Human Survivors of Disease Outbreaks Caused by Ebola or Marburg Virus Exhibit Cross-Reactive and Long-Lived Antibody Responses

Natarajan, Mohan; Jensen, Sandra; Keasey, Sarah L.; Kamata, Teddy; Kuehne, Ana I.; Stonier, Spencer W.; Lutwama, Julius J.; Lobel, Leslie; Dye, John M.; Ulrich, Robert G.

doi:10.1128/cvi.00107-16

Cited by 45 publications

(43 citation statements)

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“…A comparative study of ELISA methods using antigens prepared from all species of the genus Ebolavirus (Macneil et al, 2011) showed cross-reactivity to be considerable, but another study considered it to be more limited (Nakayama et al, 2010). In a clinical context, sera from survivors of outbreaks displayed cross-reactivity to recombinant proteins from other filovirus species, which had been bound to a protein microarray (Natesan et al, 2016), and mAbs raised against the glycoproteins (GPs) of BDBV, SUDV and EBOV exhibit some cross-specific in vitro binding. In the Table 2.…”

Section: Laboratory Evidence For Inter-specific Cross-reactivitymentioning

confidence: 99%

The serology of Ebolavirus – a wider geographical range, a wider genus of viruses or a wider range of virulence?

Formella

Gatherer

2016

Journal of General Virology

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Viruses of the genus Ebolavirus are the causative agents of Ebola virus disease (EVD), of which there have been only 25 recorded outbreaks since the discovery of Zaire and Sudan ebolaviruses in the late 1970s. Until the west African outbreak commencing in late 2013, EVD was confined to an area of central Africa stretching from the coast of Gabon through the Congo river basin and eastward to the Great Lakes. Nevertheless, population serological studies since 1976, most of which were carried out in the first two decades after that date, have suggested a wider distribution and more frequent occurrence across tropical Africa. We review this body of work, discussing the various methods employed over the years and the degree to which they can currently be regarded as reliable. We conclude that there is adequate evidence for a wider geographical range of exposure to Ebolavirus or related filoviruses and discuss three possibilities that could account for this: (a) EVD outbreaks have been misidentified as other diseases in the past; (b) unidentified, and clinically milder, species of the genus Ebolavirus circulate over a wider range than the most pathogenic species; and (c) EVD may be subclinical with a frequency high enough that smaller outbreaks may be unidentified. We conclude that the second option is the most likely and therefore predict the future discovery of other, less virulent, members of the genus Ebolavirus.

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Section: Laboratory Evidence For Inter-specific Cross-reactivitymentioning

confidence: 99%

The serology of Ebolavirus – a wider geographical range, a wider genus of viruses or a wider range of virulence?

Formella

Gatherer

2016

Journal of General Virology

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“…Several studies reported extensive serological cross-reactions between nucleoproteins of the different Ebola virus lineages. For example, a recent study by Natesan and coworkers (27) reported on reactions and cross-reactions of samples collected from 37 and 20 survivors of SUDV and BDBV infections, respectively. They found that 100% of samples from survivors of BDBV infection cross-reacted with NPs from SUDV, while this proportion was only 25% with GPs.…”

Section: Discussionmentioning

confidence: 99%

Development of a Sensitive and Specific Serological Assay Based on Luminex Technology for Detection of Antibodies to Zaire Ebola Virus

et al. 2017

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The recent Zaire Ebola virus (EBOV) outbreak in West Africa illustrates clearly the need for additional studies with humans and animals to elucidate the ecology of Ebola viruses (EBVs). In this study, we developed a serological assay based on the Luminex technology. Nine recombinant proteins representing different viral regions (nucleoprotein [NP], 40-kDa viral protein [VP40], and glycoprotein [GP]) from four of the five EBV lineages were used. Samples from 94 survivors of the EBOV outbreak in Guinea and negative samples from 108 patients in France were used to calculate test performance for EBOV detection and cross-reaction with other Ebola virus lineages. For EBOV antibody detection, sensitivities of 95.7%, 96.8%, and 92.5% and specificities of 94.4%, 95.4%, and 96.3% for NP, GP, and VP40, respectively, were observed. All EBOV-negative samples that presented a reaction, except for one, interacted with a single antigen, whereas almost all samples from EBOV survivors were simultaneously reactive with NP and GP (90/94) or with NP, GP, and VP40 (87/94). Considering as positive for past EBOV infection only samples that reacted with EBOV NP and GP, sensitivity was 95.7% and specificity increased to 99.1%. Comparing results with commercial EBOV NP and GP enzyme-linked immunosorbent assays (ELISAs; Alpha Diagnostic, San Antonio, TX), lower sensitivity (92.5%) and high specificity (100%) were observed with the same positivity criteria. Samples from EBOV survivors cross-reacted with GP from Sudan Ebola virus (GP-SUDV) (81.9%), GP from Bundibugyo Ebola virus (GP-BDBV) (51.1%), GP from Reston Ebola virus (GP-RESTV) (9.6%), VP40-SUDV (76.6%), and VP40-BDBV (38.3%). Overall, we developed a sensitive and specific high-throughput serological assay, and defined an algorithm, for epidemiological surveys with humans.KEYWORDS Ebola virus, serology, Luminex, recombinant proteins S ince 1976 and the first formal identification of Ebola virus (EBV) disease in Yambuku, in the Democratic Republic of Congo (DRC), a total of 25 outbreaks have been reported today among humans in Africa, with a fatality rate between 25% and 90% (1). Twenty-three of the 25 Ebola virus disease outbreaks occurred in Central Africa, while two occurred in West Africa, including the most devastating outbreak in Guinea/ Liberia/Sierra Leone between 2013 and 2016, infecting more than 28,000 persons and causing 11,308 deaths (2, 3). For unknown reasons, no Ebola virus disease epidemics were detected between the 1979 outbreak in DRC and the 1994 outbreak in Côte D'Ivoire. However, since 1999, the frequency of outbreaks has increased (1, 2, 4). There are currently five species of Ebola viruses: Zaire Ebola virus (EBOV) documented in the

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“…Multiplexed surveillance assays that include both endemic and nonendemic viruses will be important for monitoring disease outbreaks and spread to new geographic regions. Further, the ability to expand this multiplex assay by the addition of new antigens that are synthesized from sequence data will provide a means to rapidly incorporate assays for new pathogens into disease surveillance matrices (29)(30)(31)61).…”

Section: Figmentioning

confidence: 99%

“…In the absence of viremia, enzyme-linked immunosorbent assays (ELISAs) and plaque reduction neutralization tests can be used to detect virus-specific antibodies, but these methods are not amenable to high-throughput analysis, and live-virus assays may require biosafety level 3 laboratory containment. Alternatively, serological assays that employ individually expressed viral proteins often yield species-specific signals with fewer cross-reactive antibody interactions than those that use whole viruses (29,30). Further, assays based on protein microarrays are easily scaled to process large numbers of specimens against expandable antigen panels (29)(30)(31)).…”

mentioning

confidence: 99%

“…Alternatively, serological assays that employ individually expressed viral proteins often yield species-specific signals with fewer cross-reactive antibody interactions than those that use whole viruses (29,30). Further, assays based on protein microarrays are easily scaled to process large numbers of specimens against expandable antigen panels (29)(30)(31)). An examination of the alphavirus proteome suggests several possible antigens that could be included in a microarray for analysis of antibody responses.…”

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Human Antibody Responses to Emerging Mayaro Virus and Cocirculating Alphavirus Infections Examined by Using Structural Proteins from Nine New and Old World Lineages

Smith

Pugh

Cisney

et al. 2018

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Mayaro virus (MAYV), Venezuelan equine encephalitis virus (VEEV), and chikungunya virus (CHIKV) are vector-borne alphaviruses that cocirculate in South America. Human infections by these viruses are frequently underdiagnosed or misdiagnosed, especially in areas with high dengue virus endemicity. Disease may progress to debilitating arthralgia (MAYV, CHIKV), encephalitis (VEEV), and death. Few standardized serological assays exist for specific human alphavirus infection detection, and antigen cross-reactivity can be problematic. Therefore, serological platforms that aid in the specific detection of multiple alphavirus infections will greatly expand disease surveillance for these emerging infections. In this study, serum samples from South American patients with PCR-and/or isolation-confirmed infections caused by MAYV, VEEV, and CHIKV were examined by using a protein microarray assembled with recombinant capsid, envelope protein 1 (E1), and E2 from nine New and Old World alphaviruses. Notably, specific antibody recognition of E1 was observed only with MAYV infections, whereas E2 was specifically targeted by antibodies from all of the alphavirus infections investigated, with evidence of cross-reactivity to E2 of o'nyong-nyong virus only in CHIKV-infected patient serum samples. Our findings suggest that alphavirus structural protein microarrays can distinguish infections caused by MAYV, VEEV, and CHIKV and that this multiplexed serological platform could be useful for high-throughput disease surveillance.IMPORTANCE Mayaro, chikungunya, and Venezuelan equine encephalitis viruses are closely related alphaviruses that are spread by mosquitos, causing diseases that produce similar influenza-like symptoms or more severe illnesses. Moreover, alphavirus infection symptoms can be similar to those of dengue or Zika disease, leading to underreporting of cases and potential misdiagnoses. New methods that can be used to detect antibody responses to multiple alphaviruses within the same assay would greatly aid disease surveillance efforts. However, possible antibody cross-reactivity between viruses can reduce the quality of laboratory results. Our results demonstrate that antibody responses to multiple alphaviruses can be specifically quantified within the same assay by using selected recombinant protein antigens and further show that Mayaro virus infections result in unique responses to viral envelope proteins.

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Human Survivors of Disease Outbreaks Caused by Ebola or Marburg Virus Exhibit Cross-Reactive and Long-Lived Antibody Responses

Cited by 45 publications

References 53 publications

The serology of Ebolavirus – a wider geographical range, a wider genus of viruses or a wider range of virulence?

The serology of Ebolavirus – a wider geographical range, a wider genus of viruses or a wider range of virulence?

Development of a Sensitive and Specific Serological Assay Based on Luminex Technology for Detection of Antibodies to Zaire Ebola Virus

Human Antibody Responses to Emerging Mayaro Virus and Cocirculating Alphavirus Infections Examined by Using Structural Proteins from Nine New and Old World Lineages

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