Immunological Endpoints Research Articles

Evaluation of Tumor Vaccine Generation in a Phase II Multicenter Trial of Single Autologous Hematopoietic Cell Transplant (AutoHCT)Followed By Lenalidomide Maintenance for Multiple Myeloma (MM) with or without Vaccination with Dendritic Cell/ Myeloma Fusions (DC/MM fusion vaccine): Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1401

BMT CTN 1401 is an academically led randomized study of a personalized cancer vaccine in which the combination of DC/MM fusion vaccine and lenalidomide maintenance after autoHCT is compared with maintenance alone as upfront treatment of MM (NCT#02728102). Assessment of the percentage of patients achieving CR and therapy-induced changes in MM-specific immunity are the primary clinical and immunologic endpoints, respectively. The protocol represents a transformative open source approach to cell therapy in MM and required collection of tumor cells prior to treatment initiation and vaccine production at day 60 after autoHCT. The process featured a multi-step approach of procedural standardization, training, and centralized verification of manufactured product/release criteria. Here we present initial analysis of accrual and vaccine manufacturing. Enrollment of 203 patients completed within 26 months with 140 patients randomized. Drop-out rate from enrollment to randomization was 31% (expected 30%). Sixty-eight patients were randomized to the DC/MM fusion vaccine arm, with 63 having products successfully manufactured and approved for release at 14 manufacturing sites. Vaccine products for 5 patients were not approved for release for the following reasons: final TC/DC viability did not meet release criteria (n = 3), product failed to meet sterility release criteria (n = 1), and disease progression prior to manufacture (n = 1). Among 63 participants who received vaccine, mean DC viability and CD86 expression was 79.3% (Standard Deviation = 11.3) and 80.6% (SD = 12.9), respectively. Mean viability and percent cells co-expressing DC and tumor antigens was 78.6% (SD = 13.0) and 47.9% (SD = 11.4), respectively. The process devised for BMT CTN 1401 led to rapid patient accrual and successful point-of-care DC/MM fusion vaccine generation. Feasibility of serial sample collection and performance of immunologic correlates were demonstrated. This multi-center collaboration highlights the development of a personalized tumor vaccine platform that serves as a model for future immunotherapy trials in MM.

Consensus Report on Shigella Controlled Human Infection Model: Conduct of Studies.

Shigella causes morbidity and mortality worldwide, primarily affecting young children living in low-resource settings. It is also of great concern due to increasing antibiotic resistance, and is a priority organism for the World Health Organization. A Shigella vaccine would decrease the morbidity and mortality associated with shigellosis, improve child health, and decrease the need for antibiotics. Controlled human infection models (CHIMs) are useful tools in vaccine evaluation for early up- or down-selection of vaccine candidates and potentially useful in support of licensure. Over time, the methods employed in these models have become more uniform across sites performing CHIM trials, although some differences in conduct persist. In November 2017, a Shigella CHIM workshop was convened in Washington, District of Columbia. Investigators met to discuss multiple aspects of these studies, including study procedures, clinical and immunological endpoints, and shared experiences. This article serves as a uniform procedure by which to conduct Shigella CHIM studies.

EXTH-42. QUANTITATIVE BIODISTRIBUTION OF ADOPTIVELY TRANSFERRED T CELLS IN BRAIN TUMOR-BEARING MICE

Abstract SIGNIFICANCE Adoptive T cell therapy (ACT) has emerged as the most effective treatment strategy against advanced malignant melanoma, eliciting remarkable objective clinical responses in up to 75% of patients with refractory metastatic disease, including those with lesions within the central nervous system. Importantly, immunologic surrogate endpoints that correlate with treatment outcome have been identified in these patients, with clinical responses being dependent on the migration of transferred T cells to sites of tumor growth. OBJECTIVE We investigated the biodistribution of exogenously administered T cells in a murine model of glioblastoma at whole body, organ, and cellular levels. METHODS T cells were isolated from the spleens of DsRed transgenic C57BL/6 mice and injected intravenously, after in vitro expansion and activation, in murine KR158B glioma-bearing mice. To determine transferred T cell spatial distribution, brains, lymph nodes, hearts, lungs, spleens, livers, kidneys and stomachs were isolated for active clearing, immunostaining, and 3D imaging using light sheet microscopy, or processed for fluorescent immunohistochemistry and confocal imaging. Transferred T cell quantification in various organs was performed using flow cytometry, 2D optical imaging (IVIS), and magnetic particle imaging (MPI) after ferucarbotran nanoparticle labeling. T cell distribution was also assessed in vivo using IVIS and MPI. RESULTS The spleen, liver, and lungs accounted for more than 90% of transferred T cells in the body. The proportion of DsRed T cells in tumor-bearing brains was found to be very low, hovering below 1% (and representing ~15% of total tumor-infiltrating lymphocytes). Transferred T cells mostly concentrated at the periphery of the tumor mass and in proximity to blood vessels. CONCLUSIONS The success of ACT immunotherapy for brain tumors likely requires optimization of delivery route, dosing regimen, and modification of tumor-specific lymphocyte trafficking and effector functions in order to achieve maximal penetration and persistence at sites of invasive tumor growth.

Determining Immune and miRNA Biomarkers Related to Respiratory Syncytial Virus (RSV) Vaccine Types.

Respiratory Syncytial Virus (RSV) causes serious respiratory tract illness and substantial morbidity and some mortality in populations at the extremes of age, i.e., infants, young children, and the elderly. To date, RSV vaccine development has been unsuccessful, a feature linked to the lack of biomarkers available to assess the safety and efficacy of RSV vaccine candidates. We examined microRNAs (miR) as potential biomarkers for different types of RSV vaccine candidates. In this study, mice were vaccinated with a live attenuated RSV candidate that lacks the small hydrophobic (SH) and attachment (G) proteins (CP52), an RSV G protein microparticle (GA2-MP) vaccine, a formalin-inactivated RSV (FI-RSV) vaccine or were mock-treated. Several immunological endpoints and miR expression profiles were determined in mouse serum and bronchoalveolar lavage (BAL) following vaccine priming, boost, and RSV challenge. We identified miRs that were linked with immunological parameters of disease and protection. We show that miRs are potential biomarkers providing valuable insights for vaccine development.

Research progress of the surrogate of protection of pneumococcal conjugate vaccine

There are many limitations in evaluating vaccine efficacy by comparing the incidence of clinical endpoint events (such as morbidity, bacterial colonization) between the vaccine group and the control group. Therefore, the researchers put forward the concept of Surrogate of protection to predict vaccine protection with immunological indicators. In 2012, WHO put forward the immunological substitution endpoint of pneumococcal vaccine, using 0. 35 μg/ml as the protective antibody level of pneumococcal vaccine. But subsequent studies have found that using this threshold to assess all vaccine serotypes may not be accurate.

Functional antibodies as immunological endpoints to evaluate protective immunity against Shigella

ABSTRACTThe development, clinical advancement and licensure of vaccines, and monitoring of vaccine effectiveness could be expedited and simplified by the ability to measure immunological endpoints that can predict a favorable clinical outcome. Antigen-specific and functional antibodies have been described in the context of naturally acquired immunity and vaccination against Shigella, and their presence in serum has been associated with reduced risk of disease in human subjects. The relevance of these antibodies as correlates of protective immunity, their mechanistic contribution to protection (e.g. target antigens, interference with pathogenesis, and participation in microbial clearance), and factors that influence their magnitude and makeup (e.g. host age, health condition, and environment) are important considerations that need to be explored. In addition to facilitating vaccine evaluation, immunological correlates of protection could be useful for identifying groups at risk and advancing immune therapies. Herein we discuss the precedent and value of functional antibodies as immunological endpoints to predict vaccine efficacy and the relevance of functional antibody activity to evaluate protective immunity against shigellosis.

Synbiotics Combined with Glutamine Stimulate Brain Development and the Immune System in Preterm Pigs

Preterm infants are born with an immature gut, brain, and immune system, predisposing them to short- and long-term complications. We hypothesized that a milk diet supplemented with pre- and probiotics (i.e. synbiotics) and glutamine would improve gut, brain, and immune maturation in preterm neonates, using preterm pigs as a model. Preterm pigs (Landrace x Yorkshire x Duroc, n=40, delivered by c-section at 90% of gestation) were reared individually until day 23 after birth under highly standardized conditions. Piglets in the intervention group (PPG, n=20) were fed increasing volumes of bovine milk supplemented with prebiotics (short-chain galacto- and long chain fructo-oligosaccharides 9:1, 4-12 g/L), probiotics (Bifidobacterium breve M16-V, 3×109 CFU/d) and l-glutamine [0.15-0.30 g/(kg · d)], and compared with pigs fed bovine milk with added placebo compounds as control (CON, n=20). Clinical, gastrointestinal, immunological, cognitive, and neurological endpoints were measured. The PPG pigs showed more diarrhea but weight gain, body composition, and gut parameters were similar between the groups. Cognitive performance, assessed in a T-maze, was significantly higher in PPG pigs (P<0.01), whereas motor function and exploratory interest were similar between the groups. Using ex vivo diffusion imaging, the orientation dispersion index in brain cortical gray matter was 50% higher (P=0.04), and fractional anisotropy value was 7% lower (P=0.05) in PPG pigs compared with CON pigs, consistent with increased dendritic branching in PPG. In associative fibers, radial diffusivity was lower and fractional anisotropy was higher in PPG pigs compared with CON pigs (all P<0.05), while measures in the internal capsule showed a tendency towards reduced radial diffusivity and mean diffusivity (both P=0.09). On day 23 pigs in the PPG group showed higher blood leukocyte numbers (+43%), neutrophil counts (+100%), and phagocytic rates (+24%), relative to CON, all P<0.05. Preterm pigs supplemented with Bifidobacterium breve, galacto- and fructo-oligosaccharides, and l-glutamine showed enhanced neuronal and immunological development. The findings indicate the potential for targeted nutritional interventions after preterm birth, to support development of important systems such as immunity and brain.

Defining a correlate of protection for chikungunya virus vaccines

Chikungunya virus infection causes a debilitating febrile illness that in many affected individuals is associated with long-term sequelae that can persist for months or years. Over the past decade a large number of candidate vaccines have been developed, several of which have now entered clinical trials. The rapid and sporadic nature of chikungunya outbreaks poses challenges for planning of large clinical efficacy trials suggesting that licensure of chikungunya vaccines may utilize non-traditional approval pathways based on identification of immunological endpoint(s) predictive of clinical benefit. This report reviews the current status of nonclinical and clinical testing and potential challenges for defining a suitable surrogate or correlate of protection.

Comparison of three sample size calculation methods for non-inferiority vaccine trials with multiple continuous co-primary endpoints

ABSTRACTClinical trials that study immunogenicity of combination vaccines often have less power than desirable. To make up for the reduction in statistical power at the study level, researchers have to increase the study sample size. To study immunogenicity variables, we used the geometric mean concentration of immune response after vaccination as immunologic endpoint and compared 3 sample size calculation methods: the “Inflation factors” method, the “Incrementing” method, and the “Bonferroni correction” method when there are multiple continuous co-primary endpoints. The parameters were set according to the actual situation of the use of combination vaccines and the simulation results were used as reference. The present study demonstrates that all 3 methods are applicable when the effect size of each endpoint is similar and the endpoints are at most weakly correlated, but when there is a true difference in effect sizes among endpoints, the “Incrementing” method has the best performance.

Oral immunization of a rAd vector expressing norovirus VP1 elicits a potent mucosal immune response without an increase in anti-vector immunity

Background: Noroviruses are the leading cause of epidemic acute gastroenteritis and foodborne diarrheal disease in humans. Potential correlates of protection identified through human challenge studies include mucosal IgA, memory B cells, and serum blocking (BT50) antibody titers. We hypothesized that fecal and memory IgA responses would be significantly elevated following oral immunization. Methods & Materials: We conducted a single-site, randomized, double-blind, placebo-controlled trial to determine the safety and immunogenicity of a norovirus vaccine consisting of a non-replicating adenovirus vector expressing VP1 delivered orally by tablet. Subjects that met inclusion/exclusion criteria were enrolled and randomized 2:1 to receive either a single dose of vaccine or placebo, respectively. Two dose levels were evaluated. The primary objective was to assess safety. The secondary objective was to determine immunogenicity, primarily assessed by measuring serum BT50. Exploratory immunological assessments included serum, fecal and saliva antibody titers measured by and the frequency of memory and antibody secreting B cells (ASCs). Anti-vector immunity was assessed by measuring Ad5 neutralizing antibody responses pre and post immunization (ClinicalTrials.gov number NCT02868073). Results: Sixty-six subjects were enrolled between July and Sept 2016. The vaccine was well-tolerated. The primary immunological endpoint (BT50 titers) was met in low and high dose groups (P = 0.0014, P < 0.0001). In the high-dose group, 18/23 (78%) subjects had a two-fold or greater increase in BT50 titer after a single vaccine dose. An average of 561 IgA ASCs x106 PBMC were induced post-immunization in the high dose group. Post immunization, a 15 fold increase in the geometric mean was observed, along with a greater than 10 fold average increase in the fecal IgA VP1 specific antibody response. Anti-Ad5 neutralizing antibody responses did not significantly increase compared to the placebo group. Conclusion: The norovirus vaccine was well-tolerated (with no dose limiting toxicities), and generated immune responses to norovirus VP1, without a corresponding increase in anti-Ad5 neutralizing antibody responses. It particular, the vaccine generated memory and local effector IgA + B cells. Because mucosal IgA is the front-line defense against enteric pathogens, vaccine-derived norovirus-specific intestinal IgA may translate to superior efficacy. This is a very promising advance in the development of an oral norovirus vaccine.

Boosting Teenagers With Acellular Pertussis Vaccines Containing Recombinant or Chemically Inactivated Pertussis Toxin: A Randomized Clinical Trial.

Protection induced by acellular pertussis (aP) vaccines is partial and short-lived, especially in teenagers, calling for novel immunization strategies. We conducted an investigator-driven proof-of-concept randomized controlled trial in aP-primed adolescents in Geneva to assess the immunogenicity and reactogenicity of a novel recombinant aP (r-aP) vaccine including recombinant pertussis toxin (PT) and filamentous hemagglutinin (FHA) coadministered with tetanus-diphtheria toxoids (Td), compared to a licensed tetanus-diphtheria-aP vaccine containing chemically detoxified PT (cd/Tdap). The primary immunological endpoints were day 28/365 geometric mean concentrations (GMCs) of total and neutralizing anti-PT antibodies. Memory B cells were assessed. Sixty-two aP-primed adolescents were randomized and vaccinated with r-aP + Td or cd/Tdap. Reactogenicity, adverse events, and baseline GMCs were similar between the groups. Day 28 PT-neutralizing GMCs were low after cd/Tdap (73.91 [95% confidence interval {CI}, 49.88-109.52] IU/mL) and approximately 2-fold higher after r-aP + Td (127.68 [95% CI, 96.73-168.53] IU/mL; P = .0162). Anti-PT GMCs were also low after cd/Tdap (52.43 [95% CI, 36.41-75.50] IU/mL) and 2-fold higher after r-aP + Td (113.74 [95% CI, 88.31-146.50] IU/mL; P = .0006). Day 28 anti-FHA GMCs were similar in both groups. Day 365 anti-PT (but not PT-neutralizing) GMCs remained higher in r-aP + Td vaccinees. PT-specific memory B cells increased significantly after r-aP + Td but not cd/Tdap boosting. Boosting aP-primed adolescents with r-aP induced higher anti-PT and PT-neutralizing responses than cd/Tdap and increased PT-specific memory B cells. Despite this superior immunogenicity, r-aP may have to be given repeatedly, earlier, and/or with novel adjuvants to exert an optimal influence in aP-primed subjects. NCT02946190.

Comparative toxicity of Corexit® 9500, oil, and a Corexit®/oil mixture on the eastern oyster, Crassostrea virginica (Gmelin)

Given their particle feeding behavior, sessile nature, and abundance in coastal zones, bivalves are at significant risk for exposure to oil and oil dispersant following environmental disasters like the Deepwater Horizon oil spill. However, the effects of oil combined with oil dispersants on the health of oysters are not well studied. Therefore, eastern oysters (Crassostrea virginica) were exposed in vivo to Corexit® 9500, crude oil (high-energy water accommodated fraction; HEWAF), and a Corexit®/oil mixture (chemically-enhanced water accommodated fraction; CEWAF) to evaluate potential toxic effects on immunological (phagocytosis and respiratory burst), physiological (feeding rate), and histological endpoints. Phagocytosis was significantly increased following CEWAF exposure only. Respiratory burst was significantly decreased following Corexit® exposure, but significantly increased following exposure to the highest concentration of CEWAF. Oyster feeding rates were significantly decreased following exposure to Corexit®, HEWAF, and CEWAF, and were most sensitive to CEWAF exposure. These modulations of important immunological and physiological functions could result in serious health outcomes for oysters, such as increased parasitism and decreased growth. Our experiments showed that subtle, sub-lethal effects occurred following acute in vivo exposure to Corexit®, HEWAF, and CEWAF, though oysters were not equally sensitive to the three components. Data from this study can be used for more accurate risk assessment concerning the impact of oil and Corexit® on the health of oysters.

Physiological and immunological responses of birds and mammals to forest degradation: A meta-analysis

Dramatic changes in species composition have been found following selective logging and forest fragmentation. The different responses of bird species to these disturbances suggest that some species are more sensitive to environmental changes than others. Recent studies have suggested that the chances of species to adapt to new environments may be mediated by their stress physiology and immunity. We reviewed and performed a meta-analysis of studies that compared physiological and immunological endpoints of bird and mammal species between degraded (logged and fragmented) forests and undisturbed forests. We found that stress hormones and immunity markers show consistent changes in response to habitat degradation in birds and mammals. Higher physiological and immunological responses were found in those animals living in forests that were subjected to clear-cutting. Furthermore, we found that birds and species belonging to IUCN ‘Threatened’ categories exhibited significantly larger effect size estimates than mammals and ‘Least Concern’ species, respectively. Our meta-analysis revealed that changes in the production of stress hormones and in some immune traits are a significant consequence of forest disturbance. Physiology and immunity might be two important mediators of the adaptiveness of a given species to changing forests.

Translating Mechanism of Regulatory Action of Tolerogenic Dendritic Cells to Monitoring Endpoints in Clinical Trials.

Tolerogenic dendritic cells (tolDCs) have reached patients with autoimmune and inflammatory disease, at least in clinical trials. The safety of tolDCs as intervention therapy has been established, but the capacity to modulate autoimmune response in vivo remains to be demonstrated. Studies have revealed a diversity of regulatory mechanisms that tolDCs may employ in vivo. These mechanisms differ between various types of modulated tolDC. The most often foreseen action of tolDCs is through regulatory polarization of naïve T cells or activation of existing regulatory T cells, which should ultimately diminish autoimmune inflammation. Yet, selection of a target autoantigen remains critical to expedite tissue specific tolerance induction, while measuring immune modulation incited by tolDCs in vivo provides a great challenge. We will discuss the regulatory action of different types of tolDCs and the possible methods to monitor immunological efficacy endpoints for the next generation clinical trials.

Correlates of protection for inactivated enterovirus 71 vaccine: the analysis of immunological surrogate endpoints

ABSTRACTBackground: Inactivated Enterovirus 71 (EV71) vaccines showed significant efficacy against the diseases associated with EV71 and a neutralizing antibody (NTAb) titer of 1:16–1:32 was suggested as the correlates of the vaccine protection. This paper aims to further estimate the immunological surrogate endpoints for the protection of inactivated EV71 vaccines and the effect factors.Methods: Pre-vaccination NTAb against EV71 at baseline (day 0), post-vaccination NTAb against EV71 at day 56, and the occurrence of laboratory-confirmed EV71-associated diseases during a 24-months follow-up period were collected from a phase 3 efficacy trial of an inactivated EV71 vaccine. We used the mixed-scaled logit model and the absolute sigmoid function by some extensions in continuous models to estimate the immunological surrogate endpoint for the EV71 vaccine protection, respectively.Results: For children with a negative baseline of EV71 NTAb titers, an antibody level of 26.6 U/ml (1:30) was estimated to provide at least a 50% protection for 12 months, and an antibody level of 36.2 U/ml (1:42) may be needed to achieve a 50% protective level of the population for 24 months.Conclusion: Both the pre-vaccination NTAb level and the vaccine protective period could affect the estimation of the immunological surrogate for EV71 vaccine. A post-vaccination NTAb titer of 1:42 or more may be needed for long-term protection.Clinical trial registration: NCT01508247.

Immune Responses to an Oral Cholera Vaccine in Internally Displaced Persons in South Sudan.

Despite recent large-scale cholera outbreaks, little is known about the immunogenicity of oral cholera vaccines (OCV) in African populations, particularly among those at highest cholera risk. During a 2015 preemptive OCV campaign among internally displaced persons in South Sudan, a year after a large cholera outbreak, we enrolled 37 young children (1–5 years old), 67 older children (6–17 years old) and 101 adults (≥18 years old), who received two doses of OCV (Shanchol) spaced approximately 3 weeks apart. Cholera-specific antibody responses were determined at days 0, 21 and 35 post-immunization. High baseline vibriocidal titers (>80) were observed in 21% of the participants, suggesting recent cholera exposure or vaccination. Among those with titers ≤80, 90% young children, 73% older children and 72% adults seroconverted (≥4 fold titer rise) after the 1st OCV dose; with no additional seroconversion after the 2nd dose. Post-vaccination immunological endpoints did not differ across age groups. Our results indicate Shanchol was immunogenic in this vulnerable population and that a single dose alone may be sufficient to achieve similar short-term immunological responses to the currently licensed two-dose regimen. While we found no evidence of differential response by age, further immunologic and epidemiologic studies are needed.

Face transplant: long-term follow-up and results of a prospective open study

More than 30 face transplantations have been done worldwide since 2005 but no documented long-term follow-up has been reported in the literature. We aimed to answer remaining question about the long-term risks and benefits of face transplant. In this single-centre, prospective, open study, we assessed 20 patients presenting with facial defects. Ten patients were selected, and, after three were secondarily excluded, seven were transplanted: two with neurofibromatosis 1, one with a burn, and four with self-inflicted facial gunshot injuries. We report the long-term outcomes of six face allotransplant recipients at an average of 6 years (range 3·4-9 years) after the transplantation. All admissions to hospital except for planned revisions and immunosuppressive follow-up therapy were reported as adverse events (safety endpoint). Predefined immunological, metabolic, surgical, and social integration endpoints were collected prospectively. Patients underwent quantitative health-related quality of life assessments through Short Form 36 health questionnaires. This study was registered with ClinicalTrials.gov, number NCT00527280. Two of seven patients died: one at 65 days due to transplant destruction with concomitant pseudomonas infection and the second at 3·4 years after transplantation by suicide. The six patients alive at long-term follow-up presented with functional transplants. Safety endpoints were related to infection in the first month, acute rejection from 1 day to 7 years after transplantation, or side-effects of immunosuppressive therapy. Recurrent rejection episodes justified maintenance therapy with high-dose steroids at high levels in all patients at last follow-up, yet none of the patients developed diabetes. Three patients were found to have hypertension with one requiring therapy. All patients had a noticeable reduction in glomerular filtration rate. All recipients and their families accepted their transplant. Improvements in social integration and quality of life were highly variable among the patients and depended on baseline levels and psychiatric comorbidities. These long-term results show the crucial effect of patients' social support and pre-existing psychiatric conditions on the risk-benefit ratio of facial transplantation. Careful preoperative patient selection and long-term postoperative follow-up programmes under strict institutional review board controls should be used for any future grafts of this type. Protocole Hospitalier de Recherche Clinique (PHRC) National.

Effects of a Randomized, Controlled Trial of Daily Vitamin D3 Supplementation During Pregnancy on Regulatory Immunity and Inflammation

BackgroundVitamin D deficiency is widespread in pregnancy and has been associated with adverse health conditions for mothers and infants. Vitamin D supplementation in pregnancy may support maintenance of pregnancy by its effects on adaptive and innate immunity.ObjectiveWe assessed the effects of vitamin D supplementation during pregnancy on vitamin D status, regulatory and inflammatory T cells, markers of innate immunity, and systemic inflammation.DesignWe conducted a randomized, controlled, double‐blind intervention of two doses of vitamin D3 (400 IU/d vs. 2,000 IU/d) from &lt;20 weeks through delivery in fifty‐seven pregnant women at risk for vitamin D deficiency. Vitamin D status, immune function, and clinical endpoints were assessed in mid‐ and late pregnancy.ResultsSupplementation with 2,000 IU vitamin D had a greater effect on increasing vitamin D status than 400 IU (p&lt;0.05). The percent IL‐10+ CD4+ regulatory cells increased significantly with the 2,000 IU treatment relative to the 400 IU control (p&lt;0.05). FoxP3+ regulatory T‐cells and inflammatory T‐cells were not affected, nor were other immunologic endpoints. Pregnancy progression was associated with decreased percentage of Th1 (CD4+ IFNg+), Th17 (CD4+ IL− 17+), and FoxP3+ Treg cells in peripheral blood (p&lt;0.05), decreased ex vivo production of T cell cytokines (IL‐4, IL‐5, IL‐10), and increased plasma markers of inflammation (IL‐6, TNF‐a, neopterin).ConclusionsDaily supplementation with 2,000 IU is more effective at increasing vitamin D status in pregnant women than 400 IU and is associated with increased regulatory immunity that may prevent adverse outcomes caused by excess inflammation.Support or Funding InformationThis work was supported by the USDA‐ARS and UCDMC CTSC Vision Grant (UL1 TR000002).

The effect of probiotics on CD4 counts among people living with HIV: a systematic review.

Probiotics are defined by the WHO as 'live microorganisms which when administered in adequate amounts confer a health benefit on the host'. Ongoing research has shown probiotics provide benefits to humans, including protection and restoration of the gastrointestinal and other mucosal tracts. As human immunodeficiency virus (HIV) activates gut-associated lymphoid tissue (GALT), several studies have investigated the effect of probiotics on CD4 cell count and related outcomes among those living with HIV. These studies are summarised here. Manuscripts were identified using the search terms 'probiotics', 'synbiotics', 'HIV', and 'CD4', and were reviewed for relevance and inclusion of CD4 count as an immunologic endpoint. Bibliographies of relevant manuscripts were also reviewed for additional studies matching inclusion and exclusion criteria. The search yielded 91 results; 13 included relevant outcomes. Seven of these studies produced beneficial CD4 outcomes, while the remaining 6 reported on insignificant beneficial or negative CD4 outcomes. The studies summarised here collectively suggest that daily consumption of probiotics over a prolonged period of time may improve CD4 count in people living with HIV.

Current issues on sublingual allergen-specific immunotherapy in children with asthma and allergic rhinitis

In 1993 the European Academy of Allergy and Clinical Immunology was the first official organization to recognize that sublingual administration could be “promising route” for allergic desensitization. A few years later, the World Health Organization recommended this therapy as “a viable alternative to the injection route in adults.” The first meta-analysis showed sublingual allergen specific immunotherapy (SLIT) effectiveness for allergic rhinitis and another study showed SLIT can actually help prevent the development of asthma both in adults and in children. The main goal of this review article is to present insight into the most up-to-date understanding of the clinical efficacy and safety of immunotherapy in the treatment of pediatric patients with allergic rhinitis and asthma. A literature review was performed on PubMed from 1990 to 2015 using the terms “asthma,” “allergic rhinitis,” “children,” “allergen specific immune therapy.” Evaluating data from double-blind placebo-controlled randomized clinical trials (DB-PC-RCTs), the clinical efficacy (assessed as the reduction of symptom score and the need of rescue medicament) of SLIT for allergic rhinitis and allergic asthma, has been confirmed in various meta-analysis Outcomes such as rhinoconjunctivitis score and medication scores, combined scores, quality of life, days with severe symptoms, immunological endpoints, and safety parameters were all improved in the SLIT-tablet compared with placebo group. SLIT safety has been already proven in many DB-PC-RCTs and real-life settings. In accordance with all of the above mentioned, the goals for future trials and studies are the development of comprehensive guidelines for clinical practice on immunotherapy, embracing all the different potential participants. The importance of allergen immunotherapy is of special relevance in the pediatric age, when the plasticity and modulability of the immune system are maximal, and when preventative effects can be reasonably expected.