaccine. Of the limited strains tested, good SBAs demonstrated Initial study (33 each vaccine cohort) examined 60, 120 and 200 mg vs placebo over 0, 2 and 6 months. Subsequently participants were randomly assigned in a 2:2:1 ratio to receive 120 or 200 mg of vaccine or placebo at 0, 2 and 6 months. Total participants (randomized) for 60 mg (22), 120 mg (198) and 200 mg (198) The placebo (121) was saline
I: Adolescents (11–18 years), healthy, male or female, reliable birth control use, negative pregnancy test. E: previous meningococcal disease or MenB vaccination, anaphylaxis/severe reaction/ hypersensitivity to any vaccine component, significant chronic disease, major illness, bleeding diathesis, impaired immunity, concurrent other study involvement (and 30 days prior to start), pregnancy and breastfeeding, direct descended of study personnel. Concurrent vaccination restricted
I: Adults (18–40 years), healthy including weight and blood pressure, negative pregnancy test. E: previous with N. meningitidis or N. gonorrhoeae, MenB vaccination, previous anaphylactic/severe reaction/ hypersensitivity to any vaccine component, immunodeficiency disorder, immunosuppressive therapy, receipt blood products (including g-globulin) from 6 months prior, receipt of an inactivated vaccine from 14 days or live attenuated vaccine from 28 days before the study until the last vaccination, involvement with other investigational studies
[44]
No adverse events (local, systemic or laboratory) vaccineattributable. Immunoglobulin response noted to vaccine antigens
Cohort 1: three doses of 60 mg at 0, 2 and 6–9 months (12). Cohort 2: three doses of 120 mg at 0, 2 and 6–9 months (12). Cohort 3: three doses of 200 mg at 0, 2 and 6–9 months (12). Controlled received Tdap followed by two saline placebo doses at the same schedule (12)
I: Adults (18–40 years), healthy, male or female urinalysis and extensive blood tests in reference range, agreement to use reliable contraception. E: pregnancy and breast-feeding, previous N. meningitidis or N. gonorrhoeae infection, previous MenB vaccination, receipt of anaphylactic or severe vaccine-associated adverse reaction, known hypersensitivity to any study vaccine component, suspected or known immunity disorder, immunosuppressive therapy, blood products receipt (including g-globulin) 6 months before the first study dose or an investigational drug or device 6 weeks before the first study dose, receipt of control-vaccine components within past 5 years, contraindication to control
Ref.
Key results including safety
Vaccination Schedules (number of subjects)
Key inclusion (I)/exclusion (E) criteria
All funded by Wyeth, or Pfizer, after acquisition of Wyeth. fHbp: Factor H binding protein; MenB: Neisseria meningitidis serogroup B; SBA: Serum bactericidal activity.
Phase
Study (year)
Table 1. Summary of published Phase I and II trials for bivalent fHbp vaccine (cont.).
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MenB bivalent fHbp vaccine
Vaccine Profile
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Brendish & Read
reported adverse event in those receiving bfHbp, with a notable frequency for moderate pain (pain causing ‘interference with usual activity’) being reported for 58.1% of participants receiving the third dose of 200 mg, and severe pain (‘incapacitating, with inability to do all usual activity’) in 11.6% at that same third dose. In terms of systemic adverse reactions, bfHbp vaccines at 20 and 60 mg were broadly comparable with controls. However, fever and fatigue frequency were both notably raised in the 200 mg bfHbp cohort (35.6% at first dose and 51.2%, respectively), but with subsequent doses, each of these event frequencies decreased. Only one serious adverse event was considered vaccine related; the participant developed a ‘large localized reaction’ along with fever and was hospitalized for 1 day, having received the first 200 mg dose. Seroprotective hSBA titers (‡1:4) were generated in 68.8–97.7% of participants across all bfHbp dose levels against two of the five MenB fHbp variants tested. Seroprotective hSBA titers post-third dose of 60 or 200 mg against three other MenB strains tested were greater than controls but were broadly between 40 and 60%. Seroconversion (greater than or equal to fourfold increase of hSBA titer from baseline to postthird dose) for two strains was 68.8–95.3% over all dose levels, but for other variants were 39.5–66.7% at the higher dose levels. In general, the hSBA responses in children and adolescents in this study were higher than for toddlers but lower than in the adult studies [42]. In young adults, a Phase I, randomized, multi-center, placebocontrolled trial was the first-in-human trial, with 103 participants examining three same-level doses (at 20, 60 and 200 mg). There were four withdrawals due to pregnancy, but no mention is made of infant health. Two adverse events of elevated alanine aminotransferase were put down to other drug use (including alcohol). Among adverse events, only urticaria was thought to be related to the vaccine, and this participant had a history of potentially similar reactions. Injection-site pain was the most frequent localized reaction and whereas mild-to-moderate pain was common (81% of first dose at 20 mg was the incidence peak) only one case of severe pain (incapacitating, with inability to do usual activity) was noted and this was in the 200 mg group at the second dose. For systemic events, the occurrence of fever was never greater than one case per dose at each dose level, and fatigue (15.8–57.1% compared with control 51.5–71.4%) and headache were the most common (10.5–61.9% compared with control 39.4–45.5%). The sera were analyzed against six MenB strains with fHbp variants from the UK, Norway, the Netherlands and the USA. A total of 47–90% of participants at the 20 mg dose level, 75–100% at the 60 mg dose level, and 88–100% at the 200 mg dose level had seroprotective titers compared with 16–52% in the placebo cohort. A dose response was found for most SBA strains [43]. In adults, a Phase I randomized, open label, single-center controlled study was conducted in the USA. Forty-eight participants were randomized (1:1:1:1) to receive either three doses of 60, 120 or 200 mg, or Tdap vaccine (tetanus toxoid, diphtheria 498
toxoid and acellular pertussis; Adacel, Sanofi Pasteur) for the first dose and placebo for the subsequent two doses. Fourteen subjects were withdrawn but only one due to a vaccineunrelated adverse event. The other 13 withdrawals were due to loss of follow-up or failure to return, investigator or subject request or foreign travel. Local adverse events were broadly comparable with the Tdap control. Pain was the most common localized adverse event, of which two subjects reported severe pain after dose 2; one subject in the 120 mg group and one subject in the 200 mg group. Fever frequency was low, at most present in two subjects who received their second 120 mg dose and similarly in two subjects on their first 200 mg dose and only one participant had a fever above 39 C. One participant reported severe induration, and two reported severe erythema, all in the 120 mg dose with another severe erythema event in the 200 mg cohort. All laboratory abnormalities were reported as adverse events and none of the laboratory abnormalities were attributable to the bfHbp vaccine. At all three dose levels and from the first received dose, the bfHbp vaccine elicited a notable increase in immunoglobulin G geometric mean titers specific for both subfamily A and B fHbp proteins, with the controls showing no increase [44]. Phase II studies
A randomized, placebo-controlled, Phase II trial involving 539 healthy adolescents was conducted in 25 sites in Australia, Poland and Spain. After an initial dose selection study review from subjects tested with 60, 120 and 200 mg doses, the study examined larger numbers for three doses of 120 or 200 mg of fHbp in the final formulation developed alongside saline placebo. Twenty-five participants withdrew, of which 14 withdrew consent, four experienced adverse events, two were lost to follow-up, one violated protocol (did not return post 2nd vaccination) and for four reasons were not recorded. For withdrawals due to adverse events, one participant from each of the 120 and 200 mg groups withdrew because of mild-to-moderate reactogenicity, one in the 200 mg group withdrew because of syncope, and one in the 200 mg group withdrew because of a mild depressive episode 40 days after the first dose. This latter participant had a mental health history and the episode was judged not to be vaccine-related. Only one serious adverse event was considered related to the vaccine, and this was a case of potential anaphylaxis, where a fast-resolving rash and an episode of reported hypotension were treated with adrenaline, without respiratory compromise. Overall local reactions were more common than placebo with pain being the most common. Moderate pain (non-narcotic analgesia >24 h required to be used or interference with activity) occurred between 24.2 and 37.4% across 120 and 200 mg across different repeat doses as opposed to only 1.7% in the active control. Severe pain (preventing daily activity or requiring narcotic analgesia) was most frequent for the first dose at 200 mg (2.6%) but for the 120 mg peaked at 1.1% Expert Rev. Vaccines 14(4), (2015)
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MenB bivalent fHbp vaccine
(third dose). Severe erythema frequency was highest at 4.2% for the first dose at 200 mg. Systemic reactions were mostly headache, fatigue and muscle pain but the vast majority of these were reported at mild or moderate events. Fever was much less common than recorded in younger populations; for the 120 mg cohort, the occurrence of fever was 3.5% (second dose) to 5.1% (first dose) and for 200 mg was 3.2% (second dose) to 10.9% (first dose) compared with placebo 0–2.4%. Six strains were randomly selected as test strains against sera from 349 participants for SBA. Seroconversion for the PMB1745 reference strain was 89.5% of participants for the 60 mg dose, 92.8% for 120 mg, 94.0% for 200 mg and 5.5% for placebo. For the PMB17 reference strain, seroconversion was 81.0% of participants for the 60 mg dose, 86.6% for the 120 mg dose, 84.8% for 200 mg and 1.3% for placebo. The data for the other strains suggests reasonable seroconversion rates. Immune response did not increase in proportion with dose between the 120 and 200 mg cohorts. As the 120 mg dose was thought most likely to go forward as a candidate for Phase III trials, further analysis on two further MenB strains was undertaken with this dosing regimen, again, with the appearance of good seroconversion rates, but with a lower number of sera tested [45]. In adults, a Phase II study of 60 participants examined the final formulation of 120 mg over three doses. There was no control group and with only one study arm, no randomization. Two adverse events were considered related to the vaccine – one was the development of oral aphthous ulcers after a single dose, and the other was the development of gastroenteritis 7 days post first vaccination, but notably, the participant went on to doses two and three without recurrence. Other withdrawals were related to varied reasons: events before vaccination being subsequently diagnosed as hereditary angioedema (without recurrence during the study), pregnancy with a subsequently healthy infant, and protocol violation (one participant was underweight at 2nd vaccination and another missed a dose due to travel). For localized reactions, fever (‡38 C) was maximally present in those at the first dose (11.7%) but decreased by the third dose to only 3.6%. Mild-to-moderate pain was the most commonly recorded localized reaction with moderate pain (requiring repeated use of non-narcotic analgesia >24 h or interfering with activity) occurring in 25.0 to 38.2% of participants over the three doses. Mild pain (not interfering with activity) occurred in 54.5 to 66.7% of participants over the three doses. For systemic reactions, headache (47.4–61.7%) and fatigue (41.8–60.0%) were most frequently reported but in only one participant; each were these classified as severe. Notable adverse and serious advent events occurred but were judged to be unrelated to the vaccine. Only a single severe adverse event was considered vaccine-related and this was a severe upper respiratory tract infection recorded 7 days post second dose. The authors note that the frequency and severity of localized and systemic reactions in this study were broadly lower than those previously reported in Phase I study in adults. informahealthcare.com
Vaccine Profile
All 60 participants contributed in at least some way to immunogenicity studies. Five MenB strains were tested against for SBA, of which one strain had fHbp homology to the vaccine antigens, and the other four had 86.2–92.0% homology to the vaccine antigens. The authors comment that these five MenB strain fHbp variants are representative of over 90% of all disease-causing isolates and three of these strains were the same strains as in the Phase II adolescent study. Before vaccination, 65.4–93.2% of participants, depending on the strain, had hSBA serum titers below the level of quantification. After the third vaccination, more than 94% of participants had seroprotective hSBA titers (‡1:4) against four of the MenB strains and of the one strain variant remaining, 81.0% had seroprotective titers. Seroconversion rates tended to rise with each sequential administration of the vaccine [46]. Regulatory affairs
Clinical Phase III trials of the bivalent fHbp vaccine are underway but are not yet openly reported [47], but the FDA announced on 29 October 2014, ‘the approval of Trumenba, the first vaccine licensed in the United States to prevent invasive meningococcal disease caused by N. meningitidis serogroup B in individuals 10 through 25 years of age’ [48]. In March 2014, this vaccine had received ‘breakthrough therapy’ designation from the FDA, just as the rival 4CMenB vaccine had, with the aim to expedite development and review [49]. The FDA label includes restrictions on the use of the vaccine in children and in persons over 65 years of age. Conclusion
The burden of meningococcal disease in Europe and the USA is now predominantly due to MenB. The bivalent fHbp vaccine shows promise in Phase I and II trials except in infants, where the Phase I and II combined study was halted due to the high frequency of fever. US regulatory approval has now been granted and Phase III trial results are awaited. A summary comparison of the bivalent fHbp vaccine compared with the 4CMenB vaccine is shown in TABLE 2. Expert commentary
Although both bfHbp and 4CMenB have been characterized as ‘MenB vaccines,’ each of them is likely to have activity against N. meningitidis strains across the major prevalent serogroups. Thus, while they have been developed to plug a gap not filled by the monovalent and quadrivalent glycoconjugate vaccines, they may in future be considered as pan-meningococcal vaccines and used as part of programs, provided perhaps that new biomarkers such as the meningococcal antigen typing system assay are able to show broad coverage in specific populations. bfHbp has theoretical advantages over the 4CMenB vaccine, provided that circulating strains express fHbp. Antibodies elicited against fHbp appear to generate bactericidal activity and bfHbp offers expanded coverage against strains currently prevalent in Europe and the USA. However, Phase I/II studies have shown high rates of reactogenicity in infants (to a much greater 499
Vaccine Profile
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Table 2. Comparison of bivalent fHbp and 4CMenB vaccines. Bivalent fHbp
4CMenB
Components
Two fHbp: one from subfamily A and one from subfamily B (A05 + B01)†
fHbp (B24) + NadA + NHBA + New Zealand outbreak strain OMV‡,†
Company
Wyeth, Pfizer†
Novartis‡
US FDA regulatory approval
Approved [48]
Awaiting decision [34]
European regulatory approval
Not known to be submitted
Approved [34]
Indication for which approved and age range
Invasive MenB disease in individuals 10 to 25 years of age [48]
Invasive MenB disease; from 2 months old onwards (but no data for over 50 years old) [52]
Published Phase I results
Yes§
Yes [53]
§
Published Phase II results
Yes
Yes‡
Published Phase III results
Not yet [47]
Yes‡
†
See [54]. See [36]. § See Table 1 for references. fHbp: Factor H binding protein = LP2086; MenB: Neisseria meningitidis serogroup B; NadA: Neisseria adhesion A; NHBA: Neisseria heparin binding antigen; OMV: Outer membrane vesicle. ‡
extent than older children and adults), and Pfizer leadership appears to have terminated research and development of the vaccine for infant programs. In the opinion of author RCR, this decision could be questioned as it is not at all clear that the age-specific reactogenicity is any greater than is observed with 4CMenB, and never will be unless the vaccines are studied head-to-head. As the major disease burden continues to be in toddlers and pre-school children, this vaccine may suffer in competition with 4CMenB, which is about to be deployed in infants. Vaccination of adolescents with bfHbp will protect against the second peak of meningococcal disease, but also there is the possibility that bfHbp could afford protective herd immunity by reducing colonization and transmission in adolescents – who as stated above – have the highest asymptomatic colonization rates. It is quite possible that adolescent-age carriage prevention studies (which are currently underway in Europe) may show an effect on carriage, which would suggest that they could generate indirect herd protection of younger children. Unfortunately, a similar study conducted with 4CMenB [7] did not demonstrate a dramatic effect of that subcapsular vaccine on adolescent carriage, but only 9% of the subjects in the study were carrying serogroup B, and meningococcal antigen typing system assays (which might have shown under-representation of strains cognate to 4CMenB) were not done. We therefore await carriage studies of fHbp with great interest, as this would certainly improve greatly the potential of the vaccine. Five-year view
The real-world market for widespread MenB vaccines is only currently entering its infancy with the recent approval of
500
4CMenB in multiple regions and the likely near-future approval of the bivalent fHbp vaccine beyond the USA. A non-strain-specific MenB vaccine such as the bivalent fHbp has significant potential to reduce the disease burden and sequelae, and population-based studies showing this are anticipated. Carefully thought re-investigation in infants may be considered as this opens up this vaccine to be used in the most at-risk group, especially as the 4CMenB vaccine safety profile in this age group is broadly similar. Quadrivalent conjugate vaccines are widely deployed and safe and further research into combining serogroup B vaccines into existing multi-serogroup vaccines, or novel vaccine approaches altogether, may consolidate broad coverage N. meningitis protection. Sequential administration of a vaccine of the quadrivalent multiple serogroup vaccine (Men ACWY-CRM, Menveo) along with 4CMenB to cover laboratory workers has already shown evidence of immunogenicity and safety [50], and results related to similar, more wide-ranging trials, are expected, including a completed Phase II Novartis study [51]. Information resources
PubMed, Web of Science. Financial & competing interests disclosure
The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Expert Rev. Vaccines 14(4), (2015)
MenB bivalent fHbp vaccine
Vaccine Profile
Key issues .
The development of a widely effective vaccine against disease caused by Neisseria meningitidis serogroup B (MenB) has been significantly more prolonged compared with other widespread pathogenic serogroups (A, C, W and Y), and currently serogroup B disease accounts for a disproportionate amount of meningococcal disease, with incidence peaks in infants and adolescents.
.
A four-component vaccine, 4CMenB (Bexsero, Novartis), has recently been approved in different countries against MenB, for all age ranges.
.
This article examines a bivalent factor H binding protein (fHbp) vaccine developed initially by Wyeth (later acquired by Pfizer). fHbp is
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also known as LP2086. .
The bivalent fHbp vaccine has undergone Phase I and II trials, and Phase III trials are not yet published.
.
In a Phase I and II study involving infants (42–90 days old), the trial was terminated early due to unacceptable fever rates.
.
In other age ranges up to adults, the safety profile was acceptable.
.
Clinical efficacy, from Phase I and II data only, appears to support and suggest good immunogenicity via serum bactericidal activity assays, albeit against a limited range of MenB strains.
.
Both the bivalent fHbp and 4CMenB vaccine have the potential to be quite broadly active vaccines, rather than just MenB specific, as their targets are found across the major prevalent serogroups.
.
The bivalent fHbp vaccine, as Trumenba, has received in late October 2014 FDA approval to be first vaccine licensed in the USA to prevent MenB disease in individuals 10–25 years of age.
References
6.
Christensen H, May M, Bowen L, et al. Meningococcal carriage by age: a systematic review and meta-analysis. Lancet Infect Dis 2010;10:853-61
..
Meta-analysis of 89 studies examining meningococcal carriage rates internationally, confirming the low carriage in young children, increasing through childhood to a peak in 19 year olds, and subsequently declining in older adulthood.
Papers of special note have been highlighted as: .. of considerable interest 1.
Martin NG, Sadarangani M, Pollard AJ, Goldacre MJ. Hospital admission rates for meningitis and septicaemia caused by Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae in children in England over five decades: a population-based observational study. Lancet Infect Dis 2014;14(5):397-405
..
Interesting paper that spans decades of epidemiology for England relating to key causes of meningitis in children.
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Read RC, Baxter D, Chadwick DR, et al. Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial. Lancet 2014;384(9960):2123-31
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Frasch CE, Borrow R, Donnelly J. Bactericidal antibody is the immunologic surrogate of protection against meningococcal disease. Vaccine 2009; 27(Suppl 2):B112-16
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Madico G, Welsch JA, Lewis LA, et al. The meningococcal vaccine candidate GNA1870 binds the complement regulatory protein factor H and enhances serum resistance. J Immunol 2006;177:501-10
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Pizza M, Scarlato V, Masignani V, et al. Identification of vaccine candidates against serogroup B meningococcus by whole-genome sequencing. Science 2000; 287(5459):1816-20
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Borg J, Christie D, Coen PG, et al. Outcomes of meningococcal disease in adolescence: prospective, matched-cohort study. Pediatrics 2009;123(3):e502-9
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Viner RM, Booy R, Johnson H, et al. Outcomes of invasive meningococcal serogroup B disease in children and adolescents (MOSAIC): a case-control study. Lancet Neurol 2012;11(9):774-83
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Masignani V, Comanducci M, Giuliani MM, et al. Vaccination against Neisseria meningitidis using three variants of the lipoprotein GNA1870. J Exp Med 2003;197(6):789-99
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Flexner S. The results of the serum treatment in thirteen hundred cases of epidemic meningitis. J Exp Med 1913; 17(5):553-76
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Fletcher LD, Bernfield L, Barniak V, et al. Vaccine potential of the Neisseria meningitidis 2086 lipoprotein. Infect Immun 2004;72(4):2088-100
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Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus. I. The role of humoral antibodies. J Exp Med 1969;129(6): 1307-26
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Murphy E, Andrew L, Lee KL, et al. Sequence diversity of the factor H binding protein vaccine candidate in epidemiologically relevant strains of serogroup B Neisseria meningitidis. J Infect Dis 2009;200(3):379-89
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Giuntini S, Vu DM, Granoff DM. fH-dependent complement evasion by disease-causing meningococcal strains with absent fHbp genes or frameshift mutations. Vaccine 2013;31(38):4192-9 Welsch JA, Ram S, Koeberling O, Granoff DM. Complement-dependent synergistic bactericidal activity of antibodies against factor H-binding protein, a sparsely distributed meningococcal vaccine antigen. J Infect Dis 2008;197(7):1053-61 Costa I, Pajon R, Granoff DM. Human factor H (FH) impairs protective meningococcal anti-FHbp antibody responses and the antibodies enhance FH binding. MBio 2014;5(5):e01625-14 Jiang HQ, Hoiseth SK, Harris SL, et al. Broad vaccine coverage predicted for a bivalent recombinant factor H binding protein based vaccine to prevent serogroup B meningococcal disease. Vaccine 2010; 28(37):6086-93 Robbins JB, Schneerson R, Xie G, et al. Capsular polysaccharide vaccine for Group B Neisseria meningitidis, Escherichia coli K1, and Pasteurella haemolytica A2. Proc Natl Acad Sci USA 2011;108(44):17871-5
Sadarangani M, Pollard AJ. Serogroup B meningococcal vaccines-an unfinished story. Lancet Infect Dis 2010;10(2):112-24
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Oster P, Lennon D, O’Hallahan J, et al. MeNZB: a safe and highly immunogenic tailor-made vaccine against the New Zealand Neisseria meningitidis serogroup B disease epidemic strain. Vaccine 2005; 23(17–18):2191-6
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Koeberling O, Seubert A, Santos G, et al. Immunogenicity of a meningococcal native outer membrane vesicle vaccine with attenuated endotoxin and over-expressed factor H binding protein in infant rhesus monkeys. Vaccine 2011;29(29-30):4728-34
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Gorringe AR, Taylor S, Brookes C, et al. Phase I safety and immunogenicity study of a candidate meningococcal disease vaccine based on Neisseria lactamica outer membrane vesicles. Clin Vaccine Immunol 2009;16(8):1113-20
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Trotter CL, Andrews NJ, Kaczmarski EB, et al. Effectiveness of meningococcal serogroup C conjugate vaccine 4 years after introduction. Lancet 2004;364(9431):365-7
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serogroups vaccine for Neisseria meningitidis. PLoS One 2013;8(11):e79304
Vermont CL, van Dijken HH, Kuipers AJ, et al. Cross-reactivity of antibodies against PorA after vaccination with a meningococcal B outer membrane vesicle vaccine. Infect Immun 2003;71(4):1650-5 Boutriau D, Poolman J, Borrow R, et al. Immunogenicity and safety of three doses of a bivalent (B:4:p1.19,15 and B:4:p1.7-2,4) meningococcal outer membrane vesicle vaccine in healthy adolescents. Clin Vaccine Immunol 2007;14(1):65-73 Tondella ML, Popovic T, Rosenstein NE, et al. Distribution of Neisseria meningitidis serogroup B serosubtypes and serotypes circulating in the United States. The Active Bacterial Core Surveillance Team. J Clin Microbiol 2000;38(9):3323-8 Pinto VB, Burden R, Wagner A, et al. The development of an experimental multiple
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JCVI position statement on use of Bexsero meningococcal B vaccine in the UK. 2014. Available from: www.gov.uk/ government/publications/meningococcal-bvaccine-jcvi-position-statement [Accessed 2 September 2014] Princeton University Meningococcal Disease Outbreak; Centres for Disease Control and Prevention (CDC). Available from: www. cdc.gov/meningococcal/outbreaks/princeton. html [Accessed 2 September 2014] University of California, Santa Barbara Meningococcal Disease Outbreak; Centres for Disease Control and Prevention (CDC). Available from: www.cdc.gov/ meningococcal/outbreaks/ucsb.html [Accessed 2 September 2014]
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Esposito S, Principi N. Vaccine profile of 4CMenB: a four-component Neisseria meningitidis serogroup B vaccine. Expert Rev Vaccines 2014;13(2):193-202
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Vogel U, Taha MK, Vazquez JA, et al. Predicted strain coverage of a meningococcal multicomponent vaccine (4CMenB) in Europe: a qualitative and quantitative assessment. Lancet Infect Dis 2013;13(5): 416-25
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Martinon-Torres F, Gimenez-Sanchez F, Bernaola-Iturbe E, et al. A randomized, phase 1/2 trial of the safety, tolerability, and immunogenicity of bivalent rLP2086 meningococcal B vaccine in healthy infants. Vaccine 2014;32(40): 5206-11
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Bivalent rLP2086 vaccine study in toddlers that was terminated early due to unacceptably high fever rates.
39.
Gossger N, Snape MD, Yu LM, et al. Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial. JAMA 2012; 307(6):573-82
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Vesikari T, Esposito S, Prymula R, et al. Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials. Lancet 2013;381(9869): 825-35
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Marshall HS, Richmond PC, Nissen MD, et al. Safety and immunogenicity of a meningococcal B bivalent rLP2086 vaccine in healthy toddlers aged 18–36 months: a phase 1 randomized-controlled clinical trial. Pediatr Infect Dis J 2012;31:1061-8
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Nissen MD, Marshall HS, Richmond PC, et al. A randomized, controlled, phase 1/ 2 trial of a Neisseria meningitidis serogroup B bivalent rLP2086 vaccine in healthy children and adolescents. Pediatr Infect Dis J 2013;32(4):364-71
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Richmond PC, Nissen MD, Marshall HS, et al. A bivalent Neisseria meningitidis recombinant lipidated factor H binding protein vaccine in young adults: results of a randomised, controlled, dose-escalation phase 1 trial. Vaccine 2012;30:6163-74
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Sheldon EA, Schwartz H, Jiang Q, et al. A phase 1, randomized, open-label, active-controlled trial to assess the safety of a meningococcal serogroup B bivalent rLP2086 vaccine in healthy adults. Hum Vaccin Immunother 2012;8(7):888-95
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Richmond PC, Marshall HS, Nissen MD, et al. Safety, immunogenicity, and tolerability of meningococcal serogroup B bivalent recombinant lipoprotein 2086 vaccine in healthy adolescents: a randomised, single-blind, placebo-controlled, phase 2 trial. Lancet Infect Dis 2012;12:597-607
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Marshall HS, Richmond PC, Nissen MD, et al. A phase 2 open-label safety and immunogenicity study of a meningococcal B bivalent rLP2086 vaccine in healthy adults. Vaccine 2013;31(12):1569-75
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ClinicalTrials.gov. Available from: http:// clinicaltrials.gov/ct2/results?term=rlp2086 [Accessed 5 September 2014]
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Food and Drug Administration News Release dated. 2014. Available from: www. fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm420998.htm [Accessed 5 November 2014]
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Pfizer. Press releases. Available from: www. pfizer.com/news/press-release/press-releasedetail/pfizer_announces_fda_acceptance_ of_and_priority_review_designation_for_
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MenB bivalent fHbp vaccine
biologics_license_application_for_ investigational_meningococcal_b_vaccine [Accessed 5 September 2014]
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Kimura A, Toneatto D, Kleinschmidt A, et al. Immunogenicity and safety of a multicomponent meningococcal serogroup B vaccine and a quadrivalent meningococcal CRM197 conjugate vaccine against serogroups A, C, W-135, and Y in adults who are at increased risk for occupational exposure to meningococcal isolates. Clin Vaccine Immunol 2011;18(3):483-6
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ClinicalTrials.gov. Safety and Immunogenicity of Different Meningitis Vaccine Formulations in Adolescents and Young Adults. ClinicalTrials.gov Identifier: NCT01272180. Available from: http:// clinicaltrials.gov/ct2/show/NCT01272180 [Accessed 8 September 2014] Summary of Product Characteristics. for 4CMenB (Bexsero). Available from: www. bexsero.com/assets/SMPC-2013-01-30.pdf [Accessed 07 January 2015]
Vaccine Profile
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Toneatto D, Ismaili S, Ypma E, et al. The first use of an investigational multicomponent meningococcal serogroup B vaccine (4CMenB) in humans. Hum Vaccin 2011;7(6):646-53
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Anderson AS, Hao L, Jiang Q, et al. Potential impact of the bivalent rLP2806 vaccine on Neisseria meningitidis carriage and invasive serogroup B disease. Hum Vaccin Immunother 2013;9(3):471-9
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Neisseria meningitidis serogroup B bivalent factor H binding protein vaccine Expert Rev. Vaccines 14(4), 493–503 (2015)
Nathan James Brendish1 and Robert Charles Read*2 1 NIHR Wellcome Trust Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Mailpoint 218, West Wing, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK 2 Academic Unit of Clinical and Experimental Sciences and Institute for Life Sciences, University Hospital Southampton NHS Foundation Trust, University of Southampton, and NIHR Respiratory Biomedical Research Unit, Mailpoint 814, South Academic Block, Southampton General Hospital, Southampton, SO16 6YD, UK *Author for correspondence: Tel.: +44 023 8120 4404 [email protected]
informahealthcare.com
With the successful development of meningococcal vaccines against other serogroups, disease caused by Neisseria meningitidis serogroup B now accounts for a disproportionate frequency compared with other serogroups, particularly in the US and Europe. Infants and adolescents bear the highest incidence of disease, which typically manifests as meningitis and septicemia. This vaccine profile article examines a bivalent factor H binding protein (fHbp; also known as LP2086) vaccine that has now been approved by the US FDA for use in 10- to 25-year olds. The manufacturer has shelved plans for further investigation of its use in infants because of high rates of fever in Phase I and II trials in that age group. KEYWORDS: fHbp . MenB vaccine . meningococcal vaccine . rLP2086 . Trumenba
With the successful development of meningococcal vaccines against other serogroups, disease caused by Neisseria meningitidis serogroup B (MenB) now accounts for 87% of all microbiologically proven cases of meningococcal disease in England, and among infants, 94% [1]. In the USA, MenB disease accounted for over 40% of all meningococcal cases in 2012 [2]. The disease is sinister and carries an overall case fatality rate in Europe of 8% [3]. In one English study of invasive meningococcal disease, the case-fatality rate was 11%, with septicemia being a prominently poor prognostic feature [4]. There are broadly two peaks of incidence of meningococcal disease. In one large US report, children under 5 years old had the highest annual incidence, and most significantly at risk were infants aged less than 1 year (5.38 per 100,000). The second peak of incidence occurred in 18- to 24-year olds (0.76 per 100,000). Serogroup B disease followed the same age-distribution pattern (infants 83% sequence homology within the two identified subfamilies, denoted by A and B, and is present in all strains included in a database of 1837 invasive MenB isolates [18]. Clinical efficacy & safety Phase I & combined Phase I & II studies
Currently, there are five published Phase I studies relating to the bivalent fHbp vaccine, of which two are dual Phase I and II, and these studies encompassed infants (from 42 days old), toddlers (18–36 months), children and adolescents (8–14 years), young adults (18–25 years) and adults (18–40 years; summary in TABLE 1). There are two other Phase II trials, one in adolescents (11–18 years) and one in adults (18–40 years old). The Phase I and II study involving infants was terminated early due to a significant frequency of fever in those receiving the initial low doses. Sixty-four percent of infants who received a 20 mg dose of bfHbp and 90% who received the 60 mg dose became pyrexial (‡38 C), compared with 29% of controls. The study was a randomized, multi-center, single-blinded trial conducted in Spain, with test subjects receiving a dose of bfHbp alongside routine childhood vaccinations and controls receiving routine childhood vaccinations only. The trial originally planned to test 120 and 200 mg doses as well but was terminated before this, and no blood had been taken to test for immunogenicity by the time of termination. In total, from 46 participants randomized out of a planned 744, 32 infants had received a dose of bfHbp, of which 22 received 20 mg and 10 received 60 mg and no participant had received more than one dose. One subject developed aseptic meningitis after receiving a 60 mg dose along with routine vaccinations and the treating physician considered that this case was not vaccine related. However, the safety data review by a project-independent safety committee that was prompted by this case revealed the significant frequency of fever, which prompted the sponsor, Pfizer, to terminate the study [38]. The study authors note that a similar incidence of fever in a comparable infant population was noted in a large trial for rival informahealthcare.com
Vaccine Profile
vaccine 4CMenB, without significant concerns raised. For infants receiving 4CMenB along with routine childhood vaccinations, albeit in a much larger and Phase II study, fever recorded after any vaccine dose was 76 or 80% of infants depending on the protocol, however, at any single dose were 26 to 62% [39]. Another paper on infants looking at 4CMenB measured temperature differently, but found that 65.3% of infants receiving 4CMenB developed a temperature ‡38.5 C within 6 h of vaccination [40]. In a Phase I observer-blind, ascending-dose, randomized, multi-center study in Australian toddlers, three same-dose inoculations of bfHbp were administered at 20, 60 or 200 mg, depending on study arm, at 0, 1 and 6 months after enrollment. Controls were given a hepatitis A vaccine (VAQTA, CSL Biotherapies/Merck & Co.; with the middle dose of three being a saline placebo instead). A total of 99 toddlers were enrolled, with 67 toddlers receiving at least one of the planned three bfHbp doses, and the others, the control. One participant experienced urticaria nearly 24 h after first 60 mg study dose, which resolved with antihistamine and paracetamol treatment and this was judged to possibly be vaccine-related. One participant randomized to receive 20 mg received 200 mg in error, and was included in the 200 mg analysis regarding safety, but otherwise excluded from the study. There were three cases of severe erythema (>7 cm diameter) that did not interfere with limb movement in the 200 mg dose cohort. Fever occurred in 0–40.9% of bfHbp inoculations compared with 9.7–18.8% of control doses. At 60 mg of bfHbp, the peak incidence of fever occurred at the third dose at 31.6%, whereas at the 200 mg dose, the peak incidence of fever occurred at the first dose at 40.9%. Fever in toddlers given a comparable dose was notably lower compared with infants in the paper discussed above, although the studies were of different design. In terms of bactericidal activity, the authors conceded that the limited number of toddlers and test strains in this Phase I study, which was not powered to look for vaccine efficacy, make generalization to the wider toddler population difficult. However, whereas seroconversion rates from pre- to postvaccination after the third dose were 61.1–83.3% (rate depending on dose cohort) against a vaccine-antigen homologous strain, seroconversion rates for vaccine-antigen heterologous strains were 11.1–44.4% post-dose three at the 200 mg dose [41]. A combined Phase I and II, multi-center, randomizedcontrolled trial was done in children and adolescents in Australia. This involved 127 participants, of which 106 received at least one of three planned same-dose bfHbp vaccines (20, 60 or 200 mg), and 21 controls were given a hepatitis A and B vaccine (Twinrix, GlaxoSmithKline, Brentford, United Kingdom). The trial was halted earlier than planned originally as there was a decision to change the formulation of the vaccine for future studies, with little comment on this except that it was to ‘improve stability.’ Although adverse local events reported were higher than the controls, most were mild or moderate. Pain was the most 495
496
Randomizedcontrolled, multi-center, single blinded, open-label
I and II
I
I and II
I
MartinonTorres et al. (2014)
Marshall et al. (2012)
Nissen et al. (2013)
Richmond et al. (2012)
Key results including safety Terminated early due to unacceptable fever rates
Notable three cases of severe erythema at highest dose. Fever frequency less than in infants. Seroconversion rates dependent on fHbp variant tested
Formulation change after study to ‘improve stability’. Injection site pain a notably frequent adverse event. Seroconversion rates appear higher than in toddlers but still variable depending on fHbp variant tested First-in-human study. No significant safety concerns. Immunogenicity shown
Vaccination Schedules (number of subjects) Cohort 1: one 20 mg dose bivalent fHbp plus routine childhood vaccinations (22); Cohort 2: one 60 mg dose plus routine childhood vaccinations (10); Controls: routine childhood vaccinations only (14). Originally planned 4 doses of each study dose at 2,4,6 and 12 months age Cohort 1: three doses of 20 mg at 0, 1 and 6 months (22) vs controls (10). Cohort 2: three doses of 60 mg at 0, 1 and 6 months (23) vs controls (10). Cohort 3: three doses of 200 mg at 0, 1 and 6 months (22) vs controls (12). Controls received hepatitis A vaccine with saline placebo instead at second of three doses, over the same schedule Cohort 1: three doses of 20 mg at 0, 1 and 6 months (16). Cohort 2: three doses of 60 mg at 0, 1 and 6 months (45). Cohort 3: three doses of 200 mg at 0, 1 and 6 months (45). Controls (21) received hepatitis A and B vaccine (Twinrix, GlaxoSmithKline) over the same schedule Cohort 1: three doses of 20 mg at 0, 1 and 6 months (21). Cohort 2: three doses of 60 mg at 0, 1 and 6 months (23). Cohort 3: three does of 200 mg at 0, 1 and 6 months (24). Each cohort was against controls (total 35)
Key inclusion (I)/exclusion (E) criteria I: Infants (42–90 days old), healthy, male or female, guardian consent. E: any previous vaccination, vaccine-component anaphylaxis, significant chronic disease, confirmed Neisseria meningitidis or N. gonorrhoeae infection, blood products receipt, impaired immunity, contraindication to vaccination
I: Toddlers (18–36 months), healthy, male or female, guardian consent. E: previous MenB or control vaccination, severe reaction or anaphylaxis to vaccination, vaccine component hypersensitivity, significant chronic disease, N. meningitidis infection, impaired immunity, immunosuppressive therapy or blood products receipt in last 6 months
I: Children and Adolescents (8–14 years), healthy, male or female. E: pregnancy; previous meningococcal disease; any previous MenB vaccine; received a full schedule of hepatitis A or B vaccination; blood products recipient, another investigational study involvement, immunodeficiency disorder, bleeding disorder, hypersensitivity to vaccines, direct descendant of study site personnel
I: Young adults (18–25), healthy, hematological and serum biochemistry/hepatic profile in range. E: previous meningococcal disease or MenB vaccine, recent receipt of blood products, immunization with any live-attenuated vaccine or other meningococcal vaccine 30 days or any inactivated vaccine 14 days before administration of study vaccine. Reliable contraception required for females
All funded by Wyeth, or Pfizer, after acquisition of Wyeth. fHbp: Factor H binding protein; MenB: Neisseria meningitidis serogroup B; SBA: Serum bactericidal activity.
Randomized, placebocontrolled, multi-center, double-blind, ascending dose level
Randomized, activecontrolled, multi-center, observer-blind, parallel-group
Randomized, activecomparator/ placebocontrolled, multi-center, observer-blind, ascending-dose
Type
Phase
Study (year)
Table 1. Summary of published Phase I and II trials for bivalent fHbp vaccine.
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[43]
[42]
[41]
[38]
Ref.
Vaccine Profile Brendish & Read
Expert Rev. Vaccines 14(4), (2015)
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I
II
II
Sheldon et al. (2012)
Richmond et al. (2012)
Marshall et al. (2013)
Open-label, multi-center
Randomized, placebocontrolled, multi-center, single-blind
Randomized, open-label, active/placebocontrolled, laboratory-blindonly
Type
Overall lower rates of localized and systemic reactions compared with Phase I in adults. No serious AE related to vaccine. >94% of participants developed seroprotective SBA titers to 4 of 5 strains of MenB, 81% of remaining strain
Three doses of 120 mg at 0, 1 and 6 months (60). No controls
[46]
[45]
One possible anaphylaxis was the only serious adverse event related to vaccine. Of the limited strains tested, good SBAs demonstrated Initial study (33 each vaccine cohort) examined 60, 120 and 200 mg vs placebo over 0, 2 and 6 months. Subsequently participants were randomly assigned in a 2:2:1 ratio to receive 120 or 200 mg of vaccine or placebo at 0, 2 and 6 months. Total participants (randomized) for 60 mg (22), 120 mg (198) and 200 mg (198) The placebo (121) was saline
I: Adolescents (11–18 years), healthy, male or female, reliable birth control use, negative pregnancy test. E: previous meningococcal disease or MenB vaccination, anaphylaxis/severe reaction/ hypersensitivity to any vaccine component, significant chronic disease, major illness, bleeding diathesis, impaired immunity, concurrent other study involvement (and 30 days prior to start), pregnancy and breastfeeding, direct descended of study personnel. Concurrent vaccination restricted
I: Adults (18–40 years), healthy including weight and blood pressure, negative pregnancy test. E: previous with N. meningitidis or N. gonorrhoeae, MenB vaccination, previous anaphylactic/severe reaction/ hypersensitivity to any vaccine component, immunodeficiency disorder, immunosuppressive therapy, receipt blood products (including g-globulin) from 6 months prior, receipt of an inactivated vaccine from 14 days or live attenuated vaccine from 28 days before the study until the last vaccination, involvement with other investigational studies
[44]
No adverse events (local, systemic or laboratory) vaccineattributable. Immunoglobulin response noted to vaccine antigens
Cohort 1: three doses of 60 mg at 0, 2 and 6–9 months (12). Cohort 2: three doses of 120 mg at 0, 2 and 6–9 months (12). Cohort 3: three doses of 200 mg at 0, 2 and 6–9 months (12). Controlled received Tdap followed by two saline placebo doses at the same schedule (12)
I: Adults (18–40 years), healthy, male or female urinalysis and extensive blood tests in reference range, agreement to use reliable contraception. E: pregnancy and breast-feeding, previous N. meningitidis or N. gonorrhoeae infection, previous MenB vaccination, receipt of anaphylactic or severe vaccine-associated adverse reaction, known hypersensitivity to any study vaccine component, suspected or known immunity disorder, immunosuppressive therapy, blood products receipt (including g-globulin) 6 months before the first study dose or an investigational drug or device 6 weeks before the first study dose, receipt of control-vaccine components within past 5 years, contraindication to control
Ref.
Key results including safety
Vaccination Schedules (number of subjects)
Key inclusion (I)/exclusion (E) criteria
All funded by Wyeth, or Pfizer, after acquisition of Wyeth. fHbp: Factor H binding protein; MenB: Neisseria meningitidis serogroup B; SBA: Serum bactericidal activity.
Phase
Study (year)
Table 1. Summary of published Phase I and II trials for bivalent fHbp vaccine (cont.).
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MenB bivalent fHbp vaccine
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reported adverse event in those receiving bfHbp, with a notable frequency for moderate pain (pain causing ‘interference with usual activity’) being reported for 58.1% of participants receiving the third dose of 200 mg, and severe pain (‘incapacitating, with inability to do all usual activity’) in 11.6% at that same third dose. In terms of systemic adverse reactions, bfHbp vaccines at 20 and 60 mg were broadly comparable with controls. However, fever and fatigue frequency were both notably raised in the 200 mg bfHbp cohort (35.6% at first dose and 51.2%, respectively), but with subsequent doses, each of these event frequencies decreased. Only one serious adverse event was considered vaccine related; the participant developed a ‘large localized reaction’ along with fever and was hospitalized for 1 day, having received the first 200 mg dose. Seroprotective hSBA titers (‡1:4) were generated in 68.8–97.7% of participants across all bfHbp dose levels against two of the five MenB fHbp variants tested. Seroprotective hSBA titers post-third dose of 60 or 200 mg against three other MenB strains tested were greater than controls but were broadly between 40 and 60%. Seroconversion (greater than or equal to fourfold increase of hSBA titer from baseline to postthird dose) for two strains was 68.8–95.3% over all dose levels, but for other variants were 39.5–66.7% at the higher dose levels. In general, the hSBA responses in children and adolescents in this study were higher than for toddlers but lower than in the adult studies [42]. In young adults, a Phase I, randomized, multi-center, placebocontrolled trial was the first-in-human trial, with 103 participants examining three same-level doses (at 20, 60 and 200 mg). There were four withdrawals due to pregnancy, but no mention is made of infant health. Two adverse events of elevated alanine aminotransferase were put down to other drug use (including alcohol). Among adverse events, only urticaria was thought to be related to the vaccine, and this participant had a history of potentially similar reactions. Injection-site pain was the most frequent localized reaction and whereas mild-to-moderate pain was common (81% of first dose at 20 mg was the incidence peak) only one case of severe pain (incapacitating, with inability to do usual activity) was noted and this was in the 200 mg group at the second dose. For systemic events, the occurrence of fever was never greater than one case per dose at each dose level, and fatigue (15.8–57.1% compared with control 51.5–71.4%) and headache were the most common (10.5–61.9% compared with control 39.4–45.5%). The sera were analyzed against six MenB strains with fHbp variants from the UK, Norway, the Netherlands and the USA. A total of 47–90% of participants at the 20 mg dose level, 75–100% at the 60 mg dose level, and 88–100% at the 200 mg dose level had seroprotective titers compared with 16–52% in the placebo cohort. A dose response was found for most SBA strains [43]. In adults, a Phase I randomized, open label, single-center controlled study was conducted in the USA. Forty-eight participants were randomized (1:1:1:1) to receive either three doses of 60, 120 or 200 mg, or Tdap vaccine (tetanus toxoid, diphtheria 498
toxoid and acellular pertussis; Adacel, Sanofi Pasteur) for the first dose and placebo for the subsequent two doses. Fourteen subjects were withdrawn but only one due to a vaccineunrelated adverse event. The other 13 withdrawals were due to loss of follow-up or failure to return, investigator or subject request or foreign travel. Local adverse events were broadly comparable with the Tdap control. Pain was the most common localized adverse event, of which two subjects reported severe pain after dose 2; one subject in the 120 mg group and one subject in the 200 mg group. Fever frequency was low, at most present in two subjects who received their second 120 mg dose and similarly in two subjects on their first 200 mg dose and only one participant had a fever above 39 C. One participant reported severe induration, and two reported severe erythema, all in the 120 mg dose with another severe erythema event in the 200 mg cohort. All laboratory abnormalities were reported as adverse events and none of the laboratory abnormalities were attributable to the bfHbp vaccine. At all three dose levels and from the first received dose, the bfHbp vaccine elicited a notable increase in immunoglobulin G geometric mean titers specific for both subfamily A and B fHbp proteins, with the controls showing no increase [44]. Phase II studies
A randomized, placebo-controlled, Phase II trial involving 539 healthy adolescents was conducted in 25 sites in Australia, Poland and Spain. After an initial dose selection study review from subjects tested with 60, 120 and 200 mg doses, the study examined larger numbers for three doses of 120 or 200 mg of fHbp in the final formulation developed alongside saline placebo. Twenty-five participants withdrew, of which 14 withdrew consent, four experienced adverse events, two were lost to follow-up, one violated protocol (did not return post 2nd vaccination) and for four reasons were not recorded. For withdrawals due to adverse events, one participant from each of the 120 and 200 mg groups withdrew because of mild-to-moderate reactogenicity, one in the 200 mg group withdrew because of syncope, and one in the 200 mg group withdrew because of a mild depressive episode 40 days after the first dose. This latter participant had a mental health history and the episode was judged not to be vaccine-related. Only one serious adverse event was considered related to the vaccine, and this was a case of potential anaphylaxis, where a fast-resolving rash and an episode of reported hypotension were treated with adrenaline, without respiratory compromise. Overall local reactions were more common than placebo with pain being the most common. Moderate pain (non-narcotic analgesia >24 h required to be used or interference with activity) occurred between 24.2 and 37.4% across 120 and 200 mg across different repeat doses as opposed to only 1.7% in the active control. Severe pain (preventing daily activity or requiring narcotic analgesia) was most frequent for the first dose at 200 mg (2.6%) but for the 120 mg peaked at 1.1% Expert Rev. Vaccines 14(4), (2015)
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MenB bivalent fHbp vaccine
(third dose). Severe erythema frequency was highest at 4.2% for the first dose at 200 mg. Systemic reactions were mostly headache, fatigue and muscle pain but the vast majority of these were reported at mild or moderate events. Fever was much less common than recorded in younger populations; for the 120 mg cohort, the occurrence of fever was 3.5% (second dose) to 5.1% (first dose) and for 200 mg was 3.2% (second dose) to 10.9% (first dose) compared with placebo 0–2.4%. Six strains were randomly selected as test strains against sera from 349 participants for SBA. Seroconversion for the PMB1745 reference strain was 89.5% of participants for the 60 mg dose, 92.8% for 120 mg, 94.0% for 200 mg and 5.5% for placebo. For the PMB17 reference strain, seroconversion was 81.0% of participants for the 60 mg dose, 86.6% for the 120 mg dose, 84.8% for 200 mg and 1.3% for placebo. The data for the other strains suggests reasonable seroconversion rates. Immune response did not increase in proportion with dose between the 120 and 200 mg cohorts. As the 120 mg dose was thought most likely to go forward as a candidate for Phase III trials, further analysis on two further MenB strains was undertaken with this dosing regimen, again, with the appearance of good seroconversion rates, but with a lower number of sera tested [45]. In adults, a Phase II study of 60 participants examined the final formulation of 120 mg over three doses. There was no control group and with only one study arm, no randomization. Two adverse events were considered related to the vaccine – one was the development of oral aphthous ulcers after a single dose, and the other was the development of gastroenteritis 7 days post first vaccination, but notably, the participant went on to doses two and three without recurrence. Other withdrawals were related to varied reasons: events before vaccination being subsequently diagnosed as hereditary angioedema (without recurrence during the study), pregnancy with a subsequently healthy infant, and protocol violation (one participant was underweight at 2nd vaccination and another missed a dose due to travel). For localized reactions, fever (‡38 C) was maximally present in those at the first dose (11.7%) but decreased by the third dose to only 3.6%. Mild-to-moderate pain was the most commonly recorded localized reaction with moderate pain (requiring repeated use of non-narcotic analgesia >24 h or interfering with activity) occurring in 25.0 to 38.2% of participants over the three doses. Mild pain (not interfering with activity) occurred in 54.5 to 66.7% of participants over the three doses. For systemic reactions, headache (47.4–61.7%) and fatigue (41.8–60.0%) were most frequently reported but in only one participant; each were these classified as severe. Notable adverse and serious advent events occurred but were judged to be unrelated to the vaccine. Only a single severe adverse event was considered vaccine-related and this was a severe upper respiratory tract infection recorded 7 days post second dose. The authors note that the frequency and severity of localized and systemic reactions in this study were broadly lower than those previously reported in Phase I study in adults. informahealthcare.com
Vaccine Profile
All 60 participants contributed in at least some way to immunogenicity studies. Five MenB strains were tested against for SBA, of which one strain had fHbp homology to the vaccine antigens, and the other four had 86.2–92.0% homology to the vaccine antigens. The authors comment that these five MenB strain fHbp variants are representative of over 90% of all disease-causing isolates and three of these strains were the same strains as in the Phase II adolescent study. Before vaccination, 65.4–93.2% of participants, depending on the strain, had hSBA serum titers below the level of quantification. After the third vaccination, more than 94% of participants had seroprotective hSBA titers (‡1:4) against four of the MenB strains and of the one strain variant remaining, 81.0% had seroprotective titers. Seroconversion rates tended to rise with each sequential administration of the vaccine [46]. Regulatory affairs
Clinical Phase III trials of the bivalent fHbp vaccine are underway but are not yet openly reported [47], but the FDA announced on 29 October 2014, ‘the approval of Trumenba, the first vaccine licensed in the United States to prevent invasive meningococcal disease caused by N. meningitidis serogroup B in individuals 10 through 25 years of age’ [48]. In March 2014, this vaccine had received ‘breakthrough therapy’ designation from the FDA, just as the rival 4CMenB vaccine had, with the aim to expedite development and review [49]. The FDA label includes restrictions on the use of the vaccine in children and in persons over 65 years of age. Conclusion
The burden of meningococcal disease in Europe and the USA is now predominantly due to MenB. The bivalent fHbp vaccine shows promise in Phase I and II trials except in infants, where the Phase I and II combined study was halted due to the high frequency of fever. US regulatory approval has now been granted and Phase III trial results are awaited. A summary comparison of the bivalent fHbp vaccine compared with the 4CMenB vaccine is shown in TABLE 2. Expert commentary
Although both bfHbp and 4CMenB have been characterized as ‘MenB vaccines,’ each of them is likely to have activity against N. meningitidis strains across the major prevalent serogroups. Thus, while they have been developed to plug a gap not filled by the monovalent and quadrivalent glycoconjugate vaccines, they may in future be considered as pan-meningococcal vaccines and used as part of programs, provided perhaps that new biomarkers such as the meningococcal antigen typing system assay are able to show broad coverage in specific populations. bfHbp has theoretical advantages over the 4CMenB vaccine, provided that circulating strains express fHbp. Antibodies elicited against fHbp appear to generate bactericidal activity and bfHbp offers expanded coverage against strains currently prevalent in Europe and the USA. However, Phase I/II studies have shown high rates of reactogenicity in infants (to a much greater 499
Vaccine Profile
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Table 2. Comparison of bivalent fHbp and 4CMenB vaccines. Bivalent fHbp
4CMenB
Components
Two fHbp: one from subfamily A and one from subfamily B (A05 + B01)†
fHbp (B24) + NadA + NHBA + New Zealand outbreak strain OMV‡,†
Company
Wyeth, Pfizer†
Novartis‡
US FDA regulatory approval
Approved [48]
Awaiting decision [34]
European regulatory approval
Not known to be submitted
Approved [34]
Indication for which approved and age range
Invasive MenB disease in individuals 10 to 25 years of age [48]
Invasive MenB disease; from 2 months old onwards (but no data for over 50 years old) [52]
Published Phase I results
Yes§
Yes [53]
§
Published Phase II results
Yes
Yes‡
Published Phase III results
Not yet [47]
Yes‡
†
See [54]. See [36]. § See Table 1 for references. fHbp: Factor H binding protein = LP2086; MenB: Neisseria meningitidis serogroup B; NadA: Neisseria adhesion A; NHBA: Neisseria heparin binding antigen; OMV: Outer membrane vesicle. ‡
extent than older children and adults), and Pfizer leadership appears to have terminated research and development of the vaccine for infant programs. In the opinion of author RCR, this decision could be questioned as it is not at all clear that the age-specific reactogenicity is any greater than is observed with 4CMenB, and never will be unless the vaccines are studied head-to-head. As the major disease burden continues to be in toddlers and pre-school children, this vaccine may suffer in competition with 4CMenB, which is about to be deployed in infants. Vaccination of adolescents with bfHbp will protect against the second peak of meningococcal disease, but also there is the possibility that bfHbp could afford protective herd immunity by reducing colonization and transmission in adolescents – who as stated above – have the highest asymptomatic colonization rates. It is quite possible that adolescent-age carriage prevention studies (which are currently underway in Europe) may show an effect on carriage, which would suggest that they could generate indirect herd protection of younger children. Unfortunately, a similar study conducted with 4CMenB [7] did not demonstrate a dramatic effect of that subcapsular vaccine on adolescent carriage, but only 9% of the subjects in the study were carrying serogroup B, and meningococcal antigen typing system assays (which might have shown under-representation of strains cognate to 4CMenB) were not done. We therefore await carriage studies of fHbp with great interest, as this would certainly improve greatly the potential of the vaccine. Five-year view
The real-world market for widespread MenB vaccines is only currently entering its infancy with the recent approval of
500
4CMenB in multiple regions and the likely near-future approval of the bivalent fHbp vaccine beyond the USA. A non-strain-specific MenB vaccine such as the bivalent fHbp has significant potential to reduce the disease burden and sequelae, and population-based studies showing this are anticipated. Carefully thought re-investigation in infants may be considered as this opens up this vaccine to be used in the most at-risk group, especially as the 4CMenB vaccine safety profile in this age group is broadly similar. Quadrivalent conjugate vaccines are widely deployed and safe and further research into combining serogroup B vaccines into existing multi-serogroup vaccines, or novel vaccine approaches altogether, may consolidate broad coverage N. meningitis protection. Sequential administration of a vaccine of the quadrivalent multiple serogroup vaccine (Men ACWY-CRM, Menveo) along with 4CMenB to cover laboratory workers has already shown evidence of immunogenicity and safety [50], and results related to similar, more wide-ranging trials, are expected, including a completed Phase II Novartis study [51]. Information resources
PubMed, Web of Science. Financial & competing interests disclosure
The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Expert Rev. Vaccines 14(4), (2015)
MenB bivalent fHbp vaccine
Vaccine Profile
Key issues .
The development of a widely effective vaccine against disease caused by Neisseria meningitidis serogroup B (MenB) has been significantly more prolonged compared with other widespread pathogenic serogroups (A, C, W and Y), and currently serogroup B disease accounts for a disproportionate amount of meningococcal disease, with incidence peaks in infants and adolescents.
.
A four-component vaccine, 4CMenB (Bexsero, Novartis), has recently been approved in different countries against MenB, for all age ranges.
.
This article examines a bivalent factor H binding protein (fHbp) vaccine developed initially by Wyeth (later acquired by Pfizer). fHbp is
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also known as LP2086. .
The bivalent fHbp vaccine has undergone Phase I and II trials, and Phase III trials are not yet published.
.
In a Phase I and II study involving infants (42–90 days old), the trial was terminated early due to unacceptable fever rates.
.
In other age ranges up to adults, the safety profile was acceptable.
.
Clinical efficacy, from Phase I and II data only, appears to support and suggest good immunogenicity via serum bactericidal activity assays, albeit against a limited range of MenB strains.
.
Both the bivalent fHbp and 4CMenB vaccine have the potential to be quite broadly active vaccines, rather than just MenB specific, as their targets are found across the major prevalent serogroups.
.
The bivalent fHbp vaccine, as Trumenba, has received in late October 2014 FDA approval to be first vaccine licensed in the USA to prevent MenB disease in individuals 10–25 years of age.
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