Molecular Mimicry between Meningococcal B Factor H-Binding Protein and Human Proteins

Abstract

This study calls attention on molecular mimicry and the consequent autoimmune cross reactivity as the molecular mechanism that can cause adverse events following meningococcal B vaccination and warns against active immunizations based on entire antigen.

Keywords

molecular mimicry - Trumenba vaccine - factor H-binding protein - human proteome - adverse events

Introduction

The bacterium Neisseria meningitides (aka meningococcus) can cause a multitude of severe illnesses, collectively termed meningococcal disease.[1] Numerous vaccines are available and, among them, a meningococcal B vaccine (namely, Trumenba) has been approved for children and contains the lipoprotein factor H-binding protein (fHbp).[2] Indeed, as described by Seib et al,[3] preclinical studies demonstrated that fHbp elicits a robust bactericidal antibody response that correlates with the amount of fHbp expressed on the bacterial surface. However, according to the vaccine-prescribing informations,[4] numerous adverse events occur following fHbp vaccine administration. That is, verbatim:

• Immune system disorders.

• Hypersensitivity reactions, including anaphylactic reactions.

• Nervous system disorders.

• Syncope.

Currently, at the best of the author's knowledge, no investigation/hypothesis has been proposed to define the molecular mechanism that triggers the adverse events following the Trumenba vaccine administration. In analyzing the issue, this study posed the question of whether molecular mimicry between the vaccine antigen and the human proteins might play a role as already found in analogous research models.[5] [6]

Materials and Methods

Molecular mimicry between the bacterial fHbp antigen and human proteins was analyzed according to published methodology.[5] [6] In brief, the fHbp antigen, 274 amino acids (aa) as described at https://www.uniprot.org/uniprotkb/Q9JXV4/, was dissected into pentapeptides offset each other by one aa residue (i.e., MNRTA, NRTAF, RTAFC, and so forth) and the resulting bacterial pentapeptides were analyzed for occurrences within the human proteome.

Pentapeptides were used since a peptide grouping composed of 5 aa defines a minimal immune unit that can (1) induce highly specific antibodies and (2) determine antigen–antibody specific interaction.[7] [8] [9] [10] Peptide match and peptide search programs available at www.uniprot.org [11] were used.

Results

Following molecular mimicry analyses, it was found that fHbp pentapeptides repeatedly occur for a total of 2,809 multiple occurrences in human protein alterations which can lead to severe diseases. The bacterial versus human pentapeptide overlap is of such a dimension that obviously it cannot be reported in the context of an article. Consequently, data are reported as [Supplementary Table S1] that is a fundamental part of this report.

Table 1 Peptides shared between fHbp protein and human proteins that—when altered—are associated with myelination, neuropathy, myopathy, ataxia, etc.

Peptides[a]	Human proteins: name and associated diseases[b] [c]
KNEKL	Chondroitin sulfate N-acetylgalactosaminyltransferase 1 Neuropathy[12]
IGAVL	Claudin-11. Oligodendrocyte-specific protein. Autoantigen of autoimmune-demyelinating disease[13]
SPELN	Complex I intermediate-associated protein 30, mitochondrial Deficiency may be associated with leukodystrophy[14]
HAVIS, VDGQL	Contactin-associated protein 1 Alterations associated with hypomyelinating neuropathy[15]
GSDDA	Delta-1-pyrroline-5-carboxylate synthase Spastic paraplegia; progressive weakness, and spasticity of the lower limbs. Bladder incontinence, gait difficulties, neuropathy[16]
AAKQG	DNA polymerase subunit gamma-1 Neuronal loss, spongiform degeneration, demyelination[17]
KLKND, LADAL	DnaJ homolog subfamily C member 3 Neurodegeneration, ataxia, peripheral neuropathy, hearing loss[18]
SAEVE, VQDSE	Dystonin Hypotonia, respiratory, and feeding difficulties[19]
LTALQ	E3 ubiquitin-protein ligase LRSAM1 Disorder of the peripheral nervous system[20]
LKLAA, RIGDI	FYVE, RhoGEF, and PH domain-containing protein 4 Peripheral nerve demyelination[21]
LPEGG	Gelsolin Required for normal myelin wrapping[22]
GSDDA	Guanine nucleotide-binding protein subunit beta-4 Disorder of the peripheral nervous system[23]
TGKLK	Laminin subunit alpha-2 Muscular dystrophy[24]
KSPEL	Lysophosphatidylserine lipase ABHD12 Hearing loss, ataxia, retinitis pigmentosa, early-onset cataract[25]
GKMVA	Myelin P2 protein Neuropathy with progressive weakness and atrophy[26]
PEGGR	Myelin protein P0 Dysmyelinating neuropathy[27]
VSRFD	Neurofibromin Neuropathy with progressive weakness and atrophy[28]
KLPEG	Patatin-like phospholipase domain-containing protein 6 Mental retardation, spastic paraplegia, ataxia, blindness[29]
AEKGS	Potassium voltage-gated channel subfamily D member 3 Spinocerebellar ataxia, incoordination of gait[30]
LADAL	Prelamin-A/C Disorder of the peripheral nervous system[31]
SGEFQ	Probable helicase senataxin Spinocerebellar ataxia, neuropathy, dexterity difficulties[32]
SGGGG	Ribose-5-phosphate isomerize Leukoencephalopathy, psychomotor retardation[33]
NTGKL	RNA polymerase II subunit A C-terminal domain phosphatase Cataracts, facial dysmorphism, neuropathy[34]
DFAAK GGVAA SAEVE	Sacsin Cerebellar ataxia, hypermyelination, mitral valve prolapse[35]
SDDAS TGKLK	Serine/threonine-protein kinase DCLK2 Disorders of neuronal structure[36]
AAKQG KSLQS	Voltage-gated sodium channel subunit alpha Nav1.8 Detrimental to motor axons[37]
TSFDK	Sodium/potassium-transporting ATPase subunit alpha-3 Related to neurological disorders, epilepsy[37]
LQSLT, QGAEK	Solute carrier family 12 member 6 Sensorimotor neuropathy, mental retardation[38]
SSGGGG	Solute carrier family 25 member 46 Peripheral sensorimotor neuropathy[39]
KMVAK	Thioredoxin, mitochondrial Severe cerebellar atrophy, epilepsy, dystonia, optic atrophy[40]
LAAQG	Thymidine phosphorylase Leukoencephalopathy, cachexia, neuropathy, myopathy[41]
DIGAV	Trifunctional enzyme subunit alpha, mitochondrial Hypoglycemia, cardiomyopathy, axonopathy, weakness, hepatic dysfunction, respiratory failure[42]
LAAKQG	Wolframin Diabetes, sensorineural deafness, dementia[43]
SSGGGG	Zinc finger SWIM domain-containing protein 6 Abnormal gait, autistic features[44]
SSGGG	Beta-1,4 N-acetylgalactosaminyltransferase 1 Axonal degeneration[45]

Abbreviation: fHbp, factor H-binding protein.

^a Hexapeptides formed by overlapping pentapeptides have been underlined.

^b Human protein names are given in italic.

^c Further disease details are available in OMIM, PubMed, and UniProt databases.

In parallel, the severe diseases[12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] that could derive from the massive molecular mimicry and consequent cross-reactivity and autoimmunity are numerous. Here, only a short synopsis that gives an overview of such diseases is given in [Table 1], thus confirming the vaccine-induced injuries listed in the Trumenba vaccine-prescribing informations.[4]

Conclusion

The vast sharing of immune peptide determinants between the bacterial fHbp antigen and the human proteins warns against Trumenba utilization to prevent meningococcal diseases. Indeed, the present data speak for themselves and clearly predict a very high incidence of autoimmune pathologies in the vaccinees as a result of molecular mimicry and the consequent potential cross-reactivity, thus factually confirming what had already been stated in the prescribing information of the Trumenba vaccine.[4]

In synthesis, this report adds to numerous previous studies,[5] [6] [7] [8] [9] [10] and further references therein, that explicated how only vaccinal protocols based on peptide sequences uniquely present in the pathogenic antigens can provide therapeutic vaccines free of adverse events.

Conflict of Interest

None declared.

• References

• 1 Hollingshead S, Tang CM. An overview of Neisseria meningitidis . Methods Mol Biol 2019; 1969: 1-16
• 2 Biolchi A, Tomei S, Brunelli B. et al. 4CMenB immunization induces serum bactericidal antibodies against non-serogroup B meningococcal strains in adolescents. Infect Dis Ther 2021; 10 (01) 307-316
• 3 Seib KL, Scarselli M, Comanducci M, Toneatto D, Masignani V. Neisseria meningitidis factor H-binding protein fHbp: a key virulence factor and vaccine antigen. Expert Rev Vaccines 2015; 14 (06) 841-859
• 4 FDA. Accessed October 30, 2023 at: https://www.fda.gov/media/89936/download
• 5 Kanduc D. Molecular mimicry between respiratory syncytial virus F antigen and the human proteome. Glob Med Genet 2023; 10 (01) 19-21
• 6 Kanduc D. Exposure to SARS-CoV-2 and infantile diseases. Glob Med Genet 2023; 10 (02) 72-78
• 7 Kanduc D. Homology, similarity, and identity in peptide epitope immunodefinition. J Pept Sci 2012; 18 (08) 487-494
• 8 Kanduc D. Pentapeptides as minimal functional units in cell biology and immunology. Curr Protein Pept Sci 2013; 14 (02) 111-120
• 9 Kanduc D. Hydrophobicity and the physico-chemical basis of immunotolerance. Pathobiology 2020; 87 (04) 268-276
• 10 Kanduc D. The role of proteomics in defining autoimmunity. Expert Rev Proteomics 2021; 18 (03) 177-184
• 11 UniProt Consortium. UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res 2019; 47 (D1): D506-D515
• 12 Izumikawa T, Saigoh K, Shimizu J, Tsuji S, Kusunoki S, Kitagawa H. A chondroitin synthase-1 (ChSy-1) missense mutation in a patient with neuropathy impairs the elongation of chondroitin sulfate chains initiated by chondroitin N-acetylgalactosaminyltransferase-1. Biochim Biophys Acta 2013; 1830 (10) 4806-4812
• 13 Bronstein JM, Tiwari-Woodruff S, Buznikov AG, Stevens DB. Involvement of OSP/claudin-11 in oligodendrocyte membrane interactions: role in biology and disease. J Neurosci Res 2000; 59 (06) 706-711
• 14 Wu L, Peng J, Ma Y. et al. Leukodystrophy associated with mitochondrial complex I deficiency due to a novel mutation in the NDUFAF1 gene. Mitochondrial DNA A DNA Mapp Seq Anal 2016; 27 (02) 1034-1037
• 15 Vallat JM, Nizon M, Magee A. et al. Contactin-associated protein 1 (CNTNAP1) mutations induce characteristic lesions of the paranodal region. J Neuropathol Exp Neurol 2016; 75 (12) 1155-1159
• 16 Coutelier M, Goizet C, Durr A. et al. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain 2015; 138 (Pt 8): 2191-2205
• 17 Bao X, Wu Y, Wong LJ. et al. Alpers syndrome with prominent white matter changes. Brain Dev 2008; 30 (04) 295-300
• 18 Synofzik M, Haack TB, Kopajtich R. et al. Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration. Am J Hum Genet 2014; 95 (06) 689-697
• 19 Edvardson S, Cinnamon Y, Jalas C. et al. Hereditary sensory autonomic neuropathy caused by a mutation in dystonin. Ann Neurol 2012; 71 (04) 569-572
• 20 Guernsey DL, Jiang H, Bedard K. et al. Mutation in the gene encoding ubiquitin ligase LRSAM1 in patients with Charcot-Marie-Tooth disease. PLoS Genet 2010; 6 (08) e1001081
• 21 Stendel C, Roos A, Deconinck T. et al. Peripheral nerve demyelination caused by a mutant Rho GTPase guanine nucleotide exchange factor, Frabin/FGD4. Am J Hum Genet 2007; 81 (01) 158-164
• 22 Meretoja J. Genetic aspects of familial amyloidosis with corneal lattice dystrophy and cranial neuropathy. Clin Genet 1973; 4 (03) 173-185
• 23 Soong BW, Huang YH, Tsai PC. et al. Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease. Am J Hum Genet 2013; 92 (03) 422-430
• 24 Patton BL. Laminins of the neuromuscular system. Microsc Res Tech 2000; 51 (03) 247-261
• 25 Tingaud-Sequeira A, Raldúa D, Lavie J. et al. Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC. Neurobiol Dis 2017; 98: 36-51
• 26 Ruskamo S, Nieminen T, Kristiansen CK. et al. Molecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P2. Sci Rep 2017; 7 (01) 6510
• 27 Moldovan M, Alvarez S, Pinchenko V. et al. Na(v)1.8 channelopathy in mutant mice deficient for myelin protein zero is detrimental to motor axons. Brain 2011; 134 (Pt 2): 585-601
• 28 Rosenbaum T, Kim HA, Boissy YL, Ling B, Ratner N. Neurofibromin, the neurofibromatosis type 1 Ras-GAP, is required for appropriate P0 expression and myelination. Ann N Y Acad Sci 1999; 883: 203-214
• 29 McFerrin J, Patton BL, Sunderhaus ER, Kretzschmar D. NTE/PNPLA6 is expressed in mature Schwann cells and is required for glial ensheathment of Remak fibers. Glia 2017; 65 (05) 804-816
• 30 Duarri A, Jezierska J, Fokkens M. et al. Mutations in potassium channel kcnd3 cause spinocerebellar ataxia type 19. Ann Neurol 2012; 72 (06) 870-880
• 31 Raffaele Di Barletta M, Ricci E, Galluzzi G. et al. Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy. Am J Hum Genet 2000; 66 (04) 1407-1412
• 32 Chen YZ, Hashemi SH, Anderson SK. et al. Senataxin, the yeast Sen1p orthologue: characterization of a unique protein in which recessive mutations cause ataxia and dominant mutations cause motor neuron disease. Neurobiol Dis 2006; 23 (01) 97-108
• 33 Huck JH, Verhoeven NM, Struys EA, Salomons GS, Jakobs C, van der Knaap MS. Ribose-5-phosphate isomerase deficiency: new inborn error in the pentose phosphate pathway associated with a slowly progressive leukoencephalopathy. Am J Hum Genet 2004; 74 (04) 745-751
• 34 Varon R, Gooding R, Steglich C. et al. Partial deficiency of the C-terminal-domain phosphatase of RNA polymerase II is associated with congenital cataracts facial dysmorphism neuropathy syndrome. Nat Genet 2003; 35 (02) 185-189
• 35 Breckpot J, Takiyama Y, Thienpont B. et al. A novel genomic disorder: a deletion of the SACS gene leading to spastic ataxia of Charlevoix-Saguenay. Eur J Hum Genet 2008; 16 (09) 1050-1054
• 36 Dijkmans TF, van Hooijdonk LW, Fitzsimons CP, Vreugdenhil E. The doublecortin gene family and disorders of neuronal structure. Cent Nerv Syst Agents Med Chem 2010; 10 (01) 32-46
• 37 Boonsimma P, Michael Gasser M, Netbaramee W. et al. Mutational and phenotypic expansion of ATP1A3-related disorders: report of nine cases. Gene 2020; 749: 144709
• 38 Howard HC, Mount DB, Rochefort D. et al. The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat Genet 2002; 32 (03) 384-392
• 39 Abrams AJ, Hufnagel RB, Rebelo A. et al. Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder. Nat Genet 2015; 47 (08) 926-932
• 40 Holzerova E, Danhauser K, Haack TB. et al. Human thioredoxin 2 deficiency impairs mitochondrial redox homeostasis and causes early-onset neurodegeneration. Brain 2016; 139 (Pt 2): 346-354
• 41 Nishino I, Spinazzola A, Hirano M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 1999; 283 (5402): 689-692
• 42 Ibdah JA, Tein I, Dionisi-Vici C. et al. Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation. J Clin Invest 1998; 102 (06) 1193-1199
• 43 Strom TM, Hörtnagel K, Hofmann S. et al. Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein. Hum Mol Genet 1998; 7 (13) 2021-2028
• 44 Palmer EE, Kumar R, Gordon CT. et al; DDD Study. A recurrent de novo nonsense variant in ZSWIM6 results in severe intellectual disability without frontonasal or limb malformations. Am J Hum Genet 2017; 101 (06) 995-1005
• 45 Sheikh KA, Sun J, Liu Y. et al. Mice lacking complex gangliosides develop Wallerian degeneration and myelination defects. Proc Natl Acad Sci U S A 1999; 96 (13) 7532-7537

Publikationsverlauf

Artikel online veröffentlicht:
16. November 2023