Potential Antigenic Cross-reactivity Between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Dengue Viruses

Abstract

BACKGROUND COVID-19 and dengue fever are difficult to distinguish given shared clinical and laboratory features. Failing to consider COVID-19 due to false-positive dengue serology can have serious implications. We aimed to assess this possible cross reactivity. METHODS We analyzed clinical data and serum samples from 55 individuals with SARS-CoV-2 infection. To assess dengue serology-status, we used dengue-specific antibodies by means of lateral-flow rapid test as well as enzyme-linked-immunosorbent-assay (ELISA). Additionally, we tested SARS-CoV-2 serology-status in patients with dengue and performed in-silico protein structural analysis to identify epitope similarities. RESULTS Using the dengue lateral-flow rapid test we detected 12 positive cases out of the 55 (21.8%) COVID-19 patients versus zero positive cases in a control group of 70 healthy individuals (P= 2.5E-5). This includes nine cases of positive IgM, two cases of positive IgG and one case of positive IgM as well as IgG antibodies. ELISA testing for dengue was positive in two additional subjects using envelope-protein directed antibodies. Out of 95 samples obtained from patients diagnosed with dengue before September 2019, SARS-CoV-2 serology targeting the S protein was positive/equivocal in 21 (22%) (sixteen IgA, five IgG) versus four positives/equivocal in 102 controls (4%) (P= 1.6E-4). Subsequent in-silico analysis revealed possible similarities between SARS-CoV-2 epitopes in the HR2-domain of the spike-protein and the dengue envelope-protein. CONCLUSIONS Our findings support possible cross-reactivity between dengue virus and SARS-CoV-2, which can lead to false-positive dengue serology among COVID-19 patients and vice versa. This can have serious consequences for both patient care and public health.

Covert cases of Severe Acute Respiratory Syndrome Coronavirus 2: An obscure but present danger in regions endemic for Dengue and Chikungunya viruses

“…According to different authors, cross-reactivity with other seasonal coronavirus, such as E229, OC43, HKU1, and NL63, was not observed when COVID-19 serum samples were tested by Abbott Laboratories SARS-CoV-2 IgG CMIA [ 21 – 23 ]. Occurrence of cross-reactivity between Dengue and SARS-CoV-2 antibodies [ 10 , 12 , 24 ], was not corroborated by results presented here as well as from other authors [ 25 ]. We demonstrated that all 84 (100%) Dengue-positive samples, collected between 2009 and 2010, tested negative for the presence of anti-SARS-Cov-2 IgG ( Table 1 ; Fig 4 ).…”

“…We demonstrated that all 84 (100%) Dengue-positive samples, collected between 2009 and 2010, tested negative for the presence of anti-SARS-Cov-2 IgG ( Table 1 ; Fig 4 ). It is important to point out that previous reports suggesting cross-reactivity between Dengue and SARS-CoV-2 antibodies were based on limited sample size and exclusively on data acquired using lateral flow immunochromatographic rapid diagnostic test (RDT) [ 10 , 12 , 24 ]. In the early days of the COVID-19 pandemic, serology results were primarily obtained from RDT, which, despite a high specificity (≥99%), present a lower sensitivity when compared to CLIA/CMIA [ 25 – 27 ]; explaining why accuracy and reliability of RDT for Dengue and SARS-CoV-2 diagnosis are still so disputable [ 12 , 24 , 25 , 28 ].…”

Nucleoprotein-based ELISA for detection of SARS-COV-2 IgG antibodies: Could an old assay be suitable for serodiagnosis of the new coronavirus?

“…In countries like Brazil, where dengue fever and other arboviruses are endemic problems, the possibility of cross-reactions with SARS-CoV-2 could be a challenge ( Nath et al, 2020 ; Yan et al, 2020 ; Lustig et al, 2020 ; Lorenz et al, 2020 ). Although these arboviruses do not cause respiratory disease, they can be difficult to distinguish from COVID-19 as both can elicit similar extra-pulmonary manifestations such as fever, cutaneous rash and conjunctivitis.…”

A case of DENV and SARS-CoV-2 coinfection in Indonesia: The challenge of a dual outbreak?

“…This study noted that the structure similarity between the two viruses as the potential cause for the cross-reactivity. 14 In our setting, the failure to recognize the SARS-CoV-2 infection due to this reason may cause further spread of COVID-19 due to false sense of security and lack of isolation.…”