Grading of Recommendations Assessment, Development, and Evaluation (GRADE): Use of Serogroup B 

Meningococcal (MenB) Vaccines in Persons at Increased Risk for Serogroup B Meningococcal Disease 

Introduction 

In October 2014, the Food and Drug Administration (FDA) licensed the first serogroup B meningococcal 

(MenB) vaccine (MenB-FHbp [Trumenba®, Wyeth Pharmaceuticals, Inc., a subsidiary of Pfizer Inc., 

Philadelphia, Pennsylvania]) as a 3-dose series. The FDA licensed a second MenB vaccine (MenB-4C

[Bexsero®, Novartis Vaccines, Siena, Italy]) in January 2015 as a 2-dose series. Both vaccines were 

approved for use in persons aged 10 through 25 years. 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 persons aged ≥10 years at increased risk for serogroup B meningococcal 

disease or at increased risk for serogroup B disease because of an outbreak?”

Methods for GRADE 

The benefits outcomes considered for each vaccine included short-term immunogenicity (1 month after 

vaccination) and persistence of immunogenicity (11–24 months after vaccination, if data available). The 

harms outcome considered for each vaccine included occurrence of serious adverse events (SAEs) after 

vaccination. 

Safety and immunogenicity data from seven clinical trials (6 RCTs and one immunogenicity extension 

study) of MenB-4C (2-7) (Novartis, unpublished data) and nine clinical trials (6 RCTs and 3 open label 

studies) of MenB-FHbp (8-13) (Pfizer unpublished data) were considered in the assessment.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 (11–24 months after 

vaccination, if data available) were based on demonstration of immune response, as measured by serum 

bactericidal activity using human complement (hSBA) against a small number of serogroup B strains. In 

studies supporting US 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) (see package inserts; available at http://www.fda.gov/downloads/

BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM431447.pdf and http://www.fda.gov/

downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM421139.pdf). The LLOQ was 

defined as the lowest amount of the antibody in a sample that can be reliably quantified. 

June 10, 2015

https://www.cdc.gov/vaccines/acip/recs/grade/mening-serogroup-b.pdf
Results:

Table 1a: Use of MenB-4C (Bexsero®) in Persons at Increased Risk: Evidence Table

Outcome Design 

(# studies)

Initial 

Evidence

Risk of Bias Inconsistency Indirectness Imprecision Publication 

Bias

Others Final 

Evidence

Overall 

Evidence 

Type

Benefits

Short-term 

immunogenicity

3 RCTs 1 Not Serious Serious*

(-1)

Serious**

(-2)

Not Serious Unable to 

assess

Yes##

(+1)

3 3

2 Obs 3 Not serious Not serious Serious#

(-2)

Not Serious Unable to 

assess

None 4

Persistence of 

immunogenicity 

(11-24 months)

2 RCTs 1 Serious#*

(-1)

Not serious Serious 

**

(-2)

Not Serious Unable to 

assess

None 4 4

Harms

Serious Adverse 

Events

3 RCTs 1 Not serious Not serious Serious> 

(-1)

Serious***

(-1)

Unable to 

assess

None 3 3

Footnotes:

* High heterogeneity, I-squared > 90% across all strains – downgraded by 1

** Focused on healthy adolescents and young adults, not persons at increased risk of serogroup B meningococcal disease; studies assessed correlate of 

protection and not directly efficacy – downgraded by 2

## Strong strength of association. RR ranges between 2.46 and 4.25 – upgraded by 1

# One study focused on laboratory workers only, other groups at increased risk (e.g., persons with compliment deficiencies or asplenia) not considered; 

studies assessed correlate of protection and not directly efficacy – downgraded by 2

#* 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

> Focused on healthy adolescents and young adults, not persons at increased risk of serogroup B meningococcal disease – downgraded by 1

***The CI around the effect estimate includes both effect and non-effect – downgraded by 1
Table 1b: Use of MenB-4C (Bexsero®) During Outbreaks: Evidence Table

Outcome Design 

(# studies)

Initial 

Evidence

Risk of Bias Inconsistency Indirectness Imprecision Publication 

Bias

Others Final 

Evidence 

type

Overall 

Evidence 

Type

Benefits

Short-term 

immunogenicity

3 RCTs 1 Not Serious Serious**

(-1)

Serious#

(-1)

Not Serious Unable to 

assess

Yes##

(+1)

2 2

2 Obs 3 Not Serious Not serious Serious#

(-1)

Not Serious Unable to 

assess

None 4

Harms

Serious Adverse 

Events

3 RCTs 1 Not serious Not serious Not serious Serious***

(-1)

Unable to 

assess

None 2 2

Footnotes

** High heterogeneity, I-squared > 97% across all strains – downgraded by 1

# Studies assessed correlate of protection and not directly efficacy – downgraded by 1

## Strong strength of association. RR ranges between 2.46 and 4.25 – upgraded by 1

*** The CI around the effect estimate includes both effect and non-effect –downgraded by 1

Table 1c: Considerations for Vaccine Use: MenB-4C (Bexsero®)

Key Factors Comments

Balance between benefits and harms Vaccine is immunogenic in the short-term, and 

immunogenicity persists (1-2 years) for healthy 

adolescents and adults, and is safe. Low disease 

burden lowers overall benefits.

Evidence type for benefits and harms

Use of MenB-4C in persons at increased 

risk 

Benefits: Evidence Type: 3

Harms: Evidence Type: 3

Overall: Evidence Type: 3

Use of MenB-4C during outbreaks Benefits: Evidence Type: 2

Harms: Evidence Type: 2

Overall: Evidence Type: 2
Table 2a: Use of MenB-FHbp (Trumenba®) in Persons at Increased Risk: Evidence Table

Outcome Design 

(#studies)

Initial 

Evidence

Risk of Bias Inconsistency Indirectness Imprecision Publication 

Bias

Others Final

Evidence 

Type

Overall 

Evidence 

Type

Benefits

Short-term 

Immunogenicity

2 RCTs 1 Not serious Serious*

(-1)

Serious**

(-2)

Not serious Unable to 

assess

Yes***

(+1)

3 3

3 Obs 3 Serious>

(-1)

Minor Serious**

(-2)

Not serious Unable to 

assess

None 4

Harms

Serious Adverse 

Events

5 RCTs 1 Not serious Not serious Serious#

(-1)

Serious##

(-1)

Unable to 

assess

None 3 3

Footnotes: 

* Significant heterogeneity; I-square ranges between 40-91% – Downgraded 1

** Studies focused on healthy adolescents and young adults, not persons at increased risk of serogroup B meningococcal disease; studies assessed correlate 

of protection and not directly efficacy – downgraded by 2

*** Very strong strength of association: relative risk ranges between 4 between 9 – upgraded by 1

> In one study, no statistical consideration taken into account when determining sample size; sample size was small in a second study – downgraded by 1

# With the exception of one study, all other studies did not focus on persons at increased risk of serogroup B meningococcal disease – downgraded by 1

## The CI around the effect estimate includes both effect and non-effect – downgraded by 1

Table 2b: Use of MenB-FHbp (Trumenba®) During Outbreaks: Evidence Table

Outcome Design 

(#studies)

Initial 

Evidence

Risk of Bias Inconsistency Indirectness Imprecision Publication 

Bias

Others Final

Evidence 

Type

Overall 

Evidence 

Type

Benefits

Short-term 

Immunogenicity

2 RCTs 1 Not 

serious

Serious*

(-1)

Serious**

(-1)

Not serious Unable to 

assess

Yes***

(+1)

2 2

3 Obs 3 Serious>

(-1)

Minor* Serious**

(-1)

Not serious Unable to 

assess

None 4

Harms

Serious Adverse 

Events

5 RCTs 1 Not Serious Not serious Not serious Serious##

(-1)

Unable to 

assess

None 2 2

Footnotes: 

* Significant heterogeneity; I-square ranges between 40-91 % – downgraded by 1

** Studies assessed correlate of protection and not directly efficacy –-downgraded by 1

*** Very strong strength of association: relative risk ranges between 4 between 9 – upgraded by 1

> In one study, no statistical consideration taken into account when determining sample size; sample size was small in a second study – downgraded by 1

##The CI around the effect estimate includes both effect and non-effect –downgraded by 1
Table 2c: Considerations for Vaccine Use: MenB-FHbp (Trumenba®)

Summary: The evidence type for both vaccines was determined to be type 2 (moderate level of evidence) 

for use in outbreak settings, and type 3 (low level of evidence) for use in persons at increased risk of 

serogroup B meningococcal disease; the recommendation was designated Category A (recommended for 

all persons in an age- or risk-factor-based group). The GRADE methodology is not entirely objective and 

there are areas in the methodology that are subject to interpretation by the evaluator. A head to head 

comparison of the two vaccines was not done because the vaccines target different antigens. Certain 

groups of individuals are known to be at increased risk for meningococcal disease and are currently 

recommended to be routinely vaccinated with a quadrivalent meningococcal conjugate vaccine 

(MenACWY) which protects against serogroups A, C, W, and Y. Many of these groups are also at increased 

risk for serogroup B meningococcal disease. On February 26, 2015, the Advisory Committee on 

Immunization Practices (ACIP) recommended use of MenB vaccines among certain groups of persons aged 

≥10 years who are at increased risk for serogroup B meningococcal disease; these persons include those 

with persistent complement component deficiencies; persons with anatomic or functional asplenia; 

microbiologists routinely exposed to isolates of Neisseria meningitidis; and persons identified to be at 

increased risk because of a serogroup B meningococcal disease outbreak. Available immunogenicity and 

safety data support the use of MenB vaccines in groups at increased risk for serogroup B meningococcal 

disease. Both MenB vaccines are approved for use in individuals aged 10 through 25 years; however, due 

no theoretical differences in safety for those aged >25 years as compared to those aged 10 through 25 

years, the ACIP supported routine use of MenB vaccines in persons aged ≥10 years at increased risk for 

meningococcal disease, including in persons at increased risk because of a serogroup B meningococcal 

disease outbreak. These recommendations do not apply to children younger than 10 years of age.

References

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adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study. Lancet. 

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Key Factors Comments

Balance between benefits and harms Vaccine is immunogenic in the short-term 

for healthy adolescent and adults, and is 

safe. Low disease burden lowers overall 

benefits.

Evidence type for benefits and harms

Use of MenB-FHbp in persons at 

increased risk

Benefits: Evidence Type: 3

Harms: Evidence Type: 3

Overall: Evidence Type: 3

Use of MenB-FHbp during outbreaks Benefits: Evidence Type: 2

Harms: Evidence Type: 2

Overall: Evidence Type: 2
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