Early spatiotemporal evolution of the immune response elicited by adenovirus serotype 26 vector vaccination in mice.

As the first responder to immunological challenges, the innate immune system shapes and regulates the ensuing adaptive immune response. Many clinical studies evaluating the role of innate immunity in initiating vaccine-elicited adaptive immune responses have largely been confined to blood due to inherent difficulty in acquiring tissue samples. However, the absence of vaccine-site and draining lymph node information limits understanding of early events induced by vaccination that could potentially shape vaccine-elicited immunity.

PD-1 Inhibition-Trouble for Subsequent TIL Therapy in Patients with Melanoma?

To explore the lower efficacy of adoptive cell transfer (ACT) therapy in patients with anti-PD-1 experienced melanoma, tumor mutational burden (TMB), predicted neoantigen frequencies, and tumor-infiltrating lymphocyte (TIL) neoantigen reactivity were assessed. Reduced neoantigen-specific TIL frequencies correlated with lower ACT response even in patients with similar TMB, suggesting a potentially harmful effect of PD-1 inhibition on T-cell outgrowth. See related article by Levi et al.

Natural killer cell immunosuppressive function requires CXCR3-dependent redistribution within lymphoid tissues.

NK cell suppression of T cells is a key determinant of viral pathogenesis and vaccine efficacy. This process involves perforin-dependent elimination of activated CD4+ T cells during the first 3 days of infection. Although this mechanism requires cell-cell contact, NK cells and T cells typically reside in different compartments of lymphoid tissues at steady state.

Advances in the development of personalized neoantigen-based therapeutic cancer vaccines.

Within the past decade, the field of immunotherapy has revolutionized the treatment of many cancers with the development and regulatory approval of various immune-checkpoint inhibitors and chimeric antigen receptor T cell therapies in diverse indications. Another promising approach to cancer immunotherapy involves the use of personalized vaccines designed to trigger de novo T cell responses against neoantigens, which are highly specific to tumours of individual patients, in order to amplify and broaden the endogenous repertoire of tumour-specific T cells. Results from initial clinical studies of personalized neoantigen-based vaccines, enabled by the availability of rapid and cost-effective sequencing and bioinformatics technologies, have demonstrated robust tumour-specific immunogenicity and preliminary evidence of antitumour activity in patients with melanoma and other cancers.

Protective efficacy of an attenuated Mtb ΔLprG vaccine in mice.

Bacille Calmette-Guerin (BCG), an attenuated whole cell vaccine based on Mycobacterium bovis, is the only licensed vaccine against Mycobacterium tuberculosis (Mtb), but its efficacy is suboptimal and it fails to protect against pulmonary tuberculosis. We previously reported that Mtb lacking the virulence genes lprG and rv1410c (ΔLprG) was highly attenuated in immune deficient mice. In this study, we show that attenuated ΔLprG Mtb protects C57BL/6J, Balb/cJ, and C3HeB/FeJ mice against Mtb challenge and is as attenuated as BCG in SCID mice.

Alpha-defensin 5 differentially modulates adenovirus vaccine vectors from different serotypes in vivo.

Adenoviral vectors have shown significant promise as vaccine delivery vectors due to their ability to elicit both innate and adaptive immune responses. α-defensins are effector molecules of the innate immune response and have been shown to modulate natural infection with adenoviruses, but the majority of α-defensin-adenovirus interactions studied to date have only been analyzed in vitro. In this study, we evaluated the role of α-defensin 5 (HD5) in modulating adenovirus vaccine immunogenicity using various serotype adenovirus vectors in mice.

Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy.

The combined inhibition of histone deacetylases (HDAC) and the proteins of the bromodomain and extraterminal (BET) family have recently shown therapeutic efficacy against melanoma, pancreatic ductal adenocarcinoma, testicular, and lymphoma cancers in murine studies. However, in such studies, the role of the immune system in therapeutically controlling these cancers has not been explored. We sought to investigate the effect of the HDAC inhibitor romidepsin (RMD) and the BET inhibitor IBET151, both singly and in combination, on vaccine-elicited immune responses.

Adenovirus Vector Vaccination Impacts NK Cell Rheostat Function following Lymphocytic Choriomeningitis Virus Infection.

Natural killer (NK) cells respond rapidly as a first line of defense against infectious pathogens. In addition, NK cells may provide a "rheostat" function and have been shown to reduce the magnitude of antigen-specific T cell responses following infection to avoid immunopathology. However, it remains unknown whether NK cells similarly modulate vaccine-elicited T cell responses following virus challenge.

Rapid Cloning of Novel Rhesus Adenoviral Vaccine Vectors.

Human and chimpanzee adenovirus vectors are being developed to circumvent preexisting antibodies against common adenovirus vectors such as Ad5. However, baseline immunity to these vectors still exists in human populations. Traditional cloning of new adenovirus vaccine vectors is a long and cumbersome process that takes 2 months or more and that requires rare unique restriction enzyme sites.

Zika Virus Persistence in the Central Nervous System and Lymph Nodes of Rhesus Monkeys.

Zika virus (ZIKV) is associated with severe neuropathology in neonates as well as Guillain-Barré syndrome and other neurologic disorders in adults. Prolonged viral shedding has been reported in semen, suggesting the presence of anatomic viral reservoirs. Here we show that ZIKV can persist in cerebrospinal fluid (CSF) and lymph nodes (LN) of infected rhesus monkeys for weeks after virus has been cleared from peripheral blood, urine, and mucosal secretions.

Adenovirus serotype 5 vaccine vectors trigger IL-27-dependent inhibitory CD4 T cell responses that impair CD8 T cell function.

Adenovirus serotype 5 (Ad5) vaccine vectors elicit robust CD8 T cell responses, but these responses typically exhibit a partially exhausted phenotype. However, the immunologic mechanism by which Ad5 vectors induce dysfunctional CD8 T cells has not previously been elucidated. Here we demonstrate that, following immunization of B6 mice, Ad5 vectors elicit antigen-specific IL-10CD4 T cells with a distinct transcriptional profile in a dose-dependent fashion.

Antigen-specific NK cell memory in rhesus macaques.

Natural killer (NK) cells have traditionally been considered nonspecific components of innate immunity, but recent studies have shown features of antigen-specific memory in mouse NK cells. However, it has remained unclear whether this phenomenon also exists in primates. We found that splenic and hepatic NK cells from SHIV(SF162P3)-infected and SIV(mac251)-infected macaques specifically lysed Gag- and Env-pulsed dendritic cells in an NKG2-dependent fashion, in contrast to NK cells from uninfected macaques.

CD4 T Cell Depletion Substantially Augments the Rescue Potential of PD-L1 Blockade for Deeply Exhausted CD8 T Cells.

In various models of chronic infections and cancers, blockade of the inhibitory programmed cell death-1 (PD-1) pathway has been shown to be promising at restoring immune function. However, there is not a complete understanding of the factors that influence responsiveness to programmed death-ligand 1 (PD-L1) blockade. In particular, it is currently unclear whether the efficacy of PD-L1 blockade is dependent on the stage of disease.

Energy conservation in infants.

Energy acquisition through suckling has been widely studied in rat and human infants. Processes mediating energy conservation, however, have not received the attention that they deserve. This essay, in honor of Professor Jerry Hogan, discusses parallel behaviors used by rat and human mothers to minimize energy loss in their offspring.

Workforce development and effective evaluation of projects.

The success of a project or programme is typically determined in relation to outputs. However, there is a commitment among UK public services to spending public funds efficiently and on activities that provide the greatest benefit to society. Skills for Health recognised the need for a tool to manage the complex process of evaluating project benefits.

Accumulation and rapid decay of non-LTR retrotransposons in the genome of the three-spine stickleback.

The diversity and abundance of non-long terminal repeat (LTR) retrotransposons (nLTR-RT) differ drastically among vertebrate genomes. At one extreme, the genome of placental mammals is littered with hundreds of thousands of copies resulting from the activity of a single clade of nLTR-RT, the L1 clade. In contrast, fish genomes contain a much more diverse repertoire of nLTR-RT, represented by numerous active clades and families.

Using competences and competence tools in workforce development.

The NHS Knowledge and Skills Framework (KSF) has been a driving force in the move to competence-based workforce development in the NHS. Skills for Health has developed national workforce competences that aim to improve behavioural performance, and in turn increase productivity. This article describes five projects established to test Skills for Health national workforce competences, electronic tools and products in different settings in the NHS.

Social influences on formula intake via suckling in 7 to 14-week-old-infants.

To investigate social influences on human suckling behavior, 25 healthy, full term, 7 to 14-week-old infants were each bottle-fed their own formula twice by their mother and once in each of four experimental conditions: (a) held, provided social interaction; (b) held, without interaction; (c) not held, provided interaction; (d) not held, without interaction. Volume intake (VI), Total Sucks, infant gaze direction, and time elapsed since the last feeding were determined. There were three major findings: (1) social interaction increased VI; (2) VI was linearly related to the time since the last feeding in held infants; (3) Total Sucks and VI were both highly correlated with privation length when infants did not look at the feeder and when fed by the mother.

On the road to obesity: Television viewing increases intake of high-density foods.

Television viewing (TVV) has been linked with obesity, possibly through increased sedentary behavior and/or through increased ingestion during TVV. The proposition that TVV causes increased feeding, however, has not been subjected to experimental verification until recently. Our objective was to determine if the amount eaten of two familiar, palatable, high-density foods (pizza and macaroni and cheese) was increased during a 30-min meal when watching TV.

The ontogeny of face identity; I. Eight- to 21-week-old infants use internal and external face features in identity.

A paradigm was designed to study how infants identify live faces. Eight- to 21-week-old infants were seated comfortably and were presented an adult female, dressed in a white laboratory coat and a white turtle neck sweater, until habituation ensued. The adult then left the room.

Sucrose attenuates a negative electroencephalographic response to an aversive stimulus for newborns.

Reports that sweet taste calms crying in newborns and is analgesic against the pain caused by a heel lance served as the basis for this study. Electroencephalographic (EEG) activity, heart rate activity, and infants' facial behaviors were recorded before and after a noninvasive, but noxious, heelstroke (procedure from the Brazelton Neonatal Behavior Assessment Scale). In a randomized and controlled trial, 34 newborns were administered 2 mL of water or sucrose solution before the heelstroke.

Biological and environmental determinants of childhood obesity.

Childhood obesity reflects the confluence of three factors that minimize attention to internal physiologic satiety signals: the release of central opioids through ingestion of sweets and fats, which induces a preference for such foods; the phylogenetic quality of extending meals in response to environmental demands, as in work schedules, or through finding patches of agreeable food that are safe to consume (this is exacerbated in impoverished children, whose activity is limited); the determination of food preference through social interactions renders feeding systems open to external influences such as mass marketing and television advertising. Alternative feeding modes are presented based on studies of childhood food preferences and how children may be influenced to choose more balanced and healthier diets.

Changing determinants of crying termination in 6- to 12-week-old human infants.

Developmental change in human infant crying termination was studied in 60 infants who were 6, 9, and 12 weeks of age. They qualified by spontaneously crying for at least 30 s during the study's first minute. Infants then received either 0.

Ingestion, suckling, and the problem of identity: using criteria in the classification of ingestive behavior.

The data reported by Nizhnikov et al. [Newborn rats first suckling experience: taste differentiation and suckling plasticity (2002)] do not support the authors' claim that they shed light on suckling mechanisms. A number of accepted criteria for identifying suckling are discussed in this review.