Summary: A newly developed vaccine for meningitis and other bloodstream infections caused by the meningococcal group B bacteria will allow for the immunization of younger children. The new vaccine also addresses several limitations of the current meningitis vaccine.
Researchers have now developed a new vaccine, a native outer membrane vesicle (NOMV) vaccine, for meningitis and bloodstream infections caused by “meningococcal group B” bacteria. This will allow younger people to be vaccinated and will address several limitations of the current vaccinations. The research is published this week in mBio, a journal of the American Society for Microbiology.
“We developed the improved version of the vaccine by making several genetic changes to the strain of bacteria used to produce the vaccine, resulting in a broadly protective vaccine rather than a strain-specific vaccine,” said Peter Beernink, Ph.D., Scientist at the Center for Immunobiology and Vaccine Development, Benioff Children’s Hospital Oakland.
There are currently only two licensed vaccines for prevention of meningitis and bloodstream infections caused by “meningococcal group B” bacteria, which are only licensed for use in people age 10 years and older. Both vaccines contain a bacterial protein known as Factor H binding protein (FHbp), which can bind to a host protein known as Factor H (FH). The licensed vaccines have several limitations, which include lack of effectiveness against some bacterial strains and low immune responses of infant humans.
The researchers immunized infant rhesus monkeys with the NOMV-FHbp vaccine, which induced higher levels of protective serum antibodies than a licensed vaccine against five of six bacterial strains tested. Two macaques immunized with the licensed vaccine, which contains FHbp that binds macaque FH, developed antibodies to the host FH protein whereas none of the animals given the NOMV-FHbp vaccine or a negative control vaccine developed such antibodies.
The monkey antibody responses to the vaccines were measured in the laboratory based on the ability of serum antibodies to kill the bacteria in a test that is widely considered to predict protection in humans. The sample sizes of animals were chosen such that the results are highly statistically significant.
“The experimental NOMV vaccine extends the approach of using outer membrane vesicle vaccines, which previously have been given to millions of persons during meningitis B epidemics in Norway, Cuba and New Zealand,” said Beernink.
Thus, in a relevant infant non-human primate model, the NOMV-FHbp vaccine elicited higher levels of protective antibodies than the licensed vaccine and anti-FH antibodies in fewer animals. “This shows that the vaccine has the potential to be developed into a more broadly protective vaccine for humans, to extend coverage to infants and toddlers, which are the age groups among the highest risk of developing meningococcal disease, and to increase vaccine safety,” said Beernink.
The work was performed by Peter Beernink, Dan Granoff and colleagues at UCSF Benioff Children’s Hospital Oakland (California).
Funding: The work was funded by a research grant from the National Institute of Allergy and Infectious Diseases, National Institutes of Health.
A Meningococcal Outer Membrane Vesicle Vaccine with Overexpressed Mutant FHbp Elicits Higher Protective Antibody Responses in Infant Rhesus Macaques than a Licensed Serogroup B Vaccine
MenB-4C (Bexsero; GlaxoSmithKline Biologicals) is a licensed meningococcal vaccine for capsular B strains. The vaccine contains detergent-extracted outer membrane vesicles (dOMV) and three recombinant proteins, of which one is factor H binding protein (FHbp). In previous studies, overexpression of FHbp in native OMV (NOMV) with genetically attenuated endotoxin (LpxL1) and/or by the use of mutant FHbp antigens with low factor H (FH) binding increased serum bactericidal antibody (SBA) responses. In this study, we immunized 13 infant macaques with 2 doses of NOMV with overexpressed mutant (R41S) FHbp with low binding to macaque FH (NOMV-FHbp). Control macaques received MenB-4C (n = 13) or aluminum hydroxide adjuvant alone (n = 4). NOMV-FHbp elicited a 2-fold higher IgG anti-FHbp geometric mean titer (GMT) than MenB-4C (P = 0.003), and the anti-FHbp repertoire inhibited binding of FH to FHbp, whereas anti-FHbp antibodies to MenB-4C enhanced FH binding. MenB-4C elicited a 10-fold higher GMT against strain NZ98/254, which was used to prepare the dOMV component, whereas NOMV-FHbp elicited an 8-fold higher GMT against strain H44/76, which was the parent of the mutant NOMV-FHbp vaccine strain. Against four strains with PorA mismatched to both of the vaccines and different FHbp sequence variants, NOMV-FHbp elicited 6- to 14-fold higher SBA GMTs than MenB-4C (P ≤ 0.0002). Two of 13 macaques immunized with MenB-4C but 0 of 17 macaques immunized with NOMV-FHbp or adjuvant developed serum anti-FH autoantibodies (P = 0.18). Thus, the mutant NOMV-FHbp approach has the potential to elicit higher and broader SBA responses than a licensed group B vaccine that contains wild-type FHbp that binds FH. The mutant NOMV-FHbp also might pose less of a risk of eliciting anti-FH autoantibodies.
IMPORTANCE There are two licensed meningococcal capsular B vaccines. Both contain recombinant factor H binding protein (FHbp), which can bind to host complement factor H (FH). The limitations of these vaccines include a lack of protection against some meningococcal strains and the potential to elicit autoantibodies to FH. We immunized infant macaques with a native outer membrane vesicle (NOMV) vaccine with genetically attenuated endotoxin and overproduced mutant FHbp with low binding to FH. The NOMV-FHbp vaccine stimulated higher levels of protective serum antibodies than a licensed meningococcal group B vaccine against five of six genetically diverse meningococcal strains tested. Two of 13 macaques immunized with the licensed vaccine, which contains FHbp that binds macaque FH, but 0 of 17 macaques given NOMV-FHbp or the negative control developed serum anti-FH autoantibodies Thus, in a relevant nonhuman primate model, the NOMV-FHbp vaccine elicited greater protective antibodies than the licensed vaccine and may pose less of a risk of anti-FH autoantibody.