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

Familiarity bias and physiological responses in contagious yawning by dogs support link to empathy

In humans, the susceptibility to yawn contagion has been theoretically and empirically related to our capacity for empathy. Because of its relevance to evolutionary biology, this phenomenon has been the focus of recent investigations in nonhuman species. In line with the empathic hypothesis, contagious yawning has been shown to correlate with the level of social attachment in several primate species. Domestic dogs (Canis familiaris) have also shown the ability to yawn contagiously. To date, however, the social modulation of dog contagious yawning has received contradictory support and alternative explanations (i.e., yawn as a mild distress response) could explain positive evidence. The present study aims to replicate contagious yawning in dogs and to discriminate between the two possible mediating mechanisms (i.e., empathic vs. distress related response). Twenty-five dogs observed familiar (dog’s owner) and unfamiliar human models (experimenter) acting out a yawn or control mouth movements. Concurrent physiological measures (heart rate) were additionally monitored for twenty-one of the subjects. The occurrence of yawn contagion was significantly higher during the yawning condition than during the control mouth movements. Furthermore, the dogs yawned more frequently when watching the familiar model than the unfamiliar one demonstrating that the contagiousness of yawning in dogs correlated with the level of emotional proximity. Moreover, subjects’ heart rate did not differ among conditions suggesting that the phenomenon of contagious yawning in dogs is unrelated to stressful events. Our findings are consistent with the view that contagious yawning is modulated by affective components of the behavior and may indicate that rudimentary forms of empathy could be present in domesticated dogs

How equitable is bed net ownership and utilisation in Tanzania? A practical application of the principles of horizontal and vertical equity

BACKGROUND: Studies show that the burden of malaria remains huge particularly in low-income settings. Although effective malaria control measures such as insecticide-treated nets (ITNs) have been promoted, relatively little is known about their equity dimension. Understanding variations in their use in low-income settings is important for scaling up malaria control programmes particularly ITNs. The objective of this paper is to measure the extent and causes of inequalities in the ownership and utilisation of bed nets across socioeconomic groups (SEGs) and age groups in Tanga District, north-eastern Tanzania. METHODS: A questionnaire was administered to heads of 1,603 households from rural and urban areas. Households were categorized into SEGs using both an asset-based wealth index and education level of the household head. Concentration indices and regression-based measures of inequality were computed to analyse both vertical and horizontal inequalities in ownership and utilisation of bed nets. Focus Group Discussions (FGDs) were used to explore community perspectives on the causes of inequalities. RESULTS: Use of ITNs remained appallingly low compared to the RBM target of 80% coverage. Inequalities in ownership of ITNs and all nets combined were significantly pro-rich and were much more pronounced in rural areas. FGDs revealed that lack of money was the key factor for not using ITNs followed by negative perceptions about the effect of insecticides on the health of users. Household SES, living within the urban areas and being under-five were positively associated with bed net ownership and/or utilisation. CONCLUSION: The results highlight the need for mass distribution of ITN; a community-wide programme to treat all untreated nets and to promote the use of Long-Lasting Insecticidal nets (LLINs) or longer-lasting treatment of nets. The rural population and under-fives should be targeted through highly subsidized schemes and mass distribution of free nets. Public campaigns are also needed to encourage people to use treated nets and mitigate negative perceptions about insecticides

Ontogeny of Toll-Like Receptor Mediated Cytokine Responses of Human Blood Mononuclear Cells

Newborns and young infants suffer increased infectious morbidity and mortality as compared to older children and adults. Morbidity and mortality due to infection are highest during the first weeks of life, decreasing over several years. Furthermore, most vaccines are not administered around birth, but over the first few years of life. A more complete understanding of the ontogeny of the immune system over the first years of life is thus urgently needed. Here, we applied the most comprehensive analysis focused on the innate immune response following TLR stimulation over the first 2 years of life in the largest such longitudinal cohort studied to-date (35 subjects). We found that innate TLR responses (i) known to support Th17 adaptive immune responses (IL-23, IL-6) peaked around birth and declined over the following 2 years only to increase again by adulthood; (ii) potentially supporting antiviral defense (IFN-α) reached adult level function by 1 year of age; (iii) known to support Th1 type immunity (IL-12p70, IFN-γ) slowly rose from a low at birth but remained far below adult responses even at 2 years of age; (iv) inducing IL-10 production steadily declined from a high around birth to adult levels by 1 or 2 years of age, and; (v) leading to production of TNF-α or IL-1β varied by stimuli. Our data contradict the notion of a linear progression from an ‘immature’ neonatal to a ‘mature’ adult pattern, but instead indicate the existence of qualitative and quantitative age-specific changes in innate immune reactivity in response to TLR stimulation

Vaccination with Recombinant Microneme Proteins Confers Protection against Experimental Toxoplasmosis in Mice

Toxoplasmosis, a zoonotic disease caused by Toxoplasma gondii, is an important public health problem and veterinary concern. Although there is no vaccine for human toxoplasmosis, many attempts have been made to develop one. Promising vaccine candidates utilize proteins, or their genes, from microneme organelle of T. gondii that are involved in the initial stages of host cell invasion by the parasite. In the present study, we used different recombinant microneme proteins (TgMIC1, TgMIC4, or TgMIC6) or combinations of these proteins (TgMIC1-4 and TgMIC1-4-6) to evaluate the immune response and protection against experimental toxoplasmosis in C57BL/6 mice. Vaccination with recombinant TgMIC1, TgMIC4, or TgMIC6 alone conferred partial protection, as demonstrated by reduced brain cyst burden and mortality rates after challenge. Immunization with TgMIC1-4 or TgMIC1-4-6 vaccines provided the most effective protection, since 70% and 80% of mice, respectively, survived to the acute phase of infection. In addition, these vaccinated mice, in comparison to non-vaccinated ones, showed reduced parasite burden by 59% and 68%, respectively. The protective effect was related to the cellular and humoral immune responses induced by vaccination and included the release of Th1 cytokines IFN-γ and IL-12, antigen-stimulated spleen cell proliferation, and production of antigen-specific serum antibodies. Our results demonstrate that microneme proteins are potential vaccines against T. gondii, since their inoculation prevents or decreases the deleterious effects of the infection

Age-Dependent Maturation of Toll-Like Receptor-Mediated Cytokine Responses in Gambian Infants

The global burden of neonatal and infant mortality due to infection is staggering, particularly in resource-poor settings. Early childhood vaccination is one of the major interventions that can reduce this burden, but there are specific limitations to inducing effective immunity in early life, including impaired neonatal leukocyte production of Th1-polarizing cytokines to many stimuli. Characterizing the ontogeny of Toll-like receptor (TLR)-mediated innate immune responses in infants may shed light on susceptibility to infection in this vulnerable age group, and provide insights into TLR agonists as candidate adjuvants for improved neonatal vaccines. As little is known about the leukocyte responses of infants in resource-poor settings, we characterized production of Th1-, Th2-, and anti-inflammatory- cytokines in response to agonists of TLRs 1-9 in whole blood from 120 Gambian infants ranging from newborns (cord blood) to 12 months of age. Most of the TLR agonists induced TNFα, IL-1β, IL-6, and IL-10 in cord blood. The greatest TNFα responses were observed for TLR4, -5, and -8 agonists, the highest being the thiazoloquinoline CLO75 (TLR7/8) that also uniquely induced cord blood IFNγ production. For most agonists, TLR-mediated TNFα and IFNγ responses increased from birth to 1 month of age. TLR8 agonists also induced the greatest production of the Th1-polarizing cytokines TNFα and IFNγ throughout the first year of life, although the relative responses to the single TLR8 agonist and the combined TLR7/8 agonist changed with age. In contrast, IL-1β, IL-6, and IL-10 responses to most agonists were robust at birth and remained stable through 12 months of age. These observations provide fresh insights into the ontogeny of innate immunity in African children, and may inform development of age-specific adjuvanted vaccine formulations important for global health

Anterior cruciate ligament reconstruction is associated with greater tibial tunnel widening when using a bioabsorbable screw compared to an all-inside technique with suspensory fixation

Purpose: To compare clinical outcomes and tunnel widening following anterior cruciate ligament reconstruction (ACLR) performed with an all-inside technique (Group A) or with a bioabsorbable tibial screw and suspensory femoral fixation (Group B). Methods: Tunnel widening was assessed using computed tomography (CT) and a previously validated analytical best fit cylinder technique at approximately 1-year following ACLR. Clinical follow-up comprised evaluation with IKDC, KSS, Tegner, Lysholm scores, and knee laxity assessment. Results: The study population comprised 22 patients in each group with a median clinical follow-up of 24 months (range 21–27 months). The median duration between ACLR and CT was 13 months (range 12–14 months). There were no significant differences in clinical outcome measures between groups. There were no differences between groups with respect to femoral tunnel widening. However, there was a significantly larger increase in tibial tunnel widening, at the middle portion, in Group B (2.4 ± 1.5 mm) compared to Group A (0.8 ± 0.4 mm) (p = 0.027), and also at the articular portion in Group B (1.5 ± 0.8 mm) compared to Group A (0.8 ± 0.8 mm) (p = 0.027). Conclusion: Tibial tunnel widening after ACLR using hamstring tendon autograft is significantly greater with suspensory femoral fixation and a bioabsorbable tibial interference screw when compared to an all-inside technique at a median follow-up of 2 years. The clinical relevance of this work lies in the rebuttal of concerns arising from biomechanical studies regarding the possibility of increased tunnel widening with an all-inside technique. Level of evidence: III

Measurement of the W+W−γW^{+}W^{-} \gamma Cross-section and First direct Limits on Anomalous Electroweak Quartic Gauge Couplings

A study of W+W- events accompanied by hard photon radiation produced in e+e- collisions at LEP is presented. Events consistent with two on-shell W-bosons and an isolated photon are selected from 183pb^-1 of data recorded at root{s}=189GeV. From these data, 17 W+W-gamma candidates are selected with photon energy greater than 10GeV, consistent with the Standard Model expectation. These events are used to measure the e+e- to W+W-gamma cross-section within a set of geometric and kinematic cuts; sigma{W+W-gamma} = 136+-37+-8 fb, where the first error is statistical and the second systematic. The photon energy spectrum is used to set the first direct, albeit weak, limits on possible anomalous contributions to the {W+ W- gamma gamma} and {W+ W- gamma Z0} vertices: -0.070GeV^{-2} < a_0/Lambda^2 < 0.070GeV^{-2}, -0.13GeV^{-2} < a_c/Lambda^2 < 0.19GeV^{-2}, -0.61GeV^{-2} < a_n/Lambda^2 < 0.57GeV^{-2}, where Lambda represents the energy scale for new physics.A study of W+W- events accompanied by hard photon radiation produced in e+e- collisions at LEP is presented. Events consistent with two on-shell W-bosons and an isolated photon are selected from 183pb^-1 of data recorded at root{s}=189GeV. From these data, 17 W+W-gamma candidates are selected with photon energy greater than 10GeV, consistent with the Standard Model expectation. These events are used to measure the e+e- to W+W-gamma cross-section within a set of geometric and kinematic cuts; sigma{W+W-gamma} = 136+-37+-8 fb, where the first error is statistical and the second systematic. The photon energy spectrum is used to set the first direct, albeit weak, limits on possible anomalous contributions to the {W+ W- gamma gamma} and {W+ W- gamma Z0} vertices: -0.070GeV^{-2} < a_0/Lambda^2 < 0.070GeV^{-2}, -0.13GeV^{-2} < a_c/Lambda^2 < 0.19GeV^{-2}, -0.61GeV^{-2} < a_n/Lambda^2 < 0.57GeV^{-2}, where Lambda represents the energy scale for new physics.A study of W+W- events accompanied by hard photon radiation produced in e+e- collisions at LEP is presented. Events consistent with two on-shell W-bosons and an isolated photon are selected from 183pb^-1 of data recorded at root{s}=189GeV. From these data, 17 W+W-gamma candidates are selected with photon energy greater than 10GeV, consistent with the Standard Model expectation. These events are used to measure the e+e- to W+W-gamma cross-section within a set of geometric and kinematic cuts; sigma{W+W-gamma} = 136+-37+-8 fb, where the first error is statistical and the second systematic. The photon energy spectrum is used to set the first direct, albeit weak, limits on possible anomalous contributions to the {W+ W- gamma gamma} and {W+ W- gamma Z0} vertices: -0.070GeV^{-2} < a_0/Lambda^2 < 0.070GeV^{-2}, -0.13GeV^{-2} < a_c/Lambda^2 < 0.19GeV^{-2}, -0.61GeV^{-2} < a_n/Lambda^2 < 0.57GeV^{-2}, where Lambda represents the energy scale for new physics.A study of W+W- events accompanied by hard photon radiation produced in e+e- collisions at LEP is presented. Events consistent with two on-shell W-bosons and an isolated photon are selected from 183pb^-1 of data recorded at root{s}=189GeV. From these data, 17 W+W-gamma candidates are selected with photon energy greater than 10GeV, consistent with the Standard Model expectation. These events are used to measure the e+e- to W+W-gamma cross-section within a set of geometric and kinematic cuts; sigma{W+W-gamma} = 136+-37+-8 fb, where the first error is statistical and the second systematic. The photon energy spectrum is used to set the first direct, albeit weak, limits on possible anomalous contributions to the {W+ W- gamma gamma} and {W+ W- gamma Z0} vertices: -0.070GeV^{-2} < a_0/Lambda^2 < 0.070GeV^{-2}, -0.13GeV^{-2} < a_c/Lambda^2 < 0.19GeV^{-2}, -0.61GeV^{-2} < a_n/Lambda^2 < 0.57GeV^{-2}, where Lambda represents the energy scale for new physics.A study of W+W- events accompanied by hard photon radiation produced in e+e- collisions at LEP is presented. Events consistent with two on-shell W-bosons and an isolated photon are selected from 183pb^-1 of data recorded at root{s}=189GeV. From these data, 17 W+W-gamma candidates are selected with photon energy greater than 10GeV, consistent with the Standard Model expectation. These events are used to measure the e+e- to W+W-gamma cross-section within a set of geometric and kinematic cuts; sigma{W+W-gamma} = 136+-37+-8 fb, where the first error is statistical and the second systematic. The photon energy spectrum is used to set the first direct, albeit weak, limits on possible anomalous contributions to the {W+ W- gamma gamma} and {W+ W- gamma Z0} vertices: -0.070GeV^{-2} < a_0/Lambda^2 < 0.070GeV^{-2}, -0.13GeV^{-2} < a_c/Lambda^2 < 0.19GeV^{-2}, -0.61GeV^{-2} < a_n/Lambda^2 < 0.57GeV^{-2}, where Lambda represents the energy scale for new physics.A study of W+W- events accompanied by hard photon radiation produced in e+e- collisions at LEP is presented. Events consistent with two on-shell W-bosons and an isolated photon are selected from 183pb^-1 of data recorded at root{s}=189GeV. From these data, 17 W+W-gamma candidates are selected with photon energy greater than 10GeV, consistent with the Standard Model expectation. These events are used to measure the e+e- to W+W-gamma cross-section within a set of geometric and kinematic cuts; sigma{W+W-gamma} = 136+-37+-8 fb, where the first error is statistical and the second systematic. The photon energy spectrum is used to set the first direct, albeit weak, limits on possible anomalous contributions to the {W+ W- gamma gamma} and {W+ W- gamma Z0} vertices: -0.070GeV^{-2} < a_0/Lambda^2 < 0.070GeV^{-2}, -0.13GeV^{-2} < a_c/Lambda^2 < 0.19GeV^{-2}, -0.61GeV^{-2} < a_n/Lambda^2 < 0.57GeV^{-2}, where Lambda represents the energy scale for new physics.A study of W+W- events accompanied by hard photon radiation produced in e+e- collisions at LEP is presented. Events consistent with two on-shell W-bosons and an isolated photon are selected from 183pb^-1 of data recorded at root{s}=189GeV. From these data, 17 W+W-gamma candidates are selected with photon energy greater than 10GeV, consistent with the Standard Model expectation. These events are used to measure the e+e- to W+W-gamma cross-section within a set of geometric and kinematic cuts; sigma{W+W-gamma} = 136+-37+-8 fb, where the first error is statistical and the second systematic. The photon energy spectrum is used to set the first direct, albeit weak, limits on possible anomalous contributions to the {W+ W- gamma gamma} and {W+ W- gamma Z0} vertices: -0.070GeV^{-2} < a_0/Lambda^2 < 0.070GeV^{-2}, -0.13GeV^{-2} < a_c/Lambda^2 < 0.19GeV^{-2}, -0.61GeV^{-2} < a_n/Lambda^2 < 0.57GeV^{-2}, where Lambda represents the energy scale for new physics.A study of W+W- events accompanied by hard photon radiation produced in e+e- collisions at LEP is presented. Events consistent with two on-shell W-bosons and an isolated photon are selected from 183pb^-1 of data recorded at root{s}=189GeV. From these data, 17 W+W-gamma candidates are selected with photon energy greater than 10GeV, consistent with the Standard Model expectation. These events are used to measure the e+e- to W+W-gamma cross-section within a set of geometric and kinematic cuts; sigma{W+W-gamma} = 136+-37+-8 fb, where the first error is statistical and the second systematic. The photon energy spectrum is used to set the first direct, albeit weak, limits on possible anomalous contributions to the {W+ W- gamma gamma} and {W+ W- gamma Z0} vertices: -0.070GeV^{-2} < a_0/Lambda^2 < 0.070GeV^{-2}, -0.13GeV^{-2} < a_c/Lambda^2 < 0.19GeV^{-2}, -0.61GeV^{-2} < a_n/Lambda^2 < 0.57GeV^{-2}, where Lambda represents the energy scale for new physics.A study of W + W − events accompanied by hard photon radiation produced in e + e − collisions at LEP is presented. Events consistent with two on-shell W-bosons and an isolated photon are selected from 183 pb −1 of data recorded at s =189 GeV. From these data, 17 W + W − γ candidates are selected with photon energy greater than 10 GeV, consistent with the Standard Model expectation. These events are used to measure the e + e − →W + W − γ cross-section within a set of geometric and kinematic cuts, σ ̂ WW γ =136±37±8 fb, where the first error is statistical and the second systematic. The photon energy spectrum is used to set the first direct, albeit weak, limits on possible anomalous contributions to the W + W − γγ and W + W − γ Z 0 vertices: −0.070 GeV −