Commentary: bread and alum, syphilis and sunlight: rickets in the nineteenth century.
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Alum Compounds↗
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Adjuvants and antibody production: dispelling the myths associated with Freund's complete and other adjuvants.
Adjuvants have been used for more than 70 yr to enhance the immune response of the host animal to an antigen. Among the mechanisms that adjuvants use to enhance the immune response are the "depot" effect, antigen presentation, antigen targeting, immune activation/modulation, and cytotoxic lymphocyte induction. The immunostimulatory properties of adjuvants result in inflammation, tissue destruction, and the potential for resulting pain and distress in the host animal. The inflammatory lesions produced by adjuvants such as Freund's complete adjuvant (FCA) have led some to conclude that pain and distress are present, even in cases where the scientific evidence fails to support this conclusion. Recommendations and regulations in the literature, based on available scientific evidence, provide guidance on total adjuvant volumes, volumes per site, routes of injection, booster injections, and adjuvants used for antibody production. Among the numerous adjuvants that are used for experimental antibody production reviewed in this article, many claim to be less inflammatory, tissue destructive, and painful than FCA while producing equal or superior antibody responses. Although no adjuvant surpasses FCA for experimental antibody production against a wide range of antigenic molecules, many produce excellent antibody responses with less inflammation and tissue destruction. Balancing the requisite degree of immuno-stimulation and the extent of inflammation, necrosis, and potential pain and distress requires consideration of the nature of the antigen, the host immune responsiveness, the adjuvant's mechanisms of action, and the desired end-product. In cases where the antigen is a weak immunogen or has a very limited availability, the type and role of adjuvant becomes a critical component in producing an acceptable immune response and humoral antibody response.
Adjuvants, Immunologic↗
Gonococcal pili: safety and immunogenicity in humans and antibody function in vitro.
In a phase I clinical trial, 39 volunteers received an initial and booster subcutaneous injection of 100 or 112 microgram of a pili vaccine prepared from Neisseria gonorrhoeae strain F62 in Tris buffer with an aluminum phosphate adjuvant (alum) or 220 microgram of the F62 pili vaccine prepared in ethanolamine, with or without alum. Antibody responses were quantitated with an enzyme-linked immunosorbent assay. All four groups had significant (P less than 0.0001) responses to the vaccine preparations with peak mean antibody responses one to three weeks after the booster. Differences in antibody responses among the groups were due to the administration of alum and not to use of Tris buffer vs. ethanolamine. In vitro, postimmunization sera enhanced phagocytosis of piliated strain F62 organisms by human polymorphonuclear leukocytes; preabsorption of the sera with strain F62 pili blocked this activity. Thus, gonococcal pili given subcutaneously are immunogenic and lead to production of functional serum antibodies.
Adjuvants, Pharmaceutic↗
MF59 adjuvant enhances the antibody response to recombinant hepatitis B surface antigen vaccine in primates.
The effect of the proprietary adjuvant MF59 on the immunogenicity of a recombinant hepatitis B virus (HBV) vaccine, PreS2+SAg, was investigated in baboons. The magnitude and duration of the antibody response to hepatitis B surface antigen (anti-HBs) induced by the HBV/MF59 vaccine was compared with the same antigen combined with alum and with two licensed alum vaccines. After one immunization, the HBV/MF59 vaccine generated anti-HBs titers >10 mIU/mL in a greater proportion of animals, and mean titers were 26- to 84-fold higher than titers from alum vaccines. After a third immunization, the HBV/MF59 vaccine generated titers 38- to 127-fold higher than alum vaccines. Seven months after the third immunization, HBV/MF59 elicited titers 75- to 472-fold higher than alum vaccines. The dramatic immune response elicited by HBV/MF59 in baboons suggests that MF59 may be a desirable adjuvant for use in improved HBV vaccines for humans.
Adjuvants, Immunologic↗
Adjuvant-dependent modulation of Th1 and Th2 responses to immunization with beta-amyloid.
The role of adjuvant on the T(h)1 and T(h)2 immune responses to Abeta-immunotherapy (Abeta(42 )peptide) was examined in wild-type mice. Fine epitope analysis with overlapping oligomers of the Abeta(42) sequence identified the 1-15 region as a dominant B cell epitope. The 6-20 peptide was recognized only weakly by antisera from mice administrated with Abeta(42) peptide formulated in complete Freund's adjuvant (CFA), alum or TiterMax Gold (TMG). However, mice immunized with Abeta(42) mixed with QS21 induced a significant antibody response to the 6-20 peptide. The only T cell epitope found was within the 6-28 sequence of Abeta(42). QS21 and CFA induced the strongest humoral response to Abeta, alum was intermediate, and TMG the weakest adjuvant. Analysis of antibody isotypes specific for Abeta indicates that alum induces primarily T(h)2-type immune response, whereas TMG, CFA and QS21 shift the immune responses toward a T(h)1 phenotype. Stimulation of splenocytes from Abeta-immunized mice with Abeta(40) peptide induced strikingly different cytokine expression profiles. QS21 and CFA induced significant IFN-gamma, IL-4 and tumor necrosis factor-alpha expression, whereas alum induced primarily IL-4 production. As T(h)1-type immune responses have been implicated in many autoimmune disorders, whereas T(h)2-type responses have been shown to inhibit autoimmune disease, the choice of adjuvant may be critical for the design of a safe and effective immunotherapy for Alzheimer's disease.
Adjuvants, Immunologic↗
A subcutaneously injected UV-inactivated SARS coronavirus vaccine elicits systemic humoral immunity in mice.
The recent emergence of severe acute respiratory syndrome (SARS) was caused by a novel coronavirus, SARS-CoV. It spread rapidly to many countries and developing a SARS vaccine is now urgently required. In order to study the immunogenicity of UV-inactivated purified SARS-CoV virion as a vaccine candidate, we subcutaneously immunized mice with UV-inactivated SARS-CoV with or without an adjuvant. We chose aluminum hydroxide gel (alum) as an adjuvant, because of its long safety history for human use. We observed that the UV-inactivated SARS-CoV virion elicited a high level of humoral immunity, resulting in the generation of long-term antibody secreting and memory B cells. With the addition of alum to the vaccine formula, serum IgG production was augmented and reached a level similar to that found in hyper-immunized mice, though it was still insufficient to elicit serum IgA antibodies. Notably, the SARS-CoV virion itself was able to induce long-term antibody production even without an adjuvant. Anti-SARS-CoV antibodies elicited in mice recognized both the spike and nucleocapsid proteins of the virus and were able to neutralize the virus. Furthermore, the UV-inactivated virion induced regional lymph node T-cell proliferation and significant levels of cytokine production (IL-2, IL-4, IL-5, IFN-gamma and TNF-alpha) upon restimulation with inactivated SARS-CoV virion in vitro. Thus, a whole killed virion could serve as a candidate antigen for a SARS vaccine to elicit both humoral and cellular immunity.
Adjuvants, Immunologic↗
Murine mammary tumor virus protein vaccine: induction of antivirus immunity and inhibition or acceleration of growth of transplanted mammary tumors.
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Adjuvants, Immunologic↗
Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine.
BACKGROUND: Studies in animal models have shown that systemic immunization with a papillomavirus virus-like particle (VLP) vaccine composed of L1, a major structural viral protein, can confer protection against subsequent experimental challenge with the homologous virus. Here we report results of a double-blind, placebo-controlled, dose-escalation trial to evaluate the safety and immunogenicity of a human papillomavirus (HPV) type 16 (HPV16) L1 VLP vaccine in healthy adults. METHODS: Volunteers were given intramuscular injections with placebo or with 10- or 50-microg doses of HPV16 L1 VLP vaccine given without adjuvant or with alum or MF59 as adjuvants at 0, 1, and 4 months. All vaccine recipients were monitored for clinical signs and symptoms for 7 days after each inoculation. Immune responses were measured by an HPV16 L1 VLP-based enzyme-linked immunosorbent assay (ELISA) and by an HPV16 pseudovirion neutralization assay. The antibody titers were given as the reciprocals of the highest dilution showing positive reactivity in each assay. All statistical tests were two-sided. RESULTS: The prevaccination geometric mean ELISA titer for six seropositive individuals was 202 (range, 40--640). All vaccine formulations were well tolerated, and all subjects receiving vaccine seroconverted. Serum antibody responses at 1 month after the third injection were dose dependent in recipients of vaccine without adjuvant or with MF59 but were similar at both doses when alum was the adjuvant. With the higher dose, the geometric means of serum ELISA antibody titers (95% confidence intervals) to purified VLP 1 month after the third injection were as follows: 10,240 (1499 to 69 938) without adjuvant, 10,240 (1114 to 94 145) with MF59, and 2190 (838 to 5723) with alum. Responses of subjects within each group were similar. Neutralizing and ELISA antibody titers were highly correlated (Spearman correlation =.85), confirming that ELISA titers are valid proxies for neutralizing antibodies. CONCLUSIONS: The HPV16 L1 VLP vaccine is well tolerated and is highly immunogenic even without adjuvant, with the majority of the recipients achieving serum antibody titers that were approximately 40-fold higher than what is observed in natural infection.
Adjuvants, Immunologic↗
A review of hospital discharge rates in a population around Camelford in North Cornwall up to the fifth anniversary of an episode of aluminium sulphate absorption.
BACKGROUND: The aim of this study was to assess the impact of the pollution caused by the aluminium sulphate emptied into the water at the Lowermoor Treatment Works on the standardized hospital discharge ratios in the Camelford area, Cornwall. METHOD: Comparisons were made between the Camelford area and other localities in Cornwall of standardized hospital discharge ratios up to five years following the pollution incident. The diagnoses of discharges were defined by ICD 9 code and grouped in chapters. The figures for Camelford were compared with those for Cornwall. RESULTS: Since the pollution incident, the standardized discharge ratio has increased in the Camelford area compared with Cornwall. No similar increase was observed in other localities of Cornwall. No one diagnosis was found to cause this increase. CONCLUSIONS: The pollution of the water to the people of Camelford has raised hospital discharges. Monitoring of hospital discharges will continue.
Alum Compounds↗
The impact of pH on nitrogen retention in laboratory analysis of broiler litter.
Land application of broiler litter must fully regard agronomic and environmental issues, which requires increased precision in all aspects of land application of poultry litter. Previous researchers note that litter experiences significant nitrogen loss due to ammonia volatilization during the drying process. Others note that pH of poultry houses and litter significantly affects nitrogen loss due to ammonia volatilization. Recent work shows that acidifying agents effectively reduce ammonia generation in poultry production facilities. This concept is used in this study to adjust the pH of broiler litter samples prior to drying to reduce nitrogen loss during the drying process. Samples from four sources were used. Untreated litter was compared to litter treated with Al2(SO4)3, (10:1 wet weight basis) either in small (10 g) or large (100 g batches). Both Al2(SO4)3 treatment methods significantly lowered litter sample pH. No significant differences were observed in litter moisture analysis values. Regardless of source, litter treated in small batches had significantly higher nitrogen values than untreated litter. Large batches of treated litter did not consistently have higher nitrogen values than untreated litter. Treatment of litter samples with Al2(SO4)3 prior to drying resulted in more accurate quantification of nitrogen in litter, which can ultimately result in more accurate utilization of litter in agronomic applications.
Alum Compounds↗
Campylobacter and Salmonella populations associated with chickens raised on acidified litter.
Two commercially available acidifying litter treatments, aluminum sulfate (alum) and sodium bisulfate, were tested to determine their effects on Campylobacter and Salmonella colonization frequencies and populations associated with broilers raised on treated pine litter. To produce contaminated litter, broiler chicks were inoculated with two bacterial cocktails (multistrain mixtures of campylobacters and salmonellae) and were allowed to shed on the litter for about 6 wk. Upon bird removal, litter in duplicate pens was immediately treated with two levels of aluminum sulfate [3.63 or 7.26 kg/4.6 m2 (8 or 16 lb/50 ft2)] or sodium bisulfate 1.13 or 1.81 kg/4.6 m2 (2.5 or 4 lb/50 ft2)]; untreated pens served as controls. Immediately after treatment, day-of-hatch chicks were released in the pens. Frequency and populations of Campylobacter and Salmonella associated with ceca and whole carcass rinse (WCR) samples were determined for each duplicate pen at Weeks 1, 4, and 6. Both levels of the aluminum sulfate and sodium bisulfate litter treatments tested significantly (P < 0.05) reduced Campylobacter colonization frequency and populations in the ceca. Significantly, no Campylobacter was recovered from WCR samples associated with high level aluminum sulfate-treated pens at any time; although control pens were 95, 78, and 38% positive at Weeks 1, 4, and 6, respectively. Salmonella colonization frequency and populations in the ceca were not significantly decreased by any of the treatments investigated. Although effective pathogen control will most likely require a combination of interventions, acidifying treatment of litter in poultry production may serve as a means to help control Campylobacter and to reduce horizontal transmission of pathogens in broiler flocks.
Alum Compounds↗
Total and water-soluble phosphorus in broiler litter over three flocks with alum litter treatment and dietary inclusion of high available phosphorus corn and phytase supplementation.
Three pen trials were conducted to determine the main effect of alum addition to litter on form of poultry litter P using a 2 x 2 factorial structure of the subunit treatments: diets including high available phosphorus/low phytate corn (HAPC) and phytase (PHYT). Male broilers (1,760 per flock) were grown to 42 d having starter diets with 0.45% available P and grower diets with 0.35% available P. In the first trial, total litter P (tP) was greatest for the yellow dent corn (YDC) diet (12 g/kg) and least for the HAPC and PHYT combination (H&P) diet (6.9 g/kg) with the individual PHYT and HAPC diets falling in between at 9.1 g/kg and 9.4 g/kg tP. Also in the first trial, the litter water-soluble P (wP) was highest for PHYT (2.8 g/kg), least for the HAPC and H&P diets (1.5 g/kg) with the YDC diet falling between (2.2 g/kg). Alum was added to the litter after the first experiment. In the second and third experiments, alum inclusion significantly reduced the wP when compared with the treatments with no alum. In the third trial, the least wP was present in the alum-HAPC treatment. Phytase, YDC, and HAPC diets with no alum litter treatment generated the most wP. Since these diets appear to have little or no difference with respect to quantity of wP, this work suggests that form of litter P generated by alternative diets should be considered as criteria when attempting to reduce P in broiler litter applied to land.
6-Phytase↗
Effect of on-farm litter acidification treatments on Campylobacter and Salmonella populations in commercial broiler houses in northeast Georgia.
Two commercially available litter treatments, aluminum sulfate and sodium bisulfate, were tested to determine their effect on Campylobacter and Salmonella levels associated with commercial broilers during a 6-wk grow-out period. A total of 20 broiler houses at 10 different locations were studied; 5 aluminum sulfate-treated houses, 5 sodium bisulfate-treated houses, and 10 paired, untreated control houses. A single application rate was investigated for each treatment. Fecal samples (n=20 per house) were analyzed at wk 2, 4, and 5 and 6 for Campylobacter and Salmonella. The results indicated that, at the application rates investigated, both acidifying litter treatments caused a slight delay in the onset of Campylobacter colonization in broiler chicks. Salmonella levels remained unaffected, with no significant effect seen with either treatment (P > 0.05). Campylobacter populations and Salmonella incidence associated with unprocessed, whole-carcass rinse samples (n=10 per house) analyzed at the end of production (wk 5 and 6) were unaffected by treatment.
Alum Compounds↗
Effect of a single oral dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin on immune function in male NC/Nga mice.
Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces immunosuppression in humans and animals. However, the effect of TCDD on Th2-type immune responses such as allergic reactions has been unclear. Using NC/Nga mice that developed atopic dermatitis-like skin lesions with marked elevation in plasma of total IgE when bred under conventional conditions, we investigated the effects of a single oral dose of TCDD on immune responses. NC/Nga mice received a single oral dose (0 or 20 microg/kg body weight) of TCDD. On day 7, treatment with TCDD alone decreased the cellularity of thymus. However, treatment with TCDD modified the cellularity of spleens and mesenteric lymph nodes (MLNs) but not of the thymus on day 28. When NC/Nga mice received ip immunization with OVA and alum on the same day as the TCDD treatment (0, 5, or 20 microg/kg body weight), TCDD markedly suppressed the concentrations of Th2-type cytokines (e.g., IL-4 and IL-5) in culture supernatants of spleen cells, whereas IFN-gamma production significantly increased. TCDD exposure reduced anti-OVA and total IgE antibody titers in plasma and did not induce the development of atopic dermatitis-like lesions in the pinnae or dorsal skin of NC/Nga mice. These results suggest that in NC/Nga mice, exposure to TCDD may impair the induction of Th2-type immune responses.
Administration, Oral↗
Encephalopathy after bladder irrigation with alum: case report and literature review.
A 70-year-old man with advanced obstructive nephropathy began to hemorrhage from the bladder after decompression with a Foley catheter. Manifestations of encephalopathy appeared after continuous irrigation with 1% alum for 2 days and were associated with elevated serum aluminum concentrations. Repeated treatments with deferoxamine and hemodialysis accomplished some aluminum removal, but the patient succumbed to bronchopneumonia. Brain aluminum content was not excessive at autopsy. A literature review suggests that intact renal function is essential to rapid disposal of a parenteral aluminum load and indicates that most reported instances of encephalopathy after alum irrigation have occurred in patients with compromised renal function. We conclude that alum should not be employed as a bladder irrigant in patients with acute or chronic renal failure.
Aged↗
Adjuvants for allergen immunotherapy: experimental results and clinical perspectives.
PURPOSE OF REVIEW: Inclusion of adjuvants in immunotherapy vaccines are important to enhance immune responses to allergens. This article will cover the recent advances in adjuvant formulations described in published articles primarily over the past 2 years. RECENT FINDINGS: Traditionally, allergen immunotherapy preparations utilize aluminium hydroxide as an adjuvant. These have generally proved efficacious and have a good safety profile. However, recent advances in the understanding of immunological mechanisms underlying immunotherapy and in the design of new adjuvants may allow a more rational approach to adjuvant use. One approach is to use adjuvants such as immunostimulatory sequences or monophosphoryl lipid A, which can deviate allergy-associated Th2 immune responses towards a Th1 phenotype. Both of these adjuvants have been used in pilot controlled clinical trials which have demonstrated clinical efficacy and the induction of protective IgG antibodies. Other approaches to improve immunotherapy vaccines include microencapsulation of allergen to allow delivery of the allergen directly to the gut in order to induce immunological tolerance and vaccination with heat-killed mycobacteria. SUMMARY: There is great interest in newly designed adjuvants to improve the efficacy and safety of allergen immunotherapy. A better understanding of immunological mechanisms and further clinical trials utilizing new adjuvants are needed.
Adjuvants, Immunologic↗
Phase I/II study of a candidate vaccine designed against the B and E subtypes of HIV-1.
A phase I/II trial of a candidate vaccine to prevent HIV infection was carried out in Bangkok, Thailand, testing AIDSVAX B/E (VaxGen, Inc., Brisbane, CA), a bivalent subunit vaccine prepared by combining recombinant gp120 from a subtype B virus (HIV-1MN) with gp120 from a subtype E virus (HIV-1A244) in alum adjuvant. The studies provide human data on the immunogenicity of various dose combination of non-subtype B vaccine antigens. The results suggest that AIDSVAX B/E is safe and immunogenic in humans. The optimal dose for humans in developing countries was 300 microg of each antigen (B and E). Clade E responses were measurably increased by immunizing with gp120 B/E over B alone. Using the B/E combination did not interfere with the response to either clade. Antibodies to AIDSVAX B/E were able to bind to oligomeric gp120 on the surface of cells infected with primary isolates of HIV-1.
AIDS Vaccines↗
Hepatitis C virus polyprotein vaccine formulations capable of inducing broad antibody and cellular immune responses.
Although approximately 3 % of the world's population is infected with Hepatitis C virus (HCV), there is no prophylactic vaccine available. This study reports the design, cloning and purification of a single polyprotein comprising the HCV core protein and non-structural proteins NS3, NS4a, NS4b, NS5a and NS5b. The immunogenicity of this polyprotein, which was formulated in alum, oil-in-water emulsion MF59 or poly(dl-lactide co-glycolide) in the presence or absence of CpG adjuvant, was then determined in a murine model for induction of B- and T-cell responses. The addition of adjuvants or a delivery system to the HCV polyprotein enhanced serum antibody and T-cell proliferative responses, as well as IFN-gamma responses, by CD4+ T cells. The antibody responses were mainly against the NS3 and NS5 components of the polyprotein and relatively poor responses were elicited against NS4 and the core components. IFN-gamma responses, however, were induced against all of the individual components of the polyprotein. These data suggest that the HCV polyprotein delivered with adjuvants induces broad B- and T-cell responses and could be a vaccine candidate against HCV.
Adjuvants, Immunologic↗