Recommendations for Use of Meningococcal Conjugate Vaccines in HIV-Infected Persons — Advisory Committee on Immunization Practices, 2016

Methods

The ACIP Meningococcal Vaccines Work Group reviewed the immunogenicity and safety data from two studies of MenACWY-D in HIV-infected persons (2–4) during monthly teleconferences. No studies of immunogenicity or safety of MenACWY-CRM in HIV-infected persons are available. According to a nonsystematic literature search of PubMed using the search terms “meningococcal conjugate vaccine,” “quadrivalent,” and “HIV,” and consultation with the manufacturers, these two studies represent all known evidence for the immunogenicity and safety of these vaccines in HIV-infected persons. The work group also evaluated the evidence and unpublished surveillance data regarding meningococcal disease epidemiology among HIV-infected persons in the United States and a cost-effectiveness analysis of routine vaccination of HIV-infected persons. The cost-effectiveness analysis of routine vaccination versus no vaccination of HIV-infected persons was conducted assuming an initial vaccine efficacy of 75% (range = 37%–91%) for persons with a high CD4 count and 37% (range = 24%–60%) for persons with a low CD4 count based on the immunogenicity data reported in the literature for MenACWY-D (2–4). A summary of the data reviewed and work group discussions was presented to ACIP; recommendations for use of meningococcal conjugate vaccines among HIV-infected persons aged ≥2 months were approved by ACIP at its June 22, 2016 meeting (detailed meeting minutes are available at http://www.cdc.gov/vaccines/acip/meetings/meetings-info.html).

CDC vaccine recommendations are developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework (http://www.cdc.gov/vaccines/acip/recs/grade/index.html). The type and quality of available evidence supporting the use of meningococcal conjugate vaccines among HIV-infected persons aged ≥2 months were evaluated using GRADE. There is no available evidence for safety or effectiveness of these vaccines in HIV-infected persons aged <2 years or ≥25 years.

Meningococcal Disease in HIV-Infected Persons

Surveillance data for cases of meningococcal disease among HIV-infected persons in the United States are limited. The HIV status of patients with meningococcal disease is routinely captured in Active Bacterial Core surveillance (ABCs), an active population-based and laboratory-based surveillance system that operates in 10 sites, representing a population of approximately 43 million persons, or 14% of the U.S. population (5). However, the HIV status of patients with meningococcal disease is not reported through the National Notifiable Diseases Surveillance System (NNDSS), a passive surveillance system that operates in all U.S. states and territories. During 1995–2014, a total of 62 cases of meningococcal disease among HIV-infected persons were reported to ABCs; these cases represent 2% of the 3,951 meningococcal disease cases reported to ABCs during that period (CDC, unpublished data, 2016). Thirteen (21%) cases were serogroup B, 23 (37%) were serogroup C, three (5%) were serogroup W, 17 (27%) were serogroup Y, and six (10%) were other/unknown serogroups (CDC, unpublished data, 2016). The majority (92%) of cases of meningococcal disease among HIV-infected persons occurred in adults aged 20 through 59 years.

Although surveillance data for cases of meningococcal disease among HIV-infected persons are limited in the United States, a growing body of evidence demonstrates an increased risk for meningococcal disease among HIV-infected persons. In studies from South Africa, the United States, and the United Kingdom, the incidence of meningococcal disease in HIV-infected persons ranged from 3.4 to 6.6 per 100,000 (relative risk = 5–13 compared with HIV-uninfected persons) (Table 1) (6–9). Among HIV-infected persons, a low CD4 count or high viral load were associated with an increased risk (7). Similar increased risk for meningococcal disease was observed for both males and females with HIV infection (7,9).

Data on the case-fatality ratio of meningococcal disease in HIV-infected persons vary: in the South Africa study, the case-fatality ratio among HIV-infected patients was 20%, compared with 11% among patients who did not have HIV infection (6). However, in the most recent studies from New York City and the United Kingdom, the meningococcal disease case fatality ratio observed among HIV-infected patients was lower than that among HIV-uninfected patients (7,8).

MenACWY-D Immunogenicity and Safety in HIV-Infected Persons

The immunogenicity and safety of MenACWY-D in 324 HIV-infected adolescents and young adults aged 11 through 24 years were evaluated in an open-label trial with a randomized second dose component (2,4). At study entry, participants received 1 dose of MenACWY-D. At 24 weeks, participants with CD4 percentage (the percentage of total lymphocytes that are CD4 cells) (CD4%) ≥15% were randomized to receive or not receive a second dose of MenACWY-D; all participants with CD4% <15% received a second dose. Vaccine effectiveness was inferred from serum bactericidal antibodies, measured using a serum bactericidal assay with a rabbit complement source (rSBA). Rates of seroresponse (proportion of subjects with a ≥fourfold rise in rSBA titer compared with the baseline titer) against each meningococcal serogroup (A, C, W, Y), geometric mean titers (GMT), and the percentage of subjects with rSBA at or above a predefined titer (≥1:128) were determined from sera obtained at study entry and at weeks 4, 24, 28, and 72. Adverse events (AEs) were assessed for 6 weeks after each MenACWY-D dose through active follow-up (2,4).

Among participants with CD4% ≥15% who received 1 vaccine dose, the proportions of participants with rSBA titers ≥1:128 at 4, 28, and 72 weeks were 65%, 31%, and 21%, respectively, against serogroup C, and 83%, 75%, 63%, respectively, against serogroup Y (2). Among participants with CD4% ≥15% who received 2 doses (at 0, 24 weeks), the proportions of participants with rSBA titers ≥1:128 at 4, 28, and 72 weeks were 59%, 64%, and 35%, respectively, against serogroup C; and 73%, 83%, 71%, respectively, against serogroup Y (2). Among participants with CD4% <15%, all of whom received 2 doses (at 0, 24 weeks), the proportions of participants with rSBA titers ≥1:128 at 4, 28, and 72 weeks were 22%, 22%, and 6%, respectively, against serogroup C, and 30%, 30%, 28%, respectively, against serogroup Y (2). A serious AE was experienced by 2.2%–6.5% of participants through 6 weeks post-vaccination*; one serious AE (ocular pain) was judged to be related to MenACWY-D. Serious AE rates were inversely related to entry CD4%. Two deaths were reported, but both were determined to be unrelated to the vaccine (2,4).

The immunogenicity and safety of MenACWY-D in 59 HIV-infected children aged 2 through 10 years with CD4% ≥25% was evaluated in an open label trial (3). Participants received MenACWY-D at study entry and at week 24. Vaccine effectiveness was inferred from serum bactericidal antibodies, measured using a serum bactericidal assay with rSBA. Rates of seroresponse (proportion of subjects with a ≥fourfold rise in post-vaccination rSBA titer compared with the baseline titer) against each meningococcal serogroup (A, C, W, Y), GMTs, and the percentage of subjects with rSBA at or above a predefined titer (≥1:128) were determined from sera obtained at entry and weeks 4, 24, 28, and 72. Study participants were assessed for AEs 6 weeks after each MenACWY-D dose (3).

The proportion of participants with rSBA titers ≥1:128 after 1 dose (week 4) and 2 doses (week 28) of MenACWY-D were 96% and 96%, respectively, for serogroup A, 49% and 80%, respectively, for serogroup C, 98% and 100%, respectively, for serogroup W, and 90% and 98%, respectively, for serogroup Y (3). At week 72 the proportions of participants with rSBA titers ≥1:128 were 80% for serogroup A, 45% for serogroup C, 95% for serogroup W, and 91% for serogroup Y (3). Overall, 5% of participants reported a serious AE; no AE was judged to be related to MenACWY-D (3).

Evidence supporting the use of meningococcal conjugate vaccines in HIV-infected persons was evaluated using the GRADE framework and was determined to be type 3 (low level of evidence) (Table 2). The recommendation was designated as Category A (recommended for all persons in an age-based or risk factor–based group) because of the epidemiologic data supporting an increase in risk for meningococcal disease among HIV-infected persons.

From a lifetime perspective, it is estimated that, compared with no vaccination, approximately 122 (95% confidence interval [CI] = 116–129) cases and 23 (CI = 18–29) deaths could be prevented, and 385 (CI = 230–458) quality-adjusted life years (QALYs) could be saved, at a mean cost per QALY of $732,000 (CI = $337,000–$1,218,000) with a meningococcal conjugate vaccination program that includes a primary vaccination series followed by lifelong booster doses until age 70 years, targeting all currently HIV-infected persons aged ≥2 months in the United States (CDC, unpublished data, 2016).^†

Recommendations

HIV-infected persons aged ≥2 months should routinely receive meningococcal conjugate vaccine (Table 3). HIV- infected children aged <2 years should receive the vaccine in accordance with the age-appropriate, licensed, multidose schedule (1,10). Persons aged ≥2 years with HIV infection who have not been previously vaccinated should receive a 2-dose primary series of MenACWY conjugate vaccine. Persons aged ≥2 years with HIV infection who have been previously vaccinated with 1 dose of meningococcal conjugate vaccine should receive a booster dose at the earliest opportunity, provided at least 8 weeks have elapsed since the previous dose, and then continue to receive boosters at the appropriate interval throughout life.^§ The recommendations for children aged 2 months through 2 years and persons aged ≥25 years are based on expert opinion; the vaccine was not studied in HIV-infected persons in these age groups. On the basis of available data and expert opinion, either MenACWY-CRM or MenACWY-D may be used in HIV-infected persons.

The same vaccine product should be used for all doses. However, if the product used for previous doses is unknown or unavailable, the vaccination series may be completed with any age- and formulation-appropriate meningococcal conjugate vaccine. Although no data on interchangeability of meningococcal conjugate vaccines in HIV-infected persons are available, limited data from a postlicensure study in healthy adolescents suggests safety and immunogenicity of MenACWY-CRM are not adversely affected by prior immunization with MenACWY-D (1,11).

ACIP recommends that HIV-infected infants aged 2 through 23 months receive MenACWY-CRM. HIV-infected children should not receive MenACWY-D before age 2 years, similar to the recommendation for children with functional or anatomic asplenia. Previously, children with functional or anatomic asplenia were recommended to receive 13-valent pneumococcal conjugate vaccine (PCV13) according to the normal schedule but to delay MenACWY-D vaccination until age 2 years because of immune interference (1,12). Because MenACWY-CRM does not demonstrate immune interference with 7-valent pneumococcal conjugate vaccine (PCV7) after the 12-month dose (13–15), MenACWY-CRM can be administered concomitantly with PCV13.

In addition, new data suggest the potential for immunologic interference in the meningococcal human complement serum bactericidal assay (hSBA) responses when MenACWY-D is administered 30 days after Daptacel (diphtheria and tetanus toxoids and acellular pertussis vaccine [DTaP], Sanofi Pasteur) (16). In one study among children aged 4 through 6 years, the hSBA responses to all four meningococcal serogroups failed to meet noninferiority criteria when MenACWY-D was administered 30 days after Daptacel. In contrast, co-administration of MenACWY-D and Daptacel was not associated with reduced hSBA responses to all four meningococcal serogroups. The study objectives did not include evaluation of the potential for interference that other DTaP containing vaccines might have on meningococcal seroresponse rates (16). If MenACWY-D is to be administered to a child at increased risk for meningococcal disease, including children who are HIV-infected, it is recommended that MenACWY-D be given either before or concomitantly with DTaP.

MenACWY is recommended for HIV-infected persons aged ≥56 years because of the need for revaccination (i.e., booster doses). Meningococcal polysaccharide vaccine (MPSV4, Menomune, Sanofi Pasteur) is the only licensed meningococcal vaccine for adults aged ≥56 years; however, no data are available on use of MPSV4 in HIV-infected adults. For healthy adults who have received MenACWY previously, limited data demonstrate a higher antibody response after a subsequent dose of MenACWY compared with a subsequent dose of MPSV4 (1).

To date, no randomized, controlled clinical trials have been conducted to evaluate use of MenACWY vaccines in pregnant or lactating women. Pregnancy should not preclude indicated vaccination with MenACWY.

Precautions and Contraindications

Before administering meningococcal conjugate vaccines, health care providers should consult the package insert for precautions, warnings, and contraindications (13,16). Adverse events occurring after administration of any vaccine should be reported to the Vaccine Adverse Event Reporting System (VAERS). Reports can be submitted to VAERS online, by fax, or by mail. Additional information about VAERS is available by telephone (1-800-822-7967) or online (https://vaers.hhs.gov).