# Presentation: 859658

## 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

## 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

## Koplik’s spots

- Pathogenesis of Measles Virus Infection

- 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

- 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

- 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

## 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
- 1⁄2 with absent, delayed or unusual rash
- 3⁄4 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.

**Notes:**
Early reports of severe and unusual measles in immunocompromised children: Enders (1959) and African children with malnutrition
 MIBE and myelopathy

## Mortality Among HIV-1 Infected Children with Measles

|  | Number | Deaths (%) | Adjusted OR
(95% CI) |
| --- | --- | --- | --- |
| HIV-1 Uninfected | 992 | 45 (4.5) |  |
| HIV-1 Infected | 172 | 23 (13.4) | 2.5 
(1.4 – 4.6) |

- Moss et al. Unpublished observations.

## Mortality Among Children with Desquamating Rash

| Desquamating Rash | Number | Deaths (%) | Adjusted OR
(95% CI) |
| --- | --- | --- | --- |
| No | 725 | 32 (4.4) |  |
| Yes | 437 | 36 (8.2) | 2.2 
(1.3 – 3.6) |

- Moss et al. Unpublished observations.

## Measles Virus Persistence in HIV-1 Infected Children

|  | HIV+ | HIV- | P |
| --- | --- | --- | --- |
| Number | 11 | 36 |  |
| % Detectable MV RNA 
30-61 days after rash onset | 91 | 53 | 0.02 |

- 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

- 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

- Moss & Griffin.  Nat Rev Microbiol 2006;4:900-8.

- Neutralizing antibodies

## Antibodies to MV proteins Induced by Infection

- Graves et al., J Virol 1984:49:409-12.

## Measles and Maternal Antibodies

- Halsey et al. N Engl J Med 1985;313:544-9.

## Level of Maternal Antibody Influences Response to Vaccine

| Infant PRNT | N | Sero-conversion | P |
| --- | --- | --- | --- |
| <1:8 | 94 | 94% |  |
| >1:8 | 58 | 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 | 9 | 8 |  |
| >120 | 71 | 0 | < 0.0001 |

- Chen et al. J Infect Dis 1990;162:1036-42.

## Partial Protection: Viremia Without Rash

| PRNT | Total | Ab response | P |
| --- | --- | --- | --- |
| 217-874 | 11 | 7 |  |
| >1052 | 7 | 0 | <0.02 |

- Chen et al. J Infect Dis 1990;162:1036-42.

## Responses to DNA Immunization and Challenge

_**Vaccine**_

_**Monkey**_

_**PRNT**_

_**CTL**_

_**Challenge**_

- Fid		**1J**		**3****	****14****	****	****rash, viremia**

**9J****	****        135****	****15****	****	****    viremia**

- Hid		**3J****	****        105****	****15****	****	****rash, viremia**

- 4J	      1977	20

**7J****	****        188****	****nd****	****	****    viremia**

- F+Hid	          **22J****	****          51****	****nd****	****	****rash, viremia**

- 27J	        2130	  18

- 28J	          520	  18

- H gg	          20J	        686	23
- 	          23J	      2143	nd
- 	          25J	      1922	nd
- H+Fgg	          12J	        138	nd
- 	          **15J****	****        147****	****16****	****	****     viremia**
- 	          19J	        146	nd

- 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