Abstract
Dengue virus (DENV, family Flaviviridae, genus Flavivirus) exists as four distinct serotypes. Generally, immunity after infection with one serotype is protective and lifelong, though exceptions have been described. However, secondary infection with a different serotype can result in more severe disease for a minority of patients. Host responses to the first DENV infection involve the development of both cross-reactive antibody and T cell responses, which, depending upon their precise balance, may mediate protection or enhance disease upon secondary infection with a different serotype. Abundant evidence now exists that responses elicited by DENV infection can cross-react with other members of the genus Flavivirus, particularly Zika virus (ZIKV). Cohort studies have shown that prior DENV immunity is associated with protection against Zika. Cross-reactive antibody responses may enhance infection with flaviviruses, which likely accounts for the cases of severe disease seen during secondary DENV infections. Data for T cell responses are contradictory, and even though cross-reactive T cell responses exist, their clinical significance is uncertain. Recent mouse experiments, however, show that cross-reactive T cells are capable of mediating protection against ZIKV. In this review, we summarize and discuss the evidence that T cell responses may, at least in part, explain the cross-protection seen against ZIKV from DENV infection, and that T cell antigens should therefore be included in putative Zika vaccines.
Highlights
During the last two decades, the rate of infections with flaviviruses, dengue virus (DENV) and Zika virus (ZIKV), has risen significantly (Figure 1)
We will focus on the role of T cells during DENV and ZIKV infections in humans and in animal models, summarizing the major findings, discussing how cross-reactivity might impact immunity, and providing evidence why incorporating T cell epitopes into vaccine design is favorable
There still remains a need to develop Zika vaccines, and to better understand the cross-reactivity of flavivirus immune responses so that this can be harnessed for the emergent flaviviruses of the future
Summary
During the last two decades, the rate of infections with flaviviruses, dengue virus (DENV) and Zika virus (ZIKV), has risen significantly (Figure 1). ZIKV infection is associated with adverse fetal/neonatal outcomes such as congenital Zika syndrome (CZS) [6]. Given that these viruses share similar geographic distributions and high sequence homology, immunological cross-reactivity between DENV and ZIKV is a well-recognized and unsurprising phenomenon. DENV infections can generate cross-reactive, poorly neutralizing antibodies that bind the other serotypes [10]. Upon secondary infection with a heterologous DENV serotype, there is a risk of severe disease, thought to be mediated via a mechanism called antibody-mediated enhancement (ADE) [11, 12]. ADE arises when antibodies against one serotype can bind to, but not fully neutralize, another DENV serotype. A primary dengue infection generally results in lifelong immunity against the same serotype, homotypic DENV re-infections have been described [9]
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