Anti-tetanus Toxoid Antibody Research Articles

A Preliminary Study to Evaluate the Immune Response to a Booster Dose of the Adult Tetanus-Diphtheria Vaccine (Td) Available in Iran

Background: Despite the availability of tetanus-diphtheria (TD) vaccines in Iran, the seroconversion rate of these products as a booster dose is unknown. Objectives: This study evaluates the seroconversion rate of the Iranian Td vaccine in adults who have not been vaccinated in the past decade. Methods: In this study, 20 adult volunteers aged 18 to 60 who had not received the Td vaccine in the past decade received a booster dose of the Iranian Td vaccine. Twenty-eight days after vaccination, the seroconversion rate was evaluated using the ELISA method. Vaccine adverse events were monitored at three time points after vaccination. Results: Seroconversion rates with the Iranian Td vaccine boosters were 75% and 90%, respectively, based on a 4-fold increase in anti-tetanus toxoid antibody titers and a 2- and 4-fold combination. Significant associations were found between the demographic data, specifically female gender and age 43 years and older, with seroconversion rates. Injection-site pain was the most common adverse reaction, with a frequency of 35%. No adverse events were reported between one week and one month after vaccination. Conclusions: Results showed that a booster dose of the Iranian Td vaccine produced a protective titer (> 0.1 IU/mL) and a long-term protective titer (> 1.0 IU/mL) in 100% of participants. The seroconversion rate of the Iranian Td vaccine was comparable to other common tetanus vaccines, including Tenivac®, Adacel®, Infanrix®, Tetavax®, and Vacteta®. The proportion of suitable candidates for plasma donation, based on minimum (2 IU/mL) and maximum (10 IU/mL) anti-tetanus toxoid antibody titers, was 100% and 45%, respectively.

Serologic Immunity to Tetanus in the United States, National Health and Nutrition Examination Survey, 2015-2016.

Tetanus, a life-threatening infection, has become rare in the United States since introduction of tetanus toxoid-containing vaccines (TTCVs), recommended as a childhood series followed by decennial boosters beginning at age 11-12 years; vaccination uptake is high in children but suboptimal in adults. The objective of this study was to estimate the prevalence of sero-immunity to tetanus among persons aged ≥6 years in the United States and to identify factors associated with tetanus sero-immunity. Understanding population protection against tetanus informs current and future vaccine recommendations. Anti-tetanus toxoid antibody concentrations were measured for participants of the 2015-2016 National Health and Nutrition Examination Survey (NHANES) aged ≥6 years for whom surplus serum samples were available using a microsphere-based multiplex antibody capture assay. Prevalence of sero-immunity, defined as ≥0.10 IU/mL, was estimated overall and by demographic characteristics. Factors associated with tetanus sero-immunity were examined using multivariable regression. Overall, 93.8% of the US population aged ≥6 years had sero-protection against tetanus. Prevalence of sero-immunity was above 90% across racial/ethnic categories, sex, and poverty levels. By age, ≥ 90% had protective sero-immunity through age 69 years, but prevalence of sero-immunity declined thereafter, with 75.8% of those aged ≥80 years having protective sero-immunity. Older age (adjusted prevalence ratio [aPR]: 0.89, 95% confidence interval [CI]: .85-.92) and being born outside the United States (aPR: 0.96, 95% CI: .93-.98) were significantly associated with lower prevalence of sero-immunity. The majority of the US population has vaccine-induced sero-immunity to tetanus, demonstrating the success of the vaccination program.

Antitetanus toxoid antibodies in mothers and neonates: a single-centre study from Uganda

BackgroundNeonatal mortality due to tetanus persists in Uganda despite the mandatory vaccination of pregnant mothers. Maternal antibodies wane within a year. Uganda’s maternal vaccination guidelines do not specify the timing...

424.11: A 5-Dose IVIG Protocol Decreases the Risk of Reinfection in Solid Organ Transplant Patients With Secondary Antibody Immunodeficiency: Results of a Multicenter Randomized Clinical Trial

Introduction: Infection is a leading cause of morbidity and health spending after solid organ transplantation (SOT). Secondary antibody deficiency (SAD), defined as IgG hypogammaglobulinemia, is frequently observed after SOT. In single center, multicenter and metanalysis, IgG hypogammaglobulinemia has been demostrated as a risk factor of severe infection in all SOT. Reinfection is more common among patients with SAD after SOT. Intravenous immunoglobulins (IVIG) are used for replacement therapy in primary and secondary immunodeficiencies. In primary immunodeficiency the protocols are well established. However, in SAD, the doses, number of doses and, above all, the time of therapy are not well defined. In a multicenter randomized clinical trial we evaluated the safety and efficacy of a 5-dose IVIG protocol to decrease the rate of reinfection in SOT with severe infections and SAD. Materials and Methods: Distribution: Heart 20, Lung 15, Kidney 5, Liver transplantation 4 were randomized. Patients with post transplant severe infections and SAD (IgG < 600 mg/dL) were included. IVIG protocol: Two doses of 15 grams (interval between doses 7-15 days) followed by another 3 doses of 20 grams (interval between doses 15-30 days) of a 5% IVIG product. 39 patients that completed the protocol were analysed [IVIG in combination with conventional antimicrobial therapy (n=21) versus conventional antimicrobial therapy alone (n=18)]. Specific antibodies were tested at inclusion in the clinical trial (visit 1, V1) and 30-45 days after last IVIG dose (last-visit, V7) in a subgroup of patients performed at the coordinating center in Madrid (Gregorio Marañon Hospital). Results: The primary outcome measure (rate of reinfection) was lower in patients randomized to receive IVIG as compared with patients receiving only conventional antimicrobial therapy (28.6 vs 66.7%, chi-square test, p=0.017). Reconstitution of IgG between V1 and V7 was higher in IVIG group as compared with non IVIG group (361±223 vs 255±275 mg/dL, p=0.038). Higher levels of specific IgG anti-cytomegalovirus, IgG anticlostridium difficile toxins A and B and IgG1 anti-tetanus toxoid antibodies was demonstrated at V7 in IVIG-recipients as compared with patients that were treated with antimicrobial therapy alone. A significant increase of specific antibodies between V1 and V7 was only observed in IVIG group. A significant decrease of serum BAFF levels was demostrated in IVIG group. 16 SAE were reported in 13 patients (6/21 IVIG treated patients (28.57%) and 7/18 non-IVIG patients (38.88%), p=0.496). None of SAE was considered to be related with study drug. Conclusions: We have demonstrated that IVIG is associated with lower rate of reinfection in SOT with severe infection and SAD. Reconstitution of specific antibodies and immunemodulation of serum BAFF was only observed in IVIG-treated patients. We believe that this way of administering IVIG can be validated in future clinical trials with a larger number of patients.

Preclinical Characterization of ASP2713, a Novel Igβ and FcγRIIB Cross-Linking Antibody, for Prediction of Human Pharmacokinetics and Clinically Effective Dose

Previously, we reported the fundamental pharmacological characteristics of a novel Igβ and Fc gamma receptor IIB cross-linking antibody, ASP2713, as a new treatment option for systemic lupus erythematosus. The aims of the present study were to investigate ASP2713’s characteristics with regard to pharmacological effect, pharmacokinetics (PK), and receptor occupancy, and to predict its human PK and clinically effective dose. The relationship between the concentration and receptor occupancy of ASP2713 for Igβ of B cell receptors was examined using whole blood B cells. Calculated EC50 values in cynomolgus monkeys and healthy volunteers were 0.35 and 0.058 μg/mL, respectively. Dose-dependent inhibition of anti-tetanus toxoid (TTx) antibody production, PK, and receptor occupancy of ASP2713 in TTx-sensitized cynomolgus monkeys suggested a minimally effective dose of 1 mg/kg by single intravenous (IV) administration. Scaling-up of monkey PK parameters to humans by allometric scaling predicted a clinically effective dose of 0.4 mg/kg IV administration at 4-week intervals to maintain a trough concentration in humans which achieved the same receptor occupancy expected at the effective dose in monkeys. This study aids in understanding the characteristics of ASP2713 and can be used as a basis for clinical dose setting.

Intravenous Immunoglobulin is Associated with Lower Rates of Reinfection in Solid Organ Recipients with Infection and Secondary Antibody Deficiency: A Multicenter Randomized Clinical Trial

<h3>Purpose</h3> In a multicenter randomized clinical trial we evaluated the safety and efficacy of an intravenous immunoglobulin (IVIG) protocol to decrease the rate of reinfection in solid organ recipients with severe infections and secondary antibody deficiency. <h3>Methods</h3> Distribution: Heart 20, Lung 15, Kidney 5, Liver transplantation 4 were randomized. Patients with post transplant severe infections and secondary antibody deficiency (defined as IgG < 600 mg/dL) were included. IVIG protocol: Two doses of 15 grams (interval between doses 7-15 days) followed by another 3 doses of 20 grams (interval between doses 15-30 days) of a 5% IVIG product. 39 patients that completed the protocol were analysed [IVIG in combination with conventional antimicrobial therapy (n=21) versus conventional antimicrobial therapy alone (n=18)]. Specific antibodies were tested at inclusion in the clinical trial (V1) and 30-45 days after last IVIG dose (last-visit, V7) in a subgroup of patients to assess the kinetics of humoral immunity reconstitution. <h3>Results</h3> The primary outcome measure (rate of reinfection) was significantly lower in patients randomized to receive IVIG as compared with patients receiving only conventional antimicrobial therapy (28.6 vs 66.7%, chi-square test, p=0.017). Mean number of reinfections tended to be lower in IVIG group (0.47, interval 1-3, versus 0.89, interval 1-4, Mann-Whitney test, p=0.056). IVIG recipients tended to have lower IgG levels in V1 but disclosed significantly higher IgG concentrations at distinct visits during follow-up. Significantly higher levels of specific IgG anti-cytomegalovirus, IgG anti-clostridium difficile toxins A and B and IgG1 anti-tetanus toxoid antibodies was demonstrated at V7 in patients who received IVIG as compared with patient that were treated with antimicrobial therapy alone. A significant decrease of serum IL6 and BAFF levels (V1 versus V7) was demostrated in IVIG treated patients. IVIG infusions were well tolerated. <h3>Conclusion</h3> In a multicenter randomized clinical trial we have demonstrated that IVIG is associated with a lower rate of reinfection in solid organ transplantation with severe infection and secondary IgG hypogammaglobulinemia.

Trough Concentrations of Specific Antibodies in Primary Immunodeficiency Patients Receiving Intravenous Immunoglobulin Replacement Therapy.

Immunoglobulin replacement therapy is a mainstay therapy for patients with primary immunodeficiency (PID). The content of these preparations was studied extensively. Nevertheless, data regarding the effective specific antibodies content (especially in the nadir period), and, in different groups of PID patients is limited. We studied trough IgG concentrations as well as anti-Pneumococcus, anti-Haemophilus influenzae b, anti-Tetanus, and anti-Measles antibody concentrations in 17 PID patients receiving intravenous immunoglobulin (IVIg) compared with healthy controls matched for age and ethnicity. We also analyzed these results according to the specific PID diagnosis: X-linked agammaglobulinemia (XLA), combined immunodeficiency (CID), and ataxia telangiectasia (AT). We recorded a higher concentration of anti-pneumococcal polysaccharide antibodies in healthy controls compared to the entire group of PID patients. We also found significantly higher anti-tetanus toxoid antibody concentrations in the XLA patients, compared to CID patients. Anti-Haemophilus Influenzae b antibody titers were overall similar between all the groups. Interestingly, there were overall low titers of anti-Measles antibodies below protective cutoff antibody concentrations in most patients as well as in healthy controls. We conclude that relying on total IgG trough levels is not necessarily a reflection of effective specific antibodies in the patient’s serum. This is especially relevant to CID patients who may have production of nonspecific antibodies. In such patients, a higher target trough IgG concentration should be considered. Another aspect worth considering is that the use of plasma from adult donors with a waning immunity for certain pathogens probably affects the concentrations of specific antibodies in IVIg preparations.

A single immunogenicity assay for testing potency of combination DTaP vaccines: Simultaneous quantitation of anti-DT, anti-TT, anti-PTxd and anti-FHA antibodies in Guinea-pig serum with a Luminex®-xMAP® bead-based serological assay

The diphtheria toxoid (DT), tetanus toxoid (TT), and acellular pertussis (aP) single immunogenicity assay (DTaP SIA) is a Luminex®-xMAP®-bead-based multiplex immunoassay for estimating the potency of DTaP pediatric combination vaccines in guinea pigs. This manuscript describes the validation of this assay for the simultaneous quantitation of anti-diphtheria toxoid (anti-DT), anti-tetanus toxoid (anti-TT), anti-pertussis toxoid (anti-PTxd), and anti-filamentous hemagglutinin (anti-FHA) antibodies in guinea pig serum following injection of a DTaP vaccine formulation. The results were expressed in arbitrary units/mL (AU/mL) using reference serum for comparison. Specificity was demonstrated by ≥ 75% homologous and ≤25% heterologous inhibition for all the antigens. The results were linear for anti-DT, anti-TT, anti-PTxd and anti-FHA antibodies. Accuracy was demonstrated with recovery of between 80% and 120% for all four antibodies. The relative standard deviation of repeatability was ≤20%. The results demonstrate that this SIA can be used for the linear, accurate, and precise simultaneous detection of all four antibodies, based on both the ICH Q2 and the EMA guidelines on bioanalytical method validation.

The PI3Kδ selective inhibitor AS2541019 suppresses donor-specific antibody production in rat cardiac and non-human primate renal allotransplant models

Long-term graft survival after organ transplantation is difficult to achieve because of the development of chronic rejection. One cause of chronic rejection arises from antibody-mediated rejection (AMR), which is dependent on the production of donor-specific antibodies (DSA). Current immunosuppression in organ transplantation is effective in preventing acute T cell-mediated rejection, but the risk of DSA production and graft loss due to AMR remains unchanged. Phosphatidylinositol-3-kinase p110δ (PI3Kδ), a member of the family of PI3K lipid kinases, is a key mediator of B cell activation, proliferation and antibody production. AS2541019 is a novel PI3Kδ selective inhibitor that prevents antibody production by inhibiting B cell immunity. The purpose of this study was to evaluate the inhibitory effect of AS2541019 on DSA production in preclinical rodent and non-human primate allotransplant models. Concomitant administration of AS2541019 with tacrolimus and mycophenolate mofetil (MMF) inhibited de novo DSA production in an ACI-to-Lewis rat cardiac allotransplant model. To predict the efficacy of AS2541019 in clinical practice, we evaluated its effects in cynomolgus monkeys. AS2541019 inhibited B cell proliferation and major histocompatibility complex (MHC) class II expression on B cells in cynomolgus monkeys. Oral administration of AS2541019 inhibited MHC class II expression on peripheral B cells and anti-tetanus toxoid antibody production. In cynomolgus monkey renal allotransplant model, concomitant administration of AS2541019 with tacrolimus and MMF significantly inhibited de novo DSA production. Together, our findings indicate that the PI3Kδ selective inhibitor AS2541019 is a potential candidate for preventing AMR development by inhibiting DSA production.

Effects of different concentrations of aluminum hydroxide adjuvant and adsorption methods on the immunogenicity of diphtheria-tetanus-acellular pertussis and inactivated poliovirus combined vaccine

Objective To investigate the effects of different concentrations and adsorption methods of aluminum hydroxide adjuvant produced by different manufacturers on the immunogenicity of the diphtheria-tetanus-acellular pertussis and inactivated poliovirus combined vaccine (DTaP-sIPV). Methods Five antigens of DTaP were adsorbed onto different concentrations (0.42 mg/ml, 0.47 mg/ml and 0.52 mg/ml) of aluminum hydroxide from different manufacturers through sequential and separate adsorption. Adsorbability, anti-pertussis toxin (PT)/filamentous hemagglutinin (FHA)/pertactin (PRN)/diphtheria toxoid (DT)/tetanus toxoid (TT) antibodies and the potency of vaccines were detected. Results The adsorbability of aluminum hydroxide adjuvant slightly decreased with the reduction of concentration. No significant difference in potency and antibody level was observed between sequential and separate adsorption. Moreover, no significant difference in antibody level was observed between vaccines prepared with aluminum hydroxide adjuvant produced by General Chemical Corp and our institute. Conclusion Aluminum hydroxide adjuvant produced by our institute at the concentration of 0.52 mg/ml and separate adsorption method are suitable for preparation of DTaP-sIPV. Key words: DTaP-sIPV; Adsorbability; Vaccine potency; Anti-pertussis toxin (anti-PT) antibody; Anti-filamentous hemagglutinin (anti-FHA) antibody; Anti-pertactin (anti-PRN) antibody; Anti-diphtheria toxoid (anti-DT) antibody; Anti-tetanus toxoid (anti-TT) antibody

Supplementation of Merino ewes with vitamin E plus selenium increases α-tocopherol and selenium concentrations in plasma of the lamb but does not improve their immune function

Vitamin E and selenium have been reported to improve immune function across a range of species. Ewes lambing on poor-quality dry pasture in autumn in Western Australia are at risk of being deficient in vitamin E and selenium at lambing thus predisposing their lambs to deficiencies and increasing the risk of infection and disease. This study tested the hypotheses that (i) supplementation of autumn-lambing ewes with vitamin E plus selenium in late gestation will increase the concentrations of vitamin E and selenium in plasma in the ewe and lamb and (ii) that the increased concentrations of vitamin E and selenium in plasma in the lambs will improve their innate and adaptive immune responses and thus survival. Pregnant Merino ewes were divided into a control group (n=58) which received no supplementation or a group supplemented with vitamin E plus selenium (n=55). On days 111, 125 and 140 of pregnancy ewes in the vitamin E plus selenium group were given 4 g all-rac-α-tocopherol acetate orally. On day 111 the ewes were also given 60 mg of selenium as barium selenate by subcutaneous injection. The concentrations of α-tocopherol and selenium were measured in ewes and/or lambs from day 111 of pregnancy to 14 weeks of age±10 days (weaning). Immune function of the lamb was assessed by analysing the numbers and phagocytic capacities of monocytes and polymorphonuclear leucocytes and plasma IgG and anti-tetanus toxoid antibody concentrations between birth and 14 weeks of age±10 days. Maternal supplementation with vitamin E plus selenium increased the concentration of α-tocopherol in plasma (1.13 v. 0.67 mg/l; P<0.001) and selenium in whole blood (0.12 v. 0.07 mg/l; P<0.01) of the ewes at lambing compared with controls. Supplementation also increased the concentration of α-tocopherol (0.14 v. 0.08 mg/l; P<0.001) and selenium (0.08 v. 0.05 mg/l; P<0.01) in lambs at birth compared with controls. There was no significant effect of supplementation on immune function or survival in the lambs.

A pilot study of the relationship between preeclampsia and anti-tetanus toxoid antibody levels.

• Relationship between anti-tetanus antibody level and preeclampsia . • Higher risk of preeclampsia if anti-tetanus antibody level <1.3 IU/ml. • Anti-tetanus antibody level may distinguish between different types of preeclampsia.

Postvaccination Accumulation of the Influenza Virus Antigen in the Rat Choroid Plexus

We examined the accessibility of influenza virus and diphtheria-tetanus toxin (DiTe) antigens to the choroid plexus (CP) within the postvaccination period and the expression of CD11b molecules (by immunohistochemistry). Eighteen Dark Agouti (DA) rats were divided into three groups: (i) animals administered with influenza vaccine (Flu), (ii) animals administered with DiTe vaccine (DiTe), and (iii) nontreated (Contr) animals. The serum antibody titers following influenza and diphtheria-tetanus vaccination were detected by the ELISA test. Immunohistochemical staining revealed a great number of viral antigen-positive and CD11b-positive brain cells in Flu rats compared to a very small number of the respective cells in DiTe animals and no staining in the Contr group. DiTe- and Flu-rats showed significant increases in the serum anti-tetanus toxoid and anti-influenza virus antibody levels compared to those in the Contr group. The results obtained attract attention towards the dynamic role of the CP in the immunosurveillance of the CNS. Based on the viral antigen deposits accumulated in the CP, it has been proposed that the latter can play an active role in modulation of the immune response after influenza vaccine immunization.

Abstract PR01: T cell responses to peptide-epitopes of choice can be boosted by immune complexes of circulating anti-tetanus toxoid antibodies

Abstract The ability of dendritic cells (DCs) to boost an antigen-specific immune response is utilized in several cancer immunotherapy strategies including therapeutic vaccination using long peptides. Water-based peptide vaccines are rapidly degraded and oil-based delivery strategies trap immune cells to unwanted sites or have inappropriate adjuvant properties. To enhance the uptake of synthetic long peptides (SLP) and activation of DCs we make use of circulating antibodies to mount cellular responses against tumor antigens of interest by conjugating a B cell epitope to a T cell epitope. The conjugation of the two improves the uptake of peptide/antibody complexes and concomitant activation of the same DC in contrast to SLPs which are not conjugated. Our identified B cell epitope of choice is derived from tetanus toxin (and named MTTE = minimal tetanus toxin epitope) and can be targeted by tetanus-specific antibodies that are present in most vaccinated individuals. SLPs harbor viral or tumor-derived epitopes specific for the disease of interest. We have applied a modified chandler loop model preserving intact cascade systems, to characterize how the vaccine is targeted to human immune cells. The B cell-T cell conjugate ([MTTE]3-SLP) is taken up by human monocytes and blood DCs in an antibody-dependent manner. Rather than FcγRs, the internalization of the antigen appears to be mediated through the classical pathway of the complement system as it is partly reduced by blocking C1q but not when blocking C3. A [MTTE]3-CMV conjugate, containing a T cell epitope from the pp65 protein of cytomegalovirus (CMV), strongly reactivates memory T cells when analyzed in blood from donors with CMV-specific T cells. The CMV-specific T cells rapidly produce IFNγ in response to the conjugate illustrating that the uptake of the conjugate leads to activation of antigen-specific T cells. Uptake as well as T cell activation occurs at low concentrations of the SLP conjugate, superior to a conjugate lacking the tetanus-sequence as well as to SLPs with or without added adjuvant (LPS). Additionally, when the B and T cell epitopes are separate entities but mixed, CMV-specific T cells are not activated, illustrating the requirement of conjugating the two. Our data show that we have a unique delivery system for peptide based vaccines that can aid induction of human T cell responses, and may potentiate immune responses in cancer patients. Citation Format: E. Fletcher, W. van Maren, R. Cordfunke, J. Dinkelaar, R. Castelli, Jdc Codee, G. van der Marel, CJM Melief, JW Drijfhout, F. Ossendorp, Sm Mangsbo. T cell responses to peptide-epitopes of choice can be boosted by immune complexes of circulating anti-tetanus toxoid antibodies [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr PR01.

Immunological effect of administration of sequential doses of Haemophilus influenzae type b and pneumococcal conjugate vaccines in the same versus alternating limbs in the routine infant immunisation schedule: an open-label randomised controlled trial

The use of different limbs for the administration of sequential doses of an intradermal rabies vaccine was shown to result in reduced vaccine immunogenicity. We aimed to assess whether this phenomenon also occurs with routine infant vaccines. In this open-label, randomised, controlled study, eligible healthy infants 6-12 weeks of age recruited through five clinical trials units (four in the UK and one in Malta) were randomly assigned in a 1:1 ratio to two vaccination groups: consistent limb or alternating limb. Infants in the consistent limb group received the diphtheria-tetanus-acellular pertussis-inactived polio-Haemophilus influenzae type b combined vaccine (DTaP-IPV-Hib) at 2, 3, and 4 months of age, and the pneumococcal conjugate vaccine (PCV13) at 2, 4, and 12 months, all administered to the right leg. Infants in the alternating limb group received DTaP-IPV-Hib in the left leg at 2 months and in the right leg at 3 and 4 months; and PCV13 in the left leg at 2 months, in the right leg at 4 months, and in the left arm at 12 months. All infants in both groups received the combined H influenzae type b and capsular group C Neisseria meningitidis tetanus toxoid conjugate vaccine (Hib-MenC-TT), administered in the left leg at 12 months. Randomisation was achieved by randomly generated codes, with permuted block size of 30, and was stratified by study site. Group allocation was not masked from study staff and parents of participants after enrolment, but group allocation was masked from laboratory staff assessing blood samples. The current study was a prespecified secondary objective of a parent phase 4 trial that assessed the induction of immunity following varying schedules of vaccination with glyco-conjugate capsular group C Neisseria meningitidis (Men C) vaccines in infancy. The objective of the current study was to compare the immunogenicity and reactogenicity of vaccines delivered in either consistent or alternating limbs. Immunogenicity was assessed by comparing serum IgG geometric mean concentrations at 5, 12, 13, and 24 months, analysed per protocol. This study is registered with ClinicalTrials.gov, number NCT01129518. Between July 5, 2010, and Aug 1, 2013, we enrolled 509 infants and randomly allocated them to the consistent limb group (n=254) or the alternating limb group (n=255). Anti-H influenzae type b anti-polyribosylribitol phosphate IgG geometric mean concentrations were lower in the consistent limb group than in the alternating limb group at 5 months (consistent limb 0·41 μg/mL [95% CI 0·31-0·54] vs alternating limb 0·61 μg/mL [0·45-0·82]; p=0·0268) and at 12 months (0·35 μg/mL [0·28-0·43] vs 0·50 μg/mL [0·40-0·62]; p=0·0136). Anti-tetanus toxoid antibody IgG geometric mean concentrations were lower in the consistent limb group (1·63 IU/mL [95% CI 1·40-1·90]) than in the alternating limb group (2·30 IU/mL [1·97-2·68]) at 13 months (p=0·0008) and at 24 months (0·44 IU/mL [0·37-0·52] vs 0·61 IU/mL [0·51-0·73]; p=0·0074). Anti-pneumococcal IgG geometric mean concentrations were similar between both groups at all timepoints. The proportions of participants who had adverse events did not differ between the two groups. Use of different (alternating) limbs for sequential doses of routine infant vaccines does not reduce, and might enhance, immunogenicity. The underlying mechanism for this finding warrants further research. NIHR Oxford Biomedical Research Centre and GlaxoSmithKline Biologicals.

Infections and vaccines in the etiology of antiphospholipid syndrome

To present scientific evidence supporting the infectious origin for the antiphospholipid syndrome (APS) by molecular mimicry between pathogens, infection and vaccination with β2-glycoprotein I (β2-GPI) molecule. APS is characterized by the presence of pathogenic autoantibodies against β2-GPI. The infection etiology of APS was well established. Likewise, a link between vaccination such as tetanus toxoid may trigger antibodies targeting tetanus toxoid and β2-GPI, due to molecular mimicry between the two molecules. During the years, the pathogenic potential of anti-tetanus toxoid antibodies cross reactive with β2-GPI were found to be pathogenic in animal models, inducing experimental APS. Accumulated evidence supports that the presence of anti-β2-GPI antibodies is associated with a history of infections and the main mechanism to explain this correlation is molecular mimicry. The relationship between tetanus toxoid vaccination and APS reveals a novel view on the autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA).

Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus

To assess the effects of the B lymphocyte stimulator (BLyS)-specific inhibitor belimumab on immunologic biomarkers, including B cell and T cell populations, and maintenance of antibody titers to prior vaccines in autoantibody-positive systemic lupus erythematosus (SLE) patients. Pooled data from 2 phase III trials, the Study of Belimumab in Subjects with SLE 52-week (BLISS-52) and 76-week (BLISS-76) trials, comparing belimumab 1 mg/kg or 10 mg/kg versus placebo (plus standard SLE therapy for each group) were analyzed for changes in autoantibody, immunoglobulin, and complement levels. BLISS-76 patients were also analyzed for changes in B cell and T cell populations and effects on prior vaccine-induced antibody levels. Belimumab-treated patients experienced significant sustained reductions in IgG and autoantibodies and improvement in C3/C4 levels, resulting in greater positive-to-negative conversion rates for IgG anti-double-stranded DNA (anti-dsDNA), anti-Sm, anticardiolipin, and anti-ribosomal P autoantibodies and normalization of hypergammaglobulinemia and low C3/C4 levels. Belimumab-treated patients experienced significant decreases in the numbers of naive and activated B cells, as well as plasma cells, whereas memory B cells and T cell populations did not decrease. Belimumab did not substantially affect preexisting antipneumococcal or anti-tetanus toxoid antibody levels. Post hoc analysis showed greater reductions in SLE disease activity and the risk of severe flares in patients treated with belimumab 10 mg/kg (P≤0.01) who were anti-dsDNA positive and had low C3/C4 levels at baseline. Normalization of the C3 or anti-dsDNA level by 8 weeks, irrespective of therapy, was predictive of a reduced risk of severe flare over 52 weeks. Belimumab appears to promote normalization of serologic activity and reduce BLyS-dependent B cell subsets in serologically and clinically active SLE. Greater serologic activity may predict a better treatment response to belimumab.

The effect of anti-tetanus toxoid antibody T26 with specificity to β2-glycoprotein I on trophoblast HTR-8/SVneo cell line

The effect of anti-tetanus toxoid antibody T26 with specificity to β2-glycoprotein I on trophoblast HTR-8/SVneo cell line

A single-dose cytomegalovirus-based vaccine encoding tetanus toxin fragment C induces sustained levels of protective tetanus toxin antibodies in mice

The current commercially available vaccine used to prevent tetanus disease following infection with the anaerobic bacterium Clostridium tetani is safe and effective. However, tetanus remains a major source of mortality in developing countries. In 2008, neonatal tetanus was estimated to have caused >59,000 deaths, accounting for 1% of worldwide infant mortality, primarily in poorer nations. The cost of multiple vaccine doses administered by injection necessary to achieve protective levels of anti-tetanus toxoid antibodies is the primary reason for low vaccine coverage. Herein, we show that a novel vaccine strategy using a cytomegalovirus (CMV)-based vaccine platform induces protective levels of anti-tetanus antibodies that are durable (lasting >13 months) in mice following only a single dose. This study demonstrates the ability of a ‘single-dose’ CMV-based vaccine strategy to induce durable protection, and supports the potential for a tetanus vaccine based on CMV to impact the incidence of tetanus in developing countries.

A Conformational Change of C Fragment of Tetanus Neurotoxin Reduces Its Ganglioside-Binding Activity but Does Not Destroy Its Immunogenicity

The C fragment of tetanus neurotoxin (TeNT-Hc) with different conformations was observed due to the four cysteine residues within it which could form different intramolecular disulfide bonds. In this study, we prepared and compared three types of monomeric TeNT-Hc with different conformational components: free sulfhydryls (50 kDa), bound sulfhydryls (44 kDa), and a mixture of the two conformational proteins (half 50 kDa and half 44 kDa). TeNT-Hc with bound sulfhydryls reduced its binding activity to ganglioside G(T1b) and neuronal PC-12 cells compared to what was seen for TeNT-Hc with free sulfhydryls. However, there was no significant difference among their immunogenicities in mice, including induction of antitetanus toxoid IgG titers, antibody types, and protective capacities against tetanus neurotoxin challenge. Our results showed that the conformational changes of TeNT-Hc resulting from disulfide bond formation reduced its ganglioside-binding activity but did not destroy its immunogenicity, and the protein still retained continuous B cell and T cell epitopes; that is, the presence of the ganglioside-binding site within TeNT-Hc may be not essential for the induction of a fully protective antitetanus response. TeNT-Hc with bound sulfhydryls may be developed into an ideal human vaccine with a lower potential for side effects.