Viral Load and Cytokine Response Profile Does Not Support Antibody-Dependent Enhancement in Dengue-Primed Zika Virus–Infected Patients

Terzian, Ana Carolina Bernardes; Soares‐Schanoski, Alessandra; Mota, Mânlio Tasso de Oliveira; Silva, Rafael Alves da; Estofolete, Cássia Fernanda; Colombo, Tatiana Elias; Rahal, Paula; Hanley, Kathryn A.; Vasilakis, Nikos; Kalil, Jorge; Nogueira, Maurício Lacerda

doi:10.1093/cid/cix558

Cited by 91 publications

(87 citation statements)

References 25 publications

(35 reference statements)

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“…Nonetheless, it is imperative to consider the possible implications of virus-infection enhancement [43]. Moreover, none of the ZIKV patients in our study displayed severe symptoms to suggest occurrence of antibody-dependent enhancement (ADE) [24], and similar observations were also reported from Brazil [43,44].…”

Section: Discussionsupporting

confidence: 63%

Novel differential linear B-cell epitopes to identify Zika and dengue virus infections in patients

Amrun

Yee

Bakar

et al. 2019

Preprint

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word count: 200 words 35 Text word count: 3612 words 36 Abstract (200 words) 37 Background 38 Recent Zika virus (ZIKV) outbreaks challenged existing laboratory diagnostic 39 standards, especially for serology-based methods. Due to the genetic and structural 40 similarity of ZIKV with other flaviviruses, this results in cross-reactive antibodies 41 which confounds serological interpretations. 42 43 Methods 44 Plasma from Singapore ZIKV patients was screened longitudinally for antibody 45 responses and neutralizing capacities against ZIKV. Samples from healthy controls, 46ZIKV and DENV patients were further assessed using ZIKV and DENV peptides of 47 precursor membrane (prM), envelope (E) or non-structural 1 (NS1) viral proteins in a 48 peptide-based ELISA for epitope identification. Identified epitopes were re-validated 49 and diagnostically evaluated using sera of patients with DENV, bacteria or unknown 50 infections from Thailand. 51 52 Results 53Long-lasting ZIKV-neutralizing antibodies were elicited during ZIKV infection. 54Thirteen potential linear B-cell epitopes were identified and of these, four common 55 flavivirus, three ZIKV-specific, and one DENV-specific differential epitopes had more 56 than 50% sensitivities and specificities. Notably, ZIKV-specific peptide 26 on domain 57 I/II of E protein (amino acid residues 271-288) presented 80% sensitivity and 85.7% 58 specificity. Importantly, the differential epitopes also showed significance in 59 differentiating non-flavivirus patient samples. 60 61 Conclusions 62 Linear B-cell epitope candidates to differentiate ZIKV and DENV infections were 63 identified, providing the first step towards the design of a much-needed serology-64 based assay. 65 66 Methods 97 Ethics statement 98 Written informed consent was obtained from participants in accordance with the 99 tenets of the Declaration of Helsinki. Study protocols of Singapore ZIKV (2016-2018) 100 and DENV (2010-2012) patient cohorts were approved by the SingHealth 101 Centralized Institutional Review Board (CIRB Ref: 2016/2219) and National 102 Healthcare Group (NHG) Domain Specific Review Board (DSRB-E-2009/432) 103 respectively. Specimens from Singapore healthy donors (2010-2015) and patients 104 from Thailand (2011-2013) were collected in accordance to study guidelines of 105 approval numbers: NUS-IRB 09-256 and NUS-IRB 10-445; MUTM 2011-008-01, 106 OXTREC 42-10 and TCAB-01-11 respectively. 107 108 Study subjects and sample collection 109 Singapore ZIKV patients 110Collection of specimens from subjects during the ZIKV outbreak in 2016 was 111 previously described [24]. Briefly, 65 patients that were RT-PCR positive for ZIKV in 112 whole blood or urine, and negative for DENV RT-PCR were enrolled [25]. Whole 113 blood specimens were collected in EDTA-coated vacutainer tubes (Becton 114 Dickinson) after peripheral venipuncture and were centrifuged at 12000 rpm for 10 115 min. Plasma was collected and heat-inactivated for 30 min at 56°C before storage at 116 -80°C. Specimens were obtained over a period of si...

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Section: Discussionsupporting

confidence: 63%

Novel differential linear B-cell epitopes to identify Zika and dengue virus infections in patients

Amrun

Yee

Bakar

et al. 2019

Preprint

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“…33 Although patients from this cohort had detectable DENV IgG levels because of the high level of crossreactivity among flaviviruses, 7-10 DENV neutralisation was significantly less efficient compared to ZIKV, indicating that the antibodies were ZIKV-specific (Figure 1e, f and Supplementary figure 2). 35,36 Peptides identified from B-cell epitope mapping have been reported on flavivirus E, prM, NS1 and NS3 antigens from antibodies of patients and animal models. 34 Nonetheless, it is imperative to consider the possible implications of virusinfection enhancement.…”

Section: Discussionmentioning

confidence: 99%

“…35 Moreover, none of the ZIKV patients in our study displayed severe symptoms to suggest occurrence of antibodydependent enhancement (ADE), 30 and similar observations were also reported from Brazil. 35,36 Peptides identified from B-cell epitope mapping have been reported on flavivirus E, prM, NS1 and NS3 antigens from antibodies of patients and animal models. 31,37,38 Identification of antigenic epitopes and characterisation of cross-reactive epitopes are crucial in vaccine and immunodiagnostic developments.…”

Section: Discussionmentioning

confidence: 99%

Novel differential linear B‐cell epitopes to identify Zika and dengue virus infections in patients

et al. 2019

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Objectives Recent Zika virus (ZIKV) outbreaks challenged existing laboratory diagnostic standards, especially for serology‐based methods. Because of the genetic and structural similarity of ZIKV with other flaviviruses, this results in cross‐reactive antibodies, which confounds serological interpretations. Methods Plasma from Singapore ZIKV patients was screened longitudinally for antibody responses and neutralising capacities against ZIKV. Samples from healthy controls, ZIKV patients and DENV patients were further assessed using ZIKV and DENV peptides of precursor membrane (prM), envelope (E) or non‐structural 1 (NS1) viral proteins in a peptide‐based ELISA for epitope identification. Identified epitopes were re‐validated and diagnostically evaluated using sera of patients with DENV, bacteria or unknown infections from Thailand. Results Long‐lasting ZIKV‐neutralising antibodies were elicited during ZIKV infection. Thirteen potential linear B‐cell epitopes were identified, and of these, four common flavivirus, three ZIKV‐specific and one DENV‐specific differential epitopes had more than 50% sensitivity and specificity. Notably, ZIKV‐specific peptide 26 on domain I/II of E protein (amino acid residues 271–288) presented 80% sensitivity and 85.7% specificity. Importantly, the differential epitopes also showed significance in differentiating non‐flavivirus patient samples. Conclusion Linear B‐cell epitope candidates to differentiate between ZIKV and DENV infections were identified, providing the first step towards the design of a much‐needed serology‐based assay.

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“…More epidemiological studies in humans are necessary to establish whether clinically relevant ADE of ZIKV pathogenesis occurs. An analysis of Brazilian cohorts has not shown evidence of ADE, greater disease severity or effects on birth outcomes in DENV-experienced patients with acute ZIKV infection 198,199 .…”

Section: Emerging and Re-emerging Threatsmentioning

confidence: 98%

The continued threat of emerging flaviviruses

Pierson

Diamond²

2020

Nat Microbiol

668

627

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F laviviruses are single-stranded RNA viruses vectored principally by arthropods that cause severe illnesses in humans. The extensive global spread and epidemic transmission of flaviviruses during the last seven decades has been remarkable. The mosquito-borne dengue viruses (DENV) infect an estimated 400 million humans each year; more than a quarter of the world's population lives in areas where DENV is now endemic 1 . By comparison, only sporadic DENV epidemics were documented before the Second World War 2 . The introductions of West Nile (WNV) and Zika (ZIKV) viruses into the Western Hemisphere was followed by rapid geographical spread, large numbers of human infections and considerable morbidity 3,4 . Ongoing yellow fever virus (YFV) transmission and its encroachment on urban environments, despite the existence of an effective vaccine, poses a serious public health challenge 5-7 . Other flaviviruses present ongoing health risks or are beginning to emerge in different parts of the world, including Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV) and Usutu virus (USUV).The epidemic potential of flaviviruses reflects many factors related to the unique characteristics of their insect vectors, the consequences of poorly planned urbanization that creates ideal arthropod breeding habitats, the geographical expansion of vectors, changing environmental conditions and extensive global travel 8,9 . Beyond arthropods and humans, flaviviruses are also known to infect a wide array of animal species and can be important veterinary pathogens that threaten economically important domesticated animals 10-14 . These vertebrate animal hosts may constitute important stable reservoirs and contribute to defining conditions that support the introduction of new viral species and transmission among humans 15 . The continued threat of flavivirus emergence and re-emergence highlights a need for a detailed fundamental understanding of the biology of these viruses, the immune responses that can contain them and the possible countermeasures that can blunt their impact on public health should new outbreaks occur. Flavivirus structure and replicationFlaviviruses are small (~50 nm) spherical virus particles that incorporate a single genomic RNA of positive-sense polarity encoding three structural and seven non-structural proteins (Fig. 1a). Our knowledge of the biology of flaviviruses has advanced considerably with the availability of high-resolution structures of viral structural proteins and of virions at different stages of the replication cycle or in complex with antibodies or host factors 16 . Crystal structures of the enzymatic non-structural proteins also have been solved, accelerating advances in an understanding of virus replication and pathogenesis [17][18][19] and enabling structure-guided drug discovery, as reviewed elsewhere 20 .Virion structure and morphogenesis. Flaviviruses are assembled using three viral structural proteins (C, prM and E), a host lipid envelope and the viral genomic RNA. The structure of ...

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Viral Load and Cytokine Response Profile Does Not Support Antibody-Dependent Enhancement in Dengue-Primed Zika Virus–Infected Patients

Abstract: No signs of ADE were observed in vivo in patients with acute ZIKV infection who had prior exposure to DENV.

Cited by 91 publications

References 25 publications

Novel differential linear B-cell epitopes to identify Zika and dengue virus infections in patients

Novel differential linear B-cell epitopes to identify Zika and dengue virus infections in patients

Novel differential linear B‐cell epitopes to identify Zika and dengue virus infections in patients

The continued threat of emerging flaviviruses

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