A phase 1 dose-sparing, randomized clinical trial of seasonal trivalent inactivated influenza vaccine combined with MAS-1, a novel water-in-oil adjuvant/delivery system.

BACKGROUND: New influenza vaccines are needed to increase vaccine efficacy. Adjuvants may allow hemagglutinin (HA) dose-sparing with enhanced immunogenicity. MAS-1 is an investigational low viscosity, free-flowing, water-in-oil emulsion-based adjuvant/delivery system comprised of stable nanoglobular aqueous droplets. METHODS: A phase 1, double-blind, safety and immunogenicity, HA dose escalation, randomized clinical trial was conducted. MAS-1 adjuvant with 1, 3, 5 or 9 µg per HA derived from licensed seasonal trivalent high dose inactivated influenza vaccine (IIV, Fluzone HD 60 µg per HA) in a 0.3 mL dose were compared to standard dose IIV (Fluzone SD, 15 µg per HA). Safety was measured by reactogenicity, adverse events, and clinical laboratory tests. Serum hemagglutination inhibition (HAI) antibody titers were measured for immunogenicity. RESULTS: Seventy-two subjects, aged 18-47 years, received one dose of either 0.3 mL adjuvanted vaccine or SD IIV intramuscularly. Common injection site and systemic reactions post-vaccination were mild tenderness, induration, pain, headache, myalgia, malaise and fatigue. All reactions resolved within 14 days post-vaccination. Safety laboratory measures were not different between groups. Geometric mean antibody titers, geometric mean fold increases in antibody titer, seroconversion rates and seroprotection rates against vaccine strains were in general higher and of longer duration (day 85 and 169 visits) with MAS-1-adjuvanted IIV at all doses of HA compared with SD IIV. Adjuvanted vaccine induced higher antibody responses against a limited number of non-study vaccine influenza B and A/H3N2 viruses including ones from subsequent years. CONCLUSION: MAS-1 adjuvant in a 0.3 mL dose volume provided HA dose-sparing effects without safety concerns and induced higher HAI antibody and seroconversion responses through at least 6 months, demonstrating potential to provide greater vaccine efficacy throughout an influenza season in younger adults. In summary, MAS-1 may provide enhanced, more durable and broader protective immunity compared with non-adjuvanted SD IIV. Clinical Trial Registry: ClinicalTrials.gov # NCT02500680.

MAS-1, a novel water-in-oil adjuvant/delivery system, with reduced seasonal influenza vaccine hemagglutinin dose may enhance potency, durability and cross-reactivity of antibody responses in the elderly.

BACKGROUND: Increased influenza vaccine efficacy is needed in the elderly at high-risk for morbidity and mortality due to influenza infection. Adjuvants may allow hemagglutinin (HA) dose-sparing with enhanced immunogenicity. MAS-1 is an investigational water-in-oil emulsion-based adjuvant/delivery system comprised of stable nanoglobular aqueous droplets. METHODS: A phase 1, randomized, double-blind, safety and immunogenicity, adjuvant dose escalation trial was conducted in persons aged 65 years and older. MAS-1 adjuvant dose volumes at 0.3 mL or 0.5 mL containing 9 µg per HA derived from licensed seasonal trivalent influenza vaccine (IIV, Fluzone HD 60 µg per HA, Sanofi Pasteur) were compared to high dose (HD) IIV (Fluzone HD). Safety was measured by reactogenicity, adverse events, and safety laboratory measures. Immunogenicity was assessed by serum hemagglutination inhibition (HAI) antibody titers. RESULTS: Forty-five subjects, aged 65-83 years, were randomly assigned to receive 9 µg per HA in 0.3 mL MAS-1 (15 subjects) or HD IIV (15 subjects) followed by groups randomly assigned to receive 9 µg per HA in 0.5 mL MAS-1 (10 subjects) or HD IIV (5 subjects). Injection site tenderness, induration, and pain, and headache, myalgia, malaise and fatigue were common, resolving before day 14 post-vaccination. Clinically significant late-onset injection site reactions occurred in four of ten subjects at the 0.5 mL adjuvant dose. Safety laboratory measures were within acceptable limits. MAS-1-adjuvanted IIV enhanced mean antibody titers, mean-fold increases in antibody titer, and seroconversion rates against vaccine strains for at least 168 days post-vaccination and enhanced cross-reactive antibodies against some non-study vaccine influenza viruses. CONCLUSION: MAS-1 adjuvant provided HA dose-sparing without safety concerns at the 0.3 mL dose, but the 0.5 mL dose caused late injection site reactions. MAS-1-adjuvanted IIV induced higher HAI antibody responses with prolonged durability including against historical strains, thereby providing greater potential vaccine efficacy in the elderly throughout an influenza season. Clinical Trial Registry: ClinicalTrials.gov # NCT02500680.

MAS-1 adjuvant immunotherapy generates robust Th2 type and regulatory immune responses providing long-term protection from diabetes in late-stage pre-diabetic NOD mice.

MAS-1, a nanoparticular, emulsion-based adjuvant, was evaluated for its ability to promote Th2 and regulatory immune responses and prevent type 1 diabetes progression when given alone or as antigen-specific immunotherapy (ASI) using insulin B chain (IBC; MER3101) and its analog B:9-23(19Ala) (MER3102). MAS-1 formulations were administered to NOD mice at age 9 and 13 weeks and followed through 52 weeks. MER3101 and MER3102 provided long-term protection with 60% and 73% of mice remaining diabetes-free at week 35, and 60% and 47% at week 52. MAS-1 adjuvant emulsion by itself also provided protection with 60% and 40% of mice diabetes-free at 35 and 52 weeks, respectively. Higher levels of interleukin (IL)-10 and IL-2 positive T cells were detected among splenocytes by week 15 in MER3101 and MER3102 immunized mice, whereas MAS-1 alone induced higher levels of IL-10-positive T cells. Diabetes-free 52-week-old mice expressed significant levels of antigen-specific IL-10-positive type 1 regulatory T cells and FoxP3-positive T cells when stimulated ex vivo with IBC. Antibodies targeting IBC and B:9-23(19Ala) induced by MER3101 and MER3102 were overwhelmingly Th2 type IgG1 and IgG2b isotypes. Splenocyte cultures from 52 week diabetes-free, MER3101-treated mice secreted significantly increased levels of IL-4 and IL-5 Th2 cytokines. Based on these pre-clinical results and its clinical safety profile, MAS-1 has the requisite qualities to be considered for use in prophylactic or early stage disease settings to augment ASI to prevent disease progression in type 1 diabetes.

MER5101, a novel Aß1-15:DT conjugate vaccine, generates a robust anti-Aß antibody response and attenuates Aß pathology and cognitive deficits in APPswe/PS1ΔE9 transgenic mice.

Active amyloid-ß (Aß) immunotherapy is under investigation to prevent or treat early Alzheimer's disease (AD). In 2002, a Phase II clinical trial (AN1792) was halted due to meningoencephalitis in ∼6% of the AD patients, possibly caused by a T-cell-mediated immunological response. Thus, generating a vaccine that safely generates high anti-Aß antibody levels in the elderly is required. In this study, MER5101, a novel conjugate of Aß1-15 peptide (a B-cell epitope fragment) conjugated to an immunogenic carrier protein, diphtheria toxoid (DT), and formulated in a nanoparticular emulsion-based adjuvant, was administered to 10-month-old APPswe/PS1ΔE9 transgenic (Tg) and wild-type (Wt) mice. High anti-Aß antibody levels were observed in both vaccinated APPswe/PS1ΔE9 Tg and Wt mice. Antibody isotypes were mainly IgG1 and IgG2b, suggesting a Th2-biased response. Restimulation of splenocytes with the Aß1-15:DT conjugate resulted in a strong proliferative response, whereas proliferation was absent after restimulation with Aß1-15 or Aß1-40/42 peptides, indicating a cellular immune response against DT while avoiding an Aß-specific T-cell response. Moreover, significant reductions in cerebral Aß plaque burden, accompanied by attenuated microglial activation and increased synaptic density, were observed in MER5101-vaccinated APPswe/PS1ΔE9 Tg mice compared with Tg adjuvant controls. Last, MER5101-immunized APPswe/PS1ΔE9 Tg mice showed improvement of cognitive deficits in both contextual fear conditioning and the Morris water maze. Our novel, highly immunogenic Aß conjugate vaccine, MER5101, shows promise for improving Aß vaccine safety and efficacy and therefore, may be useful for preventing and/or treating early AD.

Terrestrial cooling in Northern Europe during the eocene-oligocene transition.

Geochemical and modeling studies suggest that the transition from the "greenhouse" state of the Late Eocene to the "icehouse" conditions of the Oligocene 34-33.5 Ma was triggered by a reduction of atmospheric pCO2 that enabled the rapid buildup of a permanent ice sheet on the Antarctic continent. Marine records show that the drop in pCO2 during this interval was accompanied by a significant decline in high-latitude sea surface and deep ocean temperature and enhanced seasonality in middle and high latitudes. However, terrestrial records of this climate transition show heterogeneous responses to changing pCO2 and ocean temperatures, with some records showing a significant time lag in the temperature response to declining pCO2. We measured the Δ47 of aragonite shells of the freshwater gastropod Viviparus lentus from the Solent Group, Hampshire Basin, United Kingdom, to reconstruct terrestrial temperature and hydrologic change in the North Atlantic region during the Eocene-Oligocene transition. Our data show a decrease in growing-season surface water temperatures (~10 °C) during the Eocene-Oligocene transition, corresponding to an average decrease in mean annual air temperature of ~4-6 °C from the Late Eocene to Early Oligocene. The magnitude of cooling is similar to observed decreases in North Atlantic sea surface temperature over this interval and occurs during major glacial expansion. This suggests a close linkage between atmospheric carbon dioxide concentrations, Northern Hemisphere temperature, and expansion of the Antarctic ice sheets.

Experimental determination of a Viviparus contectus thermometry equation.

Experimental measurements of the (18)O/(16)O isotope fractionation between the biogenic aragonite of Viviparus contectus (Gastropoda) and its host freshwater were undertaken to generate a species-specific thermometry equation. The temperature dependence of the fractionation factor and the relationship between Deltadelta(18)O (delta(18)O(carb.) - delta(18)O(water)) and temperature were calculated from specimens maintained under laboratory and field (collection and cage) conditions. The field specimens were grown (Somerset, UK) between August 2007 and August 2008, with water samples and temperature measurements taken monthly. Specimens grown in the laboratory experiment were maintained under constant temperatures (15 degrees C, 20 degrees C and 25 degrees C) with water samples collected weekly. Application of a linear regression to the datasets indicated that the gradients of all three experiments were within experimental error of each other (+/-2 times the standard error); therefore, a combined (laboratory and field data) correlation could be applied. The relationship between Deltadelta(18)O (delta(18)O(carb.) - delta(18)O(water)) and temperature (T) for this combined dataset is given by: T = - 7.43( + 0.87, - 1.13)*Deltadelta18O + 22.89(+/- 2.09) (T is in degrees C, delta(18)O(carb.) is with respect to Vienna Pee Dee Belemnite (VPDB) and delta(18)O(water) is with respect to Vienna Standard Mean Ocean Water (VSMOW). Quoted errors are 2 times standard error).Comparisons made with existing aragonitic thermometry equations reveal that the linear regression for the combined Viviparus contectus equation is within 2 times the standard error of previously reported aragonitic thermometry equations. This suggests there are no species-specific vital effects for Viviparus contectus. Seasonal delta(18)O(carb.) profiles from specimens retrieved from the field cage experiment indicate that during shell secretion the delta(18)O(carb.) of the shell carbonate is not influenced by size, sex or whether females contained eggs or juveniles.