Natural variation in immune responses to neonatal mycobacterium bovis bacillus calmette-guerin (BCG) vaccination in a cohort of Gambian infants

Background There is a need for new vaccines for tuberculosis (TB) that protect against adult pulmonary disease in regions where BCG is not effective. However, BCG could remain integral to TB control programmes because neonatal BCG protects against disseminated forms of childhood TB and many new vaccines rely on BCG to prime immunity or are recombinant strains of BCG. Interferon-gamma (IFN-) is required for immunity to mycobacteria and used as a marker of immunity when new vaccines are tested. Although BCG is widely given to neonates IFN- responses to BCG in this age group are poorly described. Characterisation of IFN- responses to BCG is required for interpretation of vaccine immunogenicity study data where BCG is part of the vaccination strategy. Methodology/Principal Findings 236 healthy Gambian babies were vaccinated with M. bovis BCG at birth. IFN-, interleukin (IL)-5 and IL-13 responses to purified protein derivative (PPD), killed Mycobacterium tuberculosis (KMTB), M. tuberculosis short term culture filtrate (STCF) and M. bovis BCG antigen 85 complex (Ag85) were measured in a whole blood assay two months after vaccination. Cytokine responses varied up to 10 log-fold within this population. The majority of infants (89-98% depending on the antigen) made IFN- responses and there was significant correlation between IFN- responses to the different mycobacterial antigens (Spearman’s coefficient ranged from 0.340 to 0.675, p=10-6-10-22). IL-13 and IL-5 responses were generally low and there were more non-responders (33-75%) for these cytokines. Nonetheless, significant correlations were observed for IL-13 and IL-5 responses to different mycobacterial antigens Conclusions/Significance Cytokine responses to mycobacterial antigens in BCG-vaccinated infants are heterogeneous and there is significant inter-individual variation. Further studies in large populations of infants are required to identify the factors that determine variation in IFN- responses

Persistence of the immune response induced by BCG vaccination.

BACKGROUND: Although BCG vaccination is recommended in most countries of the world, little is known of the persistence of BCG-induced immune responses. As novel TB vaccines may be given to boost the immunity induced by neonatal BCG vaccination, evidence concerning the persistence of the BCG vaccine-induced response would help inform decisions about when such boosting would be most effective. METHODS: A randomised control study of UK adolescents was carried out to investigate persistence of BCG immune responses. Adolescents were tested for interferon-gamma (IFN-gamma) response to Mycobacterium tuberculosis purified protein derivative (M.tb PPD) in a whole blood assay before, 3 months, 12 months (n = 148) and 3 years (n = 19) after receiving teenage BCG vaccination or 14 years after receiving infant BCG vaccination (n = 16). RESULTS: A gradual reduction in magnitude of response was evident from 3 months to 1 year and from 1 year to 3 years following teenage vaccination, but responses 3 years after vaccination were still on average 6 times higher than before vaccination among vaccinees. Some individuals (11/86; 13%) failed to make a detectable antigen-specific response three months after vaccination, or lost the response after 1 (11/86; 13%) or 3 (3/19; 16%) years. IFN-gamma response to Ag85 was measured in a subgroup of adolescents and appeared to be better maintained with no decline from 3 to 12 months. A smaller group of adolescents were tested 14 years after receiving infant BCG vaccination and 13/16 (81%) made a detectable IFN-gamma response to M.tb PPD 14 years after infant vaccination as compared to 6/16 (38%) matched unvaccinated controls (p = 0.012); teenagers vaccinated in infancy were 19 times more likely to make an IFN-gamma response of > 500 pg/ml than unvaccinated teenagers. CONCLUSION: BCG vaccination in infancy and adolescence induces immunological memory to mycobacterial antigens that is still present and measurable for at least 14 years in the majority of vaccinees, although the magnitude of the peripheral blood response wanes from 3 months to 12 months and from 12 months to 3 years post vaccination. The data presented here suggest that because of such waning in the response there may be scope for boosting anti-tuberculous immunity in BCG vaccinated children anytime from 3 months post-vaccination. This supports the prime boost strategies being employed for some new TB vaccines currently under development

Crude incidence in two-phase designs in the presence of competing risks.

BackgroundIn many studies, some information might not be available for the whole cohort, some covariates, or even the outcome, might be ascertained in selected subsamples. These studies are part of a broad category termed two-phase studies. Common examples include the nested case-control and the case-cohort designs. For two-phase studies, appropriate weighted survival estimates have been derived; however, no estimator of cumulative incidence accounting for competing events has been proposed. This is relevant in the presence of multiple types of events, where estimation of event type specific quantities are needed for evaluating outcome.MethodsWe develop a non parametric estimator of the cumulative incidence function of events accounting for possible competing events. It handles a general sampling design by weights derived from the sampling probabilities. The variance is derived from the influence function of the subdistribution hazard.ResultsThe proposed method shows good performance in simulations. It is applied to estimate the crude incidence of relapse in childhood acute lymphoblastic leukemia in groups defined by a genotype not available for everyone in a cohort of nearly 2000 patients, where death due to toxicity acted as a competing event. In a second example the aim was to estimate engagement in care of a cohort of HIV patients in resource limited setting, where for some patients the outcome itself was missing due to lost to follow-up. A sampling based approach was used to identify outcome in a subsample of lost patients and to obtain a valid estimate of connection to care.ConclusionsA valid estimator for cumulative incidence of events accounting for competing risks under a general sampling design from an infinite target population is derived

Boundary work: An interpretive ethnographic perspective on negotiating and leveraging cross-cultural identity

The complexity of global organizations highlights the importance of members’ ability to span diverse boundaries that may be defined by organization structures, national borders, and/or a variety of cultures associated with organization, nation-based societal and work cultures, industries, and/or professions. Based on ethnographic research in a Japan–US binational firm, the paper describes and analyzes the boundary role performance of the firm\u27s Japanese members. It contributes toward theory on boundary spanning by introducing a “cultural identity negotiation” conceptual framework. We show boundary spanning as a process shaped through the interplay of the contextual issues that make a boundary problematic; an individual\u27s multiple repertoires of cultural knowledge; and the individual boundary spanner\u27s “negotiation”, through interaction with others, of his/her cultural identities – the sense of “who I am” as a cultural being that is fundamental to an individual\u27s self-concept. At the same time, we make transparent the epistemological and methodological foundations of an interpretive ethnographic approach, demonstrating its value for understanding complex organizational processes. Research findings have practical implications for the selection and training of an organization\u27s employees, particularly of persons who may be considered “bicultural”

Hyperdominance in the Amazonian tree flora

The vast extent of the Amazon Basin has historically restricted the study of its tree communities to the local and regional scales. Here, we provide empirical data on the commonness, rarity, and richness of lowland tree species across the entire Amazon Basin and Guiana Shield (Amazonia), collected in 1170 tree plots in all major forest types. Extrapolations suggest that Amazonia harbors roughly 16,000 tree species, of which just 227 (1.4%) account for half of all trees. Most of these are habitat specialists and only dominant in one or two regions of the basin. We discuss some implications of the finding that a small group of species--less diverse than the North American tree flora--accounts for half of the world's most diverse tree community.This work was supported by Alberta Mennega Stichting; ALCOA Suriname; Banco de la República; Center for Agricultural Research in Suriname; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Plano Nacional de Pós-Graduação); Conselho Nacional de Desenvovimento Científico e Tecnológico of Brazil (CNPq) projects Programa de Pesquisas Ecológicas de Longa Duração (PELD) (558069/2009-6), Programa de Apoio a Núcleos de Excelência da Fundação de Amparo à Pesquisa do Estado do Amazonas (PRONEX-FAPEAM) (1600/2006), Áreas Úmidas, and MAUA; PELD (403792/2012-6), PPBio, CENBAM, Universal (479599/2008-4), and Universal 307807-2009-6; Fundação de Amparo À Pesquisa Do Estado Do Amazonas (APEAM) projects DCR/2006, Hidroveg with FAPESP, and PRONEX with CNPq; FAPESP; Colciencias; Duke University; Ecopetrol; FEPIM 044/2003; the Field Museum; Conservation International/DC (TEAM/INPA Manuas), Gordon and Betty Moore Foundation; Guyana Forestry Commission; Investissement d’Avenir grant of the French Agence Nationale de la Recherche (ANR) (Centre d’Étude de la Biodiversité Amazonienne ANR-10-LABX-0025); Margaret Mee Amazon Trust; Miquel fonds; National Geographic Society (7754-04, 8047-06 to P.M.J.); Netherlands Foundation for the Advancement of Tropical Research WOTRO grants WB85- 335 and W84-581; Primate Conservation Incorporated; Programme Ecosystèmes Tropicaux (French Ministry of Ecology and Sustainable Development; Shell Prospecting and Development Peru; Smithsonian Institution’s Biological Diversity of the Guiana Shield Program; Stichting het van Eeden-fonds; the Body Shop; the Ministry of the Environment of Ecuador; TROBIT; Tropenbos International; NSF (NSF-0743457 and NSF-0101775 to P.M.J.); USAID; Variety Woods Guyana; WWF-Brazil; WWF-Guianas; XIIéme Contrat de Plan Etat Région-Guyane (French Government and European Union); and grants to RAINFOR from the European Union, UK Natural Environment Research Council, the Gordon and Betty Moore Foundation, and U.S. National Geographic Society. O.L.P. is supported by a European Research Council Advanced Grant and a Royal Society Wolfson Research Merit Award

Vaccine responses in newborns.

Immunisation of the newborn represents a key global strategy in overcoming morbidity and mortality due to infection in early life. Potential limitations, however, include poor immunogenicity, safety concerns and the development of tolerogenicity or hypo-responsiveness to either the same antigen and/or concomitant antigens administered at birth or in the subsequent months. Furthermore, the neonatal immunological milieu is polarised towards Th2-type immunity with dampening of Th1-type responses and impaired humoral immunity, resulting in qualitatively and quantitatively poorer antibody responses compared to older infants. Innate immunity also shows functional deficiency in antigen-presenting cells: the expression and signalling of Toll-like receptors undergo maturational changes associated with distinct functional responses. Nevertheless, the effectiveness of BCG, hepatitis B and oral polio vaccines, the only immunisations currently in use in the neonatal period, is proof of concept that vaccines can be successfully administered to the newborn via different routes of delivery to induce a range of protective mechanisms for three different diseases. In this review paper, we discuss the rationale for and challenges to neonatal immunisation, summarising progress made in the field, including lessons learnt from newborn vaccines in the pipeline. Furthermore, we explore important maternal, infant and environmental co-factors that may impede the success of current and future neonatal immunisation strategies. A variety of approaches have been proposed to overcome the inherent regulatory constraints of the newborn innate and adaptive immune system, including alternative routes of delivery, novel vaccine configurations, improved innate receptor agonists and optimised antigen-adjuvant combinations. Crucially, a dual strategy may be employed whereby immunisation at birth is used to prime the immune system in order to improve immunogenicity to subsequent homologous or heterologous boosters in later infancy. Similarly, potent non-specific immunomodulatory effects may be elicited when challenged with unrelated antigens, with the potential to reduce the overall risk of infection and allergic disease in early life

Does true Gleason pattern 3 merit its cancer descriptor?

Nearly five decades following its conception, the Gleason grading system remains a cornerstone in the prognostication and management of patients with prostate cancer. In the past few years, a debate has been growing whether Gleason score 3 + 3 = 6 prostate cancer is a clinically significant disease. Clinical, molecular and genetic research is addressing the question whether well characterized Gleason score 3 + 3 = 6 disease has the ability to affect the morbidity and quality of life of an individual in whom it is diagnosed. The consequences of treatment of Gleason score 3 + 3 = 6 disease are considerable; few men get through their treatments without sustaining some harm. Further modification of the classification of prostate cancer and dropping the label cancer for Gleason score 3 + 3 = 6 disease might be warranted

Comparative Tuberculosis (TB) Prevention Effectiveness in Children of Bacillus Calmette-Guérin (BCG) Vaccines from Different Sources, Kazakhstan

Except during a 1-year period when BCG vaccine was not routinely administered, annual coverage of infants with Bacillus Calmette-Guérin (BCG) in Kazakhstan since 2002 has exceeded 95%. BCG preparations from different sources (Japan, Serbia, and Russia) or none were used exclusively in comparable 7-month time-frames, September through March, in 4 successive years beginning in 2002. Our objective was to assess relative effectiveness of BCG immunization.Although there were differences in prevention effectiveness observed among the three BCG vaccines, all were protective. The Japanese vaccine (currently used in Kazakhstan), the Serbian vaccine, and the Russian vaccine respectively were 69%, 43%, and 22% effective with respect to clinical TB notifications, and 92%, 82%, and 51% effective with respect to culture confirmed TB. All three vaccines were >70% effective with respect to TB meningitis.Potential limitations included considerations that 1) the methodology used was retrospective, 2) multiple risk factors could have varied between cohorts and affected prevention effectiveness measures, 3) most cases were clinically diagnosed, and TB culture-positive case numbers and TB meningitis case numbers were sparse, and 4) small variations in reported population TB burden could have affected relative risk of exposure for cohorts.All three BCG vaccines evaluated were protective against TB, and prevention effectiveness varied by manufacturer. When setting national immunization policy, consideration should be given to prevention effectiveness of BCG preparations