Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) for Meningococcal Conjugate Vaccines in HIV-Infected Persons
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Introduction
A growing body of evidence demonstrates an increased risk of meningococcal disease among HIV-infected persons; risk increases further with a low CD4 count or high viral load [1-3]. Meningococcal vaccination has previously been recommended for certain groups with medical conditions that increase risk for meningococcal disease [4], including persons with persistent complement component deficiencies, persons receiving eculizumab (Soliris®, Alexion Pharmaceuticals), or persons with functional or anatomic asplenia. Three meningococcal conjugate vaccines are licensed for use in the United States: two quadrivalent (serogroups A, C, W, and Y) vaccines (MenACWY-D [Menactra®, Sanofi Pasteur] and MenACWY-CRM [Menveo®, GlaxoSmithKline]) and one bivalent (serogroups C and Y) vaccine (Hib-MenCY-TT [MenHibrix®, GlaxoSmithKline]).
GRADE was used to evaluate routine vaccination of HIV-infected persons with meningococcal conjugate vaccine. The primary policy question was “Should meningococcal conjugate vaccines be administered routinely to all HIV-infected persons aged ≥2 months for prevention of meningococcal disease?” Evidence of benefits and harms were reviewed in accordance with GRADE methods [5].
Methods for GRADE
Immunogenicity and safety data from two open-label observational studies of MenACWY-D [6-8] were considered in the assessment. No studies of immunogenicity or safety of MenACWY-CRM or Hib-MenCY-TT in HIV-infected persons were available.
The benefits outcomes considered for each vaccine included short-term immunogenicity (1 month after both the first dose of vaccine [week 4] and after the second dose of vaccine [week 28]) and persistence of immunogenicity (48 weeks after the second dose of vaccine [week 72]). The harms outcome considered included occurrence of serious adverse events (SAEs) after vaccination. 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).
Clinical effectiveness studies of meningococcal vaccines among HIV-infected persons are not feasible because of low incidence of disease. Estimates of short-term immunogenicity and persistence of immunogenicity were based on demonstration of immune response, as measured by serum bactericidal assay using a baby rabbit complement source (rSBA) against each meningococcal serogroup (A, C, W, and Y). Immunogenicity was assessed by the proportion of subjects who achieved a ≥4-fold increase in rSBA titer for each of the strains tested and the proportion of subjects who achieved an rSBA titer ≥1:128.
Results
Table 1. Evidence Table: Use of MenACWY vaccines in HIV-infected persons aged ≥2 months
| Outcomes | Design (# studies) | Initial Evidence | Risk of Bias | Inconsistency | Indirectness | Imprecision | Publication Bias | Others | Final Evidence | Overall Evidence Type |
|---|---|---|---|---|---|---|---|---|---|---|
| Benefits | 3 | |||||||||
| Short-term immunogenicity after 1 dose (week 4) | 2 Obs | 3 | Not Serious | Not Serious | Serious*(-1) | Not Serious | Not Serious | Yes§ǁ (+1) | 3 | |
| Short-term immunogenicity after 2 doses (week 28) | 2 Obs | 3 | Not Serious | Not Serious | Serious*(-1) | Not Serious | Not Serious | Yes§ǁ (+1) | 3 | |
| Persistence of immunogenicity after 2 doses (week 72) | 2 Obs | 3 | Not Serious | Not Serious | Serious*(-1) | Not Serious | Not Serious | Yesǁ (+1) | 3 | |
| Harms | ||||||||||
| Serious adverse events (after any dose) | 2 Obs | 3 | Not serious | Not serious | Not Serious | Serious‡ (-1) | Not Serious | None | 4 | |
Table 1 Footnotes
‡ Total sample size not sufficient to detect rare adverse events
§ Very strong strength of association: relative risk ranges between 5 and 49
ǁ Strong dose response
Table 1b. Considerations for Vaccine Use: MenACWY vaccines in HIV-infected persons aged ≥2 months
| Key Factors | Comments |
|---|---|
| Balance between benefits and harms | Vaccine is immunogenic in HIV-infected children and adolescents in the short-term and safe. Immunogenicity persists in HIV-infected children but wanes rapidly in adolescents and young adults. Immune responses are suppressed with lower CD4 percentage and higher viral loads. Low disease burden lowers overall benefits. |
| Evidence type for benefits and harms | |
| MenACWY vaccines in HIV-infected persons aged ≥2 months | Overall Evidence Type: 3
Benefits: Harms: |
Summary
The evidence type for use of meningococcal conjugate vaccine in HIV-infected persons aged ≥2 months was determined to be type 3 (low level of evidence). After reviewing the result of the GRADE analysis and other data demonstrating increased risk of meningococcal disease among HIV-infected persons, the Advisory Committee on Immunization Practices (ACIP) recommended that HIV-infected persons aged ≥2 months be routinely vaccinated with a MenACWY vaccine to prevent meningococcal disease (recommendation Category A). The full recommendations for the use of MenACWY vaccines in HIV-infected persons aged ≥2 months are available on the ACIP website.
References
- Cohen C, Singh E, Wu HM, Martin S, de Gouveia L, Klugman KP, et al. Increased incidence of meningococcal disease in HIV-infected individuals associated with higher case-fatality ratios in South Africa. Aids. 2010 Jun 1;24(9):1351-60.
- Miller L, Arakaki L, Ramautar A, Bodach S, Braunstein SL, Kennedy J, et al. Elevated risk for invasive meningococcal disease among persons with HIV. Annals of internal medicine. 2014 Jan 7;160(1):30-7.
- Simmons RD, Kirwan P, Beebeejaun K, Riordan A, Borrow R, Ramsay ME, et al. Risk of invasive meningococcal disease in children and adults with HIV in England: a population-based cohort study. BMC Med. 2015;13:297.
- Cohn AC, MacNeil JR, Clark TA, Ortega-Sanchez IR, Briere EZ, Meissner HC, et al. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2013 Mar 22;62(RR-2):1-28.
- ACIP. Evidence-Based Recommendations–GRADE. 2015 [July 2015].
- Siberry GK, Williams PL, Lujan-Zilbermann J, Warshaw MG, Spector SA, Decker MD, et al. Phase I/II, open-label trial of safety and immunogenicity of meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine in human immunodeficiency virus-infected adolescents. The Pediatric infectious disease journal. 2010 May;29(5):391-6.
- Siberry GK, Warshaw MG, Williams PL, Spector SA, Decker MD, Jean-Philippe P, et al. Safety and immunogenicity of quadrivalent meningococcal conjugate vaccine in 2- to 10-year-old human immunodeficiency virus-infected children. The Pediatric infectious disease journal. 2012 Jan;31(1):47-52.
- Lujan-Zilbermann J, Warshaw MG, Williams PL, Spector SA, Decker MD, Abzug MJ, et al. Immunogenicity and safety of 1 vs 2 doses of quadrivalent meningococcal conjugate vaccine in youth infected with human immunodeficiency virus. J Pediatr. 2012 Oct;161(4):676-81 e2.