ABSTRACTThe NadA adhesin is a major component of 4CMenB, a novel vaccine to prevent meningococcus serogroup B (MenB) infection. Underin vitrogrowth conditions,nadAis repressed by the regulator NadR and poorly expressed, resulting in inefficient killing of MenB strains by anti-NadA antibodies. Interestingly, sera from children infected with strains that express low levels of NadA in laboratory growth nevertheless recognize the NadA antigen, suggesting that NadA expression during infection may be different from that observedin vitro. In a strain panel covering a range of NadA levels, repression was relieved through deletingnadR. AllnadRknockout strains expressed high levels of NadA and were efficiently killed by sera from subjects immunized with 4CMenB. A selected MenB strain, NGP165, mismatched for other vaccine antigens, is not killed by sera from immunized infants when the strain is grownin vitro. However, in anin vivopassive protection model, the same sera effectively protected infant rats from bacteremia with NGP165. Furthermore, we identify a novel hydroxyphenylacetic acid (HPA) derivative, reported by others to be produced during inflammation, which induces expression of NadAin vitro, leading to efficient antibody-mediated killing. Finally, using bioluminescent reporters,nadAexpression in the infant rat model was inducedin vivoat 3 h postinfection. Our results suggest that during infectious disease, NadR repression is alleviated due to niche-specific signals, resulting in high levels of NadA expression from anynadA-positive (nadA+) strain and therefore efficient killing by anti-NadA antibodies elicited by the 4CMenB vaccine.
Transcriptional Regulation of thenadAGene in Neisseria meningitidis Impacts the Prediction of Coverage of a Multicomponent Meningococcal Serogroup B Vaccine