EBV MS Prevention Trials

Infectious agents and vaccines: what are the implications for prevention and treatment?

Gavin Giovannoni

Sir Bradford-Hill: Criteria for Causation

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

1. CONSISTENCY AND UNBIASEDNESS OF FINDINGS - Yes (not 100%)

2. STRENGTH OF ASSOCIATION – ? / Yes (RR ~ 2 to 3)

3. TEMPORAL SEQUENCE - Yes

4. BIOLOGICAL GRADIENT (DOSE-RESPONSE RELATIONSHIP) - ? (not relevant to infections)

5. SPECIFICITY – No (not 100% other putative autoimmune diseases also associated with EBV)

6. COHERENCE WITH BIOLOGICAL BACKGROUND AND PREVIOUS KNOWLEDGE - Yes

7. BIOLOGICAL PLAUSABILITY - Yes

8. REASONING BY ANALOGY - Yes

9. EXPERIMENTAL EVIDENCE - ?

Questions relevant to vaccination?

1. Age?2. Sex; male, females* or both?3. Population; general population vs. high-risk?

a. High vs. intermediate vs. low prevalence countriesb. Demographic profile

4. Vaccine; live wild-type virus vs. attenuated live virus vs. component vaccine?

5. Outcome; seroprevalence (-ve) vs. IM vs. other auto-immune diseases vs. MS vs. EBV-associated malignancies (oncoprevention)

* piggy-back on HPV vaccine programme

Age

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

EBV

Thacker et al. Ann Neurol 2006;59:499–503.

Infectious mononucleosus

Thacker et al. Ann Neurol 2006;59:499–503.

Sex

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

Population

vs.

At risk High Risk RIS CIS MS

In utero childhood Adolescence / early adulthood adulthood

High riskLow risk

High risk

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

vs.

Active comparator (EBV –ve)

General Population

vs.

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

Population Demographic Profile

Does a 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

Vaccine

The Journal of Infectious Diseases 2007; 196:1749 –53.

Epstein-Barr Virus Vaccine for the Prevention of InfectiousMononucleosis—and What Else?

Balfour, JID 2007:196 (15 December)

Outcomes

Oncoprevention

Autoimmunity

Outcomes

Thacker et al. Ann Neurol 2006;59:499–503.

Oncoprevention

Serology/IM

Autoimmunity MS

Caution

Conclusions

Conclusion

1. EBV vaccination is feasible

2. New vaccine (wild-type, live-attenuated, component)

3. Age – 12-13 (males & females); piggy-back on HPV vaccine programme

4. General population

5. Primary target IM

6. Secondary target oncoprevention and autoimmunity (not MS-specific)

7. Cautious about unintended consequences

8. Life-life long immunity (VZV analogy)

Acknowledgements

Rachel FarrellRuth DobsonJens KuhleJulian GoldDavid HoldenUte MeierSreeram Ramagapolan

Dorothy CrawfordKaren McAulayDavid MillerBasil SharrackGeorge Ebers