Research Article: Sero-Prevalence and Cross-Reactivity of Chikungunya Virus Specific Anti-E2EP3 Antibodies in Arbovirus-Infected Patients

Date Published: January 8, 2015

Publisher: Public Library of Science

Author(s): Yiu-Wing Kam, Kwoon-Yong Pok, Kai Er Eng, Li-Kiang Tan, Simrandeep Kaur, Wendy W. L. Lee, Yee-Sin Leo, Lee-Ching Ng, Lisa F. P. Ng, Ann M. Powers.

Abstract: Chikungunya virus (CHIKV) and clinically-related arboviruses cause large epidemics with serious economic and social impact. As clinical symptoms of CHIKV infections are similar to several flavivirus infections, good detection methods to identify CHIKV infection are desired for improved treatment and clinical management. The strength of anti-E2EP3 antibody responses was explored in a longitudinal study on 38 CHIKV-infected patients. We compared their anti-E2EP3 responses with those of patients infected with non-CHIKV alphaviruses, or flaviviruses. E2EP3 cross-reactive samples from patients infected with non-CHIKV viruses were further analyzed with an in vitro CHIKV neutralization assay. CHIKV-specific anti-E2EP3 antibody responses were detected in 72% to 100% of patients. Serum samples from patients infected with other non-CHIKV alphaviruses were cross-reactive to E2EP3. Interestingly, some of these antibodies demonstrated clearly in vitro CHIKV neutralizing activity. Contrastingly, serum samples from flaviviruses-infected patients showed a low level of cross-reactivity against E2EP3. Using CHIKV E2EP3 as a serology marker not only allows early detection of CHIKV specific antibodies, but would also allow the differentiation between CHIKV infections and flavivirus infections with 93% accuracy, thereby allowing precise acute febrile diagnosis and improving clinical management in regions newly suffering from CHIKV outbreaks including the Americas.

Partial Text: Chikungunya virus (CHIKV) has re-emerged as an important arbovirus that has caused unprecedented Chikungunya Fever (CHIKF) epidemics in Asia, Africa and more recently in the Americas [1]–[5]. Typical symptoms caused by CHIKV infection include fever, headache, myalgia, rash and debilitating arthralgia [6], [7]. These symptoms are largely similar to those caused by other arboviruses, especially the flaviviruses such as dengue virus (DENV) [8], [9]. In regions where DENV infections are endemic, there is also a likelihood of CHIKV infection as the two viruses share the common mosquito vectors Aedes (Ae.) aegypti and Ae. albopictus. Cases of CHIKV and DENV co-infection have been reported [10]–[13], surveillance systems in endemic regions have to be revised in order to manage this complicating situation. There is an increasing need for clinicians to differentiate between these two infections, and implement disease monitoring strategies in a timely manner.

It was previously shown that E2EP3 is a dominant early serology marker in CHIKV-infected patient cohorts [20]. Here, we extend the study to another population cohort to investigate the sero-prevalence of anti-E2EP3 IgG antibodies in CHIKV-infected patients and also assess whether patients infected with other arboviruses (Fig. 1A) with similar clinical manifestations such as fever, myalgia, and arthralgia have cross-reactive antibodies against E2EP3.

In this study, the sero-prevalence of anti-E2EP3 IgG antibodies in patients infected with CHIKV as well as non-CHIKV viruses was analyzed in detail. Anti-E2EP3 IgG antibodies were detectable by ELISA as early as 1 day PIO in CHIKV-infected patients. Moreover, it was demonstrated that in comparison with the existing indirect immunofluorescence test (IIFT) for CHIKV detection, the E2EP3 peptide-based ELISA was able to detect anti-CHIKV antibodies in a higher percentage of patient samples taken during the acute and early convalescent phases of disease. More than 95% sero-prevalence of anti-E2EP3 IgG antibodies from as early as 6 days PIO was detected with the E2EP3 peptide-based ELISA. The timing of sample collection affects the detectability of antibody responses to CHIKV infection. Here, detection of anti-E2EP3 IgG antibodies would be a good early serology detection approach for samples taken from 6 days up to 29 days PIO.



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