Comparison of a novel microcrystalline tyrosine adjuvant with aluminium hydroxide for enhancing vaccination against seasonal influenza.

BACKGROUND: Vaccination against seasonal influenza strains is recommended for "high risk" patient groups such as infants, elderly and those with respiratory or circulatory diseases. However, efficacy of the trivalent influenza vaccine (TIV) is poor in many cases and in the event of an influenza pandemic, mono-valent vaccines have been rapidly developed and deployed. One of the main issues with use of vaccine in pandemic situations is the lack of a suitable quantity of vaccine early enough during the pandemic to exert a major influence on the transmission of virus and disease outcome. One approach is to use a dose-sparing regimen which inevitably involves enhancing the efficacy using adjuvants. METHODS: In this study we compare the use of a novel microcrystalline tyrosine (MCT) adjuvant, which is currently used in a niche area of allergy immunotherapy, for its ability to enhance the efficacy of a seasonal TIV preparation. The efficacy of the MCT adjuvant formulation was compared to alum adjuvanted TIV and to TIV administered without adjuvant using a ferret challenge model to determine vaccine efficacy. RESULTS: The MCT was found to possess high protein-binding capacity. In the two groups where TIV was formulated with adjuvant, the immune response was found to be higher (as determined by HAI titre) than vaccine administered without adjuvant and especially so after challenge with a live influenza virus. Vaccinated animals exhibited lower viral loads (as determined using RT-PCR) than control animals where no vaccine was administered. CONCLUSIONS: The attributes of each adjuvant in stimulating single-dose protection against a poorly immunogenic vaccine was demonstrated. The properties of MCT that lead to the reported effectiveness warrants further exploration in this and other vaccine targets - particularly where appropriate immunogenic, biodegradable and stable alternative adjuvants are sought.

The adsorption of allergoids and 3-O-desacyl-4'-monophosphoryl lipid A (MPL®) to microcrystalline tyrosine (MCT) in formulations for use in allergy immunotherapy.

Infectious disease vaccine potency is affected by antigen adjuvant adsorption. WHO and EMA guidelines recommend limits and experimental monitoring of adsorption in vaccines and allergy immunotherapies. Adsorbed allergoids and MPL® in MATA-MPL allergy immunotherapy formulations effectively treat IgE mitigated allergy. Understanding vaccine antigen adjuvant adsorption allows optimisation of potency and should be seen as good practice; however current understanding is seldom applied to allergy immunotherapies. The allergoid and MPL® adsorption to MCT in MATA-MPL allergy immunotherapy formulations was experimental determination using specific allergen IgE allerginicity and MPL® content methods. Binding forces between MPL® and MCT were investigated by competition binding experiments. MATA-MPL samples with different allergoids gave results within 100-104% of the theoretical 50µg/mL MPL® content. Unmodified drug substance samples showed significant desirable IgE antigenicity, 1040-170 QAU/mL. MATA-MPL supernatant samples with different allergoids gave results of ≤2 µg/mL MPL® and ≤0.1-1.4 QAU/mL IgE antigenicity, demonstrating approximately ≥96 & 99% adsorption respectively. Allergoid and MPL® adsorption in different MATA-MPL allergy immunotherapy formulations is consistent and meets guideline recommendations. MCT formulations treated to disrupt electrostatic, hydrophobic and ligand exchange interactions, gave an MPL® content of ≤2 µg/mL in supernatant samples. MCT formulations treated to disrupt aromatic interactions, gave an MPL® content of 73-92 µg/mL in supernatant samples. MPL® adsorption to l-tyrosine in MCT formulations is based on interactions between the 2-deoxy-2-aminoglucose backbone on MPL® and aromatic ring of l-tyrosine in MCT, such as C-H⋯π interaction. MCT could be an alternative adjuvant depot for some infectious disease antigens.

Heterotopic autotransplantation of parathyroid tissue in children undergoing total thyroidectomy.

AIM: The purpose of this study was to examine the efficacy of parathyroid autotransplantation in children undergoing total thyroidectomy. METHODS: We have prospectively evaluated 32 cases of total thyroidectomy in children. The ages ranged from 1 year to 15.7 years, and the mean was 8.9 years. In 31 cases, the indication for surgery was a diagnosis of MEN2A or 2B based on direct DNA testing. One child had suspected sporadic medullary thyroid carcinoma. All of the patients underwent heterotopic autotransplantation of parathyroid gland tissue. In 26 cases, the parathyroid tissue was placed in the nondominant forearm, while in 6 children it was autotransplanted into the sternocleidomastoid muscle. RESULTS: In 31 of 32 children (97%), the serum calcium level transiently decreased in the immediate postoperative period. All of the patients were placed on oral calcium carbonate and vitamin D supplementation, and the serum calcium levels became normal within several days. The supplemental medications were then weaned as tolerated. Within 3 months of their procedure, 30 patients (94%) had adequate parathyroid tissue engraftment, and the calcium and vitamin D medications were discontinued. One child required 9 months of calcium and vitamin D medications before she could be weaned from the medications. One child has been treated more recently, and is currently being weaned from supplemental calcium and vitamin D. Serum PTH levels in 22 patients who had placement of the tissue into their forearms were measured, and in each there was increased PTH in the grafted arm compared with the nongrafted arm. In five children who had parathyroid tissue grafted into the sternocleidomastoid muscle, the peripheral serum PTH levels were in the normal range. CONCLUSION: The heterotopic autotransplantation of resected parathyroid tissue is safe and effective in preventing permanent hypoparathyroidism.

Mediastinal tumors in children: experience with 196 cases.

BACKGROUND: Mediastinal masses are relatively common in infants and children. These lesions are often neoplastic in origin and have a high risk of malignancy. METHODS: This report concerns 196 infants and children with mediastinal tumors. Fifty-five cases (28%) were benign, and 141 (72%) were malignant. Diagnosis included Hodgkin's disease (47), neuroblastoma (46), non-Hodgkin's lymphoma (37), teratoma (18), ganglioneuroma (14), cystic hygroma (11), Schwannoma (five), germ-cell tumors (three), lipoma (three), thymic tumor (three), malignant histiocytosis (two), neurofibroma (two), mesenchymal sarcoma (one), rhabdomyosarcoma (one), peripheral neuroectodermal tumor (one), hamartoma (one), and hemangioma (one). Diagnoses were usually made by assessing the patient's age, radiologic evidence of tumor location, the presence of calcium in the tumor, and the presence of tumor markers (alpha-fetoprotein, vanillmandelic acid, human chorionic gonadotropin). Diagnoses were verified by histologic evaluation. Resection was the only treatment for benign tumors. Biopsy and chemotherapy (and/or radiation) were employed for lymphoid tumors, and resection and adjuvant therapy were used for other solid malignancies. RESULTS: Survival was achieved in 53 of 55 (96.3%) patients with benign tumors and 105 of 141 (74.4%) patients with malignant tumors. CONCLUSIONS: Seventy-two percent of mediastinal tumors in this study were malignant. Early diagnosis followed by biopsy and chemotherapy for lymphoid tumors or resection of nonlymphoid tumors along with aggressive adjuvant therapy result in high survival rates (74.4%). Children with benign tumors almost always survive (96.3%) after resection.