Research Article: Conjugate Meningococcal Vaccines Development: GSK Biologicals Experience

Date Published: July 18, 2011

Publisher: SAGE-Hindawi Access to Research

Author(s): Jacqueline M. Miller, Narcisa Mesaros, Marie Van Der Wielen, Yaela Baine.

http://doi.org/10.4061/2011/846756

Abstract

Meningococcal diseases are serious threats to global health, and new vaccines specifically tailored to meet the age-related needs of various geographical areas are required. This paper focuses on the meningococcal conjugate vaccines developed by GSK Biologicals. Two combined conjugate vaccines were developed to help protect infants and young children in countries where the incidence of meningococcal serogroup C or serogroup C and Y disease is important: Hib-MenC-TT vaccine, which offers protection against Haemophilus influenzae type b and Neisseria meningitidis serogroup C diseases, is approved in several countries; and Hib-MenCY-TT vaccine, which adds N. meningitidis serogroup Y antigen, is currently in the final stages of development. Additionally, a tetravalent conjugate vaccine (MenACWY-TT) designed to help protect against four meningococcal serogroups is presently being evaluated for global use in all age groups. All of these vaccines were shown to be highly immunogenic and to have clinically acceptable safety profiles.

Partial Text

Invasive diseases caused by Neisseria meningitidis, of which meningitis and septicaemia are the most important, are serious threats to global health [1, 2]. Sporadic as well as endemic cases occur worldwide, and N. meningitidis is the only encapsulated bacterium known to cause large epidemics of bacterial meningitis [3, 4]. Notably, extensive meningococcal disease outbreaks comprising hundreds of thousands of cases occur cyclically in an area of Sub-Saharan Africa, also called the Meningitis Belt [5–8]. Overall, about 500,000 cases of meningococcal disease occur each year causing at least 50,000 deaths [9]. Meningococcal meningitis has a case-fatality rate of 5% to 10% in industrialised countries, which can reach 20% in the developing world [10, 11]. In addition, 12% to 19% of survivors develop long-term neurological sequelae [3, 7, 12–14]. While the highest case-fatality rate is observed among persons older than 65 years and generally decreases with lower age [10], the risk of meningococcal disease is highest in infants and young children with a secondary peak in incidence during adolescence and young adulthood [15].

The effectiveness of meningococcal vaccines is challenging to evaluate in prospective, randomised efficacy studies because the incidence of endemic meningococcal disease is low, and epidemics are difficult to predict. Therefore, efficacy is inferred from immunogenicity data via laboratory markers that can reliably predict clinical protection [50]. The primary human defence to meningococcus is the activation of the complement system by antigen-specific antibodies resulting in bacterial lysis. Bactericidal assays measuring interactions of antibodies and human complement at the bacterial surface (hSBA) can be used to measure the functional activity of a tested serum against a given strain of meningococcus. Data generated in US military recruits suggested that an hSBA titre ≥1 : 4 correlated with protection against meningococcal serogroup C disease [51]. After introduction of MenC conjugate vaccines in the UK another serological correlate of protection based on a serum bactericidal assay using rabbit complement (rSBA titre ≥1 : 8) became available using both prelicensure age-stratified seroprevalence and disease incidence data, and postlicensure efficacy estimates [52–54]. The seroprotective thresholds for MenC have been extended to serogroups A, W-135, and Y. Both assays are accepted by the WHO for the assessment of the immunogenicity of meningococcal vaccines [55] and both have been used in GSK’s clinical development depending on regional health authority requirements.

Because of the severity of invasive meningococcal disease, the rapidity with which it develops, and the high frequency of long-term sequelae, development of effective meningococcal vaccines with clinically acceptable safety profiles is a public health priority. The complete portfolio of conjugate meningococcal vaccines developed by GSK Biologicals is designed to respond to the global need with prioritisation in infants and young children, followed by adolescents, the age groups at highest risk. Two vaccines, using TT as carrier protein, were designed to help protect infants and young children against meningococcal serogroup(s) C (and Y) and Hib diseases in countries where these serogroups are major contributors to meningococcal epidemiology. The first vaccine (Hib-MenC-TT) is presently approved in various countries worldwide for use as three-dose primary vaccination in infants and booster vaccination in toddlers or as one-dose vaccination in toddlers previously primed with Hib but naïve for MenC. Primary vaccination resulted in immune priming and induced immune memory as reflected by antibody persistence and response to booster vaccination. The second vaccine (Hib-MenCY-TT) adds serogroup Y antigen and an application for licensure of this vaccine as four-dose immunisation series in infants and toddlers is currently under review by the US FDA. All primary hypotheses regarding the noninferiority of both vaccines to licensed Hib (DTPa/Hib combinations or Hib standalone vaccines) and monovalent MenC conjugate vaccines were met. On the other hand, GSK Biologicals has more recently evaluated an investigational tetravalent conjugate meningococcal vaccine (MenACWY-TT) designed to offer protection against four of the six most common serogroups worldwide for use in all age groups. This vaccine was shown to be highly immunogenic in toddlers, children, adolescents, and adults. All these vaccines were shown to have an acceptable safety profile, which was comparable to licensed conjugate vaccines. As demonstrated by the broad portfolio of meningococcal conjugate vaccines, GSK remains committed to the development of meningococcal vaccines, targeting the populations at greatest risk.

J. Miller, N. Mesaros, M. V. D. Wielen, and Y. Baine are employees of GlaxoSmithKline Biologicals. Drs M. Miller, N. Mesaros, M. V. D. Wielen, and Y. Baine report ownership of stock options.

 

Source:

http://doi.org/10.4061/2011/846756

 

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