1. Measles in Immunocompetent and Immunodeficient Hosts William Moss, MD, MPH Johns Hopkins Bloomberg School of Public Health FDA Blood Products Advisory Committee August 16, 2007

2. Measles in Immuncompetent Hosts

3. Clinical Features of Measles Adapted from Infectious Diseases of Children, 9 th edition. Figure 13-1, page 224. Krugman S, Katz AL, Gershon AA, Wilfert CM. Eds. St. Louis, Mosby, 1992.

4. Measles Rash

5. Koplik’s spots Pathogenesis of Measles Virus Infection N Engl J Med 2006;354:740.

6. Immune Responses to Measles Virus Innate immune responses Antibody responses Cellular immune responses Immunologic memory Immune suppression

7. Potential Mechanisms of Immune Suppression After Measles

8. Measles in Immunocompromised Hosts

9. Observations on Measles in Persons with Impaired Immunity Deficient antibody production Measles virus is cleared Host recovers but limited protection from reinfection Deficient cellular immunity Delayed viral clearance Progressive disease

10. Clearance and Protection Clearance Elimination of infected cells and circulating virus Slowed clearance and desquamating rash with some immune deficiencies Progressive disease often without a rash with deficiencies of cellular immunity Protection Prevention of infection (clinical) Best correlate is level of neutralizing antibody

11. Rhesus Macaque Model Auwaerter et al. J Infect Dis 1999;180:950-8.

12. Effect of CD8 + T Cell Depletion on Measles Viremia in Monkeys Permar et al. J Virol 2003;77:4396-4400.

13. Effect CD20 + (B) Cell and/or CD8 + T Cell Depletion on Viremia Permar et al. J Infect Dis 2004;190:998-1005. Desquamating skin rash

14. Rashes in Immunocompromised Monkeys with Measles No suppression Anti CD20 Anti CD20+CD8 Permar et al. J Infect Dis 2004;190:998-1005

15. Failure to Clear Measles Virus Diseases Giant cell pneumonitis Measles inclusion body encephalitis Clinical Manifestations Often no rash at time of measles virus infection Progressive pulmonary or CNS disease appears weeks to months after initial infection Diagnosis may be difficult

16. Case Reports of Progressive Measles Virus Infection Associated with Immune Deficiencies Primary immune deficiencies Usually combined deficiencies of T and B cells Specific diagnosis often not made Secondary immune deficiencies Leukemia and lymphomas Immunosuppressive therapy (e.g. transplants) HIV-1 infection

17. Complications and the Rash of Measles in Malnourished Children Morley D. Paediatric Priorities in the Developing World. 1979.

18. Desquamating Rash in an HIV-1 Infected Child

19. Measles in HIV-1 Infected Children CDC 1988 severe and unusual measles in 5 HIV-infected children Case reports of 19 co-infected children in US ½ with absent, delayed or unusual rash ¾ with pneumonitis case fatality rate (CFR) 32% HIV-seropositive children in Africa Zaire (1988): no difference in CFR Zambia (1996): higher CFR (27% vs. 8%) Moss et al. Clin Infect Dis 1999;29:106-12.

20. Deaths during Hospitalization NumberDeaths (%)Adjusted OR (95% CI) HIV-1 Uninfected99245 (4.5) HIV-1 Infected17223 (13.4)2.5 (1.4 – 4.6) Moss et al. Unpublished observations. Mortality Among HIV-1 Infected Children with Measles

21. Deaths during Hospitalization Desquamating Rash NumberDeaths (%)Adjusted OR (95% CI) No72532 (4.4) Yes43736 (8.2)2.2 (1.3 – 3.6) Moss et al. Unpublished observations. Mortality Among Children with Desquamating Rash

22. Detection of MV RNA by RT-PCR HIV+HIV-P Number1136 % Detectable MV RNA 30-61 days after rash onset 91530.02 Permar et al. J Infect Dis 2001;183:532-8. Measles Virus Persistence in HIV-1 Infected Children

23. Fatal Adverse Event Due to Measles Vaccine Virus 21-year-old man with AIDS who received 2 nd MMR No rash Presented 11 months after measles vaccination No clinical evidence of severe immunosuppression Previously vaccinated against measles Thorascopic lung biopsy RT-PCR and genome sequencing identified measles vaccine virus in lung tissue Angel et al. Ann Int Med 1998;129:104-6.

24. Neurological Diseases Associated with Measles Acute disseminated encephalomyelitis Measles inclusion body encephalomyelitis Subacute sclerosing panencepalitis Occurs in immune compromised hosts Vaccine or wild type viruses Virus demonstrable in CNS

25. Studies Suggesting Antibodies May be Important for Measles Virus Clearance Levels of ADCC antibody correlate with cessation of viremia Forthal et al., J Infect Dis 1994;169:1377-80. Low antibody responses predict poor outcome Wesley et al., S Afr Med J 1982;61:663-5. Antibodies can down regulate intracellular virus replication Fujinami & Oldstone, Nature 1979;279:529-30. Schneider-Schaulies et al. J Virol 1992; 66:5534.

26. What is the role of antibody in protection from measles virus infection?

27. Evidence that Antibodies Alone Are Protective Against Measles Infants are protected by passively-acquired maternal antibody Passive administration of immune globulin can protect after exposure The best correlate for vaccine-induced protection is the level of neutralizing antibody

28. Measles Virus Moss & Griffin. Nat Rev Microbiol 2006;4:900-8. Neutralizing antibodies

29. Antibodies to MV proteins Induced by Infection Graves et al., J Virol 1984:49:409-12.

30. Halsey et al. N Engl J Med 1985;313:544-9. Measles and Maternal Antibodies

31. Level of Maternal Antibody Influences Response to Vaccine Infant PRNT NSero- conversion P <1:89494% >1:85858%<0.05 Markowitz et al. Pediatrics 1996; 97:53-8.

32. Measles Outbreak in School with Prior Blood Donor Program PRNTTotalMeaslesP <12098 >120710< 0.0001 Chen et al. J Infect Dis 1990;162:1036-42.

33. Partial Protection: Viremia Without Rash PRNTTotalAb response P 217-874117 >105270<0.02 Chen et al. J Infect Dis 1990;162:1036-42.

34. Responses to DNA Immunization and Challenge VaccineMonkeyPRNT CTLChallenge Fid1J314rash, viremia 9J 13515 viremia Hid3J 10515rash, viremia 4J 197720 7J 188nd viremia F+Hid 22J 51ndrash, viremia 27J 2130 18 28J 520 18 H gg 20J 68623 23J 2143nd 25J 1922nd H+Fgg 12J 138nd 15J 14716 viremia 19J 146nd Polack et al. Nat Med 2000;6:776-81.

35. Conclusions Clearance of MV is dependent primarily on cellular immunity Defects in clearance are associated with unusual manifestations of measles No rash and progressive infection in severe immune suppression Desquamating rash with eventual clearance in moderate immune suppression Protection from infection is best correlated with the level of neutralizing antibody >120 for protection from disease (rash) >1028 for protection from infection (viremia, Ab response)

36. Acknowledgments Diane Griffin Sallie Permar Felicity Cutts Susana Scott Mwaka Monze Francis Kasolo