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

Evaluation of different total leishmania amazonensis antigens for the development of a first-generation vaccine formulated with a toll-like receptor-3 agonist to prevent cutaneous leishmaniasis

Unfortunately, no any vaccine against leishmaniasis has been developed for human use. Therefore, a vaccine based on total Leishmania antigens could be a good and economic approach; and there are different methodologies to obtain these antigens. However, it is unknown whether the method to obtain the antigens affects the integrity and immune response caused by them. OBJECTIVES: to compare the protein profile and immune response generated by total L. amazonensis antigens (TLA) produced by different methods, as well as to analyse the immune response and protection by a first-generation vaccine formulated with sonicated TLA (sTLA) and polyinosinic:polycytidylic acid [Poly (I:C)]. METHODS: TLA were obtained by four different methodologies and their integrity and immune response were evaluated. Finally, sTLA was formulated with Poly (I:C) and their protective immune response was measured. FINDINGS: sTLA presented a conserved protein profile and induced a strong immune response. In addition, Poly (I:C) improved the immune response generated by sTLA. Finally, sTLA + Poly (I:C) formulation provided partial protection against L. amazonensis infection. MAIN CONCLUSIONS: The protein profile and immune response depend on the methodology used to obtain the antigens. Also, the formulation sTLA + Poly (I:C) provides partial protection against cutaneous leishmaniasis in mice.Fil: Germano, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Lozano, Esteban Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Sanchez, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Bruna, Flavia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Garcia Bustos, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; ArgentinaFil: Sosa Lochedino, Arianna Lourdes. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Salomón, María Cristina. Universidad Nacional de Cuyo; ArgentinaFil: Fernandes, Ana Paula. Universidade Federal de Minas Gerais; BrasilFil: Mackern Oberti, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Cargnelutti, Diego Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentin

Defining Reference Sequences for Nocardia Species by Similarity and Clustering Analyses of 16S rRNA Gene Sequence Data

International audienceBACKGROUND: The intra- and inter-species genetic diversity of bacteria and the absence of 'reference', or the most representative, sequences of individual species present a significant challenge for sequence-based identification. The aims of this study were to determine the utility, and compare the performance of several clustering and classification algorithms to identify the species of 364 sequences of 16S rRNA gene with a defined species in GenBank, and 110 sequences of 16S rRNA gene with no defined species, all within the genus Nocardia. METHODS: A total of 364 16S rRNA gene sequences of Nocardia species were studied. In addition, 110 16S rRNA gene sequences assigned only to the Nocardia genus level at the time of submission to GenBank were used for machine learning classification experiments. Different clustering algorithms were compared with a novel algorithm or the linear mapping (LM) of the distance matrix. Principal Components Analysis was used for the dimensionality reduction and visualization. RESULTS: The LM algorithm achieved the highest performance and classified the set of 364 16S rRNA sequences into 80 clusters, the majority of which (83.52%) corresponded with the original species. The most representative 16S rRNA sequences for individual Nocardia species have been identified as 'centroids' in respective clusters from which the distances to all other sequences were minimized; 110 16S rRNA gene sequences with identifications recorded only at the genus level were classified using machine learning methods. Simple kNN machine learning demonstrated the highest performance and classified Nocardia species sequences with an accuracy of 92.7% and a mean frequency of 0.578. CONCLUSION: The identification of centroids of 16S rRNA gene sequence clusters using novel distance matrix clustering enables the identification of the most representative sequences for each individual species of Nocardia and allows the quantitation of inter- and intra-species variability

Dynamic Phenotypic Clustering in Noisy Ecosystems

In natural ecosystems, hundreds of species typically share the same environment and are connected by a dense network of interactions such as predation or competition for resources. Much is known about how fixed ecological niches can determine species abundances in such systems, but far less attention has been paid to patterns of abundances in randomly varying environments. Here, we study this question in a simple model of competition between many species in a patchy ecosystem with randomly fluctuating environmental conditions. Paradoxically, we find that introducing noise can actually induce ordered patterns of abundance-fluctuations, leading to a distinct periodic variation in the correlations between species as a function of the phenotypic distance between them; here, difference in growth rate. This is further accompanied by the formation of discrete, dynamic clusters of abundant species along this otherwise continuous phenotypic axis. These ordered patterns depend on the collective behavior of many species; they disappear when only individual or pairs of species are considered in isolation. We show that they arise from a balance between the tendency of shared environmental noise to synchronize species abundances and the tendency for competition among species to make them fluctuate out of step. Our results demonstrate that in highly interconnected ecosystems, noise can act as an ordering force, dynamically generating ecological patterns even in environments lacking explicit niches

Antigenic extracts of Leishmania braziliensis and Leishmania amazonensis associated with saponin partially protects BALB/c mice against Leishmania chagasi infection by suppressing IL-10 and IL-4 production

This study evaluated two vaccine candidates for their effectiveness in protecting BALB/c mice against Leishmania chagasiinfection. These immunogenic preparations were composed of Leishmania amazonensisor Leishmania braziliensisantigenic extracts in association with saponin adjuvant. Mice were given three subcutaneous doses of one of these vaccine candidates weekly for three weeks and four weeks later challenged with promastigotes of L. chagasiby intravenous injection. We observed that both vaccine candidates induced a significant reduction in the parasite load of the liver, while the L. amazonensisantigenic extract also stimulated a reduction in spleen parasite load. This protection was associated with a suppression of both interleukin (IL)-10 and IL-4 cytokines by spleen cells in response to L. chagasiantigen. No change was detected in the production of IFN-&#947;. Our data show that these immunogenic preparations reduce the type 2 immune response leading to the control of parasite replication

Think globally, act locally: the role of local demographics and vaccination coverage in the dynamic response of measles infection to control

The global reduction of the burden of morbidity and mortality owing to measles has been a major triumph of public health. However, the continued persistence of measles infection probably not only reflects local variation in progress towards vaccination target goals, but may also reflect local variation in dynamic processes of transmission, susceptible replenishment through births and stochastic local extinction. Dynamic models predict that vaccination should increase the mean age of infection and increase inter-annual variability in incidence. Through a comparative approach, we assess national-level patterns in the mean age of infection and measles persistence. We find that while the classic predictions do hold in general, the impact of vaccination on the age distribution of cases and stochastic fadeout are mediated by local birth rate. Thus, broad-scale vaccine coverage goals are unlikely to have the same impact on the interruption of measles transmission in all demographic settings. Indeed, these results suggest that the achievement of further measles reduction or elimination goals is likely to require programmatic and vaccine coverage goals that are tailored to local demographic conditions

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