C E Frasch

Uniformed Services University of the Health Sciences, Bethesda, MD, United States

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Publications (150)663.28 Total impact

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    ABSTRACT: Pathogenic Neisseria meningitidis isolates contain a polysaccharide capsule that is the main virulence determinant for this bacterium. Thirteen capsular polysaccharides have been described, and nuclear magnetic resonance spectroscopy has enabled determination of the structure of capsular polysaccharides responsible for serogroup specificity. Molecular mechanisms involved in N. meningitidis capsule biosynthesis have also been identified, and genes involved in this process and in cell surface translocation are clustered at a single chromosomal locus termed cps. The use of multiple names for some of the genes involved in capsule synthesis, combined with the need for rapid diagnosis of serogroups commonly associated with invasive meningococcal disease, prompted a requirement for a consistent approach to the nomenclature of capsule genes. In this report, a comprehensive description of all N. meningitidis serogroups is provided, along with a proposed nomenclature, which was presented at the 2012 XVIIIth International Pathogenic Neisseria Conference.
    Emerging Infectious Diseases 04/2013; 19(4):566-73. · 6.79 Impact Factor
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    ABSTRACT: Group A meningococcal disease has been an important public health problem in sub-Saharan Africa for over a century. Outbreaks occur there annually, and large epidemics occur at intervals ranging between 8 and 12 y. The Meningitis Vaccine Project was established in 2001 with funding from the Gates Foundation with the goal of developing, testing, licensing, and introducing an affordable group A meningococcal conjugate vaccine into Africa. From 2003 to 2009 a monovalent group A conjugate vaccine, MenAfriVac(TM) , was developed at the Serum Institute of India, Ltd through an innovative public/private partnership. Preclinical studies of the new conjugate vaccine were completed in 2004 and a Phase 1 study began in India in 2005. Phase 2/3 studies in African 1-29 y olds were completed in 2009 showing the new meningococcal A conjugate vaccine to be as safe as currently licensed meningococcal polysaccharide vaccines, but much more immunogenic. After Indian market authorization (December 2009) and WHO prequalification (June 2010), MenAfriVac(TM) was introduced at public health scale using a single 10 µg dose in individuals 1-29 y of age in Burkina Faso, Mali, and Niger in December 2010. We summarize the laboratory and clinical studies leading to prequalification of MenAfriVac(TM). The 2011 epidemic season ended with no reported case of group A meningitis in vaccinated individuals.
    Human vaccines & immunotherapeutics. 06/2012; 8(6):715-24.
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    ABSTRACT: Capsular polysaccharide (CP) plays an important role in the pathogenicity and immunogenicity of Staphylococcus aureus, yet the common serotypes of S. aureus isolated from US pediatric patients have not been reported. We investigated capsular serotype as well as methicillin susceptibility, presence of Panton-Valentine leukocidin (PVL), and clonal relatedness of pediatric S. aureus isolates. Clinical isolates were tested for methicillin susceptibility, presence of mecA, lukS-PV and lukF-PV, cap5 and cap8 genes by PCR, and for capsular or surface polysaccharide expression (CP5, CP8, or 336 polysaccharide) by agglutination. Genetic relatedness was determined by pulsed-field gel electrophoresis. All S. aureus isolates encoded cap5 or cap8. Sixty-nine percent of 2004-2005 isolates were methicillin-susceptible (MSSA) and most expressed a detectable capsule. The majority of MRSA isolates (82%) were unencapsulated, exposing an expressed cell wall techoic acid antigen 336. Pulsed-field type USA300 were MRSA, PVL-positive, unencapsulated strains that were associated with deep skin infections and recurrent disease. Over half (58%) of all isolates from invasive pediatric dermatologic infections were USA300. All pediatric isolates contained either capsule type 5 or capsule type 8 genes, and roughly half of the S. aureus clinical disease isolates from our population were diverse MSSA-encapsulated strains. The majority of the remaining pediatric clinical disease isolates were unencapsulated serotype 336 strains of the PVL(+) USA300 community-associated-MRSA clone.
    FEMS Immunology & Medical Microbiology 06/2011; 63(1):16-24. · 2.68 Impact Factor
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    ABSTRACT: 7vCRM (Pfizer, Inc.) and PHiD-CV (GlaxoSmithKline Biologicals) are two pneumococcal conjugate vaccines licensed for the prevention of invasive pneumococcal disease and acute otitis media caused by the vaccine serotypes of Streptococcus pneumoniae. Neither vaccine contains serotype 19A, but both contain the closely related serotype 19F. No decrease in the incidence of serotype 19A disease has been observed following the introduction of 7vCRM, suggesting that this serotype 19F-containing vaccine provides limited cross-protection against serotype 19A. To investigate the impact that conjugation methods may have on antipolysaccharide immune responses and to determine whether this limited cross-protection is characteristic of the serotype 19F polysaccharide or rather of the 19F-CRM (cross-reacting material) conjugate, we compared naturally induced antibodies against serotypes 19F and 19A with antibodies induced after vaccination with different pneumococcal conjugate vaccines. We found that conjugation of the serotype 19F polysaccharide using reductive amination (as in 7vCRM) resulted in the formation of at least one additional epitope that is not present in the native form of the 19F polysaccharide or following 19F conjugation using a bifunctional spacer (as in the prototype vaccine 7vOMPC) or cyanylation (as in PHiD-CV). We also found that pneumococcal vaccines conjugated using cyanylation induce more opsonophagocytic antibodies against serotype 19F and a considerably higher level of cross-opsonophagocytic antibodies against serotype 19A than vaccines conjugated using reductive amination. In conclusion, these results suggest that the conjugation method can influence the functionality of the antibodies induced against the homologous serotype 19F and the cross-reactive serotype 19A of S. pneumoniae.
    Clinical and vaccine Immunology: CVI 02/2011; 18(2):327-36. · 2.60 Impact Factor
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    ABSTRACT: Capsular polysaccharide (CP) plays an important role in the pathogenicity and immunogenicity of Staphylococcus aureus, yet the common serotypes of S. aureus isolated from US pediatric patients have not been reported. We investigated capsular serotype as well as methicillin susceptibility, presence of Panton–Valentine leukocidin (PVL), and clonal relatedness of pediatric S. aureus isolates. Clinical isolates were tested for methicillin susceptibility, presence of mecA, lukS‐PV and lukF‐PV, cap5 and cap8 genes by PCR, and for capsular or surface polysaccharide expression (CP5, CP8, or 336 polysaccharide) by agglutination. Genetic relatedness was determined by pulsed‐field gel electrophoresis. All S. aureus isolates encoded cap5 or cap8. Sixty‐nine percent of 2004–2005 isolates were methicillin‐susceptible (MSSA) and most expressed a detectable capsule. The majority of MRSA isolates (82%) were unencapsulated, exposing an expressed cell wall techoic acid antigen 336. Pulsed‐field type USA300 were MRSA, PVL‐positive, unencapsulated strains that were associated with deep skin infections and recurrent disease. Over half (58%) of all isolates from invasive pediatric dermatologic infections were USA300. All pediatric isolates contained either capsule type 5 or capsule type 8 genes, and roughly half of the S. aureus clinical disease isolates from our population were diverse MSSA‐encapsulated strains. The majority of the remaining pediatric clinical disease isolates were unencapsulated serotype 336 strains of the PVL(+) USA300 community‐associated‐MRSA clone.
    FEMS Immunology & Medical Microbiology 01/2011; 63(1). · 2.68 Impact Factor
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    ABSTRACT: A unique multicomponent vaccine against serogroup B meningococci incorporates the novel genome-derived proteins fHbp, NHBA, and NadA that may vary in sequence and level of expression. Measuring the effectiveness of such vaccines, using the accepted correlate of protection against invasive meningococcal disease, could require performing the serum bactericidal assay (SBA) against many diverse strains for each geographic region. This approach is impractical, especially for infants, where serum volumes are very limited. To address this, we developed the meningococcal antigen typing system (MATS) by combining a unique vaccine antigen-specific ELISA, which detects qualitative and quantitative differences in antigens, with PorA genotyping information. The ELISA correlates with killing of strains by SBA and measures both immunologic cross-reactivity and quantity of the antigens NHBA, NadA, and fHbp. We found that strains exceeding a threshold value in the ELISA for any of the three vaccine antigens had ≥80% probability of being killed by immune serum in the SBA. Strains positive for two or more antigens had a 96% probability of being killed. Inclusion of multiple different antigens in the vaccine improves breadth of coverage and prevents loss of coverage if one antigen mutates or is lost. The finding that a simple and high-throughput assay correlates with bactericidal activity is a milestone in meningococcal vaccine development. This assay allows typing of large panels of strains and prediction of coverage of protein-based meningococcal vaccines. Similar assays may be used for protein-based vaccines against other bacteria.
    Proceedings of the National Academy of Sciences 10/2010; 107(45):19490-5. · 9.81 Impact Factor
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    ABSTRACT: The history of the pneumococcal polysaccharide enzyme-linked immunosorbent assay (ELISA) is characterized by a continuous search for increased specificity. A third-generation ELISA that uses 22F polysaccharide inhibition has increased the specificity of the assay, particularly at low antibody concentrations. The present work compared various 22F ELISAs and non-22F ELISAs. The comparisons involved three different laboratories, including a WHO reference laboratory, and included sera from subjects from different geographic areas immunized with different pneumococcal conjugate vaccines, including the licensed 7-valent Prevenar vaccine and the 10-valent Synflorix vaccine. All comparisons led to the same conclusion that the threshold defined as 0.35 microg/ml for the WHO non-22F ELISA is lower when any 22F ELISA is used. The use of highly purified polysaccharides for coating further improved the specificity of the assay. In conclusion, we confirm that the 22F ELISA can be recommended as a reference method for the determination of antibodies against pneumococcal polysaccharides.
    Clinical and vaccine Immunology: CVI 01/2010; 17(1):134-42. · 2.60 Impact Factor
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    ABSTRACT: The history of the pneumococcal polysaccharide enzyme-linked immunosorbent assay (ELISA) is characterized by a continuous search for increased specificity. A third-generation ELISA that uses 22F polysaccharide inhibition has increased the specificity of the assay, particularly at low antibody concentrations. The present work compared various 22F ELISAs and non-22F ELISAs. The comparisons involved three different laboratories, including a WHO reference laboratory, and included sera from subjects from different geographic areas immunized with different pneumococcal conjugate vaccines, including the licensed 7-valent Prevenar vaccine and the 10-valent Synflorix vaccine. All comparisons led to the same conclusion that the threshold defined as 0.35 microg/ml for the WHO non-22F ELISA is lower when any 22F ELISA is used. The use of highly purified polysaccharides for coating further improved the specificity of the assay. In conclusion, we confirm that the 22F ELISA can be recommended as a reference method for the determination of antibodies against pneumococcal polysaccharides.
    Clinical and vaccine Immunology: CVI 11/2009; 17(1):134-42. · 2.60 Impact Factor
  • Carl E Frasch
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    ABSTRACT: A conjugate can be a polysaccharide (PS) covalently attached to a protein, which provides T cell epitopes for a normally T cell independent antigen. To produce a conjugate vaccine, the purified PS must first be chemically modified to generate reactive groups that can link to the protein. Two commonly used methods for PS activation are periodate oxidation at vicinal hydroxyls and cyanylation of hydroxyls. The PS should be of known molecular size before and after activation. Low molecular weight impurities in the protein may result in inefficient conjugation. Two critical measures after conjugation and purification are the PS to protein ratio and the percent non-conjugated saccharide (free saccharide). Yield and conjugate stability are critical considerations. Typically, considerably less than 20% of the activated PS becomes conjugated. Yield can be improved using newer conjugation methods, whereby highly reactive groups are generated on both the PS and carrier protein with yields approaching 50%. Two major measures used to follow vaccine stability are changes in molecular size and percent free (unbound) PS.
    Vaccine 07/2009; 27(46):6468-70. · 3.77 Impact Factor
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    Carl E Frasch, Ray Borrow, John Donnelly
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    ABSTRACT: It has been demonstrated that antibodies induced by meningococcal polysaccharide, polysaccharide-protein conjugates and outer membrane protein vaccines protect against meningococcal disease. This review will show that the induced antibody protects via complement mediated bactericidal killing and that induction of serum bactericidal antibody (SBA) is a good surrogate for efficacy. The critical role of SBA is shown by: (1) Highest incidence of meningococcal disease occurs in infants between 6 and 18 months of age, who have the lowest levels of SBA. (2) Studies published in 1969 in US Army recruits showed a direct correlation between susceptibility to meningococcal disease and absence of SBA. (3) Meningococcal polysaccharide, polysaccharide-protein conjugates, and outer membrane vesicle vaccines all induce SBA shown to be effective in direct proportion to the percent of vaccinees with SBA activity.
    Vaccine 06/2009; 27 Suppl 2:B112-6. · 3.77 Impact Factor
  • Ron Dagan, Carl Frasch
    The Pediatric Infectious Disease Journal 05/2009; 28(4 Suppl):S63-5. · 3.57 Impact Factor
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    ABSTRACT: Periodic epidemics of group A meningococcal (Mn A) meningitis continue to occur in sub-Saharan Africa. For its prevention, a Mn A polysaccharide (PS)-tetanus toxoid (TT) conjugate vaccine was developed using reductive amination of polysaccharide aldehydes and toxoid hydrazides. In mouse immunization studies, a schedule of three bi-weekly s.c. immunizations of 0.1 or 1mug of the conjugate (PS content) without an adjuvant induced serum antibody levels of >10,000units/mL measured by enzyme-linked immunosorbent assay (ELISA) as compared to approximately 100units/mL in PS control mice. The elicited antibodies were active in bactericidal assays using either baby rabbit or human complement (titers >1500 compared to approximately 200 for the PS control group). The synthesis process is reproducible and scalable, and has been successfully used for manufacturing a Mn A PS-TT conjugate vaccine based on a paradigm of shared manufacturing with transfer of new technology [Jodar L, LaForce FM, Ceccarini C, Aguado T, Granoff DM. Meningococcal conjugate vaccine for Africa: a model for development of new vaccine for the poorest countries. Lancet 2003, 361:1092-4]. A phase 1 clinical trial of the manufactured Men A-TT conjugate vaccine has been successfully carried out in adults in India, and a phase 2 clinical trial in young children is currently underway in Africa.
    Vaccine 01/2009; 27(5):726-32. · 3.49 Impact Factor
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    ABSTRACT: Polysaccharide (PS) and tetanus toxoid (TT) protein conjugate vaccines were prepared using O-acetylated (OAc+), O-acetyl negative (OAc(-)) and chemically de-O-acetylated (de-OAc) meningococcal W135 PS. The PSs were activated by periodate oxidation and coupled to hydrazine derivatized TT. High performance anion exchange chromatography of acid hydrolysates of periodate activated W135 PSs, showed that galactose residues in OAc+ PS were more sensitive to the periodate oxidation step than they were in the OAc(-) PS or de-OAc PS. Mouse antisera against OAc(-)-TT conjugate vaccines recognized both OAc(-) and OAc+ PS by ELISAs and had high bactericidal titers against both OAc+ and OAc(-) W135 strains. Purified high molecular weight (HMW) conjugates showed higher PS to protein ratios in OAc(-)-TT(HMW) and de-OAc-TT(HMW) indicating better conjugation efficiency than OAc+-TT(HMW) conjugate. Antisera against the HMW fractions gave higher bactericidal titers than antisera against unfractionated conjugates. Inhibition ELISAs indicated that OAc(-) and OAc+ HMW conjugates induced antibodies that bound both OAc+ and OAc(-) PS. Thus, for W135, PS O-acetylation does not contribute a dominant immunogenic epitope. The OAc(-) PS may be a good starting material for preparing W135 PS-TT conjugate vaccines using periodate oxidation.
    Vaccine 12/2007; 25(46):7972-80. · 3.49 Impact Factor
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    ABSTRACT: The steps to produce, purify and control an immunogenic Brazilian conjugate vaccine against group C meningococcus (MenCPS-TT) using hydrazide-activated tetanus toxoid were developed. The conjugation methodology reduced the reaction time easily allowing scale-up. One freeze-dried pilot vaccine lot purified by tangential filtration, showed satisfactory quality control results including safety and stability. The pilot vaccine was immunogenic in mice in a dose-dependent fashion generating a 10-20-fold rise in IgG response in mice. The vaccine also induced high bactericidal titers. Vaccine concentrations of 1 and 0.1 microg showed higher avidity indices, suggesting induction of immunologic memory. These results support initiation of Phase I clinical studies with the MenCPS-TT conjugate vaccine.
    Vaccine 11/2007; 25(41):7261-70. · 3.49 Impact Factor
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    ABSTRACT: Understanding the specificity of antibody response to Neisseria meningitidis serogroup B (Men B) is a key requirement for the development of an effective vaccine. This study was designed to investigate the antigen specificity of murine IgG1 and IgG2b antibodies induced by different primary immunization schedules and the booster dose with the Cuban Men B vaccine. Immunoblotting analyses were performed using outer membrane vesicles (OMV) from the vaccine strain (B:4,7:P1.19,15). IgG subclasses binding to PorA, PorB and RmpM were determined by digital scanning of the immunoreactive bands. Bactericidal antibody response after vaccination was also evaluated. The results indicated that IgG2b anti-PorA was the main antibody response induced by two doses of the vaccine. A primary series of three doses was found important for increasing IgG2b as well as IgG1 to PorB and RmpM. The fourth dose favoured the recognition of RmpM as detected by the increase of specific IgG1 and IgG2b. IgG subclasses anti-PorA did not change significantly if animals received two, three or four doses of the vaccine during the primary immunization or after the booster dose for all vaccine groups. The booster response to PorB and RmpM of groups BC2 and BC3 showed a significant increase in IgG2b levels compared with the primary response. However, the recall and the primary response of group BC4 were similar, suggesting a saturated dose-effect response after four doses of vaccine. The same was seen for bactericidal antibody response when human complement source was used in the assay.
    Scandinavian Journal of Immunology 02/2007; 65(1):1-7. · 2.20 Impact Factor
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    ABSTRACT: This study compares the phylogenetic lineages of invasive serotype III group B streptococci (GBS) to those of colonizing strains in order to determine lineages associated with invasive disease. Isolates from 29 infants with early-onset disease (EOD) and from 196 colonized infants, collected in a prospective, multicenter study, were assigned a sequence type (ST) by multilocus sequence typing. Overall, 54.5% of the isolates were in the ST-19 complex, and 40.4% were in the ST-17 complex. Invasive strains were more likely to be in the ST-17 complex than were colonizing strains (59% versus 38%, P = 0.03). After we adjusted for potential confounders, the ST-17 complex was more likely to be associated with EOD than were other lineages (odds ratio = 2.51, 95% confidence interval = 1.02 to 6.20). These data support the hypothesis that ST-17 complex GBS are more virulent than other serotype III GBS.
    Journal of Clinical Microbiology 05/2006; 44(4):1257-61. · 4.07 Impact Factor
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    ABSTRACT: Since 2000, when a pneumococcal conjugate vaccine (Prev- nar) was introduced, pneumococcal infections in the United States among children have been dramatically reduced. The conjugate vaccine elicits antibodies to pneumococcal capsular polysaccharide, and these antibodies protect the host by opso- nizing pneumococci and thus facilitating phagocytosis. The ability of a serum sample to opsonize bacteria can be measured by various in vitro opsonophagocytosis assays (OPAs), and OPAs have been shown to be the best functional correlate of protection in various studies. A minimum opsonic titer of 1:8 confers protection in a mouse model, is correlated with pro- tection in infants vaccinated with pneumococcal conjugate vac- cine, and was shown in infants to correspond to an immuno- globulin G (IgG) antibody concentration of 0.2 to 0.35 g/ml (5). A Finnish study with an 11-valent pneumococcal conjugate vaccine conducted in the Philippines showed a good correla- tion between an opsonophagocytic killing assay and the IgG antibodies as measured by enzyme-linked immunosorbent as- say (ELISA) (12), although the correlation may be limited in some populations, as described later in this review. In the wake of the success of the conjugate vaccine (Prevnar; Wyeth Lederle Vaccines), new or improved pneumococcal vaccines for both children and adults are being actively devel- oped. Future vaccine formulations may likely contain a higher number of capsular serotypes and may be formulated to also contain vaccines against other pathogens as part of a new combination vaccine. Evaluation of these vaccines would be heavily dependent on demonstrating that the new vaccines can also induce opsonic titers that are sufficient for protection. For these reasons, various forms of opsonization assays have been developed, and there have been significant technical improve- ments in pneumococcal antibody OPAs, such as the introduc- tion of multiplexed OPAs. Thus, a workshop was held in At- lanta, Ga., on 5 June 2005 to discuss progress made for each methodology and discuss standardization of pneumococcal an- tibody opsonization assays. The workshop was supported by the National Institutes of Health, the Centers for Disease Control and Prevention, the World Health Organization, and the University of Alabama at Birmingham and was attended by various representatives from academia, industry, government agencies, and public reference laboratories. We present here a review of the current status of OPAs for anti-capsular polysac- charide antibodies as summarized during the workshop.
    Clinical and Vaccine Immunology 03/2006; 13(2):165-9. · 2.60 Impact Factor
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    ABSTRACT: Immunodeficiency is a barrier to successful vaccination in individuals with cancer and chronic infection. We performed a randomized phase 1/2 study in lymphopenic individuals after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for myeloma. Combination immunotherapy consisting of a single early post-transplant infusion of in vivo vaccine-primed and ex vivo costimulated autologous T cells followed by post-transplant booster immunizations improved the severe immunodeficiency associated with high-dose chemotherapy and led to the induction of clinically relevant immunity in adults within a month after transplantation. Immune assays showed accelerated restoration of CD4 T-cell numbers and function. Early T-cell infusions also resulted in significantly improved T-cell proliferation in response to antigens that were not contained in the vaccine, as assessed by responses to staphylococcal enterotoxin B and cytomegalovirus antigens (P < 0.05). In the setting of lymphopenia, combined vaccine therapy and adoptive T-cell transfer fosters the development of enhanced memory T-cell responses.
    Nature Medicine 12/2005; 11(11):1230-7. · 22.86 Impact Factor
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    ABSTRACT: The generation and maintenance of memory antibody response by different primary immunization schedules with the Cuban-produced outer membrane protein based vaccine was investigated in a murine model. We analyzed the duration of the antibody response (IgG-ELISA and bactericidal titer) and the effect of a booster dose on the antibody response. The IgG avidity index was determined in an attempt to find a marker for memory development. This study also included an analysis of IgG subclasses induced by primary and booster immunization. The specificity of bactericidal antibodies was investigated using local strains of the same serotype/serosubtype (4,7:P1.19,15) as the vaccine strain and mutant strains lacking major outer membrane proteins. A significant recall response was induced by a booster dose given 7 months after a primary series of 2, 3 or 4 doses of vaccine. The primary antibody response showed a positive dose-effect. In contrast, a negative dose-effect was found on the booster bactericidal antibody response. There was a significant increase in IgG1 levels after the fourth and booster doses. Three doses of vaccine were required to induce a significant increase in IgG avidity. Two injections of vaccine induced a significant antibody response to PorA protein, while 4 injections induced a larger range of specificities.
    FEMS Immunology & Medical Microbiology 05/2005; 44(1):35-42. · 2.68 Impact Factor
  • Carl E Frasch
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    ABSTRACT: Meningococcal disease, both endemic and epidemic, remains a major cause of meningitis in many countries. Protective immunity is mediated primarily by bacteriocidal antibodies against the capsular polysaccharides for serogroups other than B, and against non-capsular surface components for group B. This article focuses on the development of conjugate vaccines for serogroup A, with special emphasis on the needs of Africa. The first licensed (1999) meningococcal conjugate was against group C in the UK and was > 90% effective in infants, children and young adults. The problem now is to develop a highly immunogenic group A meningococcal conjugate vaccine for use in developing countries as an alternative to the presently licensed group AC polysaccharide vaccine. Immunogenicity studies on the group A polysaccharide show the polysaccharide itself to be uniquely immunogenic in young children compared with other polysaccharides, making comparative studies with a highly immunogenic conjugate of considerable importance.
    Expert opinion on biological therapy 02/2005; 5(2):273-80. · 3.22 Impact Factor

Publication Stats

6k Citations
663.28 Total Impact Points

Institutions

  • 2011
    • Uniformed Services University of the Health Sciences
      • Department of Pediatrics
      Bethesda, MD, United States
  • 1980–2011
    • U.S. Food and Drug Administration
      • • Center for Biologics Evaluation and Research
      • • Division of Bacterial, Parasitic & Allergenic Products
      • • Laboratory of Bacterial Polysaccharides
      • • Office of Biostatistics
      Washington, Washington, D.C., United States
  • 2009
    • Soroka Medical Center
      • Pediatric Infectious Disease Unit
      Be'er Sheva`, Southern District, Israel
    • U.S. Department of Health and Human Services
      Washington, Washington, D.C., United States
  • 2001
    • Children's & Women's Health Centre of British Columbia
      Vancouver, British Columbia, Canada
  • 1992–1998
    • Instituto Adolfo Lutz
      • Bacteriology Division
      San Paulo, São Paulo, Brazil
    • National Institute Of Public Health
      Bucureşti, Bucureşti, Romania
  • 1997
    • Walter Reed Army Institute of Research
      Silver Spring, Maryland, United States
  • 1995
    • Fundação Oswaldo Cruz
      Rio de Janeiro, Rio de Janeiro, Brazil
  • 1987
    • University of Rochester
      • Department of Biology
      Rochester, NY, United States
  • 1982
    • Boston Medical Center
      Boston, Massachusetts, United States
  • 1974
    • The Rockefeller University
      New York City, New York, United States