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Dan M Granoff - One of the best experts on this subject based on the ideXlab platform.
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bactericidal antibody responses induced by Meningococcal recombinant chimeric factor h binding protein Vaccines
Infection and Immunity, 2008Co-Authors: Peter T Beernink, Dan M GranoffAbstract:Factor H-binding protein (fHbp) is a novel Meningococcal Vaccine candidate that elicits serum antibodies that activate classical complement pathway bacteriolysis and also inhibit binding of the complement down-regulatory protein, factor H, to the bacterial surface. One limitation of fHbp as a Vaccine candidate is antigenic variability, since antibodies to fHbp in the variant 1 (v.1) antigenic group do not protect against strains expressing v.2 or v.3 proteins, and vice versa. We have identified amino acid residues of epitopes recognized by bactericidal anti-fHbp monoclonal antibodies prepared against fHbp from each of the variant groups. One epitope expressed by nearly all v.1 proteins mapped to the B domain, while epitopes expressed by fHbp v.2 or v.3 mapped to the C domain. The results provided the rationale for engineering chimeric fHbp molecules containing the A domain (which is conserved across all variant groups), a portion of the B domain of a v.1 protein, and the carboxyl-terminal portion of the B domain and the C domain of a v.2 protein. By enzyme-linked immunosorbent assay, the resulting recombinant chimeric proteins expressed epitopes from all three variant groups. In mice, the chimeric Vaccines elicited serum antibodies with bactericidal activity against a panel of genetically diverse strains expressing fHbp v.1, v.2, or v.3. The data demonstrate the feasibility of preparing a Meningococcal Vaccine from a single recombinant protein that elicits broad bactericidal activity, including group B strains, which account for 50 percent of cases of Meningococcal disease and for which there currently is no broadly protective Vaccine.
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complement dependent synergistic bactericidal activity of antibodies against factor h binding protein a sparsely distributed Meningococcal Vaccine antigen
The Journal of Infectious Diseases, 2008Co-Authors: Jo Anne Welsch, Sanjay Ram, Oliver Koeberling, Dan M GranoffAbstract:Background. Antibodies to factor H (fH)-binding protein (fHBP), a Meningococcal Vaccine antigen, activate classical complement pathway serum bactericidal activity (SBA) and block binding of the complement inhibitor fH. Methods. To understand these 2 functions in protection, we investigated the interactions of human complement and 2 anti-fHBP monoclonal antibodies (MAbs) with encapsulated Neisseria meningitidis. Results. JAR 3 (IgG3) blocks fH binding and elicits SBA against 2 strains with naturally high fHBP expression and a low-expressing strain genetically engineered to express high fHBP levels. JAR 4 (IgG2a) does not block fH binding or elicit SBA. Neither MAb alone elicits SBA against 2 other strains with low fHBP expression, but together the MAbs increase C4b binding and elicit SBA; JAR 3 alone also is bactericidal in whole blood. In nonimmune blood, fHBP knockout mutants from high-expressing stains do not survive, but mutants of low-expressing strains do. Conclusions. Expression of fHBP is a prerequisite for bacterial survival in blood only by strains with naturally high fHBP expression. In low-expressing strains, combinations of 2 nonbactericidal anti-fHBP MAbs can bind to nonoverlapping epitopes, engage C1q, activate C4, and mediate classical complement pathway SBA. In the absence of sufficient C4b binding for SBA, an individual MAb can have opsonophagocytic bactericidal activity.
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the Meningococcal Vaccine candidate gna1870 binds the complement regulatory protein factor h and enhances serum resistance
Journal of Immunology, 2006Co-Authors: Guillermo Madico, Jo Anne Welsch, Dan M Granoff, Lisa A Lewis, Anne Mcnaughton, David H Perlman, Catherine E Costello, Jutamas Ngampasutadol, Ulrich Vogel, Sanjay RamAbstract:Neisseria meningitidis binds factor H (fH), a key regulator of the alternative complement pathway. A approximately 29 kD fH-binding protein expressed in the Meningococcal outer membrane was identified by mass spectrometry as GNA1870, a lipoprotein currently under evaluation as a broad-spectrum Meningococcal Vaccine candidate. GNA1870 was confirmed as the fH ligand on intact bacteria by 1) abrogation of fH binding upon deleting GNA1870, and 2) blocking fH binding by anti-GNA1870 mAbs. fH bound to whole bacteria and purified rGNA1870 representing each of the three variant GNA1870 families. We showed that the amount of fH binding correlated with the level of bacterial GNA1870 expression. High levels of variant 1 GNA1870 expression (either by allelic replacement of gna1870 or by plasmid-driven high-level expression) in strains that otherwise were low-level GNA1870 expressers (and bound low amounts of fH by flow cytometry) restored high levels of fH binding. Diminished fH binding to the GNA1870 deletion mutants was accompanied by enhanced C3 binding and increased killing of the mutants. Conversely, high levels of GNA1870 expression and fH binding enhanced serum resistance. Our findings support the hypothesis that inhibiting the binding of a complement down-regulator protein to the neisserial surface by specific Ab may enhance intrinsic bactericidal activity of the Ab, resulting in two distinct mechanisms of Ab-mediated Vaccine efficacy. These data provide further support for inclusion of this molecule in a Meningococcal Vaccine. To reflect the critical function of this molecule, we suggest calling it fH-binding protein.
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priming for immunologic memory in adults by Meningococcal group c conjugate vaccination
Clinical and Vaccine Immunology, 2006Co-Authors: Alberdina W De Boer, Lisa Danzig, George F Santos, Bridget Canty, Betty M Flores, Dan M GranoffAbstract:Meningococcal group C polysaccharide-protein conjugate Vaccines (MCV) prime infants and children for memory anticapsular responses upon subsequent exposure to unconjugated polysaccharide. The objective of this study was to determine whether MCV primes Vaccine-naive adults and adults previously vaccinated with Meningococcal polysaccharide Vaccine (MPSV) for memory antibody responses. Meningococcal Vaccine-naive adults were randomized to receive either MCV (MCV/naive group) (n = 35) or pneumococcal conjugate Vaccine (PCV) (PCV/naive group) (n = 34). Participants with a history of receiving MPSV were given MCV (MCV/MPSV group) (n = 26). All subjects were challenged 10 months later with one-fifth of the usual dose of MPSV (10 μg of each polysaccharide). Sera were obtained before the conjugate vaccination and before and 7 days after the MPSV challenge and assayed for immunoglobulin G (IgG) anticapsular antibody concentrations and bactericidal titers. The MCV/naive group had 7- to 10-fold-higher serum IgG and bactericidal responses after the MPSV challenge than the PCV/naive group (P 2 μg/ml before the challenge; P < 0.0001). Only 3 of 11 MCV-vaccinated subjects who had received MPSV before enrollment and who had antibody concentrations of ≤2 μg/ml before the polysaccharide challenge showed more-than-twofold increases in anticapsular antibody concentration or bactericidal titer after the challenge. MCV vaccination of Meningococcal Vaccine-naive adults primes for robust memory antibody responses. There was no evidence of induction of memory by MCV in adults previously vaccinated with MPSV.
Matthew D Snape - One of the best experts on this subject based on the ideXlab platform.
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an increase in accident and emergency presentations for adverse events following immunisation after introduction of the group b Meningococcal Vaccine an observational study
Archives of Disease in Childhood, 2017Co-Authors: Viveka Nainani, Ushma Galal, Jim Buttery, Matthew D SnapeAbstract:Objectives To determine whether the introduction of the capsular group B Meningococcal Vaccine (4CMenB) in the UK has increased presentations of infants to emergency departments with adverse events following immunisation (AEFI). Participants, design and setting A retrospective review of hospital records of infants aged 1–6 months presenting to Oxford University Hospitals NHS Trust’s emergency departments from September 2013 to August 2016 with discharge diagnoses of Vaccine reactions or non-specific conditions. Immunisation history was checked by reference to centralised immunisation records. Main outcome measures Presentation classifications were ‘probable Vaccine reaction’ (ie, symptoms within 48 hours of immunisation; no alternative cause found), ‘possible Vaccine reaction’ (symptoms within 48 hours of immunisation with a possible alternative cause) or ‘not related’ (clear alternative diagnosis or not immunised within previous 48 hours). Results Prior to 4CMenB introduction (2013–15), an annual average of 12 infants presented with probable or possible AEFIs, increasing to 38 infants in the year following 4CMenB introduction (2015/2016). Rates of AEFIs per 1000 immunisation episodes increased post-4CMenB introduction from 1.03 to 3.4 (p Conclusions The increase in emergency department attendances, investigations and antibiotic use for AEFIs following 4CMenB immunisation may influence the cost-effectiveness of the 4CMenB immunisation campaign.
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persistence of bactericidal antibodies after infant serogroup b Meningococcal immunization and booster dose response at 12 18 or 24 months of age
Pediatric Infectious Disease Journal, 2016Co-Authors: Matthew D Snape, Merryn Voysey, Adam Finn, G Bona, Susanna Esposito, Nicola Principi, Javier Diezdomingo, Etienne Sokal, Dorothee Kieninger, Roman PrymulaAbstract:Background:A serogroup B Meningococcal Vaccine (4CMenB) is licensed for infant use in countries including Canada, Australia and those of the European Union. Data on serum bactericidal antibody (hSBA) waning and the ideal timing of a “toddler” booster dose are essential to optimize Vaccine utilizatio
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Persistence of bactericidal antibodies to 5 years of age after immunization with serogroup B Meningococcal Vaccines at 6, 8, 12 and 40 months of age.
The Pediatric infectious disease journal, 2014Co-Authors: Fiona Mcquaid, Matthew D Snape, Tessa M. John, Sarah Kelly, Hannah Robinson, Jennifer Houlden, Merryn Voysey, Daniela Toneatto, Claudia Kitte, Peter M. DullAbstract:Background:A serogroup B Meningococcal Vaccine (4CMenB) has been licensed by the European commission for use in various infant schedules. However, data are limited on persistence of serum bactericidal antibodies (SBA), which is necessary to inform cost-effectiveness analysis.Methods:Sera were obtain
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a multicomponent serogroup b Meningococcal Vaccine is licensed for use in europe what do we know and what are we yet to learn
Expert Review of Vaccines, 2013Co-Authors: Natalie G Martin, Matthew D SnapeAbstract:The first Meningococcal Vaccine with the potential to provide broad coverage against serogroup B disease has recently been approved for use in Europe. This Vaccine, multi-component serogroup B Vaccine (4CMenB), contains recombinant proteins and outer membrane vesicles, and has been extensively studied in clinical trials involving over 7500 adults, children and infants. As well as demonstrating immunogenicity against a range of serogroup B Meningococcal strains, these trials have also demonstrated relatively high rates of fever following infant immunization. This article will summarize the Vaccine composition, clinical trials and suggested schedules of this Vaccine, with specific attention to immunogenicity, reactogenicity, safety, potential coverage and optimal implementation of this Vaccine.
Sanjay Ram - One of the best experts on this subject based on the ideXlab platform.
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the Meningococcal Vaccine candidate neisserial surface protein a nspa binds to factor h and enhances Meningococcal resistance to complement
PLOS Pathogens, 2010Co-Authors: Lisa A Lewis, Jutamas Ngampasutadol, Ulrich Vogel, Ruth Wallace, Jane E A Reid, Sanjay RamAbstract:Complement forms an important arm of innate immunity against invasive Meningococcal infections. Binding of the alternative complement pathway inhibitor factor H (fH) to fH-binding protein (fHbp) is one mechanism meningococci employ to limit complement activation on the bacterial surface. fHbp is a leading Vaccine candidate against group B Neisseria meningitidis. Novel mechanisms that meningococci employ to bind fH could undermine the efficacy of fHbp-based Vaccines. We observed that fHbp deletion mutants of some Meningococcal strains showed residual fH binding suggesting the presence of a second receptor for fH. Ligand overlay immunoblotting using membrane fractions from one such strain showed that fH bound to a approximately 17 kD protein, identified by MALDI-TOF analysis as Neisserial surface protein A (NspA), a Meningococcal Vaccine candidate whose function has not been defined. Deleting nspA, in the background of fHbp deletion mutants, abrogated fH binding and mAbs against NspA blocked fH binding, confirming NspA as a fH binding molecule on intact bacteria. NspA expression levels vary among strains and expression correlated with the level of fH binding; over-expressing NspA enhanced fH binding to bacteria. Progressive truncation of the heptose (Hep) I chain of lipooligosaccharide (LOS), or sialylation of lacto-N-neotetraose LOS both increased fH binding to NspA-expressing meningococci, while expression of capsule reduced fH binding to the strains tested. Similar to fHbp, binding of NspA to fH was human-specific and occurred through fH domains 6-7. Consistent with its ability to bind fH, deleting NspA increased C3 deposition and resulted in increased complement-dependent killing. Collectively, these data identify a key complement evasion mechanism with important implications for ongoing efforts to develop Meningococcal Vaccines that employ fHbp as one of its components.
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complement dependent synergistic bactericidal activity of antibodies against factor h binding protein a sparsely distributed Meningococcal Vaccine antigen
The Journal of Infectious Diseases, 2008Co-Authors: Jo Anne Welsch, Sanjay Ram, Oliver Koeberling, Dan M GranoffAbstract:Background. Antibodies to factor H (fH)-binding protein (fHBP), a Meningococcal Vaccine antigen, activate classical complement pathway serum bactericidal activity (SBA) and block binding of the complement inhibitor fH. Methods. To understand these 2 functions in protection, we investigated the interactions of human complement and 2 anti-fHBP monoclonal antibodies (MAbs) with encapsulated Neisseria meningitidis. Results. JAR 3 (IgG3) blocks fH binding and elicits SBA against 2 strains with naturally high fHBP expression and a low-expressing strain genetically engineered to express high fHBP levels. JAR 4 (IgG2a) does not block fH binding or elicit SBA. Neither MAb alone elicits SBA against 2 other strains with low fHBP expression, but together the MAbs increase C4b binding and elicit SBA; JAR 3 alone also is bactericidal in whole blood. In nonimmune blood, fHBP knockout mutants from high-expressing stains do not survive, but mutants of low-expressing strains do. Conclusions. Expression of fHBP is a prerequisite for bacterial survival in blood only by strains with naturally high fHBP expression. In low-expressing strains, combinations of 2 nonbactericidal anti-fHBP MAbs can bind to nonoverlapping epitopes, engage C1q, activate C4, and mediate classical complement pathway SBA. In the absence of sufficient C4b binding for SBA, an individual MAb can have opsonophagocytic bactericidal activity.
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Factor H and Neisserial pathogenesis
Vaccine, 2008Co-Authors: Jo Anne Welsch, Sanjay RamAbstract:Both Neisseria gonorrhoeae and N. meningitidis bind to factor H which enhances their ability to evade complement-dependent killing. While porin is the ligand for human fH on gonococci, meningococci use a lipoprotein called factor H binding protein (fHbp) to bind to factor H and enhance their ability to evade complement-dependent killing. This protein is currently being intensively investigated as a Meningococcal Vaccine candidate antigen. Consistent with the observation that meningococci cause natural infection only in humans, the organism resists human complement, and are more readily killed by complement from lower animals. This human species-specific complement evasion has important implications for evaluation of Vaccine-elicited antibodies using non-human complement sources and development of animal models of disease.
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the Meningococcal Vaccine candidate gna1870 binds the complement regulatory protein factor h and enhances serum resistance
Journal of Immunology, 2006Co-Authors: Guillermo Madico, Jo Anne Welsch, Dan M Granoff, Lisa A Lewis, Anne Mcnaughton, David H Perlman, Catherine E Costello, Jutamas Ngampasutadol, Ulrich Vogel, Sanjay RamAbstract:Neisseria meningitidis binds factor H (fH), a key regulator of the alternative complement pathway. A approximately 29 kD fH-binding protein expressed in the Meningococcal outer membrane was identified by mass spectrometry as GNA1870, a lipoprotein currently under evaluation as a broad-spectrum Meningococcal Vaccine candidate. GNA1870 was confirmed as the fH ligand on intact bacteria by 1) abrogation of fH binding upon deleting GNA1870, and 2) blocking fH binding by anti-GNA1870 mAbs. fH bound to whole bacteria and purified rGNA1870 representing each of the three variant GNA1870 families. We showed that the amount of fH binding correlated with the level of bacterial GNA1870 expression. High levels of variant 1 GNA1870 expression (either by allelic replacement of gna1870 or by plasmid-driven high-level expression) in strains that otherwise were low-level GNA1870 expressers (and bound low amounts of fH by flow cytometry) restored high levels of fH binding. Diminished fH binding to the GNA1870 deletion mutants was accompanied by enhanced C3 binding and increased killing of the mutants. Conversely, high levels of GNA1870 expression and fH binding enhanced serum resistance. Our findings support the hypothesis that inhibiting the binding of a complement down-regulator protein to the neisserial surface by specific Ab may enhance intrinsic bactericidal activity of the Ab, resulting in two distinct mechanisms of Ab-mediated Vaccine efficacy. These data provide further support for inclusion of this molecule in a Meningococcal Vaccine. To reflect the critical function of this molecule, we suggest calling it fH-binding protein.
Anne Von Gottberg - One of the best experts on this subject based on the ideXlab platform.
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Recommendations for the use of Meningococcal Vaccines in South Africa
Southern African Journal of Infectious Diseases, 2017Co-Authors: Susan Meiring, Gregory Hussey, Prakash Jeena, Salim Parker, Anne Von GottbergAbstract:Background: Although Meningococcal disease (MD) incidence in South Africa is low, Neisseria meningitidis (NM) causes severe disease that is often life-threatening and can cause long-term disabilities. A quadrivalent protein-conjugated Meningococcal Vaccine (MCV4) is available, and provides protection against 75% of disease causing serogroups in South Africa. Recommendations: We advise vaccination of persons at high risk of Meningococcal disease including those with complement deficiency and asplenia; laboratory personnel from reference laboratories who work with NM; and travellers to Saudi Arabia. The need for routine Vaccine against Meningococcal disease in South Africa is controversial given the current burden of disease. However, due to the high morbidity/mortality of MD we recommend that clinicians consider vaccination of healthy infants and children; HIV-infected persons with a CD4 count 25%; students attending college /university /military academies; and miners.Conclusion: Protein-conjugated Meningococcal Vaccine is preferable to the polysaccharide Vaccine given the ability of the protein-conjugated Meningococcal Vaccine to induce immune memory, allow for booster responses and eliminate carriage of the organism in the person vaccinated.
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Recommendations for the use of Meningococcal Vaccines in South Africa
Southern African Journal of Infectious Diseases, 2017Co-Authors: Susan Meiring, Prakash Jeena, Salim Parker, Gregory D. Hussey, Anne Von GottbergAbstract:Background: Although Meningococcal disease (MD) incidence in South Africa is low, Neisseria meningitidis (NM) causes severe disease that is often life-threatening and can cause long-term disabilities. A quadrivalent protein-conjugated Meningococcal Vaccine (MCV4) is available, and provides protection against 75% of disease causing serogroups in South Africa.Recommendations: We advise vaccination of persons at high risk of Meningococcal disease including those with complement deficiency and asplenia; laboratory personnel from reference laboratories who work with NM; and travellers to Saudi Arabia.The need for routine Vaccine against Meningococcal disease in South Africa is controversial given the current burden of disease. However, due to the high morbidity/mortality of MD we recommend that clinicians consider vaccination of healthy infants and children; HIV-infected persons with a CD4 count > 25%; students attending college /university /military academies; and miners.Conclusion: Protein-conjugated meningo...
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The Global Meningococcal Initiative: Recommendations for reducing the global burden of Meningococcal disease.
Vaccine, 2011Co-Authors: Lee H. Harrison, Annelies Wilder-smith, Muhamed-kheir Taha, Anne Von Gottberg, Stephen Pelton, Johan Holst, Marco A.p. Safadi, Julio Vazquez, F. Marc Laforce, Ray BorrowAbstract:The Global Meningococcal Initiative (GMI) is composed of an international group of scientists, clinicians and public health officials with expertise in Meningococcal immunology, epidemiology and prevention. The primary goal of the GMI is the promotion of the global prevention of invasive Meningococcal disease through education and research. The GMI members reviewed global Meningococcal disease epidemiology, immunization strategies, and research needs. Over the past decade, substantial advances in Meningococcal Vaccine development have occurred and much has been learned about prevention from countries that have incorporated Meningococcal Vaccines into their immunization programs. The burden of Meningococcal disease is unknown for many parts of the world because of inadequate surveillance, which severely hampers evidence-based immunization policy. As the field of Meningococcal Vaccine development advances, global surveillance for Meningococcal disease needs to be strengthened in many regions of the world. For countries with Meningococcal vaccination policies, research on Vaccine effectiveness and impact, including indirect effects, is crucial for informing policy decisions. Each country needs to tailor Meningococcal vaccination policy according to individual country needs and knowledge of disease burden. Innovative approaches are needed to introduce and sustain Meningococcal vaccination programs in resource-poor settings with a high incidence of Meningococcal disease.
Mobeen H. Rathore - One of the best experts on this subject based on the ideXlab platform.
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Recommendations for serogroup B Meningococcal Vaccine for persons 10 years and older
Pediatrics, 2016Co-Authors: Carrie L. Byington, H. Dele Davies, Kathryn M. Edwards, Yvonne Maldonado, Elizabeth D. Barnett, Ruth Lynfield, Flor M. Munoz, Dawn Nolt, Ann-christine Nyquist, Mobeen H. RathoreAbstract:This policy statement provides recommendations for the prevention of serogroup B Meningococcal disease through the use of 2 newly licensed serogroup B Meningococcal Vaccines: MenB-FHbp (Trumenba; Wyeth Pharmaceuticals, a subsidiary of Pfizer, Philadelphia, PA) and MenB-4C (Bexsero; Novartis Vaccines, Siena, Italy). Both Vaccines are approved for use in persons 10 through 25 years of age. MenB-FHbp is licensed as a 2- or 3-dose series, and MenB-4C is licensed as a 2-dose series for all groups. Either Vaccine is recommended for routine use in persons 10 years and older who are at increased risk of serogroup B Meningococcal disease (category A recommendation). Persons at increased risk of Meningococcal serogroup B disease include the following: (1) persons with persistent complement component diseases, including inherited or chronic deficiencies in C3, C5-C9, properdin, factor D, or factor H or persons receiving eculizumab (Soliris; Alexion Pharmaceuticals, Cheshire, CT), a monoclonal antibody that acts as a terminal complement inhibitor by binding C5 and inhibiting cleavage of C5 to C5A; (2) persons with anatomic or functional asplenia, including sickle cell disease; and (3) healthy persons at increased risk because of a serogroup B Meningococcal disease outbreak. Both serogroup B Meningococcal Vaccines have been shown to be safe and immunogenic and are licensed by the US Food and Drug Administration for individuals between the ages of 10 and 25 years. On the basis of epidemiologic and antibody persistence data, the American Academy of Pediatrics agrees with the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention that either Vaccine may be administered to healthy adolescents and young adults 16 through 23 years of age (preferred ages are 16 through 18 years) to provide short-term protection against most strains of serogroup B Meningococcal disease (category B recommendation).
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Updated Recommendations on the Use of Meningococcal Vaccines
Pediatrics, 2014Co-Authors: Michael T. Brady, Carrie L. Byington, H. Dele Davies, Kathryn M. Edwards, Mary Anne Jackson, Yvonne Maldonado, Dennis L. Murray, Walter A. Orenstein, Mobeen H. Rathore, Mark H. SawyerAbstract:Since the last policy statement from the American Academy of Pediatrics (AAP) concerning Meningococcal Vaccine was published in 2011, 2 Meningococcal conjugate Vaccines have been licensed for use in infants (Hib-MenCY-TT and MenACWY-CRM). The Centers for Disease Control and Prevention (CDC) has published new recommendations, "Prevention and Control of Meningococcal Disease: Recommendations of the Advisory Committee on Immunization Practices," which have been endorsed by the AAP. However, the CDC recommendations were published before licensure of MenACWY-CRM for infant use. This policy statement updates the AAP recommendations for use of Meningococcal Vaccines in children and adolescents. A more comprehensive review of background and technical information can be found in the CDC publication.