title: Transcriptional regulation of the nadA gene in Neisseria meningitidis impacts the prediction of coverage of a multicomponent meningococcal serogroup B vaccine.
abstract: The 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.
authors.affiliation: Novartis Vaccines and Diagnotics, Research Center, Siena, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Fagnocchi
authors.forename: Alessia
authors.initials: A
authors.lastname: Biolchi
authors.forename: Francesca
authors.initials: F
authors.lastname: Ferlicca
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Boccadifuoco
authors.forename: Brunella
authors.initials: B
authors.lastname: Brunelli
authors.forename: Sébastien
authors.initials: S
authors.lastname: Brier
authors.forename: Nathalie
authors.initials: N
authors.lastname: Norais
authors.forename: Emiliano
authors.initials: E
authors.lastname: Chiarot
authors.forename: Giuliano
authors.initials: G
authors.lastname: Bensi
authors.forename: J Simon
authors.initials: JS
authors.lastname: Kroll
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Pizza
authors.forename: John
authors.initials: J
authors.lastname: Donnelly
authors.forename: Marzia Monica
authors.initials: MM
authors.lastname: Giuliani
authors.forename: Isabel
authors.initials: I
authors.lastname: Delany
mesh_terms: D018829:Adhesins, Bacterial / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000907:Antibodies, Bacterial / Q000235:genetics / Q000276:immunology; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008589:Meningococcal Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D022401:Meningococcal Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D051379:Mice; D009345:Neisseria meningitidis / Q000235:genetics* / Q000276:immunology*; D038541:Neisseria meningitidis, Serogroup B / Q000235:genetics* / Q000276:immunology*; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic
chemical_list: C570015:4CMenB vaccine; D018829:Adhesins, Bacterial; D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D022401:Meningococcal Vaccines; C501982:NadA protein, Neisseria meningitidis; C117105:NadR protein, bacteria; D012097:Repressor Proteins