Improving the immunogenicity of a trivalent Neisseria meningitidis native outer membrane vesicle vaccine by genetic modification.
Trivalent native outer membrane vesicles (nOMVs) derived from three genetically modified Neisseria meningitidis serogroup B strains have been previously evaluated immunologically in mice and rabbits. This nOMV vaccine elicited serum bactericidal activity (SBA) against multiple N. meningitidis serogroup B strains as well as strains from serogroups C, Y, W, and X. In this study, we used trivalent nOMVs isolated from the same vaccine strains and evaluated their immunogenicity in an infant Rhesus macaque (IRM) model whose immune responses to the vaccine are likely to be more predictive of the responses in human infants. IRMs were immunized with trivalent nOMV vaccines and sera were evaluated for exogenous human serum complement-dependent SBA (hSBA). Antibody responses to selected hSBA generating antigens contained within the trivalent nOMVs were also measured and we found that antibody titers against factor H binding protein variant 2 (fHbpv2) were very low in the sera from animals immunized with these original nOMV vaccines. To increase the fHbp content in the nOMVs, the vaccine strains were further genetically altered by addition of another fHbp gene copy into the porB locus. Trivalent nOMVs from the three new vaccine strains had higher fHbp antigen levels and generated higher anti-fHbp antibody responses in immunized mice and IRMs. As expected, fHbp insertion into the porB locus resulted in no PorB expression. Interestingly, higher expression of PorA, an hSBA generating antigen, was observed for all three modified vaccine strains. Compared to the trivalent nOMVs from the original strains, higher PorA levels in the improved nOMVs resulted in higher anti-PorA antibody responses in mice and IRMs. In addition, hSBA titers against other strains with PorA as the only hSBA antigen in common with the vaccine strains also increased.
Infectious Diseases and Vaccines Discovery (West Point, PA), MRL, Merck & Co., Inc., Kenilworth, NJ, United States. Electronic address: lan_zhang2@merck.com.
Lan
L
Zhang
Infectious Diseases and Vaccines Discovery (West Point, PA), MRL, Merck & Co., Inc., Kenilworth, NJ, United States.
Zhiyun
Z
Wen
Infectious Diseases and Vaccines Discovery (West Point, PA), MRL, Merck & Co., Inc., Kenilworth, NJ, United States.
Jing
J
Lin
Infectious Diseases and Vaccines Discovery (West Point, PA), MRL, Merck & Co., Inc., Kenilworth, NJ, United States.
Hui
H
Xu
Infectious Diseases and Vaccines Discovery (West Point, PA), MRL, Merck & Co., Inc., Kenilworth, NJ, United States.
Paul
P
Herbert
Infectious Diseases and Vaccines Discovery (West Point, PA), MRL, Merck & Co., Inc., Kenilworth, NJ, United States.
Xin-Min
XM
Wang
Vaccine Bioprocess Research and Development (West Point, PA), MRL, Merck & Co., Inc., Kenilworth, NJ, United States.
John T
JT
Mehl
Vaccine Bioprocess Research and Development (West Point, PA), MRL, Merck & Co., Inc., Kenilworth, NJ, United States.
Patrick L
PL
Ahl
Vaccine Bioprocess Research and Development (West Point, PA), MRL, Merck & Co., Inc., Kenilworth, NJ, United States.
Lance
L
Dieter
Vaccine Bioprocess Research and Development (West Point, PA), MRL, Merck & Co., Inc., Kenilworth, NJ, United States.
Ryann
R
Russell
Vaccine Bioprocess Research and Development (West Point, PA), MRL, Merck & Co., Inc., Kenilworth, NJ, United States.
Mike J
MJ
Kosinski
Infectious Diseases and Vaccines Discovery (West Point, PA), MRL, Merck & Co., Inc., Kenilworth, NJ, United States.
Craig T
CT
Przysiecki
D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D000917:Antibody Formation; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D005818:Genetic Engineering; D000071497:Immunogenicity, Vaccine; D008253:Macaca mulatta; D022401:Meningococcal Vaccines / Q000235:genetics / Q000276:immunology*; D009345:Neisseria meningitidis; D038541:Neisseria meningitidis, Serogroup B; D018272:Porins / Q000235:genetics; D022161:Transport Vesicles / Q000276:immunology*
D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D022401:Meningococcal Vaccines; D018272:Porins; C484699:factor H-binding protein, Neisseria meningitidis; C057699:porin protein, Neisseria
Genetic modification; Neisseria meningitidis; Outer membrane vesicle; Vaccine