Research Article: Incomplete Protection against Dengue Virus Type 2 Re-infection in Peru

Date Published: February 5, 2016

Publisher: Public Library of Science

Author(s): Brett M. Forshey, Robert C. Reiner, Sandra Olkowski, Amy C. Morrison, Angelica Espinoza, Kanya C. Long, Stalin Vilcarromero, Wilma Casanova, Helen J. Wearing, Eric S. Halsey, Tadeusz J. Kochel, Thomas W. Scott, Steven T. Stoddard, William B Messer.

Abstract: BackgroundNearly half of the world’s population is at risk for dengue, yet no licensed vaccine or anti-viral drug is currently available. Dengue is caused by any of four dengue virus serotypes (DENV-1 through DENV-4), and infection by a DENV serotype is assumed to provide life-long protection against re-infection by that serotype. We investigated the validity of this fundamental assumption during a large dengue epidemic caused by DENV-2 in Iquitos, Peru, in 2010–2011, 15 years after the first outbreak of DENV-2 in the region.Methodology/Principal FindingsWe estimated the age-dependent prevalence of serotype-specific DENV antibodies from longitudinal cohort studies conducted between 1993 and 2010. During the 2010–2011 epidemic, active dengue cases were identified through active community- and clinic-based febrile surveillance studies, and acute inapparent DENV infections were identified through contact tracing studies. Based on the age-specific prevalence of DENV-2 neutralizing antibodies, the age distribution of DENV-2 cases was markedly older than expected. Homologous protection was estimated at 35.1% (95% confidence interval: 0%–65.2%). At the individual level, pre-existing DENV-2 antibodies were associated with an incomplete reduction in the frequency of symptoms. Among dengue cases, 43% (26/66) exhibited elevated DENV-2 neutralizing antibody titers for years prior to infection, compared with 76% (13/17) of inapparent infections (age-adjusted odds ratio: 4.2; 95% confidence interval: 1.1–17.7).Conclusions/SignificanceOur data indicate that protection from homologous DENV re-infection may be incomplete in some circumstances, which provides context for the limited vaccine efficacy against DENV-2 in recent trials. Further studies are warranted to confirm this phenomenon and to evaluate the potential role of incomplete homologous protection in DENV transmission dynamics.

Partial Text: Dengue is a mosquito-borne viral illness that imposes a tremendous public health burden on tropical and sub-tropical regions. An estimated 390 million infections occur globally each year, and up to 4 billion people are at risk [1]. Dengue is caused by four dengue virus (DENV) serotypes (DENV-1 to DENV-4). Infection with any DENV can lead to a range of disease outcomes, from mild febrile illness to severe, hemorrhagic manifestations and death. Although DENV infections are often inapparent, many dengue cases require hospitalization, which can overwhelm medical infrastructure during epidemics. There are no specific antiviral therapeutics and currently no licensed vaccine.

We provide indirect evidence that challenges a fundamental assumption of dengue immunology: that infection with one serotype conveys lifelong protection to reinfection by all strains belonging to the same serotype. A newly introduced genotype of DENV-2 exhibited characteristics similar to a novel serotype in a population with a high prevalence of DENV-2 neutralizing antibodies. Moreover, we isolated DENV-2 virus from numerous individuals with pre-existing, robust DENV-2 antibody titers. Epidemiological data from long-term longitudinal cohort studies[20] show that pre-existing DENV-2 antibodies present in the adult population were mostly a product of the invasion of an American strain of DENV-2 in 1995. Although these antibodies did not appear to completely protect against infection with the new strain, they did appear to provide partial protection against febrile illness, reducing the probability of disease. Dengue epidemiology and vaccine development have long been complicated by the immunological interplay among serotypes at the level of the human host. Genetic and phenotypic heterogeneity may be sufficient to extend this interplay to the level of individual genotypes, which markedly increases the complexity of the system[7] and could present further challenges for the development of a suitable dengue vaccine[12,24].



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