Isabel Rodriguez-Barraquer

Assessing the global threat from Zika virus

Global spread of Zika virus Zika virus was identified in Uganda in 1947; since then, it has enveloped the tropics, causing disease of varying severity. Lessler et al. review the historical literature to remind us that Zikas neurotropism was observed in mice even before clinical case reports in Nigeria in 1953. What determines the clinical manifestations; how local conditions, vectors, genetics, and wild hosts affect transmission and geographical spread; what the best control strategy is; and how to develop effective drugs, vaccines, and diagnostics are all critical questions that are begging for data. Science, this issue p. 663 Assessing the global threat from Zika virus. BACKGROUND First discovered in 1947, Zika virus (ZIKV) received little attention until a surge in microcephaly cases was reported after a 2015 outbreak in Brazil. The size of the outbreak and the severity of associated birth defects prompted the World Health Organization (WHO) to declare a Public Health Emergency of International Concern on 1 February 2016. In response, there has been an explosion in research and planning as the global health community has turned its attention to understanding and controlling ZIKV. Still, much of the information needed to evaluate the global health threat from ZIKV is lacking. The global threat posed by any emerging pathogen depends on its epidemiology, its clinical features, and our ability to implement effective control measures. Whether introductions of ZIKV result in epidemics depends on local ecology, population immunity, regional demographics, and, to no small degree, random chance. The same factors determine whether the virus will establish itself as an endemic disease. The burden of ZIKV spread on human health is mediated by its natural history and pathogenesis, particularly during pregnancy, and our ability to control the virus’s spread. In this Review, we examine the empirical evidence for a global threat from ZIKV through the lens of these processes, examining historic and current evidence, as well as parallel processes in closely related viruses. ADVANCES Because ZIKV was not recognized as an important disease in humans until recently, it was little studied before the recent crisis. Nevertheless, the limited data from the decades following its discovery provide important clues into ZIKV’s epidemiology and suggest that some populations were at risk for the virus for years in the mid-20th century, although this risk may predominantly have been the result of spillover infections from a sylvatic reservoir. Recent outbreaks on Yap Island (2007) and in French Polynesia (2014) provide the only previous observations of large epidemics and are the basis for the little that we do know about ZIKV’s acute symptoms (e.g., rash, fever, conjunctivitis, and arthralgia), the risk of birth defects, such as microcephaly (estimated to be 1 per 100 in French Polynesia), and the incidence of severe neurological outcomes (e.g., Guillain-Barré is estimated to occur in approximately 2 out of every 10,000 cases). The observation of an association between ZIKV and a surge in microcephaly cases in Brazil and the subsequent declaration of a Public Health Emergency of International Concern by the WHO have rapidly accelerated research into the virus. Small, but very important, studies have begun to identify the substantial risk the virus can pose throughout a pregnancy, and careful surveillance has established that ZIKV can be transmitted sexually. Numerous modeling studies have helped to estimate the potential range of ZIKV and measured its reproductive number R0 (estimates range from 1.4 to 6.6), a key measure of transmissibility in a number of settings. Still, it remains unclear whether the recent epidemic in the Americas is the result of fundamental changes in the virus or merely a chance event. OUTLOOK ZIKV research is progressing rapidly, and over the coming months and years our understanding of the virus will undoubtedly deepen considerably. Key questions about the virus’s range, its ability to persist, and its clinical severity will be answered as the current epidemic in the Americas runs its course. Moving forward, it is important that information on ZIKV be placed within the context of its effect on human health and that we remain cognizant of the structure of postinvasion epidemic dynamics as we respond to this emerging threat. The effect of ZIKV is a function of the local transmission regime and viral pathogenesis. (A) Many countries cannot maintain ongoing vector-mediated ZIKV transmission and are only at risk from importation by travelers and limited onward transmission (e.g., through sex). (B) If conditions are appropriate, importations can lead to postinvasion epidemics with high incidence across age ranges, after which the virus may go locally extinct or remain endemic

From re-emergence to hyperendemicity: the natural history of the dengue epidemic in Brazil.

Background Dengue virus (DENV) was reintroduced into Brazil in 1986 and by 1995 it had spread throughout the country. In 2007 the number of dengue hemorrhagic fever (DHF) cases more than doubled and a shift in the age distribution was reported. While previously the majority of DHF cases occurred among adults, in 2007 53% of cases occurred in children under 15 years old. The reasons for this shift have not been determined. Methods and Findings Age stratified cross-sectional seroepidemiologic survey conducted in Recife, Brazil in 2006. Serostatus was determined by ELISA based detection of Dengue IgG. We estimated time-constant and time-varying forces of infection of DENV between 1986 and 2006. We used discrete-time simulation to estimate the accumulation of monotypic and multitypic immunity over time in a population previously completely susceptible to DENV. We projected the age distribution of population immunity to dengue assuming similar hazards of infection in future years. The overall prevalence of DENV IgG was 0.80 (n = 1427). The time-constant force of infection for the period was estimated to be 0.052 (95% CI 0.041, 0.063), corresponding to 5.2% of susceptible individuals becoming infected each year by each serotype. Simulations show that as time since re-emergence of dengue goes by, multitypic immunity accumulates in adults while an increasing proportion of susceptible individuals and those with monotypic immunity are among young age groups. The median age of those monotypically immune can be expected to shift from 24 years, 10 years after introduction, to 13 years, 50 years after introduction. Of those monotypically immune, the proportion under 15 years old shifts from 27% to 58%. These results are consistent with the dengue notification records from the same region since 1995. Interpretation Assuming that persons who have been monotypically exposed are at highest risk for severe dengue, the shift towards younger patient ages observed in Brazil can be partially explained by the accumulation of multitypic immunity against DENV-1, 2, and 3 in older age groups, 22 years after the re-introduction of these viruses. Serotype specific seroepidemiologic studies are necessary to accurately estimate the serotype specific forces of infection.

Benefits and risks of the sanofi-pasteur dengue vaccine: Modeling optimal deployment

The first approved dengue vaccine has now been licensed in six countries. We propose that this live attenuated vaccine acts like a silent natural infection in priming or boosting host immunity. A transmission dynamic model incorporating this hypothesis fits recent clinical trial data well and predicts that vaccine effectiveness depends strongly on the age group vaccinated and local transmission intensity. Vaccination in low-transmission settings may increase the incidence of more severe “secondary-like” infection and, thus, the numbers hospitalized for dengue. In moderate transmission settings, we predict positive impacts overall but increased risks of hospitalization with dengue disease for individuals who are vaccinated when seronegative. However, in high-transmission settings, vaccination benefits both the whole population and seronegative recipients. Our analysis can help inform policy-makers evaluating this and other candidate dengue vaccines.

Noninferiority of Miltefosine Versus Meglumine Antimoniate for Cutaneous Leishmaniasis in Children

BACKGROUND Children have a lower response rate to antimonial drugs and higher elimination rate of antimony (Sb) than adults. Oral miltefosine has not been evaluated for pediatric cutaneous leishmaniasis. METHODS A randomized, noninferiority clinical trial with masked evaluation was conducted at 3 locations in Colombia where Leishmania panamensis and Leishmania guyanensis predominated. One hundred sixteen children aged 2-12 years with parasitologically confirmed cutaneous leishmaniasis were randomized to directly observed treatment with meglumine antimoniate (20 mg Sb/kg/d for 20 days; intramuscular) (n = 58) or miltefosine (1.8-2.5 mg/kg/d for 28 days; by mouth) (n = 58). Primary outcome was treatment failure at or before week 26 after initiation of treatment. Miltefosine was noninferior if the proportion of treatment failures was ≤15% higher than achieved with meglumine antimoniate (1-sided test, α = .05). RESULTS Ninety-five percent of children (111/116) completed follow-up evaluation. By intention-to-treat analysis, failure rate was 17.2% (98% confidence interval [CI], 5.7%-28.7%) for miltefosine and 31% (98% CI, 16.9%-45.2%) for meglumine antimoniate. The difference between treatment groups was 13.8%, (98% CI, -4.5% to 32%) (P = .04). Adverse events were mild for both treatments. CONCLUSIONS Miltefosine is noninferior to meglumine antimoniate for treatment of pediatric cutaneous leishmaniasis caused by Leishmania (Viannia) species. Advantages of oral administration and low toxicity favor use of miltefosine in children. CLINICAL TRIAL REGISTRATION NCT00487253.

The Long-Term Safety, Public Health Impact, and Cost-Effectiveness of Routine Vaccination with a Recombinant, Live-Attenuated Dengue Vaccine (Dengvaxia): A Model Comparison Study.

Background Large Phase III trials across Asia and Latin America have recently demonstrated the efficacy of a recombinant, live-attenuated dengue vaccine (Dengvaxia) over the first 25 mo following vaccination. Subsequent data collected in the longer-term follow-up phase, however, have raised concerns about a potential increase in hospitalization risk of subsequent dengue infections, in particular among young, dengue-naïve vaccinees. We here report predictions from eight independent modelling groups on the long-term safety, public health impact, and cost-effectiveness of routine vaccination with Dengvaxia in a range of transmission settings, as characterised by seroprevalence levels among 9-y-olds (SP9). These predictions were conducted for the World Health Organization to inform their recommendations on optimal use of this vaccine. Methods and Findings The models adopted, with small variations, a parsimonious vaccine mode of action that was able to reproduce quantitative features of the observed trial data. The adopted mode of action assumed that vaccination, similarly to natural infection, induces transient, heterologous protection and, further, establishes a long-lasting immunogenic memory, which determines disease severity of subsequent infections. The default vaccination policy considered was routine vaccination of 9-y-old children in a three-dose schedule at 80% coverage. The outcomes examined were the impact of vaccination on infections, symptomatic dengue, hospitalised dengue, deaths, and cost-effectiveness over a 30-y postvaccination period. Case definitions were chosen in accordance with the Phase III trials. All models predicted that in settings with moderate to high dengue endemicity (SP9 ≥ 50%), the default vaccination policy would reduce the burden of dengue disease for the population by 6%–25% (all simulations: –3%–34%) and in high-transmission settings (SP9 ≥ 70%) by 13%–25% (all simulations: 10%– 34%). These endemicity levels are representative of the participating sites in both Phase III trials. In contrast, in settings with low transmission intensity (SP9 ≤ 30%), the models predicted that vaccination could lead to a substantial increase in hospitalisation because of dengue. Modelling reduced vaccine coverage or the addition of catch-up campaigns showed that the impact of vaccination scaled approximately linearly with the number of people vaccinated. In assessing the optimal age of vaccination, we found that targeting older children could increase the net benefit of vaccination in settings with moderate transmission intensity (SP9 = 50%). Overall, vaccination was predicted to be potentially cost-effective in most endemic settings if priced competitively. The results are based on the assumption that the vaccine acts similarly to natural infection. This assumption is consistent with the available trial results but cannot be directly validated in the absence of additional data. Furthermore, uncertainties remain regarding the level of protection provided against disease versus infection and the rate at which vaccine-induced protection declines. Conclusions Dengvaxia has the potential to reduce the burden of dengue disease in areas of moderate to high dengue endemicity. However, the potential risks of vaccination in areas with limited exposure to dengue as well as the local costs and benefits of routine vaccination are important considerations for the inclusion of Dengvaxia into existing immunisation programmes. These results were important inputs into WHO global policy for use of this licensed dengue vaccine.

Enhancing disease surveillance with novel data streams: challenges and opportunities

Novel data streams (NDS), such as web search data or social media updates, hold promise for enhancing the capabilities of public health surveillance. In this paper, we outline a conceptual framework for integrating NDS into current public health surveillance. Our approach focuses on two key questions: What are the opportunities for using NDS and what are the minimal tests of validity and utility that must be applied when using NDS? Identifying these opportunities will necessitate the involvement of public health authorities and an appreciation of the diversity of objectives and scales across agencies at different levels (local, state, national, international). We present the case that clearly articulating surveillance objectives and systematically evaluating NDS and comparing the performance of NDS to existing surveillance data and alternative NDS data is critical and has not sufficiently been addressed in many applications of NDS currently in the literature.

Revisiting Rayong: Shifting Seroprofiles of Dengue in Thailand and Their Implications for Transmission and Control

Dengue virus has traditionally caused substantial morbidity and mortality among children less than 15 years of age in Southeast Asia. Over the last 2 decades, a significant increase in the mean age of cases has been reported, and a once pediatric disease now causes substantial burden among the adult population. An age-stratified serological study (n = 1,736) was conducted in 2010 among schoolchildren in the Mueang Rayong district of Thailand, where a similar study had been conducted in 1980/1981. Serotype-specific forces of infection (λ(t)) and basic reproductive numbers (R0) of dengue were estimated for the periods 1969-1980 and 1993-2010. Despite a significant increase in the age at exposure and a decrease in λ(t) from 0.038/year to 0.019/year, R0 changed only from 3.3 to 3.2. Significant heterogeneity was observed across subdistricts and schools, with R0 ranging between 1.7 and 6.8. These findings are consistent with the idea that the observed age shift might be a consequence of the demographic transition in Thailand. Changes in critical vaccination fractions, estimated by using R0, have not accompanied the increase in age at exposure. These results have implications for dengue control interventions because multiple countries in Southeast Asia are undergoing similar demographic transitions. It is likely that dengue will never again be a disease exclusively of children.

The Hidden Burden of Dengue and Chikungunya in Chennai, India.

Background Dengue and chikungunya are rapidly expanding viruses transmitted by mosquitoes of the genus Aedes. Few epidemiological studies have examined the extent of transmission of these infections in South India despite an increase in the number of reported cases, and a high suitability for transmission. Methods and findings We conducted a household-based seroprevalence survey among 1010 individuals aged 5-40 years living in fifty randomly selected spatial locations in Chennai, Tamil Nadu. Participants were asked to provide a venous blood sample and to complete a brief questionnaire with basic demographic and daily activity information. Previous exposure to dengue and chikungunya was determined using IgG indirect ELISA (Panbio) and IgG ELISA (Novatec), respectively. We used this data to estimate key transmission parameters (force of infection and basic reproductive number) and to explore factors associated with seropositivity. While only 1% of participants reported history of dengue and 20% of chikungunya, we found that 93% (95%CI 89-95%) of participants were seropositive to dengue virus, and 44% (95%CI 37-50%) to chikungunya. Age-specific seroprevalence was consistent with long-tem, endemic circulation of dengue and suggestive of epidemic chikungunya transmission. Seropositivity to dengue and chikungunya were significantly correlated, even after adjusting for individual and household factors. We estimate that 23% of the susceptible population gets infected by dengue each year, corresponding to approximately 228,000 infections. This transmission intensity is significantly higher than that estimated in known hyperendemic settings in Southeast Asia and the Americas. Conclusions These results provide unprecedented insight into the very high transmission potential of dengue and chikungunya in Chennai and underscore the need for enhanced surveillance and control methods.

Potential opportunities and perils of imperfect dengue vaccines

Dengue vaccine development efforts have focused on the development of tetravalent vaccines. However, a recent Phase IIb trial of a tetravalent vaccine indicates a protective effect against only 3 of the 4 serotypes. While vaccines effective against a subset of serotypes may reduce morbidity and mortality, particular profiles could result in an increased number of cases due to immune enhancement and other peculiarities of dengue epidemiology. Here, we use a compartmental transmission model to assess the impact of partially effective vaccines in a hyperendemic Thai population. Crucially, we evaluate the effects that certain serotype heterogeneities may have in the presence of mass-vaccination campaigns. In the majority of scenarios explored, partially effective vaccines lead to 50% or greater reductions in the number of cases. This is true even of vaccines that we would not expect to proceed to licensure due to poor or incomplete immune responses. Our results show that a partially effective vaccine can have significant impacts on serotype distribution and mean age of cases.

Reconstruction of 60 years of chikungunya epidemiology in the Philippines demonstrates episodic and focal transmission

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.