Suggested new breakpoints of anti-MERS-CoV antibody ELISA titers: performance analysis of serologic tests
- 344 Downloads
To provide optimal cut-off values of anti-Middle East respiratory syndrome coronavirus (MERS-CoV) serologic tests, we evaluated performance of ELISA IgG, ELISA IgA, IFA IgM, and IFA IgG using 138 serum samples of 49 MERS-CoV-infected patients and 219 serum samples of 219 rRT-PCR-negative MERS-CoV-exposed healthcare personnel and patients. The performance analysis was conducted for two different purposes: (1) prediction of neutralization activity in MERS-CoV-infected patients, and (2) epidemiologic surveillance of MERS-CoV infections among MERS-CoV-exposed individuals. To evaluate performance according to serum collection time, we used ‘days post onset of illness (dpoi)’ and ‘days post exposure (dpex)’ assessing neutralization activity and infection diagnosis, respectively. Performance of serologic tests improved with delayed sampling time, being maximized after a seroconversion period. In predicting neutralization activity, ELISA IgG tests showed optimal performance using sera collected after 21 dpoi at cut-off values of OD ratio 0.4 (sensitivity 100% and specificity 100%), and ELISA IgA showed optimal performance using sera collected after 14 dpoi at cut-off value of OD ratio 0.2 (sensitivity 85.2% and specificity 100%). In diagnosis of MERS-CoV infection, ELISA IgG exhibited optimal performance using sera collected after 28 dpex, at a cut-off value of OD ratio 0.2 (sensitivity 97.3% and specificity 92.9%). These new breakpoints are markedly lower than previously suggested values (ELISA IgG OD ratio 1.1, sensitivity 34.8% and specificity 100% in the present data set), and the performance data help serologic tests to be practically used in the field of MERS management.
KeywordsMiddle East respiratory syndrome coronavirus Serology Antibody Sensitivity Specificity
We would like to express our sincerest condolences to the patients and families who suffered from the MERS outbreak. We also greatly appreciate the HCP and staff members at Samsung Medical Center and all other hospitals who worked together to overcome the MERS outbreak. Finally, we would like to thank Jinseob Kim for statistical advice and figure development, as well as Mingu Kang for IFA testing.
Compliance with ethical standards
This work was supported by a Samsung Biomedical Research Institute (SBRI) grant [#SMX1161321]. CD reports funding by EU grants Antigone (GA no. 278976) and Prepare (GA no. 602525).
Conflicts of interest
There are no potential conflicts of interest relevant to this article to report.
This study was approved by the Institutional Review Board of Samsung Medical Center.
As a retrospective study, the Institutional Review Board waived informed consent in the present study.
- 2.Arabi YM, Hajeer AH, Luke T, Raviprakash K, Balkhy H, Johani S, Al-Dawood A, Al-Qahtani S, Al-Omari A, Al-Hameed F, Hayden FG, Fowler R, Bouchama A, Shindo N, Al-Khairy K, Carson G, Taha Y, Sadat M, Alahmadi M (2016) Feasibility of using convalescent plasma immunotherapy for MERS-CoV infection, Saudi Arabia. Emerg Infect Dis 22:1554–1561. doi: 10.3201/eid2209.151164 CrossRefPubMedPubMedCentralGoogle Scholar
- 3.Ko JH, Lee JY, Baek JY, Seok H, Park GE, Lee JY, Cho SY, Ha YE, Kang CI, Kang JM, Kim YJ, Kang ES, Kim SH, Jo IJ, Chung CR, Hahn MJ, Muller MA, Drosten C, Chung DR, Song JH, Peck KR (2017) Serologic evaluation of MERS screening strategy for healthcare personnel during a hospital-associated outbreak. Infect Control Hosp Epidemiol 38:234–238. doi: 10.1017/ice.2016.251 CrossRefPubMedGoogle Scholar
- 4.Park WB, Perera RA, Choe PG, Lau EH, Choi SJ, Chun JY, Oh HS, Song KH, Bang JH, Kim ES, Kim HB, Park SW, Kim NJ, Man Poon LL, Peiris M, Oh MD (2015) Kinetics of serologic responses to MERS coronavirus infection in humans, South Korea. Emerg Infect Dis 21:2186–2189. doi: 10.3201/eid2112.151421 CrossRefPubMedPubMedCentralGoogle Scholar
- 5.Corman VM, Albarrak AM, Omrani AS, Albarrak MM, Farah ME, Almasri M, Muth D, Sieberg A, Meyer B, Assiri AM, Binger T, Steinhagen K, Lattwein E, Al-Tawfiq J, Muller MA, Drosten C, Memish ZA (2016) Viral shedding and antibody response in 37 patients with Middle East respiratory syndrome coronavirus infection. Clin Infect Dis 62:477–483. doi: 10.1093/cid/civ951 PubMedGoogle Scholar
- 6.Muller MA, Meyer B, Corman VM, Al-Masri M, Turkestani A, Ritz D, Sieberg A, Aldabbagh S, Bosch BJ, Lattwein E, Alhakeem RF, Assiri AM, Albarrak AM, Al-Shangiti AM, Al-Tawfiq JA, Wikramaratna P, Alrabeeah AA, Drosten C, Memish ZA (2015) Presence of Middle East respiratory syndrome coronavirus antibodies in Saudi Arabia: a nationwide, cross-sectional, serological study. Lancet Infect Dis 15:559–564. doi: 10.1016/s1473-3099(15)70090-3 CrossRefPubMedGoogle Scholar
- 7.Euroimmun (2014) Anti-MERS-CoV ELISA (IgG) Test instruction, EUROIMMUN, Lübeck, Germany, El_2604G_A_UK_C01.doc, Version: 06/10/2014Google Scholar
- 8.Park GE, Ko JH, Peck KR, Lee JY, Lee JY, Cho SY, Ha YE, Kang CI, Kang JM, Kim YJ, Huh HJ, Ki CS, Lee NY, Lee JH, Jo IJ, Jeong BH, Suh GY, Park J, Chung CR, Song JH, Chung DR (2016) Control of an outbreak of Middle East respiratory syndrome in a tertiary Hospital in Korea. Ann Intern Med 165:87–93. doi: 10.7326/m15-2495 CrossRefPubMedGoogle Scholar
- 9.Ko JH, Park GE, Lee JY, Lee JY, Cho SY, Ha YE, Kang CI, Kang JM, Kim YJ, Huh HJ, Ki CS, Jeong BH, Park J, Chung CR, Chung DR, Song JH, Peck KR (2016) Predictive factors for pneumonia development and progression to respiratory failure in MERS-CoV infected patients. J Inf Secur 73:468–475. doi: 10.1016/j.jinf.2016.08.005 Google Scholar
- 11.Corman VM, Eckerle I, Bleicker T, Zaki A, Landt O, Eschbach-Bludau M, van Boheemen S, Gopal R, Ballhause M, Bestebroer TM, Muth D, Muller MA, Drexler JF, Zambon M, Osterhaus AD, Fouchier RM, Drosten C (2012) Detection of a novel human coronavirus by real-time reverse-transcription polymerase chain reaction. Euro Surveill 17Google Scholar
- 12.Drosten C, Meyer B, Muller MA, Corman VM, Al-Masri M, Hossain R, Madani H, Sieberg A, Bosch BJ, Lattwein E, Alhakeem RF, Assiri AM, Hajomar W, Albarrak AM, Al-Tawfiq JA, Zumla AI, Memish ZA (2014) Transmission of MERS-coronavirus in household contacts. N Engl J Med 371:828–835. doi: 10.1056/NEJMoa1405858 CrossRefPubMedGoogle Scholar
- 13.Raj VS, Mou H, Smits SL, Dekkers DH, Muller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel V, Drosten C, Rottier PJ, Osterhaus AD, Bosch BJ, Haagmans BL (2013) Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 495:251–254. doi: 10.1038/nature12005 CrossRefPubMedGoogle Scholar
- 14.Muth D, Corman VM, Meyer B, Assiri A, Al-Masri M, Farah M, Steinhagen K, Lattwein E, Al-Tawfiq JA, Albarrak A, Muller MA, Drosten C, Memish ZA (2015) Infectious Middle East respiratory syndrome coronavirus excretion and serotype variability based on live virus isolates from patients in Saudi Arabia. J Clin Microbiol 53:2951–2955. doi: 10.1128/jcm.01368-15 CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Corman VM, Muller MA, Costabel U, Timm J, Binger T, Meyer B, Kreher P, Lattwein E, Eschbach-Bludau M, Nitsche A, Bleicker T, Landt O, Schweiger B, Drexler JF, Osterhaus AD, Haagmans BL, Dittmer U, Bonin F, Wolff T, Drosten C (2012) Assays for laboratory confirmation of novel human coronavirus (hCoV-EMC) infections. Euro Surveill 17Google Scholar
- 16.Kim CJ, Choi WS, Jung Y, Kiem S, Seol HY, Woo HJ, Choi YH, Son JS, Kim KH, Kim YS, Kim ES, Park SH, Yoon JH, Choi SM, Lee H, Oh WS, Choi SY, Kim NJ, Choi JP, Park SY, Kim J, Jeong SJ, Lee KS, Jang HC, Rhee JY, Kim BN, Bang JH, Lee JH, Park S, Kim HY, Choi JK, Wi YM, Choi HJ (2016) Surveillance of the Middle East respiratory syndrome (MERS) coronavirus (CoV) infection in healthcare workers after contact with confirmed MERS patients: incidence and risk factors of MERS-CoV seropositivity. Clin Microbiol Infect 22:880–886. doi: 10.1016/j.cmi.2016.07.017 CrossRefPubMedGoogle Scholar