Variation in sample collection, cell preservation, and laboratory techniques can affect test performance and is an important obstacle in comparing results from different studies. but only short term protection against a different serotype [2]. DENV contamination triggers an immune response that can result in protection or enhancement of subsequent contamination, thus complicating the effort to develop dengue vaccines [3]. A variety of factors including viral characteristics, host immunity and genetics, and epidemiological context, along with the relative timing of these factors, play a role in ultimately protecting against or enhancing contamination [4]. In order to address this problem, vaccine developers have sought to induce simultaneous tetravalent immunity against all four DENV serotypes. However, these efforts have been hampered by an incomplete understanding of the relevant immune responses that contribute to protection or enhancement. A better understanding of these immune parameters is usually critically needed to inform ongoing dengue vaccine development efforts. The pursuit of dengue immune correlates is further complicated by the limitations of the assays themselves as highlighted by the lack of a standardized neutralization assay making inter-study comparisons difficult [5,6]. This article will review current knowledge about humoral and cell-mediated immune responses in protection and enhancement of dengue, and prospects to define immune correlates of protection or risk for vaccine development. == Evidence of Immune-mediated Protection or Risk in Natural Infection == Studies of natural DENV contamination have shown primary contamination typically results in less severe disease than secondary contamination [7,8]. Primary contamination confers long lasting protection against the NSC 146109 hydrochloride infecting serotype. Paradoxically, the immune response to the primary contamination can result in enhancement of subsequent heterologous contamination. This potential for enhancement can vary over time. Epidemiological studies have indicated temporary protection occurs against a heterologous serotype with the duration of that protection estimated to vary from two months to three years [2,912]. After 23 years, there appears to be a higher likelihood of symptomatic disease, supporting the notion of immune enhancement [9,10]. This situation is usually mirrored in infants who appear to have temporary protection by passively acquired maternal antibody during the first few months of life followed by several months of increased risk of disease as maternal antibodies decline to presumably non-protective levels [13,14]. This disease pattern in infants implies that IgG plays an important role in disease enhancement supporting the theory of antibody-dependent enhancement (ADE) in which non-neutralizing antibodies complexed with DENV facilitate viral entry into host mononuclear cells via Fc receptors [15,16]. Relatively few field studies have been done in which immune status has been measured prior to natural contamination to indicate protection or enhancement. In a cohort study in Thailand, pre-existing neutralizing antibody levels were not consistently associated with lower Rabbit Polyclonal to Ik3-2 risk of subsequent homotypic contamination, in particular with DENV-2 infection [17]. However, in cluster studies in Thailand, lower neutralizing antibody levels to DENV-1, -2 and -4 did appear to be associated with higher risk of homotypic infection when the neutralizing NSC 146109 hydrochloride antibodies were measured within two weeks before infection [18]. Interestingly, the titer thresholds that were associated with increased risk seemed to be much higher for DENV-2 than DENV-1 or -4, although differences in subject ages among serotypes may have affected these thresholds [18]. A cohort study in Sri Lanka demonstrated that the baseline serotype-specific neutralizing antibody profile but not necessarily titer levels was associated with the risk of symptomatic secondary infection suggesting the importance of prior infection history rather than neutralizing titer levels in disease risk [19]. Cell-mediated immunity studies from a Thai cohort found that pre-existing IFN-gamma secreting memory T cells were associated with lower severity of secondary infection NSC 146109 hydrochloride [20,21] suggesting a protective role for specific functional subsets of T cells. Some epidemiological studies have indicated post-secondary infections (i.e., third or greater sequential infections) are rarely severe [22] and are more likely to be subclinical [23], suggesting repeated exposures to DENV result in cross-protective immunity. The protective immunity induced by sequential exposures and the process by which this.