Molecular Mimicry and Vaccine-Induced Immunological Damage Research Initiative (V.I.I.D.)

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1 Molecular Mimicry and Vaccine-Induced Immunological Damage Research Initiative (V.I.I.D.) Dr. James Lyons-Weiler, PhD CEO & President Rick Robertson, MD (IPAK Scientist) Institute for Pure and Applied Knowledge Pittsburgh, PA Jan 22, 2016

2 What is Molecular Mimicry? Similarity between pathogen (e.g., virus) and host (e.g., human) protein sequences Originally thought of as targeting immune system proteins only Now is seen as potentially targeting proteins of many types in many tissues Basis of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS), and Sydenham chorea (with psychiatric symptoms) Problem for pathogen-derived vaccines: Vaccine Induced Immunological Damage (V.I.I.D.) : If it s observed w/the pathogen, it s possible w/the virus (especially live or attenuated)

3 Known Example #1: Measles Virus MEASLES P3.EISDNLGQEGRASTSGTP. HUM. MYLEIN BASIC PROTEIN.EISFKLGQEGRDSRSGTP. E: 3e-10 IDENT: 78% LIKELY EFFECT IN HOST: DEMYELINATION, SEDENTARY HOST --> Transmission ALSO GERMLINE V GENE: <---FR1-IMGT---> Query_1 2 ISDNLGQEGRASTSGT 17 V 37.5% (6/16) IGLV2-11*02 10 V.GSP..SVTI.CT.. 25 V 37.5% (6/16) IGLV2-18*04 10 V.GSP..SVTI.CT.. 25 V 37.5% (6/16) IGLV2-18*03 10 V.GSP..SVTI.CT.. 25 LIKELY EFFECT IN HOST: WEAKENED IMMUNE SYSTEM AUTOIMMUNITY Image source: US CDC

4 Example #2 Herpes Simplex (disciformkeratitis) Image courtesy of Professor H.J. Meyer via the Online Journal of Ophthalmology (

5 Dendritic (epithelial) keratitis Image courtesy of Professor H.J. Meyer via the Online Journal of Ophthalmology (

6 New IPAK Data on Hypothesis, 2016 Herpes simplex virus UL6 protein vs. Ankyrin isoform 2 protein(cornea) PPPSPVG-ADFRPGASPRGRSRSR---SPGRTAQGAP PPVSPSGKTDKRPPVSPSGRTEKHPPVSPGRTEKRLP

7 Papillomavirus E2 Insulin receptor LIKELY EFFECT: TYPE 1 DIABETES SLHLESLKDS VYGLESLKDL Adenovirus 12 E1B A-gliadin 1e-05 IDENT:86% LIKELY EFFECT: CELIAC DISEASE LRRGMFRPSQCN LGQGSFRPSQQN MEASLES P3 LECIRALK CORTICOTROPIN LECIRALK E:2E-09 IDENT: 100% LIKELY EFFECT: Addison's disease (Adrenal Insufficiency) There are many other examples COXSACKIE B3 HIV POL MYOSIN BRAIN PROTEIN

8 Who Can Use this Information? Pharma to screen their vaccines, make them more safe. Policy makers to understand where increasing numbers of adverse events are coming from and in rendering science-based updated policies Individual patients/parents to rule in/ rule out specific vaccines as causalfor V.I.I.D., or better yet to avoid specific vaccines to which they are likely to react (given their genetic profile).

9 2015/2016 Zika/Guillain-Barrélink or something else?

10 Symptoms of GBS Guillain-Barre syndromeoften begins withtinglingandweaknessin the feet and legs and spreading the upper body and arms. (~10 percent of people, symptoms begin in the arms or face). AsGuillain-Barre syndrome progresses,muscle weaknesscan evolve into paralysis.

11 From the study The electromyogram confirmed a diffuse demyelinating disorder In endemic areas, clinician should be aware of the risk of diffuse demyelinating disorder in case of ZIKA infection.

12 Acute Post-Vaccination CNS Demyelination Syndrome Two case studies in 2015 this one w/in 24 hr

13 From the Study Progressive, focal, neurologic deficits within 24 h after receiving the influenza vaccine; Acute central nervous system (CNS) demyelinating episode secondary to the influenza vaccine

14 NAS 1994: Acute demyelinating disease of the central and peripheral nervous systems can follow vital and some bacterial infections and can complicate the administration of inactivated antiviral vaccines. The acute monophasic central nervous system disease is variably known as postvaccinal encephalomyelitis, postinfectious encephalomyelitis, or acute disseminated encephalomyelitis (ADEM). The peripheral nervous system complication is known as postinfectiousneuritis, acute inflammatory demyelinating polyneuritis, or the Guillain-Barrésyndrome(GBS), and is characterized by the rapid onset of flaccid motor weakness with depression of tendon reflexes and inflammatory demyelination of peripheral nerves ADEM also has been seen after natural infections with measles, varicella, mumps, rubella, and other viruses

15 Possible Explanation of Zika-Induced Microencephalopathy

16 Dr. R.A. Perez-Ricketson In consideration of the Zikavirus and the high incidence of microcephaly, an extensive search of the literature regarding the Rubella virus (RV) capsid protein identified on particular study by Megyeriathat demonstrated the RV capsid protein induced apoptosis (cell death) and implicated a p53- dependent apoptotic pathway in the cytopathogenicityof RV, thereby suggesting a mechanism by which RV exerts its teratogenic effects. A MSA of the human cytomegalovirus UL133 protein, the Rubella capsid protein (accession number AA ) along with the structural protein of Zikavirus, Spondwenivirus and the Japanese encephalomyelitis virus was performed using the CLUSTAL Omega algorithm and visualized with Jalview. The region from demonstrated 47% homology between Zikavirus and Rubella virus. Further research into the p53 pathway and the Zikavirus structural protein will be necessary towards identifying a possible teratogenic effect by this domain in the Zikapolyprotein and other flaviviruses.

17 From the Rubella virus study "These data implicate a p53-dependent apoptotic pathway in the cytopathogenicityof RV, thereby suggesting a mechanism by which RV exerts its teratogenic effects Like Rubella, Zika is a Flavirus

18 Three Hypotheses: 1. V.I.I.D. Vaccinations in these regions have mimicry to myelin, causing post-vaccination demyelination syndrome vs. 2. Zika-associated paralysis (pot. Molecular mimicry) 3. Other, unknown cause

19 Putative Molecular Mimicry Hits 1 Zikavs. Homo sapiens Bitter taste receptor Query 7 KRMAVS-GDDCVVK---PIDDR-FAHALRFL 32 KR A S DCV K I R F H L FL Sbjct 6 KRQALSNSSDCV-KKCKSI-SRLFLHGLLFL 34

20 Putative Molecular Mimicry Hits 2 Zikavs. Homo sapiens E-protein vs Immunoglobulin (heavy chain) Query 100 GWGNGCGLFGKGSLV 114 G+ +GCG +G+G+LV Sbjct 1 GYSSGCGYWGQGTLV 15

21 Molecular Mimicry Caused by H. influenza attenuation? B-cell Epitope in an Attenuated and Wild Type Hemagglutinin Protein A. Attenuated HA protein (H3N2) B. Wild type (wt) viral HA protein (H3N2) Deleted sequence is labeled (blue arrow). Robertson & Lyons-Weiler, in prep.

22 Consequences of Attenuation Multiple studies have described adverse autoimmune reactions following immunizations not seen in the disease from wild type (wt) infections Process of attenuation (genetic manipulation of the virus to reduce infectivity) results in a significant change in a linear or conformational epitope resulting in a new autoimmune phenomena not previously recognized. In simpler terms, in changing the virus to attenuate for a vaccine, additional changes occur that may make people sick from taking the vaccine. (Hypothesis)

23 Numerous B-Cell Epitopes Position Epitope Score Comment 166 LIKKNNAYPTIKRSYNNTNQ 1 Not in WT 93 SYIVEKDNPVNGLCYPGDFN 1 Not in WT 258 ESNGNFIAPEYAYKIVKKGD PKYVKSDRLVLATGLRNVGA 1 Not in WT 208 QNPTTYVSVGTSTLNQRSVP RNGTYDYPQYSEEARLNREE QIIPRSSWSNHDASSGVSSA PKVNGQSGRMEFFWTILKPN HSNEQGSGYAADKESTQKAI EYGNCNTKCQTPMGAINSSM LYDKVRLQLRDNAKELGNGC 0.962

24 One Similar to MyleinProtein SYIVEKDNPVNGLCYPGDFN epitope (H3N2) myelin protein zero-like protein MPZL1b Query 2 YIVEKDN-PV 10 Y+VEK+N PV Sbjct 29 YVVEKENLPV 38 myelin protein zero-like protein MPZL1b [Homo sapiens] GenBank: AAD

25 Myelin basic protein and Hepatitis Hepatitis B virus GRDSRSGSPMAR GRTSRSGSIRAR Hepatitis C virus GVDAQGTLS GVDAQGPLS

26 IPAK V.I.I.D. Work Flow Pathogen/Host Protein Sequences In silico hypothesis development In vivo (mouse) V.I.I.D. risk assay In Homo antibody/reactivity scan

27 A Planned Vaccine w/molecular Mimicry to Myelin Basic Protein: We Can Prevent Human Pain & Suffering Human metapneumorvirus glycoprotein Query 7 SKRTADPKNAWQDAHPADPGSRPH 30 SK A +N+ Q ADP S+PH Sbjct 173 SKNGATTQNSDQTTQAADPSSKPH 196

28 H1N1 Virus Attenuation Peptide and Glutathione S-transferase TLVEPGDKITFEAT GDKITF GDKITF Likely effect: Autism

29 You Can Help IPAK s V.I.I.D Initiative! Funding: Crowdsource Model IPAK is a 501(c)(3) pure public charity research institute dedicated to the reduction of human pain & suffering through knowledge. No federal funding involved to date Donate online: IPAK: Reducing Human Pain & Suffering Through Knowledge