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New Advances in Vaccine Technologies and Applications
Vaccine, Vol. 13, No. 16, pp. 1623-1625, 1995 Copyright 0 1995 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0264&410X/95 $lO+O.OO
0264-410X(95)00112-3
Meeting Report New Advances in Vaccine Technologies and Applications 13-15 February 1995, Bethesda, Maryland, USA
This meeting was organized by the International Business Communications, Southborough, MA, USA as its 2nd Annual Conference on vaccines. Approximately 170 scientists from several countries participated in the Conference. The Conference was organized into four sessions: International Commercialization Strategies, Innovative Technological Developments, Delivery Systems and Adjuvant Formulations, and Specific Applications: Challenges and Successes with a Special Guest Presentation by Jonas Salk on “Immunological Memory and Immunity to Diseases” There were 30 other presentations of 25-30 minutes. Commercialization issues The first session on International Commercialization Strategies started a presentation by William with Hausdorff (USAID) describing the role and aims of international agencies such as the Children’s Vaccine Initiative, Global Programme for Vaccines and immunizations in controlling infectious diseases through immunizations; and the obstacles and key issues in the introduction of new and improved vaccines in the developing countries. Variations between developed and developing countries with regard to disease epidemiology, immune responsiveness, immunization schedules, nutritional status, logistical issues in combining new vaccines with the existing vaccines, cost and licensing or technology transfer are key issues needed to be addressed to get the maximum benefits of immunizations in developing countries. The differences between cost of routine vaccines (diphtheria, tetanus and pertussis (DTP) vaccine, oral polio vaccine and measles vaccines) between US private sector and UNICEF (vaccines bought for developing countries) were dramatic: in some cases, more than lOO-fold. It was suggested that employment of research and development strategies, including more extensive use of non-proprietary technology, or decreasing size, could have effects on the cost of new vaccines for developing countries. Though the vaccine cost thus far has not been the major expense for the immunization programme, this may change with the addition of newer vaccines to developing country
schedules. Kenneth Meyers from a law firm outlined the new strategies for obtaining patent protection on vaccine technology with emphasis on effects of the North American Free Trade Agreement (NAFTA) and the General Agreement on Tariffs and Trades (GATT) on US patent law with regard to patent term and first-to-invent versus first-tofile concepts. Robert MacWright, also from a law firm, described the provisions in licensing agreement and how one can get maximum benefits and protection from a licensing agreement. Immunologic memory The scientific programme started with an excellent presentation by Jonas Salk, in which he emphasized the functional dependence of the immune system upon memory. The immune memory may be of cell- or antibody-mediated types which depend upon the dose of antigen and interval between doses. High doses of antigens elicited primarily humoral response with Th2-type cells, whereas low doses of antigens elicited primarily Thl-type cells with cell-mediated response including delayed-type hypersensitivity (DTH). Two doses given at 6-month intervals produced a higher booster response than those given at l-, 2- or 3-month intervals. Jonas mentioned that it takes up to 6 months to get peak memory responses. For cellassociated pathogens, one needs cellmediated immune memory, whereas for cell-free pathogens the humoral response plays an important role. Diseases with shorter incubation periods (for example, influenza) occur despite the presence of memory as compared to those with longer incubation periods (for example, measles). To prevent diseases with shorter incubation periods, high antibody levels are essential. He emphasized that for prevention of HIV, cellmediated immune memory is essential and mentioned that mortality in DTHpositive HIV-positive individuals was much lower than DTH-negative individuals over a period of seven years. Cancer vaccines The majority of the other presentations in three scientific sessions described
the use of different adjuvants or delivery systems for development of new vaccines against infectious diseases and cancer. The use of various adjuvants and delivery systems such as liposomes, biodegradable polymer microspheres, bacterial or viral vectors was repeatedly mentioned in most of the presentations. Jeffrey Scholm (NIH) described the development of recombinant vaccine for cancer immunotherapy by inserting genes coding for a tumor-associated antigen into vaccinia virus. This construct elicited anti-tumor responses in a murine model and T-cell responses in mice and non-human primates. Phase I clinical trial in patients with carcinomas showed induction of specific T-cell responses. Mice and monkeys did not show any toxicity with a vaccinia-based construct, whereas humans showed typical reactions of smallpox vaccine at the site of injection. Robert Chestnut (Cytel Corporation) described the use of disease-specific antigenic peptides to induce cytotoxic T lymphocytes (CTL) for the prevention and treatment of infectious diseases and cancer. Typically 8-10 amino acid peptides binding major histocompatibility complex (MHC) are identified and then modified to make them immunogenic. Mark Reddish (Biomira, Inc.) talked about an approach for active specific immunotherapy of adenocarcinomas using synthetic carbohydrate, peptide and glycopeptide epitopes coupled to keyhole limpet hemocyanin (KLH). Phase I and II clinical trials with the formulation showed responses in breast and ovarian cancer patients. Further studies are being planned with an adjuvant formulation which would generate CTL- and Thl-type cells. This kind of treatment would be most effective when used with low doses of chemotherapeutic agents and other response modifiers such as cytokines. DNA vaccines Jeffery Ulmer (Merck) gave a comprehensive view about the DNA vaccines. On the advantages of DNA vaccines, he enlisted the stimulation of CTL responses, persistence of antigen thus producing long-lived immune response, generation of conformational epitope, and technology being a more predictable and valuable research tool. On safety, his major concerns were integration with chromosomal DNA, autoimmune diseases, immune tolerance and gene toxicity. Several unresolved issues include mechanism of DNA internalization, nature of antigen-presenting cells, DNA formulations and safety.
Vaccine 1995 Volume 13 Number 16 1623
Meeting Report: R.K. Gupta HIV vaccines On the development of HIV vaccines, the use of adjuvants in modulating the immune response was emphasized by various speakers. Deborah Birx (Walter Reed Army Institute of Research) analysed the humoral and cellular epitopes after natural infection and identification of additional recognition sites after immune manipulation. She summarized various Phase I HIV vaccine trials and emphasized on the role of cell-mediated immunity in protection against HIV. Chris Walker (Biocine/Chiron) described the induction of both humoral and cellular immunity (CTL) with recombinant gpl20 envelope protein formulation with MF59 adjuvant. Karl Hasel (Progenies Pharmaceuticals) presented comparative immunogenicity of alum and Ribi’s Detox Adjuvant with gpl20. He showed that Ribi’s Detox Adjuvant was superior to alum with regard to the humoral response in guinea pigs and elicited higher T-cell responses in mice. Alum did not induce any CTL, whereas Ribi’s adjuvant showed CTL responses. Frederick Vogel (NIAID), in his nice review on different adjuvants and modulation of immune response by adjuvants, presented comparative data on adjuvants including aluminum hydroxide, MF59, Syntex adjuvant formulation, a mixture of liposomes/monophosphoryl lipid A (MPL)/alum, MPL/squalene and QS21 with recombinant gpl20 in monkeys and humans. Different adjuvant formulations did not behave similarly in monkeys and humans. Fred emphasized on the role of adjuvants in the development of vaccines against HIV and described a rabbit model for evaluating safety and immunogenicity of new adjuvant formulations. Vaccine adjuvants and delivery systems Continuing on the role of adjuvants in modulating the immune response to antigen, Michael Powell gpl20 (Genetech) comparatively analysed the antibody response in guinea pigs to gpl20 given with various adjuvants: alum, complete Freund’s adjuvant, Syntex adjuvant formulation, MF59, QS21 and biodegradable polymer microspheres. All adjuvants elicited higher anti-gp120 antibodies than Al(OH), but the neutralizing antibodies showed much variation among various adjuvants. QS21 showed more persistence of antibodies than alum in baboons. Biodegradable microspheres with encapsulated QS21 and gpl20 antigen showed higher antibody responses than those with gpl20 antigen alone or antigen adsorbed onto aluminum hydroxide. Justin Hanes (MIT) reviewed the use of polymer microspheres for vaccine delivery. The vaccine antigens may be targeted to mucosal surfaces or may be released in continuous or pulsatile manners after
1624
parenteral injection. He emphasized on the polymers with intrinsic adjuvant activity to achieve the goal of developing single dose vaccines. I showed data on the encapsulation of tetanus toxoid in biodegradable polymer microspheres and emphasized the problems of instability of tetanus toxoid during encapsulation, during storage of microspheres and during hydration of microspheres. Tetanus toxoid in the microspheres elicited similar response in mice and guinea pigs to aluminum-adsorbed vaccine. For obtaining higher responses with microencapsulated tetanus toxoid, need for other adjuvants inside or mixed with microspheres was stressed. Data were also shown on the adjuvanticity of nonphospholipid liposomes in rabbits and with diphtheria and tetanus mice toxoids. Tetanus toxoid encapsulated inside these non-phospholipid liposomes elicited more persistent antibody response in mice than antigen mixed with liposomes. Stanley Cryz (Swiss Serum and Vaccine Institute) described a novel liposome system called virosome (glorified liposomes) prepared by incorporating the hemagglutinin of influenza A into phosphatidylcholine and phosphatidylethanoleamine liposomes. Virosomes with influenza hemagglutinins or with hepatitis A virus antigens were significantly more immunogenic in humans than conventional vaccines. Virosomes were safe in humans without any induction of anti-phospholipid antibodies. Other presentations on adjuvants made at the meeting included physicochemical characterization of aluminum adjuvants by Philip Klepak (Reheis, Inc.) with emphasis on the effect of charge on aluminum adjuvants, particle morphology and surface area on the adsorption of antigens onto aluminum adjuvants and their adjuvant properties. John Clements (Tulane University) described the mutant heat labile (LT) enterotoxin from E. coli as an oral adjuvant. The mutant LT toxin was non-toxic and was devoid of ADPribosyltransferase activity. LT differed from cholera toxin (CT) with regard to chemical, biological and adjuvant properties. LT induced a mixture of Thl and Th2 responses, whereas CT induced a Th2-type response only. Shahida Baqar (Naval Medical Research Institute) described the effect of interleukins as mucosal adjuvants when given orally in mice with Campylobacter jejuni. Interleukins administered orally retained their biological activity and showed adjuvant effect with killed bacteria. Jon Rudbach (Ribi ImmunoChem Research) gave a nice review of MPL as an adjuvant with vaccines composed of proteins and polysaccharide-protein conjugates. MPL with or without trehalose diester (TDM) or cell-wall skeleton from Myco-
Vaccine 1995 Volume 13 Number 16
bacterium elicited CTL and DTH responses. Subclass of IgG antibodies could be modulated with the use of these adjuvants. Jon proposed a mechanism of adjuvant action of MPL by early production of interferon y leading to stimulation of Thl cells. Charlotte Kensil (Cambridge Biotech Corporation) reviewed the development and properties of QS21 adjuvant which is water-soluble and stable to freeze-drying and lyophilization. QS21 elicited the production of highest levels of IL-2 and interferon 2’as compared with alum and complete Freund’s adjuvant. QS21 exhibited adjuvanticity in mice, guinea-pigs, rabbits, dogs, monkeys, baboons and man. Polysaccharide-protein conjugate and combination vaccines Ali Fattom (Univax Biologics) discussed various methods of conjugating polysaccharides to proteins which affected their immunogenicity. The immune response to polysaccharideprotein conjugates was further modulated by the use of adjuvants such as MPL, QS21 and non-phospholipid liposomes. Ali further discussed the specific application of conjugates made from the capsular polysaccharide of StapltJdococcal aureus. These conjugates were immunogenic in hemodialysis patients. Antibodies to capsular polysaccharide were opsonophagocytic. Peter Paradiso (Lederle-Praxis Biologicals) gave a nice overview of combining vaccine antigens. DTP vaccine with conjugate vaccine from the capsular polysaccharide of Haemophilus injuenzae type b (Hib) has already been licensed in the US and promising results of combining DTP vaccine containing acellular pertussis vaccine with Hib conjugate vaccine were shown. Data were presented on combining conjugate vaccines from capsular polysaccharides from pneumococcal types. Combination strategies included: (1) vaccine for meningitis containing Hib conjugate and conjugates from pneumococcal and meningococcal capsular polysaccharides; (2) vaccine for otitis media would contain pneumococcal conjugates, nontypable H. injfuenzae vaccine, respiratory syncytial virus (RSV) vaccine, influenza vaccine; and (3) vaccine for viral pneumonia would have RSV, influenza, parainfluenza and adenovirus vaccines. The use of adjuvants including MPL and biodegradable polymer microspheres was also described to reduce the dose of antigens in combination vaccines. Bacterial vectors Bryan Roberts (Virus Research Institute) reviewed the use of the watersoluble polyphosphazene polymer as an adjuvant for vaccine antigen and showed that influenza hemagglutinins with
Meeting polyphosphazene adjuvant elicited high levels of long-lasting functional antibodies. Polyphosphazene was found to be a good adjuvant with other antigens including gp120. In the second part of his talk, Bryan described the development of live oral Vibrio cholerae for use as vector for delivering antigens and also as a vaccine against cholera. The live vaccine against cholera showed safety and efficacy in volunteers challenged with virulent V. cholerae. Plasmid bearing O-antigen from Shigelh sonnei expressed in V. cholerne showed immunogenicity and protection in rabbits orally fed with the construct. The use of recombinant BCG as a vector for antigens to elicit systemic and mucosal immune responses was elegantly described by Solomon Langermann (MedImmune, Inc.). Vaccination with recombinant BCG produced highly sustained, protective humoral IgG responses against a variety of antigens. Mark Hansen (MedImmune, Inc.) described the development of vaccines against Lyme disease based on Borreliu outer membrane lipoproteins, particularly OspA. Subunit OspA vaccines in alum or in other formulations are in clinical trials. The use of BCG as a vector for a vaccine for Lyme disease was also described. Myron Levine (University of Maryland) gave a nice overview of the live vaccines against
cholera, typhoid and shigellosis by using recombinant organisms. The attenuated organisms have been shown to be welltolerated, immunogenic and protective after a single dose in humans. The organisms can also be used as vectors for delivering other antigens. John Clements described that oral delivery of Sulmoneh vaccine vectors elicited a cellmediated immune response with upregulation of IL-12. Dennis Hruby (M6 Pharmaceuticals) described genetically engineered commensal bacteria Streptococcus gordonii to express conserved determinants of the M protein of Streptococcus pyogenes. Other proteins which have been expressed in Streptococcus gordonii include peptide from gp120 containing V3 loop and T-helper epitope, T- and B-cell epitopes from foot and mouth disease virus and Ag5.2 hornet toxin. Subunit vaccines Thomas Monath (Oravax) described the development of a subunit oral vaccine against Helicobacter pylori. The vaccine comprising of urease, a major surface-exposed protein of the bacteria, was delivered orally with a mucosal adjuvant (CT or LT) and showed mucosal immune response and protection in animals. The vaccine is under Phase I clinical trial. The meeting ended with a
Report:
R.K. Gupta
presentation by Steven Mento (Viagene, Inc.) on the prospects of developing retrovector gene transfer products. These products can be used for the treatment of severe viral infections, cancers and other diseases. The conference was followed by a half-day workshop on Clinical Trial Design for Vaccines which is not covered in this report. Conclusion The conference provided an introduction and update of technologies being evaluated for developing new vaccines. The important message from the conference was that the adjuvants and delivery systems are the key to the success of new vaccines. Adjuvants and delivery systems can modulate the immune system to the desired type required for a particular disease. Another message was that the results obtained in animals with different adjuvants do not necessarily reproduce in humans. It may be worthwhile to go to clinical trials once the safety and toxicology profiles of new formulations are established. Rajesh K. Gupta Massachusetts Public Health Biologic Laboratories, Boston, MA 02130, USA
Vaccine
1995 Volume
13 Number
16 1625
0264-410X(95)00112-3
Meeting Report New Advances in Vaccine Technologies and Applications 13-15 February 1995, Bethesda, Maryland, USA
This meeting was organized by the International Business Communications, Southborough, MA, USA as its 2nd Annual Conference on vaccines. Approximately 170 scientists from several countries participated in the Conference. The Conference was organized into four sessions: International Commercialization Strategies, Innovative Technological Developments, Delivery Systems and Adjuvant Formulations, and Specific Applications: Challenges and Successes with a Special Guest Presentation by Jonas Salk on “Immunological Memory and Immunity to Diseases” There were 30 other presentations of 25-30 minutes. Commercialization issues The first session on International Commercialization Strategies started a presentation by William with Hausdorff (USAID) describing the role and aims of international agencies such as the Children’s Vaccine Initiative, Global Programme for Vaccines and immunizations in controlling infectious diseases through immunizations; and the obstacles and key issues in the introduction of new and improved vaccines in the developing countries. Variations between developed and developing countries with regard to disease epidemiology, immune responsiveness, immunization schedules, nutritional status, logistical issues in combining new vaccines with the existing vaccines, cost and licensing or technology transfer are key issues needed to be addressed to get the maximum benefits of immunizations in developing countries. The differences between cost of routine vaccines (diphtheria, tetanus and pertussis (DTP) vaccine, oral polio vaccine and measles vaccines) between US private sector and UNICEF (vaccines bought for developing countries) were dramatic: in some cases, more than lOO-fold. It was suggested that employment of research and development strategies, including more extensive use of non-proprietary technology, or decreasing size, could have effects on the cost of new vaccines for developing countries. Though the vaccine cost thus far has not been the major expense for the immunization programme, this may change with the addition of newer vaccines to developing country
schedules. Kenneth Meyers from a law firm outlined the new strategies for obtaining patent protection on vaccine technology with emphasis on effects of the North American Free Trade Agreement (NAFTA) and the General Agreement on Tariffs and Trades (GATT) on US patent law with regard to patent term and first-to-invent versus first-tofile concepts. Robert MacWright, also from a law firm, described the provisions in licensing agreement and how one can get maximum benefits and protection from a licensing agreement. Immunologic memory The scientific programme started with an excellent presentation by Jonas Salk, in which he emphasized the functional dependence of the immune system upon memory. The immune memory may be of cell- or antibody-mediated types which depend upon the dose of antigen and interval between doses. High doses of antigens elicited primarily humoral response with Th2-type cells, whereas low doses of antigens elicited primarily Thl-type cells with cell-mediated response including delayed-type hypersensitivity (DTH). Two doses given at 6-month intervals produced a higher booster response than those given at l-, 2- or 3-month intervals. Jonas mentioned that it takes up to 6 months to get peak memory responses. For cellassociated pathogens, one needs cellmediated immune memory, whereas for cell-free pathogens the humoral response plays an important role. Diseases with shorter incubation periods (for example, influenza) occur despite the presence of memory as compared to those with longer incubation periods (for example, measles). To prevent diseases with shorter incubation periods, high antibody levels are essential. He emphasized that for prevention of HIV, cellmediated immune memory is essential and mentioned that mortality in DTHpositive HIV-positive individuals was much lower than DTH-negative individuals over a period of seven years. Cancer vaccines The majority of the other presentations in three scientific sessions described
the use of different adjuvants or delivery systems for development of new vaccines against infectious diseases and cancer. The use of various adjuvants and delivery systems such as liposomes, biodegradable polymer microspheres, bacterial or viral vectors was repeatedly mentioned in most of the presentations. Jeffrey Scholm (NIH) described the development of recombinant vaccine for cancer immunotherapy by inserting genes coding for a tumor-associated antigen into vaccinia virus. This construct elicited anti-tumor responses in a murine model and T-cell responses in mice and non-human primates. Phase I clinical trial in patients with carcinomas showed induction of specific T-cell responses. Mice and monkeys did not show any toxicity with a vaccinia-based construct, whereas humans showed typical reactions of smallpox vaccine at the site of injection. Robert Chestnut (Cytel Corporation) described the use of disease-specific antigenic peptides to induce cytotoxic T lymphocytes (CTL) for the prevention and treatment of infectious diseases and cancer. Typically 8-10 amino acid peptides binding major histocompatibility complex (MHC) are identified and then modified to make them immunogenic. Mark Reddish (Biomira, Inc.) talked about an approach for active specific immunotherapy of adenocarcinomas using synthetic carbohydrate, peptide and glycopeptide epitopes coupled to keyhole limpet hemocyanin (KLH). Phase I and II clinical trials with the formulation showed responses in breast and ovarian cancer patients. Further studies are being planned with an adjuvant formulation which would generate CTL- and Thl-type cells. This kind of treatment would be most effective when used with low doses of chemotherapeutic agents and other response modifiers such as cytokines. DNA vaccines Jeffery Ulmer (Merck) gave a comprehensive view about the DNA vaccines. On the advantages of DNA vaccines, he enlisted the stimulation of CTL responses, persistence of antigen thus producing long-lived immune response, generation of conformational epitope, and technology being a more predictable and valuable research tool. On safety, his major concerns were integration with chromosomal DNA, autoimmune diseases, immune tolerance and gene toxicity. Several unresolved issues include mechanism of DNA internalization, nature of antigen-presenting cells, DNA formulations and safety.
Vaccine 1995 Volume 13 Number 16 1623
Meeting Report: R.K. Gupta HIV vaccines On the development of HIV vaccines, the use of adjuvants in modulating the immune response was emphasized by various speakers. Deborah Birx (Walter Reed Army Institute of Research) analysed the humoral and cellular epitopes after natural infection and identification of additional recognition sites after immune manipulation. She summarized various Phase I HIV vaccine trials and emphasized on the role of cell-mediated immunity in protection against HIV. Chris Walker (Biocine/Chiron) described the induction of both humoral and cellular immunity (CTL) with recombinant gpl20 envelope protein formulation with MF59 adjuvant. Karl Hasel (Progenies Pharmaceuticals) presented comparative immunogenicity of alum and Ribi’s Detox Adjuvant with gpl20. He showed that Ribi’s Detox Adjuvant was superior to alum with regard to the humoral response in guinea pigs and elicited higher T-cell responses in mice. Alum did not induce any CTL, whereas Ribi’s adjuvant showed CTL responses. Frederick Vogel (NIAID), in his nice review on different adjuvants and modulation of immune response by adjuvants, presented comparative data on adjuvants including aluminum hydroxide, MF59, Syntex adjuvant formulation, a mixture of liposomes/monophosphoryl lipid A (MPL)/alum, MPL/squalene and QS21 with recombinant gpl20 in monkeys and humans. Different adjuvant formulations did not behave similarly in monkeys and humans. Fred emphasized on the role of adjuvants in the development of vaccines against HIV and described a rabbit model for evaluating safety and immunogenicity of new adjuvant formulations. Vaccine adjuvants and delivery systems Continuing on the role of adjuvants in modulating the immune response to antigen, Michael Powell gpl20 (Genetech) comparatively analysed the antibody response in guinea pigs to gpl20 given with various adjuvants: alum, complete Freund’s adjuvant, Syntex adjuvant formulation, MF59, QS21 and biodegradable polymer microspheres. All adjuvants elicited higher anti-gp120 antibodies than Al(OH), but the neutralizing antibodies showed much variation among various adjuvants. QS21 showed more persistence of antibodies than alum in baboons. Biodegradable microspheres with encapsulated QS21 and gpl20 antigen showed higher antibody responses than those with gpl20 antigen alone or antigen adsorbed onto aluminum hydroxide. Justin Hanes (MIT) reviewed the use of polymer microspheres for vaccine delivery. The vaccine antigens may be targeted to mucosal surfaces or may be released in continuous or pulsatile manners after
1624
parenteral injection. He emphasized on the polymers with intrinsic adjuvant activity to achieve the goal of developing single dose vaccines. I showed data on the encapsulation of tetanus toxoid in biodegradable polymer microspheres and emphasized the problems of instability of tetanus toxoid during encapsulation, during storage of microspheres and during hydration of microspheres. Tetanus toxoid in the microspheres elicited similar response in mice and guinea pigs to aluminum-adsorbed vaccine. For obtaining higher responses with microencapsulated tetanus toxoid, need for other adjuvants inside or mixed with microspheres was stressed. Data were also shown on the adjuvanticity of nonphospholipid liposomes in rabbits and with diphtheria and tetanus mice toxoids. Tetanus toxoid encapsulated inside these non-phospholipid liposomes elicited more persistent antibody response in mice than antigen mixed with liposomes. Stanley Cryz (Swiss Serum and Vaccine Institute) described a novel liposome system called virosome (glorified liposomes) prepared by incorporating the hemagglutinin of influenza A into phosphatidylcholine and phosphatidylethanoleamine liposomes. Virosomes with influenza hemagglutinins or with hepatitis A virus antigens were significantly more immunogenic in humans than conventional vaccines. Virosomes were safe in humans without any induction of anti-phospholipid antibodies. Other presentations on adjuvants made at the meeting included physicochemical characterization of aluminum adjuvants by Philip Klepak (Reheis, Inc.) with emphasis on the effect of charge on aluminum adjuvants, particle morphology and surface area on the adsorption of antigens onto aluminum adjuvants and their adjuvant properties. John Clements (Tulane University) described the mutant heat labile (LT) enterotoxin from E. coli as an oral adjuvant. The mutant LT toxin was non-toxic and was devoid of ADPribosyltransferase activity. LT differed from cholera toxin (CT) with regard to chemical, biological and adjuvant properties. LT induced a mixture of Thl and Th2 responses, whereas CT induced a Th2-type response only. Shahida Baqar (Naval Medical Research Institute) described the effect of interleukins as mucosal adjuvants when given orally in mice with Campylobacter jejuni. Interleukins administered orally retained their biological activity and showed adjuvant effect with killed bacteria. Jon Rudbach (Ribi ImmunoChem Research) gave a nice review of MPL as an adjuvant with vaccines composed of proteins and polysaccharide-protein conjugates. MPL with or without trehalose diester (TDM) or cell-wall skeleton from Myco-
Vaccine 1995 Volume 13 Number 16
bacterium elicited CTL and DTH responses. Subclass of IgG antibodies could be modulated with the use of these adjuvants. Jon proposed a mechanism of adjuvant action of MPL by early production of interferon y leading to stimulation of Thl cells. Charlotte Kensil (Cambridge Biotech Corporation) reviewed the development and properties of QS21 adjuvant which is water-soluble and stable to freeze-drying and lyophilization. QS21 elicited the production of highest levels of IL-2 and interferon 2’as compared with alum and complete Freund’s adjuvant. QS21 exhibited adjuvanticity in mice, guinea-pigs, rabbits, dogs, monkeys, baboons and man. Polysaccharide-protein conjugate and combination vaccines Ali Fattom (Univax Biologics) discussed various methods of conjugating polysaccharides to proteins which affected their immunogenicity. The immune response to polysaccharideprotein conjugates was further modulated by the use of adjuvants such as MPL, QS21 and non-phospholipid liposomes. Ali further discussed the specific application of conjugates made from the capsular polysaccharide of StapltJdococcal aureus. These conjugates were immunogenic in hemodialysis patients. Antibodies to capsular polysaccharide were opsonophagocytic. Peter Paradiso (Lederle-Praxis Biologicals) gave a nice overview of combining vaccine antigens. DTP vaccine with conjugate vaccine from the capsular polysaccharide of Haemophilus injuenzae type b (Hib) has already been licensed in the US and promising results of combining DTP vaccine containing acellular pertussis vaccine with Hib conjugate vaccine were shown. Data were presented on combining conjugate vaccines from capsular polysaccharides from pneumococcal types. Combination strategies included: (1) vaccine for meningitis containing Hib conjugate and conjugates from pneumococcal and meningococcal capsular polysaccharides; (2) vaccine for otitis media would contain pneumococcal conjugates, nontypable H. injfuenzae vaccine, respiratory syncytial virus (RSV) vaccine, influenza vaccine; and (3) vaccine for viral pneumonia would have RSV, influenza, parainfluenza and adenovirus vaccines. The use of adjuvants including MPL and biodegradable polymer microspheres was also described to reduce the dose of antigens in combination vaccines. Bacterial vectors Bryan Roberts (Virus Research Institute) reviewed the use of the watersoluble polyphosphazene polymer as an adjuvant for vaccine antigen and showed that influenza hemagglutinins with
Meeting polyphosphazene adjuvant elicited high levels of long-lasting functional antibodies. Polyphosphazene was found to be a good adjuvant with other antigens including gp120. In the second part of his talk, Bryan described the development of live oral Vibrio cholerae for use as vector for delivering antigens and also as a vaccine against cholera. The live vaccine against cholera showed safety and efficacy in volunteers challenged with virulent V. cholerae. Plasmid bearing O-antigen from Shigelh sonnei expressed in V. cholerne showed immunogenicity and protection in rabbits orally fed with the construct. The use of recombinant BCG as a vector for antigens to elicit systemic and mucosal immune responses was elegantly described by Solomon Langermann (MedImmune, Inc.). Vaccination with recombinant BCG produced highly sustained, protective humoral IgG responses against a variety of antigens. Mark Hansen (MedImmune, Inc.) described the development of vaccines against Lyme disease based on Borreliu outer membrane lipoproteins, particularly OspA. Subunit OspA vaccines in alum or in other formulations are in clinical trials. The use of BCG as a vector for a vaccine for Lyme disease was also described. Myron Levine (University of Maryland) gave a nice overview of the live vaccines against
cholera, typhoid and shigellosis by using recombinant organisms. The attenuated organisms have been shown to be welltolerated, immunogenic and protective after a single dose in humans. The organisms can also be used as vectors for delivering other antigens. John Clements described that oral delivery of Sulmoneh vaccine vectors elicited a cellmediated immune response with upregulation of IL-12. Dennis Hruby (M6 Pharmaceuticals) described genetically engineered commensal bacteria Streptococcus gordonii to express conserved determinants of the M protein of Streptococcus pyogenes. Other proteins which have been expressed in Streptococcus gordonii include peptide from gp120 containing V3 loop and T-helper epitope, T- and B-cell epitopes from foot and mouth disease virus and Ag5.2 hornet toxin. Subunit vaccines Thomas Monath (Oravax) described the development of a subunit oral vaccine against Helicobacter pylori. The vaccine comprising of urease, a major surface-exposed protein of the bacteria, was delivered orally with a mucosal adjuvant (CT or LT) and showed mucosal immune response and protection in animals. The vaccine is under Phase I clinical trial. The meeting ended with a
Report:
R.K. Gupta
presentation by Steven Mento (Viagene, Inc.) on the prospects of developing retrovector gene transfer products. These products can be used for the treatment of severe viral infections, cancers and other diseases. The conference was followed by a half-day workshop on Clinical Trial Design for Vaccines which is not covered in this report. Conclusion The conference provided an introduction and update of technologies being evaluated for developing new vaccines. The important message from the conference was that the adjuvants and delivery systems are the key to the success of new vaccines. Adjuvants and delivery systems can modulate the immune system to the desired type required for a particular disease. Another message was that the results obtained in animals with different adjuvants do not necessarily reproduce in humans. It may be worthwhile to go to clinical trials once the safety and toxicology profiles of new formulations are established. Rajesh K. Gupta Massachusetts Public Health Biologic Laboratories, Boston, MA 02130, USA
Vaccine
1995 Volume
13 Number
16 1625