In this study, we have demonstrated, for the first time, that vaccines comprised of N. lactamica antigens protect against meningococcal disease in a murine infection model.
Carriage of commensal Neisseria
spp., particularly N. lactamica
, has been considered important for the development and maintenance of natural immunity to meningococcal disease in young children, and both antibody cross-reactivity and bactericidal antibodies to meningococci have been determined following N. lactamica
carriage in humans (10
). Cross-reacting bactericidal antibodies between meningococci and N. lactamica
were demonstrated in a survey of schoolchildren following an outbreak of meningococcal disease (30
), in which bactericidal activity of sera toward the outbreak strain could be reduced by adsorption of the sera with N. lactamica
. In contrast, a study with sera obtained from patients indicated a lack of association between antibodies to meningococcal OMPs and carriage of N. lactamica
In the present study, antibodies raised against OMVs prepared from N. lactamica
and N. meningitidis
showed a high degree of cross-reactivity with a range of meningococcal strains by whole-cell ELISA. Bactericidal antibodies were not observed in this study in sera from mice immunized with N. lactamica
vaccines, even though mice immunized with the same preparations were protected against meningococcal challenge. It is becoming apparent that bactericidal antibody titer may not be a good correlate of protection in the mouse meningococcal infection model. Bactericidal antibodies are undoubtedly a good correlate with protection for meningococcal vaccines based on capsular polysaccharide (3
) and are important for prediction of protection provided by meningococcal OMV vaccines containing PorA (8
), which do elicit bactericidal antibodies in mice.
The lack of in vitro bactericidal activity in sera from mice immunized with N. lactamica
indicates that other protective mechanisms, such as opsonophagocytosis, may be operating. Protection in mice in the absence of bactericidal antibodies has also been observed following immunization with meningococcal transferrin binding protein A (TbpA) (28
). Human antibodies against TbpA and -B following disease have been demonstrated to have opsonic activity (19
). It will therefore be important to assess human immune responses to N. lactamica
-based vaccines and determine the range of functional responses elicited.
This study has confirmed the vaccine potential of N. lactamica
with a mouse intraperitoneal challenge model. We recognize that this is not an ideal model of meningococcal disease, as it does not follow the natural pathogenesis of the disease in humans and an exogenous iron source is required to establish meningococcemia. However, this model of bacteremia allows assessment of active immunization and protection. It also permits comparison of the protection provided by different vaccines (12
), and a range of challenge strains can be used. With this model, we were able to confirm that N. lactamica
whole cells and various antigen preparations protected against challenge by meningococcal isolates representing different clonal lineages belonging to serogroups B and C.
The <43-kDa protein pool provided protection greater than or equivalent to that afforded by the original detergent extract of whole cells, indicating that protective components may have been concentrated in this fraction. Cross-reaction between the LOS of N. meningitidis
and N. lactamica
has been demonstrated previously (17
). However, the role of LOS in protection in this study is not clear. Purified N. lactamica
LOS did not protect against meningococcal challenge, but the experimental N. lactamica
vaccines described here contain LOS in various amounts, perhaps in a more native and immunogenic form. Experiments are in progress to determine the relative contribution of protein and LOS components to protection.
Existing meningococcal vaccines based on capsular polysaccharide offer protection that is serogroup specific, and the effectiveness of vaccines based on meningococcal OMVs is affected by variation in the immunodominant serosubtyping antigen PorA (21
). Unlike N. meningitidis
, N. lactamica
does not possess PorA (17
), potentially enabling it to provide protection that is not serosubtype specific. The protection observed against a diverse panel of meningococcal isolates is further evidence that N. lactamica
has the potential to provide a serogroup- and serosubtype-independent vaccine against meningococcal disease. Such a vaccine could be based on isolated antigens, OMVs, or live organisms. There has been discussion of construction of live attenuated meningococcal vaccines for intranasal use (25
). This study suggests that N. lactamica
would be a better, and potentially safer, alternative to this approach, mimicking and enhancing the natural immunization that occurs through natural carriage.