Rubella viruses (RV) have been found in an association with granulomas in children with primary immune deficiencies (PID). Here, we report the recovery and characterization of infectious immunodeficiency-related vaccine-derived rubella viruses (iVDRV) from diagnostic skin biopsies of four patients. Sequence evolution within PID hosts was studied by comparison of the complete genomic sequences of the iVDRVs with the genome of the vaccine virus RA27/3. The degree of divergence of each iVDRV correlated with the duration of persistence indicating continuous intrahost evolution. The evolution rates for synonymous and nonsynonymous substitutions were estimated to be 5.7 x 10−3 subs/site/year and 8.9 x 10−4 subs/site/year, respectively. Mutational spectra and signatures indicated a major role for APOBEC cytidine deaminases and a secondary role for ADAR adenosine deaminases in generating diversity of iVDRVs. The distributions of mutations across the genes and 3D hotspots for amino acid substitutions in the E1 glycoprotein identified regions that may be under positive selective pressure. Quasispecies diversity was higher in granulomas than in recovered infectious iVDRVs. Growth properties of iVDRVs were assessed in WI-38 fibroblast cultures. None of the iVDRV isolates showed complete reversion to wild type phenotype but the replicative and persistence characteristics of iVDRVs were different from those of the RA27/3 vaccine strain, making predictions of iVDRV transmissibility and teratogenicity difficult. However, detection of iVDRV RNA in nasopharyngeal specimen and poor neutralization of some iVDRV strains by sera from vaccinated persons suggests possible public health risks associated with iVDRV carriers. Detection of IgM antibody to RV in sera of two out of three patients may be a marker of virus persistence, potentially useful for identifying patients with iVDRV before development of lesions. Studies of the evolutionary dynamics of iVDRV during persistence will contribute to development of infection control strategies and antiviral therapies.

The external expert panel concluded that the elimination of endemic measles, rubella, and CRS from the United States was sustained through 2011. However, international importation continues, and health care providers should suspect measles or rubella in patients with febrile rash illness, especially when associated with international travel or international visitors, and should report suspected cases to the local health department.

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Rubella virus infection is typically diagnosed by the identification of rubella virus-specific immunoglobulinSymptomatic rubella is characterized by a mild fever and a maculopapular rash of short duration. The clinical diagnosis of rubella is unreliable, and many rash illnesses, such as those caused by measles virus and parvovirus B19, mimic rubella (2). Therefore, laboratory confirmation is essential for the diagnosis of rubella and is typically done by testing serum samples for rubella virus (RV)-specific immunoglobulin M (IgM) antibodies. Serum IgM and IgG responses to RV develop rapidly in the first few days after the onset of rash. However, approximately 50% of samples collected on the day of rash onset test negative for RV-specific IgM antibodies (1, 9, 17). Often, only a single serum sample taken near the time of rash onset is available, resulting in the lack of serologic confirmation of many rubella cases. Thus, the development of a rapid laboratory diagnostic tool for the confirmation of rubella within the first few days of symptom onset would improve the ability to confirm rubella.The isolation of virus in cell culture or the detection of viral RNA by reverse transcription-PCR (RT-PCR) also provides reliable evidence of RV infection (26). Unfortunately, blood is not a good sample for use for the detection of RV, because the highest viral titers in blood typically occur before the onset of rash and virus is undetectable in blood by 2 days after rash onset (6). The virus titer in throat swabs, however, usually reaches a peak titer on the day of rash onset and the titers in throat swabs decline more slowly than those in blood, so that virus can be detected for up to 5 to 7 days after rash onset (6). Several RT-PCR assays for the detection of the RV genome in clinical samples have been described (3,7,15,16,20,25). Templates for the determination of viral sequences for molecular epidemiology can also be made by using RT-PCR.The use of alternative specimens could help reduce the obstacles to specimen collection, storage, and transport in the field (22). Oral fluid (OF), which is collected by rubbing an absorptive device between the gum and the cheek, can be obtained by a method that is relatively noninvasive, is easier to obtain than blood, and has the advantage that it can be used for both RVspecific antibody detection and RV genome detection (12,19,20). Currently, in the United Kingdom, OF samples from notified clinically diagnosed cases are collected between 1 and 6 weeks after the onset of symptoms and are transported by mail to the Central Public Health Laboratory, where they are tested for specific antibody and viral RNA by RT-PCR. By the use of this strategy, specimens from 54.6% of rubella notifications from 1995 through 2001 were obtained for laboratory testing and specimens from 12.7% of the rubella notifications were confirmed to represent rubella cases (20,21).