Prevention MS Trials

MS Prevention

Gavin Giovannoni

EBV Vitamin D

SmokingGenes

Very low risk

ageplace of residence

outdoor activity / sun exposure / sun screendiet / vitamin D supplements

age of exposure to EBVsmoking

At risk High Risk

Low risk

RIS CIS MS

family historygenetics

sexmonth of birthplace of birth

Unfavourable disease-modifying factorsdynamic risk factorsstatic risk factors

dynamic protective factorsstatic protective factors

MRI / evoked potentials changes

Peripheral immunological changesT-regs (), NK cells, CD8 ()

Clinical disease

In utero childhood Adolescence / early adulthood adulthood

1. Declining Physiology – “peripheral immunological endophenotype”2. Biological disease threshold – “CNS endophenotype”3. Asymptomatic disease – RIS (abnormal MRI and/or evoked potentials)4. Clinical disease

a. Clinically isolated syndrome (CIS)b. Relapsing MSc. Relapsing secondary progressive MSd. Non-relapsing secondary progressive MS

Favourable disease-modifying factors

protective HLA haplotypes

CNS changes(OCBs and microscopic pathology)

2

3

24b 24c 24d

24a

1

Smoking

Statistics on Smoking, England 2013. Health & Social Care Information Centre. Table 2.1.

Prevalence of cigarette smoking among young adults - England

www.digestingscience.co.uk

vD

Population

vs.

Questions

• Age group– In utero, childhood, adolescence, adulthood

• Dose– Fixed-dosing– Target (what target? Population mean vs. Evolutionary Medicine)– Food fortification

• Comparator– Placebo– Active (400U/day)

• Outcome– MS vs. basket of related diseases (T1DM > MS, etc.)

• Adherence• Case definitions• Logistics

Old-World PrimatesHumans exposing full

skin surface to Sunshine’s UVB

Winter 43o N Latitude

“Normal”0

40

120

160

Vitamin D Status in Primates and Early Humans

Sources, include Cosman, Osteoporosis Int 2000; Fuleihan NEJM 1999; Scharla Osteoporosis Int 1998; Vieth AJCN 1999, 2000

80

Physiological adult intake

Blood Levels when taking 25 mcg/d

1000 IU/day

Northern PeopleTaking

100 mcg/d 4000 IU/day

Slide adapted from Reinhold Vieth

Maasai median 25(OH)D = 104 nmol/L = 41 ng/mL

Luxwolda et al. British Journal of Nutrition (2012), 108, 1557–1561

40 ng/mL

Slide adapted from Reinhold Vieth

Veith Am J Clin Nutr 1999;69:842–56.

Level of vD supplementation

At risk High Risk RIS CIS MS

In utero childhood Adolescence / early adulthood adulthood

High riskLow risk

High risk

Cohort 1 – in utero (pregnancy)

Cohort 2 – Childhood

Cohort 3 – Adolescence

Cohort 4 – Early adulthoodvs.

Cohorts 5-8 – Comparator population (historical or contemporary)

+ve family history – 1° & 2° relatives

Risk of MS to children

Borisow et al. EPMA J. 2012 Jun 22;3(1):9.

RR ~ 7.5

Sex

Orton et al, 2006; Koch-Henriksen and Sorenson 2010

The rate of MS in females is increasing rapidly while the male rate of MS has remained stable.

.

Peak age of MS onset is between 20-40 years old

Paty and Ebers, 1998

~70% → ~6 year follow-up ~20% of incidence cases

Population Demographic Profile

High risk

+ve family history – 1° & 2° relatives

Prevalence: 150/100,000 (1in 500-1,000)Incidence: 7.5/100,000 (6-9/100,000) Sex ratio: females:male: 3:1Relative risk: x7.5 (1° & 2° relatives)Prevalence in at risk: 1125/100,000

Age: 16-36 → ~70% = 788 incident cases/100,000~39.4 incident case/100,000/yr~4 incident case/10,000/yr

2-years ≥5-years

Does the risk score provide an estimate of MS risk?

Area under

curve (95% CI)

Risk score including genetic contribution

from HLA-DRB15*1501 only

0.77

(0.70 – 0.84)

Risk score including genetic contribution

from all MS risk alleles

0.80

(0.74 – 0.87)

Risk score including genetic contribution

from HLA-DRB1*1501 only; excluding

serum 25-OHvD level

0.80

(0.73 – 0.87)

Risk score including genetic contribution

from all MS risk alleles; excluding serum

25-OHvD level

0.82

(0.75 – 0.88)

Ruth Dobson, unpublished data

Odds ratio of having MS varies according to risk score category

Risk score calculated using full genetic information

Markedly increased risk of being in the top risk score category compared to the lowest risk score category (OR 1296.00; 95% CI 78 – 21,527;p<0.00001)

Ruth Dobson, unpublished data

Google or Big Data StudyGary Cutter – 10,000,000 study

10,000,000

Randomisation

400U 2,000U 10,000U

Annual end-of-winter blood spots

Biobank

Follow-up x 10 years

Annual health questionnaire Events Confirmation

Inclusion/Exclusion

Online volunteeringPublic engagement

Multiple nested case-control study

PR / Media

Social Media

EBV

Population based vaccine

vs.

Questions

• Need a vaccine– GSK / Medimmune gp350– NIH new initiative

• Age group– Childhood, adolescence, early adulthood

• Vaccine programme– Piggy-back on HPV programme

• Comparator– Placebo

• Primary outcome– IM

• Secondary outcome– Population surveillance (autoimmune / oncology)

High risk

Infant/childhood vs. early adulthood & adolescence (EBV –ve)

vs.

Active comparator (EBV –ve)

General Population

vs.

PD

High riskLow risk

Intermediate Phenotypes1. Smell (UPSIT)2. REM-sleep behavioural disorder3. Tapping speed (BRAIN TEST)4. Genomics (LRRK2 / GBA)PD Phenotypes1. Clinical (UPDR / PD)2. Imaging (US / DAT)

High vs. Low risk

Conclusion

• Is MS preventable? Yes

• Smoking

• 20% of cases in general population

• 40% familial cases

• Vitamin D

• General population

• At risk

• Enrichment (endophenotype)

• EBV

• Vaccination

• prevent wildtype infection

• wildtype early infection (vD replete)

• IM

• Prevention (vaccine)

• Treatment

Acknowledgements

Rachel FarrellRuth DobsonJens KuhleJulian GoldDavid HoldenUte MeierSreeram Ramagapolan

Dorothy CrawfordKaren McAulayDavid MillerBasil SharrackGeorge Ebers