EBV MS Prevention Trials
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Transcript of 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