Epstein-Barr Virus in MS

Potential Therapeutic Interventions

Gavin Giovannoni�

7th MENACTRIMS CONGRESS, Cairo, 11:40-12:00 Session VII: European Charcot Foundation (ECF) Symposium 12-Nov-2022

Disclosures

Over the last 5 years I have received personal compensation for participating in advisory boards in relation to clinical trial design, trial steering committees, and data and safety monitoring committees from: Abbvie, Atara Bio, Biogen, Canbex, Sanofi-Genzyme, Genentech, GSK, MSD, Merck-Serono, Novartis, Roche, Synthon BV and Teva.

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Epstein-Barr Virus in MS�Potential Therapeutic Interventions��7th MENACTRIMS CONGRESS, Cairo, 11:40-12:00 Session VII: European Charcot Foundation (ECF) Symposium 12-Nov-2022

Gavin Giovannoni

#PreventMS

Disclosures

Over the last 5 years I have received personal compensation for participating in advisory boards in relation to clinical trial design, trial steering committees, and data and safety monitoring committees from: Abbvie, Atara Bio, Biogen, Canbex, Sanofi-Genzyme, Genentech, GSK, MSD, Merck-Serono, Novartis, Roche, Synthon BV and Teva.

Background

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

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

How does EBV cause MS?

‘ - EBV

Priming of latent autoimmunity

persistent EBV infection

1° EBV infection

direct CNS infection

dual infection model

e.g. HERV transactivation

Infectious mononucleosis

molecular mimicry

B-cell survival advantage

Multiple Sclerosis

other environmental factors/triggers

At-risk

Asymptomatic MS (RIS)

Prodromal MS

CIS

Multiple Sclerosis

High-risk

EBV Infection

↑Raised neurofilament levels

Disease state - MS pathology

�Inflammation / Demyelination / Neuroaxonal loss / Gliosis�

Intrathecal synthesis of oligoclonal IgG

Dawson’s fingers

Subpial lesions

Slowly expanding lesions

At-risk

Asymptomatic MS (RIS)

Prodromal MS

CIS

Multiple Sclerosis

High-risk

EBV vaccine

MS prevented

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

Vaccines

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

Questions: EBV vaccination prevention trial design

1. Component vaccine vs. early wild-type or attenuated EBV infection
2. Component vaccine
1. GSK / Medimmune gp350
2. New vaccines (NIH, Moderna, GSK, ….)
3. Sterilizing or non-sterilizing immunity
3. General population vs. high-risk group
4. Age-group
• Childhood vs. adolescence vs. early adulthood
5. Vaccine programme
• Separate EBV-vaccine programme vs. piggyback on another vaccine (e.g. HPV programme)
6. Comparator
• Active (e.g. VZV) vs. placebo-controlled
7. Primary outcome
• IM and/or seroconversion
8. Secondary outcome
• Population surveillance (autoimmune / oncology)
9. Logistic & costs
10. Potential negative consequences at a population level

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EBV vaccine strategies

‘ - EBV

Priming of latent autoimmunity

persistent EBV infection

1° EBV infection

direct CNS infection

dual infection model

e.g. HERV transactivation

Infectious mononucleosis

molecular mimicry

B-cell survival advantage

Multiple Sclerosis

other environmental factors/triggers

Sterilizing

Vaccine

Non-sterilizing

Vaccine

MBP

MOG

PLP

MAG

MOBP

CNPase

Anoctamin-2

GDP-L-FS

RASGRP2

GlialCAM

FABP7

PROK2

RTN3

SNAP91

𝛂B-crystallin

Septin-9

Transaldolase

S100𝛽

𝛽-synuclein

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

Primary outcome / Indication

Non-benign

Post-viral fatigue

School / University

Military

Mortality (hepatitis / ruptured spleen)

Economic arguments

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.

At risk

High Risk

RIS

CIS

MS

In utero

childhood

Adolescence / early adulthood

adulthood

Does a risk score provide a good enough estimate of MS risk?

Dobson et al. PLoS One. 2016 Nov 1;11(11):e0164992.

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+ve family history – 1° & 2° relatives

Prevalence: 150/100,000 (1 in 500-1,000)

Incidence: 7.5/100,000 (6-9/100,000)

Sex ratio: females:male: 3:1

Relative risk: x7.5 (1° & 2° relatives)

Prevalence in at risk: 1125/100,000

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Age: 16-36 → ~70% = 788 incident cases/100,000

~39.4 incident case/100,000/yr

~4 incident case/10,000/yr

�Sample size: 90% power,⬇3-fold n ≅ 21,000 per group^#

2-years

≥5-years

Power calculations

(not for EBV vaccination study)

^#Gary Cutter, unpublished

Online webportal Prevent-MS

1st, 2nd and 3rd degree relatives

Consent

Questionnaire (risk profiling)

Population

Controls

Buccal swab & blood spot

Annual bloodspot

EBV-ve

EBV serology

Annual follow-up

MS, etc.

Outcomes

Objectives:

​

1. Feasibility
2. Validation of risk profiling
3. Trial ready cohort
4. Community
5. Education

Yes

Yes

No

No

>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

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

​

PR / Media

Social Media

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

Power calculation (Gary Cutter, unpublished)

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Assuming an MS incidence ~ 7.5 per 100,000.

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

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

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

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

>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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Dysregulated EBV infection in the MS brain

Serafini et al. J Exp Med. 2007 Nov 26;204(12):2899-912. 

https://www.atarabio.com/

https://tevogen.com/

EBV therapeutic vaccines

https://www.modernatx.com/research/product-pipeline

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

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Sanofi, ….

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

Antivirals

EBV antivirals

‘ - EBV

Priming of latent autoimmunity

persistent EBV infection

1° EBV infection

direct CNS infection

dual infection model

e.g. HERV transactivation

Infectious mononucleosis

molecular mimicry

B-cell survival advantage

Multiple Sclerosis

other environmental factors/triggers

Memory B Cells are Major Targets for Effective Immunotherapy in MS

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Baker et al. EBioMedicine. 2017 Feb;16:41-50.

Memory B Cells are Major Targets for Effective Immunotherapy in MS

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Baker et al. EBioMedicine. 2017 Feb;16:41-50.

N Engl J Med 2008;358:676-88.

Please note rituximab is the only licensed anti-EBV drug!

REBOUND ACTIVITY AFTER NATALIZUMAB/FINGOLIMOD WITHDRAWAL

Rigau et al. Neurology 2012;79:2214-6.

Alroughani et al. BMJ Case Rep. 2014 Oct 15;2014. pii: bcr2014206314.

Rituximab vs. Fingolimod after Natalizumab

Alping et al. Ann Neurol. 2016 Jun;79(6):950-8.

Massive intracerebral Epstein-Barr virus reactivation in lethal multiple sclerosis relapse after natalizumab withdrawal.

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Serafini et al. J Neuroimmunol. 2017 Jun 15;307:14-17.

Highly-active RRMS, severe neurologic impairment (EDSS 7)

Treated with natalizumab - EDSS 4.5

Due to severe depression, stopped Nz after 37 infusions.

3½ months later rapid disease worsening

Brain MRI showed >50 T2-lesions, mostly Gd-enhancing

JCV-PCR -ve in CSF

Rapidly worsened, died d17

PM active MS rebound

JCV-PCR -ve in brain

Saha & Robertson. DOI: 10.1158/1078-0432.CCR-10-2578 Published May 2011

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EBV & B-cell biology

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)

ClinicalTrials.gov ID: NCT01767701

Questions: EBV antiviral trial design

1. Latent vs. lytic vs. latent and 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

Does agent X have an impact on lytic EBV infection (Agent-X-EBV Saliva study)?

MS on natalizumab

> 12 months

No antiviral therapies

Consent

Natalizumab + Agent X

12-week open-label add-on treatment phase

Primary outcome: Salivary EBV shedding

Secondary outcomes: Exploratory blood biomarkers of EBV infection

Control phase

Barts-MS, version 1.0, 30-June-2022

Power n = 30 subjects

W0

W8

W12

W16

W24

W4

W20

Natalizumab - no treatment

12-week

Active treatment phase

Weekly saliva samples

4-weekly blood samples

No objections to this study design, except some biological queries about whether or not salivary shedding of EBV is relevant to MS.

Does agent X have an impact on MS (Agent-X-EBV MS study)?

16-week blinded phase

Agent X

Placebo

MS on natalizumab

> 12 months�All-comers

Informed consent

Randomised

Restart natalizumab in combination with Agent X

32-week open-label phase

Primary outcome: Safety

Secondary outcomes: MRI - Gd-enhancing and new T2 lesions W8, 12 and 16

Plasma neurofilament levels (AUC - W4-W16)

Blinded phase

Unblinded open-label phase

Barts-MS, version 1.0, 30-June-2022

Power exploratory n = 30 / arm

W0

W8

W12

W16

W24

W48

W4

W36

Lumbar puncture & CSF

Rescue arm

restart natalizumab

Conclusions

Recommendations

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1. Setup registries
1. High-risk (1°, 2° and 3° relatives)
2. Pregnancy
2. Policy initiatives
3. Set-up an international consortium
4. Not only focus on vaccines
• Antivirals (lytic and/or latent infection)
• Treating IM

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

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Oxford:

George Ebers

Sreeram Ramagopalan

Adam Handel

Giulio DeSanto

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Epidemiology, Oxford:

Raph Goldacre

Michael Goldacre

David Yeates�

The Albion Centre, Sydney:

Julian Gold

Hubert Maruszak�

UCL:

Robin Weiss

Rachel Farrell

Jeremy Garson

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VU Amsterdam:

Jaap Middeldorp

Sandra Amor

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Edinburgh:

Dorothy Crawford

Karen McCauley

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Aarhus University:

Tove Christiansen

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www.ms-res.org / www.clinicspeak.com / www.msbrainhealth.org / @GavinGiovannoni / www.slideshare.net/gavingiovannoni / www.medium.com/@gavin_24211

Thank You!

#PreventMS

Questions