Increase in Serogroup C Meningococcal Disease in Canada Is Associated with Antigenic Changes in the Protein Antigens of the ET‐15 Clone of<i>Neisseria meningitidis</i>

To the Editor—Harrison et al. [1] recently reported that antigenic shifts in meningococci were responsible for the increased incidence of meningococcal disease activity in the United States during the 1990s. They reported that the increase in serogroup Y disease during the mid‐1990s was associated with changes detected in the outer membrane protein (OMP) antigens of PorB, PorA, and FetA. Serogroup Y strains isolated during the early 1990s expressed class 2 PorB, P1.5‐1, 2‐2 PorA, and F.5‐8 FetA, whereas strains isolated during the late 1990s expressed class 3 PorB, P1.5‐2, 10‐1, and F.4‐1 FetA. The increase in serogroup C disease in 15–24‐year‐olds was due to the ST‐11 clone, which was also associated with a change in the FetA protein from F.1‐30 during the early 1990s to F.3‐6 during the late 1990s, whereas the PorB and PorA types remained unchanged as class 2 PorB and P1.5,2 PorA. We concur with Harrison et al.’s suggestion that these changes in the OMPs allowed bacteria to evade host immune response and, hence, were at an advantage to cause infections. In Canada, the hypervirulent serogroup C ET‐15 clone was first detected at some point during the late 1980s or early 1990s; it rapidly caused outbreaks and increased disease activity across the country [2] and soon spread to the United States, Europe, and Australia [3]. This ET‐15 clone has been described as a genetic variant of the ET‐37 clone, and, like the ET‐37 clone, it expressed the serotype:serosubtype antigens of 2a:P1.5,2 [4]. After a decade of endemic disease, genetic variants of this serogroup C ET‐15 clone were observed that coincided with a second wave of outbreaks that spread through several provinces in Canada during 2000–2001 [5]. This resurgence of serogroup C disease activity could be explained by waning immunity in the population, especially given that several provinces instituted either targeted or provincewide immunization campaigns to control the first wave of outbreaks that occurred during the early 1990s. However, laboratory investigations of the disease isolates recovered from patients in 2001 showed unique genetic and antigenic variations in not only the PorA protein (serosubtype antigen) but also in the PorB OMP (serotype antigen) [5]. The most dramatic change we noticed was in the strain that caused outbreaks in Quebec in 2001 [6]; this strain expressed serosubtype antigens (P1.7,1) that were totally different from those of the parent strain, which expressed P1.5,2 antigens (table 1). The changes involved both the variable region (VR) 1 and VR2 surface‐accessible loops of the PorA OMP, and we postulated that this had resulted from a recombination event involving the C:2a:P1.5,2 parent strain exchanging part of its porA gene with a meningococcus strain expressing the P1.7,1 serosubtype antigens [6]. Amino acid composition of the PorA variable region (VR) 1 and VR2, the PorB VR3 of the C:2a:P1.5,2 parent strain, and its genetic and antigenic variants (C:2a:P1.7,1; C:2a:P1.5; and the nonserotypeable phenotype showing a mutational hot spot). In British Columbia, the strain that caused an outbreak in 2001 was characterized as being C:2a:P1.5. DNA sequencing of the porA gene from strains obtained during this outbreak showed PorA VR types of 5‐1 for VR1 and 10‐8 or 10‐4 for VR2, with both VRs showing amino acid differences from the P1.5,2 phenotype of the parent strain (table 1). Besides documenting these changes in the PorA OMP of the serogroup C ET‐15 clone, we have also reported another genetic‐phenotypic variant that caused an outbreak of meningococcal disease among men who have sex with men in Toronto, Ontario, Canada. In this outbreak, the responsible strain was found to have a genetic mutation involving its PorB OMP, leading to a nonserotypeable phenotype [7]. Since then, we have documented the presence of a mutational hot spot on the PorB OMP among nonserotypeable strains of the serogroup C ET‐15 clone [8]. It is interesting to note that all these genetic changes that led to phenotypic variants are associated with outbreaks of disease activity in the provinces of British Columbia, Ontario, and Quebec [5]. This suggests that changes in the subcapsular protein antigens may indeed offer the bacteria some advantages with respect to causing disease in a population who, although having developed some natural immunity because of the endemic nature of this serogroup C ET‐15 clone, may remain naive to these altered antigenic subcapsular protein components. Therefore, we concur with Harrison et al. that antigenic shifts are potentially significant in allowing an endemic strain to change to an extent that it is capable of evading the host’s immune response, which otherwise would have been able to control the infection by bactericidal and/or opsonic‐phagocytic mechanisms. Despite these antigenic shifts in protein antigens, the variants are still susceptible to the immunity elicited by the currently licensed vaccines, which are all directed against the surface capsular polysaccharides [9, 10].

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