Transcriptional Regulation of the nadA Gene in Neisseria meningitidis Impacts the Prediction of Coverage of a Multicomponent Meningococcal Serogroup B Vaccine

Abstract

bThe NadA adhesin is a major component of 4CMenB, a novel vaccine to prevent meningococcus serogroup B (MenB) infection. Under in vitro growth conditions, nadA is 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 observed in vitro. In a strain panel covering a range of NadA levels, repression was relieved through deleting nadR. All nadR knockout 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 grown in vitro. However, in an in vivo passive 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 NadA in vitro, leading to efficient antibody-mediated killing. Finally, using bioluminescent reporters, nadA expression in the infant rat model was induced in vivo at 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 any nadA-positive (nadA ؉ ) strain and therefore efficient killing by anti-NadA antibodies elicited by the 4CMenB vaccine.

Structure of the meningococcal vaccine antigen NadA and epitope mapping of a bactericidal antibody

“…NadA expression levels can vary among isolates by more than 100-fold, and its expression is up-regulated in vivo by nichespecific signals (15). NadA induces high levels of bactericidal antibodies in humans (16)(17)(18) and is recognized by serum antibodies of children convalescent after IMD (19), suggesting that it is expressed and is immunogenic during IMD.…”

Neisseria Adhesin A Variation and Revised Nomenclature Scheme

“…Expression can be induced by the use of 4-hydroxyphenyl acetic acid, a small molecule secreted in human saliva, which inhibits NadRdependent repression (14). Recent data indicate protein upregulation in vivo (15). In addition, MtrR, a transcriptional regulator, has a negative regulatory impact on NadA expression, especially when overexpressed (17).…”

“…Further, children recovering from invasive meningococcal disease produce specific antibody responses against this antigen (11). NadA expression is regulated at the transcriptional level by the length variation of a tandem repeat region located in the gene promoter (12,13), with expression regulated by NadR, a repressor molecule (14)(15)(16). Expression can be induced by the use of 4-hydroxyphenyl acetic acid, a small molecule secreted in human saliva, which inhibits NadRdependent repression (14).…”

Serum Bactericidal Antibody Responses of Adults Immunized with the MenB-4C Vaccine against Genetically Diverse Serogroup B Meningococci

“…These isolates showed much lower levels of susceptibility to vaccineinduced SBA than the NadA reference strain. The anti-NadA resistance of the test isolates was possibly related to previous findings that, in vitro, expression of NadA can be repressed by the regulator NadR (29). Irrespective of the mechanism, the titers against the NadA reference strain overestimate the strain coverage by anti-NadA antibodies.…”