Immune correlates for dengue vaccine development

Srikiatkhachorn, Anon,Yoon, In-Kyu 'Informa Healthcare (Expert Reviews, LTD)' 2016 Expert review of vaccines Vol.15 No.4

<P>Dengue virus is the leading cause of vector-borne viral disease with four serotypes in circulation. Vaccine development has been complicated by the potential for both protection and disease enhancement during heterologous infection. Secondary infection triggers cross-reactive immune memory responses that have varying functional and epitope specificities that determine protection or risk. Strongly neutralizing antibodies to quaternary epitopes may be especially important for virus neutralization. Cell-mediated immunity dominated by Th1 functions may also play an important role. Determining an immune correlate of protection or risk would be highly beneficial for vaccine development but is hampered by mechanistic uncertainties and assay limitations. Clinical efficacy trials and human infection models along with a systems approach may provide future opportunities to elucidate such correlates.</P>

Resolution of a Chikungunya Outbreak in a Prospective Cohort, Cebu, Philippines, 2012–2014

Srikiatkhachorn, Anon,Alera, Maria Theresa,Lago, Catherine B.,Tac-An, Ilya A.,Villa, Daisy,Fernandez, Stefan,Thaisomboonsuk, Butsaya,Klungthong, Chonticha,Levy, Jens W.,Velasco, John Mark,Roque Jr., V U.S. Department of Health and Human Services * Cen 2016 Emerging Infectious Diseases Vol.22 No.10

Incidence of Dengue Virus Infection in Adults and Children in a Prospective Longitudinal Cohort in the Philippines

Alera, Maria Theresa,Srikiatkhachorn, Anon,Velasco, John Mark,Tac-An, Ilya A.,Lago, Catherine B.,Clapham, Hannah E.,Fernandez, Stefan,Levy, Jens W.,Thaisomboonsuk, Butsaya,Klungthong, Chonticha,Macare Public Library of Science 2016 PLoS neglected tropical diseases Vol.10 No.2

<▼1><P><B>Background</B></P><P>The mean age of dengue has been increasing in some but not all countries. We sought to determine the incidence of dengue virus (DENV) infection in adults and children in a prospective cohort study in the Philippines where dengue is hyperendemic.</P><P><B>Methodology/Principal Findings</B></P><P>A prospective cohort of subjects ≥6 months old in Cebu City, Philippines, underwent active community-based surveillance for acute febrile illnesses by weekly contact. Fever history within the prior seven days was evaluated with an acute illness visit followed by 2, 5, and 8-day, and 3-week convalescent visits. Blood was collected at the acute and 3-week visits. Scheduled visits took place at enrolment and 12 months that included blood collections. Acute samples were tested by DENV PCR and acute/convalescent samples by DENV IgM/IgG ELISA to identify symptomatic infections. Enrolment and 12-month samples were tested by DENV hemagglutination inhibition (HAI) assay to identify subclinical infections. Of 1,008 enrolled subjects, 854 completed all study activities at 12 months per-protocol undergoing 868 person-years of surveillance. The incidence of symptomatic and subclinical infections was 1.62 and 7.03 per 100 person-years, respectively. However, in subjects >15 years old, only one symptomatic infection occurred whereas 27 subclinical infections were identified. DENV HAI seroprevalence increased sharply with age with baseline multitypic HAIs associated with fewer symptomatic infections. Using a catalytic model, the historical infection rate among dengue naïve individuals was estimated to be high at 11–22%/year.</P><P><B>Conclusions/Significance</B></P><P>In this hyperendemic area with high seroprevalence of multitypic DENV HAIs in adults, symptomatic dengue rarely occurred in individuals older than 15 years. Our findings demonstrate that dengue is primarily a pediatric disease in areas with high force of infection. However, the average age of dengue could increase if force of infection decreases over time, as is occurring in some hyperendemic countries such as Thailand.</P></▼1><▼2><P><B>Author Summary</B></P><P>The average age of dengue has been increasing in some but not all dengue endemic countries. To investigate the age pattern of dengue in people of all ages ≥6 months old, a prospective community-based cohort study was undertaken in Cebu City, Philippines where dengue virus has been circulating for many decades. Active surveillance for acute fevers was performed, and acute/convalescent blood samples were tested for evidence of symptomatic dengue. Blood was also collected at enrolment and one year later, and tested serologically to identify subclinical infections. Overall, 1.62 symptomatic and 7.03 subclinical infections per 100 person-years of surveillance were detected. Among people older than 15 years, only one symptomatic dengue case occurred while 27 subclinical infections were identified. By analyzing age-specific dengue serology data, the historical infection rate among people with no prior dengue virus infection was found to be high at around 11–22% per year. Our results show that dengue is primarily a childhood disease in endemic settings where the historical infection rate has been high. However, the average age of dengue could increase if the infection rate decreases over time as is happening in some endemic countries like Thailand.</P></▼2>

Reconstruction of 60 Years of Chikungunya Epidemiology in the Philippines Demonstrates Episodic and Focal Transmission

Salje, Henrik,Cauchemez, Simon,Alera, Maria Theresa,Rodriguez-Barraquer, Isabel,Thaisomboonsuk, Butsaya,Srikiatkhachorn, Anon,Lago, Catherine B.,Villa, Daisy,Klungthong, Chonticha,Tac-An, Ilya A.,Fern Oxford University Press 2016 The Journal of Infectious Diseases Vol.213 No.4

<P>Proper understanding of the long-term epidemiology of chikungunya has been hampered by poor surveillance. Outbreak years are unpredictable and cases often misdiagnosed. Here we analyzed age-specific data from 2 serological studies (from 1973 and 2012) in Cebu, Philippines, to reconstruct both the annual probability of infection and population-level immunity over a 60-year period (1952–2012). We also explored whether seroconversions during 2012–2013 were spatially clustered. Our models identified 4 discrete outbreaks separated by an average delay of 17 years. On average, 23% (95% confidence interval [CI], 16%–37%) of the susceptible population was infected per outbreak, with >50% of the entire population remaining susceptible at any point. Participants who seroconverted during 2012–2013 were clustered at distances of <230 m, suggesting focal transmission. Large-scale outbreaks of chikungunya did not result in sustained multiyear transmission. Nevertheless, we estimate that >350 000 infections were missed by surveillance systems. Serological studies could supplement surveillance to provide important insights on pathogen circulation.</P>

Epidemiology of Infant Dengue Cases Illuminates Serotype-Specificity in the Interaction between Immunity and Disease, and Changes in Transmission Dynamics

Clapham, Hannah,Cummings, Derek A. T.,Nisalak, Ananda,Kalayanarooj, Siripen,Thaisomboonsuk, Butsaya,Klungthong, Chonticha,Fernandez, Stefan,Srikiatkhachorn, Anon,Macareo, Louis R.,Lessler, Justin,Reis Public Library of Science 2015 PLoS neglected tropical diseases Vol.9 No.12

<▼1><P><B>Background</B></P><P>Infants born to dengue immune mothers acquire maternal antibodies to dengue. These antibodies, though initially protective, decline during the first year of life to levels thought to be disease enhancing, before reaching undetectable levels. Infants have long been studied to understand the interaction between infection and disease on an individual level.</P><P><B>Methods/Findings</B></P><P>Considering infants (cases <1 year old) as a unique group, we analyzed serotype specific dengue case data from patients admitted to a pediatric hospital in Bangkok, Thailand. We show differences in the propensity of serotypes to cause disease in individuals with dengue antibodies (infants and post-primary cases) and in individuals without dengue antibodies (primary cases). The mean age of infant cases differed among serotypes, consistent with previously observed differential waning of maternal antibody titers by serotype. We show that trends over time in epidemiology of infant cases are consistent with those observed in the whole population, and therefore with trends in the force of infection.</P><P><B>Conclusions/Significance</B></P><P>Infants with dengue are informative about the interaction between antibody and the dengue serotypes, confirming that in this population DENV-2 and DENV-4 almost exclusively cause disease in the presence of dengue antibody despite infections occurring in others. We also observe differences between the serotypes in the mean age in infant cases, informative about the interaction between waning immunity and disease for the different serotypes in infants. In addition, we show that the mean age of infant cases over time is informative about transmission in the whole population. Therefore, ongoing surveillance for dengue in infants could provide useful insights into dengue epidemiology, particularly after the introduction of a dengue vaccine targeting adults and older children.</P></▼1><▼2><P><B>Author Summary</B></P><P>Infants born to dengue immune mothers acquire maternal dengue antibodies. These antibodies, though initially protective, decline during the first year of life to levels thought to be disease enhancing, before reaching undetectable levels. We show that in this population, DENV-2 and DENV-4 almost exclusively cause disease in the presence of dengue antibody, despite infections occurring in others. We also observe serotype-specificity in the mean age of infant cases, consistent with differential waning of antibody to each serotype. These results highlight serotype-specificity in the way the immune response interacts with infection to cause disease. In addition, we show that the mean age of infant cases over time is informative about transmission in the whole population. Therefore, ongoing surveillance for dengue in infants could provide useful insights into dengue epidemiology, particularly after the introduction of a dengue vaccine targeting adults and older children.</P></▼2>