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Multiple sclerosis

�“A road less traveled …., with miles to go before I sleep .…”��Mansell Competition Guest Lecture, Medical Society of London, Monday 10th June 2024

Gavin Giovannoni

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Disclosures

In the last two years, Professor Gavin Giovannoni has received compensation for serving as a consultant or speaker or research support from Astoria Biologica, Aurinia Pharmaceuticals, Biogen, BMS-Celgene, GlaxoSmithKline, Janssens/J&J, Japanese Tobacco, Merck KGaA/EMD Serono, Moderna, Novartis, Sandoz, Sanofi, Roche/Genentech, Vir Biotechnology and Viracta.

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The charter of the Medical Society of London was

“..to give the practitioners in the healing art frequent opportunities of meeting together, and conferring with each other concerning difficult or uncommon cases which may have occurred; or communicating any new discoveries in medicine which may have been made at home or abroad.”

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10. Medical Society. Council minutes. London: Medical Society, 22 March 1802

Edward Jenner

(17 May 1749 – 26 January 1823)

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Arthur Schopenhauer’s Dictum

All truth passes through three stages:�

  1. It is ridiculed
  2. It is violently opposed
  3. It is accepted as self-evident

1788-1860

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Causation - Koch’s Postulates

  1. The specific organism should be shown to be present in all cases of animals suffering from a specific disease but should not be found in healthy animals.

​

  1. The specific microorganism should be isolated from the diseased animal and grown in pure culture on artificial laboratory media.

​

  1. This freshly isolated microorganism, when inoculated into a healthy laboratory animal, should cause the same disease seen in the original animal.

​

  1. The microorganism should be reisolated in pure culture from the experimental infection.

1843-1910

“On March 24, 1882, Dr. Robert Koch announced the discovery of Mycobacterium tuberculosis, the bacteria that causes tuberculosis (TB).”

https://www.cdc.gov/tb/worldtbday/history.htm

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Hardcover  /  Plenum Pub Corp �March 1993  /  0306442833

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Sir Bradford-Hill: Criteria for Causation

Bradford-Hill A. The environment and disease: association or causation? Proc Royal Soc Med 1966; 58:295.

Giovannoni et al. Lancet Neurol. 2006 Oct;5(10):887-94.

​

  1. CONSISTENCY AND UNBIASEDNESS OF FINDINGS 
  2. STRENGTH OF ASSOCIATION
  3. TEMPORAL SEQUENCE
  4. BIOLOGICAL GRADIENT (DOSE-RESPONSE RELATIONSHIP)
  5. SPECIFICITY
  6. COHERENCE WITH BIOLOGICAL BACKGROUND AND PREVIOUS KNOWLEDGE
  7. BIOLOGICAL PLAUSIBILITY
  8. REASONING BY ANALOGY
  9. EXPERIMENTAL EVIDENCE�

Theodor Billroth

Robert Koch

Doll & Bradford-Hill

Marshall & Warren

Montagnier & Sinoussi

Zur Hausen

​

​

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González-Scorano & Rima. Trends Microbiol. 1999 Dec;7(12):475-7.

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Sir Bradford-Hill: Criteria for Causation

Bradford-Hill A. The environment and disease: association or causation? Proc Royal Soc Med 1966; 58:295.

Giovannoni et al. Lancet Neurol. 2006 Oct;5(10):887-94.

​

  1. CONSISTENCY AND UNBIASEDNESS OF FINDINGS 
  2. STRENGTH OF ASSOCIATION
  3. TEMPORAL SEQUENCE
  4. BIOLOGICAL GRADIENT (DOSE-RESPONSE RELATIONSHIP)
  5. SPECIFICITY
  6. COHERENCE WITH BIOLOGICAL BACKGROUND AND PREVIOUS KNOWLEDGE
  7. BIOLOGICAL PLAUSIBILITY
  8. REASONING BY ANALOGY
  9. EXPERIMENTAL EVIDENCE�

EBV causes multiple sclerosis

​

​

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Rapid adoption of innovations has the potential to improve MS care

Reproduced and adapted from Rogers EM. Diffusion of innovation. New York: Simon and Schuster, 2003

100

80

60

40

20

0

Proportion of adopters (%)

Innovators

Early adopters

Majority adopters

Late adopters

Laggards

30% tipping point

Time

"Ev" Rogers

(March 6, 1931 – October 21, 2004)

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Odds ratio of MS in subjects seronegative for EBV

Ascherio & Munger. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol. 2007 Apr;61(4):288-99.

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Odds ratio of MS in subjects seronegative for EBV

Pakpoor et al. Mult Scler. 2013 Feb;19(2):162-6.

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Longitudinal analysis reveals high prevalence of EBV associated with MS

Bjornevik et al. Science. 2022 Jan 21;375(6578):296-301.

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The ugly fact

“The great tragedy of science; the slaying of a beautiful hypothesis by an ugly fact.” �

Thomas Henry Huxley

(4 May 1825 – 29 June 1895)

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Viral serologies in children with MS

Banwell et al. Lancet Neurology, Sept. 2007

?

Fadda et al. Ann Neurol. 2024 Apr;95(4):700-705.

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Genetics

Month�of

Birth

Low�Vitamin D

EBV

Infectious�Mono

High�anti-EBNA1

Obesity

Smoking

Female�sex

MS

Giovannoni et al. Mult Scler Relat Disord. 2022 Feb;58:103636.

“EBV is necessary but not sufficient for someone to develop MS”

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Odds ratio of MS in subjects seronegative for EBV

Ascherio & Munger. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol. 2007 Apr;61(4):288-99.

Primary prevention with a vaccine

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Genetics

Month�of

Birth

Low�Vitamin D

EBV

Infectious�Mono

High�anti-EBNA1

Obesity

Smoking

Female�sex

MS

EBV vaccine

Genetics

Month�of

Birth

Low�Vitamin D

EBV

Infectious�Mono

High�anti-EBNA1

Obesity

Smoking

Female�sex

MS

STOP

STOP

STOP

Giovannoni et al. Mult Scler Relat Disord. 2022 Feb;58:103636.

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Sir Bradford-Hill: Criteria for Causation

Bradford-Hill A. The environment and disease: association or causation? Proc Royal Soc Med 1966; 58:295.

Giovannoni et al. Lancet Neurol. 2006 Oct;5(10):887-94.

​

  1. CONSISTENCY AND UNBIASEDNESS OF FINDINGS 
  2. STRENGTH OF ASSOCIATION
  3. TEMPORAL SEQUENCE
  4. BIOLOGICAL GRADIENT (DOSE-RESPONSE RELATIONSHIP)
  5. SPECIFICITY
  6. COHERENCE WITH BIOLOGICAL BACKGROUND AND PREVIOUS KNOWLEDGE
  7. BIOLOGICAL PLAUSIBILITY
  8. REASONING BY ANALOGY
  9. EXPERIMENTAL EVIDENCE�

EBV causes multiple sclerosis

​

​

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2017 - https://www.slideshare.net/gavingiovannoni/ebv-immunisation-and-ms-prevention-workshop-report-web-edition

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  1. Medimmune - monovalent (Gp350)
    1. Resuscitated (non-sterilizing)�
  2. NIH (Jeff Cohen)
    • Monovalent - Gp350
    • Bivalent - gH/gL
    • Trivalent gH/gL/gp42�
  3. Moderna
    • IM - pentavalent (Gp350/gH/gL/gp42/gB)
      1. Gp350, gH/gL/gp42 - B-cells
      2. gH/gL - epithelial cells
      3. gB - all cells
    • Therapeutic �
  4. Citravani Biosciences
  5. City of Hope
  6. GSK
  7. Sanofi
  8. BionTech
  9. Etc ….

​

Escalante et al. Front Immunol. 2022 Apr 14;13:867918.

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At risk

High Risk

RIS

CIS

MS

In utero

childhood

Adolescence / early adulthood

adulthood

High risk

Low risk

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Infectious mononucleosis (1° outcome / indication)

Non-benign

Post-viral fatigue

School / University

Military

Mortality (hepatitis / ruptured spleen)

Economic arguments

​

New case definition required

Misdiagnosed

Delayed diagnosis (need point-of-care)

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>10,000,000

Cases vs. Controls

Unvaccinated

Vaccinated - EBV-ve

Vaccinated - EBV+ve

Annual end-of-winter blood spots

Biobank

Follow-up x 10 years

Annual database checks / online questionnaires

Events*

Confirmation

Inclusion/Exclusion

National Register / EPR

Public engagement

PR / Media

Social Media

*IM, … // MS, SLE, Sjogren’s, PBC, …. // HD, lymphoma, ….

All comers multiple nested case-control study post EBV vaccine licensing

​

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>10,000,000

Cases vs. Controls

Unvaccinated

Vaccinated - EBV-ve

Vaccinated - EBV+ve

Annual end-of-winter blood spots

Biobank

Follow-up x 10 years

Annual database checks / online questionnaires

Events*

Confirmation

Inclusion/Exclusion

National Register / EPR

Public engagement

PR / Media

Social Media

*IM, … // MS, SLE, Sjogren’s, PBC, …. // HD, lymphoma, ….

All comers multiple nested case-control study post EBV vaccine licensing

​

Power calculation (Gary Cutter, unpublished)

​

Assuming an MS incidence ~ 7.5 per 100,000.

​

Aim: To reduced incidence down to 2.5 per 100,000, a ratio of 3 to 1 in the control to active groups.

​

80% power, n ~ 210,000 EBV-ve

90% power, n ~ 300,000 EBV-ve

​

80% seropositivity at age 12-13 ~1 to 1.5 million ➡ International efforts

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Epidemiology of EBV infection and IM in the UK

Kuri et al. BMC Public Health. 2020 Jun 12;20(1):912.

Sterilizing

Vaccine

Non-sterilizing

Vaccine

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>10,000,000

Cases vs. Controls

Unvaccinated

Vaccinated - EBV-ve

Vaccinated - EBV+ve

Annual end-of-winter blood spots

Biobank

Follow-up x 10 years

Annual database checks / online questionnaires

Events*

Confirmation

Inclusion/Exclusion

National Register / EPR

Public engagement

PR / Media

Social Media

*IM, … // MS, SLE, Sjogren’s, PBC, …. // HD, lymphoma, ….

Dysregulated

EBV immunity

All comers multiple nested case-control study post EBV vaccine licensing

​

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A vaccine to prevent herpes zoster and�postherpetic neuralgia in older adults

Oxman et al. N Engl J Med. 2005 Jun 2;352(22):2271-84.

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Sir Bradford-Hill: Criteria for Causation

Bradford-Hill A. The environment and disease: association or causation? Proc Royal Soc Med 1966; 58:295.

Giovannoni et al. Lancet Neurol. 2006 Oct;5(10):887-94.

​

  1. CONSISTENCY AND UNBIASEDNESS OF FINDINGS 
  2. STRENGTH OF ASSOCIATION
  3. TEMPORAL SEQUENCE
  4. BIOLOGICAL GRADIENT (DOSE-RESPONSE RELATIONSHIP)
  5. SPECIFICITY
  6. COHERENCE WITH BIOLOGICAL BACKGROUND AND PREVIOUS KNOWLEDGE
  7. BIOLOGICAL PLAUSIBILITY
  8. REASONING BY ANALOGY
  9. EXPERIMENTAL EVIDENCE�

EBV causes multiple sclerosis

​

​

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EBV as a target to prevent and treat MS

- EBV

Priming of latent autoimmunity

persistent EBV infection

1° EBV infection

direct CNS infection

dual viral infection model

e.g. HERV transactivation

‘Hit-and-run’

hypothesis

Infectious mononucleosis

molecular mimicry

B-cell survival advantage

Multiple Sclerosis

other environmental factors/triggers

‘Driver’

hypothesis

‘Trojan horse’ hypothesis

Giovannoni et al. Mult Scler Relat Disord. 2022 Dec;68:104434.

EBV antiviral - latent & lytic (EBNA-1)

BTKi / anti-CD20 / anti-CD19 / CAR T-cells / etc..

EBV antiviral - latent & lytic (EBNA-1)

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Questions: EBV antiviral trial design

  1. Latent vs. lytic vs. latent & lytic
  2. Peripheral vs. CNS penetration
  3. Monotherapy or post-depletion (e.g. post anti-CD20)
  4. CIS vs. RRMS vs. progressive vs. all-comers
  5. Biomarkers
    1. EBV saliva
    2. EBV peripheral blood
    3. EBV secondary lymphoid organs
    4. EBV CNS
    5. Other (LCLs, EVs, antibodies, T-cell responses, etc.)
  6. MS vs other EBV associated diseases (e.g. IM, EBV associated lymphoproliferative disorders, …)
  7. Novel or existing antivirals
  8. Single agent vs. combination therapy
  9. Immunotherapy vs. small molecule antiviral

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Could antiretroviral drugs be effective in MS? A case report

  1. Labella et al. HIV infection and multiple sclerosis: a case with unexpected "no evidence of disease activity" status. J Int Med Res. 2021 Mar;49(3):300060521999577.�
  2. Torkildsen et al. Tenofovir as a treatment option for multiple sclerosis. Mult Scler Relat Disord. 2020 Nov;46:102569. �
  3. Drosu et al. Could antiretrovirals be treating EBV in MS? A case report. Mult Scler Relat Disord. 2018 May;22:19-21.�
  4. Chalkley & Berger. Multiple sclerosis remission following antiretroviral therapy in an HIV-infected man. J Neurovirol. 2014 Dec;20(6):640-3.

Maruszak et al. Eur J Neurol. 2011 Sep;18(9):e110-1.

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Charcot Project: viral aetiology

HIV and lower risk of MS: beginning to unravel a mystery using a record-linked database study

Nexø et al. Epidemiology 2013; 24:331-2

Treatment of HIV and Risk of Multiple Sclerosis

Gold et al. JNNP August 4, 2014 as 10.1136/jnnp-2014-307932.

Raltegravir → RRMS (INSPIRE STUDY) => negative study

ClinicalTrials.gov ID: NCT01767701

Canada / Sweden / USA (Kaiser & VA)

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Odds ratio of MS in subjects seronegative for EBV

Ascherio & Munger. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol. 2007 Apr;61(4):288-99.

Primary prevention with a vaccine

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Odds ratio of MS in subjects seronegative for EBV

Ascherio & Munger. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol. 2007 Apr;61(4):288-99.

Secondary prevention targeting IM

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10. Medical Society. Council minutes. London: Medical Society, 22 March 1802

Edward Jenner

(17 May 1749 – 26 January 1823)

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Suit opens in Tokyo court over cervical cancer vaccine side effects

Plaintiffs suing the government and drugmakers over health problems allegedly caused by cervical cancer vaccines head to the Tokyo District Court on Monday for the opening of their trial. | KYODO

The Japan Times, Feb 13, 2017

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Cervical Cancer Protection in Japan: Where Are We?

Yagi et al. Vaccines (Basel). 2021 Nov 1;9(11):1263.

  • June of 2013 Japan's Ministry of Health, Labor, and Welfare (MHLW) suspended governmental recommendation for HPV vaccination. ��HPV vaccination rate dropped from 70 % of age-eligible girls to almost zero.

​

  • In 2021 Japan's government ended the HPV vaccine suspension finally ended. ��However, Japan has failed to re-establish any credible level of HPV vaccination.

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Impact of HPV vaccine hesitancy on cervical cancer in Japan: a modelling study

Simms et al. Lancet Public Health. 2020, 5(4):e223-e234

Castanon et al. Lancet Public Health. 2018 Jan;3(1):e34-e43.

Prediction of cervical cancer incidence in England, up to 2040, under four scenarios

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Confirmed cases of measles in England by month, age and region: 2023

https://www.gov.uk/government/publications/measles-epidemiology-2023/confirmed-cases-of-measles-in-england-by-month-age-and-region-2023

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Conclusion: EBV is the cause of MS�“EBV is necessary but not sufficient for someone to develop MS”

​

https://www.poetryfoundation.org/poems

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Acknowledgements

QMUL: Ute Meier

Monica Marta

Sreeram Ramagopalan

Ruth Dobson

Jo Topping

Georgina Burrow

Cosimo Maggiore

Hadi Amir-Maghzi

Chris Hawkes

Klaus Schmierer

David Baker

Jack Cuzick

Nick Wald

David Holden

Louisa James

Adekunle Adeniran

Angray Kang

Benjamin Jacobs

Bryan Ceronie

Oxford: George Ebers

Sreeram Ramagopalan

Adam Handel

Giulio DeSanto

​

​

​

Warwick: Lawrence Young

Epidemiology, Oxford:

Raph Goldacre

Michael Goldacre

David Yeates

Julia Pakpoor

The Albion Centre, Sydney:

Julian Gold

Hubert Maruszak

UCL: Robin Weiss

Rachel Farrell

Jeremy Garson

Judy Breuer

Imperial: Paul Farrell

VU Amsterdam: Jaap Middeldorp

Sandra Amor

Edinburgh: Dorothy Crawford

Karen McCauley

Aarhus: Tove Christiansen

​

​