Chemistry of a new investigational quadrivalent meningococcal conjugate vaccine that is immunogenic at all ages

Abstract

Meningococcal disease is a serious medical condition that can prove fatal within hours in otherwise healthy individuals. Disease incidence is highest in infants, yet there is no broadly protective quadrivalent vaccine that covers this age group. A new investigational quadrivalent meningococcal glycoconjugate vaccine against meningococcal serogroups A, C, W-135, and Y (MenACWY-CRM, Novartis Vaccines, Siena, Italy), has been developed to meet this medical need. This article discusses the vaccine technology behind MenACWY-CRM, focusing on the heritage of CRM₁₉₇, the conjugation chemistry, the sizing of the oligosaccharides, and the advantages that these may confer on the vaccine. We highlight the differences between available vaccines and look at the clinical experience with vaccines against other diseases, demonstrating the importance of each component to the immunogenicity of conjugate vaccines. The specific technological approach, including conjugation of meningococcal oligosaccharides of defined length to the CRM₁₉₇ protein, has led to a vaccine that has the potential to provide broad meningococcal protection against serogroups A, C, W-135, and Y for all ages.

Introduction

Meningococcal disease is an illness of sudden onset that is often fatal [1], and its individual and societal impact is not fully reflected by its overall incidence. In the absence of preventive strategies, the highest incidence of disease is in infants <1 year of age, although many countries experience a second peak in adolescents, which is often associated with an increased case-fatality rate [2]. Onset of disease is rapid and can be fatal within 24 h, and as more classic clinical symptoms occur relatively late (13–22 h), the time window for clinical diagnosis and treatment is narrow; even with timely and appropriate treatment, case-fatality rate is 10–14% and up to 20% of survivors suffer serious permanent sequelae.

Of 13 known Neisseria meningitidis serogroups, which differ immunologically due to structural differences in the polysaccharide content of their outer capsule (Fig. 1), five (serogroups A, B, C, W-135, and Y) cause the majority of disease [3].

The epidemiology of meningococcal disease is dynamic, varying over time and across regions. Because of the unpredictable nature of disease epidemiology, broad protection against as many serogroups as possible and for all ages might be the optimal prevention policy. The polysaccharide capsule is one of the major virulence factors of the meningococcus, and the bacterial-cell-surface polysaccharides serve as key antigens for the development of vaccines. Polysaccharide-based meningococcal vaccines were first introduced in the 1970s following work by Gotschlich et al. [4], [5], [6]. To date, similar approaches have failed to produce an effective vaccine against a wide spectrum of serogroup B meningococcal strains because native serogroup B polysaccharide is poorly immunogenic [7]. Vaccines raised against proteins in outer membrane vesicles, rather than polysaccharides, have been effective in controlling epidemics, but these are strain-specific, and are therefore only regionally applicable [7]. Until the challenge of a broadly protective serogroup B vaccine is overcome, the first step towards comprehensive protection against meningococcal disease is vaccination against serogroups A, C, W-135, and Y across all age groups. Bivalent and quadrivalent polysaccharide vaccines, and more recently, monovalent and quadrivalent polysaccharide–protein conjugate vaccines, have been developed to provide protection against meningococcal disease caused by these serogroups.