Immunogenicity and safety of a tetanus toxoid,reduced diphtheria toxoid and three-component acellular pertussis vaccine in adults 19–64 years of age

Purpose

This study was conducted to assess the immunogenicity and safety of a tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine containing three pertussis antigens (Boostrix^®, Tdap3v), currently licensed in the US for use in adolescents 10–18 years of age, in adults 19–64 years of age.

Methods

2284 healthy adults, aged 19–64 years, were randomized to receive a single dose of Tdap vaccine, either Tdap3v or a five-pertussis component Tdap vaccine (Adacel^®, Tdap5v) licensed for adult use in the US. Blood samples were taken before and 1 month after vaccination. Reactogenicity was assessed for 15 days after vaccination.

Results

Tdap3v was comparable to Tdap5v in eliciting seroprotective levels of antibodies to diphtheria and tetanus toxoids, with >98% of subjects having post-vaccination seroprotective antibody levels (≥0.1 IU/mL) against diphtheria or tetanus toxoids. The pertussis components of Tdap3v were shown to be immunogenic in adults, with booster responses to pertussis toxoid (PT), filamentous hemagglutinin (FHA), and pertactin (PRN) observed in 77.2%, 96.9%, and 93.2%, respectively, of Tdap3v recipients, and in 47.1%, 94.0%, and 91.7%, respectively, of Tdap5v recipients. Anti-pertussis antibody GMCs in Tdap3v recipients exceeded those observed in infants following primary DTaP vaccination, in whom efficacy against pertussis disease was subsequently demonstrated. Injection site reactions (pain, redness, and swelling) and fever ≥37.5 °C (99.5 °F) were reported significantly more often (p < 0.05) by Tdap5v recipients than by Tdap3v recipients. Fatigue preventing normal daily activities was reported by a small but significantly greater percentage of Tdap3v recipients (2.5%) than Tdap5v recipients (1.2%, p < 0.05).

Conclusion

In adult recipients, Tdap3v was comparable to an approved Tdap vaccine in providing seroprotection against diphtheria and tetanus, and produced immune responses to pertussis antigens consistent with protection against disease. The overall safety profile of Tdap3v was generally comparable to that of Tdap5v [NCT #106316].     

Cost–benefit analysis of hospital based postpartum vaccination with combined tetanus toxoid,reduced diphtheria toxoid,and acellular pertussis vaccine (Tdap)

Objective

To assess the economic benefits associated with hospital-based postpartum Tdap (combined tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis) vaccination.

Methods

A decision tree model was constructed to calculate the potential cost–benefit of this strategy from both a health care system and a societal perspective. Probabilities and costs were derived from published literature, data reported to Centers for Disease Control and Prevention, and recommendations from expert panels. The maternal vaccination protection period for infants was defined as 7 months, and 10 years of waning immunity following Tdap for birth mothers was estimated in the model. All cost estimates were inflated to year 2012 US dollars and discounted at a 3% annual discount rate.

Results

In the base case from a societal perspective, the expected costs per vaccinated and unvaccinated mother were estimated at $129.27 and $187.97, respectively, suggesting an expected net benefit of $58.70 per vaccinated mother. The overall societal benefits in the cohort of 3.6 million U.S. birth mothers ranged from $52.8–126.8 million, depending on the vaccination coverage level. If including direct medical costs only, the strategy would not generate net savings from a health care system perspective. Annual incidence of pertussis in birth mothers and Tdap efficacy exhibited substantial impact on the model as shown in one-way and two-way sensitivity analyses.

Conclusions

Although postpartum Tdap vaccination is not cost-beneficial from a health care system perspective in the base case, this strategy is likely to generate net benefits from a societal perspective.     

Frequent failure of adolescent booster responses to tetanus toxoid despite infant immunization: Waning of infancy-induced immune memory?

To define the capacity of a tetanus toxoid booster to reactivate infant-triggered immunity, anti-tetanus antibodies were assessed before and after boosting 162 adolescents and 219 children from Mfou (Cameroon). Among 63 adolescents with 3 recorded dose of infant DTP, 29/63 (46%) responded with a ≥4-fold increase of antibody titers, 35/63 (55%) reaching the 0.10 UI/ml threshold. Response rates were slightly higher (62%) in children aged 10–11 years. Responders and non-responders only differed significantly in their baseline anti-tetanus antibodies. Thus, early life immune immaturity may limit the persistence of infant-induced immunity and subsequent boosters may be required for sustained protection.     

Persistence of bactericidal antibodies 4 years after a booster dose of quadrivalent meningococcal diphtheria toxoid conjugate vaccine (MenACWY-D)

One dose of quadrivalent meningococcal conjugate vaccine (MenACWY) was first recommended for US adolescents (ages 11–12?years) in 2005 to protect against invasive meningococcal disease (IMD). In 2010, after evidence emerged about waning protection within 5?years after MenACWY vaccination, the US Advisory Committee on Immunization Practices (ACIP) recommended a MenACWY booster at age 16?years. We used a serum bactericidal assay with human complement (hSBA) to evaluate antibody persistence after a MenACWY-D booster in a sample of 110 participants who received the booster 4?years earlier in a phase 2 study. High proportions (89.9–98.2%) of participants maintained hSBA titers (≥1:4) associated with protection against IMD; a majority (81.7–97.2%) also had hSBA titers ≥1:8, a more conservative threshold. These findings support ACIP recommendations regarding MenACWY booster vaccination, which are aimed at protecting adolescents and young adults throughout the period in which they are at increased risk of IMD.     

Immunogenicity and safety of LBVH0101, a new Haemophilus influenzae type b tetanus toxoid conjugate vaccine, compared with Hiberix™ in Korean infants and children: a randomized trial

Background

The World Health Organization (WHO) recommends that all countries adopt Haemophilus influenzae type b (Hib) vaccine into routine child immunization programs to protect children from the significant burden of life-threatening pneumonia and meningitis.

Methods

In this blind, comparative, randomized, phase-III Korean multicenter study, we assessed immunogenicity and safety following primary vaccination of a new H. influenzae type b tetanus toxoid conjugate vaccine, LBVH0101 (LG Life Sciences, Ltd., Seoul, Korea) compared with Hiberix™ (GSK, Rixensart, Belgium) in Korean children at 2, 4 and 6 months of age followed by a booster vaccination at 12–15 months. Serum anti-PRP IgG concentration and bactericidal activity were determined. Local/systemic symptoms were assessed after vaccination. Serious adverse events were recorded throughout the study.

Results

A total of 185 infants were included in immunogenicity evaluations. After the second and third doses of LBVH0101, 90.32% and 100% of infants achieved an antibody level ≥1 μg/mL, respectively, compared with 78.26% and 96.74% of those who received Hiberix™. After the second vaccination, the geometric mean concentration (GMC) of LBVH0101 recipients was 7.34 μg/mL and was higher than that of Hiberix™ recipients (3.55 μg/mL). After the third vaccination, the GMCs were 14.59 μg/mL and 12.15 μg/mL in the LBVH0101 and Hiberix™ recipients, respectively. The booster dose produced higher antibody concentrations: 30.25 μg/mL and 71.64 μg/mL for LBVH0101 and Hiberix™ recipients, respectively. Bactericidal capacity and antibody potency of anti-PRP IgG induced by LBVH0101 was 35.05 and 116.27 after the second and third vaccinations, respectively, compared with 53.76 and 79.64 for Hiberix™. Anti-PRP IgG seroprotection rate and GMC were similar post-primary immunization between the groups; both showed functional maturation and similar booster responses. LBVH0101 had comparable safety results as the control vaccine, Hiberix™, as most of the solicited adverse events and unsolicited adverse events upon LBVH0101 administration were mild in severity. No serious vaccination-related adverse reactions were observed.

Conclusions

LBVH0101 showed a good immunogenicity and safety profile in infants and children. The two-dose infant-priming schedule with a booster dose may suffice for Hib immunization in Korean infants (Clinical trial registration numbers: NCT01019772 and NCT01251133).     

Inclusion of a universal tetanus toxoid CD4 T cell epitope P2 significantly enhanced the immunogenicity of recombinant rotavirus ΔVP8* subunit parenteral vaccines

Currently available live oral rotavirus vaccines, Rotarix^® and RotaTeq^®, are highly efficacious in developed countries. However, the immunogenicity and efficacy of such vaccines in some developing countries are low. We reported previously that bacterially-expressed rotavirus ΔVP8* subunit vaccine candidates with P[8], P[4] or P[6] specificity elicited high-titer virus neutralizing antibodies in animals immunized intramuscularly. Of note was the finding that antibodies induced with the P[8]ΔVP8* vaccine neutralized both homotypic P[8] and heterotypic P[4] rotavirus strains to high titer. To further improve its vaccine potential, a tetanus toxoid universal CD4⁺ T cell epitope P2 was introduced into P[8] or P[6]ΔVP8* construct. The resulting recombinant fusion proteins expressed in Escherichia coli were of high solubility and were produced with high yield. Two doses (10 or 20 μg/dose) of the P2-P[8]ΔVP8* vaccine or P2-P[6]ΔVP8* vaccine with aluminum phosphate adjuvant elicited significantly higher geometric mean homologous neutralizing antibody titers than the vaccines without P2 in intramuscularly immunized guinea pigs. Interestingly, high levels of neutralizing antibody responses induced in guinea pigs with 3 doses of the P2-P[8]ΔVP8* vaccine persisted for at least 6 months. Furthermore, in the gnotobiotic piglet challenge study, three intramuscular doses (50 μg/dose) of the P2-P[8]ΔVP8* vaccine with aluminum phosphate adjuvant significantly delayed the onset of diarrhea and significantly reduced the duration of diarrhea and the cumulative diarrhea score after oral challenge with virulent human rotavirus Wa (G1P[8]) strain. The P2-P[8]ΔVP8* vaccine induced serum virus neutralizing antibody and VP4-specific IgG antibody production prechallenge, and primed the pigs for higher antibody and intestinal and systemic virus-specific IFN-γ producing CD4⁺ T cell responses postchallenge. These two subunit vaccines could be used at a minimum singly or preferably in bivalent formulation to provide antigenic coverage of most of the G types of global importance.     

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Length of maternity leave and health of mother and child – a review

Summary Objectives: Assessment of the literature on the length of maternity leaves and health of mothers and children; evaluation of the Swiss situation in view of the maternity leave policy implemented in 2005. Methods: Review of thirteen original studies identified by PubMed using topic-related terms. Results: A positive association was shown between the length of maternity leave and mother’s mental health and duration of breastfeeding. Extended maternity leaves were also associated with lower perinatal, neonatal and post-neonatal mortality rates as well as lower child mortality; however, results are obtained in ecological studies. There is less evidence regarding other health outcomes. The new policy in Switzerland extends maternity leave for a considerable number of women to 14 weeks. With this prolongation, fewer depressive symptoms and longer breastfeeding duration can be expected, while benefits regarding other health outcomes would warrant longer leaves. Conclusions: Longer maternity leaves are likely to produce health benefits. The new policy in Switzerland will probably improve the situation of those women, who previously were granted only minimal leave and/or mothers with additional social risk factors. Submitted: 21 October 2005; Revised: 10 October 2006; Accepted: 5 December 2006     

Older Adults’ Use of Online and Offline Sources of Health Information and Constructs of Reliance and Self-Efficacy for Medical Decision Making

We know little about older adults' use of online and offline health information sources for medical decision making despite increasing numbers of older adults who report using the Internet for health information to aid in patient–provider communication and medical decision making. Therefore we investigated older adult users and nonusers of online and offline sources of health information and factors related to medical decision making. Survey research was conducted using random digit dialing of Florida residents' landline telephones. The Decision Self-Efficacy Scale and the Reliance Scale were used to measure relationships between users and nonusers of online health information. Study respondents were 225 older adults (age range = 50?92 years, M = 68.9, SD = 10.4), which included users (n = 105) and nonusers (n = 119) of online health information. Users and nonusers differed in frequency and types of health sources sought. Users of online health information preferred a self-reliant approach and nonusers of online health information preferred a physician-reliant approach to involvement in medical decisions on the Reliance Scale. This study found significant differences between older adult users and nonusers of online and offline sources of health information and examined factors related to online health information engagement for medical decision making.     

Interactions of Fat and Carbohydrate Metabolism—New Aspects and Therapies: (Section of Therapeutics and Pharmacology)

NO one has so far produced anything approaching a clear picture of either fat or carbohydrate metabolism and the interactions of the two are still more involved and elusive although they clearly exist. Plants and animals build up reserves of fat from carbohydrate, but the reverse process (fat into carbohydrate), proved in plant seeds, is still unproven in animals, although theoretically possible.In normal human metabolism fat-carbohydrate interactions are almost hidden. The disturbances shown in the metabolism of a diabetic seem to give us the clearest indications of these interactions. Either carbohydrate or fat can be used as the main source of body fuel, but their metabolic course is very different, both as regards chemistry and function. It is only whep carbohydrate is not available, either in starvation or severe diabetes, that fat provides the fuel of the body; this contrast is also manifest in the blood and internal organs, especially the liver. Under the commonest normal conditions of diet carbohydrate is predominantly and preferentially used for metabolism. The liver is rich in glycogen, poor in fat; the blood fat is minimal and ketone bodies, although perhaps present in small amount in the blood at most times, are absent on common tests. As soon as carbohydrate is insufficiently available for the needs of metabolism, depot fat flows to the liver and is there catabolized to ketone bodies which recent proof has shown to be burned peripherally in the muscles independent of carbohydrate metabolism. This is a normal process, harmful only in diabetes, and especially harmful when it occurs suddenly, e.g. when insulin is cut off from a fat diabetic dog or human patient. A diabetic supports with ease a prolonged severe ketosis but suffers from one of sudden onset, although of milder severity. Insulin in the diabetic and sugar in the starved switches metabolism from fat to carbohydrate usage very quickly and ketonuria usually disappears in three to six hours.“Diabetic obesity” is very common and is often seen in the earliest stages and again after insulin treatment. It seems probable that hyperglycæmia causes this obesity and this has been clearly established by observations on an unusual case of lipæmia, diabetes and lipodystrophy.Lipæcmia may occur in two opposite phases of metabolism, one anabolic—when fat is on its way to storage, the other catabolic—when it is flowing from stores to the liver. The latter is the usual condition obvious in disease.Work has also been done which suggests that other lipotropic factors—choline, lipocaic, &c., exert an influence on carbohydrate-fat balance, more specifically the glycogen-fat balance in the liver.In America attention has been drawn to the frequent and persistenzt occurrence of fatty enlargement of the liver in diabetic children. The author has seen many diabetic children (usually in a state of chronic ketosis) with enlarged livers, but such enlargement has rapidly disappeared with better management of the diabetes. Only two out of some 500 diabetic children have clearly shown the unmistakable syndrome of “hepatomegalic dwarfism ”. In these two cases choline and lipocaic were given over prolonged periods without any effect: the liver, however, of one of these cases has since become normal by the addition of zinc protamine insulin.     

Inhibition of α-glucosidase and α-amylase by diaryl derivatives of imidazole-thione and 1,2,4-triazole-thiol

The in vivo and in vitro effects of 4,5-diphenylimidazole-2-thione (1), 4,5-diphenyl-1,2,4-triazole-3-thiol (2) and 5-(2-hydroxyphenyl)-4-phenyl-1,2,4-triazole-3-thiol (3) on α-glucosidase and α-amylase were investigated. The in vivo inhibition has been found to be dose-dependent and to occur at a value less than LD50. The in vitro treatment of the enzymes by 4,5-diphenylimidazole-2-thione exhibited a reversible inhibition of the non-competitive type with Ki value of 3.5 and 6.5×10(-5) M for α-glucosidase and α-amylase, respectively. 4,5-diphenyl-1,2,4-triazole-3-thione showed a reversible inhibition of the competitive and non-competitive types, with Ki value of 10(-5) M magnitude, for α-glucosidase and α-amylase. On the other hand, 5-(o-hydroxyphenyl)-4-phenyl-1,2,4-triazole-3-thione did not display an inhibitory effect towards α-amylase but showed a potent inhibition of the competitive type for hepatic α-glucosidase with 10(-5) M magnitude of Ki value.     

Development and relative validity of a food frequency questionnaire for the estimation of intake of retinol and β‐carotene

The aim of this study was to develop and validate a semiquantitative food frequency questionnaire to classify individuals according to their intakes of retinol and β‐carotene. Food items for the questionnaire were selected both on the basis of their contribution to total population intake of retinol and β‐carotene and on the proportion of between‐person variation explained, which was as calculated from data of two study populations in the Netherlands. Thus, 15 products containing retinol and 15 products containing β‐carotene were selected. These contributed over 90% to the total intake and explained 99% of the variation of retinol and β‐carotene, respectively. The questionnaire was validated against a dietary history in a population of 82 women (aged 30–49 years). The time elapsed between the two interviews was (on average) 25 days. Spearman rank‐order correlation coefficients comparing the questionnaire with the dietary history were 054, 0.59, and 0.64 for retinol, β‐carotene, and total vitamin A, respectively. The proportion of exact agreement in the two extreme categories of vitamin A intake, based on quintiles, was 56%. The corresponding gross misclassification (from 1 extreme category into the opposite) was 3%. These data indicate that a very short questionnaire can classify subjects into categories according to their vitamin A intake.     

Evaluation of Cuprimine® and Syprine® for decorporation of radioisotopes of cesium, cobalt, iridium and strontium

Cuprimine? and Syprine? are therapeutics approved by the USFDA to treat copper overload in Wilson Disease (a genetic defect in copper transport) by chelation and accelerated excretion of internally-deposited copper. These oral therapeutics are based on the respective active ingredients D-penicillamine (DPA) and N,N'-bis (2-aminoethyl) -1,2-ethanediamine dihydrochloride (Trien). Cuprimine is considered the primary treatment, although physicians are increasingly turning to Syprine as a first-line therapy. Both drugs exhibit oral systemic activity and low toxicity; their biological effects and safety are established. Previous in vivo studies using a rodent animal model established the decorporation potential of Cuprimine and Syprine for (60)Co and (210)Po. Currently these studies are being expanded to evaluate the in vivo decorporation efficacy of these drugs for several additional radionuclides. In this report, results of this investigation are discussed using the radionuclides (137)Cs, (60)Co, (192)Ir and (85)Sr. Short-term 48-h pilot studies were undertaken to evaluate DPA and Trien for their in vivo decorporation potential using male Wistar-Han rats. In these studies, a radionuclide solution was administered to the animals by intravenous (IV) injection, followed by a single IV dose of either DPA or Trien. Control animals received the radionuclide alone. Results show effective decorporation of (60)Co by DPA within the time frame evaluated. DPA and Trien were also modestly effective in decorporation of (137)Cs and (85)Sr, respectively. The study did not find DPA or Trien effective for decorporation of (192)Ir. Based on these encouraging findings, further studies to evaluate the dose-response profiles and timing of the chelator administration post exposure to radionuclides are warranted.     

Effects of Prenatal Alcohol and Pair Feeding on Lipopolysaccharide-Induced Secretion of TNF-α and Corticosterone

Fetal alcohol exposure (FAE) produces profound alterations in immunological and neuroendocrine functions. The present study examined the effects of FAE on the secretion of tumor necrosis factor (TNF-α) and corticosterone following administration of lipopolysaccharide (LPS) in normal (N) adult rats, in adult offspring of dams fed a liquid diet supplemented with ethanol (E), and in pair-fed control offspring (P). LPS-induced TNF-α secretion was not affected by either gender or prenatal treatment. In contrast, LPS-induced corticosterone secretion was significantly greater in female than in male rats, and at 60-min post-LPS was significantly higher in E and P, compared to N females. Ovariectomy significantly inhibited LPS-induced TNF-α secretion in E, but not in P and N, rats and chronic replacement with 17-β-estradiol markedly inhibited TNF-α secretion in ovariectomized E and N, but not in P, rats. In contrast, ovariectomy reduced the effects of LPS on corticosterone secretion in all groups, and chronic replacement with 17-β-estradiol reversed this effect. These findings indicate that LPS-induced secretion of corticosterone, but not TNF-α, is affected by prenatal manipulations and by gender. In addition, alterations in the hormonal environment in females modulate LPS-induced corticosterone secretion in all prenatal treatment groups, but differentially influence TNF-α secretion in rats exposed to alcohol, restricted feeding, or normal diets in utero.     

Development and Principle Content of the Guidelines of Japanese Society for Parenteral and Enteral Nutrition

Promulgation of safe and effective patient care by nu-trition support practitioners is a critical role of the Japa-nese Society for Parenteral and Enteral Nutrition (JSPEN)organization, which is quite same as that of other societiessuch as American Society for Parenteral and Enteral Nutri-tion (ASPEN), European Society for Parenteral and En-teral Nutrition (ESPEN) and so on.In order to ensurethe right nutritional support to right patient at the righttime and in the right place, the …     

Uncharitable and out of control?

This article explores the current state of the law governing partnerships and other collaborations between tax-exempt health care organizations and private health care providers. The author sets out the regulatory maze through which exempt entities and private parties must navigate in attempting to maintain Internal Revenue Code (IRC) Section 501(c)(3) status for the exempt entity in these relationships. The article discusses and comments on general principles through an examination of case law, statutes, regulations, revenue rulings, revenue procedures, and information letters, as well as state law issues, with an emphasis on maintaining charitable purposes, effecting control, and dealing with ownership and compensation issues.     

Health hazards of unemployment--only a boom phenomenon? A study of young men and women during times of prosperity and times of recession

BACKGROUND: It has been suggested that high unemployment rates in society may be less harmful to the health of people than low unemployment rates. Therefore, a study was carried out to compare, among young men and women, the relationship between health and long-term unemployment during periods of rapid economic growth 'boom' and economic recession. METHODS: Two study groups were chosen at age 21 y (5 y after compulsory schooling ended) from an industrial town in northern Sweden. The first group (number 1083) was chosen and surveyed in 1986 (under 'boom' conditions); the second (number 898) was chosen in 1994 (under economic recession conditions). The non-response rate was 2% for the boom group and 10% for the recession group. The main outcome measurements examined were somatic and psychological symptoms. RESULTS: Health criteria for general health among long-term unemployed young men and women did not differ between the group surveyed in boom conditions and the group surveyed in recession conditions. The only exception was for psychological symptoms, which scored lower among the men in the recession group. Individual unemployment had a high explanatory power for poor health, in particular, psychological ill health. CONCLUSIONS: When comparing periods of boom and recession there was no difference in somatic and psychological symptoms for those who were long-term unemployed. Thus, the trade cycle appeared to have had no impact on their health.