My presentation delivered at the MS Symposium of the Jewish Hospital Berlin (https://www.juedisches-krankenhaus.de/home.html) held on 29 Nar 2023 at the Centrum Judaicum, Oranienburger Strasse, Berlin

1. Pathophysiologisch orientierte Immuntherapie
in Zeiten der Pandemie
29 Mar 2023
Klaus Schmierer, MBBS PhD FRCP
Professor of Neurology
@KlausSchmierer

2. Disclosures
Member of Merck’s MAGNIFY-MS steering committee, the Multiple Sclerosis Global Adviser
Network and the MS Masters Advisory Group
Chief investigator of ChariotMS, a multicentre trial supported by NIHR-EME, the MS Society of
Great Britain and Northern Ireland, the National MS Society (USA), Barts Charity and Merck
Chief investigator of AttackMS, a multicentre trial supported by Biogen
Chief investigator (joint with icometrix, Belgium) of AssistMS, a multicentre trial supported by
NIHR-AAC
Research and NHS service support from Merck, Novartis and Roche
Speaking honoraria from, and/or served in an advisory role for, Biogen, EMD Serono, Merck,
Novartis, Roche, Sanofi Genzyme and Teva
Remuneration for teaching activities from AcadeMe, Medscape, Neurodiem and Neurology
Academy

3. • Wie aktuell sind die aktuellen MS Phänotypen?
• Annäherung an die effektive MS-Kontrolle
• Einsichten und Folgen von COVID-19
Überblick

4. Was ist der Phänotyp?

5. •Afro-Caribbean heritage
•Diagnosed with MS in 2009
•Examination at baseline: brain stem signs
(bilateral INO), hemiparesis on right, walking
range 100-200m. EDSS= 5.5.
•Enrolled in a DMT trial
Lorna, 38

6. May 2011 Dec 2014
EQ-5D
May 2011 Dec 2014
EDSS
May 2011 Dec 2014
9-HPT
Dec 2014
Lorna, 38
Alvarez-Gonzalez C, et al. Ann Clin Trans Neurol 2017 DOI: 10.1002/acn3.410

7. Lorna, 38

8. •Afro-Caribbean heritage
•Diagnosed with primary progressive MS in 2009
•Enrolled in trial of fingolimod (INFORMS) in 2011
•Examination at baseline: brain stem signs
(bilateral INO), hemiparesis on right, walking
range 100-200m. EDSS= 5.5.
Lorna, 38

9. EDSS= 8 EDSS= 7
Lorna, 38
Alvarez-Gonzalez C, et al. Ann Clin Trans Neurol 2017 DOI: 10.1002/acn3.410

10. •There were plenty of active lesions*
•She responded to DMT 1 licensed for relapsing MS
•She had a severe relapse after stopping it
•She responded to DMT 2 licensed for active SPMS
Why is this PPMS when…
?
*”…multiple sclerosis lesions in PPMS are scarce, develop more slowly over time, and lesion load
is lower in comparison to RRMS or SPMS (Thompson et al., 1990b).1”
*Correale J, et al. Brain 2017;140:527–46

11. Wann beginnt die progressive phase bei der MS?

12. Brain atrophy: from day 1
n= 963 pwMS
De Stefano N et al. Neurology 2010;74:1868–76.
RIS
Amato et al. Neurology 2012;78:309-14.

13. - 39%
MS No MS
Carassiti D et al. Neuropathol Appl
Neurobiol 2018;44:377-90.
Brain atrophy ~ neuronal loss

14. 57%
7%
‐20%
0%
20%
40%
60%
Cognition
CIS Patients
n = 40
Healthy Controls
n = 30
p < 0.0001
Deficits in memory, speed
of information processing,
attention and executive
functioning
Patients failing
≥ 2 cognitive
tests
Feuillet L et al. Mult Scler 2007;13:124–7

15. Progression independent of relapse activity (PIRA) is evident in RMS
NB: Patients were rebaselined according to a roving EDSS reference system vs a fixed study baseline;
*Defined as a relapse that was recorded from ≤30 days prior to the reference EDSS assessment to ≤30 days post
EDSS, Expanded Disability Status Scale; RRMS, relapsing-remitting MS; progression assessment. Adapted from Kappos L, et al. Mult Scler 2018;24:963–973.
Cumulative
probability
(%)
100
90
80
70
60
50
40
30
20
10
0
0 24 48 72 96 120 144 168 192 216 240 264 288
Weeks from the first natalizumab infusion
Confirmed EDSS progression unrelated to concurrent relapse*
Overall confirmed EDSS worsening
37.1
%
24.5
%
~2/3
Analysis of 5,562 patients with RRMS in the Tysabri Observational Programme (TOP)
PIRA represented 66%
of overall confirmed
disability worsening

16. Incomplete remission ~ stepwise progression
Relapse Remission Relapse Remission Relapse
Remission
Relapse
Relapse Remission
Remission?
Etc.
No symptoms

17. https://www.google.com/search?q=progression&rlz=1C1GGRV_enGB752GB752&oq=progression&aqs=chro
me..69i57j0i433l2j0l2j46i199i291j69i60j69i61.2982j0j7&sourceid=chrome&ie=UTF-8

18. • Wie aktuell sind die aktuellen MS Phänotypen?
• Annäherung an die effektive MS-Kontrolle
• Einsichten und Folgen von COVID-19
Überblick

19. Einsichten & Konsequenzen der Pathologie

20. Axonal damage & degeneration
Trapp, et al. NEJM 1998

21. Axonal loss in the spinal cord
D Carassiti
F Scaravilli
N Petrova
- 60%
Petrova, et al. Brain Pathol 2018;28:334-48.

22. Inflammatory demyelination denudes and destroys axons
(here: lateral cortico-spinal tract)
Above lesion
Lesion
Below lesion
- 42%
- 48%
Petrova, et al. Brain Pathol 2018;28:334-48.
Myelin (MBP) Axons (SMI31; phosphorylated neurofilaments)

24. Spinal cord network pathology in MS
Petrova N, et al. Ann Neurol 2020;88:619-25.

25. Petrova N, et al. Ann Neurol 2020;88:619-25. - 96%
Control MS
Control MS non demy MS demy
Not only myelin & axons: Destruction of synapses

26. Brain Pathol 2020;30:779-93
B-cell infiltration Demyelination, axonal loss

27. B cells
CD8+ T cell
CD4+ T cells
Active Demyelination
Perivascular
Lesion
Machado-Santos, et al. Brain 2018;141:2066-82.
(CD20) B cells in Active Lesion
(CD20) B cells in Active Lesion
Courtesy of Sandra Amor©. Amsterdam
Courtesy of Sandra Amor©. Amsterdam
(CD20) B cells in Active Lesion
Courtesy of Sandra Amor©. Amsterdam
An ineffectively regulated immune-response leads to
tissue damage in the MS CNS

28. Miller DH, et al N Engl J Med 2003;348:15-23.
Blocking the adaptive immune-response from the CNS inhibits MS

29. Landscape of MS therapies1,2
Product labelling (including indications, safety information and monitoring requirements) may vary by country; for more detailed information on recommendations and
contraindications for each DMT, refer to your local prescribing information
ORAL
THERAPIES
Alemtuzumab (Lemtrada)
Teriflunomide
(Aubagio)
DMF (Tecfidera)
Interferon beta
(Avonex, Betaferon,
Rebif)
Glatiramer acetate
(Copaxone)
Ocrelizumab (Ocrevus)
IV,
IM,
AND
SC
THERAPIES
Mitoxantrone
(Novantrone)
Natalizumab (Tysabri)
Approved
Fingolimod (Gilenya)
Cladribine
(Mavenclad)
Siponimod#
RRMS / RMS Active SPMS PPMS
Pipeline
Interferon beta
Ocrelizumab
(Ocrevus)
Ublituximab
Ponesimod
Ozanimod (Zeposia)
(SMC only)
Ofatumumab (Kesimpta)
1. Rae−Grant A et al. Neurology. 2018;90(17):777−788; 2. Montalban X et al. Mult Scler. 2018;24(2):96−120.

30. MS pathogenesis
Impact of positive,
and well-conducted
negative clinical
trials
Genetics &
Biology
Response to
Therapy
Pathology
Biology
(Models)
Immune Cells in Lesions
White & Grey Matter Damage
Neuronal/Axonal Loss
Demyelination
Immune
Susceptibility
Genes
Experimental Autoimmune
Encephalomyelitis
CD4 Th1/Th17
Disease
B Cell Driven
Response to
Therapy
Adapted from:
Baker D et al. Ebiomedicine 2017; 16:41.
Baker D et al. Brain 2018; 141:2834

31. 3
1
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
0.5
0.4
0.3
0.2
0.1
0.0
T
cells
(x10
9
/L)
B
cells
(x10
9
/L)
Pre Post
(Day 2)
3 6 9 12 15 18
Months after alemtuzumab (20 mg x 5)
B cells CD8+ T cells CD4+ T cells
AUC, area under the curve; EDSS, Expanded Disability Status Scale; GBM, glomerular basement membrane; ITP, immune thrombocytopenic purpura;
SRD, sustained reduction in disability.
Refer to alemtuzumab EU Summary of Product Characteristics for further information.
Coles AJ, et al. Lancet 1999;354:1691–5. Tuohy O, et al. J Neurol Neurosurg Psychiatry 2015;86:208–15. Alemtuzumab EU
Summary of Product Characteristics.
• Up to 50% autoimmune diseases
• 36% autoimmune thyroid disorders3
• 1% serious events of ITP3
• 0.3% nephropathies (including anti-GBM disease)3
Haematological changes after alemtuzumab1
12-month sustained
reduction in disability2
Months since first treatment
%
SRD
of
at-risk
population
60
0 12 24 36 48 60 72 84 96 108 120
50
40
30
20
10
0
EDSS-years
30
20
10
0
-10
-30
-50
-20
-40
Net better
n=43 (50%)
Net unchanged
n=9 (10%)
Net worse
n=35 (40%)
AUC values: EDSS change from
baseline vs follow-up2
“Non selective immune reconstitution therapy is highly
effective!”

32. NEDA
p<0.0001
Hauser S, et al. N Engl J Med 2017;376:221-34.
B cell depletion appears very effective too

33. Baker D, et al. JAMA Neurol 2017.
CD52 depletion – B cell boost & autoimmunity

34. aImmature (transitional CD10+, CD19+, CD27−) B cells, mature (naive CD19+, CD38+) B cells and memory (CD19+, CD27+) B cells
bData are from multiple sources as indicated in labels; CD, cluster of differentiation
1. Wiendl H et al. Neurology N2, in press; 2. Baker D et al. Mult Scler Relat Disord 2019;30:176–86; 3. Baker D et al. Clin Exp Immunol 2020;202:149–61
Cladribine – B cell depletion, no autoimmunity

35. Response to therapy – understanding treatment
Memory
B cell
Mature
(Naïve)
B Cell
Immature
(Transitional)
B Cell
Plasmablasts
Germinal
Centre B
Clonal
Expansion
Spleen & Lymph
Nodes
Bone Marrow
Plasma
Cells
Pre
B cell
Antibodies
Mature
(Naïve)
B Cell
Stem cell
B cell subsets are
Formed In
Bone Marrow
B cell subsets are formed
in Secondary
Lymphoid Tissue
Repopulate the
Blood Rapidly
following Depletion
Repopulate the
Blood Slowly
following Depletion
CD19+ B Cells
Th1 Naive
CD4 Th2 Central Memory
CB8 Th17 Effector Memory
Tr1 Effector
Regulatory
Cytotoxic
Suppressor
Adapted from Baker D et al. Brain 2018; 141:28341

36. Memory B cells: response to therapy
Treatment B Memory Cell
in Blood
Availability to Enter
the CNS
Relapse Rate Reference
Glatiramer acetate
Beta Interferon
Teriflunomide
Dimethyl fumarate
Fingolimod
Mitoxantrone
Natalizumab
Alemtuzumab
Daclizumab*
Rituximab
Atacicept
Cladribine
HSCT
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Increased
Reduced
Reduced*
Reduced
Increased
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced*
Reduced
Increased
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced*
Reduced
Increased
Reduced
Reduced
Ireland SJ et al. JAMA Neurol 2014;71:1421
Rizzo F et al. J. Immunol Cell Biol 2016; 94:886
Gandoglia I et al. Neurol Neuroimmunol and Neuroinflamm 2017; 4:e403
Lundy SK et al. Neurol Neuroimmunol and Neuroinflamm 2016; 3:e211Hh
Grutzke B et al Ann Clin Transl Neurol 215; 2: 119
Duddy M et al. J. Immunol 2007; 178;6092
Planas R et al. Eur J Immunol 2012;42;790
Thompson SA et al. J Clin Immunol 2010;30;99
Gold R et al. BMC Neurol 2016;16:117
Palanichamy A et al. J. Immunol 2014;193:580
Sergott RC et al. Neurol Sci 2015; 15:175
Ceronie B et al. J Neurol 2018;265:1199
Burns DM et al. Blood 2015; 126:2665
DEPLETION OF MEMORY B CELLS BY CURRENT MS THERAPEUTICS
Adapted from Baker D et al. EBioMedicine 2017; 16;41 * Not in MS

37. Durability of efficacy after memory B cell depletion
4 cycles
3 Cycles
Placebo
Interferonβ
Ocrelizumab Ocrelizumab
Ocrelizumab
Ocrelizumab
Treatment Free
0
B CELL DEPLETION & REPOPULATION3,4
T CELL DEPLETION & REPOPULATION3,4
B CELL REPLETION2,3
Treatment Free
100
100
6 MONTH CONFIRMED PROGRESSION2,3
Treatment Free
No/Limited Depletion
Adjusted ANNUALISED RELAPSE RATE2,3,8
Treatment Free
Treatment Free
No/Limited Depletion
4
Elimination of half-life
of Ocrelizumab = 26
days7
2 x 10mg Ocrelizumab
half-life depletes B
cells
to similar levels to
2 x 300mg
Ocrelizumab9
Ocrelizumab Phase II1
Extension study2,3,4
(NTC00676715)
Adapted from
1.Kappos et al. Lancet. 2011; 378:1779. 2 Kappos et al. P352. ECTRIMS. Mult Scler 2012;18(Suppl.4):140. 3. Hauser et al. AAN S31.004. Neurol 2013; 80 (7 Suppl) S31.004, 4.Giovannoni PEGS Summit
2017. Lisbon, 5. Baker D et al. Neurol Neuroimmunol Neuroinflamm. 2017;4:e360. 6. Comi et al. Mult Scler Rel Disord. 2019. doi.org/10.1016/ j.msard.2019.01.038. 7. Ocrevus® EU SmPC Sept 2018. 8 Baker
et al. EBiomedicine 2017; 16:41. 9 Genovese et al. Arth Rheumatol. 2008; 58:2652.
Treatment Median Repletion
Alemtuzumab ~ 6 months5
Cladribine tablet ~15 months6
Ocrelizumab 15-18 months (Range 27-175)2,7
Licenced dosing is
every 6 months7

38. Antibody Secretion
Cytokine
Secretion
APC
Function
CD21
C3d Receptor
(EBV receptor)
Memory
B cell
MHC
Y
EBV
Alemtuzumab
Effective
Anti‐Immune Effect
Eliminate
Viral Reservoir
Memory B cells link clinical observation, immune
phenotyping and biology of disease

39. https://www.youtube.com/watch?v=BodBAsojPhY&list=PLikEiUw0hWHIvc8ywaw_XmGYHn7SvME61
Some videos for your patients…

40. Treatment
options
1994 1996 2000
1998 2002 2004 2006 2008 2010 2012 2014
SC IFN β-1b1
1995 (RMS)
IM IFN β-1a2
1997 (RMS)
SC IFN β-1a3
1998 (RMS)
Natalizumab7
2006 (RRMS)
Glatiramer acetate6
20 mg/mL
2003 (RMS)
Fingolimod8
2011 (RRMS)
Alemtuzumab9
2013 (RRMS)
Teriflunomide10
2013 (RRMS)
2016
Dimethyl fumarate11
2014 (RRMS)
SC Peg IFNβ-1a14
2014 (RRMS)
Glatiramer acetate15
40 mg/mL
2015 (RMS)
Ocrelizumab13
2018 (RMS/PPMS)
Cladribine tablets12 †
2017 (RMS)
2018
BMT/HSCT23‡
1997 (RMS)
Mitoxantrone4,5,*
2000 (RMS)
Daclizumab22
2016 (RMS)
X
2019
Siponimod16
2019 (SPMS)
Diroxymel fumarate17¶
2021 (RMS)
*Licensed in the UK, US, Cyprus, Finland, France, Germany, Greece, Italy,
Romania, Slovenia, Spain, Sweden, Iceland and Norway
†Licensed in Europe
‡ Unlicensed
¶Licenced in US only (not EMA approved)
§Drug indication is shown as per EMA SmPC, when a drug not licenced by
EMA FDA USPI is shown
Ozanimod18 2020 (RRMS)
Ofatumumab19 2021(RMS)
2020
Evolving therapeutic landscape
2021
Ponesimod21
2021 RMS
IM Peg IFNβ-1a14
2021 (RRMS)
Monomethyl fumarate20¶
2020 (RMS)
EMA, European Medicines Agency; BMT/HSCT, bone marrow transplant/haematopoietic stem cell transplantation; FDA, Food and Drug Administration; IFN, interferon; IM, intramuscular; Peg IFN, peginterferon; RMS, relapsing multiple sclerosis, RRMS, relapsing-remitting
multiple sclerosis; SC, subcutaneous; SmPC, summary of product characteristics; SPMS, secondary progressive multiple sclerosis; UK, United Kingdom; US, United States, USPI, United States prescribing information.
1. Betaferon® (interferon beta-1b) SmPC. December 2020; 2. Avonex® (interferon beta-1a) SmPC. March 2021; 3. Rebif® (interferon beta-1a) SmPC. January 2021; 4. Novantrone® (mitoxantrone) SmPC. July 2016; 5. Novantrone® (mitoxantrone) FDA USPI. 2000; 6.
Copaxone® (Glatiramer acetate) 20 mg/ml UK SmPC. September 2020; 7. Tysabri® (natalizumab) SmPC. November 2021; 8. Gilenya® (fingolimod) SmPC. December 2018; 9. Lemtrada® (alemtuzumab) SmPC. September 2021; 10. Aubagio® (teriflunomide) SmPC. August
2021; 11. Tecfidera® (dimethyl fumarate) SmPC. April 2021; 12. Mavenclad® (cladribine) SmPC. April 2021; 13. Ocrevus® (ocrelizumab) SmPC. May 2021; 14. Plegridy® (Peg IFNβ-1a) SmPC. March 2021; 15. Copaxone® 40 mg/ml UK SmPC. September 2021. 16.
Mayzent® (siponimod) SmPC. January 2021; 17. Vulmerity® (diroxymel fumarate) FDA USPI. 2019; 18. Zeposia® (ozanimod) SmPC. November 2021; 19. Kesimpta® (ofatumumab) SmPC. June 2021; 20. Bafiertam® (monomethyl fumarate) FDA USPI. 2020; 21. Ponvory®
(ponesimod) SmPC. May 2021; 22. EMA zinbryta ® (daclizumab) Available at https://www.ema.europa.eu/en (accessed November 2021); 23. Fassas A, et al. Bone Marrow Transplant. 1997;20:631–638. 24. Briumi (Ublituximab) SmPC 2022
All SmPCs are Available at https://www.ema.europa.eu/en; All FDA labels Available at: https://acessdatafda.gov (all accessed November 2022).
Ublituximab24
2022 RMS
2022 2023

41. Curr Opin Neurol 2021;34:286-94.
From 1st DMT
From disease onset
From year 6 after disease onset
DMTs: rituximab, ocrelizumab, mitoxantrone, alemtuzumab, natalizumab

42. Time matters in MS

44. Natalizumab for the treatment of people with inflammatory demyelination suggestive of
multiple sclerosis, or definite multiple sclerosis, at first presentation
IRAS project 1003822
Contact: bartshealth.attackms@nhs.net
NCT05418010
EudraCT No 2021-002255-11

45. • Early treatment has long term benefits – but how early is early?
• Can we change current practice to facilitate brain health?
(outcome)
• Is highly effective anti-inflammatory treatment an effective way to
remyelinate? (outcome)
• Which compound is most useful in such acute scenario and has no
license for the indication clinically isolated syndrome (funding)
Rationale

46. Natalizumab IV
Placebo IV
CIS/McDonald MS
(optic neuritis, brainstem, spinal cord, other)
MRI suggestive of demyelination
(at least 2 lesions in typical location)
Primary objectives:
- To establish whether it is feasible to enrol people at first manifestation of a clinically isolated syndrome of
demyelination (CIS), or McDonald MS, within 14 days
- To test Natalizumab (Tysabri®) 300mg, intravenously over 24 weeks for safety, efficacy, and to advance
mechanistic understanding in pwMS.
Blinded phase Open label
Baseline W8
W4
CSF (PI discretion)
Overview
n = 20/arm
Placebo
Nz
W12 W16 W24
W20
Primary outcome:
lesion MTR
End of study
OCT & VEP OCT & VEP
DMT
Nz as per routine care, or switch to
different DMT (NHSE approved!)
Randomisation within 14 days
of symptom onset
Placebo
Nz Nz
Nz
Nz
Nz
Nz
Nz
sNfL
MRI High dose steroids may be
given prior to, or alongside 1st
IMP administration and/or if
relapse(s) occur during study
bartshealth.attackms@nhs.net

47. The Royal London
Chelsea & Westminster
Three recruitment sites
+ one MRI site
Queen Square (MRI)

48. The Guardian, 1 Sep 2022

49. • Wie aktuell sind die aktuellen MS Phänotypen?
• Annäherung an die effektive MS-Kontrolle
• Einsichten und Folgen von COVID-19
Überblick

50. • It was bad
• It wasn’t as bad as expected
• Vaccination moved centre stage
• Decisions on disease-modifying immunotherapy have
become a little, but not excessively, more complex
COVID-19

51. “multiple sclerosis”
Paper inflation
“COVID19”

52. Vaccinations and multiple sclerosis

53. Viral
RNA
SARS-CoV-2
PNEUMOCYTES 1-3
Direct virus-induced cytopathic effects
Pro-inflammatory cytokines/chemokines
LUNGS1,2
INNATE IMMUNE RESPONSE1,2
Macrophages/ (PMN)
Pro-inflammatory cytokines/chemokines
Activation
Recruitment
ADAPTIVE IMMUNE RESPONSE1,2
Anti-viral CD8+ Response
Anti-viral B cell responses & Antibodies
Lymphopenia, impairing
Delayed type I interferon response
Impaired downregulation
of innate immune response
Apoptosis
Impaired
anti-viral
Response
1
COMPLMENT SYSTEM1-3
Generation of C3a, C5a, and
Membrane attack complex
HYPER-INFLAMATION
Acute Lung Injury/
Acute Respiratory Distress Syndrome
HYPOXEMIA1,2
ENDOTHELIUM1,2,4,5
Endothelial activation and damage
Endothelial dysfunction, leading to
Vascular Leakage
RENIN ANGIOTENSIN SYSTEM1,2
Downregulation of ACE2 leading to
Increased ACE/AT1
Pro-inflammatory effects
Pro-oxidative effects
vasoconstriction
PLATELETS1,2
COAGULATION SYSTEM1,2
Activation
Activation
Activation
THROMBOSIS1,2,4,5
Pathobiology of COVID‐19
Oxidative stress due to inhibition of
Angiotensin II being converted to Angiotensin 1,7
may leads to super-oxide induced vascular damage
leading to von willebrand factor release and clot formation2,4,5
ADAPTIVE IMMUNE RESPONSE1,2
Inhibition of re-infection CD8+
Response
Anti-viral B cell responses &
Neutralizing antibodies
Viral Elimination Inhibition of re-infection
Viral Escape
Viral Infection
AT angiotensin ACE angiotensin converting enzyme
Deep Vein
Thrombosis6
1 Henry et al. Clin Chim Aca 2020 pii:S0009-8981 (20)30183, 2 .Baker et al. Clin Exp Immunol. 2020 202:149. 3. Magro et al.
Transl Res 2020 220:1, 4, Seheult. 2020 Medcram 37. 5,Seheult 2020 Medcram 61. 6. Ackermann et al. N. Eng J. Med 2020
383:120

54. 1.UK Health Security Agency Technical briefing 49. 11:01:2023 https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/
1129169/variant-technical-briefing-49-11-january-2023.pdf.
alpha Delta
BA.2
BA.1
BA.4
BA.5 BQ.1
BA.2.75 CH1.1
BA.4.6
AY4.2
Omicron
XBB
Variant prevalence (UKHSA designated variant definitions only) of available sequenced cases for England1
Prevalence of SARS‐CoV‐2 variants
Immune-Escape and Infectivity
Infectivity Infectivity & Virulence
New variant
XBB.1.5
March 2023
Technical
briefing 51
Kraken

55. Importance of SARS‐CoV‐2 antibody titre in viral neutralization
Anti-SARS-CoV-2 S antibody titres using Elecsys® immunoassay
following double dose mRNA vaccine sera1
1. Jochum et al. MedRxiv 2022: https://doi.org/10.1101/2021.10.04.21264521 2. Resman et al. J Clin Virol. 2021;139:104820. 3,. Bekliz et al.. Nat Comm 2022; 13:3840
Used for illustrative purpose only
10000
1000
100
10
Day 1
ACOV2S
[U/mL]
1
Visit
Day 15 Day 29 Day 43 Day 57
Below
0.8U/mL
Neutralizing titre 133u/mL2
45.6x Neutralizing titre2,3
85.7x Neutralizing titre2,3
Elecsys® SARS-CoV-2 assay
Alpha/Delta
neutralization
range
Omicron
neutralization
range
2021 2022
SARS-CoV-2 variant prevalence in England1
Alpha Delta
Omicron
BA.1 BA.2
BA.4
BA.5
B2.75
BA4.6
10000
1000
2.8X
100
10
1
PRNT
90
titre
85.7X
5.4X 3.5X 4.3X
6.9X
Serum neutralization of SARS-CoV-2 variants
following double-dose mRNA vaccine2
SARS-CoV2 variant
Plaque reduction neutralization tests (PRNT) to 90% reduction 90 titre
Pre-variant of concern (VOC) before alpha
Reduction in neutralization compared to B.1
2.2X 45.6X
3.6X 3.1X 25.8x
2.7X
Double dose vaccine
Convalescent pre-VOC

56. • Increased risk of symptomatic COVID-19
with CD20 depleting antibodies3-6
Treatment Effects on COVID‐19
• Early studies suggested minimal impact of
MS disease modifying treatments on COVID-191,2
• No increased risk of symptomatic COVID-19
with Fingolimod4,6
Adjusted Odds Ratio
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Suspected COVID-19
Confirmed COVID-19
Untreated
Glatiramer acetate
Beta interferon
Teriflunomide
Dimethyl Fumarate
Fingolimod
Natalizumab
Ocrelizumab
Rituximab
Cladribine
Alemtuzumab
**
**
*
*
*
*
COVID-19 suspected n=2340
confirmed n=1683
Risk of Hospitalization associated with use of DMT7
Adjusted for age, sex, phenotype & Expanded disability status scale * P<0.05 ** P<0.01
1.Sormani et al. Lancet Neurol 2020 19:481, 2. Louapre et al. JAMA Neurol 2020 77:1079., 3. Safavi et al. Mult Scler Relat Disord. 2020;43:102195. 4. Sormani et al. Ann
Neurol. 2021;89:780, 5. Reder et al. CNS Drugs. 2021. 35:317. 6. Somarni et al. 2020 SSRN http://dx.doi.org/10.2139/ssrn.3631244, Ann Neurol 2021 89:760, Simpson-
Yap et al. 2021 medRxiv doi: https://doi.org/10.1101/2021.02.08.21251316. Neurol 2021:97:e1870
• Increased risk of severe COVID-19
with CD20 depleting antibodies7
• No increased risk of severe COVID-19
with Fingolimod7

57. 1. Hjorth et al. PLoS One. 2020;15:e0228380.
Mechanism of action of sphingosine‐1‐phosphate modulators
CD4+ Naive CD4+ Effector
Inhibited Inhibited
CD8+ Naive
CD4+ Central memory
CD8+ Central memory CD8+ Effector memory
CD4+ Effector memory
CD8+ Effector
P=0.011
P<0.001
P<0.001
P<0.001
P<0.001 P<0.001
P<0.001 n.s.
Inhibited Relatively spared
Selective peripheral cell immune depletion following fingolimod1
Important in anti-viral response
Important in control of MS

58. Treatment effects and symptomatic COVID‐19
10.0
7.5
5.0
2.5
0.0
CoV-2-IgG
Antibody
Titre
Untreated
Multiple Sclerosis1
Lymphocyte Count
Cladribine Fingolimod Ocrelizumab
<500
Healthy controls
500-100
>1000
HC
Vaccine Responses1
Interval between
cladribine
and vaccine >4 months1
1.Achiron et al. Ther Adv Neurol Disord 2021,14:1. 2. Tallantyre et al. Anal Neurol 2021 91:89., . 3Gombolay et al. Ann Clin Transl Neurol. 2022; 9:1321. 4. Wu et al. EBioMedicine.
2022;81:104102
IgG
titre
tertile
1
3
2
No
DMT anti-
CD20
natalizuma
b alemtuzuma
b
cladribin
e
Interferon
beta teriflunomid
e
fingolimo
d
Glatiramer
acetate
dimethyl
fumarate
0
Vaccine Responses inhibited with anti-CD20 and fingolimod2
Influences are relatively consistent amongst classes of treatment3,4

59. Optimizing antibody Responses
1. Baker et al. Mult Scler Relat Disord Clin Exp Immunol 2021.Nov uxab015,.
• Extended interval dosing-1

60. B cell depleting antibodies inhibit seroconversion
1.Tallantyre et al. Anal Neurol 2021 https://doi.org/10.1002/ana.26251. 2. Baker et al. Mult Scler Rel Disord 2022:57:103448 3.Genovese et al. Arthritis Rheum. 2008; 58:2652-2661, 4
Vital et al. Arthritis Rheum. 2011; 63:603. 5 Signoriello et al. Mult Scler Relat Disord. 2020; 43:102186. 6. Ellwardt et al. Neurol Neuroimmunol Neuroinflamm. 2018 ;5:e463.
7.MabThera® SpMC, 8. Ocrevus® SpMC, 9. Kespimta® SpMC. 10. Disanto et al. JAMA Neurol. 2021;78:1529. 11. Madelon et al. Clin Infect Dis 2021 Nov17:ciab954, 12. Gadani et al.
.EBioMedicine. 2021 Nov;73:103636 . 13. Toorop et al. J Neurol Neurosurg Psychiatry. 2023 jnnp-2022-330793 14. Asplund Högelin et al. Eur J Neurol. 2022;29:3317
15. Apostolidis et al. Nat Med 2021:27:1990.16. Iannetta et al. Mult Scler Rel Disord 2021 55:103157
Seroconversion following COVID-19 vaccination1
• Antibody Dose3,4,8,9
• Demographics/Body Mass Index5,6
Varied Degree of Depletion2-6
• Nature of Antibody7-9
Varied Degree of Seroconversion, based on assay10-14
• Nature of Assay (Type)10-14
• Nature of Assay (Spike verses RBD)10-14
CD4 and CD8 T cell responses in seronegative cases11,12, 15, 16
RBD receptor binding domain
• B cell repopulation level10-12
• Timing of depletion to vaccination10-12
• Circulating antibody level13,14

61. Summary
• Immune reconstitution therapies appear to have limited influence on vaccinations
when administered following drug elimination.
• Platform therapies exhibit limited inhibitory influences of vaccine responses.
• Continuous potent immunosuppressive agents blunt vaccination(and infection)-associated B cell
responses
• CD20-depleting antibodies deplete naïve B cells and inhibit seroconversion following vaccination
• CD20-depleting antibodies do not rapidly deplete antibody forming plasma B cells
• Some sphingosine-1-phosphate receptor modulators inhibit antibody formation and peripheral T
cell responses
• Strategies could be developed to increase anti-viral responses, but safety needs to be assured

62. Not in the picture:
- MS Nurse specialists
- Statistician
- PhD students
- Mousedoctor
…