NCT00231907.

Abstract. The plasma protein fibronectin is an important opsonin in wound repair and host defense. To better understand the process of fibronectin-mediated phagocytosis, we have transfectod K562 cells, which endogenously express 0~5fll, with a,f13. In these transfectants, antibodies to t~fl3 block phagocytosis of fibronectin-opsonized beads completely, even though half the ingestion occurs through endogenous 0t5/3~ receptors, c~5/31-mediated adhesion to fibronectincoated surfaces is unaffected by c~j33 ligation. Neither av/$5 nor O/M/~2 ligation affects O~5/~1 phagocytic function in transfectants expressing these receptors. Pharmacologic data suggest that o~v/~3 ligation suppresses the phagocytic competence of high affinity ot5/$1 receptors through a signal transduction pathway, perhaps involving protein kinase C. In addition to its significance for phagocytosis, otv/33 regulation of o~5/31 function may be significant for its roles in cell migration, metastasis, and angiogenesis. MACROPHAGE interaction with fibronectin (Fn) 1 is recognized as an important aspect of host defense and wound repair. Fibronectin opsonlzation is necessary for macrophage recognition and phagocytosis of particulate debris released from tissues after bum and trauma (23,41,53,58), resolution of bacteremia during sepsis (48, 53), and clearance of fibrin during disseminated intravascular coagulation (9,11,60). In addition, macrophage adhesion to fibronectin-coated surfaces affects a variety of macrophage functions including chemotaxis (25, 50), differentiation (8), secretion (7,45), and phagocytosis via immunologic receptors (12,52,66). Nonetheless, the moleculax nature of the interactions leading to these critical macrophage functions is unknown.Studies which have examined fibronectin receptors on macrophages in detail have demonstrated an unexpectedly large number of integrin and non-integrin fibronectin-binding proteins (10,13,16,17,29,42,59,63). Four integrin receptors with fibronectin binding capability have been identified on mononuclear phagocytes. Fibronectin binding to VLA-5 (ot5/~1), the vitronectin receptor (otJ~3) and the Leukocyte Response Integrin (LRI) appears dependent on the RGD adhesion sequence (13, 16, 29); (VLA-4 (~,) binds fibronectin independent of this sequence (28). Additional macrophage integrins ~J~5, VLA-3 (ot3/~,), and OtM/~2, may also Please address all correspondence to Dr. Eric J. Brown, Infectious Diseases, Campus Box 8051, Washington University School of Medicine, St. Louis, MO 63110. bind fibronectin (1%42,59,63). To add to the complexity of fibronectin binding by macrophages, several of these receptors can recognize alternative, potentially competing ligands. Moreover, a~/31 and perhaps other of these integrins can assume two affinity states for fibronectin (26). The existence of these distinct but related receptors for the same ligand suggest that they may have different roles in macrophage function. The purpose of the present work was to begin to determine how these various receptors contributed to adhe...

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ClincalTrials.gov identifier: http://www.clinicaltrials.gov/ct2/show/NCT00280033?term= NCT00280033&rank=1 NCT00280033 .

To improve immune responses to influenza vaccine, a trivalent inactivated vaccine containing 60 µg of the HA of each component (A/H3N2, A/H1N1, B) was compared to a licensed vaccine containing 15 µg of the HA of each. More local and systemic reactions were reported by subjects given the high dosage but only local pain and myalgias were significantly increased. The high dosage vaccine induced a higher frequency of serum antibody increases (≥4 fold) in both hemagglutination-inhibiting (HAI) and neutralization tests for all three vaccine viruses in the total group as well as subjects vaccinated and those not vaccinated the previous year. Mean titers of antibody attained, the magnitude of antibody increases and the frequencies of persons with final HAI antibody titers ≥1:32, ≥1:64, and ≥1:128 were all greater for the high dosage group in both serologic tests, for all groups, and for all vaccine viruses. These increased immune responses should provide increased protection against influenza in the elderly. KeywordsInfluenza; vaccines; elderly IntroductionTrivalent inactivated influenza vaccines (TIV) are effective for prevention of influenza and its complications among the elderly. However, there is a need to improve these vaccines because the degree of protection is variable and sometimes low [1,2]. One option for improving TIV is to increase vaccine dosage so as to increase serum antibody responses to the hemagglutinin (HA) as measured in hemagglutination-inhibiting (HAI) and neutralization (neut) tests. Increasing antibody to the HA in serum correlates with increasing protection against infection and illness after exposure to influenza and available information indicates that this antibody is the primary mediator of immunity to infection [3,5].A number of studies have shown that increasing the dosage of TIV will induce an increase in the serum antibody response [6][7][8][9][10][11][12][13][14][15][16][17][18]. Dosages as high as 135 µg of each HA in TIV (containing an A/H3N2, A/H1N1 and B virus strain) have been shown to be safe in elderly subjects and to induce significantly greater serum antibody responses as dosage was increased [15,17]. In a recent study, we tested the 2000-2001 formulation of licensed trivalent vaccine containing the standard 15 µg of the HA of each component as well as unlicensed concentrations of the same vaccine containing 30 ug and 60 ug of each HA; the increased dosage was well tolerated and induced an increased antibody response [16]. To confirm this finding and to evaluate a high dosage vaccine designed for clinical development, a larger number of elderly subjects were given a new 60 µg per HA TIV. The gelatin and thimerosal components in licensed vaccine were removed and only the three viral components used in [2004][2005] Materials and Methods Study DesignThis was a multi-site, phase II, randomized, double-blind, stratified study. The primary hypothesis was that the new TIV containing 60 µg of each antigen would be well tolerated and induce a significantly greater serum HAI ...

IMPORTANCE Human infections with the avian influenza A(H7N9) virus were first reported in China in 2013 and continue to occur. Hemagglutinin H7 administered alone is a poor immunogen necessitating evaluation of adjuvanted H7N9 vaccines.OBJECTIVE To evaluate the immunogenicity and safety of an inactivated H7N9 vaccine with and without AS03 adjuvant, as well as mixed vaccine schedules that included sequential administration of AS03-and MF59-containing formulations and of adjuvanted and unadjuvanted formulations. DESIGN, SETTING, AND PARTICIPANTS Double-blind, phase 2 trial at 5 US sites enrolled 980 adults aged 19 through 64 years from September 2013 through November 2013; safety follow-up was completed in January 2015. INTERVENTIONSThe H7N9 vaccine was given on days 0 and 21 at nominal doses of 3.75 μg, 7.5 μg, 15 μg, and 45 μg of hemagglutinin with or without AS03 or MF59 adjuvant mixed on site. MAIN OUTCOMES AND MEASURESProportions achieving a hemagglutination inhibition antibody (HIA) titer of 40 or higher at 21 days after the second vaccination; vaccine-related serious adverse events through 12 months after the first vaccination; and solicited signs and symptoms after vaccination through day 7.RESULTS Two doses of vaccine were required to induce detectable antibody titers in most participants. After 2 doses of an H7N9 formulation containing 15 μg of hemagglutinin given without adjuvant, with AS03 adjuvant, or with MF59 adjuvant, the proportion achieving an HIA titer of 40 or higher was 2% (95% CI, 0%-7%) without adjuvant (n = 94), 84% (95% CI, 76%-91%) with AS03 adjuvant (n = 96), and 57% (95% CI, 47%-68%) with MF59 adjuvant (n = 92) (P < .001 for comparison of the AS03 and MF59 schedules). The 2 schedules alternating AS03-and MF59-adjuvanted formulations led to lower geometric mean titers (GMTs) of (41.5 [95% CI, 31.7-54.4]; n = 92) and (58.6 [95% CI,; n = 96) than the group induced by 2 AS03-adjuvanted formulations (n = 96) (103.4 [95% CI, 78.7-135.9]; P < .001) but higher GMTs than 2 doses of MF59-adjuvanted formulation (n = 94) (29.0 [95% CI, 22.4-37.6]; P < .001). CONCLUSIONS AND RELEVANCEThe AS03 and MF59 adjuvants augmented the immune responses to 2 doses of an inactivated H7N9 influenza vaccine, with AS03-adjuvanted formulations inducing the highest titers. This study of 2 adjuvants used in influenza vaccine formulations with adjuvant mixed on site provides immunogenicity information that may be informative to influenza pandemic preparedness programs.

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The present study was undertaken with controls using equal doses ID and IM plus the standard full dose IM to assess the role of route of vaccine in immunogenicity of inactivated influenza vaccine. The study was a prospective, randomized, active-controlled, open label clinical trial conducted in healthy young adult outpatients to compare the effect of route (IM vs ID) on antibody responses to influenza vaccine. Volunteers received 3, 6 or 9 μg of vaccine by ID or IM route; 15 μg IM was also studied. Low doses of vaccine given by either route were almost as immunogenic as the standard 15 μg IM dose of influenza vaccine. ID route was not superior to IM vaccine at inducing antibodies. ID vaccine induced significantly more local inflammatory response than IM vaccine.