Targeting vaccinations for the licensed dengue vaccine: considerations for serosurvey design

Background The CYD-TDV vaccine was unusual in that the recommended target population for vaccination was originally defined not only by age, but also by transmission setting as defined by seroprevalence. WHO originally recommended countries consider vaccination against dengue with CYD-TDV vaccine in geographic settings only where prior infection with any dengue serotype, as measured by seroprevalence, was >170% in the target age group. Vaccine was not recommended in settings where seroprevalence was <50%. Test-and-vaccinate strategies suggested following new analysis by Sanofi will still require age-stratified seroprevalence surveys to optimise age-group targeting. Here we address considerations for serosurvey design in the context of vaccination program planning. Methods To explore how the design of seroprevalence surveys affects estimates of transmission intensity, 100 age-specific seroprevalence surveys were simulated using a beta-binomial distribution and a simple catalytic model for different combinations of age-range, survey size, transmission setting, and test sensitivity/specificity. We then used a Metropolis-Hastings Markov Chain Monte-Carlo algorithm to estimate the force of infection from each simulated dataset. Results Sampling from a wide age-range led to more accurate estimates than merely increasing sample size in a narrow age-range. This finding was consistent across all transmission settings. The optimum test sensitivity and specificity given an imperfect test differed by setting with high sensitivity being important in high transmission settings and high specificity important in low transmission settings. Conclusions When assessing vaccination suitability by seroprevalence surveys, countries should ensure an appropriate age-range is sampled, considering epidemiological evidence about the local burden of disease

Associations between red blood cell variants and malaria among children and adults from three areas of Uganda: a prospective cohort study.

BACKGROUND: Multiple red blood cell (RBC) variants appear to offer protection against the most severe forms of Plasmodium falciparum malaria. Associations between these variants and uncomplicated malaria are less clear. METHODS: Data from a longitudinal cohort study conducted in 3 sub-counties in Uganda was used to quantify associations between three red blood cell variants Hb [AA, AS, S (rs334)], alpha thalassaemia 3.7 kb deletion, and glucose-6-phosphate dehydrogenase deficiency A-(G6PD 202A genotype) and malaria incidence, parasite prevalence, parasite density (a measure of anti-parasite immunity) and body temperature adjusted for parasite density (a measure of anti-disease immunity). All analyses were adjusted for age, average household entomological inoculation rate, and study site. Results for all variants were compared to those for wild type genotypes. RESULTS: In children, HbAS was associated, compared to wild type, with a lower incidence of malaria (IRR = 0.78, 95% CI 0.66-0.92, p = 0.003), lower parasite density upon infection (PR = 0.66, 95% CI 0.51-0.85, p = 0.001), and lower body temperature for any given parasite density (- 0.13 ℃, 95% CI - 0.21, - 0.05, p = 0.002). In children, HbSS was associated with a lower incidence of malaria (IRR = 0.17, 95% CI 0.04-0.71, p = 0.02) and lower parasite density upon infection (PR = 0.31, 95% CI 0.18-0.54, p < 0.001). α-/αα thalassaemia, was associated with higher parasite prevalence in both children and adults (RR = 1.23, 95% CI 1.06-1.43, p = 0.008 and RR = 1.52, 95% CI 1.04-2.23, p = 0.03, respectively). G6PD deficiency was associated with lower body temperature for any given parasite density only among male hemizygote children (- 0.19 ℃, 95% CI - 0.31, - 0.06, p = 0.003). CONCLUSION: RBC variants were associated with non-severe malaria outcomes. Elucidation of the mechanisms by which they confer protection will improve understanding of genetic protection against malaria

High hepatitis e seroprevalence among displaced persons in South Sudan

Large protracted outbreaks of hepatitis E virus (HEV) have been documented in displaced populations in Africa over the past decade though data are limited outside these exceptional settings. Serological studies can provide insights useful for improving surveillance and disease control. We conducted an age-stratified serological survey using samples previously collected for another research study from206 residents of an internally displaced person campin Juba, South Sudan.We tested serumfor anti-HEV antibodies (IgMand IgG) and estimated the prevalence of recent and historical exposure to the virus. Using data on individuals' serostatus, camp arrival date, and state of origin, we used catalytic transmission models to estimate the relative risk of HEV infection in the camp compared with that in the participants' home states. The age-adjusted seroprevalence of anti-HEV IgG was 71% (95% confidence interval = 63-78), and 4% had evidence of recent exposure (IgM). We estimated HEV exposure rates to be more than 2-fold (hazard ratio = 2.3, 95% credible interval = 0.3-5.8) higher in the camp than in the participants' home states, although this difference was not statistically significant. HEV transmission may be higher than previously appreciated, even in the absence of reported cases. Improved surveillance in similar settings is needed to understand the burden of disease and minimize epidemic impact through early detection and response

Scoping review on vector-borne diseases in urban areas : transmission dynamics, vectorial capacity and co-infection

BACKGROUND: Transmission dynamics, vectorial capacity, and co-infections have substantial impacts on vector-borne diseases (VBDs) affecting urban and suburban populations. Reviewing key factors can provide insight into priority research areas and offer suggestions for potential interventions. MAIN BODY: Through a scoping review, we identify knowledge gaps on transmission dynamics, vectorial capacity, and co-infections regarding VBDs in urban areas. Peer-reviewed and grey literature published between 2000 and 2016 was searched. We screened abstracts and full texts to select studies. Using an extraction grid, we retrieved general data, results, lessons learned and recommendations, future research avenues, and practice implications. We classified studies by VBD and country/continent and identified relevant knowledge gaps. Of 773 articles selected for full-text screening, 50 were included in the review: 23 based on research in the Americas, 15 in Asia, 10 in Africa, and one each in Europe and Australia. The largest body of evidence concerning VBD epidemiology in urban areas concerned dengue and malaria. Other arboviruses covered included chikungunya and West Nile virus, other parasitic diseases such as leishmaniasis and trypanosomiasis, and bacterial rickettsiosis and plague. Most articles retrieved in our review combined transmission dynamics and vectorial capacity; only two combined transmission dynamics and co-infection. The review identified significant knowledge gaps on the role of asymptomatic individuals, the effects of co-infection and other host factors, and the impacts of climatic, environmental, and socioeconomic factors on VBD transmission in urban areas. Limitations included the trade-off from narrowing the search strategy (missing out on classical modelling studies), a lack of studies on co-infections, most studies being only descriptive, and few offering concrete public health recommendations. More research is needed on transmission risk in homes and workplaces, given increasingly dynamic and mobile populations. The lack of studies on co-infection hampers monitoring of infections transmitted by the same vector. CONCLUSIONS: Strengthening VBD surveillance and control, particularly in asymptomatic cases and mobile populations, as well as using early warning tools to predict increasing transmission, were key strategies identified for public health policy and practice

Sex-based differences in clearance of chronic Plasmodium falciparum infection.

Multiple studies have reported a male bias in incidence and/or prevalence of malaria infection in males compared to females. To test the hypothesis that sex-based differences in host-parasite interactions affect the epidemiology of malaria, we intensively followed Plasmodium falciparum infections in a cohort in a malaria endemic area of eastern Uganda and estimated both force of infection (FOI) and rate of clearance using amplicon deep-sequencing. We found no evidence of differences in behavioral risk factors, incidence of malaria, or FOI by sex. In contrast, females cleared asymptomatic infections at a faster rate than males (hazard ratio [HR]=1.82, 95% CI 1.20 to 2.75 by clone and HR = 2.07, 95% CI 1.24 to 3.47 by infection event) in multivariate models adjusted for age, timing of infection onset, and parasite density. These findings implicate biological sex-based differences as an important factor in the host response to this globally important pathogen

Rapid shifts in the age-specific burden of malaria following successful control interventions in four regions of Uganda.

BACKGROUND: Malaria control using long-lasting insecticidal nets (LLINs) and indoor residual spraying of insecticide (IRS) has been associated with reduced transmission throughout Africa. However, the impact of transmission reduction on the age distribution of malaria cases remains unclear. METHODS: Over a 10-year period (January 2009 to July 2018), outpatient surveillance data from four health facilities in Uganda were used to estimate the impact of control interventions on temporal changes in the age distribution of malaria cases using multinomial regression. Interventions included mass distribution of LLINs at all sites and IRS at two sites. RESULTS: Overall, 896,550 patient visits were included in the study; 211,632 aged  15 years. Over time, the age distribution of patients not suspected of malaria and those malaria negative either declined or remained the same across all sites. In contrast, the age distribution of suspected and confirmed malaria cases increased across all four sites. In the two LLINs-only sites, the proportion of malaria cases in  15 years increased from 40 to 61% and 29 to 39%, respectively. In the sites receiving LLINs plus IRS, these proportions increased from 19 to 44% and 18 to 31%, respectively. CONCLUSIONS: These findings demonstrate a shift in the burden of malaria from younger to older individuals following implementation of successful control interventions, which has important implications for malaria prevention, surveillance, case management and control strategies

Estimating malaria incidence from routine health facility-based surveillance data in Uganda.

BACKGROUND: Accurate measures of malaria incidence are essential to track progress and target high-risk populations. While health management information system (HMIS) data provide counts of malaria cases, quantifying the denominator for incidence using these data is challenging because catchment areas and care-seeking behaviours are not well defined. This study's aim was to estimate malaria incidence using HMIS data by adjusting the population denominator accounting for travel time to the health facility. METHODS: Outpatient data from two public health facilities in Uganda (Kihihi and Nagongera) over a 3-year period (2011-2014) were used to model the relationship between travel time from patient village of residence (available for each individual) to the facility and the relative probability of attendance using Poisson generalized additive models. Outputs from the model were used to generate a weighted population denominator for each health facility and estimate malaria incidence. Among children aged 6 months to 11 years, monthly HMIS-derived incidence estimates, with and without population denominators weighted by probability of attendance, were compared with gold standard measures of malaria incidence measured in prospective cohorts. RESULTS: A total of 48,898 outpatient visits were recorded across the two sites over the study period. HMIS incidence correlated with cohort incidence over time at both study sites (correlation in Kihihi = 0.64, p < 0.001; correlation in Nagongera = 0.34, p = 0.045). HMIS incidence measures with denominators unweighted by probability of attendance underestimated cohort incidence aggregated over the 3 years in Kihihi (0.5 cases per person-year (PPY) vs 1.7 cases PPY) and Nagongera (0.3 cases PPY vs 3.0 cases PPY). HMIS incidence measures with denominators weighted by probability of attendance were closer to cohort incidence, but remained underestimates (1.1 cases PPY in Kihihi and 1.4 cases PPY in Nagongera). CONCLUSIONS: Although malaria incidence measured using HMIS underestimated incidence measured in cohorts, even when adjusting for probability of attendance, HMIS surveillance data are a promising and scalable source for tracking relative changes in malaria incidence over time, particularly when the population denominator can be estimated by incorporating information on village of residence

Impacts of Zika emergence in Latin America on endemic dengue transmission

In 2015 and 2016, Zika virus (ZIKV) swept through dengue virus (DENV) endemic areas of Latin America. These viruses are of the same family, share a vector and may interact competitively or synergistically through human immune responses. We examine dengue incidence from Brazil and Colombia before, during, and after the Zika epidemic. We find evidence that dengue incidence was atypically low in 2017 in both countries. We investigate whether subnational Zika incidence is associated with changes in dengue incidence and find mixed results. Using simulations with multiple assumptions of interactions between DENV and ZIKV, we find cross-protection suppresses incidence of dengue following Zika outbreaks and low periods of dengue incidence are followed by resurgence. Our simulations suggest correlations in DENV and ZIKV reproduction numbers could complicate associations between ZIKV incidence and post-ZIKV DENV incidence and that periods of low dengue incidence are followed by large increases in dengue incidence

Dramatic resurgence of malaria after 7 years of intensive vector control interventions in Eastern Uganda

Tororo District, Uganda experienced a dramatic decrease in malaria burden from 2015-19 during 5 years of indoor residual spraying (IRS) with carbamate (Bendiocarb) and then organophosphate (Actellic) insecticides. However, a marked resurgence occurred in 2020, which coincided with a change to a clothianidin-based IRS formulations (Fludora Fusion/SumiShield). To quantify the magnitude of the resurgence, investigate causes, and evaluate the impact of a shift back to IRS with Actellic in 2023, we assessed changes in malaria metrics in regions within and near Tororo District. Malaria surveillance data from Nagongera Health Center, Tororo District was included from 2011-2023. In addition, a cohort of 667 residents from 84 houses was followed from August 2020 through September 2023 from an area bordering Tororo and neighboring Busia District, where IRS has never been implemented. Cohort participants underwent passive surveillance for clinical malaria and active surveillance for parasitemia every 28 days. Mosquitoes were collected in cohort households every 2 weeks using CDC light traps. Female Anopheles were speciated and tested for sporozoites and phenotypic insecticide resistance. Temporal comparisons of malaria metrics were stratified by geographic regions. At Nagongera Health Center average monthly malaria cases varied from 419 prior to implementation of IRS; to 56 after 5 years of IRS with Bendiocarb and Actellic; to 1591 after the change in IRS to Fludora Fusion/SumiShield; to 155 after a change back to Actellic. Among cohort participants living away from the border in Tororo, malaria incidence increased over 8-fold (0.36 vs. 2.97 episodes per person year, p&lt;0.0001) and parasite prevalence increased over 4-fold (17% vs. 70%, p&lt;0.0001) from 2021 to 2022 when Fludora Fusion/SumiShield was used. Incidence decreased almost 5-fold (2.97 vs. 0.70, p&lt;0.0001) and prevalence decreased by 39% (70% vs. 43%, p&lt;0.0001) after shifting back to Actellic. There was a similar pattern among those living near the border in Tororo, with increased incidence between 2021 and 2022 (0.93 vs. 2.40, p&lt;0.0001) followed by a decrease after the change to Actellic (2.40 vs. 1.33, p&lt;0.001). Among residents of Busia, malaria incidence did not change significantly over the 3 years of observation. Malaria resurgence in Tororo was temporally correlated with the replacement of An. gambiae s.s. by An. funestus as the primary vector, with a marked decrease in the density of An. funestus following the shift back to IRS with Actellic. In Busia, An. gambiae s.s. remained the primary vector throughout the observation period. Sporozoite rates were approximately 50% higher among An. funestus compared to the other common malaria vectors. Insecticide resistance phenotyping of An. funestus revealed high tolerance to clothianidin, but full susceptibility to Actellic. A dramatic resurgence of malaria in Tororo was temporally associated with a change to clothianidin-based IRS formulations and emergence of An. funestus as the predominant vector. Malaria decreased after a shift back to IRS with Actellic. This study highlights the ability of malaria vectors to rapidly circumvent control efforts and the importance of high-quality surveillance systems to assess the impact of malaria control interventions and generate timely, actionable data

Pareto rules for malaria super-spreaders and super-spreading

Heterogeneity in transmission is a challenge for infectious disease dynamics and control. An 80-20 “Pareto” rule has been proposed to describe this heterogeneity whereby 80% of transmission is accounted for by 20% of individuals, herein called super-spreaders. It is unclear, however, whether super-spreading can be attributed to certain individuals or whether it is an unpredictable and unavoidable feature of epidemics. Here, we investigate heterogeneous malaria transmission at three sites in Uganda and find that super-spreading is negatively correlated with overall malaria transmission intensity. Mosquito biting among humans is 90-10 at the lowest transmission intensities declining to less than 70-30 at the highest intensities. For super-spreaders, biting ranges from 70-30 down to 60-40. The difference, approximately half the total variance, is due to environmental stochasticity. Super-spreading is thus partly due to super-spreaders, but modest gains are expected from targeting super-spreaders