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Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) for Infant Meningococcal Vaccines																									Related Pages
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			Methods for GRADE: Infant Meningococcal VaccinesTablesReferences
		
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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 cost-effectiveness were reviewed in accordance with GRADE methods[1].  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  Data from four unpublished observational studies (Obs) and 1 unpublished RCT were reviewed for MenACWY-D; data from nine randomized controlled trials (RCT) were reviewed for Hib-MenCY-TT[2-10]. 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].
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Tables for GRADE: Infant Meningococcal Vaccines
Table 1. MenACWY-D vaccine for routine use in infants: Evidence Type of Benefits and Harms
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 TypeBenefitsShort-term efficacy
Obs (3)
No serious*
No serious
No serious
No serious
No serious
3Long-term efficacy (3 yr)
Obs (1)
No serious*
No serious
No serious
No serious
No serious
3HarmsSerious Adverse Events
Obs (3)
Yes (-1)*
No serious
No serious
No serious
No serious
4Serious Adverse Events
RCT (1)
Yes (-1)*
No serious
No serious
Yes (-1)†
No serious
3Interference with Coadministered Vaccines
RCT (1)
No serious*
No serious
No serious
No serious
No serious
1Table 1 Footnotes
*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
Table 2. Hib-MenCY-TT vaccine for routine use in infants: Evidence Type of Benefits and Harms
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 TypeBenefitsShort-term efficacy* (infant series)
RCT (5)
No serious**
No serious
No serious
No serious
No serious
1Short-term efficacy* (full series)
RCT (4)
No serious**†
No serious
No serious
No serious
No serious
1Long-term efficacy*
RCT (1)

NA (only 1 study per group)(1 yr)
No serious*
No serious
No serious
No serious
1(3 yr)
No serious*
No serious
Yes (-1)***
No serious
2(5 yr)
No serious*
No serious
Yes (-1)***
No serious
2HarmsSerious Adverse Events
RCT (5)
Yes (-1)**†
No serious
No serious
No serious
No serious
2Serious Adverse Events
RCT (2)
No serious**
No serious
No serious
No serious
No serious
1Table 2 Footnotes
* 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
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 disease[11].  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 disease[12].  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 methods[1].  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-TT[2-10]; data from three published RCT[13-15] 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]
**Top of Page
Table 3. MenACWY-D vaccine for routine use in increased risk infants: Evidence Type of Benefits and Harms
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 TypeBenefitsShort-term efficacy
Obs (3)
No serious*
No serious
Yes (-1)**
No serious
No serious
4Long-term efficacy (3 yr)
Obs (1)
No serious*
No serious
Yes (-1)**
No serious
No serious
4HarmsSerious Adverse Events
Obs (3)
Yes (-1)*
No serious
Yes (-1)**
No serious
No serious
4Serious Adverse Events
RCT (1)
Yes (-1)*
No serious
Yes (-1)**
Yes (-1)†
No serious
4Interference with Coadministered Vaccines
RCT (1)
No serious*
No serious
Yes (-1)**
No serious
No serious
2Table 3 Footnotes
*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
Table 4. Hib-MenCY-TT vaccine for routine use in increased risk infants: Evidence Type of Benefits and Harms
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 TypeBenefitsShort-term efficacy* (infant series)
RCT (5)
No serious**
No serious
Yes (-1)‡
No serious
No serious
2Short-term efficacy* (full series)
RCT (4)
No serious**†
No serious
Yes (-1)‡
No serious
No serious
2Long-term efficacy*
RCT (1)

NA (only 1 study per group)(1 yr)
No serious**
Yes (-1)‡
No serious
No serious
2(3 yr)
No serious**
Yes (-1)‡
Yes (-1)***
No serious
3(5 yr)
No serious**
Yes (-1)‡
Yes (-1)***
No serious
3HarmsSerious Adverse Events
RCT (5)
Yes (-1)**†
No serious
Yes (-1)‡
No serious
No serious
3Interference with Coadministered Vaccines
RCT (2)
No serious**
No serious
Yes (-1)‡
No serious
No serious
2Table 4 Footnotes
*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
Table 5. MenACWY-CRM vaccine for routine use in increased risk infants: Evidence Type of Benefits and Harms
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 TypeBenefitsShort-term efficacy* (infant series)
RCT (3)
No serious*
No serious
Yes (-1)†
No serious
No serious
2Short-term efficacy* (full series)
RCT (1)
No serious*
NA (only 1 study per group)
Yes (-1)†
No serious
NA (only 1 study per group)
2Obs (1)
No serious*
NA (only 1 study per group)
Yes (-1)†
No serious
NA (only 1 study per group)
4Long-term efficacy*
RCT (1)(28 months)
No serious*
NA (only 1 study per group)
Yes (-1)†
Yes (-1)‡
NA (only 1 study per group)
3HarmsSerious Adverse Events
RCT (4)
Yes (-1)*
No serious
Yes (-1)†
No serious
No serious
3Interference with Coadministered Vaccines
RCT (3)
No serious*
No serious**
Yes (-1)†
No serious**
No serious
2Table 5 Footnotes
*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.
Benefits Evidence Type: 3
Harms Evidence Type: 3
Overall Evidence Type: 3
**Top of Page
References
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.
Bryant KA, Marshall GS, Marchant CD, et al. Immunogenicity and Safety of *H. influenzae* Type b-*N meningitidis* C/Y Conjugate Vaccine in Infants.Pediatrics 2011;127:e1375.
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.
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.
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.
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.
Miller JM. Hib-MenCY-TT: Product and Clinical Data Overview.  COID; April 17, 2012.
Nolan T, Lambert S, Roberton D, et al. A novel combined *Haemophilus influenzae* type b-*Neisseria 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.
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.
Rinderknecht S, Bryant KA, Nolan T, et al. The safety profile of *Haemophilus influenzae* type b-*Neisseria meningitidis* serogroups C and Y tetanus toxoid conjugate vacine (HibMenCY). Human Vaccines and Immunotherapeutics 2012;8:1-8.
CDC. Prevention and Control of Meningococcal Disease:  Recommendations of the Advisory Commitee on Immunization Practices (ACIP). MMWR 2013;62.
CDC. Infant Meningococcal Vaccination:  Advisory Commitee on Immuniation Practices (ACIP) Recommendations and Rationale. MMWR 2013;62:52-4.
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.
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.
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.**Top of Page

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