Comparison of the Sensitivity of Laboratory Diagnostic Methods from a Well-Characterized Outbreak of Mumps in New York City in 2009

Rota, Jennifer S.; Rosen, Jennifer B; Doll, Margaret K.; McNall, Rebecca J.; McGrew, Marcia; Williams, Nobia J.; Lopareva, Elena N.; Barskey, Albert E.; Punsalang, Amado; Rota, Paul A.; Oleszko, William R.; Hickman, Carole J.; Zimmerman, Christopher; Bellini, William J.

doi:10.1128/cvi.00660-12

Cited by 75 publications

(69 citation statements)

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“…The Ebola virus outbreak in West Africa in 2014 (1) and the pandemic influenza A virus H1N1 outbreak in 2009 (2) are two recent examples. Some pathogens appear to reemerge in spite of available vaccines, such as mumps virus and measles virus (3)(4)(5). Effective controls are needed to combat these pathogens.…”

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confidence: 99%

Releasing the Genomic RNA Sequestered in the Mumps Virus Nucleocapsid

Severin

Terrell

Zengel

et al. 2016

J Virol

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In a negative-strand RNA virus, the genomic RNA is sequestered inside the nucleocapsid when the viral RNA-dependent RNA polymerase uses it as the template for viral RNA synthesis. It must require a conformational change in the nucleocapsid protein (N) to make the RNA accessible to the viral polymerase during this process. The structure of an empty mumps virus (MuV) nucleocapsid-like particle was determined to 10.4-Å resolution by cryo-electron microscopy (cryo-EM) image reconstruction. By modeling the crystal structure of parainfluenza virus 5 into the density, it was shown that the ␣-helix close to the RNA became flexible when RNA was removed. Point mutations in this helix resulted in loss of polymerase activities. Since the core of N is rigid in the nucleocapsid, we suggest that interactions between this region of the mumps virus N and its polymerase, instead of large N domain rotations, lead to exposure of the sequestered genomic RNA. Some pathogens appear to reemerge in spite of available vaccines, such as mumps virus and measles virus (3-5). Effective controls are needed to combat these pathogens. In order to develop more effective countermeasures, the mechanism of NSV replication should be better understood. One of the unique features in NSVs is that the genomic RNA is sequestered in the nucleocapsid (6). During transcription and replication, the viral RNA-dependent RNA polymerase (vRdRp) must be able to gain access to the sequestered genomic RNA in order to use it as the template. For Rhabdoviridae and Paramyxoviridae, the virus encodes a single nucleocapsid protein (N) that polymerizes as a linear capsid to encapsidate the genomic RNA (7). The viral polymerase complex consists of the large protein (L) and the phosphoprotein (P). IMPORTANCE Mumps virus (MuVThe structure of the nucleocapsid or a nucleocapsid-like particle has been solved for several members of Rhabdoviridae and Paramyxoviridae by X-ray crystallography or cryo-electron microscopy (cryo-EM) three-dimensional (3D) reconstruction (8-12). The common features among various structures are that the N protein has an N-terminal domain and C-terminal domain in its core, composed mostly of ␣-helices. When the N subunits assemble into a polymeric capsid, they are aligned in parallel in a linear fashion (13). There are extensive side-by-side interactions between the neighboring domains and domain swaps of extended loops and long termini. The genomic RNA is encapsidated in a cavity formed between the two core domains. Most of the RNA bases are stacked, some of which face the exterior and some the interior of the N protein core. The tight assembly of the nucleocapsid clearly suggests that vRdRp must open the N protein core in order to unveil the genomic RNA. How this action is carried out remains to be discovered. The interaction of the polymerase cofactor P with the nucleocapsid may provide some insights on this subject. The C-terminal domain of vesicular stomatitis virus (VSV) P protein binds between the extended loops in the C-terminal domains ...

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confidence: 99%

Releasing the Genomic RNA Sequestered in the Mumps Virus Nucleocapsid

Severin

Terrell

Zengel

et al. 2016

J Virol

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“…This is especially so where an enzyme immunoassay (EIA) is used as the diagnostic serology test, as this does not enable accurate quantification of antibody responses (18). Detection of IgM also presents diagnostic difficulties in vaccinated individuals, as a demonstrable increase in IgM levels following infection is often delayed or altogether absent in such individuals, even among those with positive RT-PCR results (16,18,22). The fact that the three IgM-positive serology specimens (see Table S3 [footnote]) had all been collected at Ն8 days after the onset of symptoms may be an indication of the need for delayed specimen collection when using IgM detection as a diagnostic test for mumps virus infection in vaccinated individuals.…”

Section: Discussionmentioning

confidence: 99%

“…With respect to serology, interpretation of results depends in part on the immunization history of the individual and the local prevalence of mumps, with most IgM-positive results in low-prevalence populations being false positives. Results of serological tests for IgM are often negative in individuals with acute wild-type mumps virus infections who have previously been vaccinated (16,19). In general, IgM analysis is considered acceptable as a diagnostic confirmatory test only if used in a patient who has been to a country where mumps is endemic or who is a contact of a patient with a confirmed case.…”

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confidence: 99%

“…Of these two tests, RT-PCR is considered the more sensitive and specific; however, virus is most likely to be detected in specimens taken from day 7 before to day 9 after the onset of symptoms, with one study reporting that the likelihood of detection of RNA, despite the use of a relatively sensitive technique, declined for specimens collected from a highly vaccinated outbreak population more than 2 days after symptom onset (3,15,16). The recommended collection time window for testing buccal and throat swabs in Ontario provincial guidelines is Յ9 days after symptom onset and, for urine, Յ14 days after onset (17).…”

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Challenges in Interpretation of Diagnostic Test Results in a Mumps Outbreak in a Highly Vaccinated Population

Trotz-Williams

Mercer

Paphitis

et al. 2017

Clin Vaccine Immunol

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In spite of a greatly reduced incidence rate due to vaccination, mumps outbreaks continue to occur in several areas of the world, sometimes in vaccinated populations. This article describes an outbreak in a highly vaccinated population in southwestern Ontario, Canada, and the challenges encountered in interpreting the results of diagnostic tests used in the outbreak. During the outbreak, patients were interviewed and classified according to the outbreak case definition, and specimens were collected for diagnostic testing according to Ontario guidelines. Twentyseven individuals were classified as confirmed cases (n ϭ 19) or suspect cases (n ϭ 8) according to the case definition, only 9 of which were laboratory-confirmed cases: 7 confirmed by reverse transcriptase PCR (RT-PCR) and 2 by IgM serology. All 19 confirmed cases represented patients who were associated with secondary schools in the local area and had been vaccinated against mumps with one (n ϭ 2) or two (n ϭ 17) doses of the measles-mumps-rubella (MMR) vaccine. This is the first published report of an outbreak of mumps in Ontario in which all confirmed cases had been vaccinated against the disease. It highlights the limitations of and difficulties in interpreting current mumps diagnostic tests when used in vaccinated individuals.

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“…In a previously vaccinated case the timing of serum collection and the choice of the assay are both important as these individuals may not produce adequate levels of detectable mumps-specific IgM. 36 During this outbreak, of the 183 case-patients with documented 2 doses of MMR vaccine, 27 (15%) were found to be mumps IgM antibody positive while among the 17 case-patients with documented 1 dose of MMR vaccine, 2 (12%) were found to be mumps IgM antibody positive. PCR testing was conducted initially but with the confirmation of the outbreak, it was stopped.…”

Section: Discussionmentioning

confidence: 99%