PRECLINICAL STUDIES AND CLINICAL TRIALS IN DETERMINATION OF SAFETY AND EFFICACY OF MENINGOCOCCAL VACCINES: PRESENT SCENARIO
Meningitis, a serious communicable inflammatory disease continues to be a worldwide threat especially in sub-Saharan Africa affecting millions of people with high death rates every year. Strains from six serogroups of the principal causative organism Neisseria meningitidis are found to be responsible for the majority of infections. Incidences of antibiotic resistance and efforts to provide mass protection have necessitated the development of meningococcal vaccines since the latter half of the 20th century. Aiming to ostracize meningitis by 2030, the World Health Organization focuses on vaccination as an important strategy to reach the goal. Due to limited efficacy and stability issues of earlier polysaccharide and protein conjugate vaccines respectively, outer membrane vesicle (OMV) vaccines were developed. Gene manipulations have also led to the development of more efficacious tailor-made OMV vaccines due to over-expression of antigenic outer membrane proteins along with lesser pyrogenicity. Available data from preclinical studies in animal models and clinical trials, on meningococcal vaccine candidates report the strength of immune response measured by serological tests such as enzyme-linked immunosorbent assay and serum bactericidal assay. Post-immunization adverse reactions have been also monitored as a part of safety assessment. The novelty of the present review lies in summarizing the outcomes of the preclinical animal studies and clinical trials conducted on various types of meningococcal vaccines till date and thereby highlighting the paucities in the existing information which can facilitate understanding the present scenario, challenges, and future scope in the field of meningococcal vaccine development.
2. World Health Organization. Control of Epidemic Meningococcal Disease: WHO Practical Guidelines. 2nd ed. Geneva: World Health Organization; 1997. Available from: https://www.who.int/csr/resources/ publications/meningitis/WHO_EMC_BAC_98_3_EN/en.
3. WHO Guideline 2007. Standardized Treatment of Bacterial Meningitis in Africa in Epidemic and Non Epidemic Situations. Available from: https://www.apps.who.int/iris/bitstream/handle/10665/69475/WHO_ CDS_EPR_2007.3_eng.pdf?sequence=1&isAllowed=y.
4. World Health Organization. WHO Report. Antimicrobial and Support Therapy for Bacterial Meningitis in Children. Report of the Meeting of 18-20 June 1997, Geneva, Switzerland: World Health Organization; 1997. Available from: https://www.who.int/csr/resources/publications/ meningitis/whoemcbac982.pdf?ua=1.
5. Antibiotic-resistant N. meningitidis Emerges in US. Available from: https://www.healio.com/news/pediatrics/20200619/antibioticresistant-n-meningitidis-emerges-in-us. [Last accessed on 2020 Jun 19].
6. Bai X, Borrow R, Bukovski S, Caugant DA, Culic D, Delic S, et al. Prevention and control of meningococcal disease: Updates from the global meningococcal initiative in Eastern Europe. J Infect 2019;79:528-41.
7. Annex I of WHO Technical Report Series, No. 927. WHO Guidelines on Nonclinical Evaluation of Vaccines; 2005. Available from: https:// www.who.int/biologicals/publications/trs/areas/vaccines/nonclinical_ evaluation/ANNEX%201Nonclinical.P31-63.pdf?ua=1.
8. Committee for Proprietary Medicinal Products. Human Medicines Evaluation Unit. The European Agency for the Evaluation of Medicinal Products 1997. Note for Guidance on Preclinical Pharmacological and Toxicological Testing of Vaccines. Available from: https://www. ema.europa.eu/en/documents/scientific-guideline/note-guidance-preclinical-pharmacological-toxicological-testing-vaccines_en.pdf.
9. Bakke H, Lie K, Haugen IL, Korsvold GE, Høiby EA, Naess LB, et al. Meningococcal outer membrane vesicle vaccine given intranasally can induce immunological memory and booster responses without evidence of tolerance. Infect Immun 2001;69:5010-15.
10. González S, Caballero E, Soria Y, Cobas K, Granadillo M, Pajón R. Immunization with Neisseria meningitidis outer membrane vesicles prevents bacteremia in neonatal mice. Vaccine 2006;24:1633-43.
11. Holst J, Martin D, Arnold R, Huergo CC, Oster P, Hallahan JO, et al. Properties and clinical performance of vaccines containing outer membrane vesicles from Neisseria meningitidis. Vaccine 2009;27S:B3-12.
12. Sadarangani M, Pollard AJ. Serogroup B meningococcal vaccines-an unfinished story. Lancet Infect Dis 2010;10:112-24.
13. Keiser PB, Biggs-Cicatelli S, Moran EE, Schmiel DH, Pinto VB, Burden RE, et al. A phase 1 study of a meningococcal native outer membrane vesicle vaccine made from a group B strain with deleted lpxL1 and synX, over-expressed factor H binding protein, two PorAs and stabilized OpcA expression. Vaccine 2011;29:1413-20.
14. Centers for Disease Control and Prevention. Meningococcal disease. In: Epidemiology and Prevention of Vaccine-preventable Diseases. 13th ed. Atlanta, GA: Centers for Disease Control and Prevention; 2015. p. 231-45. Available from: https://www.cdc.gov/VACCINEs/pubs/ pinkbook/downloads/mening.pdf.
15. Meningococcal Disease, World Health Organization. Available from: https://www.who.int/ith/vaccines/meningococcal/en.
16. Girard PM, Preziosi MP, Aguado MT, Kieny MP. A review of vaccine research and development: Meningococcal disease. Vaccine 2006;24:4692-700.
17. Goldblatt D, Borrow R, Miller E. Natural and vaccine-induced immunity and immunologic memory to Neisseria meningitidis serogroup C in young adults. J Infect Dis 2002;185:397-400.
18. Test ST, Mitsuyoshi J, Connolly CC, Lucas AH. Increased immunogenicity and induction of class switching by conjugation of complement C3D to pneumococcal serotype 14 capsular polysaccharide. Infect Immun 2001;69:3031-40.
19. Zhang Q, Finn A. Mucosal immunology of vaccines against pathogenic nasopharyngeal bacteria. J Clin Pathol 2004;57:1015-21.
20. Ravenhorst MB, Bijlsma MW, Houten MA, Struben VM, Anderson AS, Eiden J. Meningococcal carriage in Dutch adolescents and young adults; A cross-sectional and longitudinal cohort study. Clin Microbiol Infect 2017;23:573.e1-573.e7.
21. Caugant DA, Maiden MC. Meningococcal carriage and disease-- population biology and evolution. Vaccine 2009;27S:B64-70.
22. Burrage M, Robinson A, Borrow A, Andrews N, Southern J, Findlow J. Effect of vaccination with carrier protein on response to meningococcal C conjugate vaccines and value of different immunoassays as predictors of protection. Infect Immun 2002;70:4946-54.
23. Cai W, Kesavan DK, Wan J, Abdelaziz MH, Su Z, Xu H. Bacterial outer membrane vesicles, a potential vaccine candidate in interactions with host cells based. Diagn Pathol 2018;13:1-12.
24. Sanders H, Feavers IM. Adjuvant properties of meningococcal outer membrane vesicles and the use of adjuvants in Neisseria meningitidis protein vaccines. Expert Rev Vaccines 2011;10:323-34.
25. Kim SH, Kim KS, Lee SR, Kim E, Kim MS, Lee EU, et al. Structural modifications of outer membrane vesicles to refine them as vaccine delivery vehicles. Biochim Biophys Acta 2009;1788:2150-9.
26. Qing G, Gong N, Chen X, Chen J, Zhang H, Wang Y, et al. Natural and engineered bacterial outer membrane vesicles. Biophys Rep 2019;5:184-98.
27. Van der Pol L, Stork M, van der Ley P. Outer membrane vesicles as platform vaccine technology. Biotechnol J 2015;10:1689-706.
28. Zariri A, Beskers J, Waterbeemd BV, Hamstra HJ, Bindels TH, Riet EV, et al. Meningococcal outer membrane vesicle composition-dependent activation of the innate immune response. Infect Immun 2016;84:3024-33.
29. Beresford NJ, Martino A, Feavers IM, Corbel MJ, Bai X, Borrow R, et al. Quality, immunogenicity and stability of meningococcal serogroup ACWY-CRM 197, DT and TT glycoconjugate vaccines. Vaccine 2017;35:3598-606.
30. Mantilla JD, Troconiz IF, Garrirdo MJ. ADME processes in vaccines and PK/PD approaches for vaccine optimization. In: ADME and Translational Pharmacokinetics/Pharmacodynamics of Therapeutic Proteins: Applications in Drug Discovery and Development. 1st ed., Ch. 23. New York: Wiley; 2016. p. 347-68.
31. Hudu SA, Shinkafi SH, Umar S. An overview of recombinant vaccine technology, adjuvants and vaccine delivery methods. Int J Pharm Pharm Sci 2016;8:19-24.
32. Aase A, Naess LM, Sandin RH, Herstad TK, Oftung F, Holst J, et al. Comparison of functional immune responses in humans after intranasal and intramuscular immunisations with outer membrane vesicle vaccines against group B meningococcal disease. Vaccine 2003;21:2042-51.
33. Zollinger WD, Mandrell RE, Altieri P, Berman S, Lowenthal J, Artenstein MS. Safety and immunogenicity of a Neisseria meningitidis Type 2 protein vaccine in animals and humans. J Infect Dis 1978;137:728-39.
34. Simple/Rapid Tests, World Health Organization. Available from: https://www.who.int/diagnostics_laboratory/faq/simple_rapid_tests/en.
35. Necchi F, Saul A, Rondini S. Development of a high-throughput method to evaluate serum bactericidal activity using bacterial ATP measurement as survival readout. PLoS One 2017;12:e0172163.
36. Finney M, Halliwell D, Gorringe AR. Can animal models predict protection provided by meningococcal vaccines? Drug Discov Today Dis Models 2006;3:77-80.
37. Haren SD, Ganapathi L, Bergelson I, Dowling DJ, Banks M, Samuels RC, et al. In vitro cytokine induction by TLR-activating vaccine adjuvants in human blood varies by age and adjuvant. Cytokine 2016;83:99-109.
38. Gorringe AR, Pajon R. Bexero: A multicomponent vaccine for prevention of meningococcal disease. Hum Vaccines Immunother 2012;8:174-83.
39. Boccadifuoco G, Brunelli B, Mori E, Agnusdei M, Gianfaldoni C, Giuliani MM. Meningococcal Antigen Typing System (MATS): A tool to estimate global coverage for 4CMenB, a multicomponent meningococcal B vaccine. Methods Mol Biol 2019;1969:205-15.
40. Patnala K, Zaveri K. Screening of putative therapeutic candidates in superbug (Staphylococcus aureus): A systematic in silico approach. Asian J Pharm Clin Res 2016;9:283-91.
41. Momose H, Mizukami T, Ochiai M, Hamaguchi I, Yamaguchi K. A new method for the evaluation of vaccine safety based on comprehensive gene expression analysis. J Biomed Biotechnol 2010;2010:361841.
42. Christodoulides M, Heckels J. Novel approaches to Neisseria meningitidis vaccine design. Pathog Dis 2017;75:1-16.
43. Annex I: WHO Guidelines on Clinical Evaluation of Vaccines: Regulatory Expectations. Available from: https://www.who.int/ biologicals/publications/clinical_guidelines_ecbs_2001.pdf?ua=1.
44. Marchetti E, Mazarin-Diop V, Chaumont J, Martellet L, Makadi MF, Viviani S, et al. Conducting vaccine clinical trials in sub-Saharan Africa: Operational challenges and lessons learned from the Meningitis Vaccine Project. Vaccine 2012;30:6859-63.
45. Stratton K, Ford A, Rusch E, Clayton EW. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: National Academies Press; 2011.
46. de Moraes JC, Perkins BA, Camargo MC, Hidalgo NT, Barbosa HA, Sacchi CT, et al. Protective efficacy of a serogroup B meningococcal vaccine in Sao Paulo, Brazil. Lancet 1992;340:1074-8.
47. Bjune G, Høiby EA, Grønnesby JK, Arnesen Ø, Holst Fredriksen J, Halstensen A, et al. Effect of outer membrane vesicle vaccine against serogroup B meningococcal disease in Norway. Lancet 1991;338:1093-6.
48. Holst J, Feiring B, Fuglesang JE, Høiby EA, Nøkleby H, Aaberge IS, et al. Serum bactericidal activity correlates with the vaccine efficacy of outer membrane vesicle vaccines against Neisseria meningitidis serogroup B disease. Vaccine 2003;21:734-7.
49. Rosenqvist E, Høiby EA, Wedege E, Bryn K, Kolberg J, Klem A, et al. Human antibody responses to meningococcal outer membrane antigens after three doses of the Norwegian group B meningococcal vaccine. Infect Immun 1995;63:4642-52.
50. Peeters CC, van der Voort EM, Schuller M, Kuipers AJ, van der Ley P, Poolman JT. Phase I clinical trial with a hexavalent PorA containing meningococcal outer membrane vesicle vaccine. Vaccine 1996;14:1009-15.
51. Oster P, O’Hallahan J, Aaberge I, Timan S, Ypma E, Martin D. Immunogenicity and safety of a strain-specific MenB OMV vaccine delivered to under 5-year olds in New Zealand. Vaccine 2007;25:3075-9.
52. Galloway Y, Stehr-Green P, McNicholas A, O’Hallahan J. Use of an observational cohort study to estimate the effectiveness of the New Zealand group B meningococcal vaccine in children aged under 5 years. Int J Epidemiol 2009;38:413-8.
53. Tatley MV, Kunac DL, McNicholas A, Zhou L, Ballantyne S, Ashton J, et al. The intensive vaccines monitoring programme (IVMP): An electronic system to monitor vaccine safety in New Zealand. Vaccine 2008;26:2746-52.
54. Stehr-Green P, Galloway Y, Kieft C, McNicholas A. The risk of bronchiolitis hospitalisation following administration of a group B meningococcal vaccine in New Zealand. N Z Med J 2007;120:1-4.
55. Stehr-Green P, Radke S, Kieft C, Galloway Y, McNicholas A, Reid S. The risk of simple febrile seizures after immunisation with a new group B meningococcal vaccine, New Zealand. Vaccine 2008;26:739-42.
56. Sexton K, McNicholas A, Galloway Y, Radke S, Kieft C, Stehr-Green P, et al. Henoch-Schönlein purpura and meningococcal B vaccination. Arch Dis Child 2009;94:224-6.
57. LaForce FM, Okwo-Bele JM. Eliminating epidemic group A meningococcal meningitis in Africa through a new vaccine. Health Aff (Millwood) 2011;30:1049-57.
58. Djingarey MH, Barry R, Bonkoungou M, Tiendrebeogo S, Sebgo R, Kandolo D, et al. Effectively introducing a new meningococcal A conjugate vaccine in Africa: The Burkina Faso experience. Vaccine 2012;30:B40-5.
59. Hirve S, Bavdekar A, Pandit A, Juvekar S, Patil M, Preziosi MP, et al. Immunogenicity and safety of a new meningococcal A conjugate vaccine in Indian children aged 2-10 years: A phase II/III double-blind randomized controlled trial. Vaccine 2012;30:6456-60.
60. Sow S, Okoko B, Diallo A, Viviani S, Borrow R, Carlone G, et al. Immunogenicity and safety of a meningococcal A conjugate vaccine in Africans. N Engl J Med 2011;364:2293-304.
61. Bjune G, Høiby EA, Grønnesby JK, Arnesen O, Fredriksen JH, Halstensen A, et al. Effect of outer membrane vesicle vaccine against group B meningococcal disease in Norway. Lancet 1991;338:1093-6.
62. Feiring B, Fuglesang J, Oster P, Naess LM, Helland OS, Tilman S, et al. Persisting immune responses indicating long-term protection after booster dose with meningococcal group B outer membrane vesicle vaccine. Clin Vaccine Immunol 2006;13:790-6.
63. Oster P, Lennon D, O’Hallahan J, Mulholland K, Reid S, Martin D. MeNZB: A safe and highly immunogenic tailor-made vaccine against the New Zealand Neisseria meningitidis serogroup B disease epidemic strain. Vaccine 2005;23:2191-6.
64. Miller E. Safety and Immunogenicity of Novartis Meningococcal Serogroup B Vaccine (MenB Vaccine) after Three Doses Administered in Infancy. Graz, Austria: 26th Annual Meeting of the European Society for Paediatric Infectious Diseases; 2008.
65. Snape MD. Immunogenicity and Reactogenicity of a Novel Serogroup B Neisseria meningitidis Vaccine Administered from 6 Months of Age. Rotterdam, Netherlands: 16th International Pathogenic Neisseria Conference; 2008.
66. Uria MJ, Zhang Q, Li Y, Chan A, Exley RM, Gollan B, et al. A generic mechanism in Neisseria meningitidis for enhanced resistance against bactericidal antibodies. J Exp Med 2008;205:1423-34.
67. Haneberg B, Holst J. Can nonliving nasal vaccines be made to work? Expert Rev Vaccines 2002;1:227-32.
68. FDA Guideline 2006. Guidance for Industry: Considerations for Developmental Toxicity Studies for Preventive and Therapeutic Vaccines for Infectious Disease Indications. Available from: https:// www.fda.gov/files/vaccines,%20blood%20&%20biologics/published/ Guidance-for-Industry--Considerations-for-Developmental-Toxicity- Studies-for-Preventive-and-Therapeutic-Vaccines-for-Infectious- Disease-Indications.pdf.
69. Rid A, Saxena A, Baqui AH, Bhan A, Bines J, Bouesseau MC, et al. Placebo use in vaccine trials: Recommendations of a WHO expert panel. Vaccine 2014;32:4708-12.
70. World Health Organization. Expert Consultation on the Use of Placebos in Vaccine Trials. Geneva: World Health Organization; 2013. Available from: https://www.apps.who.int/iris/bitstream/ handle/10665/94056/9789241506250_eng.pdf.
This work is licensed under a Creative Commons Attribution 4.0 International License.
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.