Dengue virus evolution in Southern Vietnam over the last ten years and utility of DENV-NSI as a diagnostic marker

Vu Thi Ty Hang (2010). Dengue virus evolution in Southern Vietnam over the last ten years and utility of DENV-NSI as a diagnostic marker. PhD thesis The Open University.



Dengue is a major public health problem in many parts of the tropical developing world. Dengue is caused by infection with one of four serotypes of dengue virus (DENV1-4), which are arboviruses belonging to the Flaviviridae family. Although most DENV infections are asymptomatic, mild, or self-limited, a proportion of dengue fever cases result in clinically apparent disease that varies in severity from mild undifferentiated fever through to more severe syndromes, primarily dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS).

The main work described in this thesis was to examine molecular epidemiology of DENV over the last 10 years in southern Vietnam (1999-2008) and to document DENV molecular epidemiology in the 2007 dengue outbreak in Dong Thap province, a Mekong Delta province, southern Vietnam. A further purpose was to assess the utility of two commercial NS1 antigen test kits, Platelia NSI-ELISA and NSI-Lateral Flow Rapid (NSI-LFRT), for early diagnosis of acute dengue infection in relation to immune status, DENV-reactive measurable IgM/lgG, viraemia level, and duration of illness prior to patient specimen collection.

Sequence analyses of Vietnamese DENV-1 and DENV-2 revealed that these viruses comprised significant genetic diversity. DENV-2 exhibits 3 distinct genotypes, American/Asian, Asian I and Cosmopolitan. DENV-1 viruses have become predominant in Vietnam since 2006, and circulate as 6 distinct lineages within genotype 1. The most striking finding of this work was the replacement of DENV-2 genotype in the context of serotype shift occurring in southern Vietnam; both of which were temporally linked to increased disease incidence. The American/Asian genotype which has circulated in HCMC and surrounding provinces since at least 1987 was displaced by the DENV-2 Asian I genotype preceding the change in serotype from DENV-2 to DENV-1. However, negative selection appears to be the major evolutionary factor impacting DENV population dynamics.

Evaluation of the diagnostic accuracy for the two commercial NS1 test kits consistently showed that viraemia level in acute phase NS1-positive patients is higher than in NS1-negative patients. NS1 sensitivity was also greater in patients with primary infection.

Proportion of NS1 positivity was generally greater in DF cases. Duration of fever time prior to patient blood samples collected also contributes to NS I sensitivity. Both DENY-reactive IgG and IgM were negatively correlated with NS1 sensitivity, but IgG showed stronger influence on NS1 positivity rate. NS1 sensitivity is also different in individual infecting serotypes; DENY-2 consistently shows lower positive NS1 results for both test kits. Overall, NS1-LFRT was modestly less sensitive than Platelia NS1-ELISA but importantly, both Platelia NS1-ELISA and NS1-LFRT retain extremely high specificity of 100%.

With a large number of whole DENY genome sequences generated in this study, it is a massive contribution to the DENY genome data in GenBank. In addition, results presented in this study contribute to current knowledge of the DENY genetic diversity which is of a fundamental importance in vaccine or drug designs. Results from the evaluation of the utility of NS1 antigen as a diagnostic marker provide further information of the strength and the weakness of the current NS1 antigen detection assays.

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