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Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) for Use of Serogroup B Meningococcal (MenB) Vaccines in Adolescents and Young Adults (Including College Students)																									Related Pages
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			IntroductionMethods for GRADEResultsSummary
		
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Introduction
Two serogroup B meningococcal (MenB) vaccines have recently been licensed for use in the U.S. (MenB-FHbp [Trumenba, Wyeth Pharmaceuticals, Inc.] and MenB-4C [Bexsero, Novartis Vaccines]). Both vaccines were approved for use in persons aged 10 through 25 years. MenB-FHbp was licensed as a three-dose series and MenB-4C was licensed as two-dose series. Evidence of benefits and harms were reviewed in accordance with GRADE methods (1). The primary policy question was “Should MenB vaccines be administered routinely to all adolescents and young adults (including college students)?”
**Top of Page
Methods for GRADE
The benefits outcomes considered for each vaccine included short-term immunogenicity (1 month after vaccination), persistence of immunogenicity (11–48 months after vaccination, if data available), and MenB immunogenicity with concomitant vaccines. The harms outcome considered for each vaccine included occurrence of serious adverse events (SAEs) after vaccination and safety of concomitant administration with other vaccines.
Immunogenicity and safety data from five clinical trials (3 randomized controlled trials (RCT), 1 randomized uncontrolled trial, and 1 immunogenicity extension study) of MenB-4C (2-6) and seven clinical trials (5 RCTs and 2 open label studies) of MenB-FHbp (7-10) (Pfizer, unpublished data) were considered in the assessment. The evidence type for each outcome was derived through a review of study design, risk of bias, inconsistency, indirectness, imprecision and other considerations (strength of association, dose response gradient and opposing plausible residual confounding or bias).
Estimates of short-term immunogenicity and persistence of immunogenicity (11–48 months after vaccination, if data available) were based on demonstration of immune response, as measured by human serum bactericidal activity (hSBA) against a small number of serogroup B strains. In studies supporting U.S. licensure, immunogenicity was assessed by the proportion of subjects who achieved a ≥4-fold increase in hSBA titer for each of the strains tested, and the proportion of subjects who achieved a titer greater than or equal to the lower limit of quantitation (LLOQ) of the assay for all strains (composite response). The LLOQ was defined as the lowest amount of the antibody in a sample that can be reliably quantified.
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Results
Table 1a: Use of MenB-4C (Bexsero®) in adolescents and young adults (including college students): Evidence Table
Use of MenB-4C (Bexsero®) in adolescents and young adults
Outcome
Design (# studies)
Initial Evidence
Risk of Bias
Inconsistency
Indirectness
Imprecision
Publication Bias
Others
Final Evidence
Overall Evidence TypeBenefitsShort-term
immunogenicity
3 RCTs
1
Not serious
Serious**
(-1)
Serious***
(-1)
Not Serious
Unable to assess
Yes##
(+1)
2
21 Obs
3
Not serious
Not serious
Serious***
(-1)
Not Serious
Unable to assess
None
4Persistence of immunogenicity (11-24 months)
2 RCTs
1
Serious*
(-1)
Not serious
Serious***
(-1)
Not Serious
Unable to assess
None
3
3MenB Immunogenicity with concomitant vaccination
No available studiesHarmsSerious Adverse Events
3 RCTs
1
Not serious
Not serious
Not Serious
Serious#
(-1)
Unable to assess
None
2
2Serious Adverse Events following concomitant vaccination
No available studiesTable 1a Footnotes
* No formal statistical hypothesis testing or sample size calculation planned in the protocol for one study. Potential selection bias for participants in the other study – downgraded by 1
** High heterogeneity, I-squared > 90% across all strains – downgraded by 1
*** Studies assessed correlate of protection and not directly efficacy – downgraded by 1# The CI around the effect estimate includes both effect and non-effect – downgraded by 1## Strong strength of association. RR ranges between 4.44 and 5.19 – upgraded by 1

Table 1b: Considerations for Vaccine Use: MenB-4C (Bexsero®)
Considerations for Vaccine Use: MenB-4C
Key Factors
CommentsBalance between benefits and harms
Among healthy adolescents and young adults (including college students), the vaccine is immunogenic in the short-term and persists 1-2 years after vaccination. Low disease burden lowers overall benefits.Evidence type for benefits and harms**MenB-4C vaccine use among healthy adolescents and young adults (including college students)**
**Benefits:**
Short-term immunogenicity: **Evidence Type 2**
Persistence in immunogenicity (11-24 months): **Evidence Type 3**
MenB immunogenicity with concomitant vaccination: **Not assessed**
**Harms:**
Serious Adverse Events: **Evidence Type 2**SAEs following concomitant vaccination: **Not assessed**
Table 2a: Use of MenB-FHbp (Trumenba®) in adolescents and young adults (including college students): Evidence Table
Use of MenB-FHbp (Trumenba®) in adolescents and young adults (including college students): Evidence Table
Outcome
Design (# studies)
Initial Evidence
Risk of Bias
Inconsistency
Indirectness
Imprecision
Publication Bias
Others
Final Evidence
Overall Evidence TypeBenefitsShort-term
immunogenicity
2 RCTs
1
Not serious
Serious**
(-1)
Serious***
(-1)
Not Serious
Unable to assess
Yes##
(+1)
2
21 Obs
3
Not serious
Not applicable
Serious***
(-1)
Not Serious
Unable to assess
None
4Persistence in Immunogenicity 48 months post vaccination
1 Obs
3
Serious*
(-1)
Not applicable
Serious***
(-1)
Minor+#
Unable to assess
None
4
4MenB Immunogenicity with concomitant vaccination (Non-inferiority)+
2 RCTs
1
Not serious
Not serious
Serious***
(-1)
Not Serious
Unable to assess
None
2
2HarmsSerious Adverse Events (SAEs)
5 RCTs
1
Not serious
Not serious
Not Serious
Serious#
(-1)
Unable to assess
None
2
2Safety with Concomitant vaccination (SAEs)
2 RCTs
1
Not serious
Not serious
Not Serious
Serious#
(-1)
Unable to assess
None
2
2Table 2a Footnotes
+ Concomitant administration with Tdap/IPV or 4vHPV
* Very small sample size
** Significant heterogeneity; I-square ranges between 43-81% – Downgraded 1
*** Studies assessed correlate of protection and not directly efficacy – downgraded by 1
*# The CI around the effect estimate includes both effect and non-effect in two strains not common in the U.S.# The CI around the effect estimate includes both effect and non-effect – downgraded by 1## Very strong strength of association: relative risk ranges between 4.64 between 12.26 – upgraded by 1

Table 2b: Considerations for Vaccine Use: MenB-FHbp (Trumenba®)
Considerations for Vaccine Use: MenB-FHbp
Key Factors
CommentsBalance between benefits and harms
Among healthy adolescents and young adults (including college students), the vaccine is immunogenic in the short-term and persists up to 4 years after vaccination. MenB-FHbp is safe for concomitant vaccination with 4vHPV, MenACWY, Tdap and Tdap/IPV. Low disease burden lowers overall benefits.Evidence type for benefits and harms**MenB-4C vaccine use among healthy adolescents and young adults (including college students)**
**Benefits:**
Short-term immunogenicity: **Evidence Type 2**
Persistence in immunogenicity (48 months): **Evidence Type 4**
MenB immunogenicity with concomitant vaccination:**Evidence Type 2**
**Harms:**
Serious Adverse Events: **Evidence Type 2**SAEs following concomitant vaccination:**Evidence Type 2****Top of Page
Summary
After reviewing the available data, including the result of the GRADE analysis, the Advisory Committee on Immunization Practices (ACIP) recommended that adolescents and young adults aged 16 through 23 years may be vaccinated with a MenB vaccine to provide short term protection against most strains of serogroup B meningococcal disease. The preferred age for MenB vaccination is 16 through 18 years of age (recommendation Category B). Category B recommendations are made for individual clinical decision making. See the Use of MenB vaccines in adolescents and young adults (including college students) ACIP recommendation.
**Top of Page
References
ACIP. Evidence-Based Recommendations–GRADE. 2015 [July 2015].
Block SL, Szenborn L, Daly W, et al. A comparative evaluation of two investigational meningococcal ABCWY vaccine formulations: Results of a phase 2 randomized, controlled trial. Vaccine. 2015 May 15;33(21):2500-10.
Perrett KP, McVernon J, Richmond PC, et al. Immune responses to a recombinant, four-component, meningococcal serogroup B vaccine (4CMenB) in adolescents: A phase III, randomized, multicentre, lot-to-lot consistency study. Vaccine. 2015 Sep 22;33(39):5217-24.
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 Dec 13;384(9960):2123-31.
Santolaya ME, O’Ryan M, Valenzuela MT, et al. Persistence of antibodies in adolescents 18-24 months after immunization with one, two, or three doses of 4CMenB meningococcal serogroup B vaccine. Human vaccines & immunotherapeutics. 2013 Nov;9(11):2304-10.
Santolaya ME, O’Ryan ML, Valenzuela MT, et al. Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study. Lancet. 2012 Feb 18;379(9816):617-24.
Bhuyan P, Eiden J, Jones TR, et al. Immunogenicity of Human Papilloma Vaccine Coadministered With an Investigational Bivalent rLP2086 Vaccine Against Meningococcal Serogroup B in Healthy Adolescents. IDWeek; 2014; Philadelphia, PA.
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. The Lancet Infectious diseases. 2012 Aug;12(8):597-607.
Vesikari T, Ostergaard L, Diez-Domingo J, et al. Meningococcal Serogroup B Bivalent rLP2086 Vaccine Elicits Broad and Robust Serum Bactericidal Responses in Healthy Adolecents. J Ped Infect Dis. 2015 Aug.
Vesikari T, Wysocki J, Kieninger D, et al.. Immunogenicity, Safety, and Tolerability of Bivalent rLP2086 Meningococcal Group B Vaccine Administered Concomitantly with Diphtheria, Tetanus, Acellular Pertussis and Inactivated Poliomyelitis Vaccine to Healthy Adolescents. 32nd Annual Meeting of the European Society for Paediatric Infectious Diseases; 2014; Dublin, Ireland.**Top of Page

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								Page last reviewed:  October 21, 2015						Content source:  	National Center for Immunization and Respiratory Diseases homeACIP Home
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