Serum Concentrations Of Antibodies Research Articles

Reproduction of respiratory mycoplasmosis in calves by exposure to an aerosolised culture of Mycoplasma bovis

Mycoplasma bovis is an important pathogen of cattle, causing pneumonia, arthritis and otitis media in young calves, and mastitis in lactating cows, resulting in increased morbidity and, in some instances, mortality. The objective of this study was to evaluate the survival of a M. bovis isolate following nebulisation and to establish whether respiratory disease similar to that seen in the field could be induced in calves by exposing them to an aerosolised culture of M. bovis. A group of eight M. bovis-free calves 14–28days old were exposed to an aerosolised culture of a field isolate of M. bovis that had originally been recovered from a joint lesion in a calf. Three weeks after aerosol exposure necropsies were conducted on all calves. Lung lesions were seen in 7 of 8 calves exposed to the aerosol of M. bovis, whilst calves exposed to the culture medium alone did not develop lesions. Two calves in the infected group had detectable concentrations of serum antibody against M. bovis on day 7 post infection and 4 calves had detectable concentrations of serum antibody against M. bovis on day 21 post infection when tested by MilA IgG ELISA. M. bovis was reisolated from the upper trachea of 6 of the 8 infected calves. The infection method described here appeared to induce lung lesions typical of naturally occurring disease associated with infection with M. bovis and should be applicable to testing the safety and efficacy of attenuated vaccine candidates to control disease caused by this pathogen.

Recombinant flagellin-PAL fusion protein of Legionella pneumophila induced cell-mediated and protective immunity against bacteremia in BALB/c mice.

We report a new recombinant fusion protein composed of full-length Legionella pneumophila flagellin A and peptidoglycan-associated lipoprotein (PAL), rFLA-PAL, capable of inducing protective immunity against L. pneumophila. The recombinant protein was over expressed in Escherichia coli strain BL21 (DE3) using pET-28a (+) expression vector (pET28a-flaA-pal) and purified by Ni2+ exchange chromatography. Immunological properties of rFLA-PAL were assessed in a mouse model. Female BALB/c mice, immunized with rFLA-PAL, exhibited a rapid increase in serum antibody concentration against each of its protein portions. Furthermore, a strong activation of both innate and adaptive cell-mediated immunity was observed as indicated by antigen-specific splenocyte proliferation, IFN-γ and IL-12 production, and early production of TNF-α in the serum and in splenocyte cultures which were separately assessed against PAL and FLA. BALB/c mice were challenged with a lethal dose of L. pneumophila intravenously. In a 10-days follow-up after intravenous lethal challenge with L. pneumophila, a 100% survival rate was observed for mice immunized with rFLA-PAL, same as for those immunized with a sublethal dose of L. pneumophila. Based on the potent immune responses observed in mice immunized with rFLA-PAL, this recombinant fusion protein could be a potential vaccine candidate against the intracellular pathogen L. pneumophila.

Autoantibodies to desmogleins 1 and 3 in patients with lichen planus

There is controversy about the role of autoantibodies against desmoglein 1 and 3 (Dsg1 and 3) in the pathogenesis of lichen planus (LP); the authors planned this study to determine the presence of circulating levels of these antibodies in patients with different types of oral LP and to compare that with cutaneous LP and healthy controls. The enzyme-linked immunosorbent assay test was performed on serum samples of 24 cases of erosive oral LP, 29 cases of reticular oral LP, 30 cases of cutaneous LP and 30 healthy controls. The severity of oral LP was evaluated by Reticulation, Erosion and Ulceration scoring system. There were no significant differences in the concentrations of autoantibodies to Dsg1 between the four groups. Autoantibodies to Dsg3 were increased in erosive oral LP compared with healthy controls (p value=0.005) but no increase was observed between other groups. We did not detect a correlation between the severity of the disease and the levels of anti-Dsg1 and 3 in patients with erosive and reticular types of oral LP. In conclusion, regardless of the increased level of anti-Dsg3 antibody in erosive oral LP, serum concentrations of antibodies were under cut-off values. Moreover, the pathogenic role of anti-Dsg3 antibodies in erosive oral LP is uncertain.

Safety/tolerability of the anti-semaphorin 4D Antibody VX15/2503 in a randomized phase 1 trial.

Objective:To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VX15/2503 in a randomized, single-dose, dose-escalation, double-blind, placebo-controlled study enrolling adult patients with MS.Methods:Single IV doses of VX15/2503 or placebo were administered. Ten patients each were randomized (4:1 randomization ratio) into 5 ascending dose cohorts of 1, 3, 6, 10, or 20 mg/kg. Safety, immunogenicity, PK/PD, MRI, ECG, and lymphocyte subset levels were evaluated. A Dose Escalation Safety Committee (DESC) approved each dose escalation.Results:VX15/2503 was well tolerated, and all participants completed the study. Antibody treatment–related adverse events were primarily grade 1 or 2 and included urinary tract infection (12.5%) and muscle weakness, contusion, and insomnia (each 7.5%). No dose-limiting toxicities were observed, and no maximum tolerated dose was determined. One subject (20 mg/kg) experienced disease relapse 3 months before study entry and exhibited a grade 3 (nonserious) increase in brain lesions by day 29, possibly related to VX15/2503. Twenty-nine patients exhibited human anti-humanized antibody responses; 5 with titer ≥100. No anti-VX15/2503 antibody responses were fully neutralizing. VX15/2503 Cmax, area under the time-concentration curve, and mean half-life increased with dose level; at 20 mg/kg, the T1/2 was 20 days. Cellular SEMA4D saturation occurred at serum antibody concentrations ≤0.3 μg/mL, resulting in decreased cSEMA4D expression. At 20 mg/kg, cSEMA4D saturation persisted for ≥155 days. Total sSEMA4D levels increased with dose level and declined with antibody clearance.Conclusions:These results support the continued investigation of VX15/2503 in neurodegenerative diseases.ClinicalTrials.gov identifier:NCT01764737.Classification of evidence:This study provides Class III evidence that anti-semaphorin 4D antibody VX15/2503 at various doses was safe and well tolerated vs placebo, although an increase in treatment-emergent adverse events in the treatment group could not be excluded (risk difference −0.7%, 95% CI −28.0% to 32.7%).

Construction of an enantiopure bivalent nicotine vaccine using synthetic peptides.

Clinical outcomes of anti-nicotine vaccines may be improved through enhancements in serum antibody affinity and concentration. Two strategies were explored to improve vaccine efficacy in outbred mice: the use of enantiopure haptens and formulation of a bivalent vaccine. Vaccines incorporating natural (-) nicotine haptens improved relative antibody affinities >10-fold over (+) haptens, stimulated a two-fold boost in nicotine serum binding capacity, and following injection with 3 cigarette equivalents of nicotine, prevented a larger proportion of nicotine (>85%) from reaching the brain. The activity of a bivalent vaccine containing (-) 3’AmNic and (-) 1’SNic haptens was then compared to dose-matched monovalent groups. It was confirmed that antisera generated by these structurally distinct haptens have minimal cross-reactivity and stimulate different B cell populations. Equivalent antibody affinities were detected between the three groups, but the bivalent group showed two-fold higher titers and an additive increase in nicotine serum binding capacity as compared to the monovalent groups. Mice immunized with the bivalent formulation also performed better in a nicotine challenge experiment, and prevented >85% of a nicotine dose equivalent to 12 cigarettes from reaching the brain. Overall, enantiopure conjugate vaccines appear to improve serum antibody affinity, while multivalent formulations increase total antibody concentration. These findings may help improve the performance of future clinical candidate vaccines.

Effects of feeding pregnant beef cows selenium-enriched alfalfa hay on selenium status and antibody titers in their newborn calves.

ABSTRACTIn newborn dairy calves, it has been demonstrated that supranutritional maternal and colostral Se supplementation using Se yeast or sodium selenite, respectively, improves passive transfer of IgG. In beef cattle, agronomic biofortification with Se is a more practical alternative for Se supplementation, whereby the Se concentration of hay is increased through the use of Se-containing fertilizer amendments. It has been previously demonstrated that agronomic Se biofortification is an effective strategy to improve immunity and performance in Se-replete weaned beef calves. The objective of this experiment was to determine the effects of feeding beef cows Se-enriched alfalfa (Medicago sativa) hay during the last 8 to 12 wk of gestation on passive transfer of antibodies to calves. At 10 wk ± 16 d before calving, 45 cows were assigned to 1 of 3 treatment groups with 3 pens (5 cows/pen) per treatment: Control cows were fed non-Se-fortified alfalfa hay plus a mineral supplement containing 120 mg/kg Se from sodium selenite, Med-Se cows were fed alfalfa hay fertilized with 45.0 g Se/ha as sodium selenate, and High-Se cows were fed alfalfa hay fertilized with 89.9 g Se/ha as sodium selenate; both the Med-Se and the High-Se groups received mineral supplement without added Se. Colostrum and whole blood (WB) were collected from cows at calving, and WB was collected from calves within 2 h of calving and at 12, 24, 36, and 48 h of age. Concentrations of IgG1 and J-5 Escherichia coli antibody in cow colostrum and calf serum were quantified using ELISA procedures. Selenium concentrations linearly increased in WB (P < 0.001) and colostrum (P < 0.001) of cows and in WB of newborn calves (P < 0.001) with increasing Se concentration in alfalfa hay. Colostrum concentrations of IgG1 (P = 0.03) were increased in cows fed Se-biofortified alfalfa hay, but J-5 E. coli antibody (P = 0.43) concentrations were not. Calf serum IgG1 (P = 0.43) and J-5 E. coli antibody (P = 0.44) concentrations during the first 48 h of age were not affected by prior Se treatment of cows. These data suggest that feeding Se-biofortified alfalfa hay promotes the accumulation of Se and antibodies in colostrum but does not affect short-term serum antibody concentrations in calves.

A case of stiff dog syndrome associated with anti-glutamic acid decarboxylase antibodies

BackgroundThe stiff person syndrome (SPS) is a rare and debilitating autoimmune disorder with an unknown pathogenesis and variable clinical presentation that can present a diagnostic challenge. Although entities that clinically mimic stiff-person spectrum disorders (SPSD) have manifested in horses, they have not been reported in dogs.Case presentationWe describe a 2-year-old beagle dog presented for progressive attacks of muscular rigidity and lordosis with superimposed spasms of the appendicular muscles triggered by tactile stimulation which resulted in marked gait impairment. Resting electromyography revealed continuous motor unit activity in the axial musculature. Compared to age-matched healthy beagle dogs, this patient had elevated glutamic acid decarboxylase antibody concentrations in serum and cerebrospinal fluid.ConclusionThis dog presented with phenotypic, electrodiagnostic, and immunologic criterion consistent with an SPSD, including elevated anti-GAD antibody titers, which we have termed the “stiff dog syndrome (SDS)”. Durable clinical improvement was achieved with symptomatic and immunosuppressive treatments including baclofen, gabapentin, prednisone, and intravenous immunoglobulin.

Oral Gavage Delivery of PR8 Antigen with β-Glucan-Conjugated GRGDS Carrier to Enhance M-Cell Targeting Ability and Induce Immunity.

Oral gavage is known as one of most convenient routes for therapeutic administration in comparison with other available routes such as intravenous, intra muscular, suppository, etc. An oral vaccine delivery system has additional potential as it may provide a convenient way to prevent infectious diseases by introducing optimum immunization in mucus. Although oral vaccine delivery has attracted tremendous interest in vaccine delivery research, various limitations have prevented its rate of progress up to the level that was initially expected. However, the major problems of oral vaccine delivery are vaccine instability and lack of absorbability, resulting from degradation of the sophisticated antigens in the acidic medium in the stomach. In order to obtain adequate microfold-cell (M-cell) targeting and uptake, the therapeutic material is required to pass through the stomach and reach the small intestine without degradation. In this project, we have introduced a conjugate of β-glucan and Glycine-Arginine-Glycine-Aspartic acid-Serine (GRGDS) that is effective for simultaneous protection of the antigen (PR8) and M-cell targeting. According to the experimental results, the cationic β-glucan-GRGDS conjugate can encapsulate a certain amount of anionic PR8 through electrostatic interaction, which forms nanoparticles with a range of diameter of 200-250 nm. Also, the PR8 incorporated nanoparticles showed high cell viability and stability in diverse environments. Finally, excellent M-cell targeting ability was verified in an in vitro M-cell model. Most importantly, the in vivo test obviously demonstrated the superiority of this system, which significantly increases antibody concentration in serum, intestine, and mucus as measured 21 days after immunization.

Placental and colostral transfer of antibodies reactive with enteropathogenic Escherichia coli intimins α, β, or γ

ObjectiveIntimins are protein adhesins of enteropathogenic Escherichia coli and enterohemorrhagic E. coli capable of inducing attachment and effacement lesions in enterocytes. Anti-intimin antibodies are important for the protection from enteropathogenic E. coli and enterohemorrhagic E. coli infections because these antibodies inhibit bacterial adhesion and impair the initial step of the pathogenesis. We studied the transfer of maternal anti-intimin antibodies from healthy Brazilian mothers to their newborns through the placenta and colostrum. MethodsSerum immunoglobulin G and secretory immunoglobulin A antibodies against conserved and variable regions of intimins α, β, and γ were analyzed using an enzyme linked-immunosorbent assay in the blood and colostrum from 45 healthy women as well as cord blood serum samples from their newborns. ResultsThe concentrations of antibodies reactive with α intimin were significantly lower than those of anti-γ and anti-conserved intimin antibodies in the colostrum samples. IgG serum antibodies reactive with all the subtypes of intimins were transferred to the newborns, but the concentrations of anti-conserved intimin serum antibodies were significantly higher in mothers and newborns than concentrations of antibodies against variable regions. The patterns of IgG transfer from mothers to newborns were similar for all anti-intimin antibodies. These values are similar to the percentage transference of total IgG. ConclusionsAnti-intimin antibodies are transferred from mothers to newborns through the placenta, and reinforce the protection provided by breastfeeding against diarrheagenic E. coli infections.

Smith-Magenis Syndrome Patients Often Display Antibody Deficiency but Not Other Immune Pathologies

Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder associated with recurrent otitis. Most SMS cases result from heterozygous interstitial chromosome 17p11.2 deletions that encompass not only the intellectual disability gene retinoic acid-induced 1 but also other genes associated with immunodeficiency, autoimmunity, and/or malignancy. The goals of this study were to describe the immunological consequence of 17p11.2 deletions by determining the prevalence of immunological diseases in subjects with SMS and by assessing their immune systems via laboratory methods. We assessed clinical histories of 76 subjects with SMS with heterozygous 17p11.2 deletions and performed in-depth immunological testing on 25 representative cohort members. Laboratory testing included determination of serum antibody concentrations, vaccine titers, and lymphocyte subset frequencies. Detailed reactivity profiles of SMS serum antibodies were performed using custom-made antigen microarrays. Of 76 subjects with SMS, 74 reported recurrent infections including otitis (88%), pneumonia (47%), sinusitis (42%), and gastroenteritis (34%). Infections were associated with worsening SMS-related neurobehavioral symptoms. The prevalence of autoimmune and atopic diseases was not increased. Malignancy was not reported. Laboratory evaluation revealed most subjects with SMS to be deficient of isotype-switched memory B cells and many to lack protective antipneumococcal antibodies. SMS antibodies were not more reactive than control antibodies to self-antigens. Patients with SMS with heterozygous 17p.11.2 deletions display an increased susceptibility to sinopulmonary infections, but not to autoimmune, allergic, or malignant diseases. SMS sera display an antibody reactivity profile favoring neither recognition of pathogen-associated antigens nor self-antigens. Prophylactic strategies to prevent infections may also provide neurobehavioral benefits to selected patients with SMS.

Estimated exposures to perfluorinated compounds in infancy predict attenuated vaccine antibody concentrations at age 5-years

Perfluorinated alkylate substances (PFASs) are highly persistent and may cause immunotoxic effects. PFAS-associated attenuated antibody responses to childhood vaccines may be affected by PFAS exposures during infancy, where breastfeeding adds to PFAS exposures. Of 490 members of a Faroese birth cohort, 275 and 349 participated in clinical examinations and provided blood samples at ages 18 months and 5 years. PFAS concentrations were measured at birth and at the clinical examinations. Using information on duration of breastfeeding, serum-PFAS concentration profiles during infancy were estimated. As outcomes, serum concentrations of antibodies against tetanus and diphtheria vaccines were determined at age 5. Data from a previous cohort born eight years earlier were available for pooled analyses. Pre-natal exposure showed inverse associations with the antibody concentrations five years later, with decreases by up to about 20% for each two-fold higher exposure, while associations for serum concentrations at ages 18 months and 5 years were weaker. Modeling of serum-PFAS concentration showed levels for age 18 months that were similar to those measured. Concentrations estimated for ages 3 and 6 months showed the strongest inverse associations with antibody concentrations at age 5 years, particularly for tetanus. Joint analyses showed statistically significant decreases in tetanus antibody concentrations by 19–29% at age 5 for each doubling of the PFAS exposure in early infancy. These findings support the notion that the developing adaptive immune system is particularly vulnerable to immunotoxicity during infancy. This vulnerability appears to be the greatest during the first 6 months after birth, where PFAS exposures are affected by breast-feeding.

Effects of feeding pregnant beef cows selenium-enriched alfalfa hay on selenium status and antibody titers in their newborn calves

In newborn dairy calves, it has been demonstrated that supranutritional maternal and colostral Se supplementation using Se yeast or sodium selenite, respectively, improves passive transfer of IgG. In beef cattle, agronomic biofortification with Se is a more practical alternative for Se supplementation, whereby the Se concentration of hay is increased through the use of Se-containing fertilizer amendments. It has been previously demonstrated that agronomic Se biofortification is an effective strategy to improve immunity and performance in Se-replete weaned beef calves. The objective of this experiment was to determine the effects of feeding beef cows Se-enriched alfalfa (Medicago sativa) hay during the last 8 to 12 wk of gestation on passive transfer of antibodies to calves. At 10 wk ± 16 d before calving, 45 cows were assigned to 1 of 3 treatment groups with 3 pens (5 cows/pen) per treatment: Control cows were fed non-Se-fortified alfalfa hay plus a mineral supplement containing 120 mg/kg Se from sodium selenite, Med-Se cows were fed alfalfa hay fertilized with 45.0 g Se/ha as sodium selenate, and High-Se cows were fed alfalfa hay fertilized with 89.9 g Se/ha as sodium selenate; both the Med-Se and the High-Se groups received mineral supplement without added Se. Colostrum and whole blood (WB) were collected from cows at calving, and WB was collected from calves within 2 h of calving and at 12, 24, 36, and 48 h of age. Concentrations of IgG1 and J-5 Escherichia coli antibody in cow colostrum and calf serum were quantified using ELISA procedures. Selenium concentrations linearly increased in WB (P < 0.001) and colostrum (P < 0.001) of cows and in WB of newborn calves (P < 0.001) with increasing Se concentration in alfalfa hay. Colostrum concentrations of IgG1 (P = 0.03) were increased in cows fed Se-biofortified alfalfa hay, but J-5 E. coli antibody (P = 0.43) concentrations were not. Calf serum IgG1 (P = 0.43) and J-5 E. coli antibody (P = 0.44) concentrations during the first 48 h of age were not affected by prior Se treatment of cows. These data suggest that feeding Se-biofortified alfalfa hay promotes the accumulation of Se and antibodies in colostrum but does not affect short-term serum antibody concentrations in calves.

Modeling pneumococcal nasopharyngeal acquisition as a function of anticapsular serum antibody concentrations after pneumococcal conjugate vaccine administration

BackgroundA prior 7- and 13-valent pneumococcal conjugate vaccine (PCV7 and PCV13) study provided sufficient data (N=1754; Jewish, n=1154; Bedouin, n=595; other, n=5) to investigate the association between nasopharyngeal (NP) acquisition of common PCV7 serotypes and cross-reacting 6A (PCV7+6A) and IgG concentrations. MethodsUsing a logistic regression model, serotype specific association between postinfant series IgG concentration (age 7months) and new NP acquisition between ages 7 and 24months was assessed and adjusted for ethnicity. From a subset of subjects with new NP acquisition (n=9–152 across serotypes studied), new acquisition percentiles and associated IgG concentrations were calculated. ResultsFor the serotypes studied, new NP acquisition rates decreased as IgG concentrations increased. Ethnicity did not influence these associations despite differences in carriage rates. From the subset with new acquisitions, 50% of the events occurred at IgG concentrations >0.61–5.58μg/mL; and 10% of the acquisitions occurred at IgG concentrations >2.48–17.69μg/mL. ConclusionRemarkably high IgG concentrations are required to reduce NP acquisition. These IgG concentrations differ between serotypes. Ethnicity did not influence the association between high IgG concentrations and prevention of carriage despite differences in carriage rates. Since carriage determines transmission, these results may have important implications for herd protection.Trial registration: ClinicalTrials.gov number, NCT00508742; http://clinicaltrials.gov/ct2/show/NCT00508742

A bivalent pneumococcal histidine triad protein D-choline-binding protein A vaccine elicits functional antibodies that passively protect mice from Streptococcus pneumoniae challenge

ABSTRACTVaccines based on conserved pneumococcal proteins are being investigated because serotype coverage by pneumococcal polysaccharide and polysaccharide conjugate vaccines is incomplete and may eventually decrease due to serotype replacement. Here, we examined the functionality of human antibodies induced by a candidate bivalent choline-binding protein A- pneumococcal histidine triad protein D (PcpA-PhtD) vaccine. Pre- and post-immune sera from subjects who had been vaccinated with the PcpA-PhtD candidate vaccine were tested in an established passive protection model in which mice were challenged by intravenous injection with Streptococcus pneumoniae serotype 3 strain A66.1. Serum antibody concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Bacterial surface binding by serum antibodies was determined by a flow cytometry-based assay. Sera from 20 subjects were selected based on low activity of pre-immune samples in the passive protection model. Bacterial surface binding correlated more strongly with anti-PcpA (0.87; p < 0.0001) than with anti-PhtD (0.71; p < 0.0001). The odds ratio for predicting survival in the passive protection assay was higher for the anti-PcpA concentration (470 [95% confidence interval (CI), 46.8 to >999.9]) than for the anti-PhtD concentration (3.4 [95% CI, 1.9 to 5.6]) or bacterial surface binding (9.4 [95% CI, 3.6 to 24.3]). Pooled post-immune serum also protected mice against a challenge with S. pneumoniae serotype 3 strain WU2. Both anti-PcpA and anti-PhtD antibodies induced by the bivalent candidate vaccine mediate protection against S. pneumoniae. The results also showed that the ELISA titer might be useful as a surrogate for estimating the functional activity of antibodies induced by pneumococcal protein vaccines.

Linking the seroresponse to infection to within-host heterogeneity in antibody production

A recently published model for the serum antibody response to infection appeared well suited for use in statistical analyses of longitudinal serological data. The published model assumed exponential decay with fixed rates for pathogen and serum antibody kinetics, ignoring any within-host heterogeneity in the seroresponse. A bi-exponential model shows that there is rapid initial decay followed by a prolonged period of persistent low serum antibody concentrations. We propose a small modification of the decay model that greatly increases its flexibility by allowing for non-exponential antibody decay.The modified model produces power functions that may be interpreted as a mixture of exponential decay curves, with a mixing distribution representing the relative contribution of many centres of antibody production to the serum antibody concentration.Fitting the power function decay model to observed longitudinal data for pertussis shows improved goodness of fit compared to the exponential decay model, with estimates for the shape parameter (r=2.2; 95% CI (1.7–2.8)) that differ from exponential shape (r=1).The power function decay model predicts more persistent antibody concentrations in the long term (symptomatic threshold reached >30 years after infection) which, when used in biomarker studies, will lead to lower estimates of seroconversion rates compared to exponential antibody decay.

Pre-exposure Prophylaxis With OspA-Specific Human Monoclonal Antibodies Protects Mice Against Tick Transmission of Lyme Disease Spirochetes.

Tick transmission of Borrelia spirochetes to humans results in significant morbidity from Lyme disease worldwide. Serum concentrations of antibodies against outer surface protein A (OspA) were shown to correlate with protection from infection with Borrelia burgdorferi, the primary cause of Lyme disease in the United States. Mice transgenic for human immunoglobulin genes were immunized with OspA from B. burgdorferi to generate human monoclonal antibodies (HuMabs) against OspA. HuMabs were generated and tested in in vitro borreliacidal assays and animal protection assays. Nearly 100 unique OspA-specific HuMabs were generated, and 4 HuMabs (221-7, 857-2, 319-44, and 212-55) were selected as lead candidates on the basis of borreliacidal activity. HuMabs 319-44, 857-2, and 212-55 were borreliacidal against 1 or 2 Borrelia genospecies, whereas 221-7 was borreliacidal (half maximal inhibitory concentration, < 1 nM) against B. burgdorferi, Borrelia afzelii, and Borrelia garinii, the 3 main genospecies endemic in the United States, Europe, and Asia. All 4 HuMabs completely protected mice from infection at 10 mg/kg in a murine model of tick-mediated transmission of B. burgdorferi Our study indicates that OspA-specific HuMabs can prevent the transmission of Borrelia and that administration of these antibodies could be employed as preexposure prophylaxis for Lyme disease.

Stunting correlates with high salivary and serum antibody levels after 13-valent pneumococcal conjugate vaccination of Venezuelan Amerindian children

ObjectiveTo determine the impact of pre-vaccination nutritional status on vaccine responses in Venezuelan Warao Amerindian children vaccinated with the 13-valent pneumococcal conjugate vaccine (PCV13) and to investigate whether saliva can be used as read-out for these vaccine responses. MethodsA cross-sectional cohort of 504 Venezuelan Warao children aged 6 weeks – 59 months residing in nine geographically isolated Warao communities were vaccinated with a primary series of PCV13 according to Centers for Disease Control and Prevention (CDC)-recommended age-related schedules. Post-vaccination antibody concentrations in serum and saliva of 411 children were measured by multiplex immunoassay. The influence of malnutrition present upon vaccination on post-vaccination antibody levels was assessed by univariate and multivariable generalized estimating equations linear regression analysis. ResultsIn both stunted (38%) and non-stunted (62%) children, salivary antibody concentrations correlated well with serum levels for all serotypes with coefficients varying from 0.61 for serotype 3–0.80 for serotypes 5, 6A and 23F (all p<0.01).Surprisingly, higher serum and salivary antibody levels were observed with increasing levels of stunting in children for all serotypes. This was statistically significant for 5/13 and 11/13 serotype-specific serum and saliva IgG concentrations respectively. ConclusionStunted Amerindian children showed generally higher antibody concentrations than well-nourished children following PCV13 vaccination, indicating that chronic malnutrition influences vaccine response.Saliva samples might be useful to monitor serotype-specific antibody levels induced by PCV vaccination. This would greatly facilitate studies of vaccine efficacy in rural settings, since participant resistance generally hampers blood drawing.The study was registered in a primary registry of the World Health Organization with identifier number RPCEC00000158.

Highlights of This Issue

The authors evaluated the safety and tolerability of the antisemaphorin 4D antibody VX15/2503 in a first-in-human study. Treatment-related adverse events were primarily Grade 1 or 2; one patient (15 mg/kg) experienced a Grade 3 DLT. No MTD was determined. Complete cellular SEMA4D saturation was generally observed at serum antibody concentrations ≥0.3 μg/mL, resulting in decreased ligand expression. One patient (20 mg/kg) experienced a PR and 27 patients exhibited SD for ≥8 weeks; subjects with elevated B/T lymphocytes exhibited longer progression-free survival. Preclinical studies suggest that combining VX15/2503 with immune modulating agents may improve the clinical activity of checkpoint blockade inhibitors.Triple-negative breast cancers (TNBCs) were reported in population-based studies to be more aggressive with a higher 5-year mortality than non-TNBCs. Podo and colleagues compared phenotype features and survival rates of invasive TNBCs versus non-TNBCs detected during the Italian 18-center HIBCRIT-1 study on screening of asymptomatic women at high genetic-familial risk for breast cancer. Combining an annual screening including magnetic resonance imaging with adequate treatment options, the 5-year overall survival (86% versus 93%) and disease-free survival (77% versus 76%, respectively) were not significantly different, thus showing the possibility of reducing the gap in outcome between TNBCs and non-TNBCs in high-risk women.There is a vital need for effective targeted therapeutics for triple-negative breast cancer (TNBC) patients, yet treatment strategies are challenged by the substantial intertumoral heterogeneity within TNBC. The receptor tyrosine kinase MET is highly expressed in several TNBC subtypes and is a promising therapeutic target. Using the tyrosine kinase inhibitor cabozantinib (XL184), Sameni and colleagues demonstrated that cabozantinib significantly inhibited TNBC growth and invasion in 3D in vitro models and in vivo, yet was ineffective against METneg TNBC cells. These results demonstrate that cabozantinib inhibition may be an effective treatment strategy for TNBC patients.RhoA, the founding member of the Rho GTPase family, is mutated in a large proportion of human diffuse gastric cancers (DGC). To explore the clinical significance, Yoon and colleagues examined RhoA activity in DGC cells, xenografts, and human tumors. RhoA was found to maintain DGC stem-like cells, promote epithelial to mesenchymal transition and chemotherapy resistance, and correlate with poor overall survival in DGC patients. Chemotherapy resistance could be overcome with RhoA inhibition, and thus RhoA is a promising new target in DGC.

Dynamics of naturally acquired antibody against Haemophilus influenzae type a capsular polysaccharide in a Canadian Aboriginal population.

Severe infections caused by Haemophilus influenzae type a (Hia) have reached alarming rates in some Canadian Aboriginal communities. We sought to estimate the frequency of exposure to this pathogen and timelines for boosting protective antibodies.We developed a model of secondary antigenic challenge (natural exposure), and used data for anti-Hia antibodies in serum samples of healthy and immunocompromised adults in a population of Northwestern Ontario, Canada. We parameterized the model with available estimates from previous studies for the decay rate of antibody and its protective levels against both Hia carriage and invasive disease. Simulations were initialized using antibody concentrations from data. We investigated both the duration of immunity without secondary antigenic challenge and the average time between subsequent exposures to Hia.When there was no new natural exposure, serum antibody concentrations in healthy Aboriginal individuals decreased below the level (1 μg/ml) assumed for protection against invasive Hia disease 3 years after primary exposure. This period was shorter (about 2 years) for Aboriginal individuals suffering from chronic renal failure. We estimated that a new antigenic challenge occurs once in 5 and 2 years for healthy and immunocompromised Aboriginal individuals, respectively. More frequent natural exposure was required to maintain protective antibody levels for non-Aboriginal individuals compared to Aboriginal individuals.The findings suggest that frequent boosting of natural immunity is required to maintain the anti-Hia antibody levels protecting against invasive Hia disease, particularly in individuals with underlying medical conditions. This information has important implications for immunization when an anti-Hia vaccine becomes available.

Anti-Heat Shock Protein-27 Antibody Levels in Women with Breast Cancer: Association with Disease Complications and Two-Year Disease-Free Survival

Background and Aim:Breast cancer is a major healthcare problem in women. There are many reports about up-regulation of Hsp27 in cancer tissues but less is known about the potential relationship between Hsp27 antibody levels and breast cancer complications. We here investigated concentrations of serum Hsp27 antigen and antibodies in subjects with and without breast cancer and assessed potential associations with two-year disease-free survival, histological grade and number of lymph nodes.Materials and Methods:Specifically, serum Hsp27 antigen and antibody levels from 97 patients with breast cancer, and 65 healthy controls were determined by enzyme-linkedimmunosorbent assays (ELISAs).Results:Serum Hsp27 and antibody levels were significantly (p<0.001) higher in patients with breast cancer compared to the control group, but no relationship were found with two-year disease free survival, histological grade or number of lymph nodes (p> 0.6, 0.2 and 0.9 respectively).Conclusions:Elevated levels of Hsp27 antibody occur with women with breast cancer but do not appear to be associated with the presence of disease clinical complications.