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GRADE: Serogroup B Meningococcal (MenB) vaccines for persons at increased risk for serogroup B meningococcal diseaseGrading of Recommendations, Assessment, Development, and Evaluation										Related Pages
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			IntroductionMethods for GRADESummary
		
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Introduction
Two serogroup B meningococcal (MenB) vaccines are currently licensed by the Food and Drug Administration and approved for use in the United States in persons aged 10–25 years: MenB-FHbp (Trumenba, Pfizer) and MenB-4C (Bexsero, GlaskoSmithKline). In 2015, the Advisory Committee on Immunization Practices (ACIP) recommended that the following groups of persons aged ≥10 years at increased risk for serogroup B meningococcal disease receive a MenB primary series for the prevention of serogroup B meningococcal disease [1, 2]:
Persons with persistent complement component deficiencies (including persons taking a complement inhibitor (e.g., eculizumab [Soliris®])
Persons with functional or anatomic asplenia
Microbiologists routinely exposed to isolates of *Neisseria meningitidis*
Persons identified as at increased risk during a serogroup B meningococcal disease outbreakBecause of concerns for waning of immunity following MenB vaccination, ACIP reviewed evidence and considerations regarding MenB booster doses in persons at increased risk for meningococcal disease who have previously completed a MenB primary series.
**Top of Page
Methods and GRADE
A systematic review and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) of the evidence for both MenB vaccines were conducted and presented to ACIP in February 2019.  No conflicts of interest were reported by CDC staff or the ACIP Meningococcal Vaccines Work Group members involved in the GRADE analysis. As a basis for the GRADE analysis, the policy question consisting of the population, intervention, comparison, and outcomes of interest was defined (Table 1). Because goals of a booster dose may differ according to population (e.g., long-term increased risk of meningococcal disease vs. short-term risk of increased exposure), populations of interest were divided into two groups: 1) persons who are at ongoing increased risk of meningococcal disease because of certain underlying conditions or because they are a  microbiologist routinely exposed to *N. meningitidis*isolates, and 2) persons at increased risk during an outbreak.
Table 1: Policy question and definition of the Population, Intervention, Comparison, and Outcome for GRADE analysis.
Table 1
Policy question: Should persons vaccinated with a MenB primary series who remain at increased risk for serogroup B meningococcal disease receive a MenB booster dose?Population
Persons aged ≥10 years who have previously completed a MenB-FHbp or MenB-4C primary series who remain at increased risk for serogroup B meningococcal disease because of:
Persistent complement component deficiencies, complement inhibitor use, functional or anatomic asplenia, or routine exposure to isolates of *Neisseria meningitidis* as a microbiologist, *or*
An outbreak of serogroup B meningococcal diseaseIntervention
MenB-FHbp or MenB-4C booster doseComparison
No MenB-FHbp or MenB-4C booster doseOutcome
**Benefits:**
**MenB booster vaccine effectiveness against serogroup B meningococcal disease**
**Short-term immunogenicity of booster dose**
Persistence of immune response to booster dose**Harms:**
Immune interference due to co-administration of booster dose with other vaccines
**Serious adverse events from booster dose**
Bold font indicates outcomes considered by the Work Group as “Critical” for GRADE analysis
Four separate GRADE analyses were conducted, including one for each vaccine (MenB-FHbp and MenB-4C) and population (persons at increased risk because of either persistent complement component deficiencies, complement inhibitor use, functional or anatomic asplenia, or routine exposure to isolates of *Neisseria meningitidis* as a microbiologist; and persons at increased risk during an outbreak of serogroup B meningococcal disease) (Table 1).
A systematic review of studies in any language from PubMed, Medline, Embase, CINAHL, Cochrane, Scopus, and clinicaltrials.gov was conducted using the search string of “booster” AND [“serogroup B meningococcal vaccine” OR “recombinant meningococcal B vaccine” OR “MenB vaccine” OR “Bexsero” OR “MenB-4C” OR “rMenB±OMV NZ” OR “4CMenB” OR “Trumenba” OR “rLP2086” OR “Factor H binding protein vaccine” OR “FHbp”].  Efforts were made to obtain unpublished data.
Studies were included if they presented primary data on MenB booster doses in subjects who received a licensed MenB primary series at age ≥10 years. An investigational serogroups A, B, C, W, Y meningococcal vaccine (MenABCWY) booster dose was used as a proxy for a MenB booster dose if the MenB vaccine component was identical to the licensed MenB formulation. Among 131 references screened for title and abstract and four full-text articles screened, three studies from two published articles, along with one unpublished study, were included in the GRADE analysis [3, 4; Pfizer, unpublished data]: 1 unpublished study for MenB-FHbp, 2 published studies for MenB-4C, and 1 published study for MenABCWY. Characteristics of these studies are presented in Table 2 for MenB-FHbp and Table 8 for MenB-4C.
Beneficial and harmful outcomes for the GRADE assessment were selected by the Work Group during Work Group calls and via an email survey in which the members were asked to rank the relative importance of each outcome. The Work Group deemed MenB booster vaccine effectiveness against serogroup B meningococcal disease, short-term immunogenicity of booster dose, and serious adverse events (SAEs) from booster dose as critical outcomes (Table 1). Persistence of the immune response to a booster dose and immune interference due to co-administration of the booster dose with other vaccines were deemed important outcomes. Short-term immunogenicity of the booster dose, persistence of the immune response to the booster dose, and SAEs from the booster dose were included in the evidence profiles. Evidence included in the profiles is the same for both populations at increased risk.
Table 2. Characteristics of the included study for a MenB-FHbp booster dose.
Table 2
Study
Type
Population
Intervention
Comparison
Outcomes measuredUnpublished data, Pfizer
Observational*
Healthy persons aged 15–23 years in 4 European countries
MenB-FHbp booster dose at 48m following either 2- or 3-dose schedule†
(n=270)
None
Immunogenicity
Persistence
SAEs
Table 2 Footnotes
* Extension study including participants previously enrolled in phase 2 randomized, single-blinded trials to assess immunogenicity and safety of MenB primary series (ClinicalTrials.gov number NCT01299480, NCT01323270).
† 2-dose schedule: 0, 6 months. 3-dose schedule: 0, 2, 6 months.
Table 3. Data on short-term immunogenicity of a MenB-FHbp booster dose.
Table 3
Time point after booster
Primary series schedule*
No. of subjects†
% of subjects with hSBA‡ titer ≥1:4 (95% Confidence Interval)Test strainA22
A56
B24
B44
Composite§1m
2-dose A
(0, 6m)
62–64
**96.8**
(88.8, 99.6)
**98.4**
(91.6, 100)
**96.9**
(89.2, 99.6)
**93.7**
(84.5, 98.2)
**91.8**
(81.9, 97.3)3-dose A
(0, 2, 6m)
57–59
**100**
(93.9, 100)
**100**
(93.7, 100)
**100**
(93.8, 100)
**100**
(93.9, 100)
**100**
(93.6, 100)3-dose B
(0, 2, 6m)
31–32
**96.9**
(83.8, 99.9)
**100**
(88.8, 100)
**96.9**
(83.8, 99.9)
**100**
(89.1, 100)
Not available
Table 3 Footnotes
* Results from extension study reported separately by original parent study participation. Study A refers to participants from parent study NCT01299480 and Study B refers to participants from parent study NCT01323270.
† Number of subjects who received the booster vaccination and who had at least one valid and determinate assay result
‡ Human complement serum bactericidal antibody assay
§ hSBA titer ≥1:8 (1:16 for A22) for all 4 primary strains
Table 4. Data on persistence of the immune response to a MenB-FHbp booster dose.
Table 4
Time point after booster
Primary series schedule*
No. of subjects†
% of subjects with hSBA‡ titer ≥1:4 (95% Confidence Interval)Test strainA22
A56
B24
B44
Composite§12m
2-dose A
(0, 6m)
61–64
**82.3**
(70.5, 99.6)
**82.0**
(70.0, 90.6)
**78.1**
(66.0, 87.5)
**61.9**
(48.8, 73.9)
**62.7**
(49.1, 75.0)3-dose A
(0, 2, 6m)
54–56
**78.2**
(65.0, 88.2)
**91.4**
(80.4, 97.0)
**72.7**
(59.0, 83.9)
**79.6**
(66.5, 89.4)
**63.3**
(48.3, 76.6)3-dose B
(0, 2, 6m)
21–27
**93.1**
(77.2, 99.2)
**87.5**
(67.6, 97.3)
**74.2**
(55.4, 88.1)
**83.9**
(66.3, 94.5)
Not available26m
2-dose A
(0, 6m)
42–45
**65.9**
(50.1, 79.5)
**66.7**
(50.5, 80.4)
**59.1**
(43.2, 73.7)
**62.2**
(46.5, 76.2)
**42.1**
(26.3, 59.2)3-dose A
(0, 2, 6m)
30–35
**74.3**
(56.7, 87.5)
**90.0**
(73.5, 97.9)
**76.5**
(58.8, 89.3)
**70.6**
(52.5, 84.9)
**46.4**
(27.5, 66.1)
Table 4 Footnotes
* Results from extension study reported separately by original parent study participation. Study A refers to participants from parent study NCT01299480 and Study B refers to participants from parent study NCT01323270.
† Number of subjects who received the booster vaccination and who had at least one valid and determinate assay result
‡ hSBA titer ≥1:8 (1:16 for A22) for all 4 primary strains
Table 5. Data on serious adverse events from a MenB-FHbp booster dose.
Table 5
Primary series schedule*
No. of subjects
No. of reported SAEs
No. of reported deaths2-dose A (0, 6m)
116
0
03-dose A (0, 2, 6m)
114
0
03-dose A  (0, 2, 6m)
40
0
0
Table 5 Footnotes
* Results from extension study reported separately by original parent study participation. Study A refers to participants from parent study NCT01299480 and Study B refers to participants from parent study NCT01323270.
Table 6. GRADE Summary of Evidence table: MenB-FHbp booster dose for persons with persistent complement component deficiencies, complement inhibitor use, functional or anatomic asplenia, and microbiologists.
Table 6
Outcome
Design
(# studies)
Initial Evidence Type
Risk of Bias
Inconsistency
Indirectness
Imprecision
Other
Final Evidence TypeBenefitsShort-term immunogenicity
Observational (1)
3
Serious*
N/A†
Serious‡
Not Serious
N/A†
4Persistence of immune response
Observational (1)
3
Serious*
N/A†
Serious‡
Serious§
N/A†
4HarmsSerious adverse events
Observational (1)
3
Serious*
N/A†
Serious‡
Serious¶
N/A†
4
Table 6 Footnotes
* Concern of selection bias from parent study to extension study
† N/A: Not applicable, as only one study has available data.
‡ Data were available for healthy persons, but not for persons with certain underlying medical conditions.
§ Wide confidence intervals due to small number of subjects
¶ Small number of subjects may not be able to detect rare serious adverse events.
Table 7. GRADE Summary of Evidence table: MenB-FHbp booster dose for persons at increased risk during a serogroup B meningococcal disease outbreak.
Table 7
Outcome
Design
(# studies)
Initial Evidence Type
Risk of Bias
Inconsistency
Indirectness
Imprecision
Other
Final Evidence TypeBenefitsShort-term immunogenicity
Observational (1)
3
Serious*
N/A†
Serious‡
Not Serious
N/A†
4Persistence of immune response
Observational (1)
3
Serious*
N/A†
Serious‡
Serious‡
N/A†
4HarmsSerious adverse events
Observational (1)
3
Serious*
N/A†
Serious‡
Serious§
N/A†
4
Table 7 Footnotes
* Concern of selection bias from parent study to extension study
† N/A: Not applicable, as only one study has available data.
‡ Wide confidence intervals due to small number of subjects
§ Small number of subjects may not be able to detect rare serious adverse events.
Table 8. Characteristics of the included studies for a MenB-4C booster dose.
Table 8
Study
Type
Population
Intervention
Comparison
Outcomes measuredNolan, 2019 [3]
Observational*
Healthy persons aged 15–21y in Australia, Canada
MenB-4C booster at 4y (n=145)
1st MenB-4C dose
(n=105)
Immunogenicity
SAEsNolan, 2019 [3]
Observational†
Healthy persons aged 17–24y in Chile
MenB-4C booster at 7.5y (n=131)
1st MenB-4C dose
(n=150)
Immunogenicity
SAEsSzenborn, 2018 [4]
Randomized Clinical Trial
Healthy persons aged 12–27y in United States and Poland
MenABCWY booster at 2y (n=11)
1st MenB-containing (MenABCWY) dose
(n=21)
Immunogenicity
Persistence
SAEs
Table 8 Footnotes
* Extension study including participants previously enrolled in a phase 3 observer-blind randomized controlled trial to assess lot consistency, immunogenicity, and safety of MenB-4C series (ClinicalTrials.gov number NCT01423084).
† Extension study including participants previously enrolled in a phase 2b/3 randomized, observer-blind, placebo-controlled trial to assess immunogenicity and safety of MenB-4C primary series (ClinicalTrials.gov number NCT00661713).
Table 9. Data on short-term immunogenicity of a MenB-4C booster dose.
Table 9
Time point
Site
Intervention
No. of subjects*
% of subjects with hSBA titer ≥1:4†
(95% Confidence Interval)AntigenFHbp
NadA
NHBA
PorA1m
Australia, Canada
MenB-4C booster
134–144
**98.0**
(93.9, 99.6)
**100**
(97.1, 100)
**99.0**
(96.1, 99.9)
**94.0**
(89.2, 97.5)1st MenB-4C dose
100–105
**81.0**
(71.9, 87.8)
**87.0**
(78.2, 92.7)
**84.0**
(76.0, 90.0)
**41.0**
(31.2, 50.9)Chile
MenB-4C booster
120–131
**100**
(97.1, 100)
**100**
(96.4, 100)
**99.0**
(95.7, 99.9)
**93.0**
(87.3, 97.1)1st MenB-4C dose
139–150
**81.0**
(73.3, 86.6)
**84.0**
(76.7, 89.7)
**93.0**
(87.2, 96.3)
**62.0**
(53.8, 70.0)US, Poland
MenABCWY booster
11
**100**
(71.5, 100)
**100**
(71.5, 100)
**91.0**
(58.7, 99.8)
**82.0**
(48.2, 97.7)1st MenB-containing (MenABCWY) dose
20–21
**35.0**
(15.4, 59.2)
**25.0**
(8.7, 49.1)
**33.0**
(14.6, 57.0)
**19.0**
(5.4, 41.9)
Table 9 Footnotes
* Number of subjects who received the booster vaccination and who had at least one valid and determinate assay result; †1:5 in MenABCWY study
Table 10. Data on persistence of the immune response to a MenB-4C booster dose.
Table 10
Time point
Site
Intervention
No. of subjects*
% of subjects with hSBA titer ≥1:5
(95% Confidence Interval)AntigenFHbp
NadA
NHBA
PorA12m
US, Poland
MenABCWY booster
11
**82.0**
(48.2, 97.7)
**100**
(71.5, 100)
**82.0**
(48.2, 97.7)
**45.0**
(16.7, 76.6)1st MenB-containing (MenABCWY) dose
20–21
**14.0**
(3.0, 36.3)
**15.0**
(3.2, 37.9)
**29.0**
(11.3, 52.2)
**19.0**
(5.4, 41.9)
Table 10 Footnotes
* Number of subjects who received the booster vaccination and who had at least one valid and determinate assay result
Table 11. Data on serious adverse events from a MenB-4C booster dose.
Table 11
Booster dose
(Site)
Primary series received
Length of monitoring period post-booster
No. of subjects†
No. of reported serious adverse events
No. of reported deaths**MenB-4C**
(Australia, Canada,
Chile*)
MenB-4C
30 days
266
0
0**MenABCWY**
(United States and Poland)
MenB-4C
1 year
11
0
0
Table 11 Footnotes
* Participants from the Australia/Canada and Chile studies were analyzed as one study for safety outcomes, as per the vaccine manufacturer.
† Single booster dose in the primed group
Table 12. GRADE Summary of Evidence table: MenB-4C booster dose for persons with persistent complement component deficiencies, complement inhibitor use, functional or anatomic asplenia, and microbiologists.
Table 12
Outcome
Design
(# studies)
Initial Evidence Type
Risk of Bias
Inconsistency
Indirectness
Imprecision
Other
Final Evidence TypeBenefitsShort-term immunogenicity
Observational (2)
3
Serious*
Not serious
Serious‡
Not Serious
None
4RCT (1)
1
Not Serious
N/A†
Very Serious‡§
Serious¶
N/A†
4Persistence of immune response
RCT (1)
1
Not Serious
N/A†
Very Serious‡§
Serious¶
N/A†
4HarmsSerious adverse events
Observational (1)
3
Serious*
N/A†
Serious‡
Serious**
N/A†
4RCT (1)
1
Not Serious
N/A†
Very Serious‡§
Serious**
N/A†
4
Table 12 Footnotes
* Concern of selection bias from parent study to extension study
† N/A: Not applicable, as only one study has available data.
‡ Data were available for healthy persons, but not for persons with certain underlying medical conditions.
§ Investigational MenABCWY vaccine used as a proxy for MenB-4C booster in one study.
¶ Wide confidence intervals due to small number of subjects
** Small number of subjects may not be able to detect rare serious adverse events.
Table 13. GRADE Summary of Evidence table: MenB-4C booster dose for persons at increased risk during a serogroup B meningococcal disease outbreak.
Table 13
Outcome
Design
(# studies)
Initial Evidence Type
Risk of Bias
Inconsistency
Indirectness
Imprecision
Other
Final Evidence TypeBenefitsShort-term immunogenicity
Observational (2)
3
Serious*
Not serious
Not Serious
Not Serious
None
4RCT (1)
1
Not Serious
N/A†
Serious‡
Serious§
N/A†
3Persistence of immune response
RCT (1)
1
Not Serious
N/A†
Serious‡
Serious§
N/A†
3HarmsSerious adverse events
Observational (1)
3
Serious*
N/A†
Not Serious
Serious¶
N/A†
4RCT (1)
1
Not Serious
N/A†
Serious‡
Serious¶
N/A†
3
Table 13 Footnotes
* Concern of selection bias from parent study to extension study
† N/A: Not applicable, as only one study has available data.
‡ Investigational MenABCWY vaccine used as a proxy for MenB-4C booster in one study.
§ Wide confidence intervals due to small number of subjects
¶ Small number of subjects may not be able to detect rare serious adverse events.
**Top of Page
Summary
The evidence type for a MenB-FHbp booster dose in persons with persistent complement component deficiencies, complement inhibitor use, functional or anatomic asplenia, or routine exposure to N. meningitidis isolates, and for persons at risk during a serogroup B outbreak was determined to be type 4 (very low evidence quality). For a MenB-4C booster dose, the evidence type was determined to be type 4 (very low evidence quality) in persons with persistent complement component deficiencies, complement inhibitor use, functional or anatomic asplenia, or routine occupational exposure to N. meningitidis isolates, and ranged from 3–4 (low evidence quality) for persons at risk during a serogroup B outbreak.
ACIP reviewed the results of both the GRADE analysis and the Evidence to Recommendations framework in February 2019 and voted to recommend MenB booster doses in persons at increased risk for serogroup B meningococcal disease in June 2019.
**Top of Page
References
MacNeil J. R. et al. (2015). “Use of Serogroup B Meningococcal Vaccine in Adolescents and Young Adults: Recommendation of the Advisory Committee on Immunization Practices, 2015”. Morbidity and Mortality Weekly Report. 64 (41): 1171-1176.
Patton M. E. et al. (2017). “Updated Recommendations Use of MenB-FHbp Serogroup B Meningococcal Vaccine – Advisory Committee on Immunization Practices, 2016”. Morbidity and Mortality Weekly Report. 66 (19): 509-513.
Nolan T. et al. (2019). “Antibody persistence and booster response in adolescents and young adults 4 and 7.5 years after immunization with 4CMenB vaccine.” Vaccine. https://doi.org/10.1016/j.vaccine.2018.12.059external icon
Szenborn L. et al. (2018). “Immune Responses to Booster Vaccination with Meningococcal ABCWY Vaccine After Primary Vaccination with Either Investigational or Licensed Vaccines.” Pediatric Infectious Diseases Journal 37: 475-482.
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