Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/02—Bacterial antigens
  • A61K39/08—Clostridium, e.g. Clostridium tetani
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
  • A61K2039/541—Mucosal route
  • A61K2039/542—Mucosal route oral/gastrointestinal
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
  • A61K2039/55511—Organic adjuvants
  • A61K2039/55577—Saponins; Quil A; QS21; ISCOMS

Definitions

• the immune system uses many mechanisms for attacking pathogens; however, not all of these mechanisms are necessarily activated after immunization.
• Protective immunity induced by vaccination is dependent on the capacity of the vaccine to elicit the appropriate immune response to resist or eliminate the pathogen. Depending on the pathogen, this may require a cell- mediated and/or humoral immune response.
• T cells can be separated into subsets on the basis of the cytokines they produce, and that the distinct cytokine profile observed in these cells determines their function.
• This T cell model includes two major subsets: TH-1 cells that produce IL- 2 and interferon
• an adjuvant A substance that enhances the immunogenicity of an antigen with which it is administered is known as an adjuvant.
• lymphokines have been shown to have adjuvant activity, thereby enhancing the immune response to an antigen (Nencioni et al . , J. Immunol . 135:800-804 (1987); EP285441 to Howard et al . ) .
• a purified saponin e.g., QS-21
• TT tetanus toxoid
• OVA ovalbumin
• compositions of the present invention comprising a purified saponin and an antigen, modulate the protective immune response to the antigen; that is, the vaccine composition is capable of quantitatively and/or qualitatively improving the vaccinated host ' s antibody response, and increasing cell -mediated immunity for a protective response to a pathogen.
• This can be accomplished, for example, by increasing the numbers of antibodies produced upon immunization with the antigen (e.g., a quantitative improvement), or by altering the profile of the immune response, such as from a Thl response to a Th2 response (e.g., a qualitative improvement) .
• the invention also pertains to methods for eliciting or increasing a host's humoral and/or cell- mediated immune response, comprising administering to a vertebrate host an effective amount of an immunogenic composition comprising an antigen and a purified saponin in suspension in a physiologically acceptable solution.
• the purified saponin is QS-21.
• the invention also pertains to methods for eliciting or increasing a vaccinate ' s humoral and/or cell-mediated immunity, for a protective immune response, comprising administering to a vertebrate host an effective amount of a vaccine composition comprising an antigen and a purified saponin m suspension in a physiologically acceptable solution.
• the purified saponin is QS-21.
• Figures 1A and IB illustrate the TT-specific IgG ( Figure 1A) and IgM ( Figure IB) antibody titers at specific intervals after co-oral immunization with TT and varying doses of QS-21.
• Figure 2 shows an analysis of the immunoglobulin subclasses produced after co-oral immunization with TT and varying doses of QS-21.
• Figures 3A and 3B show the differential effect of QS-21 doses observed for IgE responses. Responses were detected for both polyclonal ( Figure 3A) and TT-specific ( Figure 3B) IgE responses with 50 ⁇ g QS-21 at day 7, and lower or no IgE responses were detected with 100 and 500 ⁇ g of QS-21, respectively.
• Figure 4 shows an analysis of fecal extracts indicating that 3 of 5 mice generated mucosal anti-TT IgA titers of 1:64 at the 50 ⁇ g dose of QS-21, and minimal IgA responses were detected at the 100 or 500 ⁇ g dosage .
• Figure 5 shows the total serum IgG and subclass endpoint titers at day 42 after administration of 20 ⁇ g TT alone, or 20 ⁇ g TT given intranasally with 20 or 40 ⁇ g of QS-21 to 3 groups of 5 mice. Doses of 15 ⁇ l were given in PBS on day 0, 14, and 28.
• Figure 6 shows the serum TT-specific IgA endpoint titers after administration of 20 ⁇ g TT alone, or 20 ⁇ g TT given intranasally with 20 or 40 ⁇ g of QS-21 to 3 groups of 5 mice. Doses of 15 ⁇ l were given in PBS on day 0, 14, and 28.
• Figures 7A and 7B show the presence of TT-specific IgA (Figure 7A) and IgG ( Figure 7B) in vaginal wash samples after administration of 20 ⁇ g TT alone, or 20 ⁇ g TT given intranasally with 20 or 40 ⁇ g of QS-21 to 3 groups of 5 mice. Doses of 15 ⁇ l were given in PBS on day 0, 14, and 28.
• Figure 8 shows that both spleen and Peyer ' s patches secrete both Thl and Th2 cytokines after C57BL/6 mice were orally immunized at days 0, 7, and 14 with 250 ⁇ g tetanus toxoid and 50 ⁇ g QS-21.
• Figures 9A and 9B show a comparison of cholera toxin (CT) adjuvant and QS-21 adjuvant as oral adjuvants for raising serum antibody titers.
• Figure 9A shows IgM, IgA and IgG titers, which are generally comparable between the two adjuvants (although serum IgA is slightly lower with QS-21 immunization) .
• Figure 9B shows serum IgG isotypes .
• Figures 10A and 10B show the serum IgE response ( Figure 10A) and reciprocal PCA titer (Figure 10B) , measured at days 7, 14, and 21, induced by cholera toxin and QS-21.
• Figure 11 shows an analysis of fecal extracts and vaginal washes for tetanus toxoid-specific IgA.
• Figure 12 shows the mucosal and systemic immune responses to ovalbumin co-orally administered with QS- 21.
• Saponins are glycosidic products composed of a ring structure (the aglycone) to which is attached one or more sugar chains .
• the saponins are grouped together based on several common properties.
• saponins are surfactants which display hemolytic activity and form complexes with cholesterol.
• Saponins are also somewhat structurally diverse, in that the aglycone can be asteroid, triterpenoid or a steroidalalkaloid, and the number of sugars attached to the glycosidic bonds vary. Saponins are found mainly in plants but have also been found in certain marine animals, particularly echinoderms such as starfish and sea cucumbers .
• compositions e.g., vaccine compositions, comprising an antigen and a purified saponin.
• the purified saponin is QS-21.
• the purified saponin is selected from the group consisting of QS-7, QS-17, QS-18, QS-21 and combinations thereof.
• Purified saponins can be produced from crude saponin extracts or partially purified saponin fractions obtained from a variety of sources.
• the term "extract" is intended to encompass both liquid and solid forms.
• the saponin can be obtained from plants of the genus Chrysanthellum (see, for example, U.S. Patent 4,335,113), from the South American tree Quillaja saponaria (e.g., Quillaja saponaria Molina) (see, for example, U.S. Patent 5,057,540), from Aesculus hippocastanum seeds (see, for example, U.S. Patent No. 5,118,671), from Glyccyrrhiza glabra (see, for example, U.S.
• Patent 5,147,859 from Centella asia tica and Terminalia sp . (see, for example, U.S. Patent 5,166,139) and from Chenopodium quinoa (see, for example, U.S. Patent 5, 597, 807) .
• purified saponin is intended to mean a substantially pure saponin which is purified to one or more of the following standards: 1) appearing as only one major carbohydrate staining band on silica gel TLC (EM Science HPTLC Si60) in a solvent system of 40 mM acetic acid in chloroform/methanol/water (60/45/10, v/v/v) ; 2) appearing as only one major carbohydrate staining band on reverse phase TLC (EM Science Silica Gel RP-8) in a solvent system of methanol/water (70/30, v/v) ; or 3) appearing as only one major peak upon reverse-phase HPLC on Vydac C4 (5 ⁇ m particle size, 330
• Saponin preparations can be purified from a suitable source or extract using methods known in the art, such as column chromatography, HPLC, immunoadsorbent techniques, affinity chromatography and immunoprecipitation (see, for example, U.S. Patent Nos. 5,057,540 and 4,501,734).
• column chromatography HPLC
• immunoadsorbent techniques affinity chromatography
• immunoprecipitation see, for example, U.S. Patent Nos. 5,057,540 and 4,501,734.
• the preparation of substantially pure saponins from aqueous extracts of Quillaja saponaria Molina bark is described in U.S. Patent 5,057,540, the teachings of which are incorporated herein by reference in their entirety.
• Purified saponin preparations such as Stimulon ® QS-21, QS-7, QS-17 and QS-18 (also known as QA-21, QA-7, QA-17 and QA-18, respectively) are also commercially available (Aquila Biopharmaceuticals , Inc., Worcester, MA) . Also useful in the present invention are biologically active subunits or fragments of purified saponins. The invention also encompasses the use of natural and pharmaceutically acceptable salts of purified saponins of the invention.
• the antigen of this invention e.g., a bacterial antigen such as tetanus toxoid antigen
• a bacterial antigen such as tetanus toxoid antigen
• this composition can be used to elicit an immune response to the antigen in a vertebrate such as a mammalian host.
• the antigen can be a tetanus toxin or ovalbumin antigen or a portion thereof which retains the ability to stimulate an immune response.
• portions of a given antigen to stimulate an immune response can be assessed by art- recognized methods, such as enzyme immunoassay against specific peptides within a portion to detect antibodies that recognize that particular portion (humoral response) or a delayed-type hypersensitivity assay against specific peptides in that portion to detect cell -mediated immune response thereto.
• the term "antigen" is intended to include a molecule which contains one or more epitopes which stimulate a host's immune system to produce a humoral, cellular and/or secretory immunological response.
• the antigen of the invention can be a subunit antigen, as well as killed, attenuated or inactivated bacteria, viruses, protozoa, fungi, parasites or other microbes.
• the antigen can be, for example, a protein, peptide, polysaccharide, lipid or DNA antigen.
• Suitable antigens can be derived from, for example, Pasteurella, Actinobacillus , Haemophilus, Salmonella and Eimeria species, as well as rotaviruses, herpes viruses (e.g., BHV-1, EHV-1, PRV, parvovirus, rabiesvirus, influenza viruses, parainfluenza viruses, hepatitis viruses, HIV cornaviruses , tumor antigens, hormones, hormone analogs and the like.
• herpes viruses e.g., BHV-1, EHV-1, PRV, parvovirus, rabiesvirus, influenza viruses, parainfluenza viruses, hepatitis viruses, HIV cornaviruses , tumor antigens, hormones, hormone analogs and the like.
• immunological adjuvant activity of a purified saponin can be assessed using methods known in the art, such as ELISAs, hemagglutination assays and neutralization assays.
• immunological adjuvant activity is intended to mean the ability to potentiate an immunological response in a host to which the saponin and antigen are administered.
• the purified saponin will be administered with the antigen, either in the same admixture or composition (see, for example, International Publication No. WO 93/05789), or at the same time but in a separate composition or formulation; however, the purified saponin can be administered prior to or subsequent to the administration of the antigen.
• the purified saponin can be orally administered in the absence of a particular antigen to elicit a non-specific immune response.
• Adjuvant activity includes, but is not limited to, the ability to enhance the immunological response to the antigen by increasing the immunogenicity of the antigen or by reducing the dose or level of antigen required to produce an immune response .
• an "immune response” or “immunological response” to a particular antigen is intended to include the production of a secretory, cellular, humoral or antibody-mediated response to the antigen (or a generalized response) .
• the manifestation of the response in the immunized host can include the production of antibodies (e.g., IgA, IgD, IgE, IgG or IgM antibodies) , proliferation of B and/or T lymphocytes, stimulation of cytotoxic T lymphocytes that recognize antigen-presenting cells, expansion of T cell populations and the potentiation of signals which cause differentiation, activation or growth of cells of the immune system.
• the administration of the purified saponin adjuvants of the invention will cause or result in an enhanced immune response to an antigen of interest.
• "enhanced” is intended to mean that the immune response to the antigen is greater in the presence of the purified saponin than in the absence of the purified saponin.
• Comparisons of immune responses in the presence and absence of purified saponin adjuvants can be performed by routine methods, such as antibody titer comparisons by radioimmunoassay or ELISA of saponin-adjuvanted compositions and appropriate controls.
• Purified saponins can be used as described herein as adjuvants to enhance the immunological response to an antigen or to elicit a non-specific immune response.
• the purified saponin is an oral adjuvant.
• the purified saponin can be used in a composition to immunize a mammal against a particular pathogen or subunit antigen, or to prime an immune response to a particular antigen.
• the method of the present invention comprises administering to a mammal, particularly a human or other primate, an immunologically effective dose of a vaccine composition comprising an antigen, e.g., a tetanus toxoid antigen, and an adjuvant amount of a purified saponin, e.g., QS-21.
• an "adjuvant amount” or an “effective amount” of purified saponin is intended to mean an amount which enhances an immune response to a coadministered antigen, or an amount which stimulates non-specific immunity in the absence of antigen.
• doses of from about 0.5 ⁇ g to about 500 ⁇ g, and more particularly from about 10 ⁇ g to about 100 ⁇ g will typically be effective to provide an adjuvant effect; however, variations in these dosage ranges will occur depending upon the particular purified saponin.
• the particular dosage will depend upon the age, weight and medical condition of the mammal to be treated, as well as on the method of administration. Suitable doses will be readily determined by the skilled artisan.
• the vaccine composition can be optionally administered in a pharmaceutically or physiologically acceptable vehicle, such as physiological or phosphate buffered saline, water, dextrose, ethanol polyols (such as glycerol or propylene glycol) , and combinations thereof.
• a pharmaceutically or physiologically acceptable vehicle such as physiological or phosphate buffered saline, water, dextrose, ethanol polyols (such as glycerol or propylene glycol) , and combinations thereof.
• a pharmaceutically or physiologically acceptable vehicle such as physiological or phosphate buffered saline, water, dextrose, ethanol polyols (such as glycerol or propylene glycol) , and combinations thereof.
• a small amount of detergent may also be included to enhance vaccine stability.
• the vaccine composition may optionally comprise additional components, such as buffering agents, preservatives, emulsifying agents and adjuvants, such as vegetable oils or emulsions thereof, surface active substances, e.g., hexadecylamin, octadecyl amino acid esters, octadecylamine, lysolecithin, dimethyl- dioctadecylammonium bromide, N, -dicoctadecyl-N' -N' bis ( 2 -hydroxyethyl -propane diamine) , methoxyhexadecylglycerol, and pluronic polyols; polyamines, e.g., pyran, dextransulfate, poly IC, carbopol; peptides, e.g., muramyl dipeptide, dimethylglycine, tuftsin; immune stimulating complexes; oil emulsions; lipo
• the antigens of this invention can also be incorporated into liposomes, cochleates, biodegradable polymers such as poly-lactide, poly-glycolide and poly-lactide-co-glycolides, or ISCOMS (immunostimulating complexes), and supplementary active ingredients may also be employed.
• Antigens of the present invention can also be administered in combination with bacterial toxins and their attenuated derivatives as carrier molecules.
• suitable carrier molecules include serum albumins, keyhole limpet hemocyanin, immunoglobulin molecules, immunoglobulin, ovalbumin, polysaccharides (e.g., sepharose, agarose, cellulose), inactive virus particles, and amino acid copolymers.
• the antigens of the invention can also be administered in combination with lymphokines including, but not limited to, interleukin-2, IFN- ⁇ and GM-CSF.
• the antigens of the invention can also be expressed in vivo after administration of DNA encoding these antigens.
• the vaccines can be administered to a human or animal by a variety of routes, including but not limited to parenteral, intraarterial , intradermal, transdermal (such as by the use of slow release polymers) , intramuscular, intraperitoneal , intravenous, subcutaneous, oral and intranasal routes of administration.
• the composition is administered orally.
• the amount of antigen employed in such vaccines will vary depending upon the identity of the antigen. Adjustment and manipulation of established dosage ranges used with traditional carrier antigens for adaptation to the present vaccine is well within the ability of those skilled in the art.
• the vaccines of the present invention are intended for use in the treatment of both immature and adult warm-blooded animals, and, in particular, humans. Typically, the antigen and the purified saponin will be administered at the same time.
• the oral adjuvant action of purified saponins has a number of important implications.
• the oral adjuvanticity of purified saponins can increase the concentration of protective antibodies produced against an oral antigen in the vaccinated organism. As a result, effective vaccination can be achieved with a smaller quantity of antigen than would be normally required. This reduction in the required amount of antigen may lead to more widespread use of vaccines which are difficult and costly to prepare.
• the use of purified saponins as oral adjuvants can enhance the ability of antigens which are weakly antigenic or poorly immunogenic, particularly when administered orally, to elicit an immune response. It may also provide for safer vaccination when the antigen is toxic at the concentration normally required for effective oral immunization. By reducing the amount of antigen, the risk of toxic reaction is reduced. It may also provide for safer vaccination by enabling the use of an antigen or vaccine formulation which is safe by oral route but toxic by parenteral route .
• vaccination regimens call for the administration of antigen over a period of weeks or months in order to stimulate a "protective" immune response.
• a protective immune response is an immune response sufficient to prevent infection or reduce the severity of infection (compared with severity of infection in the absence of the elicited immune response) caused by a particular pathogen or pathogens to which the vaccine is directed.
• the use of purified saponins as adjuvants for an oral antigen may reduce the time course of effective vaccination regimens. In some instances, it may result in the generation of a protective response in a single dose.
• the vaccine compositions of this invention are also useful therapeutically, to reduce the number and severity of symptomatic episodes in subjects already infected with the antigen.
• the vaccine compositions may also be used as an oral booster immunization for parenterally administered antigens.
• a purified saponin e.g., QS-21
• TT tetanus toxoid
• OVA ovalbumin
• a purified saponin, QS-21 has been used in oral immunizations with TT and OVA, and QS-21 has exhibited adjuvant activity by this delivery route.
• the total serum IgG anti-TT antibody responses were comparable to those obtained when cholera toxin (CT) or E. coli heat labile toxin (LT) was administered orally to C57BL/6 mice.
• CT cholera toxin
• LT heat labile toxin
• TT tetanus toxoid
• CT mucosal adjuvant cholera toxin
• LT E . coli heat labile toxin
• mice Prior to immunization, C57BL/6 mice were deprived of food for 2 hours, and 30 minutes before oral immunization they received 0.5 ml of a solution consisting of 8 parts Hank's balanced salt solution and 2 parts 7.5% sodium bicarbonate in order to neutralize stomach acidity. Mice received 250 ⁇ g of TT at days zero 0, 7, 14 together with 50, 100 or 500 ⁇ g of QS-21 in 0.25 ml of PBS by gavage . Serum and fecal extracts were collected at days 7, 15 and 21 and analyzed for TT- specific antibody responses.
• mice generated mucosal anti-TT IgA titers of 1:64 at the 50 ⁇ g dose of QS-21, and minimal IgA responses were detected at the 100 or 500 ⁇ g dosage ( Figure 4) .
• IgA is typically considered to be enhanced by Th2 cytokines, again indicating that higher doses of QS-21 down- regulated the Th2 response.
• C57BL/6 mice were orally immunized at days 0, 7, and 14 with 250 ⁇ g tetanus toxoid and 50 ⁇ g QS-21.
• spleen or Peyer's patch were isolated.
• CD4+ cells were isolated, which were then stimulated with antigen (tetanus toxoid) .
• the antigen stimulated CD4+ cells then secreted cytokines associated with either CD4+ cells of Thl type (cytokines IL-2, and interferon- gamma (IFN-g) or of Th2 type (cytokines IL-4, IL-5, IL- 6, and IL-10) .
• Thl-associated cytokine IFN- gamma is stimulated to >250 pg/ml in Ag-stimulated CD4 cells from Peyer's patches.
• IFN-gamma is stimulated ⁇ 25 pg/ml by oral cholera toxin/TT (data not shown) .
• Figure 9 shows a comparison of cholera toxin (CT) adjuvant and QS-21 adjuvant as oral adjuvants for raising serum antibody titers.
• CT cholera toxin
• QS-21 QS-21 adjuvant as oral adjuvants for raising serum antibody titers.
• a dose of 10 ug cholera toxin was used and a dose of 50 ug QS-21 was used.
• Serum titers were determined after 3 oral immunizations (days 0, 7, 14) , with collection of sera at day 21.
• Figure 9A shows IgM, IgA and IgG titers, which are generally comparable between the two adjuvants although serum IgA is slightly lower with QS-21 immunization.
• Figure 9B shows serum IgG isotypes . Again, the serum titers are comparable although IgGl responses are higher with cholera toxin (consistent with the Th2-induction by this adjuvant) .
• Another marker of a Th2 response is the serum IgE response. This response, measured at days 7, 14, and 21, is induced by cholera toxin and is largely absent with QS-21 ( Figure 10A) .
• PCA passive cutaneous anaphylaxis
• Table 1 shows both the effect of QS-21 of stimulating serum IgG to an oral immunization with tetanus toxoid as well as the positive effect of QS-21 on protection from challenge with tetanus toxin.
• C57BL/6 mice were immunized orally with tetanus toxoid on days 0, 7, and 14. They received 0, 50 or 100 ⁇ g QS- 21 as the adjuvant.
• sera for tetanus toxoid- specific IgG was collected. They were then challenged by subcutaneous route with 1 ug or 100 ug of tetanus toxin (1 or 100 minimum lethal doses, respectively) .
• mice orally immunized on days 0, 7 and 14 with tetanus toxoid (TT) and indicated doses of QS-21 as adjuvant were challenged on day 21 by subcutaneous injection of indicated doses of tetanus toxin in 0.5 ml of PBS- 0.2% gelatin. Death of unprotected mice occurred within 48 hours .
• TT tetanus toxoid
• mice that were orally immunized with tetanus toxoid in absence of QS-21 were not protected from challenge (0 survivors/5 mice receiving 1 ⁇ g tetanus toxin challenge and 0/3 mice receiving 100 ug tetanus toxin challenge) .
• the addition of either 50 or 100 ⁇ g QS-21 to the tetanus toxoid vaccine was then sufficient to protect all mice against challenge with the more rigorous challenge (100 minimum lethal doses of tetanus toxin) .
• FIG. 12 shows that QS-21 can act as an oral adjuvant for enhancement of systemic and mucosal immune response to other orally administered antigens.
• C57BL/6 mice were orally immunized at days 0, 7, and 14 with 500 ⁇ g ovalbumin with or without 50 ⁇ g QS-21.
• QS-21 administration resulted in enhanced serum IgM, IgG, IgA, IgGl and IgG2b titers and fecal IgA titers on samples that were collected at day 21.
• the first protocol consisted of administering 20 ⁇ g TT alone, or 20 ⁇ g TT given with 20 or 40 ⁇ g of QS-21 to 3 groups of 5 mice. Doses of 15 ⁇ l were given in PBS on day 0, 14, and 28. The total serum IgG and subclass endpoint titers at day 42 are shown in Figure 5.
• a second intranasal protocol was initiated during the course of the initial protocol.
• groups of 5 mice were intranasally immunized with 50 ⁇ g TT with and without 40 ⁇ g of QS-21 on days 0, 5 and 14.
• the total antigen-specific IgG levels will be similar to Figure 5;
• the IgG subclass responses were predominately composed of IgGl and IgG2b, although IgG2a is also detected;
• vaginal IgA is elevated in mice given QS-21 (1:32) versus control (1:8) .
• the levels of anti-TT fecal IgA were also examined in this experiment. Intranasal immunization resulted in an endpoint titer of 1:128 on day 21 with TT only and was not further elevated in QS-21-treated mice.

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