Immunogenicity and safety of primary and booster vaccination with 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens in a hexavalent DTPa-HBV-IPV/Hib combination vaccine in comparison with the licensed Infanrix hexa

Safety and immunogenicity of 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens of the combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliomyelitis-Hib vaccine (DTPa-HBV-IPV/Hib) were evaluated in a Primary (NCT01248884) and a Booster vaccination (NCT01453998) study. In the Primary study, 721 healthy infants (randomized 1:1:1) received 3 doses of DTPa-HBV-IPV/Hib formulation A (DATAPa-HBV-IPV/Hib), or B (DBTBPa-HBV-IPV/Hib) or the licensed DTPa-HBV-IPV/Hib vaccine (Infanrix hexa, GSK; control group) at 2, 3, 4 months of age. Infants were planned to receive a booster dose at 12–15 months of age with the same formulation received in the Primary study; however, following high incidence of fever associated with the investigational formulations in the Primary study, the Booster study protocol was amended and all infants yet to receive a booster dose (N = 385) received the licensed vaccine. In the Primary study, non-inferiority of 3-dose vaccination with investigational formulations compared with the licensed vaccine was not demonstrated due to anti-pertactin failing to meet the non-inferiority criterion. Post-primary vaccination, most infants had seroprotective levels of anti-diphtheria (100% of infants), anti-tetanus antigens (100%), against hepatitis B (≥ 97.5% across groups), polyribosyl-ribitol-phosphate (≥ 88.0%) and poliovirus types 1–3 (≥ 90.5%). Seropositivity rates for each pertussis antigen were 100% in all groups. Higher incidence of fever (> 38°C) was reported in infants receiving the investigational formulations (Primary study: 75.0% [A] and 72.1% [B] vs 58.8% [control]; Booster study, before amendment: 49.4% and 46.6% vs 37.4%, respectively). The development of the investigational formulations was not further pursued

Keeping health staff healthy: evaluation of a workplace initiative to reduce morbidity and mortality from HIV/AIDS in Malawi

ABSTRACT: BACKGROUND: In Malawi, the dramatic shortage of human resources for health is negatively impacted by HIV-related morbidity and mortality among health workers and their relatives. Many staff find it difficult to access HIV care through regular channels due to fear of stigma and discrimination. In 2006, two workplace initiatives were implemented in Thyolo District: a clinic at the district hospital dedicated to all district health staff and their first-degree relatives, providing medical services, including HIV care; and a support group for HIV-positive staff. METHODS: Using routine programme data, we evaluated the following outcomes up to the end of 2009: uptake and outcomes of HIV testing and counselling among health staff and their dependents; uptake and outcomes of antiretroviral therapy (ART) among health staff; and membership and activities of the support group. In addition, we included information from staff interviews and a job satisfaction survey to describe health workers' opinions of the initiatives. RESULTS: Almost two-thirds (91 of 144, 63%) of health workers and their dependents undergoing HIV testing and counselling at the staff clinic tested HIV positive. Sixty-four health workers had accessed ART through the staff clinic, approximately the number of health workers estimated to be in need of ART. Of these, 60 had joined the support group. Cumulative ART outcomes were satisfactory, with more than 90% alive on treatment as of June 2009 (the end of the study observation period). The availability, confidentiality and quality of care in the staff clinic were considered adequate by beneficiaries. CONCLUSIONS: Staff clinic and support group services successfully provided care and support to HIV-positive health workers. Similar initiatives should be considered in other settings with a high HIV prevalence

Immunogenicity and safety following primary and booster vaccination with a hexavalent diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus and Haemophilus influenzae type b vaccine: a randomized trial in the United States

Combined hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliomyelitis and Haemophilus influenzae type b vaccine (DTaP-HBV-IPV/Hib) can further reduce the number of injections in pediatric immunization schedules of countries currently using pentavalent DTaP combination vaccines. This open-label, randomized, multicenter study (NCT02096263) conducted in the United States evaluated the immunogenicity and safety of DTaP-HBV-IPV/Hib vaccine compared with concomitant administration of DTaP-HBV-IPV and HibA or DTaP-IPV/Hib and HBV vaccines. We randomized (1:1:1) infants to receive 3-dose priming with DTaP-HBV-IPV/Hib boosted with DTaP+ HibB, DTaP-HBV-IPV+ HibA boosted with DTaP+ HibA, or DTaP-IPV/Hib+ HBV boosted with DTaP-IPV/Hib, at 2, 4, 6, and 15–18 months of age. We enrolled and vaccinated 585 participants, 486 received a booster, and 476 completed the study. Of these, 466 participants were included in the primary and 408 in the booster according-to-protocol cohorts for immunogenicity. We demonstrated non-inferiority of DTaP-HBV-IPV/Hib vaccine to DTaP-HBV-IPV+ HibA co-administered vaccines in terms of geometric mean concentrations for pertussis antibodies post-primary vaccination. Post-primary vaccination, seroprotection/seropositivity rates for all vaccine antigens were similarly high between DTaP-HBV-IPV/Hib (≥ 94.8%), DTaP-HBV-IPV+ HibA (≥ 98.1%) or DTaP-IPV/Hib+ HBV (≥ 97.8%) groups. We observed robust immune responses post-booster, indicating effective priming by the 3 regimens. Reactogenicity was similar in the 3 groups. Twenty-eight serious adverse events were reported during the study; 3 were considered related to vaccination and resolved by the end of the study. These results confirm that DTaP-HBV-IPV/Hib could be a valuable additional source of pediatric DTaP, IPV, HBV, and Hib-containing vaccine in countries that currently use multivalent vaccines

Long-term antibody persistence against hepatitis B in adolescents 14–15-years of age vaccinated with 4 doses of hexavalent DTPa-HBV-IPV/Hib vaccine in infancy

We evaluated antibody persistence against hepatitis B virus (HBV) in adolescents previously vaccinated with a hexavalent diphtheria-tetanus-acellular pertussis-HBV-inactivated poliovirus-Haemophilus influenzae type b conjugate vaccine (DTPa-HBV-IPV/Hib), as part of the national newborn immunization program in Germany. We also assessed the anamnestic response to a challenge dose of a monovalent HBV vaccine. In this phase 4, open-label, non-randomized study (NCT02798952), 302 adolescents aged 14–15 years, primed in their first 2 years of life with 4 DTPa-HBV-IPV/Hib doses, received one challenge dose of monovalent HBV vaccine. Blood samples were taken before and one month post-vaccination and used to determine antibody levels against hepatitis B surface antigen (HBs). Reactogenicity and safety were also assessed post-challenge dose. Pre-challenge dose, 53.7% of 268 participants included in the according-to-protocol cohort for immunogenicity had anti-HBs antibody concentrations ≥10 mIU/mL (seroprotection cut-off) and 16.8% had anti-HBs antibody concentrations ≥100 mIU/mL. One month post-challenge dose, 93.3% of adolescents had anti-HBs antibody concentrations ≥10 mIU/mL and 87.3% had antibody concentrations ≥100 mIU/mL. An anamnestic response was mounted in 92.5% of adolescents. Injection site pain (in 33.6% of participants) and fatigue (30.2%) were the most frequently reported solicited local and general symptoms, respectively. Six of the 55 unsolicited adverse events reported were considered vaccination-related. Two vaccination-unrelated serious adverse events were reported during the study. Long-term antibody persistence against hepatitis B was observed in 14–15 years old adolescents previously primed in infancy with DTPa-HBV-IPV/Hib. A challenge dose of monovalent HBV vaccine induced strong anamnestic response, with no safety concerns

Hexavalent vaccines: increasing options for policy-makers and providers. A review of the data supporting interchangeability (substitution with vaccines containing fewer antigens) and mixed schedules from the same manufacturer

Introduction: Combination vaccines improve vaccine uptake and open the infant immunization space for additional vaccines. Hexavalent vaccines have been marketed since 2000. Infanrix hexa (combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-Haemophilus influenzae type b conjugate vaccine, DTPa-HBV-IPV/Hib, GSK) is longest on the market, providing 16 years post-marketing experience. Each DTPa-HBV-IPV/Hib vaccine component is licensed alone and/or in smaller combination vaccines. Programmatic considerations sometimes require an interchange between vaccines due to unavailability, program change or mixed schedules (when the number of required antigens differs across scheduled primary vaccination visits). Areas covered: Immunogenicity and safety data from 11 GSK-sponsored clinical trials support the interchangeability of DTPa-HBV-IPV/Hib within the same vaccines family, and use of DTPa-HBV-IPV/Hib in mixed primary vaccination schedules. Expert commentary: Data show acceptability of interchange of DTPa-HBV-IPV/Hib with other products within the same vaccines family and its use in mixed immunization schedules. This aligns with WHO recommendations that vaccines of the same family from the same manufacturer be used to complete the infant vaccination schedule. Interchangeability and suitability for use in mixed schedules is of interest for policy-makers/providers in the framework of vaccination recommendations as it provides flexibility. Given the complexity of larger combination vaccines, interchangeability or sequential use needs careful assessment

Quantification of growth hormone receptor extra- and intracellular domain gene expression in chicken liver by quantitative competitive RT-PCR

The very sensitive competitive reverse transcription-polymerase chain reaction (RT-PCR) was used to investigate the expression of the extracellular (GHRe) and intracellular (GHRi) parts of the growth hormone receptor (GHR) in the liver tissue of chickens. Two competitors (internal standards), pGHRi MUT and pGHRe MUT, specific to the GHRi and GHRe genes, respectively, were constructed by site-specific mutagenesis. The internal standards defined PCR products of 394 bp for the pGHRi MUT and 330 bp for the GHRe MUT. These were used as competitors to the wild-type GHRi or GHRe which defined PCR products of 382 and 328 bp, respectively. Coamplification, under standardized conditions, of the native RNA in competition with serial dilutions of the mutant RNA in the same PCR reaction followed by enzymatic digestion produced the expected sizes of internal standard cDNA and predicted target cDNA. Expression Levels of GHRe and GHRi were determined from standard curves generated. The method was sensitive enough to detect expressions down to picogram levels. Applying this method, the effect of GH and T-3 injection on GHRe and GHRi mRNA expression was determined in the liver of adult female Hisex birds and 1-day-old normal and dwarf chickens. Intravenous GH injection (25 mug/kg body weight) increased plasma levels of GH in Hisex birds after 10 min but rapidly decreased at 60 min followed by an increase in T-3. GH injection significantly increased the expression of the GHRe 60 min after injection but not at 10 min, when the CH level in plasma was high. In the liver of saline-treated dwarf (dw) and non-dwarf (Dw) chicks, the level of expression of GHRe was similar in both strains despite disparate levels of basal GH and T-3. However, the level of GHRi was higher in Dw than in dw chicks. Although GH levels increased in both strains after intravenous GH injection (250 mug/kg body wt), the expression of GHRe in both strains was unaffected. However, the mRNA for the GHRi was significantly depressed by injection in the Dw but unaffected in dw chicks. Intravenous injection of T-3 (0.5 and 5 mug/kg body wt) increased plasma levels in both strains but caused depression of GHRi in Dw but not in dw chicks. T-3 injections had no effect on GHRe in either Dw or dw chicks. It is concluded that the expression of the GHRe in adult chickens is GH regulated either directly or indirectly. In contrast, in 1-day-old chicks, GH or T-3 had no effects on the GHRe but regulated the expression of GHRi in Dw chicks, whereas in dwarf chicks both had no effect on GHRe or GHRi expression. It is postulated that GHRe and GHRi gene expression may be regulated by different agonists/antagonists in different strains and depending on the age of the chicken. (C) 2001 Academic Press.status: publishe

Immunogenicity and safety of a combined DTPa-IPV/Hib vaccine administered as a three-dose primary vaccination course and a booster dose in healthy children in Russia: a phase III, non-randomized, open-label study

We assessed the immunogenicity and safety of the combined diphtheria-tetanus-acellular pertussis-inactivated poliovirus/Haemophilus influenzae type b vaccine (DTPa-IPV/Hib) in children in Russian Federation aiming to support the registration of the vaccine in Russia. In this phase 3, non-randomized, open-label study (NCT02858440), healthy children received three primary doses at 3, 4.5, and 6 months of age (N = 235) and a booster dose at 18 months of age (N = 225). Seroprotection rates against diphtheria, tetanus, Hib, and poliovirus 1–3, seropositivity rates against pertussis antigens, and antibody geometric mean concentrations/titers for all antigens were evaluated one month post-primary and post-booster vaccinations. Solicited local and general adverse events (AEs) were collected during a 4-day period and unsolicited AEs during a 31-day period post-vaccination. Serious AEs were recorded throughout the study. At post-primary vaccination, all infants were seroprotected against diphtheria, tetanus, and poliovirus 1 and 2, 99.3% against poliovirus 3, and 98.4% against Hib. At least 98.9% of participants were seropositive for the three pertussis antigens. At post-booster vaccination, all toddlers were seroprotected/seropositive against all vaccine components. The most frequent local and general solicited AEs were redness, reported for 52.6% and 44.9% of children, and irritability, reported for 64.7% and 39.1% of children, post-primary and post-booster vaccination, respectively. Unsolicited AEs were reported for 20.4% (post-primary) and 5.8% of children (post-booster vaccination). Most AEs were mild or moderate in intensity. Six serious AEs were reported in three (0.4%) children; none were fatal or assessed as vaccination-related. DTPa-IPV/Hib proved immunogenic and well tolerated in the Russian pediatric population

Effects of adenine nucleosides and nucleotides on neuromuscular transmission to the prostatic stroma of the rat

1. The aim of this study was to investigate the effects of adenine nucleosides and nucleotides on contractility of the smooth muscle of rat prostate gland. 2. Nerve terminals within rat isolated prostatic tissues were electrically field stimulated (60 V, 0.5 ms, 10 Hz, 20 pulses every 60 s). Adenosine 5′-triphosphate (ATP), adenosine 5′-diphosphate (ADP), adenosine 5′-monophosphate (AMP) and adenosine had no effect on baseline smooth muscle tone but concentration-dependently inhibited electrically-evoked contractile responses. The relative order of potency was ATP ≅ AMP ≅ adenosine>ADP. 3. The inhibition by ATP and adenosine of field stimulation-induced contractions in the rat prostate was antagonized by 8-phenyltheophylline (10 μM), but not by suramin (100 μM) and only slightly by reactive blue 2 (5 μM). 4. The adenosine metabolizing enzyme adenosine deaminase (0.1 unit ml(−1)) inhibited the inhibitory effects of ATP and adenosine. The P2 purinoceptor agonist 2-methylthio ATP (10 nM–0.1 mM), had no effect on field stimulation-induced contractions of the rat prostate. 5. ATP and adenosine did not modify the contractile responses of the rat prostate to exogenously added noradrenaline (10 μM). 6. Inhibitory concentration-response curves to a number of adenosine analogues with differing stabilities and selectivities for the different adenosine receptors yielded a relative rank order of agonist potency of: N(6)-cyclopentyladenosine (CPA)>N(6)-cyclohexyladenosine (CHA) ≅ (−)-N(6)-(2-phenylisopropyl)-adenosine (R-PIA) ≅ 5′-(N-ethylcarboxamido)-adenosine (NECA)>(+)-N(6)-(2-phenylisopropyl)-adenosine (S-PIA)>2-p-[2-carboxyethyl]phenethyl-amino-5′-N-ethylcarboxamido-adenosine (CGS 21680). 7. These results indicate that adenine nucleoside and nucleotide induced inhibition of electrically-evoked contractions in the rat prostate occurs through activation of adenosine but not ATP receptors. The relative order of potency of adenosine analogues is consistent with activation of receptors of the A(1)-adenosine receptor subtype. These receptors appear to be prejunctional

The BElgian PREnatal MicroArray (BEMAPRE) database: A systematic nationwide repository of fetal genomic aberrations.

OBJECTIVE: With the replacement of karyotyping by chromosomal microarray (CMA) in invasive prenatal diagnosis, new challenges have arisen. By building a national database, we standardize the classification and reporting of prenatally detected copy number variants (CNVs) across Belgian genetic centers. This database, which will link genetic and ultrasound findings with postnatal development, forms a unique resource to investigate the pathogenicity of variants of uncertain significance and to refine the phenotypic spectrum of pathogenic and susceptibility CNVs. METHODS: The BElgian PREnatal MicroArray (BEMAPRE) consortium is a collaboration of all genetic centers in Belgium. We collected data from all invasive prenatal procedures performed between May 2013 and July 2016. RESULTS: In this three-year period, 13266 prenatal CMAs were performed. By national agreement, a limited number of susceptibility CNVs and no variants of uncertain significance were reported. Added values for using CMA versus conventional karyotyping were 1.8% in the general invasive population and 2.7% in cases with an ultrasound anomaly. Of the reported CNVs 31.5% would have remained undetected with NIPT as the first-tier test. CONCLUSION: The establishment of a national database for prenatal CNV data allows for a uniform reporting policy and the investigation of the prenatal and postnatal genotype-phenotype correlation