Tiffany Kottukkal

Background: Bacterial meningitis is a global health concern due to its significant mortality and is the fourth leading cause of disability^1,2,3. Meningitis is an infectious disease due to the inflammation and infection of the meninges around the spinal cord and brain¹. Meningococcal meningitis is a type of bacterial meningitis caused by the gram-negative bacteria Neisseria meningitidis^1,2,3.  Gram negative bacteria naturally release outer membrane vesicles (OMVs) during an infection⁴. Isolated OMVs cannot cause disease but can elicit an immune response leading to the successful development of an OMV vaccine for meningococcal meningitis that is used globally⁴. Through bioengineering, OMV vaccines can be modified to exhibit increased overall efficacy^1,2.

Objective: In this review, we explored different strategies in bioengineering to modify the OMV vaccine for meningococcal meningitis to increase its efficacy.

Search Methods: The PubMed database was used to conduct an online search from 2018 to 2023 using the following keywords: “meningococcal meningitis”, “outer membrane vesicle (OMV) vaccine”, “OMV vaccine for meningitis”, and “bioengineered OMV vaccine”.

Results: Studies explored how proteins in OMV vaccines can affect efficacy^5,9. An OMV vaccine created using OMVs with a deletion of porin proteins A and B had a greater increase in IgG and was more bactericidal against all strains of meningococcal meningitis^5,9. The alteration of vaccine administration routes can also have indications for long term immunity. The current administration of the OMV vaccine for meningitis is intramuscularly⁶. Vaccines given both intranasally and intramuscularly had IgG that persisted for more time indicating longer term immunity compared to the intramuscular route⁶. The use of different adjuvants given with OMV vaccines was analyzed⁷. Adjuvants given with OMV vaccines produced a stronger immune response overall⁷. Aluminum hydroxide as an adjuvant had the greatest persistence of IgG further supporting its current use in the OMV vaccine for meningitis⁷. Lastly, the alteration of proteins in OMV vaccines through the introduction of mutations and their effects on efficacy were explored. Factor H binding proteins (FHbp) in bacteria were mutated to have a lower binding affinity for the host’s factor H to prevent autoantibody production⁸. The mutant FHbp was used to make an experimental OMV vaccine⁸. The current OMV vaccine for meningitis has a risk of autoantibodies which can disrupt the immune system⁸. The experimental OMV vaccine did not produce autoantibodies and had a higher protective antibody response through an increase in IgG⁸.

Conclusions: Overall, studies have shown that altering OMV protein composition such as deleting porin proteins or overexpressing mutant FHbp can increase the overall efficacy of OMV vaccines for meningococcal meningitis. Intranasal and intramuscular routes of vaccine administration along with the use of adjuvants were found to be conducive to long term immunity due to the persistence of IgG. Modifications of outer membrane vesicle vaccines through bioengineering can increase vaccine efficacy for meningococcal meningitis while also paving the way for future applications in the prevention of other infectious diseases through future vaccine development.

Works Cited:

1. Oordt-Speets AM, Bolijn R, van Hoorn RC, Bhavsar A, Kyaw MH. Global etiology of bacterial meningitis: A systematic review and meta-analysis. PLoS One. 2018;13(6):e0198772. Published 2018 Jun 11. doi:10.1371/journal.pone.0198772
2. Parikh SR, Campbell H, Bettinger JA, et al. The everchanging epidemiology of meningococcal disease worldwide and the potential for prevention through vaccination. J Infect. 2020;81(4):483-498. doi:10.1016/j.jinf.2020.05.079
3. Poplin V, Boulware DR, Bahr NC. Methods for rapid diagnosis of meningitis etiology in adults. Biomark Med. 2020;14(6):459-479. doi:10.2217/bmm-2019-0333
4. Gerritzen MJH, Salverda MLM, Martens DE, Wijffels RH, Stork M. Spontaneously released Neisseria meningitidis outer membrane vesicles as vaccine platform: production and purification. Vaccine. 2019;37(47):6978-6986. doi:10.1016/j.vaccine.2019.01.076
5. Matthias KA, Reveille A, Connolly KL, Jerse AE, Gao YS, Bash MC. Deletion of major porins from meningococcal outer membrane vesicle vaccines enhances reactivity against heterologous serogroup B Neisseria meningitidis strains. Vaccine. 2020;38(10):2396-2405. doi:10.1016/j.vaccine.2020.01.038
6. Izeli Portilho A, Araujo Correa V, Dos Santos Cirqueira C, De Gaspari E. Intranasal and Intramuscular Immunization with Outer Membrane Vesicles from Serogroup C Meningococci Induced Functional Antibodies and Immunologic Memory. Immunol Invest. 2022;51(7):2066-2085. doi:10.1080/08820139.2022.2107931
7. Trzewikoswki de Lima G, Rodrigues TS, Portilho AI, Correa VA, Gaspar EB, De Gaspari E. Immune responses of meningococcal B outer membrane vesicles in middle-aged mice. Pathog Dis. 2020;78(5):ftaa028. doi:10.1093/femspd/ftaa028
8. Beernink PT, Vianzon V, Lewis LA, Moe GR, Granoff DM. 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. mBio. 2019;10(3):e01231-19. Published 2019 Jun 18. doi:10.1128/mBio.01231-19
9. Gilmore WJ, Johnston EL, Zavan L, Bitto NJ, Kaparakis-Liaskos M. Immunomodulatory roles and novel applications of bacterial membrane vesicles. Mol Immunol. 2021;134:72-85. doi:10.1016/j.molimm.2021.02.027