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      Use of Serogroup B Meningococcal Vaccines in Persons Aged ≥10 Years at Increased Risk for Serogroup B Meningococcal Disease: Recommendations of the Advisory Committee on Immunization Practices, 2015

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          Abstract

          In October 2014, the Food and Drug Administration (FDA) licensed the first serogroup B meningococcal (MenB) vaccine (MenB-FHbp [Trumenba, Wyeth Pharmaceuticals, Inc.]) as a 3-dose series. In January 2015, FDA licensed a second MenB vaccine (MenB-4C [Bexsero, Novartis Vaccines]) as a 2-dose series. Both vaccines were approved for use in persons aged 10–25 years. Following outbreaks of serogroup B meningococcal disease on two college campuses in 2013, both MenB vaccines were granted Breakthrough Therapy designations, which expedites drug development and review by FDA, and were licensed based on accelerated approval regulations (1). 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. This report summarizes information on MenB administration and provides recommendations and guidance for use of these vaccines among persons aged ≥10 years in certain groups who are at increased risk for serogroup B meningococcal disease, and reviews the evidence considered by ACIP to make these recommendations. Recommendations for broader use of MenB vaccines in adolescents and college students will be considered separately by ACIP. Methods The ACIP Meningococcal Vaccines Work Group reviewed safety and immunogenicity data from seven clinical trials of MenB-4C (2–7) (Novartis, unpublished data) and nine clinical trials of MenB-FHbp (8–13) (Pfizer, unpublished data) during its monthly teleconferences. The Work Group also evaluated published peer-reviewed literature and unpublished data on meningococcal disease epidemiology in the United States. A summary of the data reviewed and Work Group discussions was presented to ACIP, and recommendations for use of MenB vaccines among persons aged ≥10 years at increased risk for serogroup B meningococcal disease were approved by ACIP at its February 26, 2015, meeting (meeting minutes are available at http://www.cdc.gov/vaccines/acip/meetings/meetings-info.html). The type and quality of evidence supporting the use of MenB vaccines in persons aged ≥10 years at increased risk for serogroup B meningococcal disease was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework (14), and 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 for serogroup B meningococcal disease. The recommendation was designated Category A (recommended for all persons in an age-based or risk-factor–based group) (15). Persons at Increased Risk for Meningococcal Disease Persons who have persistent deficiencies (e.g., genetic deficiencies) in the complement pathway (e.g., C3, properdin, Factor D, Factor H, or C5–C9) have up to a 10,000-fold increased risk for meningococcal disease and can experience recurrent disease (16,17). Persons receiving eculizumab (Soliris, Alexion Pharmaceuticals) for treatment of atypical hemolytic uremic syndrome or paroxysmal nocturnal hemoglobinuria also are at increased risk because the drug binds to C5 and inhibits the terminal complement pathway (information available at http://soliris.net/sites/default/files/assets/soliris_pi.pdf). Similarly, persons with functional or anatomic asplenia (including persons with sickle cell disease) appear to be at increased risk for meningococcal disease, and have a higher mortality rate (40%–70%) from the disease than healthy populations (18). Among microbiologists who routinely work with Neisseria meningitidis isolates, the attack rate of laboratory-acquired meningococcal infection has been estimated at 13 per 100,000 persons, which is many fold higher than the rate for adults in the general population (19). In the United States, 97%–98% of all cases of meningococcal disease are sporadic; however, outbreaks continue to occur. Recently, outbreaks of serogroup B meningococcal disease have been reported from several college campuses. Data from four college campus outbreaks (March 2013–May 2015) showed a 200 to 1,400–fold increase in risk for meningococcal disease among students at these colleges during the outbreak period compared with the general population in this age group (Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, CDC, unpublished data, 2015). MenB Vaccine Immunogenicity and Safety Because of the low incidence of serogroup B meningococcal disease, vaccine efficacy estimates 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 U.S. 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 quantification of the assay for all strains (composite response) (20,21). The lower limit of quantification was defined as the lowest amount of the antibody in a sample that can be reliably quantified. MenB-4C Vaccine MenB-4C consists of three recombinant proteins (Neisserial adhesin A [NadA], factor H binding protein [FHbp] fusion protein, and Neisserial Heparin Binding Antigen [NHBA] fusion protein), and outer membrane vesicles (OMVs) containing outer membrane protein PorA serosubtype P1.4. MenB-4C is licensed as a 2-dose series, with doses administered at least 1 month apart, although in some studies, MenB-4C doses were administered up to 6 months apart. In persons aged ≥10 years, safety and immunogenicity of MenB-4C were evaluated in seven clinical trials: six randomized controlled trials and one immunogenicity extension study (2–7) (Novartis, unpublished data). In one randomized controlled trial conducted in the United Kingdom, a subset of enrolled subjects (university students aged 18–24 years) received 2 doses of MenB-4C vaccine 1 month apart. One month following the second dose, 88% (95% confidence interval [CI] = 82%–93%) of subjects had a composite hSBA response to all three test strains; 66% (CI = 58%–72%) of the subjects had a composite hSBA response to all three test strains at 11 months after the second dose (20). In a randomized controlled trial conducted in Australia and Canada, persons aged 11–17 years received 2 doses of MenB-4C 1 month apart. One month following the second dose, 63% (CI = 57%–68%) of subjects had a composite hSBA response to all three test strains (20). In an open-label study conducted in Germany and Italy, antibody responses to MenB-4C were assessed in laboratory workers aged 18–50 years who were routinely exposed to Neisseria meningitidis. Among the subjects, 83% (CI = 69%–92%) achieved an hSBA titer ≥1:8 against at least one of the three test strains 1 month after the second dose of MenB-4C (3). In three clinical trials for which a control group was available, serious adverse events were assessed in 2,716 participants who received at least 1 dose of MenB-4C and for whom safety data were collected through 6 months postvaccination (2,4,6). Five serious adverse events were considered by the study investigator to be related (or possibly related) to the vaccine.* Rates of serious adverse events were similar in the vaccine and the control groups. In addition, information about serious adverse events was collected during three prelicensure vaccination campaigns in response to three outbreaks of serogroup B meningococcal disease (at two universities in the United States and in one region in Canada). A total of 59,091 participants in the vaccination campaigns received at least 1 dose of MenB-4C. Three serious adverse events were considered by the study investigator to be related (or possibly related) to the vaccine†; all resolved with no sequelae (CDC and Novartis, unpublished data). No deaths were considered to be related to MenB-4C in the clinical trials or campaigns. The most common solicited adverse reactions observed in the 7 days after receipt of MenB-4C in the clinical trials were pain at the injection site, myalgia, erythema, fatigue, headache, induration, nausea, and arthralgia (9,20). Safety and immunogenicity data regarding MenB-4C when co-administered with vaccines routinely administered to U.S. adolescents are not available. MenB-FHbp Vaccine MenB-FHbp consists of two purified recombinant FHbp antigens. One antigen from each FHbp subfamily (A and B) is included in the vaccine. MenB-FHbp is licensed as a 3-dose series, with the second and third doses administered 2 and 6 months after the first dose. Safety and immunogenicity of MenB-FHbp in persons aged ≥10 years were evaluated in nine clinical trials: six randomized controlled trials and three open label studies (8–13) (Pfizer, unpublished data). In a multicenter trial conducted in the United States, persons aged 11–17 years were randomly assigned to one of three groups. Group 1 received MenB-FHbp and quadrivalent human papillomavirus vaccine (4vHPV, [Gardasil Merck and Co.]), group 2 received MenB-FHbp and saline, and group 3 received 4vHPV and saline. One month following the third dose, 81% (CI = 78.0%–83.7%) of subjects in group 1 and 83.9% (CI = 81.1%–86.4%) of subjects in group 2 had a composite hSBA response to all four test strains (13,21). After the second of 3 doses, approximately 50% of the subjects in each study group had a composite hSBA response to all test strains. In studies conducted among European persons aged 11–18 years, the hSBA responses in subjects who received MenB-FHbp according to the same schedule were similar to hSBA antibody responses in subjects in the U.S. study (9,21). In one open label study, immunogenicity was assessed among a small number of meningococcal laboratory workers who received the vaccine. Among the subjects, 50% achieved a titer greater than or equal to the lower limit of quantification to all four test strains (Pfizer, unpublished data). Concomitant administration of MenB-FHbp with vaccines routinely administered to U.S. adolescents has been evaluated in three trials. Subjects received MenB-FHbp co-administered with 4vHPV (Gardasil, Merck and Co.), MenACWY (Menactra, Sanofi Pasteur), Tdap (Adacel, Sanofi Pasteur) or dTaP/IPV (Repevax, Sanofi Pasteur) vaccines. Except for the antibody response to HPV type 18, no immunologic interference was observed for serogroup B or concomitant vaccine antigens (HPV types 6, 11, 16, MenACWY, tetanus, diphtheria, pertussis and IPV antigens) when MenB-FHbp was administered concomitantly (11,13) (Pfizer, unpublished data). For HPV type 18, noninferiority criteria (lower bound of the CI of the geometric mean titer ratio >0.67) were not met for the geometric mean titer ratio at 1 month after the third 4vHPV vaccination (lower bound of the CI for the geometric mean titer ratio was 0.62); however, ≥99% of subjects achieved seroconversion for all four HPV antigens. In four clinical trials (9,11–13) a total of 2,557 subjects received at least 1 dose of MenB-FHbp; four subjects reported seven serious adverse events that were considered by the study investigator to be related (or possibly related) to the vaccine.§ All vaccine-related serious adverse events resolved without sequelae. No increased risk for any specific serious adverse event considered to be clinically significant was identified in any of the studies. No deaths were considered to be related to MenB-FHbp. The most common solicited adverse reactions observed in the 7 days after receipt of MenB-FHbp in the clinical trials were pain at the injection site, fatigue, headache, myalgia, and chills (21). Rationale for Recommendations Certain groups of persons known to be at increased risk for meningococcal disease are recommended to be routinely vaccinated with a quadrivalent meningococcal conjugate vaccine (MenACWY), which protects against serogroups A, C, W, and Y (16). Many of these groups are also at increased risk for serogroup B meningococcal disease. 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 persons aged 10–25 years; however, because there are no theoretical differences in safety for persons aged >25 years compared with those aged 10–25 years, ACIP supported routine use of MenB vaccines in persons aged ≥10 years who are at increased risk for serogroup B meningococcal disease. These recommendations do not apply to children aged <10 years. Recommendations Certain persons aged ≥10 years who are at increased risk for meningococcal disease should receive MenB vaccine. These persons include: Persons with persistent complement component deficiencies.¶ Persons with anatomic or functional asplenia.** Microbiologists routinely exposed to isolates of Neisseria meningitidis. Persons identified as at increased risk because of a serogroup B meningococcal disease outbreak. Certain other groups are included in the MenACWY recommendations for persons at increased risk, but are not included in this recommendation. MenB vaccines are not licensed for children aged <10 years and are not currently recommended for children aged 2 months–9 years who are at increased risk for serogroup B meningococcal disease. MenB vaccine is not recommended for persons who travel to or reside in countries where meningococcal disease is hyperendemic or epidemic because the risk for meningococcal disease in these countries generally is not caused by serogroup B. The vaccine is not currently recommended for routine use in first-year college students living in residence halls, military recruits, or all adolescents. Recommendations for broader use of MenB vaccines in adolescents and college students will be considered separately by the ACIP. What is currently recommended? The Advisory Committee on Immunization Practices recommends routine vaccination with quadrivalent meningococcal conjugate vaccine (MenACWY) of certain groups of persons at increased risk for meningococcal disease: persons who have persistent complement component deficiencies; persons who have anatomic or functional asplenia; microbiologists who routinely are exposed to isolates of Neisseria meningitidis; persons identified to be at increased risk because of a meningococcal disease outbreak attributable to serogroup A, C, W, or Y; military recruits; first-year college students living in residence halls; and persons who travel to or reside in areas in which meningococcal disease is hyperendemic or epidemic. Why are the recommendations being modified now? Two serogroup B meningococcal (MenB) vaccines were recently licensed by the Food and Drug Administration and approved for use in persons aged 10–25 years. The evidence supporting the use of MenB vaccines in persons at increased risk for serogroup B meningococcal disease was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation framework and 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 for serogroup B meningococcal disease. The recommendation was designated as Category A (recommended for all persons in an age- or risk-factor–based group). What are the new recommendations? Certain persons aged ≥10 years at increased risk for meningococcal disease should receive MenB vaccine. 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. MenB vaccine should be administered as either a 2-dose series of MenB-4C or a 3-dose series of MenB-FHbp. The same vaccine product should be used for all doses. Based on available data and expert opinion, MenB-4C or MenB-FHbp may be administered concomitantly with MenACWY vaccines, but at a different anatomic site, if feasible. Precautions and Contraindications Before administering MenB vaccines, providers should consult the package insert for precautions, warnings, and contraindications (20,21). 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 (http://vaers.hhs.gov).

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          Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP).

          Meningococcal disease describes the spectrum of infections caused by Neisseria meningiditis, including meningitdis, bacteremia, and bacteremic pneumonia. Two quadrivalent meningococcal polysaccharide-protein conjugate vaccines that provide protection against meningococcal serogroups A, C, W, and Y (MenACWY-D [Menactra, manufactured by Sanofi Pasteur, Inc., Swiftwater, Pennsylvania] and MenACWY-CRM [Menveo, manufactured by Novartis Vaccines, Cambridge, Massachusetts]) are licensed in the United States for use among persons aged 2 through 55 years. MenACWY-D also is licensed for use among infants and toddlers aged 9 through 23 months. Quadrivalent meningococcal polysaccharide vaccine (MPSV4 [Menommune, manufactured by sanofi pasteur, Inc., Swiftwater, Pennsylvania]) is the only vaccine licensed for use among persons aged ≥56 years. A bivalent meningococcal polysaccharide protein conjugate vaccine that provides protection against meningococcal serogroups C and Y along with Haemophilus influenzae type b (Hib) (Hib-MenCY-TT [MenHibrix, manufactured by GlaxoSmithKline Biologicals, Rixensart, Belgium]) is licensed for use in children aged 6 weeks through 18 months. This report compiles and summarizes all recommendations from CDC's Advisory Committee on Immunization Practices (ACIP) regarding prevention and control of meningococcal disease in the United States, specifically the changes in the recommendations published since 2005 (CDC. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2005;54 [No. RR-7]). As a comprehensive summary of previously published recommendations, this report does not contain any new recommendations; it is intended for use by clinicians as a resource. ACIP recommends routine vaccination with a quadrivalent meningococcal conjugate vaccine (MenACWY) for adolescents aged 11 or 12 years, with a booster dose at age 16 years. ACIP also recommends routine vaccination for persons at increased risk for meningococcal disease (i.e., persons who have persistent complement component deficiencies, persons who have anatomic or functional asplenia, microbiologists who routinely are exposed to isolates of N. meningitidis, military recruits, and persons who travel to or reside in areas in which meningococcal disease is hyperendemic or epidemic). Guidelines for antimicrobial chemoprophylaxis and for evaluation and management of suspected outbreaks of meningococcal disease also are provided.
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            Safety, immunogenicity, and tolerability of meningococcal serogroup B bivalent recombinant lipoprotein 2086 vaccine in healthy adolescents: a randomised, single-blind, placebo-controlled, phase 2 trial.

            Neisseria meningitidis serogroup B is a major cause of invasive meningococcal disease, but a broadly protective vaccine is not currently licensed. A bivalent recombinant factor H-binding protein vaccine (recombinant lipoprotein 2086) has been developed to provide broad coverage against diverse invasive meningococcus serogroup B strains. Our aim was to test the immune response of this vaccine. This randomised, placebo-controlled trial enrolled healthy adolescents from 25 sites in Australia, Poland, and Spain. Exclusion criteria were previous invasive meningococcal disease or serogroup B vaccination, previous adverse reaction or known hypersensitivity to the vaccine, any significant comorbidities, and immunosuppressive therapy or receipt of blood products in the past 6 months. Participants were randomly assigned with a computerised block randomisation scheme to receive ascending doses of vaccine (60, 120, or 200 μg) or placebo at 0, 2, and 6 months. Principal investigators, participants and their guardians, and laboratory personnel were masked to the allocation; dispensing staff were not. Immunogenicity was measured by serum bactericidal assays using human complement (hSBA) against eight diverse meningococcus serogroup B strains. The co-primary endpoints were seroconversion for the two indicator strains (PMB1745 and PMB17) analysed by the Clopper-Pearson method. Local and systemic reactions and adverse events were recorded. The study is registered at ClinicalTrials.gov, number NCT00808028. 539 participants were enrolled and 511 received all three study vaccinations--116 in the placebo group, 21 in the 60 μg group, 191 in the 120 μg group, and 183 in the 200 μg group. The proportion of participants responding with an hSBA titre equal to or greater than the lower limit of quantitation of the hSBA assays (reciprcocal titres of 7 to 18, depending on test strain) was similar for the two largest doses and ranged from 75·6 to 100·0% for the 120 μg dose and 67·9 to 99·0% for the 200 μg dose. Seroconversion for the PMB1745 reference strain was 17 of 19 (89·5%) participants for the 60 μg dose, 103 of 111 (92·8%) participants for the 120 μg dose, 94 of 100 (94·0%) participants for the 200 μg dose, and four of 73 (5·5%) participants for placebo. For the PMB17 reference strain seroconversion was 17 of 21 (81·0%) participants for the 60 μg dose, 97 of 112 (86·6%) participants for the 120 μg dose, 89 of 105 (84·8%) participants for the 200 μg dose, and one of 79 (1·3%) participants for placebo. The hSBA response was robust as shown by the high proportion of responders at hSBA titres up to 16. Mild-to-moderate injection site pain was the most common local reaction (50 occurrences with the 60 μg dose, 437 with the 120 μg dose, 464 with the 200 μg dose, and 54 with placebo). Systemic events, including fatigue and headache, were generally mild to moderate. Overall, adverse events were reported by 18 participants (81·8%) in the 60 μg group, 77 (38·9%) in the 120 μg group, 92 (47·2%) in the 200 μg group, and 54 (44·6%) in the placebo group. Fevers were rare and generally mild (one in the 60 μg group, 24 in the 120 μg group, 35 in the 200 μg group, and five in the placebo group; range, 0-6·3% after each dose). Incidence and severity of fever did not increase with subsequent vaccine dose within groups. One related serious adverse event that resolved without sequelae occurred after the third dose (200 μg). The bivalent recombinant lipoprotein 2086 vaccine is immunogenic and induces robust hSBA activity against diverse invasive meningococcus serogroup B disease strains and the vaccine is well tolerated. Recombinant lipoprotein 2086 vaccine is a promising candidate for broad protection against invasive meningococcus serogroup B disease. Wyeth, Pfizer. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Assessing the risk of laboratory-acquired meningococcal disease.

              Neisseria meningitidis is infrequently reported as a laboratory-acquired infection. Prompted by two cases in the United States in 2000, we assessed this risk among laboratorians. We identified cases of meningococcal disease that were possibly acquired or suspected of being acquired in a laboratory by placing an information request on e-mail discussion groups of infectious disease, microbiology, and infection control professional organizations. A probable case of laboratory-acquired meningococcal disease was defined as illness meeting the case definition for meningococcal disease in a laboratorian who had occupational exposure to an N. meningitidis isolate of the same serogroup within 14 days of illness onset. Sixteen cases of probable laboratory-acquired meningococcal disease occurring worldwide between 1985 and 2001 were identified, including six U.S. cases between 1996 and 2000. Nine cases (56%) were serogroup B; seven (44%) were serogroup C. Eight cases (50%) were fatal. All cases occurred among clinical microbiologists. In 15 cases (94%), isolate manipulation was performed without respiratory protection. We estimated that an average of three microbiologists are exposed to the 3,000 meningococcal isolates seen in U.S. laboratories yearly and calculated an attack rate of 13/100,000 microbiologists between 1996 and 2001, compared to 0.2/100,000 among U.S. adults in general. The rate and case/fatality ratio of meningococcal disease among microbiologists are higher than those in the general U.S. population. Specific risk factors for laboratory-acquired infection are likely associated with exposure to droplets or aerosols containing N. meningitidis. Prevention should focus on the implementation of class II biological safety cabinets or additional respiratory protection during manipulation of suspected meningococcal isolates.
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                Author and article information

                Journal
                MMWR Morb Mortal Wkly Rep
                MMWR Morb. Mortal. Wkly. Rep
                MMWR
                MMWR. Morbidity and Mortality Weekly Report
                U.S. Centers for Disease Control
                0149-2195
                1545-861X
                12 June 2015
                12 June 2015
                : 64
                : 22
                : 608-612
                Affiliations
                [1 ]Epidemic Intelligence Service, CDC
                [2 ]Advisory Committee on Immunization Practices Meningococcal Vaccines Work Group, Steven and Alexandra Cohen Children’s Medical Center of New York, New Hyde Park, New York and Hofstra North Shore-LIJ School of Medicine, Hempstead, NY
                [3 ]Meningitis and Vaccine Preventable Diseases Branch, Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, CDC
                Author notes
                Corresponding author: Jessica R. MacNeil, jmacneil@ 123456cdc.gov .
                Article
                608-612
                4584923
                26068564
                acf49d0a-bbfb-401e-8e50-b9ac92fe8a4b

                All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated.

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