Cancer Prevention Clinical Trials in America Peter Greenwald, M.D., Dr. P.H.
EBV MS Prevention Trials
-
Upload
gavin-giovannoni -
Category
Health & Medicine
-
view
1.717 -
download
1
Transcript of EBV MS Prevention Trials
![Page 1: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/1.jpg)
Infectious agents and vaccines: what are the implications for prevention and treatment?
Gavin Giovannoni
![Page 2: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/2.jpg)
![Page 3: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/3.jpg)
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 - ?
![Page 4: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/4.jpg)
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
![Page 5: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/5.jpg)
Age
![Page 6: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/6.jpg)
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
![Page 7: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/7.jpg)
EBV
Thacker et al. Ann Neurol 2006;59:499–503.
![Page 8: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/8.jpg)
Infectious mononucleosus
Thacker et al. Ann Neurol 2006;59:499–503.
![Page 9: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/9.jpg)
Sex
![Page 10: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/10.jpg)
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.
![Page 11: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/11.jpg)
.
Peak age of MS onset is between 20-40 years old
Paty and Ebers, 1998
~70% → ~6 year follow-up ~20% of incidence cases
![Page 12: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/12.jpg)
Population
![Page 13: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/13.jpg)
Population
vs.
![Page 14: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/14.jpg)
At risk High Risk RIS CIS MS
In utero childhood Adolescence / early adulthood adulthood
High riskLow risk
![Page 15: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/15.jpg)
High risk
Infant/childhood vs. early adulthood & adolescence (EBV –ve)
vs.
Active comparator (EBV –ve)
General Population
vs.
![Page 16: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/16.jpg)
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
![Page 17: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/17.jpg)
Population Demographic Profile
![Page 18: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/18.jpg)
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
![Page 19: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/19.jpg)
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
![Page 20: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/20.jpg)
Vaccine
![Page 21: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/21.jpg)
The Journal of Infectious Diseases 2007; 196:1749 –53.
![Page 22: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/22.jpg)
Epstein-Barr Virus Vaccine for the Prevention of InfectiousMononucleosis—and What Else?
Balfour, JID 2007:196 (15 December)
![Page 23: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/23.jpg)
![Page 24: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/24.jpg)
Outcomes
![Page 25: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/25.jpg)
![Page 26: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/26.jpg)
Oncoprevention
![Page 27: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/27.jpg)
Autoimmunity
![Page 28: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/28.jpg)
Outcomes
Thacker et al. Ann Neurol 2006;59:499–503.
Oncoprevention
Serology/IM
Autoimmunity MS
![Page 29: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/29.jpg)
Caution
![Page 30: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/30.jpg)
![Page 31: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/31.jpg)
Conclusions
![Page 32: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/32.jpg)
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)
![Page 33: EBV MS Prevention Trials](https://reader031.fdocuments.us/reader031/viewer/2022022414/5873982a1a28ab85438b5e51/html5/thumbnails/33.jpg)
Acknowledgements
Rachel FarrellRuth DobsonJens KuhleJulian GoldDavid HoldenUte MeierSreeram Ramagapolan
Dorothy CrawfordKaren McAulayDavid MillerBasil SharrackGeorge Ebers