Characterizing the inhibitory action of zinc oxide nanoparticles on allergic-type mast cell activation.

The development of nanoparticles (NPs) for commercial products is undergoing a dramatic expansion. Many sunscreens and cosmetics now use zinc oxide (ZnO) or titania (TiO2) NPs, which are effective ultraviolet (UV) filters. Zinc oxide topical creams are also used in mild anti-inflammatory treatments. In this study we evaluated the effect of size and dispersion state of ZnO and TiO2 NPs, compared to "bulk" ZnO, on mast cell degranulation and viability. ZnO and TiO2 NPs were characterized using dynamic light scattering and disc centrifugation. Rat basophilic leukaemia (RBL-2H3) cells and primary mouse bone marrow-derived mast cells (BMMCs) were exposed to ZnO and TiO2 NPs of different sizes (25-200 nm) and surface coatings at concentrations from 1 to 200 µg/mL. The effect of NPs on immunoglobulin E (IgE)-dependent mast cell degranulation was assessed by measuring release of both ß-hexosaminidase and histamine via colorimetric and ELISA assays. The intracellular level of Zn(2+) and Ca(2+) ions were measured using zinquin ethyl ester and Fluo-4 AM fluorescence probes, respectively. Cellular viability was determined using the soluble tetrazolium-based MTS colorimetric assay. Exposure of RBL-2H3 and primary mouse BMMC to ZnO NPs markedly inhibited both histamine and ß-hexosaminidase release. This effect was both particle size and dispersion dependent. In contrast, TiO2 NPs did not inhibit the allergic response. These effects were independent of cytotoxicity, which was observed only at high concentrations of ZnO NPs, and was not observed for TiO2 NPs. The inhibitory effects of ZnO NPs on mast cells were inversely proportional to particle size and dispersion status, and thus these NPs may have greater potential than "bulk" zinc in the inhibition of allergic responses.

Aprotinin and similar protease inhibitors as drugs against influenza.

Efforts to develop new antiviral chemotherapeutic approaches are focusing on compounds that target either influenza virus replication itself or host factor(s) that are critical to influenza replication. Host protease mediated influenza hemagglutinin (HA) cleavage is critical for activation of virus infectivity and as such is a chemotherapeutic target. Influenza pathogenesis involves a "vicious cycle" in which host proteases activate progeny virus which in turn amplifies replication and stimulates further protease activities which may be detrimental to the infected host. Aprotinin, a 58 amino acid polypeptide purified from bovine lung that is one of a family of host-targeted antivirals that inhibit serine proteases responsible for influenza virus activation. This drug and similar agents, such as leupeptin and camostat, suppress virus HA cleavage and limit reproduction of human and avian influenza viruses with a single arginine in the HA cleavage site. Site-directed structural modifications of aprotinin are possible to increase its intracellular targeting of cleavage of highly virulent H5 and H7 hemagglutinins possessing multi-arginine/lysine cleavage site. An additional mechanism of action for serine protease inhibitors is to target a number of host mediators of inflammation and down regulate their levels in virus-infected hosts. Aprotinin is a generic drug approved for intravenous use in humans to treat pancreatitis and limit post-operative bleeding. As an antiinfluenzal compound, aprotinin might be delivered by two routes: (i) a small-particle aerosol has been approved in Russia for local respiratory application in mild-to-moderate influenza and (ii) a proposed intravenous administration for severe influenza to provide both an antiviral effect and a decrease in systemic pathology and inflammation.

The CO2-SFE crude lipid extract and the free fatty acid extract from Perna canaliculus have anti-inflammatory effects on adjuvant-induced arthritis in rats.

The anti-inflammatory (AI) activity of a supercritical fluid extract (CO(2)-SFE) of tartaric acid-stabilised Perna canaliculus mussel powder, and of the free fatty acid (FFA) class separated from the CO(2)-SFE extract by column chromatography, was investigated in the rat adjuvant arthritis model. Administration of the CO(2)-SFE extract (100 mg/kg BW/day s.c.) for 15 days post-adjuvant inoculation significantly reduced rear paw swelling by 34% and the deterioration in total body condition by 52% in arthritic rats, compared to vehicle controls. These observations were accompanied by a decreased serum ceruloplasmin oxidase activity, and reduced inflammatory response of the spleen. The mussel FFA extract given at one third of the dose (30 mg/kg BW/day s.c.) and for a shorter treatment period (5 days during the inflammatory phase) achieved an even greater AI activity, and was equipotent to piroxicam (2 mg/kg BW/day s.c.). Preliminary toxicology assessment using both arthritic and non-arthritic (healthy) rats revealed no significant differences between the mussel treatment groups and respective vehicle controls in either organ weights, tissue histology or selected biochemical parameters. These results indicate the CO(2)-SFE crude lipid extract and its FFA components from stabilised P. canaliculus mussel powder contain biologically significant AI activity in vivo, with no apparent adverse side effects.

Novel anti-inflammatory omega-3 PUFAs from the New Zealand green-lipped mussel, Perna canaliculus.

The present study has identified in the marine mollusc, Perna canaliculus, an homologous series of novel omega 3 polyunsaturated fatty acids (omega-3 PUFA) with significant anti-inflammatory (AI) activity. The free fatty acid (FFA) class was isolated from a supercritical-CO2 lipid extract of the tartaric acid-stabilised freeze-dried mussel powder by normal phase chromatography, followed by reversed-phase high performance liquid chromatography (RP-HPLC). The RP-HPLC involved separation based on carbon numbers, followed by argentation-HPLC (Ag-HPLC) of the methyl esters based on degree of unsaturation. Identification of the FFA components was performed using gas chromatography (GC) with flame ionisation detection, and individual structures were assigned by GC-mass spectroscopy (GC-MS). Inhibition of leukotriene production by stimulated human neutrophils was used as an in vitro screening method to test the AI activity of the purified PUFAs. A structurally related family of omega-3 PUFAs was identified in the most bioactive fractions, which included C18:4, C19:4, C20:4, and C21:5 PUFA. The C20:4 was the predominant PUFA in the extract, and was a structural isomer of arachidonic acid (AA). The novel compounds may be biologically significant as AI agents, as a result of their in vitro inhibition of lipoxygenase products of the AA pathway.

Anti-cyclooxygenase effects of lipid extracts from the New Zealand green-lipped mussel, Perna canaliculus.

Total lipid extracts of P. canaliculus (a bivalve marine mollusc native to New Zealand, commonly called the green-lipped mussel) and Mytilus edulis (commonly called the common blue mussel) moderately inhibited ovine COX-1 and COX-2 pure enzymes in vitro. The inhibition was increased after the mussel extracts were saponified by KOH hydrolysis. Protease- and protease-lipase-hydrolysed lipid extracts of P. canaliculus exhibited similarly strong COX inhibition as the KOH-hydrolysed extract. Lyprinol(R) (a commercial extract from P. canaliculus) also exhibited strong inhibition of both COX isoforms, an effect that was increased 10-fold upon subsequent hydrolysis. In contrast, fish oil was not as anti-COX active as Lyprinol. The Lyprinol free fatty acid fraction, and to a lesser extent the Lyprinol triglyceride fraction, were the only lipid classes of Lyprinol to exhibit strong inhibition of the COX isoforms. The purified PUFA extracts were all bioactive, potently inhibiting COX-1 and COX-2. Incubation of Lyprinol in the absence of exogenous arachidonic acid (AA) showed the appearance of alternate prostaglandin metabolites, confirming Lyprinol PUFA as a competitive substrate inhibitor of AA metabolism.

Is fluoroacetate-specific defluorinase a glutathione S-transferase?

Fluoroacetate-specific defluorinase (FSD) is a critical enzyme in the detoxication of fluoroacetate. This study investigated whether FSD can be classed as a glutathione S-transferase (GST) isoenzyme with a high specificity for fluoroacetate detoxication metabolism. The majority of FSD and GST activity, using 1-chloro-2,4-dinitrobenzene (CDNB) and 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP) as GST substrates, in rat liver was cytosolic. GSTT1 specific substrate, EPNP caused a slight non-competitive inhibition of FSD activity. CDNB, a general substrate of GST isoenzyme, was a more potent non-competitive inhibitor of FSD activity. The fluoroacetate defluorination activity by GST isoenzymes was determined in this study. The results showed that the GSTZ1C had the highest fluoroacetate defluorination activity of the various GST isoenzymes studied, while GSTA2 had a limited activity toward fluoroacetate. The human GSTZ1C recombinant protein then was purified from a human GSTZ1C cDNA clone. Our experiments showed that GSTZ1C catalysed fluoroacetate defluorination. GSTZ1 shares many of the characteristics of FSD; however, it accounts only for 3% of the total cytosolic FSD activity. GSTZ1C based enzyme kinetic studies has low affinity for fluoroacetate. The evidence suggests that GSTZ1 may not be the major enzyme defluorinating fluoroacetate, but it does detoxify the fluoroacetate. To clarify the identity of enzymes responsible for fluoroacetate detoxication, further studies of the overall FSD activity are needed.

A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

Characterization of the fluoroacetate detoxication enzymes of rat liver cytosol.

Two forms of fluoroacetate-specific defluorinase (FSD) were purified from rat hepatic cytosol. The first form, FSD1 (molecular weight 38 kDa), contained 81% of the total cytosolic fluoroacetate defluorination activity and did not bind to the glutathione-affinity, orange A or mono P columns used in the purification procedures. The second form, FSD2 (molecular weight 27 kDa), contained only 13% of the fluoroacetate defluorination activity, had a pI = 7.8, and exhibited a high glutathione S-transferase (GST)-like activity towards dichloroacetic acid. The FSD1 proteins were identified from peptide mass data and best matched with rat sorbitol dehydrogenase (SDH) (short form), although pure sheep liver SDH enzyme did not possess defluorination activity when subsequently investigated. The FSD2 protein was identified from peptide mass data and best matched with the amino acid sequence of mouse and human Zeta 1 of glutathione S-transferase (GSTZ1) and showed a high GSTZ1 specific activity. This study suggests that the major FSD component (FSD1) represents a new and unique dehalogenating or dehydrogenating enzyme present in rat liver cytosol. The minor FSD component (FSD2) is due to the GSTZ1 present in rat liver cytosol. However, it is not yet clear that FSD1 is indeed SDH and FSD2 is indeed GSTZ1, due to sequence homology being less than 60 and 45%, respectively.

Immune correlates of protection against influenza in the human challenge model.

Intranasal administration of laboratory passaged wild-type influenza viruses to adults induces a mild upper respiratory illness accompanied by nasopharyngeal shedding of virus. A second model has used inoculation of children with attenuated viruses as a surrogate for wild-type infection. Generally, results of studies of antiviral or vaccine approaches in the challenge model have been predictive of efficacy in the real world, but it is recognized that the model does not reproduce naturally acquired illness well and both viral shedding and symptoms in the challenge model are mostly restricted to the upper respiratory tract. Serum antibody plays a major role in protection in this model and it is difficult to infect adults who have serum HI titres of > 1:8. Among adults with lower levels of HI antibody, a variety of protective factors have been described, including nasal IgA and serum NI antibody, and CTL. In some challenge studies, subjects have been protected despite lack of a measurable immune response to vaccination. Because measurement of mucosal antibody has been difficult to standardize, there is not a level that can be considered a cut-off for susceptibility. Use of a consistent method for assessing mucosal IgA between studies may help to derive a target level for vaccination.

Efficacy of inactivated and cold-adapted vaccines against influenza A infection, 1985 to 1990: the pediatric experience.

BACKGROUND: Influenza is a common and potentially serious infection in children. Although there is interest in broadening the use of influenza vaccine in healthy children, there are few large, randomized, controlled trials that evaluate the safety and efficacy of inactivated vaccine in the pediatric population. METHODS: From 1985 through 1990 a randomized, controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease was conducted at Vanderbilt University, and the cumulative results from this trial in patients of all ages have been previously published. We reanalyzed the data from this trial in the subset of patients who were younger than 16 years at the time of their participation. We determined vaccine safety, immunogenicity and efficacy, based on culture-positive illness and seroconversion, in this subset of patients. RESULTS: During the 5 years of the study, 791 children younger than 16 years received 1809 doses of either inactivated or cold-adapted vaccine or placebo. The vaccines were well-tolerated, and there were no serious reactions. Inactivated trivalent influenza vaccines were 91.4 and 77.3% efficacious in preventing symptomatic, culture-positive influenza A H1N1 and H3N2 illness, respectively. The efficacy of the inactivated vaccine based on hemagglutination inhibition assay seroconversion was 67.1 and 65.5%, respectively, for H1N1 and H3N2 serotypes. CONCLUSIONS: Inactivated trivalent influenza A vaccines are well-tolerated and efficacious in the prevention of influenza A disease in children 1 to 16 years old.

The burden of influenza illness in children with asthma and other chronic medical conditions.

OBJECTIVE: Although influenza immunization is recommended for children with high-risk medical conditions, the majority of such children do not receive influenza vaccine. This study was designed to measure the burden of influenza among children with asthma and other chronic medical conditions. STUDY DESIGN: We performed a retrospective cohort study of children younger than 15 years with medically treated asthma or other chronic medical conditions enrolled in the Tennessee Medicaid program from 1973 to 1993. We determined rates of hospitalization for acute cardiopulmonary disease, outpatient visits, and antibiotic courses throughout the year. Annual differences between event rates when influenza virus was circulating and event rates during winter months when there was no influenza in the community were used to calculate influenza-attributable morbidity. RESULTS: Influenza accounted for an average of 19, 8, and 2 excess hospitalizations for cardiopulmonary disease yearly per 1000 high-risk children aged <1 year, 1 to <3 years, and 3 to <15 years, respectively. For every 1000 children, an estimated 120 to 200 outpatient visits and 65 to 140 antibiotic courses were attributable to influenza annually. CONCLUSIONS: Children younger than 15 years with asthma and other chronic medical conditions experience substantial morbidity requiring inpatient and outpatient care during influenza season. More effective targeting of this population for annual influenza immunization is warranted.

Rates of hospitalization for respiratory syncytial virus infection among children in medicaid.

OBJECTIVE: To determine rates of hospitalization associated with respiratory syncytial virus (RSV) infection among children with and without specific medical conditions. STUDY DESIGN: Retrospective cohort study of all children <3 years old enrolled in the Tennessee Medicaid program from July 1989 through June 1993 (248,652 child-years). RESULTS: During the first year of life, the estimated number of RSV hospitalizations per 1000 children was 388 for those with bronchopulmonary dysplasia, 92 for those with congenital heart disease, 70 for children born at < or = 28 weeks' gestation, 66 for those born at 29 to <33 weeks, 57 for those born at 33 to <36 weeks, and 30 for children born at term with no underlying medical condition. In the second year of life, children with bronchopulmonary dysplasia had an estimated 73 RSV hospitalizations per 1000 children, whereas those with congenital heart disease had 18 and those with prematurity 16 per 1000. Overall, 53% of RSV hospitalizations occurred in healthy children born at term. CONCLUSIONS: Children with bronchopulmonary dysplasia have high rates of RSV hospitalization until 24 months of age. In contrast, after the first year of life, children with congenital heart disease or prematurity have rates no higher than that of children at low risk who are <12 months old.

Human nasopharyngeal-associated lymphoreticular tissues. Functional analysis of subepithelial and intraepithelial B and T cells from adenoids and tonsils.

Subepithelial and intraepithelial lymphocytes of human adenoids and tonsils were characterized and directly compared to determine the potential contribution of these tissues to mucosal and systemic immune responses. The distribution of T and B cell subsets, cytokine patterns, and antibody (Ab) isotype profiles were similar for adenoids and tonsils. Both tissues contained predominantly B cells ( approximately 65%), approximately 5% macrophages, and 30% CD3(+) T cells. The T cells were primarily of the CD4(+) subset ( approximately 80%). Tonsillar intraepithelial lymphocytes were also enriched in B cells. The analysis of dispersed cells revealed a higher frequency of cells secreting IgG than IgA and the predominant Ig subclass profiles were IgG1 > IgG3 and IgA1 > IgA2, respectively. In situ analysis also revealed higher numbers of IgG- than IgA-positive cells. These IgG-positive cells were present in the epithelium and in the subepithelial zones of both tonsils and adenoids. Mitogen-triggered T cells from tonsils and adenoids produced both Th1- and Th2-type cytokines, clearly exhibiting their pluripotentiality for support of cell-mediated and Ab responses. Interestingly, antigen-specific T cells produced interferon-gamma and lower levels of interleukin-5. These results suggest that adenoids and tonsils of the nasopharyngeal-associated lymphoreticular tissues represent a distinct component of the mucosal-associated lymphoreticular tissues with features of both systemic and mucosal compartments.

Evaluation of a live, cold-passaged, temperature-sensitive, respiratory syncytial virus vaccine candidate in infancy.

A live-attenuated, intranasal respiratory syncytial virus (RSV) candidate vaccine, cpts-248/404, was tested in phase 1 trials in 114 children, including 37 1-2-month-old infants-a target age for RSV vaccines. The cpts-248/404 vaccine was infectious at 104 and 105 plaque-forming units in RSV-naive children and was broadly immunogenic in children >6 months old. Serum and nasal antibody responses in 1-2 month olds were restricted to IgA, had a dominant response to RSV G protein, and had no increase in neutralizing activity. Nevertheless, there was restricted virus shedding on challenge with a second vaccine dose and preliminary evidence for protection from symptomatic disease on natural reexposure. The cpts-248/404 vaccine candidate did not cause fever or lower respiratory tract illness. In the youngest infants, however, cpts-248/404 was unacceptable because of upper respiratory tract congestion associated with peak virus recovery. A live attenuated RSV vaccine for the youngest infant will use cpts-248/404 modified by additional attenuating mutations.

Safety and immunogenicity of adjuvanted and unadjuvanted subunit influenza vaccines administered intranasally to healthy adults.

Antigen-specific mucosal immunity is thought to be important for protection against influenza virus infection. Currently licensed parenteral influenza vaccines stimulate the production of serum antibodies, but are poor inducers of mucosal immunity. The adjuvant MF59 has been shown to enhance the humoral immune response to parenteral influenza vaccine in humans and the mucosal immune response to intranasally-administered influenza vaccine in mice. We conducted an open-label safety study followed by an observer-blind, randomized trial comparing the immune response to intranasally-administered subunit influenza vaccine adjuvanted with MF59, unadjuvanted subunit influenza vaccine, and placebo. Adverse reactions did not occur significantly more frequently in vaccinees than placebo recipients. Of 31 subjects receiving 2 doses of MF59-adjuvanted influenza vaccine, 19 (61%), 8 (26%), and 11 (35%) developed a mucosal IgA response to influenza A/H1N1, A/H3N2, and B, respectively. The percentage of subjects with a serum antibody response was slightly lower. The immune responses to adjuvanted vaccine were not significantly different from those to unadjuvanted vaccine. Both vaccines gave more frequent responses than seen in placebo recipients, indicating the potential of intranasal inactivated vaccines to stimulate local IgA responses.

The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children.

BACKGROUND: Despite high annual rates of influenza in children, influenza vaccines are given to children infrequently. We measured the disease burden of influenza in a large cohort of healthy children in the Tennessee Medicaid program who were younger than 15 years of age. METHODS: We determined the rates of hospitalization for acute cardiopulmonary conditions, outpatient visits, and courses of antibiotics over a period of 19 consecutive years. Using the differences in the rates of these events when influenzavirus was circulating and the rates from November through April when there was no influenza in the community, we calculated morbidity attributable to influenza. There was a total of 2,035,143 person-years of observation. RESULTS: During periods when influenzavirus was circulating, the average number of hospitalizations for cardiopulmonary conditions in excess of the expected number was 104 per 10,000 children per year for children younger than 6 months of age, 50 per 10,000 per year for those 6 months to less than 12 months, 19 per 10,000 per year for those 1 year to less than 3 years, 9 per 10,000 per year for those 3 years to less than 5 years, and 4 per 10,000 per year for those 5 years to less than 15 years. For every 100 children, an annual average of 6 to 15 outpatient visits and 3 to 9 courses of antibiotics were attributable to influenza. In winter, 10 to 30 percent of the excess number of courses of antibiotics occurred during periods when influenzavirus was circulating. CONCLUSIONS: Healthy children younger than one year of age are hospitalized for illness attributable to influenza at rates similar to those for adults at high risk for influenza. The rate of hospitalization decreases markedly with age. Influenza accounts for a substantial number of outpatient visits and courses of antibiotics in children of all ages.

Effects of orally administered viable Lactobacillus rhamnosus GG and Propionibacterium freudenreichii subsp. shermanii JS on mouse lymphocyte proliferation.

Immunomodulation by probiotics is a subject of growing interest, but the knowledge of dose response and time profile relationships is minimal. In this study we examined the effects of Lactobacillus rhamnosus GG (LGG) and Propionibacterium freudenreichii subsp. shermanii JS (PJS) on the proliferative activity of murine lymphocytes ex vivo. Dose dependency was assessed by treating animals perorally with a low or a high dose (i.e., 10(9) or 10(12) viable bacteria/kg of body weight) for 7 days. The lower dose levels of each strain appeared to enhance T-cell proliferation at the optimal concanavalin A (ConA) concentration (by 69 to 84%) and B-cell proliferation at the optimal and supraoptimal concentrations of lipopolysaccharide (by 57 to 82%). B-cell proliferation was also enhanced by the high LGG dose (by 32 to 39%) but was accompanied by a marginal decrease in T-cell proliferation (by 8%) at the optimal ConA concentration. The time profiles of the immune responses were assessed after daily treatment with the higher dose for 3, 7, and 14 days. A significant decrease in basal lymphoproliferation (by 32 to 42%) was observed with PJS treatment after the 3- and 7-day periods; however, this activity returned to control levels after 14 days of treatment, which also resulted in significantly enhanced T-cell proliferation at optimal and supraoptimal ConA concentrations (by 24 to 80%). The 14-day LGG treatment also enhanced the latter activity (by 119%). In conclusion, LGG and PJS have specific dose- and duration-dependent immunomodulatory effects on the proliferative activity of B and T lymphocytes and may also reduce lymphocyte sensitivity to the cytotoxic effects of lectin mitogens.

The effect of orally administered viable probiotic and dairy lactobacilli on mouse lymphocyte proliferation.

Four common Lactobacillus strains were screened for their effects on proliferation of mouse splenic lymphocytes. Mice received perorally 10(9) viable bacteria kg(-1) body weight for 7 days. Lactobacillus acidophilus treatment enhanced ex vivo basal proliferation (by 43%) and B-cell response at suboptimal and optimal concentrations of lipopolysaccharide (LPS) (by 27-28%). Conversely, Lactobacillus casei, Lactobacillus gasseri and Lactobacillus rhamnosus inhibited both basal proliferation (by 14-51%) and mitogen-stimulated lymphoproliferation, particularly at supra-optimal concentrations of concanavalin A (by 43-68%) and LPS (by 23-62%). Therefore, these Lactobacillus strains demonstrate strain-specific effects on B- and T-cells and may also alter the splenocyte sensitivity to the cytotoxic effects of mitogens.

Mucosal immune response to trivalent live attenuated intranasal influenza vaccine in children.

Intranasal trivalent, cold-adapted, live attenuated influenza vaccine (CAIV-T) is a promising alternative to inactivated vaccine for protection against influenza in children. However, correlates of immunity are not well defined. To determine the mucosal immune response to CAIV-T, 19 children ages 15-55 months were randomized to receive two doses of CAIV-T or placebo. Influenza-specific IgA to the haemagglutinin of each of three contemporary strains was measured in nasal washes collected pre- and postvaccination using a kinetic enzyme-linked immunosorbent assay. After two doses of study drug, 62, 69 and 85% of CAIV-T recipients demonstrated a mucosal IgA response to influenza A/H1N1, A/H3N2, and B strains respectively; in comparison, 33, 0 and 17% of placebo recipients demonstrated an IgA response to the same strains (p = 0.35, 0.01 and 0.01). Overall, seropositive vaccinees were 4.5 times more likely to develop a mucosal immune response than an HAI response (p = 0.015). Two doses of CAIV-T induce a mucosal IgA response to all three influenza vaccine antigens in the majority of children. In addition, a mucosal antibody response may be the only indication of a vaccine take in a seropositive child.

Immunization with envelope MN rgp120 vaccine in human immunodeficiency virus-infected pregnant women.

Twenty-six human immunodeficiency virus (HIV)-infected pregnant women participated in a placebo-controlled study of immunogenicity and safety of multiple doses of MN rgp120 vaccine over the last half of pregnancy. The women had CD4 lymphocyte counts>400/mm3, no AIDS-defining illness and normal pregnancies. Vaccination was well tolerated, with no significant local or systemic reactions in the women and no adverse outcomes in the infants attributable to the vaccine. Vaccination did not alter plasma RNA reverse transcriptase-polymerase chain reaction copy number; moreover, immunization was not associated with changes in CD4 counts or HIV binding and neutralization antibody titers. Infants were followed up until 18 months of age. Five of 26 infants (19%) were HIV infected, with infection occurring in children of both vaccinated and placebo women. Analysis of factors that influence transmission did not disclose associations with immunization status, viral load, CD4 count, or maternal viral neutralization titers.