Grading of Recommendations, Assessment, Development, and Evaluation 

(GRADE) for Infant Meningococcal Vaccines

Methods for GRADE: Infant Meningococcal Vaccines 

Two meningococcal vaccines, MenACWY-D and Hib-MenCY-TT, were licensed for use in infants in April 

2011 and June 2012, respectively. Evidence of benefits, harms, values and preferences, and costeffectiveness were reviewed in accordance with GRADE methods1

. The primary policy question was 

“Should meningococcal vaccines be administered routinely to all infants for prevention of 

meningococcal disease?”. The evidence for these two meningococcal vaccines were evaluated to 

answer these specific questions: “Should the meningococcal vaccine MenACWY-D be administered to all 

infants at 9 and 12 months of age for prevention of meningococcal disease?” and “Should the 

meningococcal vaccine Hib-MenCY-TT be administered routinely to all infants at 2, 4, 6, and 12 months 

of age for prevention of meningococcal disease?”. 

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

vaccination) and long-term efficacy (1, 3 and 5 years after vaccination, if data available). The harms 

outcomes considered for each vaccine included occurrence of serious adverse events (SAE) after 

vaccination and interference with other co-administered vaccines. Data from four unpublished 

observational studies (Obs) and 1 unpublished RCT were reviewed for MenACWY-D; data from nine 

randomized controlled trials (RCT) were reviewed for Hib-MenCY-TT2-10. The evidence type for each 

outcome was derived through a review of study design, risk of bias, inconsistency, indirectness, 

imprecision, and other considerations (Tables 1 and 2). 

Evidence Type 1: Randomized controlled trials, or overwhelming evidence from observational studies. 

Evidence Type 2: Randomized controlled trials with important limitations, or exceptionally strong 

evidence from observational studies. Evidence Type 3: Observational studies. Evidence Type 4: Clinical 

experience and observations, observational studies, or randomized controlled trials with notable 

limitations.1

 

https://www.cdc.gov/vaccines/acip/recs/grade/mening-vac-infants.pdf 2/4/2014
2/4/2014

Tables for GRADE: Infant Meningococcal Vaccines

Table 1. MenACWY-D vaccine for routine use in infants: Evidence Type of Benefits and Harms

Outcome Design (# 

studies)

Risk of 

Bias

Inconsistency Indirectness Imprecision Other

(Publication 

Bias)

Evidence 

Type

Benefits

Short-term 

efficacy

Obs (3) No 

serious* 

No serious No serious No serious No serious 3

Long-term 

efficacy (3 yr) 

Obs (1) No 

serious* 

No serious No serious No serious No serious 3 

Harms

Serious Adverse 

Events 

Obs (3) Yes (-1)* No serious No serious No serious No serious 4

Serious Adverse 

Events 

RCT (1) Yes (-1)* No serious No serious Yes (-1)† No serious 3

Interference 

with 

Coadministered 

Vaccines 

RCT (1) No 

serious* 

No serious No serious No serious No serious 1

*Large proportion of subject withdrawal or no information about subject withdrawal, single-blind or no

blinding †Sample size <300, high upper confidence interval

MenACWY-D Summary: Vaccine is immunogenic in the short-term and safe. Low meningococcal 

disease burden lowers overall benefits of routine use in infants. 

Benefits Evidence Type: 3

Harms Evidence Type: 3

Overall Evidence Type: 3

https://www.cdc.gov/vaccines/acip/recs/grade/mening-vac-infants.pdf
2/4/2014

Table 2. Hib-MenCY-TT vaccine for routine use in infants: Evidence Type of Benefits and Harms

Outcome Design (# 

studies)

Risk of Bias Inconsistency Indirectness Imprecision Other 

(Publication 

Bias)

Evidence 

Type

Benefits

Short-term 

efficacy* (infant 

series) 

RCT (5) No serious** No serious No serious No serious No serious 1

Short-term 

efficacy* (full 

series) 

RCT (4) No 

serious**† 

No serious No serious No serious No serious 1

Long-term 

efficacy*

(1 yr) 

(3 yr) 

(5 yr) 

RCT (1)

No serious** 

No serious** 

No serious** 

NA (only 1 

study per 

group) No serious

No serious

No serious

No serious

Yes (-1)*** 

Yes (-1)*** 

No serious

No serious

No serious

1

2

2 

Harms

Serious Adverse 

Events 

RCT (5) Yes (-1)**† No serious No serious No serious No serious 2 

Interference 

with 

Coadministered 

Vaccines

RCT (2) No serious** No serious No serious No serious No serious 1 

*Efficacy of both the Hib and MenCY components of the vaccine were evaluated **Single-blind or no

blinding; †One study with large proportion of subject withdrawal; ***Sample size <300, lower limit of 

Confidence Interval shows only small difference 

HibMenCY-TT Summary: Vaccine is safe and immunogenic for Hib and MenCY in the short-term and 5 

years post-vaccination. Low meningococcal disease burden lowers overall benefits of routine use in 

infants for protection against meningococcal serogroups C and Y. 

Benefits Evidence Type: 2

https://www.cdc.gov/vaccines/acip/recs/grade/mening-vac-infants.pdf
2/4/2014

Harms Evidence Type: 2

Overall Evidence Type: 2

In June 2011, the Advisory Committee on Immunization Practices (ACIP) voted to recommend 

vaccination against meningococcal disease with MenACWY-D for children aged 9 through 23 months of 

age at increased risk for meningococcal disease11. In October 2012 the ACIP voted to recommend 

vaccination against meningococcal serogroups C and Y with HibMenCY-TT for children aged 6 weeks 

through 18 months at increased risk for meningococcal disease12. Increased risk infants and toddlers 

include those with persistent complement pathway deficiencies or anatomic or functional asplenia, 

those living in communities with a meningococcal disease outbreak for which vaccination is 

recommended, and those traveling to or residing in areas with hyperendemic or epidemic 

meningococcal disease. A third meningococcal vaccine, MenACWY-CRM, was licensed for use in infants 

in August 2013.

In light of the recommendations for routine meningococcal vaccination only for infants who are at 

increased risk for meningococcal disease, the GRADE tables for MenACWY-D and HibMenCY-TT were 

updated to evaluate the evidence for vaccine use in increased risk infants. The evidence of benefits, 

harms, values and preferences, and cost-effectiveness for MenACWY-CRM was also reviewed in 

accordance with GRADE methods1

. The evidence for MenACWY-D, Hib-MenCY-TT, and MenACWY-CRM

were evaluated to answer the questions: “Should the meningococcal vaccine MenACWY-D be 

administered to all infants 9 and 12 months of age at increased risk meningococcal disease?” and 

“Should the meningococcal vaccines Hib-MenCY-TT and MenACWY-D be administered to all infants 2, 4, 

6, and 12 months of age at increased risk for meningococcal disease?”. 

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

vaccination) and long-term efficacy (1, 3 and 5 years after vaccination, if data available). The harms 

outcomes considered for each vaccine included occurrence of serious adverse events (SAE) after 

vaccination and interference with other co-administered vaccines. Data from four unpublished 

observational studies (Obs) and 1 unpublished RCT were reviewed for MenACWY-D; data from nine 

randomized controlled trials (RCT) were reviewed for Hib-MenCY-TT2-10; data from three published 

RCT13-15 and one unpublished RCT were reviewed for MenACWY-CRM. The evidence type for each 

outcome was derived through a review of study design, risk of bias, inconsistency, indirectness, 

imprecision, and other considerations (Tables 3,4, and 5).

Evidence Type 1: Randomized controlled trials, or overwhelming evidence from observational studies. 

Evidence Type 2: Randomized controlled trials with important limitations, or exceptionally strong 

evidence from observational studies. Evidence Type 3: Observational studies. Evidence Type 4: Clinical 

experience and observations, observational studies, or randomized controlled trials with notable 

limitations.1

 

https://www.cdc.gov/vaccines/acip/recs/grade/mening-vac-infants.pdf
2/4/2014

Table 3. MenACWY-D vaccine for routine use in increased risk infants: Evidence Type of Benefits and 

Harms

Outcome Design (# 

studies)

Risk of 

Bias

Inconsistency Indirectness Imprecision Other

(Publication 

Bias)

Evidence 

Type

Benefits

Short-term 

efficacy

Obs (3) No 

serious* 

No serious Yes (-1)** No serious No serious 4

Long-term 

efficacy (3 yr) 

Obs (1) No 

serious* 

No serious Yes (-1)** No serious No serious 4 

Harms

Serious Adverse 

Events 

Obs (3) Yes (-1)* No serious Yes (-1)** No serious No serious 4

Serious Adverse 

Events 

RCT (1) Yes (-1)* No serious Yes (-1)** Yes (-1)† No serious 4

Interference 

with 

Coadministered 

Vaccines 

RCT (1) No 

serious* 

No serious Yes (-1)** No serious No serious 2

*Large proportion of subject withdrawal or no information about subject withdrawal, single-blind or no 

blinding; **Data from healthy infants; †Sample size <300, high upper confidence interval

MenACWY-D Summary: Vaccine is immunogenic in the short-term and safe. 

Benefits Evidence Type: 4

Harms Evidence Type: 4

Overall Evidence Type: 4

https://www.cdc.gov/vaccines/acip/recs/grade/mening-vac-infants.pdf
2/4/2014

Table 4. Hib-MenCY-TT vaccine for routine use in increased risk infants: Evidence Type of Benefits 

and Harms

Outcome Design (# 

studies)

Risk of Bias Inconsistency Indirectness Imprecision Other 

(Publication 

Bias)

Evidence 

Type

Benefits

Short-term 

efficacy* (infant 

series) 

RCT (5) No serious** No serious Yes (-1)‡ No serious No serious 2

Short-term 

efficacy* (full 

series) 

RCT (4) No 

serious**† 

No serious Yes (-1)‡ No serious No serious 2

Long-term 

efficacy*

(1 yr) 

(3 yr) 

(5 yr) 

RCT (1)

No serious**

No serious**

No serious**

NA (only 1 

study per 

group)

Yes (-1)‡

Yes (-1)‡

Yes (-1)‡

No serious

Yes (-1)***

Yes (-1)***

No serious

No serious

No serious

2 

3 

3 

Harms

Serious Adverse 

Events 

RCT (5) Yes (-1)**† No serious Yes (-1)‡ No serious No serious 3

Interference 

with 

Coadministered 

Vaccines

RCT (2) No serious** No serious Yes (-1)‡ No serious No serious 2

*Efficacy of both the Hib and MenCY components of the vaccine were evaluated **Single-blind or no 

blinding; †One study with large proportion of subject withdrawal; ‡Data from healthy infants; 

***Sample size <300, lower limit of Confidence Interval shows only small difference 

HibMenCY-TT Summary: Vaccine is safe and immunogenic for Hib and MenCY in the short-term and 5 

years post-vaccination. 

Benefits Evidence Type: 3

Harms Evidence Type: 3

Overall Evidence Type: 3

https://www.cdc.gov/vaccines/acip/recs/grade/mening-vac-infants.pdf
2/4/2014

Table 5. MenACWY-CRM vaccine for routine use in increased risk infants: Evidence Type of Benefits 

and Harms

Outcome Design (# 

studies)

Risk of Bias Inconsistency Indirectness Imprecision Other 

(Publication 

Bias)

Evidence 

Type

Benefits

Short-term 

efficacy* (infant 

series) 

RCT (3) No serious* No serious Yes (-1)† No serious No serious 2

Short-term 

efficacy* (full 

series) 

RCT (1)

Obs (1)

No serious*

No serious*

NA (only 1 

study per 

group)

NA (only 1 

study per 

group)

Yes (-1)† No serious NA (only 1 

study per 

group)

NA (only 1 

study per 

group)

2

4

Long-term 

efficacy*

28 months

RCT (1)

No serious* NA (only 1 

study per 

group)

Yes (-1)† Yes (-1)‡ NA (only 1 

study per 

group)

3

Harms

Serious Adverse 

Events 

RCT (4) Yes (-1)* No serious Yes (-1)† No serious No serious 3

Interference 

with 

Coadministered 

Vaccines

RCT (3) No serious* No serious** Yes (-1)† No 

serious**

No serious 2

*No blinding; **Data for Hepatitis B antigen showed inconsistency and imprecision; †Data from healthy 

infants; ‡Sample size <300, lower limit of Confidence Interval shows only small difference 

MenACWY-CRM Summary: Vaccine is safe and immunogenic in the short-term. Duration of protection 

2 years post-4th dose varies by serogroup. 

https://www.cdc.gov/vaccines/acip/recs/grade/mening-vac-infants.pdf
2/4/2014

Benefits Evidence Type: 3

Harms Evidence Type: 3

Overall Evidence Type: 3

References

1. Ahmed F, Temte J, Campos-Outcalt D, Schunemann H, ACIP Evidence Based Recommendations 

Work Group. Methods for developing evidence-based recommendations by the Advisory Committee on 

Immunization Practices (ACIP) of the U.S. Centers for Disease Control and Prevention (CDC). Vaccine 

2011;29:9171-6.

2. Bryant KA, Marshall GS, Marchant CD, et al. Immunogenicity and Safety of H. influenzae Type bN meningitidis C/Y Conjugate Vaccine in Infants. Pediatrics 2011;127:e1375.

3. Marchant CD, Miller JM, Marshall GS, et al. Randomized Trial to Assess Immunogenicity and 

Safety of Haemophilus influenzae Type B and Neisseria meningitidis Serogroups C and Y-Tetanus Toxoid 

Conjugate Vaccine in Infants. The Pediatric Infectious Diseases Journal 2010;29:48-52.

4. Marshall GS, Marchant CD, Blatter M, et al. Immune Response and One-Year Antibody 

Persistence after a Fourth Dose of a Novel Haemophilus influenzae Type B and Neisseria Meningitidis 

Serogroups C and Y-Tetanus Toxoid Conjugate Vaccine (HibMenCY) at 12 to 15 Months of Age. The 

Pediatric Infectious Diseases Journal 2010;29:469-71.

5. Marshall GS, Marchant CD, Blatter M, Friedland LR, Aris E, Miller JM. Co-administration of a 

novel Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y-tetanus toxoid 

conjugate vaccine dose not interfere with the immune response to antigens contained in infant vaccines 

routinely used in the United States. Human Vaccines 2011;7:258-64.

6. Marshall GS, Mesaros N, Aris E, Marchant CD, Blatter M, Miller JM. Persistence of Immunity 

Three Years after an Investigational Haemophilus influenzae type b and Neisseria meningitidis 

Serogroups C and Y Tetanus Toxoid (HibMenCY-TT) Conjugate Vaccine. 45th National Immunization 

Conference (NIC); March 28-31, 2011; Washington, D.C.

7. Miller JM. Hib-MenCY-TT: Product and Clinical Data Overview. COID; April 17, 2012.

8. Nolan T, Lambert S, Roberton D, et al. A novel combined Haemophilus influenzae type bNeisseria meningitids serogroups C and Y-tetanus-toxoid conjugate vaccine is immogenic and induces 

immune memory when co-administered with DTPa-HBV-IPV and conjugate pneumococcal vaccines in 

infants. Vaccine 2007;25:8487-99.

9. Nolan T, Richmond P, Marshall H, et al. Immunogenicity and Safety of an Investigational 

Combined Haemophilus influenzae Type B-Neisseria meningitidis Serogouprs C and Y-Tetanus Toxoid 

Conjugate Vaccine. The Pediatric Infectious Diseases Journal 2011;30:190-6.

10. Rinderknecht S, Bryant KA, Nolan T, et al. The safety profile of Haemophilus influenzae type bNeisseria meningitidis serogroups C and Y tetanus toxoid conjugate vacine (HibMenCY). Human Vaccines 

and Immunotherapeutics 2012;8:1-8.

11. CDC. Prevention and Control of Meningococcal Disease: Recommendations of the Advisory 

Commitee on Immunization Practices (ACIP). MMWR 2013;62.

12. CDC. Infant Meningococcal Vaccination: Advisory Commitee on Immuniation Practices (ACIP) 

Recommendations and Rationale. MMWR 2013;62:52-4.

13. Klein NP, Reisinger KS, Johnston W, et al. Safety and Immunogenicity of a Novel Quadrivalent 

Meningococcal CRM-conjugate Vaccine Given Concomitantly with Routine Vaccinations in Infants. 

Pediatric Infectious Disease Journal 2012;31:64-71.

https://www.cdc.gov/vaccines/acip/recs/grade/mening-vac-infants.pdf
2/4/2014

14. Tregnaghi M, Tregnaghi M, D'Andrea U, Grana MG, Dull P, Bedell L. Imunogenicity of a 

Quadrivalent MenACWY-CRM Conjugate Vaccine Administered in Various Schedules to Argentinean 

Infants and Toddlers. 29th ESPID Meeting; June 7-11, 2011; The Hague, The Netherlands.

15. Nolan T, Naz A, Hohenboken M, Bedell L, Odrljin T, Dull P. Safety and Immunogenicity of 

Meningococcal Quadrivalent Conjugate Vaccine (MenACWY-CRM) Given Concomitantly with Routine 

Infant and Toddler Vaccines in Infants from 2 Months of Age. IDWeek; October 17-21, 2012; San Diego, 

CA.

https://www.cdc.gov/vaccines/acip/recs/grade/mening-vac-infants.pdf