Cross-protective immunity can account for the alternating epidemic pattern of dengue virus serotypes circulating in Bangkok

Abstract

Dengue virus, the causative agent of dengue fever and its more serious manifestation dengue hemorrhagic fever, is widespread throughout tropical and subtropical regions. The virus exists as four distinct serotypes, all of which have cocirculated in Bangkok for several decades with epidemic outbreaks occurring every 8 -10 years. We analyze time-series data of monthly infection incidence, revealing a distinctive pattern with epidemics of serotypes 1, 2, and 3 occurring at approximately the same time and an isolated epidemic of serotype 4 occurring in the intervening years. Phylogenetic analysis of virus samples collected over the same period shows that clade replacement events are linked to the epidemic cycle and indicates that there is an interserotypic immune reaction. Using an epidemic model with stochastic seasonal forcing showing 8-to 10-year epidemic oscillations, we demonstrate that moderate cross-protective immunity gives rise to persistent out-of-phase oscillations similar to those observed in the data, but that strong or weak cross-protection or cross-enhancement only produces in-phase patterns. This behavior suggests that the epidemic pattern observed in Bangkok is the result of cross-protective immunity and may be significantly altered by changes in the interserotypic immune reaction.cross-immunity ͉ mathematical model ͉ phylogenetics ͉ rsv ͉ phase pattern

Persistence of Th1/Tc1 responses one year after tetravalent dengue vaccination in adults and adolescents in Singapore

“…These cytokines are most likely secreted by serotype-specific CD4 + cells. 19 PBMCs were isolated from 3 mL of whole blood diluted 1:2 with medium (RPMI 1640 + 2% Glutamine + antibiotics) and layered above 3 …”

“…1,2 Immune responses to natural infection are thought to provide lifelong protection against homoserotypic strains, but limited cross-protection between serotypes. 3 Secondary infections with a different serotype have been associated with a higher risk of developing severe disease due to inappropriate heterologous humoral and cellular immune responses. Low-affinity heterologous T-cell responses, excessive production of soluble pro-inflammatory mediators and complement activation have been linked to disease severity 4,5 while other response profiles are considered indicative of a safe immune response to infection or vaccination.…”

The pathogenesis of dengue

“…Typically, one serotype is dominant for a period of 2-4 years, after which it declines in prevalence as a different serotype(s) emerges to replace it. 116,117 The basis for the decline in prevalence of a serotype is presumably the accumulation of herd immunity such that the number of susceptible humans available is diminished. This cycling may also be due to immune enhancement when a new serotype is encountered.…”

A limited host immune range facilitates the creation and maintenance of diversity in parasite virulence

“…Prime examples of this include influenza [11] and whooping cough [12]. Furthermore, it has been argued that cross-immunity can account for the coexistence of multiple strains (of varying virulence levels) of dengue virus in East Asia [13], where partial immunity is the cause of the varying outbreaks of different strains at different times through the year. It is therefore important to explore how partial cross-immunity, or 'immune range', impacts selection on parasites.…”

“…In reality, however, the acquired immune memory developed by hosts may be highly specific (e.g. in dengue virus [13]). Thus, while parasite strains with very similar antigenic configurations may be recognized by the hosts' immune systems, those emerging from larger mutations are likely to escape the hosts' recognition systems.…”