The immune space: a concept and template for rationalizing vaccine development.

Abstract Empirical testing of candidate vaccines has led to the successful development of a number of lifesaving vaccines. The advent of new tools to manipulate antigens and new methods and vectors for vaccine delivery has led to a veritable explosion of potential vaccine designs. As a result, selection of candidate vaccines suitable for large-scale efficacy testing has become more challenging. This is especially true for diseases such as dengue, HIV, and tuberculosis where there is no validated animal model or correlate of immune protection. Establishing guidelines for the selection of vaccine candidates for advanced testing has become a necessity. A number of factors could be considered in making these decisions, including, for example, safety in animal and human studies, immune profile, protection in animal studies, production processes with product quality and stability, availability of resources, and estimated cost of goods. The "immune space template" proposed here provides a standardized approach by which the quality, level, and durability of immune responses elicited in early human trials by a candidate vaccine can be described. The immune response profile will demonstrate if and how the candidate is unique relative to other candidates, especially those that have preceded it into efficacy testing and, thus, what new information concerning potential immune correlates could be learned from an efficacy trial. A thorough characterization of immune responses should also provide insight into a developer's rationale for the vaccine's proposed mechanism of action. HIV vaccine researchers plan to include this general approach in up-selecting candidates for the next large efficacy trial. This "immune space" approach may also be applicable to other vaccine development endeavors where correlates of vaccine-induced immune protection remain unknown.

Immune activation alters cellular and humoral responses to yellow fever 17D vaccine.

Background. Defining the parameters that modulate vaccine responses in African populations will be imperative to design effective vaccines for protection against HIV, malaria, tuberculosis, and dengue virus infections. This study aimed to evaluate the contribution of the patient-specific immune microenvironment to the response to the licensed yellow fever vaccine 17D (YF-17D) in an African cohort. Methods. We compared responses to YF-17D in 50 volunteers in Entebbe, Uganda, and 50 volunteers in Lausanne, Switzerland. We measured the CD8+ T cell and B cell responses induced by YF-17D and correlated them with immune parameters analyzed by flow cytometry prior to vaccination. Results. We showed that YF-17D-induced CD8+ T cell and B cell responses were substantially lower in immunized individuals from Entebbe compared with immunized individuals from Lausanne. The impaired vaccine response in the Entebbe cohort associated with reduced YF-17D replication. Prior to vaccination, we observed higher frequencies of exhausted and activated NK cells, differentiated T and B cell subsets and proinflammatory monocytes, suggesting an activated immune microenvironment in the Entebbe volunteers. Interestingly, activation of CD8+ T cells and B cells as well as proinflammatory monocytes at baseline negatively correlated with YF-17D-neutralizing antibody titers after vaccination. Additionally, memory T and B cell responses in preimmunized volunteers exhibited reduced persistence in the Entebbe cohort but were boosted by a second vaccination. Conclusion. Together, these results demonstrate that an activated immune microenvironment prior to vaccination impedes efficacy of the YF-17D vaccine in an African cohort and suggest that vaccine regimens may need to be boosted in African populations to achieve efficient immunity. Trial registration. Registration is not required for observational studies. Funding. This study was funded by Canada's Global Health Research Initiative, Defense Threat Reduction Agency, National Institute of Allergy and Infectious Diseases, Bill & Melinda Gates Foundation, and United States Agency for International Development.

The influence of drinking pattern, at individual and aggregate levels, on alcohol-related negative consequences.

AIM: To determine the extent drinking patterns (at the individual and country level) are associated with alcohol-related consequences over and above the total alcohol the person consumes. METHODS: Hierarchical linear models were estimated based on general population surveys conducted in 18 countries participating in the GENACIS project. RESULTS: In general, the positive association between drinking pattern scores and alcohol-related consequences was found at both the individual and country levels, independent of volume of drinking. In addition, a significant interaction effect indicated that the more detrimental the country's drinking pattern, the less steep the association between the volume of drinking and its consequences. CONCLUSION: Drinking patterns have an independent impact on consequences over and above the relationship between volume and consequences.

Alcohol may not cause partner violence but it seems to make it worse: a cross national comparison of the relationship between alcohol and severity of partner violence.

This study assesses whether severity of physical partner aggression is associated with alcohol consumption at the time of the incident, and whether the relationship between drinking and aggression severity is the same for men and women and across different countries. National or large regional general population surveys were conducted in 13 countries as part of the GENACIS collaboration. Respondents described the most physically aggressive act done to them by a partner in the past 2 years, rated the severity of aggression on a scale of 1 to 10, and reported whether either partner had been drinking when the incident occurred. Severity ratings were significantly higher for incidents in which one or both partners had been drinking compared to incidents in which neither partner had been drinking. The relationship did not differ significantly for men and women or by country. We conclude that alcohol consumption may serve to potentiate violence when it occurs, and this pattern holds across a diverse set of cultures. Further research is needed that focuses explicitly on the nature of alcohol's contribution to intimate partner aggression. Prevention needs to address the possibility of enhanced dangers of intimate partner violence when the partners have been drinking and eliminate any systemic factors that permit alcohol to be used as an excuse. Clinical services for perpetrators and victims of partner violence need to address the role of drinking practices, including the dynamics and process of aggressive incidents that occur when one or both partners have been drinking.

C'est la plume qui fait le conte : "Die sechs Schwäne" des frères Grimm et "De vilde Svaner" de Hans Christian Andersen

Dans De vilde Svaner (Les cygnes sauvages), conte des Eventyr, fortalte for Børn (Contes, racontés aux enfants), H. C. Andersen raconte une histoire très proche de celle de Die sechs Schwäne (Les six cygnes), des Kinder- und Hausmärchen (Contes de l'enfance et du foyer) des Grimm. On peut fort justement se demander si l'auteur danois ne réécrit pas le Märchen de 1812 lorsqu'il publie son eventyr, en 1838. Mais l'étude de plusieurs récits d'enfants transformés en cygnes - de l'histoire du septième sage du Dolopathos de Jean de Haute-Seille, à la fin du xiie siècle, et Die sieben Schwäne, un Feen-Märchen de 1801, à De elleve Svaner de Winther, en 1823 - montre qu'Andersen réécrit vraisemblablement ce dernier texte danois et que le dialogue intertextuel avec les Grimm s'effectue sur un autre mode. L'auteur des Eventyr, fortalte for Børn se positionne par rapport aux Kinder- und Hausmärchen, développant ainsi une nouvelle conception du genre qui ressort de la comparaison des manières de raconter propres à chaque auteur, leur plume. It is the pen which makes the tale. the Grimm brothers' Die sechs Schwäne and Christian Andersen's De vilde Svaner In De vilde Svaner, a tale from Eventyr, fortale for Børn, H. C. Andersen tells a story that is very close to that of Die sechs Schwäne from the Grimms' Kinder- und Hausmärchen. One could legitimately wonder whether the Danish author was inspired by the 1812 Märchen when he published his own eventyr in 1838. The study of other narratives about children transformed into swans (including the story of the seventh wise man in Jean de Haute-Seille's Dolopathos at the end of the twelth century; Die sieben Schwäne, a Feen-Märchen from 1801; and Winther's 1823 De elleve Svaner) shows that Andersen rewrote this last Danish text and that the intertextual dialogue with the Grimms takes place at another level. Andersen distinguishes himself from the Grimms by developing a new conception of the genre, which becomes clear in his very different way of telling a tale.

Failure to thrive in a girl born into a family affected by familial dysalbuminemic hyperthyroxinemia

Autosomal dominant familial dysalbuminemic hyperthyroxinemia (FDH)is characterized by modified human serum albumin (HSA) inducing asubstantially higher affinity for thyroxine (T4). Histidin or prolinsubstitution on residue R218 produces localized conformationalchanges of HSA creating additional room for T4 binding, leadingto 14-20 fold normal total T4 (TT4) levels. Affected individuals areconsidered euthyroid. Our patient is an 18 months-old swiss girl bornto a mother known for the rare R218P mutation in the HSA gene.She presented with severe failure to thrive (height -2.92 SD, weight-3.6 SD), habitual hip dislocation without anatomical anomaly, latefontanelle closing and protruding ears. Psychomotor development isslightly retarded. Thyroid function testing confirmed extremely high TT4(1446.0 nmol/l) levels, which are similar to her brother's values (1534.4nmol/l and 1757.6 nmol/l respectively). Free T4 seems slightly elevated(26 pmol/l), probably due to methodological reasons. TSH (0.92 mU/l),free T3 (4.4 pmol/l) and thyroxin binding globulin (32 mg/l) are withinthe normal range. Her two half-brothers, affected by the samemutation, are now 18.7 (P1) and 16.6 (P2) years old and wereoriginally described by S. Pannain et al. in 2000. Both werecharacterized by growth retardation (-2.1 and -2.2 SD) before the ageof 4 years. P1 has reached a normal adult height (-0.4 SD) and P2has caught up to normal growth (-0.68 SD) with moderate bonematuration delay. Pubertal development and anterior pituitary functionare adequate. Primary growth and developmental retardation in thefirst years of life with adequate catch-up seem to be a distinctcharacteristic in FDH with R218P mutation. Hip dislocation is typicallyseen in other situations associated to thyroid disorders, like Downsyndrome. These findings might be explained by altered early thyroidhormone utilization in children with FDH.

Alcohol may not "cause" partner violence but it seems to make it worse : a cross-national comparison of partner aggression involving alcohol with aggression not involving alcohol

This study assesses whether severity of physical partner aggression is associated with alcohol consumption at the time of the incident, and whether the relationship between drinking and aggression severity is the same for men and women and across different countries. National or large regional general population surveys were conducted in 13 countries as part of the GENACIS collaboration. Respondents described the most physically aggressive act done to them by a partner in the past 2 years, rated the severity of aggression on a scale of 1 to 10, and reported whether either partner had been drinking when the incident occurred. Severity ratings were significantly higher for incidents in which one or both partners had been drinking compared to incidents in which neither partner had been drinking. The relationship did not differ significantly for men and women or by country. We conclude that alcohol consumption may serve to potentiate violence when it occurs, and this pattern holds across a diverse set of cultures. Further research is needed that focuses explicitly on the nature of alcohol's contribution to intimate partner aggression. Prevention needs to address the possibility of enhanced dangers of intimate partner violence when the partners have been drinking and eliminate any systemic factors that permit alcohol to be used as an excuse. Clinical services for perpetrators and victims of partner violence need to address the role of drinking practices, including the dynamics and process of aggressive incidents that occur when one or both partners have been drinking.

Clinical spectrum of tuberculous optic neuropathy.

PURPOSE: Tuberculous optic neuropathy may follow infection with Mycobacterium tuberculosis or administration of the bacille Calmette-Guerin. However, this condition is not well described in the ophthalmic literature. METHODS: Ophthalmologists, identified through professional electronic networks or previous publications, collected standardized clinical data relating to 62 eyes of 49 patients who they had managed with tuberculous optic neuropathy. RESULTS: Tuberculous optic neuropathy was most commonly manifested as papillitis (51.6 %), neuroretinitis (14.5 %), and optic nerve tubercle (11.3 %). Uveitis was an additional ocular morbidity in 88.7 % of eyes. In 36.7 % of patients, extraocular tuberculosis was present. The majority of patients (69.4 %) had resided in and/or traveled to an endemic area. Although initial visual acuity was 20/50 or worse in 62.9 % of 62 eyes, 76.7 % of 60 eyes followed for a median of 12 months achieved visual acuities of 20/40 or better. Visual field defects were reported for 46.8 % of eyes, but these defects recovered in 63.2 % of 19 eyes with follow-up. CONCLUSION: Visual recovery from tuberculous optic neuropathy is common, if the diagnosis is recognized and appropriate treatment is instituted. A tuberculous etiology should be considered when evaluating optic neuropathy in persons from endemic areas.

Sex allocation conflict in ants: when the queen rules.

Insect societies are paramount examples of cooperation, yet they also harbor internal conflicts whose resolution depends on the power of the opponents. The male-haploid, female-diploid sex-determining system of ants causes workers to be more related to sisters than to brothers, whereas queens are equally related to daughters and sons. Workers should thus allocate more resources to females than to males, while queens should favor an equal investment in each sex. Female-biased sex allocation and manipulation of the sex ratio during brood development suggest that workers prevail in many ant species. Here, we show that queens of Formica selysi strongly influenced colony sex allocation by biasing the sex ratio of their eggs. Most colonies specialized in the production of a single sex. Queens in female-specialist colonies laid a high proportion of diploid eggs, whereas queens in male-specialist colonies laid almost exclusively haploid eggs, which constrains worker manipulation. However, the change in sex ratio between the egg and pupae stages suggests that workers eliminated some male brood, and the population sex-investment ratio was between the queens' and workers' equilibria. Altogether, these data provide evidence for an ongoing conflict between queens and workers, with a prominent influence of queens as a result of their control of egg sex ratio.

A novel HIV vaccine adjuvanted by IC31 induces robust and persistent humoral and cellular immunity.

The HIV vaccine strategy that, to date, generated immune protection consisted of a prime-boost regimen using a canarypox vector and an HIV envelope protein with alum, as shown in the RV144 trial. Since the efficacy was weak, and previous HIV vaccine trials designed to generate antibody responses failed, we hypothesized that generation of T cell responses would result in improved protection. Thus, we tested the immunogenicity of a similar envelope-based vaccine using a mouse model, with two modifications: a clade C CN54gp140 HIV envelope protein was adjuvanted by the TLR9 agonist IC31®, and the viral vector was the vaccinia strain NYVAC-CN54 expressing HIV envelope gp120. The use of IC31® facilitated immunoglobulin isotype switching, leading to the production of Env-specific IgG2a, as compared to protein with alum alone. Boosting with NYVAC-CN54 resulted in the generation of more robust Th1 T cell responses. Moreover, gp140 prime with IC31® and alum followed by NYVAC-CN54 boost resulted in the formation and persistence of central and effector memory populations in the spleen and an effector memory population in the gut. Our data suggest that this regimen is promising and could improve the protection rate by eliciting strong and long-lasting humoral and cellular immune responses.

Effects of sample size on the performance of species distribution models

A wide range of modelling algorithms is used by ecologists, conservation practitioners, and others to predict species ranges from point locality data. Unfortunately, the amount of data available is limited for many taxa and regions, making it essential to quantify the sensitivity of these algorithms to sample size. This is the first study to address this need by rigorously evaluating a broad suite of algorithms with independent presence-absence data from multiple species and regions. We evaluated predictions from 12 algorithms for 46 species (from six different regions of the world) at three sample sizes (100, 30, and 10 records). We used data from natural history collections to run the models, and evaluated the quality of model predictions with area under the receiver operating characteristic curve (AUC). With decreasing sample size, model accuracy decreased and variability increased across species and between models. Novel modelling methods that incorporate both interactions between predictor variables and complex response shapes (i.e. GBM, MARS-INT, BRUTO) performed better than most methods at large sample sizes but not at the smallest sample sizes. Other algorithms were much less sensitive to sample size, including an algorithm based on maximum entropy (MAXENT) that had among the best predictive power across all sample sizes. Relative to other algorithms, a distance metric algorithm (DOMAIN) and a genetic algorithm (OM-GARP) had intermediate performance at the largest sample size and among the best performance at the lowest sample size. No algorithm predicted consistently well with small sample size (n < 30) and this should encourage highly conservative use of predictions based on small sample size and restrict their use to exploratory modelling.

What matters for predicting spatial distributions of trees: techniques, data, or species' characteristics?

Data characteristics and species traits are expected to influence the accuracy with which species' distributions can be modeled and predicted. We compare 10 modeling techniques in terms of predictive power and sensitivity to location error, change in map resolution, and sample size, and assess whether some species traits can explain variation in model performance. We focused on 30 native tree species in Switzerland and used presence-only data to model current distribution, which we evaluated against independent presence-absence data. While there are important differences between the predictive performance of modeling methods, the variance in model performance is greater among species than among techniques. Within the range of data perturbations in this study, some extrinsic parameters of data affect model performance more than others: location error and sample size reduced performance of many techniques, whereas grain had little effect on most techniques. No technique can rescue species that are difficult to predict. The predictive power of species-distribution models can partly be predicted from a series of species characteristics and traits based on growth rate, elevational distribution range, and maximum elevation. Slow-growing species or species with narrow and specialized niches tend to be better modeled. The Swiss presence-only tree data produce models that are reliable enough to be useful in planning and management applications.