What measles virus genotypes are associated with the development of Subacute Sclerosing Panencephalitis (SSPE) in children and young adults?

Measles Virus Genotypes Associated with SSPE

Direct Answer

SSPE is caused by wild-type measles virus strains across multiple genotypes, not by vaccine strains, with documented cases linked to genotypes C, D1, D4.2, D6, D7, F, G3, H1, and potentially others—essentially any wild-type measles genotype can cause SSPE, with the possible exception of genotype B3. 1, 2

Genotypes Documented in SSPE Cases

The following wild-type measles virus genotypes have been definitively identified in SSPE patients through molecular sequencing:

• Genotype C: Identified in patients who acquired measles infection in the 1950s 2
• Genotype D1: Found in patients infected during the 1960s and 1970s 2
• Genotype D4.2: Recently reported and noted as one of the most antigenically altered genotypes 3
• Genotype D6: Documented in a Canadian SSPE case with significant genetic divergence 4, 2
• Genotype D7: Identified in patients infected during the 1980s 2
• Genotype F: Associated with SSPE case SMa79 5
• Genotype G3: Documented in SSPE cases 5
• Genotype H1: Noted as one of the most antigenically altered genotypes 3

Critical Molecular Marker: The PEA Motif

A specific molecular signature in the matrix (M) protein—the PEA motif (residues P64, E89, and A209)—appears to be a consistent marker for wild-type measles viruses capable of causing SSPE. 1

Key Findings About the PEA Motif:

• All known SSPE viruses possess the PEA motif (P64, E89, A209) in their M proteins, particularly the A209 residue which is linked to increased viral spread 1
• Vaccine strains have different residues: Moraten vaccine strain has SKT (S64, K89, T209), while other vaccine strains may have PKT 1
• 9 of 10 sequenced wild-type genotypes have the PEA motif, with genotype B3 being the sole exception (having PET instead) 1
• Genotype B3 has never been reported to cause SSPE, suggesting the PEA motif may be essential for SSPE pathogenesis 1

Why Vaccine Strains Never Cause SSPE

Measles vaccine strains have never been documented to cause SSPE, and when SSPE occurs in previously vaccinated children, molecular evidence consistently shows wild-type virus, not vaccine strains. 6, 7, 2

• In a comprehensive UK study of 11 SSPE cases spanning 1965-2000, no vaccine strains were detected despite five patients having been previously immunized 2
• Children who developed SSPE after vaccination likely had unrecognized wild-type measles infection before vaccination 7, 3
• The molecular difference lies in the M protein structure: vaccine strains lack the PEA motif that characterizes SSPE-causing wild-type viruses 1

Antigenic Properties and Genotype Risk

SSPE-causing viruses show similar antigenic properties to currently circulating wild-type measles genotypes, and there is no evidence that antigenic drift or specific antigenic changes predispose certain genotypes to cause SSPE. 5

• Genotypes A, G3, and F (SSPE case SMa79) showed intact antigenic structure 5
• Genotypes D7 and F showed enhanced neutralization by monoclonal antibodies targeting antigenic site IIa 5
• The absence of correlation between antigenic changes and SSPE predisposition suggests antigenic drift is not the primary pathogenetic mechanism 5

Genetic Characteristics of SSPE Viruses

SSPE measles virus strains are defective and unable to produce progeny virions due to extensive mutations, particularly in the M gene, which shows characteristic biased hypermutations. 4, 2

• The M gene shows the greatest sequence divergence (17.6% nucleotide and 31% amino acid variation in one D6 strain) 4
• Premature termination codons in the M gene were detected in 5 of 11 SSPE sequences 2
• The L gene shows the least variation (1.3% nucleotide and 0.7% amino acid differences) 4
• Overall genome nucleotide variability compared to wild-type strains is approximately 3% 4

Clinical Implications

Any child who contracts wild-type measles infection is at risk for SSPE (approximately 4-11 per 100,000 measles cases), with highest risk in children infected before age 5 years. 6, 8

• Children residing in areas with poor vaccination coverage are at increased risk 8
• Children with or exposed to HIV infection who contract measles may be at increased risk 8
• The only effective prevention is measles vaccination, which has essentially eliminated SSPE in highly vaccinated populations 6, 7