Measles in Immunocompetent and Immunodeficient Hosts

Measles in Immunocompetent and Immunodeficient Hosts FDA Blood Products Advisory Committee August 16, 2007 William Moss, MD, MPH Johns Hopkins Bloomberg School of Public Health Measles in Immuncompetent Hosts Clinical Features of Measles Adapted from Infectious Diseases of Children, 9th edition. Figure 13-1, page 224. Krugman S, Katz AL, Gershon AA, Wilfert CM. Eds. St. Louis, Mosby, 1992. Measles Rash Pathogenesis of Measles Virus Infection Koplik’s spots N Engl J Med 2006;354:740. Immune Responses to Measles Virus • Innate immune responses • Antibody responses • Cellular immune responses • Immunologic memory • Immune suppression Potential Mechanisms of Immune Suppression After Measles Measles in Immunocompromised Hosts 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 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 Rhesus Macaque Model 8000 7000  Lymphocytes/ l 6000 5000 4000 3000 2000 1000 lymphocyte count viremia rash 0 3 7 10 14 16 21 28 35 42 Days after infection IT inoculation of wild type measles virus Bilthoven Auwaerter et al. J Infect Dis 1999;180:950-8. Effect of CD8+ T Cell Depletion on Measles Viremia in Monkeys Permar et al. J Virol 2003;77:4396-4400. Effect CD20+ (B) Cell and/or CD8+ T Cell Depletion on Viremia Desquamating skin rash Permar et al. J Infect Dis 2004;190:998-1005. Rashes in Immunocompromised Monkeys with Measles No suppression Anti CD20 Anti CD20+CD8 Permar et al. J Infect Dis 2004;190:998-1005 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 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 Complications and the Rash of Measles in Malnourished Children Morley D. Paediatric Priorities in the Developing World. 1979. Desquamating Rash in an HIV-1 Infected Child 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. Mortality Among HIV-1 Infected Children with Measles Deaths during Hospitalization Number HIV-1 Uninfected HIV-1 Infected 992 172 Deaths (%) 45 (4.5) 23 (13.4) 2.5 (1.4 – 4.6) Adjusted OR (95% CI) Moss et al. Unpublished observations. Mortality Among Children with Desquamating Rash Deaths during Hospitalization Desquamating Rash No Yes Number 725 437 Deaths (%) 32 (4.4) 36 (8.2) 2.2 (1.3 – 3.6) Adjusted OR (95% CI) Moss et al. Unpublished observations. Measles Virus Persistence in HIV-1 Infected Children Detection of MV RNA by RT-PCR HIV+ Number 11 HIV36 P 0.02 % Detectable MV RNA 30-61 days after rash onset 91 53 Permar et al. J Infect Dis 2001;183:532-8. Fatal Adverse Event Due to Measles Vaccine Virus 21-year-old man with AIDS who received 2nd 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. Neurological Diseases Associated with Measles rash measles virus infection 7 ADEM MIBE SSPE 14 days 21 1 3 6 9 months 1 3 6 9 years 12 Acute disseminated encephalomyelitis Measles inclusion body encephalomyelitis Subacute sclerosing panencepalitis Occurs in immune compromised hosts Vaccine or wild type viruses Virus demonstrable in CNS 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. What is the role of antibody in protection from measles virus infection? 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 Measles Virus Neutralizing antibodies Moss & Griffin. Nat Rev Microbiol 2006;4:900-8. Antibodies to MV proteins Induced by Infection Graves et al., J Virol 1984:49:409-12. Measles and Maternal Antibodies The measles problem in developing countries 60 50 40 % unresponsive to immunization with live measles vaccine % who have had measles Percent 30 20 10 0 6 7 8 9 10 11 12 Months of age Halsey et al. N Engl J Med 1985;313:544-9. Level of Maternal Antibody Influences Response to Vaccine Infant PRNT N Seroconversion P <1:8 >1:8 94 58 94% 58% <0.05 Markowitz et al. Pediatrics 1996; 97:53-8. Measles Outbreak in School with Prior Blood Donor Program PRNT Total Measles P <120 >120 9 71 8 0 < 0.0001 Chen et al. J Infect Dis 1990;162:1036-42. Partial Protection: Viremia Without Rash PRNT 217-874 >1052 Total 11 7 Ab response 7 0 P <0.02 Chen et al. J Infect Dis 1990;162:1036-42. Responses to DNA Immunization and Challenge Vaccine Fid Hid Monkey 1J 9J 3J 4J 7J 22J 27J 28J 20J 23J 25J 12J 15J 19J PRNT 3 135 105 1977 188 51 2130 520 686 2143 1922 138 147 146 CTL 14 15 15 20 nd nd 18 18 23 nd nd nd 16 nd Challenge rash, viremia viremia rash, viremia viremia rash, viremia F+Hid H gg H+Fgg viremia Polack et al. Nat Med 2000;6:776-81. 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) Acknowledgments • • • • • • Diane Griffin Sallie Permar Felicity Cutts Susana Scott Mwaka Monze Francis Kasolo