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Hem, Stanley L., Cliff T. Johnston, and Harm HogenEsch. "Imject® Alum is not aluminum hydroxide adjuvant or aluminum phosphate adjuvant." Vaccine 25, no. 27 (June 2007): 4985–86. http://dx.doi.org/10.1016/j.vaccine.2007.04.078.
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Davison, Clara J., Haley A. Partlow, Stephanie K. Lathrop, Karthik Siram, Walid Abdelwahab, David J. Burkhart, and Jay Evans. "Combinations of alum and synthetic toll-like receptor agonists as adjuvants for CoVID-19 vaccines." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 30.07. http://dx.doi.org/10.4049/jimmunol.206.supp.30.07.
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Abstract Aluminum-based adjuvants (“alum”) are the most widely-used adjuvants for human vaccines, with an extensive history of safety and efficacy. Alum is known to elicit high antibody titers by driving a Th2-based immune response, which may not be optimal for many viral infections, such as SARS-CoV-2. Therefore, combining the strong safety and efficacy attributes of alum with a Th1-polarizing adjuvant could improve immunity against viral antigens. Here we test the combination of alum with synthetic TLR4- and TLR7/8 -ligands in vaccines against SARS-CoV-2. The combination of alum and TLR agonists resulted in efficient adjuvantation of both humoral and cell-mediated immunity. Alum adsorption studies showed low association between the small, positively-charged receptor binding domain (RBD) antigen and aluminum hydroxide (Alhydrogel) and high adsorption to negatively charged aluminum phosphate (Adju-phos). However, Adju-phos and Alhydrogel both enhanced immunity to the SARS-CoV-2 RBD antigen, suggesting antigen adsorption may not be required for the immune enhancing effects of alum. These data demonstrated that adjuvants combining alum with a TLR agonist result in an improved anti-viral immune response. However, the ability of alum to adsorb to an antigen may not predict its ability to effectively adjuvant.
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Near, Karen A., Anthony W. Stowers, Dragana Jankovic, and David C. Kaslow. "Improved Immunogenicity and Efficacy of the Recombinant 19-Kilodalton Merozoite Surface Protein 1 by the Addition of Oligodeoxynucleotide and Aluminum Hydroxide Gel in a Murine Malaria Vaccine Model." Infection and Immunity 70, no. 2 (February 2002): 692–701. http://dx.doi.org/10.1128/iai.70.2.692-701.2002.
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ABSTRACT Vaccination of mice with yeast-secreted Plasmodium yoelii-derived 19-kilodalton merozoite surface protein 1 (yMSP119) has been shown to afford protection from challenge with a lethal strain of P. yoelii. Sterile immunity can be achieved when MSP119 is emulsified in Freund adjuvant but not when it is adsorbed to aluminum hydroxide gel (alum). Because complete Freund adjuvant is not an acceptable adjuvant for use in humans, alternative adjuvants must be identified for formulating MSP119 as a vaccine for use in humans. To determine whether oligodeoxynucleotides with CpG motifs (ODN), reported to be a powerful new class of adjuvants, could enhance the immunogenicity of yMSP119, C57BL/6 mice were vaccinated either with yMSP119 formulated with Freund adjuvant, with alum, or with ODN plus alum and challenged intravenously with P. yoelii 17XL asexual blood-stage parasites. Adsorption of immunogen and adjuvant to alum was optimized by adjusting buffer (phosphate versus acetate) and pH. We found that the adjuvant combination of ODN plus alum with yMSP119, injected intraperitoneally (i.p.), increased immunoglobulin G (IgG) yMSP119-specific antibody production 12-fold over Freund adjuvant given i.p., 3-fold over Freund adjuvant given subcutaneously (s.c.), 300-fold over alum given i.p., and 48-fold over alum given s.c. The predominant antibody isotype in the group receiving alum-ODN-yMSP119 was IgG1. Increased antibody levels correlated to protection from a challenge with P. yoelii 17XL. Supernatant cytokine levels of gamma interferon in yMSP119-stimulated splenocytes were dramatically elevated in the alum-ODN-yMSP119 group. Interleukin-10 (IL-10) levels were also elevated; however, no IL-5 was detected. The cytokine profile, as well as the predominant IgG1 antibody isotype, suggests the protective immune response was a mixed Th1/Th2 response.
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Karacs, Jasmine, Manuel Reithofer, Claudia Kitzmüller, Markus Kraller, Stefanie Schmalz, Sonja Bleichert, Johannes B. Huppa, Hannes Stockinger, Barbara Bohle, and Beatrice Jahn-Schmid. "Adjuvants and Vaccines Used in Allergen-Specific Immunotherapy Induce Neutrophil Extracellular Traps." Vaccines 9, no. 4 (April 1, 2021): 321. http://dx.doi.org/10.3390/vaccines9040321.
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Aluminum hydroxide (alum) and monophosphoryl-lipid A (MPLA) are conventional adjuvants in vaccines for allergen-specific immunotherapy (AIT). Alum triggers the release of neutrophil extracellular traps (NETs) by neutrophils. NETs contain expelled decondensed chromatin associated with granular material and may act as danger-associated molecular patterns and activate antigen-presenting cells. We investigated whether adjuvant-induced NETs contribute to innate responses to AIT-vaccines. Human neutrophils were incubated with alum, MPLA and adjuvant-containing AIT-vaccine preparations. NETs were verified by time-lapse and confocal fluorescence microscopy and quantitatively assessed by DNA and elastase release and ROS production. In contrast to MPLA, alum represented a potent trigger for NET release. Vaccine formulations containing alum resulted in less NET release than alum alone, whereas the vaccine containing MPLA induced stronger NET responses than MPLA alone. NETs and alum alone and synergistically increased the expression of molecules involved in antigen presentation, i.e., CD80, CD86 and CD83, by peripheral blood monocytes. Monocyte priming with NETs resulted in individually differing IL-1β- and IL-6-responses. Thus, NETs induced by adjuvants in AIT-vaccines can provide autonomous and cooperative effects on early innate responses. The high diversity of individual innate responses to adjuvants and AIT-vaccines may affect their therapeutic efficacy.
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Prior, J. Timothy, Christopher Davitt, Jonathan Kurtz, Patrick Gellings, James B. McLachlan, and Lisa A. Morici. "Bacterial-Derived Outer Membrane Vesicles are Potent Adjuvants that Drive Humoral and Cellular Immune Responses." Pharmaceutics 13, no. 2 (January 20, 2021): 131. http://dx.doi.org/10.3390/pharmaceutics13020131.
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Discovery and development of novel adjuvants that can improve existing or next generation vaccine platforms have received considerable interest in recent years. In particular, adjuvants that can elicit both humoral and cellular immune responses would be particularly advantageous because the majority of licensed vaccines are formulated with aluminum hydroxide (alum) which predominantly promotes antibodies. We previously demonstrated that bacterial-derived outer membrane vesicles (OMV) possess inherent adjuvanticity and drive antigen-specific antibody and cellular immune responses to OMV components. Here, we investigated the ability of OMVs to stimulate innate and adaptive immunity and to function as a stand-alone adjuvant. We show that OMVs are more potent than heat-inactivated and live-attenuated bacteria in driving dendritic cell activation in vitro and in vivo. Mice immunized with OMVs admixed with heterologous peptides generated peptide-specific CD4 and CD8 T cells responses. Notably, OMV adjuvant induced much greater antibody and B cell responses to co-delivered ovalbumin compared to the responses elicited by the adjuvants alum and CpG DNA. Additionally, pre-existing antibodies raised against the OMVs did not impair OMV adjuvanticity upon repeat immunization. These results indicate that vaccines adjuvanted with OMVs elicit robust cellular and humoral immune responses, supporting further development of OMV adjuvant for use in next-generation vaccines.
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Kool, Mirjam, Thomas Soullié, Menno van Nimwegen, Monique A. M. Willart, Femke Muskens, Steffen Jung, Henk C. Hoogsteden, Hamida Hammad, and Bart N. Lambrecht. "Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells." Journal of Experimental Medicine 205, no. 4 (March 24, 2008): 869–82. http://dx.doi.org/10.1084/jem.20071087.
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Alum (aluminum hydroxide) is the most widely used adjuvant in human vaccines, but the mechanism of its adjuvanticity remains unknown. In vitro studies showed no stimulatory effects on dendritic cells (DCs). In the absence of adjuvant, Ag was taken up by lymph node (LN)–resident DCs that acquired soluble Ag via afferent lymphatics, whereas after injection of alum, Ag was taken up, processed, and presented by inflammatory monocytes that migrated from the peritoneum, thus becoming inflammatory DCs that induced a persistent Th2 response. The enhancing effects of alum on both cellular and humoral immunity were completely abolished when CD11c+ monocytes and DCs were conditionally depleted during immunization. Mechanistically, DC-driven responses were abolished in MyD88-deficient mice and after uricase treatment, implying the induction of uric acid. These findings suggest that alum adjuvant is immunogenic by exploiting “nature's adjuvant,” the inflammatory DC through induction of the endogenous danger signal uric acid.
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Zhang, Zhe, Xin-Pu Li, Feng Yang, Jin-Yin Luo, Xu-Rong Wang, Long-hai Liu, and Hong-Sheng Li. "Immune Responses in Mice Immunized with Mastitis Multiple Vaccines Using Different Adjuvants." Acta Scientiae Veterinariae 46, no. 1 (August 10, 2018): 8. http://dx.doi.org/10.22456/1679-9216.84088.
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Background: Bovine mastitis, a serious disease associated with both high incidence and significant economic losses, posing a major challenge to the global dairy industry. The development of vaccines for protection from new infections by mastitis pathogens is of considerable interest to the milk production industry. Vaccination is a common and easy strategy for the control of infectious diseases, and the adjuvants used in the formulation is a critical factor for vaccine efficacy improvement. The main objective of the present study was to evaluate three different adjuvants for their ability to enhance immune responses of mice that vaccinated with Bovine Mastitis Multiple Vaccine.Materials, Methods & Results: The thymus and spleen index, the phagocytic ability of macrophage and the serum antibody levels of mice were detected after vaccination, respectively. The results showed that the thymus index, spleen index, and the phagocytic ability of macrophage of mice in Aluminum group exhibited a significant higher level (P < 0.05) compared with those in the control groups. The difference of the serum antibody levels was significant (P < 0.05) between experimental groups and control group after vaccination. The serum antibody concentration of mice in FIA group was higher compared with other groups and had a longer duration. The antibody concentration of mice in France 206 oil group can not increase as fast as the antibody concentration of Aluminum group, but it can last a longer time at a high level. In conclusion, multiple vaccines mixed with three different adjuvants could enhance the immunity of mice and Freund’s incomplete adjuvant is the best choice for this vaccine.Discussion: Adjuvants play an important role in increasing the efficacy of a number of different vaccines. In this study, three kinds of adjuvants (Aluminum hydroxide, France 206 oil and FIA) were evaluated for their adjuvant effects for multiple vaccine of bovine mastitis in mice and aluminum hydroxide did best as the vaccine adjuvant from the results. Aluminum hydroxide is a universally accepted adjuvant for both human and veterinary vaccines. The goal of vaccination is to generate strong immune response providing protection against infection for a time. Different protective effects will usually obtained by different adjuvants even use same antigen. In this work, FIA, Alum and 206 oil were chosen as adjuvants for inactivated antigens of Streptococcus agalactiae, Streptococcus dysgalactiae and Staphylococcus aureus. The results showed that there was a significantly higher antibody levels in vaccinated mice compared with those in control group. In addition, the mice in France 206 oil and FIA group performed a higher antibody levels and stronger immunity than mice in Aluminum hydroxide groups. These findings suggest that Freund’s incomplete adjuvant (FIA) would be the best candidate as the adjuvant for mastitis multiple vaccines investigated in this study.
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Chen, Qiuting, Nan Wu, Yuhui Gao, Xiaojun Wang, Jie Wu, and Guanghui Ma. "Alum Pickering Emulsion as Effective Adjuvant to Improve Malaria Vaccine Efficacy." Vaccines 9, no. 11 (October 26, 2021): 1244. http://dx.doi.org/10.3390/vaccines9111244.
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Malaria is a life-threatening global epidemic disease and has caused more than 400,000 deaths in 2019. To control and prevent malaria, the development of a vaccine is a potential method. An effective malaria vaccine should either combine antigens from all stages of the malaria parasite’s life cycle, or epitopes of multiple key antigens due to the complexity of the Plasmodium parasite. Malaria’s random constructed antigen-1 (M.RCAg-1) is one of the recombinant vaccines, which was selected from a DNA library containing thousands of diverse multi-epitope chimeric antigen genes. Moreover, besides selecting an antigen, using an adjuvant is another important procedure for most vaccine development procedures. Freund’s adjuvant is considered an effective vaccine adjuvant for malaria vaccine, but it cannot be used in clinical settings because of its serious side effects. Traditional adjuvants, such as alum adjuvant, are limited by their unsatisfactory immune effects in malaria vaccines, hence there is an urgent need to develop a novel, safe and efficient adjuvant. In recent years, Pickering emulsions have attracted increasing attention as novel adjuvant. In contrast to classical emulsions, Pickering emulsions are stabilized by solid particles instead of surfactant, having pliability and lateral mobility. In this study, we selected aluminum hydroxide gel (termed as “alum”) as a stabilizer to prepare alum-stabilized Pickering emulsions (ALPE) as a malaria vaccine adjuvant. In addition, monophosphoryl lipid A (MPLA) as an immunostimulant was incorporated into the Pickering emulsion (ALMPE) to further enhance the immune response. In vitro tests showed that, compared with alum, ALPE and ALMPE showed higher antigen load rates and could be effectively endocytosed by J774a.1 cells. In vivo studies indicated that ALMPE could induce as high antibody titers as Freund’s adjuvant. The biocompatibility study also proved ALMPE with excellent biocompatibility. These results suggest that ALMPE is a potential adjuvant for a malaria vaccine.
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Hawksworth, David, and Joan Tyner. "Evaluation of Adjuvant Regimens for Antibody Development in Rabbits (36.29)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S17—S18. http://dx.doi.org/10.4049/jimmunol.178.supp.36.29.
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Abstract Several adjuvant regimens were assessed for their ability to safely develop a high titer, high affinity antibody response in rabbits. Female, New Zealand White (NZW) rabbits were given five monthly 20 ug immunizations with a 25 KDa recombinant protein using one of four adjuvant programs: Adjulite® Complete and Adjulite® Incomplete Freund’s adjuvants,Alhydrogel® Aluminum hydroxide gel adjuvant in combination with oligodeoxynucleotides containing unmethylated CpG dinucleotides (Alum/CpG),Difco Freund’s adjuvant alternating with MPL+TDM+CWS orDifco Freund’s adjuvant alternating with Quil A supplemented with CpG-ODN. Sera samples taken following all booster immunizations were evaluated for antibody titer and relative affinity in a microtiter enzyme immunoassay by testing for antibody reactivity to limiting amounts of the administered antigen. Animals were also monitored during the immunization period for any reaction at the sites of injection. Results show that the Adjulite® animals elicited a higher average titer compared to animals immunized using any of the alternate strategies. Additionally, Adjulite® rabbits developed an average relative antibody affinity similar to that for the Alum/CpG animals and higher than either of the groups employing Difco Freund’s adjuvant. One Adjulite® rabbit developed a temporary nodule at the site of injection compared to none of the Alum/CpG animals. Two of the five animals using Difco Freund’s adjuvant developed a nodule, both of which progressed to lesions. This study demonstrates that Adjulite® adjuvant can serve as a safe alternative to other adjuvant regimens for the development of a high titer, high affinity antibody response in rabbits.
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Sasaki, Eita, Hideki Asanuma, Haruka Momose, Keiko Furuhata, Takuo Mizukami, and Isao Hamaguchi. "Nasal alum-adjuvanted vaccine promotes IL-33 release from alveolar epithelial cells that elicits IgA production via type 2 immune responses." PLOS Pathogens 17, no. 8 (August 30, 2021): e1009890. http://dx.doi.org/10.1371/journal.ppat.1009890.
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Aluminum hydroxide salts (alum) have been added to inactivated vaccines as safe and effective adjuvants to increase the effectiveness of vaccination. However, the exact cell types and immunological factors that initiate mucosal immune responses to alum adjuvants are unclear. In this study, the mechanism of action of alum adjuvant in nasal vaccination was investigated. Alum has been shown to act as a powerful and unique adjuvant when added to a nasal influenza split vaccine in mice. Alum is cytotoxic in the alveoli and stimulates the release of damage-associated molecular patterns, such as dsDNA, interleukin (IL)-1α, and IL-33. We found that Ag-specific IgA antibody (Ab) production was markedly reduced in IL-33-deficient mice. However, no decrease was observed in Ag-specific IgA Ab production with DNase I treatment, and no decrease was observed in IL-1α/β or IL-6 production in IL-33-deficient mice. From the experimental results of primary cultured cells and immunofluorescence staining, although IL-1α was secreted by alveolar macrophage necroptosis, IL-33 release was observed in alveolar epithelial cell necroptosis but not in alveolar macrophages. Alum- or IL-33-dependent Ag uptake enhancement and elevation of OX40L expression were not observed. By stimulating the release of IL-33, alum induced Th2 immunity via IL-5 and IL-13 production in group 2 innate lymphoid cells (ILC2s) and increased MHC class II expression in antigen-presenting cells (APCs) in the lung. Our results suggest that IL-33 secretion by epithelial cell necroptosis initiates APC- and ILC2-mediated T cell activation, which is important for the enhancement of Ag-specific IgA Ab production by alum.
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Mabel Cruz, Rodríguez, Báez Gretchen Bergado, Luna Yerandy Hechevarría, Fernández Diana Rosa Hernández, Palomo Addys González, Suárez Narjara González, Castillo Carlos Yordan González, Lorenzo María del Carmen Luzardo, García Lisset Chao, and Ramírez Belinda Sánchez. "The combination of very-small size proteoliposomes and alum is a safe adjuvant alternative for inducing anti-EGF antibodies: a preclinical study." Archives of Cancer Science and Therapy 6, no. 1 (September 20, 2022): 018–30. http://dx.doi.org/10.29328/journal.acst.1001029.
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Immunization with human recombinant EGF chemically bound to the P64k protein of Neisseria meningitides (hrEGF-P64k) and adjuvanted in Montanide ISA 51 VG (Montanide) is an efficient strategy to induce polyclonal antibodies (PAbs) response targeting this self -antigen in cancer patients, which is the basis of the CIMAvax-EGF vaccine. The neutralizing potential of EGF-specific induced PAbs supports promising clinical data obtained to date with this vaccine. Herein, we evaluated a combination of very small-size proteoliposomes (VSSP) and aluminum hydroxide (Alum) as a novel adjuvant to induce specific PAbs with neutralizing and anti-proliferative properties on tumor cells, considering EGF as a model antigen. Toxicity at the injection site was not detected for the vaccine formulation containing VSSP/Alum, and it was immunogenic in BALB/c mice, as evidenced by the induction of high titers of EGF-specific polyclonal antibodies (PAbs). While schedule optimization increased the magnitude of the PAbs response induced by VSSP/Alum, induced PAbs’s avidity and intrinsic neutralizing potential were comparable to the humoral response induced by Montanide. Also, VSSP addition switched IgG subclasses distribution into a Th1-like pattern, as obtained with Montanide and desirable for a cancer vaccine. Finally, equivalent PAbs titers were induced by the vaccine formulations adjuvanted in VSSP/Alum or Montanide in tumor-bearing-mice, and immunosuppressed mice, suggesting the feasibility of the VSSP/Alum combined adjuvant for inducing anti-EGF antibodies in cancer patients at advanced stages of the disease.
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Saleh, Maryam, Jamileh Nowroozi, Fatemeh Fotouhi, and Behrokh Farahmand. "Physicochemical study of the influenza A virus M2 protein and aluminum salt adjuvant interaction as a vaccine candidate model." Future Virology 14, no. 8 (August 2019): 523–36. http://dx.doi.org/10.2217/fvl-2019-0019.
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Aim: The present study evaluated the structural changes resulting from the interaction between a recombinant influenza A virus M2 protein and aluminum hydroxide adjuvant to investigate the antigen for further immunological studies. Materials & methods: Membrane protein II was produced from the H1N1 subtype of human influenza A virus. The interaction between M2 protein and alum inum hydroxide adjuvant was evaluated by physicochemical techniques including scanning electron microscope, UV-Vis spectra, Fourier-transform infrared spectroscopy and circular dichroism spectroscopy. Results: Physicochemical methods showed high-level protein adsorption and accessibility to the effective parts of the protein. Conclusion: It was concluded that M2 protein secondary structural perturbations, including the α-helix-to-β-sheet transition, enhanced its mechanical properties toward adsorption.
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Sun, Jianhua, Xiaoming Song, and Songhua Hu. "Ginsenoside Rg1 and Aluminum Hydroxide Synergistically Promote Immune Responses to Ovalbumin in BALB/c Mice." Clinical and Vaccine Immunology 15, no. 2 (December 19, 2007): 303–7. http://dx.doi.org/10.1128/cvi.00448-07.
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ABSTRACT The combined adjuvant effect of ginsenoside Rg1 and aluminum hydroxide (alum) on immune responses to ovalbumin (OVA) in mice was investigated. BALB/c mice were subcutaneously (s.c.) inoculated twice with OVA alone or in combination with Rg1, alum, or Rg1 plus alum. Samples were collected 2 weeks after the boosting for the measurement of anti-OVA immunoglobulin G (IgG) isotypes in sera and gamma interferon (IFN-γ) and interleukin-5 (IL-5) produced in singular splenocyte cultures. Delayed-type hypersensitivity (DTH) responses were measured in mice immunized as described above. After 10 days, the mice were injected s.c. with OVA at the footpads. Thereafter, the thickness of the footpads was measured once daily for 5 days. The results indicated that alum enhanced mainly Th2 (IgG1 and IL-5) responses (P < 0.05), while Rg1 enhanced both Th1 (IgG1 and IL-5) and Th2 (IgG2a, IFN-γ, and DTH) responses (P < 0.05). The highest immune responses were found in the mice injected with OVA solution containing both alum and Rg1. In addition, the hemolytic activity of Rg1 was much lower than that of Quil A. Therefore, Rg1 deserves further studies in order to tailor desired immune responses when a mixed Th1/Th2 immune response is needed.
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Wu, Shuenn-Jue, Dan Ewing, Appavu K. Sundaram, Hua-Wei Chen, Zhaodong Liang, Ying Cheng, Vihasi Jani, et al. "Enhanced Immunogenicity of Inactivated Dengue Vaccines by Novel Polysaccharide-Based Adjuvants in Mice." Microorganisms 10, no. 5 (May 16, 2022): 1034. http://dx.doi.org/10.3390/microorganisms10051034.
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Dengue fever, caused by any of four dengue viruses (DENV1-4), is a major global burden. Currently, there is no effective vaccine that prevents infection in dengue naïve populations. We tested the ability of two novel adjuvants (Advax-PEI and Advax-2), using aluminum hydroxide (alum) as control, to enhance the immunogenicity of formalin- or psoralen-inactivated (PIV or PsIV) DENV2 vaccines in mice. Mice were vaccinated on days 0 and 30, and serum samples were collected on days 30, 60, 90, and 101. Neutralizing antibodies were determined by microneutralization (MN) assays, and the geometric mean 50% MN (MN50) titers were calculated. For the PIV groups, after one dose MN50 titers were higher in the novel adjuvant groups compared to the alum control, while MN50 titers were comparable between the adjuvant groups after the second dose. For the PsIV groups, both novel adjuvants induced higher MN50 titers than the alum control after the second dose. Spleen cells were collected on days 45 and 101 for enzyme-linked immunospot (ELISPOT) for IFNγ and IL4. Both PIV and PsIV groups elicited different degrees of IFNγ and IL4 responses. Overall, Advax-2 gave the best responses just ahead of Advax-PEI. Given Advax-2’s extensive human experience in other vaccine applications, it will be pursued for further development.
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Monaris, D., M. E. Sbrogio-Almeida, C. C. Dib, T. A. Canhamero, G. O. Souza, S. A. Vasconcellos, L. C. S. Ferreira, and P. A. E. Abreu. "Protective Immunity and Reduced Renal Colonization Induced by Vaccines Containing Recombinant Leptospira interrogans Outer Membrane Proteins and Flagellin Adjuvant." Clinical and Vaccine Immunology 22, no. 8 (June 24, 2015): 965–73. http://dx.doi.org/10.1128/cvi.00285-15.
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ABSTRACTLeptospirosis is a global zoonotic disease caused by differentLeptospiraspecies, such asLeptospira interrogans, that colonize the renal tubules of wild and domestic animals. Thus far, attempts to develop effective leptospirosis vaccines, both for humans and animals, have failed to induce immune responses capable of conferring protection and simultaneously preventing renal colonization. In this study, we evaluated the protective immunity induced by subunit vaccines containing seven different recombinantLeptospira interrogansouter membrane proteins, including the carboxy-terminal portion of the immunoglobulinlike protein A (LigAC) and six novel antigens, combined with aluminum hydroxide (alum) orSalmonellaflagellin (FliC) as adjuvants. Hamsters vaccinated with the different formulations elicited high antigen-specific antibody titers. Immunization with LigAC, either with alum or flagellin, conferred protective immunity but did not prevent renal colonization. Similarly, animals immunized with LigACor LigACcoadministered with six leptospiral proteins with alum adjuvant conferred protection but did not reduce renal colonization. In contrast, immunizing animals with the pool of seven antigens in combination with flagellin conferred protection and significantly reduced renal colonization by the pathogen. The present study emphasizes the relevance of antigen composition and added adjuvant in the efficacy of antileptospirosis subunit vaccines and shows the complex relationship between immune responses and renal colonization by the pathogen.
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Sanchez-Pescador, L., R. L. Burke, G. Ott, and G. Van Nest. "The effect of adjuvants on the efficacy of a recombinant herpes simplex virus glycoprotein vaccine." Journal of Immunology 141, no. 5 (September 1, 1988): 1720–27. http://dx.doi.org/10.4049/jimmunol.141.5.1720.
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Abstract A recombinant, truncated HSV type 1 glycoprotein D secreted by Chinese hamster ovary cells (rgD1) was used to compare the ability of several adjuvants to stimulate protective immunity in guinea pigs. Adjuvants tested included CFA, aluminum hydroxide (alum), a lipophilic derivative of muramyl tripeptide (MTP-PE), and a muramyl dipeptide (MDP) covalently conjugated to rgD1. Animals were immunized three times with rgD1 plus the various adjuvants and antibody titers were determined by ELISA. Four weeks after the last immunization, the animals were challenged intravaginally with HSV type 2 and were monitored daily for clinical signs of disease, including frequency and severity of herpetic lesions, incidence of urinary retention, and mortality during the 14-day post-challenge observation period. Animals immunized in the foot-pad with rgD1 formulated with CFA showed the highest antibody titers. Animals immunized in the footpad with rgD1 using MTP-PE in a 4% squalene formulation, alum, or rgD1 conjugated to MDP showed mean antibody titers that were 57, 16, and 13% of the CFA titers, respectively. Immunization with rgD1 plus MTP-PE, alum, or rgD1-MDP conjugate by the i.m. route elicited lower antibody titers than the footpad route of immunization. Results of the viral challenge indicated that clinical symptoms of the groups immunized with rgD1 with CFA or MTP-PE as adjuvant were similar in magnitude and were markedly reduced compared with unimmunized control groups. Animals immunized with rgD1 combined with alum or rgD1-MDP conjugate showed clinical symptoms significantly more severe than the CFA or MTP-PE groups. The protective immunity observed after i.m. immunization of animals with rgD1 and MTP-PE was only slightly lower than animals immunized with the same Ag-adjuvant combination in the footpad. The results indicate that MTP-PE is an effective adjuvant for the recombinant herpes gD vaccine.
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Li, Qiao, Zhihua Liu, Yi Liu, Chen Liang, Jiayi Shu, Xia Jin, Chuanyou Li, and Zhihua Kou. "A Combined Adjuvant TF–Al Consisting of TFPR1 and Aluminum Hydroxide Augments Strong Humoral and Cellular Immune Responses in Both C57BL/6 and BALB/c Mice." Vaccines 9, no. 12 (November 29, 2021): 1408. http://dx.doi.org/10.3390/vaccines9121408.
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TFPR1 is a novel adjuvant for protein and peptide antigens, which has been demonstrated in BALB/c mice in our previous studies; however, its adjuvanticity in mice with different genetic backgrounds remains unknown, and its adjuvanticity needs to be improved to fit the requirements for various vaccines. In this study, we first compared the adjuvanticity of TFPR1 in two commonly used inbred mouse strains, BALB/c and C57BL/6 mice, in vitro and in vivo, and demonstrated that TFPR1 activated TLR2 to exert its immune activity in vivo. Next, to prove the feasibility of TFPR1 acting as a major component of combined adjuvants, we prepared a combined adjuvant, TF–Al, by formulating TFPR1 and alum at a certain ratio and compared its adjuvanticity with that of TFPR1 and alum alone using OVA and recombinant HBsAg as model antigens in both BALB/c and C57BL/6 mice. Results showed that TFPR1 acts as an effective vaccine adjuvant in both BALB/c mice and C57BL/6 mice, and further demonstrated the role of TLR2 in the adjuvanticity of TFPR1 in vivo. In addition, we obtained a novel combined adjuvant, TF–Al, based on TFPR1, which can augment antibody and cellular immune responses in mice with different genetic backgrounds, suggesting its promise for vaccine development in the future.
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Kenney, Richard T., David L. Sacks, Joseph P. Sypek, Luciano Vilela, Albert A. Gam, and Kamela Evans-Davis. "Protective Immunity Using Recombinant Human IL-12 and Alum as Adjuvants in a Primate Model of Cutaneous Leishmaniasis." Journal of Immunology 163, no. 8 (October 15, 1999): 4481–88. http://dx.doi.org/10.4049/jimmunol.163.8.4481.
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Abstract Protection from cutaneous leishmaniasis, a chronic ulcerating skin lesion affecting millions, has been achieved historically using live virulent preparations of the parasite. Killed or recombinant Ags that could be safer as vaccines generally require an adjuvant for induction of a strong Th1 response in murine models. Murine rIL-12 as an adjuvant with soluble Leishmania Ag has been shown to protect susceptible mice. We used 48 rhesus macaques to assess the safety, immunogenicity, and efficacy of a vaccine combining heat-killed Leishmania amazonensis with human rIL-12 (rhIL-12) and alum (aluminum hydroxide gel) as adjuvants. The single s.c. vaccination was found to be safe and immunogenic, although a small transient s.c. nodule developed at the site. Groups receiving rhIL-12 had an augmented in vitro Ag-specific IFN-γ response after vaccination, as well as increased production of IgG. No increase in IL-4 or IL-10 was found in cell culture supernatants from either control or experimental groups. Delayed hypersensitivity reactions were not predictive of protection. Intradermal forehead challenge infection with 107 metacyclic L. amazonensis promastigotes at 4 wk demonstrated protective immunity in all 12 monkeys receiving 2 μg rhIL-12 with alum and Ag. Partial efficacy was seen with lower doses of rhIL-12 and in groups lacking either adjuvant. Thus, a single dose vaccine with killed Ag using rhIL-12 and alum as adjuvants was safe and fully effective in this primate model of cutaneous leishmaniasis. This study extends the murine data to primates, and provides a basis for further human trials.
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Guasconi, L., M. C. Serradell, J. Borgonovo, A. P. Garro, H. Varengo, G. Caffe, and D. T. Masih. "Immunization with crude antigens plus aluminium hydroxide protects cattle fromFasciola hepaticainfection." Journal of Helminthology 86, no. 1 (March 3, 2011): 64–69. http://dx.doi.org/10.1017/s0022149x11000022.
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AbstractThe ability of total homogenate (TH) ofFasciola hepaticaconjugated with aluminium hydroxide (alum) or Freund's complete adjuvant (FCA) to protect cattle against experimental fasciolosis was evaluated. Compared with the infected group, the immunized animals with alum-TH and FCA-TH presented a significant reduction in fluke burden (85.9% and 96.8%, respectively), a higher percentage of short-sized worms, a marked reduction in the released eggs in faeces (89% and 57%, respectively), as well as an increased production of specific antibodies before infection. The alum-TH immunized group also showed a significant increase in the antigen-specific proliferation of peripheral blood mononuclear cells (PBMC) as early as 4 weeks before infection. Although both immunized groups (alum-TH and FCA-TH) were able to develop an efficient protective immune response to metacercarial challenge, an earlier PBMC response, lower hepatic damage and less effect on weight gain were found in alum-immunized animals. Therefore, alum is a good candidate for future immunization against bovine fasciolosis.
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Su, Zhong, Mi-Fong Tam, Dragana Jankovic, and Mary M. Stevenson. "Vaccination with Novel Immunostimulatory Adjuvants against Blood-Stage Malaria in Mice." Infection and Immunity 71, no. 9 (September 2003): 5178–87. http://dx.doi.org/10.1128/iai.71.9.5178-5187.2003.
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ABSTRACT An important aspect of malaria vaccine development is the identification of an appropriate adjuvant which is both capable of stimulating a protective immune response and safe for use by humans. Here, we investigated the feasibility of using novel immunostimulatory molecules as adjuvants combined with a crude antigen preparation and coadsorbed to aluminum hydroxide (alum) as a vaccine against blood-stage Plasmodium chabaudi AS malaria. Prior to challenge infection, immunization of genetically susceptible A/J mice with the combination of malaria antigen plus recombinant interleukin-12 (IL-12) in alum induced a Th1 immune response with production of high levels of gamma interferon (IFN-γ) and diminished IL-4 levels by spleen cells stimulated in vitro with parasite antigen compared to mice immunized with antigen alone, antigen in alum, or antigen plus IL-12. Mice immunized with malaria antigen plus recombinant IL-12 in alum had high levels of total malaria-specific antibody and immunoglobulin G2a. Compared to unimmunized mice, immunization with antigen plus IL-12 in alum induced the highest level of protective immunity against challenge infection with P. chabaudi AS, which was evident as a significantly decreased peak parasitemia level and 100% survival. Protective immunity was dependent on CD4+ T cells, IFN-γ, and B cells and was long-lasting. Replacement of IL-12 as an adjuvant by synthetic oligodeoxynucleotides (ODN) containing CpG motifs induced a similar level of vaccine-induced protection against challenge infection with P. chabaudi AS. These results illustrate that it is possible to enhance the potency of a crude malaria antigen preparation delivered in alum by inclusion of immunostimulatory molecules, such as IL-12 or CpG-ODN.
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McAnally, James L., Likang Xu, Matteo Villain, and J. Edwin Blalock. "The Role of Adjuvants in the Efficacy of a Peptide Vaccine for Myasthenia Gravis." Experimental Biology and Medicine 226, no. 4 (April 2001): 307–11. http://dx.doi.org/10.1177/153537020122600407.
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Myasthenia gravis (MG) and its animal model, experimental autoimmune (EA) MG, are caused by interference with neuromuscular transmission by autoantibodies against the nicotinic acetylcholine receptor (AChR) on muscle. Previously, we have shown that two peptides, denoted RhCA 67-16 and RhCA 611-001, designed to be complementary in structure to the main immunogenic region and the dominant Lewis rat T cell epitope (α-chain residues 100-116) of the AChR, respectively, are effective vaccines that prevent EAMG in rats by inducing anti-idiotypic/clonotypic antibodies (Ab) and lowering levels of AChR Ab. These studies employed keyhole limpet hemocyanin (KLH) as a carrier and complete Freunds adjuvant (CFA). In advance of a clinical trial the present study tested the efficacy of RhCA 611-001 when combined with different adjuvants that are approved for use in humans. Adjuvants chosen for comparison were incomplete Freunds adjuvant (IFA) and aluminum hydroxide (Alum). As a second goal we evaluated diphtheria toxin (DT) as an alternative carrier protein to KLH. Alum was found to be an effective adjuvant, particularly when used with the peptide conjugated to DT. This combination of carrier and adjuvant provided protection against EAMG comparable with that observed with CFA and KLH. Using enzyme-linked immunosorbent assays for Ab against RhCA 611-001, it was found that disease protection is qualitatively, but not quantitatively, related to the anti-peptide Ab response. Our results demonstrate a vaccine formulation that should be useful in the first soon-to-be-conducted clinical trials of peptide vaccines to specifically correct aberrant T and B cell responses in an autoimmune disease.
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Jankovic, D., P. Caspar, M. Zweig, M. Garcia-Moll, S. D. Showalter, F. R. Vogel, and A. Sher. "Adsorption to aluminum hydroxide promotes the activity of IL-12 as an adjuvant for antibody as well as type 1 cytokine responses to HIV-1 gp120." Journal of Immunology 159, no. 5 (September 1, 1997): 2409–17. http://dx.doi.org/10.4049/jimmunol.159.5.2409.
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Abstract A series of protocols were tested to examine the adjuvant effects of IL-12 on humoral and type 1 cytokine responses elicited in mice by recombinant gp120 envelope protein from HIV-1. This Ag fails to induce detectable Ab responses when administered s.c. alone, but stimulates low Ab levels when combined with aluminum hydroxide (alum). Moreover, when i.p. injected rIL-12 was included in the immunization, no increase in Ab production was observed. Importantly, optimal gp120 Ab responses were achieved by immunizing mice s.c. with gp120 and rIL-12 simultaneously coadsorbed to alum. These animals displayed a highly polarized, type 1 cytokine profile, with the emergence of anti-gp120 Ig belonging to the IgG2 and IgG3 isotypes. In addition, a major increase occurred in Ab of the IgG1 subclass. The superior adjuvant activity of alum-adsorbed IL-12 compared with that of the free cytokine correlated with the prolonged detection of IFN-gamma in the sera of animals immunized using the former procedure. In related experiments, in vitro neutralization of IL-12 was shown to inhibit IFN-gamma production by spleen cells from mice immunized with gp120 plus alum, but not by splenocytes from mice primed in the presence of IL-12, suggesting that the latter protocol induces a stable type 1 phenotype. These studies demonstrate that presentation of IL-12 on alum enhances its immunomodulatory effects and establish a protocol for the use of the cytokine as an adjuvant for simultaneously promoting both humoral Ab and type 1 cytokine responses.
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Vaughn, Marla, Bernadette Callejo, Tracy Hill, and Jeffery Fairman. "Vaccine with cationic lipid DNA adjuvant (JVRS-100) provides durable protection against heterosubtypic influenza strain (45.15)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 45.15. http://dx.doi.org/10.4049/jimmunol.184.supp.45.15.
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Abstract Influenza A infection causes annual substantial morbidity and mortality worldwide. Current vaccines, are administered either unadjuvanted or adjuvanted with aluminum hydroxide (alum). Efficacy is highly dependent on close matching of the hemagglutinin and neuraminidase surface proteins of the vaccine with currently circulating virus. The optimal adjuvant for influenza would elicit a robust, durable antibody response and provide protection against strains of drifted or heterosubtypic strains of influenza. An adjuvant consisting of cationic lipid DNA complexes (JVRS-100) has been evaluated with whole inactivated influenza in mice. Heat-inactivated HKx31 (H3N2) or PR/8/34 (H1N1) influenza virus (5µg) with or without the JVRS-100 adjuvant (20µg) alone was administered intramuscularly at week 0 and 2. At three months post the final injection animals were either terminated for immunogenicity tests or challenged intranasally with live HKx31 (1xMLD50). Vaccination with JVRS-100 resulted in a significant increase in hemagglutination inhibiting (HAI) antibodies and an IgG2a isotype switch compared to virus alone. Furthermore, the animals vaccinated with the heterosuptypic strain plus adjuvant had decreased morbidity and mortality compared to the non-adjuvanted group. The results suggest that the JVRS-100 adjuvant increases the magnitude, durability and quality of the immune response, making it an attractive candidate for adjuvanting influenza vaccines.
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Schmidt, Michael, Gregory Papastoitsis, Howard Kaufman, Darrell Irvine, and K. Wittrup. "721 Intratumoral immunotherapy with aluminum hydroxide-tethered IL-12 induces potent local and systemic immunity with minimal toxicity." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A750. http://dx.doi.org/10.1136/jitc-2021-sitc2021.721.
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BackgroundInterleukin-12 (IL-12) is a potent pro-inflammatory cytokine that promotes Th1 skewing, IFNγ expression, T- and NK-cell activation, and antigen presentation. In animal models, IL-12 can elicit robust anti-tumor responses through activation of both innate and adaptive immunity. However, clinical translation of IL-12 has been hindered by significant immune-related toxicity when delivered systemically, necessitating low doses that are often insufficient for efficacy. Intratumoral (IT) administration can expand the therapeutic window of IL-12 by increasing the local tumor concentration relative to systemic exposure but is in turn limited by rapid vascular and lymphatic clearance of injected drug from the tumor and corresponding systemic accumulation. Here we describe an approach to locally retain intratumorally administered IL-12 by complexing it to the common vaccine adjuvant aluminum hydroxide (alum) through a novel phosphopeptide linkage.MethodsSingle-chain murine IL-12 (mIL12) was genetically fused at its c-terminus to a short alum-binding peptide (ABP) that is specifically phosphorylated on multiple serines when co-expressed with the kinase Fam20C. Phosphorylated mIL12-ABP proteins were complexed with a 10x mass excess of aluminum hydroxide through a naturally occurring ligand exchange reaction between the phosphoserines in the ABP and surface hydroxyl groups on alum. mIL12-ABP/alum complexes were characterized for in vitro potency and in vivo efficacy in multiple syngeneic tumor models including MC38, CT26, A20, 4T1, and B16F10 following IT administration. Immune analyses and re-challenge experiments are in progress.Results mIL12-ABP is phosphorylated on multiple sites when co-expressed with Fam20C and is stably retained on aluminum hydroxide in vitro under elution conditions containing phosphate and serum. Alum-bound mIL12-ABP remains active in cellular assays with a 3–4 fold increase in EC50 compared to free protein. Following intratumoral administration, the mIL12-ABP/alum complexes have significantly extended tumor retention compared to unmodified mIL12, leading to potent local immune activation for >1 week. One or two doses of IT administered mIL12-ABP/alum is sufficient to induce robust monotherapy efficacy in diverse syngeneic tumor models including cold tumors resistant to checkpoint blockade and other immunotherapies. Locally administered mIL12-ABP/alum is further able to prime a systemic immune response leading to efficacy against non-injected tumors and spontaneous metastases. Doses required for optimal efficacy are well tolerated in mice with no significant weight loss or other evidence of systemic toxicity.ConclusionsAnkyra's platform is a differentiated approach to expand the therapeutic window of IL-12 and other cytokine drugs by enhancing tumor retention following IT administration.
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Li, Dongdong, Mengjie Xu, Gaotian Li, Yu Zheng, Yong Zhang, Dandan Xia, Shaoning Wang, and Yan Chen. "Mg/Al-LDH as a nano-adjuvant for pertussis vaccine: a evaluation compared with aluminum hydroxide adjuvant." Nanotechnology 33, no. 23 (March 17, 2022): 235102. http://dx.doi.org/10.1088/1361-6528/ac56f3.
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Abstract Background. Layered double hydroxide (LDH) has been demonstrated as a highly efficient antigen platform to induce effective and durable immune response. However, whether LDH nanoparticles could act as an adjuvant for pertussis vaccines is still unknown. Here we evaluated the potential of Mg/Al-LDH as a nano-adjuvant to improve immune response against pertussis and compared it with commercial aluminum hydroxide (AH) adjuvant. Method. The Mg/Al-LDH nanoparticles were synthesized by a hydrothermal reaction. The morphology, structure and size of Mg/Al-LDH were characterized by transmission electron microscope, x-ray diffraction and MALVERN particle analysis. The ovalbumin and Pertussis toxin (PTd) was adsorbed to Mg/Al-LDH. The immune response of antigen-LDH complex was evaluated in mice, compared with commercial adjuvant alum. Hematoxylin-eosin staining was used to evaluate the inflammatory response at injection site. Results. The synthetic Mg/Al-LDH nanoparticles showed a typical hexagonal lamellar structure. The average size of synthetic nanoparticles was 102.9 nm with PDI of 0.13 and zeta potential was 44.4 mV. Mg/Al-LDH nanoparticles effectively adsorbed protein antigen and mediated antigen uptake by DC cells. Animal experiments showed that Mg/Al-LDH gave enhancement in anti-pertussis toxin (PTd) humoral immune response, which was considerable to commercial AH adjuvant. Finally, Mg/Al-LDH produced a slighter inflammatory response than AH at injection site and this injury was quickly recovered. Conclusion. Our study demonstrated the potential of Mg/Al-LDH as an effective adjuvant for pertussis vaccine, which induced comparable antibody response and had a better safety compared with commercial AH adjuvant.
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Cui, Xuemei, Xiangfei Xu, Pan Huang, Guolian Bao, and Yan Liu. "Safety and Efficacy of the Bordetella bronchiseptica Vaccine Combined with a Vegetable Oil Adjuvant and Multi-Omics Analysis of Its Potential Role in the Protective Response of Rabbits." Pharmaceutics 14, no. 7 (July 8, 2022): 1434. http://dx.doi.org/10.3390/pharmaceutics14071434.
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Infectious respiratory diseases caused by Bordetella bronchiseptica (Bb) are seriously endangering the development of the rabbit industry in China. Unfortunately, no licensed vaccines are available for this pathogen. The present study was designed to determine whether the inactivated Bb antigen formulated with vegetable oil adjuvant (named E515) which contains soybean oil, vitamin E, and ginseng saponins, functions as a safe and effective vaccine (E515-Bb) against Bb infection in rabbits. Based on local and systemic reactions, both the E515 adjuvant alone and the E515-Bb vaccine exhibited good safety in rabbits. Immune response analysis implies that rabbits immunized with the E515-Bb vaccine produced significantly higher, earlier, and longer-lasting specific antibody responses and activated Th1/Th2/Th17 cell responses than those immunized with the aluminum hydroxide (Alum)-adjuvanted Bb vaccine (Alum-Bb) or Bb antigen alone. Moreover, the E515-Bb vaccine effectively protected rabbits from Bb infection. Additionally, integrated multi-omics analysis revealed that the immunoprotective effect of the E515-Bb vaccine was achieved through upregulation of the complement and coagulation cascades and cell adhesion molecule (CAM) pathways, and the downregulation of the P53 pathway. Overall, these results indicate that the E515-Bb vaccine is safe, elicits an efficient immune response and provides good protection against Bb infection in rabbits. Thus, the E515-adjuvanted Bb vaccine can be considered a promising candidate vaccine for preventing Bb infection.
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Correa, Victor Araujo, Amanda Izeli Portilho, and Elizabeth De Gaspari. "Immunological Effects of Dimethyldioctadecylammonium Bromide and Saponin as Adjuvants for Outer Membrane Vesicles from Neisseria meningitidis." Diseases 10, no. 3 (July 19, 2022): 46. http://dx.doi.org/10.3390/diseases10030046.
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The meningococcal disease is a global health threat, but is preventable through vaccination. Adjuvants improve meningococcal vaccines and are able to trigger different aspects of the immune response. The present work evaluated the immune response of mice against Neisseria meningitidis outer membrane vesicles (OMV) complexed with the adjuvants aluminium hydroxide (AH), via subcutaneous route; and dimethyldioctadecylammonium bromide (DDA) or Saponin (Sap), via intranasal/subcutaneous routes. ELISA demonstrated that all adjuvants increased IgG titers after the booster dose, remaining elevated for 18 months. Additionally, adjuvants increased the avidity of the antibodies and the bactericidal titer: OMVs alone were bactericidal until 1:4 dilution but, when adjuvanted by Alum, DDA or Sap, it increased to 1/32. DDA and Sap increased all IgG isotypes, while AH improved IgG1 and IgG2a levels. Thus, Sap led to the recognition of more proteins in Immunoblot, followed by DDA and AH. Sap and AH induced higher IL-4 and IL-17 release, respectively. The use of adjuvants improved both cellular and humoral immune response, however, each adjuvant contributed to particular parameters. This demonstrates the importance of studying different adjuvant options and their suitability to stimulate different immune mechanisms, modulating the immune response.
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Pravetoni, Marco, Christine Robinson, Shirdi E. Schmiel, and Daniel L. Mueller. "Alum adjuvant is more effective than MF59 in promoting early germinal center formation in response to peptide-protein conjugates and enhancing efficacy of candidate vaccines against opioid abuse in adult and old mice." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 181.20. http://dx.doi.org/10.4049/jimmunol.200.supp.181.20.
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Abstract Heroin and prescription opioid abuse and overdose have been declared a national emergency in the United States. Compared to current medications, vaccines provide a complementary long-lasting, safe and cost-effective therapeutic strategy. Since the efficacy of vaccines against drugs of abuse is contingent upon achieving high antibody levels in immunized subjects, this study tested whether vaccines against oxycodone were more effective when formulated in the well-established aluminum hydroxide or the squalene-based oil-in-water emulsion MF59 adjuvant. Alum was more effective in inducing early expansion of hapten-specific germinal center (GC) B cells, and in inducing oxycodone-specific serum IgG antibodies that were effective in blocking oxycodone-induced motor activity in BALB/c adult mice. Alum was also more effective than MF59 in promoting early, but not late, differentiation of antigen-specific MHCII-restricted GC-Tfh cells in C57Bl/6 adult mice immunized with a model peptide-protein conjugate vaccine. Finally, alum and MF59 adjuvants displayed equivalent stimulation of hapten-specific B cells and peptide-specific T cells in old mice. Alum was significantly more effective, or at least equivalent to MF59 in eliciting protective responses against the highly-abused prescription opioid oxycodone and inducing early germinal center formation in response to hapten and peptide antigens in both adult and aging mice.
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Hong, David K., Stella Chang, Crystal M. Botham, Thierry D. Giffon, Jeffery Fairman, and David B. Lewis. "Cationic Lipid/DNA Complex-Adjuvanted Influenza A Virus Vaccination Induces Robust Cross-Protective Immunity." Journal of Virology 84, no. 24 (October 13, 2010): 12691–702. http://dx.doi.org/10.1128/jvi.00769-10.
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ABSTRACT Influenza A virus is a negative-strand segmented RNA virus in which antigenically distinct viral subtypes are defined by the hemagglutinin (HA) and neuraminidase (NA) major viral surface proteins. An ideal inactivated vaccine for influenza A virus would induce not only highly robust strain-specific humoral and T-cell immune responses but also cross-protective immunity in which an immune response to antigens from a particular viral subtype (e.g., H3N2) would protect against other viral subtypes (e.g., H1N1). Cross-protective immunity would help limit outbreaks from newly emerging antigenically novel strains. Here, we show in mice that the addition of cationic lipid/noncoding DNA complexes (CLDC) as adjuvant to whole inactivated influenza A virus vaccine induces significantly more robust adaptive immune responses both in quantity and quality than aluminum hydroxide (alum), which is currently the most widely used adjuvant in clinical human vaccination. CLDC-adjuvanted vaccine induced higher total influenza virus-specific IgG, particularly for the IgG2a/c subclass. Higher levels of multicytokine-producing influenza virus-specific CD4 and CD8 T cells were induced by CLDC-adjuvanted vaccine than with alum-adjuvanted vaccine. Importantly, CLDC-adjuvanted vaccine provided significant cross-protection from either a sublethal or lethal influenza A viral challenge with a different subtype than that used for vaccination. This superior cross-protection afforded by the CLDC adjuvant required CD8 T-cell recognition of viral peptides presented by classical major histocompatibility complex class I proteins. Together, these results suggest that CLDC has particular promise for vaccine strategies in which T cells play an important role and may offer new opportunities for more effective control of human influenza epidemics and pandemics by inactivated influenza virus vaccine.
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Siriwattananon, Konlavat, Suwimon Manopwisedjaroen, Balamurugan Shanmugaraj, Eakachai Prompetchara, Chutitorn Ketloy, Supranee Buranapraditkun, Kittipan Tharakhet, et al. "Immunogenicity Studies of Plant-Produced SARS-CoV-2 Receptor Binding Domain-Based Subunit Vaccine Candidate with Different Adjuvant Formulations." Vaccines 9, no. 7 (July 5, 2021): 744. http://dx.doi.org/10.3390/vaccines9070744.
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Due to the rapid transmission of the coronavirus disease 2019 (COVID-19) causing serious public health problems and economic burden, the development of effective vaccines is a high priority for controlling the virus spread. Our group has previously demonstrated that the plant-produced receptor-binding domain (RBD) of SARS-CoV-2 fused with Fc of human IgG was capable of eliciting potent neutralizing antibody and cellular immune responses in animal studies, and the immunogenicity could be improved by the addition of an alum adjuvant. Here, we performed a head-to-head comparison of different commercially available adjuvants, including aluminum hydroxide gel (alum), AddaVax (MF59), monophosphoryl lipid A from Salmonella minnesota R595 (mPLA-SM), and polyinosinic-polycytidylic acid (poly(I:C)), in mice by combining them with plant-produced RBD-Fc, and the differences in the immunogenicity of RBD-Fc with different adjuvants were evaluated. The specific antibody responses in terms of total IgG, IgG1, and IgG2a subtypes and neutralizing antibodies, as well as vaccine-specific T-lymphocyte responses, induced by the different tested adjuvants were compared. We observed that all adjuvants tested here induced a high level of total IgG and neutralizing antibodies, but mPLA-SM and poly (I:C) showed the induction of a balanced IgG1 and IgG2a (Th2/Th1) immune response. Further, poly (I:C) significantly increased the frequency of IFN-γ-expressing cells compared with control, whereas no significant difference was observed between the adjuvanted groups. This data revealed the adjuvants’ role in enhancing the immune response of RBD-Fc vaccination and the immune profiles elicited by different adjuvants, which could prove helpful for the rational development of next-generation SARS-CoV-2 RBD-Fc subunit vaccines. However, additional research is essential to further investigate the efficacy and safety of this vaccine formulation before clinical trials.
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Brewer, James M., Margaret Conacher, Christopher A. Hunter, Markus Mohrs, Frank Brombacher, and James Alexander. "Aluminium Hydroxide Adjuvant Initiates Strong Antigen-Specific Th2 Responses in the Absence of IL-4- or IL-13-Mediated Signaling." Journal of Immunology 163, no. 12 (December 15, 1999): 6448–54. http://dx.doi.org/10.4049/jimmunol.163.12.6448.
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Abstract Previous studies demonstrate that aluminium hydroxide adjuvant (alum) produces increased Th1 responses in IL-4-deficient mice compared with wild-type animals, although the continued production of IL-5 by spleen cells from these mice also indicates that Th2 responses are induced. In the present study, we demonstrate that alum can induce Th2-associated IL-4 and IL-5 production in the absence of IL-4 signaling in mice deficient in either IL-4Rα or Stat6. The Th2 responses observed could not be due to IL-13 as IL-13 responses are also impaired in IL-4Rα- and Stat6-deficient mice. We also detected higher levels of IL-4 in IL-4Rα gene-deficient, though not Stat6-deficient, mice compared with their wild-type counterparts. The increased levels of IL-4 could be explained by the IL-4R being unavailable to neutralize this cytokine in IL-4Rα-deficient mice. While levels of IL-5 production in IL-4Rα- or Stat6-deficient mice were similar to IL-4-deficient and wild-type mice, other type 2-associated responses, which are largely or wholly IL-4 dependent, such as the production of IgG1 or IgE Abs, were either reduced or absent. We conclude that alum adjuvants can induce IL-4 production and Th2 responses independently of IL-4 or IL-13, negating the requirement for an early source of IL-4 in the Th2 response induced by this adjuvant.
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Wu, Cheng-Jang, Pin-Hsun Tseng, Cheng-Chi Chan, Sara Quon, Li-Chen Chen, and Ming-Ling Kuo. "OK-432 Acts as Adjuvant to Modulate T Helper 2 Inflammatory Responses in a Murine Model of Asthma." Journal of Immunology Research 2018 (October 8, 2018): 1–9. http://dx.doi.org/10.1155/2018/1697276.
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Enhanced type 2 helper T (Th2) cell responses to inhaled harmless allergens are strongly associated with the development of allergic diseases. Antigen formulated with an appropriate adjuvant can elicit suitable systemic immunity to protect individuals from disease. Although much has been learned about Th1-favored immunomodulation of OK-432, a streptococcal preparation with antineoplastic activity, little is known about its adjuvant effect for allergic diseases. Herein, we demonstrate that OK-432 acts as an adjuvant to favor a systemic Th1 polarization with an elevation in interferon- (IFN-) γ and ovalbumin- (OVA-) immunoglobulin (Ig) G2a. Prior vaccination with OK-432 formulated against OVA attenuated lung eosinophilic inflammation and Th2 cytokine responses that were caused by challenging with OVA through the airway. This vaccination with OK-432 augmented the ratios of IFN-γ/interleukin- (IL-) 4 cytokine and IgG2a/IgG1 antibody compared to the formulation with Th2 adjuvant aluminum hydroxide (Alum) or antigen only. The results obtained in this study lead us to propose a potential novel adjuvant for clinical use such as prophylactic vaccination for pathogens and immunotherapy in atopic diseases.
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Liao, Hung-Chun, Wan-Ling Wu, Chen-Yi Chiang, Min-Syuan Huang, Kuan-Yin Shen, Yu-Ling Huang, Suh-Chin Wu, Ching-Len Liao, Hsin-Wei Chen, and Shih-Jen Liu. "Low-Dose SARS-CoV-2 S-Trimer with an Emulsion Adjuvant Induced Th1-Biased Protective Immunity." International Journal of Molecular Sciences 23, no. 9 (April 28, 2022): 4902. http://dx.doi.org/10.3390/ijms23094902.
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During the sustained COVID-19 pandemic, global mass vaccination to achieve herd immunity can prevent further viral spread and mutation. A protein subunit vaccine that is safe, effective, stable, has few storage restrictions, and involves a liable manufacturing process would be advantageous to distribute around the world. Here, we designed and produced a recombinant spike (S)-Trimer that is maintained in a prefusion state and exhibits a high ACE2 binding affinity. Rodents received different doses of S-Trimer (0.5, 5, or 20 μg) antigen formulated with aluminum hydroxide (Alum) or an emulsion-type adjuvant (SWE), or no adjuvant. After two vaccinations, the antibody response, T-cell responses, and number of follicular helper T-cells (Tfh) or germinal center (GC) B cells were assessed in mice; the protective efficacy was evaluated on a Syrian hamster infection model. The mouse studies demonstrated that adjuvating the S-Trimer with SWE induced a potent humoral immune response and Th1-biased cellular immune responses (in low dose) that were superior to those induced by Alum. In the Syrian hamster studies, when S-Trimer was adjuvanted with SWE, higher levels of neutralizing antibodies were induced against live SARS-CoV-2 from the original lineage and against the emergence of variants (Beta or Delta) with a slightly decreased potency. In addition, the SWE adjuvant demonstrated a dose-sparing effect; thus, a lower dose of S-Trimer as an antigen (0.5 μg) can induce comparable antisera and provide complete protection from viral infection. These data support the utility of SWE as an adjuvant to enhance the immunogenicity of the S-Trimer vaccine, which is feasible for further clinical testing.
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Davis, Heather L., Risini Weeranta, Thomas J. Waldschmidt, Lorraine Tygrett, Joachim Schorr, and Arthur M. Krieg. "CpG DNA Is a Potent Enhancer of Specific Immunity in Mice Immunized with Recombinant Hepatitis B Surface Antigen." Journal of Immunology 160, no. 2 (January 15, 1998): 870–76. http://dx.doi.org/10.4049/jimmunol.160.2.870.
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Abstract Unmethylated CpG dinucleotides in bacterial DNA or synthetic oligodeoxynucleotides (ODN) cause B cell proliferation and Ig secretion, monocyte cytokine secretion, and activation of NK cell lytic activity and IFN-γ secretion in vivo and in vitro. The potent immune activation by CpG ODN suggests possible utility for enhancing immune responses to vaccines. Mice immunized with recombinant hepatitis B virus surface Ag and a CpG ODN as an immune enhancer have titers of Abs against HBsAg (anti-HBs) that are five times higher than those of mice immunized with HBsAg and the standard adjuvant, aluminum hydroxide (alum). Ab titers in mice immunized with HBsAg and both CpG ODN plus alum were 35 times higher than the titers in mice immunized with alum alone, indicating a strong synergistic interaction between the CpG ODN and alum. ODN without CpG motifs had little or no immune-enhancing activity at the doses used herein. Alum induces a Th2 humoral response (mostly IgG1) and no CTL. In contrast, CpG ODN gives a strong Th1 response with predominantly IgG2a Abs and CTL, even when mixed with alum. In vitro studies to determine possible mechanisms of CpG immune-enhancing effects show that CpG ODN induce expression of costimulatory molecules on Ag-presenting cells and drive B cell isotype switching in the appropriate cytokine milieu. These studies demonstrate that CpG ODN are promising new immune enhancers for vaccination applications.
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Pal, Sukumar, Heather L. Davis, Ellena M. Peterson, and Luis M. de la Maza. "Immunization with the Chlamydia trachomatis Mouse Pneumonitis Major Outer Membrane Protein by Use of CpG Oligodeoxynucleotides as an Adjuvant Induces a Protective Immune Response against an Intranasal Chlamydial Challenge." Infection and Immunity 70, no. 9 (September 2002): 4812–17. http://dx.doi.org/10.1128/iai.70.9.4812-4817.2002.
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ABSTRACT Recently, we have shown that a vaccine consisting of a purified preparation of the Chlamydia trachomatis mouse pneumonitis (MoPn) major outer membrane protein (MOMP) and Freund's adjuvant can protect mice against a genital challenge. Here, we wanted to determine if CpG motifs could be used as an immune modulator to the MOMP to induce protection in mice against an intranasal (i.n.) challenge. One-week-old BALB/c mice were immunized intramuscularly and subcutaneously either once or three times at 2-week intervals with MOMP and CpG suspended in aluminum hydroxide (alum). Negative controls received ovalbumin, CpG, and alum. Positive controls were immunized i.n. with C. trachomatis MoPn elementary bodies (EB). Six weeks after the last immunization, mice were challenged i.n. with 104 inclusion-forming units (IFU) of the C. trachomatis MoPn serovar. Mice that received MOMP, CpG, and alum had a strong immune response, as shown by a high titer of serum antibodies to Chlamydia and significant lymphoproliferation of T-cells following stimulation with C. trachomatis EB. After the i.n. challenge mice immunized with MOMP, CpG, and alum showed significantly less body weight loss than the corresponding control mice immunized with ovalbumin, CpG, and alum. Ten days after the challenge the animals were euthanized, their lungs were weighed, and the numbers of IFU in the lungs were determined. The average weight of the lungs of the mice immunized with MOMP, CpG, and alum was significantly less than average weight of the lungs of the mice immunized with ovalbumin, CpG, and alum. Also, the average number of IFU recovered per mouse immunized with MOMP, CpG, and alum was significantly less than the average number of IFU per mouse detected in the mice inoculated with ovalbumin, CpG, and alum. In conclusion, our data show that CpG sequences can be used as an effective adjuvant with the C. trachomatis MoPn MOMP to elicit a protective immune response in mice against a chlamydial respiratory challenge.
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Zhang, Yuntao, Xiaotong Zheng, Wang Sheng, Hongyang Liang, Yuxiu Zhao, Xiujuan Zhu, Rong Yang, et al. "Alum/CpG Adjuvanted Inactivated COVID-19 Vaccine with Protective Efficacy against SARS-CoV-2 and Variants." Vaccines 10, no. 8 (July 29, 2022): 1208. http://dx.doi.org/10.3390/vaccines10081208.
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Since the beginning of the COVID-19 pandemic, numerous variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged, including five variants of concern (VOC) strains listed by the WHO: Alpha, Beta, Gamma, Delta and Omicron. Extensive studies have shown that most of these VOC strains, especially the currently dominant variant Omicron, can escape the host immune response induced by existing COVID-19 vaccines to different extents, which poses considerable risk to the health of human beings around the world. In the present study, we developed a vaccine based on inactivated SARS-CoV-2 and an adjuvant consisting of aluminum hydroxide (alum) and CpG. The immunogenicity and safety of the vaccine were investigated in rats. The candidate vaccine elicited high titers of SARS-CoV-2-spike-specific IgG antibody and neutralizing antibody in immunized rats, which not only neutralize the original SARS-CoV-2, but also showed great cross-neutralization activity against the Beta, Delta and Omicron variants.
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Bogaert, Pieter, Thomas Naessens, Stefaan De Koker, Benoit Hennuy, Jonathan Hacha, Muriel Smet, Didier Cataldo, et al. "Inflammatory signatures for eosinophilic vs. neutrophilic allergic pulmonary inflammation reveal critical regulatory checkpoints." American Journal of Physiology-Lung Cellular and Molecular Physiology 300, no. 5 (May 2011): L679—L690. http://dx.doi.org/10.1152/ajplung.00202.2010.
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Contrary to the T-helper (Th)-2 bias and eosinophil-dominated bronchial inflammation encountered in most asthmatic subjects, other patients may exhibit neutrophil-predominant asthma subphenotypes, along with Th-1 and Th-17 cells. However, the etiology of many neutrophil-dominated asthma subphenotypes remains ill-understood, in part due to a lack of appropriate experimental models. To better understand the distinct immune-pathological features of eosinophilic vs. neutrophilic asthma types, we developed an ovalbumin (OVA)-based mouse model of neutrophil-dominated allergic pulmonary inflammation. Consequently, we probed for particular inflammatory signatures and checkpoints underlying the immune pathology in this new model, as well as in a conventional, eosinophil-dominated asthma model. Briefly, mice were OVA sensitized using either aluminum hydroxide (alum) or complete Freund's adjuvants, followed by OVA aerosol challenge. T-cell, granulocyte, and inflammatory mediator profiles were determined, along with alveolar macrophage genomewide transcriptome profiling. In contrast to the Th-2-dominated phenotype provoked by alum, OVA/ complete Freund's adjuvants adjuvant-based sensitization, followed by allergen challenge, elicited a pulmonary inflammation that was poorly controlled by dexamethasone, and in which Th-1 and Th-17 cells additionally participated. Analysis of the overall pulmonary and alveolar macrophage inflammatory mediator profiles revealed remarkable similarities between both models. Nevertheless, we observed pronounced differences in the IL-12/IFN-γ axis and its control by IL-18 and IL-18 binding protein, but also in macrophage arachidonic acid metabolism and expression of T-cell instructive ligands. These differential signatures, superimposed onto a generic inflammatory signature, denote distinctive inflammatory checkpoints potentially involved in orchestrating neutrophil-dominated asthma.
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Taubman, Martin A., Xiaozhe Han, Karen B. LaRosa, Sigmund S. Socransky, and Daniel J. Smith. "Periodontal Bacterial DNA Suppresses the Immune Response to Mutans Streptococcal Glucosyltransferase." Infection and Immunity 75, no. 8 (May 21, 2007): 4088–96. http://dx.doi.org/10.1128/iai.00623-07.
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ABSTRACT Certain CpG motifs found in bacterial DNA enhance immune responses through Toll-like receptor 9 (TLR-9) and may also demonstrate adjuvant properties. Our objective was to determine if DNA from bacteria associated with periodontal disease could affect the immune response to other bacterial antigens in the oral cavity. Streptococcus sobrinus glucosyltransferase (GTF), an enzyme involved in dental caries pathogenesis, was used as a test antigen. Rowett rats were injected with aluminum hydroxide (alum) with buffer, alum-GTF, or alum-GTF together with either Escherichia coli DNA, Fusobacterium nucleatum DNA, or Porphyromonas gingivalis DNA. Contrary to expectation, animals receiving alum-GTF plus bacterial DNA (P. gingivalis in particular) demonstrated significantly reduced serum immunoglobulin G (IgG) antibody, salivary IgA antibody, and T-cell proliferation to GTF compared to animals immunized with alum-GTF alone. A diminished antibody response was also observed after administration of alum-GTF with the P. gingivalis DNA either together or separately, indicating that physical complexing of antigen and DNA was not responsible for the reduction in antibody. Since TLR triggering by DNA induces synthesis of prospective suppressive factors (e.g., suppressor of cytokine signaling [SOCS]), the effects of P. gingivalis DNA and GTF exposure on rat splenocyte production of SOCS family molecules and inflammatory cytokines were investigated in vitro. P. gingivalis DNA significantly up-regulated SOCS1 and SOCS5 expression and down-regulated interleukin-10 expression by cultured splenocytes. These results suggested that DNA from periodontal disease-associated bacteria did not enhance, but in fact suppressed, the immune response to a protein antigen from cariogenic streptococci, potentially through suppressive SOCS components triggered by innate mechanisms.
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Schellenbacher, Christina, Richard Roden, and Reinhard Kirnbauer. "Chimeric L1-L2 Virus-Like Particles as Potential Broad-Spectrum Human Papillomavirus Vaccines." Journal of Virology 83, no. 19 (July 29, 2009): 10085–95. http://dx.doi.org/10.1128/jvi.01088-09.
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ABSTRACT The amino (N) terminus of the human papillomavirus (HPV) minor capsid protein L2 can induce low-titer, cross-neutralizing antibodies. The aim of this study was to improve immunogenicity of L2 peptides by surface display on highly ordered, self-assembled virus-like particles (VLP) of major capsid protein L1, and to more completely characterize neutralization epitopes of L2. Overlapping peptides comprising amino acids (aa) 2 to 22 (hereafter, chimera or peptide 2-22), 13 to 107, 18 to 31, 17 to 36, 35 to 75, 75 to 112, 115 to 154, 149 to 175, and 172 to 200 of HPV type 16 (HPV16) L2 were genetically engineered into the DE surface loop of bovine papillomavirus type 1 L1 VLP. Except for chimeras 35-75 and 13-107, recombinant fusion proteins assembled into VLP. Vaccination of rabbits with Freund's adjuvanted native VLP induced higher L2-specific antibody titers than vaccination with corresponding sodium dodecyl sulfate-denatured proteins. Immune sera to epitopes within residues 13 to 154 neutralized HPV16 in pseudovirion neutralization assays, whereas chimera 17-36 induced additional cross-neutralization to divergent high-risk HPV18, -31, -45, -52, and -58; low-risk HPV11; and beta-type HPV5 (titers of 50 to 10,000). Aluminum hydroxide-monophosphoryl lipid A (Alum-MPL)-adjuvanted VLP induced similar patterns of neutralization in both rabbits and mice, albeit with 100-fold-lower titers than Freund's adjuvant. Importantly, Alum-MPL-adjuvanted immunization with chimeric HPV16L1-HPV16L2 (peptide 17-36) VLP induced neutralization or cross-neutralization of HPV16, -18, -31, -45, -52, and -58; HPV6 and -11; and HPV5 (titers of 50 to 100,000). Immunization with HPV16 L1-HPV16 L2 (chimera 17-36) VLP in adjuvant applicable for human use induces broad-spectrum neutralizing antibodies against HPV types evolutionarily divergent to HPV16 and thus may protect against infection with mucosal high-risk, low-risk, and beta HPV types and associated disease.
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Yokokawa, Hiroshi, Atsunori Higashino, Saori Suzuki, Masaki Moriyama, Noriko Nakamura, Tomohiko Suzuki, Ryosuke Suzuki, et al. "Induction of humoural and cellular immunity by immunisation with HCV particle vaccine in a non-human primate model." Gut 67, no. 2 (October 26, 2016): 372–79. http://dx.doi.org/10.1136/gutjnl-2016-312208.
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ObjectiveAlthough HCV is a major cause of chronic liver disease worldwide, there is currently no prophylactic vaccine for this virus. Thus, the development of an HCV vaccine that can induce both humoural and cellular immunity is urgently needed. To create an effective HCV vaccine, we evaluated neutralising antibody induction and cellular immune responses following the immunisation of a non-human primate model with cell culture-generated HCV (HCVcc).DesignTo accomplish this, 10 common marmosets were immunised with purified, inactivated HCVcc in combination with two different adjuvants: the classically used aluminum hydroxide (Alum) and the recently established adjuvant: CpG oligodeoxynucleotide (ODN) wrapped by schizophyllan (K3-SPG).ResultsThe coadministration of HCVcc with K3-SPG efficiently induced immune responses against HCV, as demonstrated by the production of antibodies with specific neutralising activity against chimaeric HCVcc with structural proteins from multiple HCV genotypes (1a, 1b, 2a and 3a). The induction of cellular immunity was also demonstrated by the production of interferon-γ mRNA in spleen cells following stimulation with the HCV core protein. These changes were not observed following immunisation with HCVcc/Alum preparation. No vaccination-related abnormalities were detected in any of the immunised animals.ConclusionsThe current preclinical study demonstrated that a vaccine included both HCVcc and K3-SPG induced humoural and cellular immunity in marmosets. Vaccination with this combination resulted in the production of antibodies exhibiting cross-neutralising activity against multiple HCV genotypes. Based on these findings, the vaccine created in this study represents a promising, potent and safe prophylactic option against HCV.
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Tonui, Willy K., J. Santiago Mejia, Lisa Hochberg, M. Lamine Mbow, Jeffrey R. Ryan, Adeline S. T. Chan, Samuel K. Martin, and Richard G. Titus. "Immunization with Leishmania major Exogenous Antigens Protects Susceptible BALB/c Mice against Challenge Infection with L. major." Infection and Immunity 72, no. 10 (October 2004): 5654–61. http://dx.doi.org/10.1128/iai.72.10.5654-5661.2004.
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ABSTRACT The potential of Leishmania major culture-derived soluble exogenous antigens (SEAgs) to induce a protective response in susceptible BALB/c mice challenged with L. major promastigotes was investigated. Groups of BALB/c mice were immunized with L. major SEAgs alone, L. major SEAgs coadministered with either alum (aluminum hydroxide gel) or recombinant murine interleukin-12 (rmIL-12), L. major SEAgs coadministered with both alum and rmIL-12, and L. major SEAgs coadministered with Montanide ISA 720. Importantly and surprisingly, the greatest and most consistent protection against challenge with L. major was seen in mice immunized with L. major SEAgs alone, in the absence of any adjuvant. Mice immunized with L. major SEAgs had significantly smaller lesions that at times contained more than 100-fold fewer parasites. When lymphoid cells from L. major SEAg-immunized mice were stimulated with leishmanial antigen in vitro, they proliferated and secreted a mixed profile of type 1 and type 2 cytokines. Finally, analyses with Western blot analyses and antibodies against three surface-expressed and secreted molecules of L. major (lipophosphoglycan, gp46/M2/PSA-2, and gp63) revealed that two of these molecules are present in L. major SEAgs, lipophosphoglycan and the molecules that associate with it and gp46/M2/PSA-2.
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EL-FAHAM, MARWA H., KATHERINE J. WHEATCROFT-FRANCKLOW, HELEN P. PRICE, JON R. SAYERS, and MICHAEL J. DOENHOFF. "Schistosoma mansoni cercarial elastase (SmCE): differences in immunogenic properties of native and recombinant forms." Parasitology 144, no. 10 (May 8, 2017): 1356–64. http://dx.doi.org/10.1017/s0031182017000658.
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SUMMARYThe Schistosoma mansoni cercarial elastase (SmCE) has previously been shown to be poorly immunogenic in mice. However, a minority of mice were able to produce antibodies against SmCE after multiple immunizations with crude preparations containing the enzyme. These mice were partially protected against challenge infections of S. mansoni. In the present study, we show that in contrast to the poor immunogenicity of the enzymatically active native form of SmCE derived from a crude preparation (cercarial transformation fluid), immunization of CBA/Ca mice with two enzymatically inactive forms, namely purified native SmCE or a recombinant SmCE fused to recombinant Schistosoma japonicum glutathione S-transferase (rSmCE-SjGST), after adsorption onto aluminum hydroxide adjuvant, induced specific anti-SmCE immunoglobulin G (IgG) in all mice within 2 weeks of the second immunization. The IgG antibody response to rSmCE-SjGST was mainly of the IgG1 subclass. These results suggest that inactive forms of the antigen could be used to obtain the optimum immunogenic effects as a vaccine candidate against schistosomiasis. Mice immunized with the rSmCE-SjGST on alum had smaller mean worm burdens and lower tissue egg counts when compared with adjuvant alone- and recombinant SjGST-injected controls. The native SmCE was antigenically cross-reactive with homologous enzymes of Schistosoma haematobium and Schistosoma margrebowiei.
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Dillard, Jake, Sharon Taft-Benz, Audrey C. Knight, Elizabeth J. Anderson, Sanjay Sarkar, Jennifer F. Loome, Katia D. Pressey, Victoria K. Baxter, and Mark T. Heise. "An inactivated SARS-CoV-2 vaccine causes enhanced type 2 inflammation in mice during coronavirus challenge." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 65.28. http://dx.doi.org/10.4049/jimmunol.208.supp.65.28.
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Abstract Inactivated vaccines administered with the adjuvant aluminum hydroxide (Alum) are currently the most widely used COVID-19 vaccines in the world and have been critical to responding to the SARS-CoV-2 pandemic. Although these vaccines are efficacious against homologous virus infection in healthy young adults, the emergence of novel SARS-CoV-2 variants has resulted in significant vaccine breakthrough. Pre-clinical studies with inactivated SARS-CoV-1 and MERS-CoV vaccines have reported enhanced immunopathology upon breakthrough infection, characterized by pulmonary eosinophilia and upregulation of type 2 cytokines. These previous reports therefore raise the concern that inactivated COVID-19 vaccines may cause enhanced immunopathology upon vaccine breakthrough. To investigate this possibility, we vaccinated female BALB/c mice with inactivated SARS-CoV-2 (iCoV2) prior to coronavirus challenge. Although iCoV2 protected mice from severe clinical disease and pulmonary pathology upon homologous challenge with pathogenic SARS-CoV-2, we observed increased pulmonary pathology and pulmonary eosinophilia upon challenge in mice vaccinated with iCoV2 and Alum (iCoV2 + Alum) compared to mice vaccinated with iCoV2 alone. Furthermore, to model vaccine breakthrough upon heterologous coronavirus infection, we challenged iCoV2-vaccinated mice with a zoonotic SARS-like coronavirus (SHC014). Upon SHC014 challenge, iCoV2 + Alum vaccination failed to control virus replication and caused enhanced pulmonary pathology, pulmonary eosinophilia and upregulation of pulmonary type 2 cytokines. Ongoing studies are investigating the mechanism of iCoV2-related immunopathology, including the role of specific iCoV2 antigens. Supported by grants from NIH (K01 OD026529, U19 AI100625, U19 AI109680, and MSTP T32 GM008719), Infectious Disease Drug Discovery Program (ID3), Rapidly Emerging Antiviral Drug Development Initiative (READDI), NCTraCS and Emerging Challenges in Biomedical Research COVID Pilot Award, SOM Junior Investigator Development Award, Department of Pathology and Laboratory Medicine.
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Paoletti, L. C., M. A. Rench, D. L. Kasper, D. Molrine, D. Ambrosino, and C. J. Baker. "Effects of Alum Adjuvant or a Booster Dose on Immunogenicity during Clinical Trials of Group B Streptococcal Type III Conjugate Vaccines." Infection and Immunity 69, no. 11 (November 1, 2001): 6696–701. http://dx.doi.org/10.1128/iai.69.11.6696-6701.2001.
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ABSTRACT Phase 1 and 2 clinical trials of group B streptococcal (GBS) capsular polysaccharide (CPS)-protein conjugate vaccines in healthy adults have demonstrated their safety and improved immunogenicity compared with uncoupled CPSs. Two recent trials sought to determine (i) whether adsorption of conjugate vaccine to aluminum hydroxide would improve immunogenicity and (ii) whether the CPS-specific immunoglobulin G (IgG) response could be boosted by administration of a second dose. Adsorption of GBS type III CPS-tetanus toxoid (III-TT) conjugate vaccine to alum did not improve the immune response to a 12.5-μg dose in healthy adult recipients. Four weeks after vaccination, the geometric mean antibody concentrations (GMCs) for the 15 recipients of III-TT with or without alum were 3.3 and 3.6 μg/ml, respectively. In the second trial, 36 healthy adults vaccinated previously with GBS III-TT conjugate were given a second 12.5-μg dose 21 months later. At 4 weeks after the second dose, the GMCs of type III CPS-specific IgG were similar to those measured 4 weeks after the primary vaccination, suggesting a lack of a booster response. However, 8 (22%) of the 36 participants who had undetectable III CPS-specific IgG (<0.05 μg/ml) before the first dose of III-TT conjugate exhibited a booster response to the second dose, with a fourfold-greater GMC of type III CPS-specific IgG than after the initial immunization. These results suggest that prior natural exposure to type III GBS or a related antigen may be responsible for the brisk IgG response to CPS noted in most adults after vaccination. However, a second dose of GBS III-TT conjugate vaccine may be required for adults whose initial CPS-specific IgG concentrations are very low and would also restore the initial peak-specific III CPS-IgG in responders to previous vaccination.
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Bagnoli, Fabio, Maria Rita Fontana, Elisabetta Soldaini, Ravi P. N. Mishra, Luigi Fiaschi, Elena Cartocci, Vincenzo Nardi-Dei, et al. "Vaccine composition formulated with a novel TLR7-dependent adjuvant induces high and broad protection against Staphylococcus aureus." Proceedings of the National Academy of Sciences 112, no. 12 (March 9, 2015): 3680–85. http://dx.doi.org/10.1073/pnas.1424924112.
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Both active and passive immunization strategies against Staphylococcus aureus have thus far failed to show efficacy in humans. With the attempt to develop an effective S. aureus vaccine, we selected five conserved antigens known to have different roles in S. aureus pathogenesis. They include the secreted factors α-hemolysin (Hla), ess extracellular A (EsxA), and ess extracellular B (EsxB) and the two surface proteins ferric hydroxamate uptake D2 and conserved staphylococcal antigen 1A. The combined vaccine antigens formulated with aluminum hydroxide induced antibodies with opsonophagocytic and functional activities and provided consistent protection in four mouse models when challenged with a panel of epidemiologically relevant S. aureus strains. The importance of antibodies in protection was demonstrated by passive transfer experiments. Furthermore, when formulated with a toll-like receptor 7-dependent (TLR7) agonist recently designed and developed in our laboratories (SMIP.7–10) adsorbed to alum, the five antigens provided close to 100% protection against four different staphylococcal strains. The new formulation induced not only high antibody titers but also a Th1 skewed immune response as judged by antibody isotype and cytokine profiles. In addition, low frequencies of IL-17–secreting T cells were also observed. Altogether, our data demonstrate that the rational selection of mixtures of conserved antigens combined with Th1/Th17 adjuvants can lead to promising vaccine formulations against S. aureus.
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Gärtner, Frank, Frederick W. Alt, Robert J. Monroe, and Katherine J. Seidl. "Antigen-Independent Appearance of Recombination Activating Gene (Rag)-Positive Bone Marrow B Cells in the Spleens of Immunized Mice." Journal of Experimental Medicine 192, no. 12 (December 11, 2000): 1745–54. http://dx.doi.org/10.1084/jem.192.12.1745.
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Splenic B lineage cells expressing recombination activation genes (RAG+) in mice immunized with 4-hydroxy-3-nitrophenyl-acetyl coupled to chicken γ-globulin (NP-CGG) and the adjuvant aluminum-hydroxide (alum) have been proposed to be mature B cells that reexpress RAG after an antigen encounter in the germinal center (GC), a notion supported by findings of RAG expression in peripheral B lymphocyte populations activated in vitro. However, recent studies indicate that these cells might be immature B cells that have not yet extinguished RAG expression. Here, we employ RAG2–green fluorescent protein (GFP) fusion gene knock-in mice to show that RAG+ B lineage cells do appear in the spleen after the administration of alum alone, and that their appearance is independent of T cell interactions via the CD40 pathway. Moreover, splenic RAG+ B lineage cells were detectable in immunized RAG2-deficient mice adoptively transferred with bone marrow (BM) cells, but not with spleen cells from RAG+ mice. Although splenic RAG+ B cells express surface markers associated with GC B cells, we also find the same basic markers on progenitor/precursor BM B cells. Finally, we did not detect RAG gene expression after the in vitro stimulation of splenic RAG− mature B cells with mitogens (lipopolysaccharide and anti-CD40) and cytokines (interleukin [IL]-4 and IL-7). Together, our studies indicate that RAG+ B lineage cells from BM accumulate in the spleen after immunization, and that this accumulation is not the result of an antigen-specific response.
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Yang, Chunfu, William E. Collins, JoAnn S. Sullivan, David C. Kaslow, Lihua Xiao, and Altaf A. Lal. "Partial Protection against Plasmodium vivaxBlood-Stage Infection in Saimiri Monkeys by Immunization with a Recombinant C-Terminal Fragment of Merozoite Surface Protein 1 in Block Copolymer Adjuvant." Infection and Immunity 67, no. 1 (January 1, 1999): 342–49. http://dx.doi.org/10.1128/iai.67.1.342-349.1999.
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ABSTRACT Merozoite surface protein 1 is a candidate for blood-stage vaccines against malaria parasites. We report here an immunization study ofSaimiri monkeys with a yeast-expressed recombinant protein containing the C terminus of Plasmodium vivax merozoite surface protein 1 and two T-helper epitopes of tetanus toxin (yP2P30Pv20019), formulated in aluminum hydroxide (alum) and block copolymer P1005. Monkeys immunized three times with yP2P30Pv20019 in block copolymer P1005 had significantly higher prechallenge titers of immunoglobulin G (IgG) antibodies against the immunogen and asexual blood-stage parasites than those immunized with yP2P30Pv20019 in alum, antigen alone, or phosphate-buffered saline (PBS) (P < 0.05). Their peripheral blood mononuclear cell proliferative responses to immunogen stimulation 4 weeks after the second immunization were also significantly higher than those from the PBS control group (P < 0.05). Upon challenge with 100,000 asexual blood-stage parasites 5 weeks after the last immunization, monkeys immunized with yP2P30Pv20019 in block copolymer P1005 had prepatent periods longer than those for the control alone group (P > 0.05). Three of the five animals in this group also had low parasitemia (peak parasitemia, ≤20 parasites/μl of blood). Partially protected monkeys had significantly higher levels of prechallenge antibodies against the immunogen than those unprotected (P < 0.05). There was also a positive correlation between the prepatent period and titers of IgG antibodies against the immunogen and asexual blood-stage parasites and a negative correlation between accumulated parasitemia and titers of IgG antibodies against the immunogen (P < 0.05). These results indicate that when combined with block copolymer and potent T-helper epitopes, the yeast-expressed P2P30Pv20019 recombinant protein may offer some protection against malaria.
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Martínez-Donato, G., B. Piniella, D. Aguilar, S. Olivera, A. Pérez, Y. Castañedo, L. Alvarez-Lajonchere, et al. "Protective T Cell and Antibody Immune Responses against Hepatitis C Virus Achieved Using a Biopolyester-Bead-Based Vaccine Delivery System." Clinical and Vaccine Immunology 23, no. 4 (February 17, 2016): 370–78. http://dx.doi.org/10.1128/cvi.00687-15.
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ABSTRACTHepatitis C virus (HCV) infection is a major worldwide problem. Chronic hepatitis C is recognized as one of the major causes of cirrhosis, hepatocellular carcinoma, and liver failure. Although new, directly acting antiviral therapies are suggested to overcome the low efficacy and adverse effects observed for the current standard of treatment, an effective vaccine would be the only way to certainly eradicate HCV infection. Recently, polyhydroxybutyrate beads produced by engineeredEscherichia colishowed efficacy as a vaccine delivery system. Here, an endotoxin-freeE. colistrain (ClearColi) was engineered to produce polyhydroxybutyrate beads displaying the core antigen on their surface (Beads-Core) and their immunogenicity was evaluated in BALB/c mice. Immunization with Beads-Core induced gamma interferon (IFN-γ) secretion and a functional T cell immune response against the HCV Core protein. With the aim to target broad T and B cell determinants described for HCV, Beads-Core mixed with HCV E1, E2, and NS3 recombinant proteins was also evaluated in BALB/c mice. Remarkably, only three immunization with Beads-Core+CoE1E2NS3/Alum (a mixture of 0.1 μg Co.120, 16.7 μg E1.340, 16.7 μg E2.680, and 10 μg NS3 adjuvanted in aluminum hydroxide [Alum]) induced a potent antibody response against E1 and E2 and a broad IFN-γ secretion and T cell response against Core and all coadministered antigens. This immunological response mediated protective immunity to viremia as assessed in a viral surrogate challenge model. Overall, it was shown that engineered biopolyester beads displaying foreign antigens are immunogenic and might present a particulate delivery system suitable for vaccination against HCV.
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Baccili, Camila C., Camila Cecilia Martin, Karen N. Silva, Marcílio Nichi, Eduardo F. Flores, Aníbal E. Vercesi Filho, Edviges Maristela Pituco, and Viviani Gomes. "Serological response against bovine herpesvirus and bovine viral diarrhea virus induced by commercial vaccines in Holstein heifers." Pesquisa Veterinária Brasileira 39, no. 11 (November 2019): 870–78. http://dx.doi.org/10.1590/1678-5150-pvb-6208.
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ABSTRACT: Vaccination is a strategy to the prevention and control of reproductive diseases caused by bovine viral diarrhea virus (BVDV) and bovine herpesvirus type 1 (BoHV-1), however the various compositions of commercial vaccines should be evaluated for their ability to induce protection mediated by antibodies. The objective of this research was to evaluate the production of specific neutralizing Abs against BVDV-1 and 2, and BoHV-1 induced by commercial vaccines composed by different adjuvants. Holstein heifers were vaccinated and distributed in three experimental groups: Group I (G1) was vaccinated with a commercial vaccine containing inactivated BVDV-1, BVDV-2 and BoHV-1 diluted in alum hydroxide as adjuvant (n=9); Group II (G2) was vaccinated with an product containing inactivated strains of BVDV-1, BVDV-2, BoHV-1 and BoHV-5 diluted in oil emulsion as adjuvant (n=10); Group III (G3) was vaccinated with a commercial vaccine containing inactivated BVDV-1 and BVDV-2, besides live modified thermosensitive BoHV-1, diluted in Quil A, amphigen and cholesterol (n=10); A control, non-vaccinated group (n=6) was mock vaccinated with saline. Heifers received two subcutaneous doses of 5mL of each commercial vaccine on the right side of the neck, with 21 days interval. Humoral immune response was assessed by the virus neutralization test (VN) against BVDV-1 (NADL and Singer strains), BVDV-2 (SV253 strain) and BoHV-1 (Los Angeles strain) in serum samples collected on vaccination days zero (D0), 21 (D21) and 42 (D42; 21 days after boosting). Neutralizing Abs against BVDV-1 NADL was detected only in D42, regardless of the vaccine used. Similar geometric mean titers (GMT) for BVDV-1 NADL were observed between G1 (log2=5.1) and G3 (log2=5.1). The seroconversion rate (%) was higher in G1 (78%) when compared to G2 (10%) and G3 (40%). For BVDV-1 Singer, it was also possible to detect Abs production in G1 (log2=5.8, 100% seroconversion rate) and G3 (log2=3.5, seroconversion rate = 60%), only after the booster dose (D42). Neutralizing Abs to BVDV-2 (SV253) were detected only in G3, observing 90% seroconversion associated with high titers of Abs (log2=6.7) after the 2nd dose of vaccine (D42). Heifers from G1 and G3 responded to BoHV-1 after the first dose (D21): G1 (log2=2.5, seroconversion rate = 67%) and G3 (log2=0.7, seroconversion rate = 80%). In D42, a higher magnitude response was observed in the heifers from G3 (log2=6.1, 100%) compared with G1 (log2=4.3, 100%) and G2 (log2=2.7, 60%). Based on the data obtained, it can be concluded that the commercial vaccine contained aluminum hydroxide (G1) was most effective in the induction of antibodies against BVDV-1. On the other hand, this vaccine did not induce the production of neutralizing Abs against BVDV-2. Only the heifers from G3 (Quil A, amphigen and cholesterol) generated neutralizing Abs against BVDV-2. The animals that received commercial vaccine containing oil emulsion as adjuvant (G2) had a weak/undetectable response against BVDV-1 and BVDV-2. The best protective response against BoHV-1 was observed in heifers vaccinated with the live modified thermosensitive virus.
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Chen, Keyan, Kui Zhao, Wenqi He, Wei Gao, Chuanbo Zhao, Li Wang, Wei Pan, Deguang Song, Chengli Wang, and Feng Gao. "Comparative Evaluation of Two Hemagglutinating Encephalomyelitis Coronavirus Vaccine Candidates in Mice." Clinical and Vaccine Immunology 19, no. 7 (April 18, 2012): 1102–9. http://dx.doi.org/10.1128/cvi.05716-12.
Full textAbstract:
ABSTRACTPorcine hemagglutinating encephalomyelitis (PHE) is caused by the coronavirus hemagglutinating encephalomyelitis virus (PHE-CoV), and the recent, rapid spread of PHE-CoV in piglets from many countries emphasizes the urgent need for a PHE-CoV vaccine. Here we use a murine model for evaluation of the induction of humoral and cellular immune responses by inactivated and PHE-CoV DNA vaccines in order to define the immune correlates for protection against PHE-CoV. The inactivated vaccine was composed of purified PHE-CoV and aluminum hydroxide gel (alum), which was chosen as an adjuvant because of its long history of safety for human use. The PHE-CoV DNA vaccine was constructed by subcloning the S1 gene of PHE-CoV into the pVAX1 vector to create the recombinant plasmid pV-S1. Our results showed that the inactivated PHE-CoV vaccine (IPV) elicited a high level of humoral immunity, resulting in good protection efficacy against PHE-CoV challenge. The IPV induced the IgG1 subclass of serum antibodies and expression of the cytokine interleukin-4 (IL-4), suggesting that the IPV generated a predominantly Th2-type immune response. The DNA vaccine was found to mediate primarily a cellular immune response with high levels of IgG2a and the cytokines IL-2 and gamma interferon (IFN-γ). However, mice that were vaccinated twice with the DNA vaccine and boosted with the IPV could mount a sufficient neutralizing antibody response against live PHE-CoV, with little variation in IgG1 and IgG2a levels, and showed high levels of IL-2 and IL-4. This response may activate both B and T cells to mount a specific humoral and cellular immune response that could, in turn, elicit a phagocyte-mediated defense against PHE-CoV infections to achieve viral clearance.