Lisa DeTora

Biochemical and biological characteristics of cross-reacting material 197 (CRM197), a non-toxic mutant of diphtheria toxin: Use as a conjugation protein in vaccines and other potential clinical applications

The biochemical and biological characteristics of CRM(197) are reviewed. Polysaccharide protein conjugate vaccines represent an important technological advancement that allowed for protection against dangerous diseases in vulnerable populations such as infants. The first carrier proteins, diphtheria and tetanus toxoids, were chosen in the context of an extensive body of information describing their immunogenicity and safety profiles in clinical use. These carriers perform well, and they require detoxification. A non-toxic mutant of diphtheria toxin, cross-reacting material 197 (CRM(197)), is a useful carrier protein with several manufacturing and other potential advantages over toxoids. For over a decade, several important and widely used routine childhood glycoconjugate vaccines against serious illnesses, including Haemophilus influenzae type b and pneumococcal disease, have employed CRM(197) as carrier protein. Additional clinical applications of CRM(197), as in chemotherapy, also exist.

Interlaboratory Standardization of the Sandwich Enzyme-Linked Immunosorbent Assay Designed for MATS, a Rapid, Reproducible Method for Estimating the Strain Coverage of Investigational Vaccines

ABSTRACT The meningococcal antigen typing system (MATS) sandwich enzyme-linked immunosorbent assay (ELISA) was designed to measure the immunologic cross-reactivity and quantity of antigens in target strains of a pathogen. It was first used to measure the factor H-binding protein (fHbp), neisserial adhesin A (NadA), and neisserial heparin-binding antigen (NHBA) content of serogroup B meningococcal (MenB) isolates relative to a reference strain, or “relative potency” (RP). With the PorA genotype, the RPs were then used to assess strain coverage by 4CMenB, a multicomponent MenB vaccine. In preliminary studies, MATS accurately predicted killing in the serum bactericidal assay using human complement, an accepted correlate of protection for meningococcal vaccines. A study across seven laboratories assessed the reproducibility of RPs for fHbp, NadA, and NHBA and established qualification parameters for new laboratories. RPs were determined in replicate for 17 MenB reference strains at laboratories A to G. The reproducibility of RPs among laboratories and against consensus values across laboratories was evaluated using a mixed-model analysis of variance. Interlaboratory agreement was very good; the Pearson correlation coefficients, coefficients of accuracy, and concordance correlation coefficients exceeded 99%. The summary measures of reproducibility, expressed as between-laboratory coefficients of variation, were 7.85% (fHbp), 16.51% (NadA), and 12.60% (NHBA). The overall within-laboratory measures of variation adjusted for strain and laboratory were 19.8% (fHbp), 28.8% (NHBA), and 38.3% (NadA). The MATS ELISA was successfully transferred to six laboratories, and a further laboratory was successfully qualified.

Imported Human Rabies Cases in Europe, the United States, and Japan, 1990 to 2010

Rabies is an irreversible, fatal disease most frequently characterized by acute encephalitis that causes approximately 55,000 deaths annually in Africa and Asia. Disease occurs when rabies virus, a Lyssavirus , is transmitted to a human via the saliva of an infected mammalian carnivore or bat, usually a dog, if it comes in contact with mucous membranes or enters the body via a bite, scratch, or lick on broken skin. Animal reservoirs for rabies exist in all continental areas worldwide. Deaths are presumed to be underreported in areas with poor access to medical facilities. Children are considered to be at a higher risk than adults.1,2 Although the risk of contracting rabies in developed countries is generally low, those who travel to areas with high epizootic endemicity are at increased risk of exposure and death. Steffen and co‐workers evaluated the risk of rabies infection due to animal bites in travelers to developing countries and found an incidence rate per month between 0.1% and 1%.3 An epidemiological study of travelers presenting to GeoSentinel sites worldwide performed by the US Centers for Disease Control and Prevention (CDC) and the International Society of Travel Medicine (ISTM) found that 4.7% of this population required rabies post‐exposure prophylaxis.4 After acquisition of the virus, the incubation period is variable, usually between 20 and 90 d, although occasionally disease develops after only a few days, and, in rare cases, more than a year following exposure. Usually patients develop a furious form of the disease, with episodes of generalized hyperexcitability separated by lucid periods. Encephalitis results from viral replication in the brain. In 20% of cases, a paralytic form of the disease results in progressive immobility. Both forms of rabies, furious and paralytic, are always fatal. One documented case of recovery from symptomatic disease has been reported; … Corresponding Author: Claudius Malerczyk, MD, Novartis Vaccines and Diagnostics GmbH, Emil‐von‐Behring Strase 76, D‐35041 Marburg, Germany. E‐mail: claudius.malerczyk{at}novartis.com

Menveo®: a novel quadrivalent meningococcal CRM197 conjugate vaccine against serogroups A, C, W-135 and Y

Meningococcal disease remains a global public health concern despite the wide availability of polysaccharide and polysaccharide–protein conjugate vaccines. The latter often afford a greater duration and scope of protection compared with the former. A novel quadrivalent meningococcal conjugate vaccine, Menveo® (MenACWY-CRM; Novartis Vacines, Bellaria-Rosia, Italy) has recently been licensed in Europe, the USA, Canada and other countries to protect adolescents and adults against disease caused by serogroups A, C, W-135 and Y. MenACWY-CRM has an immunogenicity and tolerability profile in adolescents and adults supported by an extensive clinical development program. MenACWY-CRM induced immune responses that were at least as good as those induced by Menactra® (MenACWY-D; Sanofi Pasteur [Swiftwater, PA, USA]), a quadrivalent meningococcal polysaccharide–protein conjugate vaccine) against serogroups A, C, W-135 and Y. Immune responses were also observed in a population of subjects 56–65 years of age. Published information also shows immunogenicity in infants, toddlers and children. Tolerability outcomes were similar for MenACWY-CRM, MenACWY-D and a plain polysaccharide quadrivalent vaccine against meningococcal serogroups A, C, W-135 and Y. Given its potential for protecting infants and persons over 55 years of age, MenACWY-CRM offers promise to fulfil an unmet global need for preventing invasive meningococcal disease in vulnerable populations for which no vaccine is available.

Early clinical experience with a candidate meningococcal B recombinant vaccine (rMenB) in healthy adults.

Background: The development of a broadly protective vaccine against meningococcal serogroup B is a well-recognized public health need. Whole-genome sequencing was used to identify meningococcal surface proteins that are conserved across strains. These proteins were incorporated into two investigational vaccines. Methods: Three randomized studies were performed to evaluate a three-component recombinant meningococcal serogroup B vaccine (rMenB) and rMenB plus outer membrane vesicles from the Norwegian outbreak strain 44/76 (rMenB+OMVNW). Participants were randomized to receive 3 or 4 doses of rMenB or rMenB+OMVNW or control vaccines and provided sera for exploratory immunogenicity testing against a panel of meningococcal serogroup B strains. A booster dose was administered 12 months after the initial primary series in one of the studies. The control cohort received a licensed quadrivalent meningococcal polysaccharide vaccine against serogroups A, C, W-135 and Y as well as hepatitis B vaccine as safety comparators. Solicited reactions within 7 days of any vaccination and adverse events throughout the studies were recorded. Results: One hundred four participants enrolled into the clinical trials. Both rMenB and rMenB+OMVNW induced immune responses to multiple serogroup B strains in the majority of participants. Compared with rMenB, rMenB+OMVNW appeared somewhat more immunogenic and reactogenic; the study was not adequately powered for statistical assessment of these small differences. Both investigational vaccines were more reactogenic than the licensed vaccines. Few vaccinees discontinued any study due to reactogenicity to any study vaccine administered. Conclusion: Based on the immunogenicity and reactogenicity results in these participants, both rMenB and rMenB+OMVNW were promising candidates for further investigation.

The challenge of post-implementation surveillance for novel meningococcal vaccines.

Novel serogroup B meningococcal vaccines are currently in late stage development and may be used in mass immunisation campaigns over the coming years. This represents an exciting development in the prevention of childhood meningitis, however monitoring the impact of these vaccines on meningococcal disease epidemiology will provide significant challenges. Although designed to prevent serogroup B meningococcal disease the vaccine antigens are not serogroup specific, creating the potential for multiple definitions of vaccine effectiveness and vaccine failure.

Critical appraisal of a quadrivalent CRM(197) conjugate vaccine against meningococcal serogroups A, C W-135 and Y (Menveo) in the context of treatment and prevention of invasive disease.

Worldwide, invasive meningococcal disease affects about 500,000 people annually. Case fatality in developed countries averages 10%, and higher rates are reported in less prosperous regions. According to the World Health Organization, the most important pathogenic serogroups are A, B, C, W-135, X, and Y. Clinical features of invasive meningococcal disease make diagnosis and management difficult. Antibiotic measures are recommended for prophylaxis after exposure and for treatment of invasive meningococcal disease cases; however, resistant strains may be emerging. Vaccines are generally regarded as the best preventative measure for invasive meningococcal disease. Polysaccharide vaccines against serogroups A, C, W-135, and Y using protein conjugation technology have clear advantages over older plain polysaccharide formulations without a protein component. The first quadrivalent meningococcal conjugate vaccine (MenACWY-D) was licensed in the US in 2005. More recently, MenACWY-CRM (Menveo®) was licensed in Europe, the US, the Middle East, and Latin America. MenACWY-CRM uses cross-reactive material 197, a nontoxic mutant of diphtheria toxin, as the carrier protein. MenACWY-CRM offers robust immunogenicity in all age groups, with a tolerability profile similar to that of a plain polysaccharide vaccine. Given its potential for protecting persons from infancy to old age, MenACWY-CRM offers the opportunity to protect broad populations against invasive meningococcal disease. The most optimal strategy for use of the vaccine has to be assessed country by country on the basis of local epidemiology, individual health care systems, and need.

Increase of meningococcal serogroup Y cases in Europe: a reason for concern?

Neisseria meningitidis is differentiated into 12 distinct serogroups of which A, B, C, W-135, X and Y are medically most important and represent a major health problem in one or more parts of the world. The epidemiology of N. meningitidis is unpredictable over time and across geographic regions. A sudden increase or decrease of IMD or meningococcal carriage may occur anywhere at any time. Recent epidemiological surveillance indicates an increase of serogroup Y IMD in some parts of Europe and data from various European countries are presented.