AIDS RESEARCH AND HUMAN RETROVIRUSES Volume 8, Number 8, 1992 Mary Ann Liebert, Int., Publishers
Summary: Adjuvants/Clinical Trials Working Group CARL R.
ALVING,1
MARTA
GLASS,2
Downloaded by Gothenburg University Library from www.liebertpub.com at 01/24/19. For personal use only.
BACKGROUND
A
scientists was convened in an open workshop to assess the most recent advances in adjuvant reserch, to identify the challenges and problems associated with an adjuvanted HIV vaccine, and to formulate an agenda for the future aimed at identifying effective adjuvants for use in an AIDS vaccine. Five major questions were highlighted for discussion: panel OF international
1. Are adjuvants necessary: What is the historical background? How do adjuvants work? 2. What should be the strategies and goals? 3. What is allowable (oxicity? 4. What are the regulatory issues? 5. What adjuvants are available currently and what should be the future directions?
The following summary presents highlights from the spirited flow of discussion that involved both the panelists themselves and many participants from the audience. This was not meant to be a comprehensive review of the field.
ARE ADJUVANTS NECESSARY? WHAT IS THE HISTORICAL BACKGROUND? There is a critical need for adjuvants. Modern biotechnology has produced a wonderful profusion of unique, safe, simplified, and useful synthetic antigens. Although safety has been achieved by simplification, this has resulted in greatly reduced immunogenicity of most synthetic antigens when compared to the epitopes as they occur on the original organisms. An important role of adjuvants is to increase the complexity of the formulation that is presented to the immune system and to do this in a safe manner. Certain live vaccines may not require adjuvants because of constant antigen presentation. Certain living vectors may provide an adjuvant effect but this may not be adequate since most live vectors are not persistent. Under some
and BARBARA
DETRICK3
conditions live vectors can also present safety problems. Because HIV is a weak immunogen, synthetic epitopes that are used as antigens almost certainly will require adjuvants. There is a long and successful history of use of adjuvants in humans. The only adjuvant licensed for use in the United States is an aluminum salt adjuvant (alum). It has been in use since 1940 and generates protective antibody responses in some vaccines but has only modest adjuvant activity in certain other vaccines. Currently, alum is used in DPT and hemophilus vaccines. Alum is not recognized as an adjuvant for inducing effective cell-mediated immune responses. When used in boosting injections, as in tetanus toxoid booster, it can sometimes cause swelling of the arm. When given by subcutaneous inoculation, alum can cause reactogenicity. Therefore, intramuscular injection is the recommended route of administration. Although there can be differences among different formulations of alum, this adjuvant is the benchmark for comparison of all other adjuvants in humans. Incomplete Freund's adjuvant (IFA) is an adjuvant that has been widely used in human trials around the world. The panel members suggested that IFA was a more potent adjuvant than alum. This adjuvant contains a nonbiodegradable mineral oil and a heterogeneous stabilizer that contains mannide monooleate (Arlacel A). In the 1950s IFA was given to tens of thousands of persons as a component of polio and influenza vaccines in the United States. Initial difficulties, particularly with IFA in a cholera vaccine that was used for 18 months in the Philippines, resulted in instances of tissue breakdown due to liberation of free fatty acids from the Arlacel A. However, batches of IFA that did not induce liberation of free fatty acids have had minimal toxic effects in humans. Studies with male Swiss mice have indicated the IFA adjuvant may be involved in the induction of tumors. However, follow-up studies conducted by the Institute of Medicine on humans injected, particularly among individuals in the U.S. military, have not revealed any increases in tumors or autoimmune diseases among those who received vaccines containing IFA; in fact the life span of vaccinated individuals has been longer. It was felt by the workshop panelists that IFA is more toxic when formulated with bacteria than with viruses. Because of concerns about reactoge-
'Department of Membrane Biochemistry. Walter Reed Army Institute of Research, Washington, DC 20307-5100. Division of AIDS. National Allergy and Infectious Deseases. Bethesda. MD 02892. 'Department of Pathology. George Washington University Medical Center.
Institute of
Washington.
DC 20037.
1427
ALVINO ET AL.
1428
mechanism. It is therefore important to analyze the desired goals for each vaccine being developed and to devise a rational approach using one or more adjuvants by analysis of adjuvant mechanisms. Reconstitution of membrane-associated antigens with adjuvants or carriers can result in different types of immunological presentation. Soluble antigens may be presented to lymphocytes, dendritic cells, and macrophages, while paniculate antigen formulations may be presented only to phagocytic cells, such as macrophages. The intracellular processing of antigen by APCs can determine whether antibody production or cytotoxic T lymphocytes (CTLs) will be the induced. Generally, antigens that are present in the cytoplasm, (e.g., viral and tumor antigens) have a capability of inducing CTLs, while exogenous extracellular antigens such as bacteria may have a capability of inducing antibodies but not CTLs. Liposomes can stimulate both production of antibodies and CTLs, and it is thought that liposomes can cause both major histocompatibility complex (MHC) class 1-dependent and class Il-dependent immune responses. Immune stimulatory complexes (ISCOMS) also have the ability to induce CTLs. In considering the possibility of developing a vaccine for individuals who are HIV + it was felt that the first vaccine injection would actually consist of a boosting immunization since the individuals are already primed. In this case cellmediated immunity, particularly induction of CTLs, may be more important than antibody production. It was pointed out that although polio is an example of a vaccine that relies on humoral immunity, an HIV vaccine would need an adjuvant that induces both humoral and cellular immunity.
nicity IFA has been withdrawn as a candidate for widespread use as a general adjuvant for human use, but it does have potential applicability for use in HIV individuals. One exercise that was attempted by the workship participants was to identify a long list of potential adjuvants. These adjuvants were identified by panel and audience members based on previous animal and human studies (Table 1). Extension of the list was constrained by the time available for compilation and the list is not meant to be comprehensive. Nevertheless, this list underscores the diversity of the numerous adjuvant approaches that might be possible. MECHANISMS OF ADJUVANT ACTIONS
Downloaded by Gothenburg University Library from www.liebertpub.com at 01/24/19. For personal use only.
The mechanisms of adjuvant action •
•
are numerous, some are:
Depot effect for slow release of antigen Effects on antigen-presenting cells (APCs) Targeting to APCs Activation of APCs Recruitment of APCs (including helper and suppressor
lymphocytes)
• •
,
Reconstitution of antigen and exposure of new Induction of cytokines
epitopes
A useful strategy in developing a vaccine formulation would be not to rely on a single adjuvant and not to be dependent on a single underlying mechanism of adjuvant action. Combinations of adjuvants could take advantage of more than one adjuvant
Table 1. Partial List
of
Possible Adjuvants (shown proposed by
in the order that they were
participants)
Alum
Incomplete Freund's adjuvant (IFA) Liposomes Liposomes (containing MPL) + Alum Monophosphoryl lipid A (MPL) Muramyl tripeptide-phosphatidylethanolamine (MTP-PE) (Biocine) Muramyl dipeptide (MDP) M DP + IFA
Threonyl MDP + oil + pluronic block polymer (Syntex adjuvant formulation, SAF) Keyhole limpet hemocyanin (KLH) + alum MPL + oil + cell walls (Detox) (Ribi ImmunoChem
Research)
Interferon—alpha Interferon—gamma Glycoprotein of Klebsiella pneumoniae Immunostimulating complexes (ISCOMS) Liposomes (containing MTP-PE) QS-21 (saponin-like component from Quil A) (Cambridge Biotech) Interleukin 1 (IL-1) Nonionic block polymer (L 180) (CytRx) Aluminum + human growth factor Guanosine analogues Cholera toxin Lipospheres (fat core with surface-imbedded Cholesterol derivatives Virus envelope proteins Tween
phospholipids) (Nova Pharmaceutical)
ADJUVANTS/CLINICAL TRIALS WORKING GROUP The question arose as to the importance of the half-life of the antibody and the rapidity of the immune response desired. A considerable time may be rquired for induction of effective memory cells. Memory response after injection of polio vaccine may require 6 to 12 months. Adjuvants can drive modulation of accessory T cells, or may change the relative balance of helper and suppressor T cells and this can greatly influence the time course of the immune response. Monophosphoryl lipid A has the capability of overcoming suppressor T-cell activity.
Downloaded by Gothenburg University Library from www.liebertpub.com at 01/24/19. For personal use only.
SAFETY AND TOXICITY OF ADJUVANTS As noted earlier, various adjuvants may be associated with local reactogenicity, mainly at the site of injection. Systemic effects can also occur, mainly due to stimulation of cytokines, such as interleukin 1 (IL-1). Lipid A is an example of an adjuvant that has considerable ability to cause systemic toxicities. The most effective way to monitor the toxicities of adjuvants containing lipid A is through pyrogenicity testing in rabbits. Adjuvants that pass pyrogenicity testing are much less likely to be toxic in humans. For monitoring endotoxic reactions pyrogenicity testing (but not merely Limulus lysate assay) should be sufficient as a quality control test for a vaccine; however, IL-6 secretion can be useful for following toxic effects in humans. It was also pointed out that tolerable reactogenicity of adjuvants may differ considerably for HIV+ and HIV~ individuals. For this reason, different adjuvants may be required for different vaccinated populations. There was some disagreement among the panel members as to whether reactogenicity should be ignored as an important factor at this time because of the urgency of the AIDS epidemic. On the one hand, the reasoning was put forth that for a killed vaccine in disease-free people safety would be a more important issue than efficacy, but for development of an HIV vaccine, efficacy was more important than safety, particularly for HIV+ individuals. Those who pursued this line of reasoning concluded that immediate testing in humans should not have to wait for extensive scientific inquiries into adjuvant mechanisms and toxicities. On the other hand, a representative of the pharmaceutical industry disagreed with this approach and pointed out that pharmaceutical companies will always be very sensitive to potential liability issues. Cooperation by pharmaceutical companies will be critical in the development of HIV vaccines, and regardless of the efficacy of a given vaccine the enthusiasm for development of vaccines containing toxic adjuvants will be greatly limited. Overall the feeling was expressed that companies would not be willing to take on the responsibilities of liability even if scientists and the population as a whole would wish them to do so.
IMPACT OF REGULATORY ISSUES ON ADJUVANT DEVELOPMENT It was pointed out that, from a regulatory standpoint, the mandate of the U.S. Food and Drug Administration is to protect the public from the harmful side effects of products, rather than to actively develop drugs or vaccines. However, there was
1429
general accord that the FDA would be willing to take whatever measures might be possible to facilitate adjuvant development. It was also pointed out that the investigational new drug application (IND) and the final license application are very different regulatory processes. Both safety and adjuvant activity
in the form of immunostimulation must be documented in order license. A question arose concerning the potential for the development of generic adjuvants that could be widely used with different antigens. However, a possible drawback of this approach may be the lack of benefits to volunteers injected with adjuvants alone, and this might limit the licensing of adjuvants in the absence of a specific vaccine. In addition, the adjuvant might or might not work in a formulation with a given antigen, again limiting the development of an adjuvant by itself. to obtain a
CURRENT REPERTOIRE OF ADJUVANTS
Adjuvant formulations that have gained current popularity for human vaccine trials include the following (those that were discussed are listed below, along with some brief comments that arose in the discussion): • •
Alum IFA: It
felt that this should be used as an adjuvant in HIV for immunotherapy. As a result of this, data would be obtained at the same time on the effectiveness of IFA as an adjuvant for prophylactic immunization. Monophosphoryl lipid A (MPL) (partially detoxified lipid A): This adjuvant has been used intramuscularly with oil (Detox formulation) or water. The Detox formulation has produced both humoral and cell-mediated immunity in cancer patients, and also has been used in malaria vaccine trials. was
séropositives
•
•
•
•
Muramyl tripeptide-phosphatidylethanolamine (MTP-PE).
This adjuvant is reactogenic. However, it is an active adjuvant that increases antibody responses when compared with alum. Liposomes (containing MPL) + alum: In a malaria vaccine trial in humans this adjuvant gave high antibody titers against a poorly immunogenic synthetic antigen. It had low reactogenicity and was well tolerated. When used in mice the liposomal formulation induced CTLs. Muramyl dipeptide (MDP): This adjuvant has been tested in the United States. It apparently had no significant side effects. It stimulated humoral activity, but studies on cell-mediated
immunity were not performed. DIRECTIONS FOR THE FUTURE AND DISCUSSION OF THE ROLE OF THE NATIONAL INSTITUTES OF HEALTH
Although vaccinology is flowering, one must focus on the immediate issues required by the crisis of the AIDS epidemic. The panel members agreed that there is a variety of avenues to pursue in the selection of an appropriate adjuvant(s) for use in an HIV vaccine. An effective and safe adjuvanted HIV vaccine should be one which induces comprehensive and long-lasting immunity, including mucosal immunity. However, there was
ALVING ET AL.
1430 among the group that the end point for an in an HIV vaccine should be prevention of disease rather than prevention of infection. Over the years the Vaccine Research & Development Branch (VRDB), Division of AIDS, National Institute of Allergy and Infectious Diseases has had a strong commitment to adjuvant research. To that end, they have focused their efforts on identifying new and novel adjuvants and expanding the understanding of the mechanisms of adjuvant action. Recently, a large comparative adjuvant study also was set up for systematic, direct comparison of potentially promising adjuvants in the SIV model. Finally, the VRDB currently is sponsoring Phase I clinical trials of selected adjuvants in humans. It is anticipated that insights gleaned from this workshop will help to encourage ongoing strategies of the VRDB as well as to provide new suggestions that will help to expedite the identification of effective adjuvants that will be used in an HIV vaccine.
also
a consensus
Downloaded by Gothenburg University Library from www.liebertpub.com at 01/24/19. For personal use only.
adjuvant
ADJUVANT WORKSHOP PARTICIPANTS Organizer: Dr. Barbara Detrick; Chair: Dr. Carl R. Alving; Participants: Dr. Abram Benenson, Dr. David Chernoff, Dr.
Barbara Detrick, Dr. Michel DeWilde, Dr. Diño Dina, Dr. Raphael Dolin, Dr. Friedrich Dorner, Dr. Robert Edelman, Dr. Robert Hunter, Dr. Raphael Mannino, Dr. Thomas Merigan, Dr. Mark Newman, Dr. Abe Osterhaus, Dr. Jon Rudbach, Dr. Jonas Salk, and Dr. Gayle Smith
Address
reprint requests
to:
Carl R. Alving Department of Membrane Biochemistry Walter Reed Army Institute of Research Washington. DC 20307-5100
Summary: Adjuvants/Clinical Trials Working Group CARL R.
ALVING,1
MARTA
GLASS,2
Downloaded by Gothenburg University Library from www.liebertpub.com at 01/24/19. For personal use only.
BACKGROUND
A
scientists was convened in an open workshop to assess the most recent advances in adjuvant reserch, to identify the challenges and problems associated with an adjuvanted HIV vaccine, and to formulate an agenda for the future aimed at identifying effective adjuvants for use in an AIDS vaccine. Five major questions were highlighted for discussion: panel OF international
1. Are adjuvants necessary: What is the historical background? How do adjuvants work? 2. What should be the strategies and goals? 3. What is allowable (oxicity? 4. What are the regulatory issues? 5. What adjuvants are available currently and what should be the future directions?
The following summary presents highlights from the spirited flow of discussion that involved both the panelists themselves and many participants from the audience. This was not meant to be a comprehensive review of the field.
ARE ADJUVANTS NECESSARY? WHAT IS THE HISTORICAL BACKGROUND? There is a critical need for adjuvants. Modern biotechnology has produced a wonderful profusion of unique, safe, simplified, and useful synthetic antigens. Although safety has been achieved by simplification, this has resulted in greatly reduced immunogenicity of most synthetic antigens when compared to the epitopes as they occur on the original organisms. An important role of adjuvants is to increase the complexity of the formulation that is presented to the immune system and to do this in a safe manner. Certain live vaccines may not require adjuvants because of constant antigen presentation. Certain living vectors may provide an adjuvant effect but this may not be adequate since most live vectors are not persistent. Under some
and BARBARA
DETRICK3
conditions live vectors can also present safety problems. Because HIV is a weak immunogen, synthetic epitopes that are used as antigens almost certainly will require adjuvants. There is a long and successful history of use of adjuvants in humans. The only adjuvant licensed for use in the United States is an aluminum salt adjuvant (alum). It has been in use since 1940 and generates protective antibody responses in some vaccines but has only modest adjuvant activity in certain other vaccines. Currently, alum is used in DPT and hemophilus vaccines. Alum is not recognized as an adjuvant for inducing effective cell-mediated immune responses. When used in boosting injections, as in tetanus toxoid booster, it can sometimes cause swelling of the arm. When given by subcutaneous inoculation, alum can cause reactogenicity. Therefore, intramuscular injection is the recommended route of administration. Although there can be differences among different formulations of alum, this adjuvant is the benchmark for comparison of all other adjuvants in humans. Incomplete Freund's adjuvant (IFA) is an adjuvant that has been widely used in human trials around the world. The panel members suggested that IFA was a more potent adjuvant than alum. This adjuvant contains a nonbiodegradable mineral oil and a heterogeneous stabilizer that contains mannide monooleate (Arlacel A). In the 1950s IFA was given to tens of thousands of persons as a component of polio and influenza vaccines in the United States. Initial difficulties, particularly with IFA in a cholera vaccine that was used for 18 months in the Philippines, resulted in instances of tissue breakdown due to liberation of free fatty acids from the Arlacel A. However, batches of IFA that did not induce liberation of free fatty acids have had minimal toxic effects in humans. Studies with male Swiss mice have indicated the IFA adjuvant may be involved in the induction of tumors. However, follow-up studies conducted by the Institute of Medicine on humans injected, particularly among individuals in the U.S. military, have not revealed any increases in tumors or autoimmune diseases among those who received vaccines containing IFA; in fact the life span of vaccinated individuals has been longer. It was felt by the workshop panelists that IFA is more toxic when formulated with bacteria than with viruses. Because of concerns about reactoge-
'Department of Membrane Biochemistry. Walter Reed Army Institute of Research, Washington, DC 20307-5100. Division of AIDS. National Allergy and Infectious Deseases. Bethesda. MD 02892. 'Department of Pathology. George Washington University Medical Center.
Institute of
Washington.
DC 20037.
1427
ALVINO ET AL.
1428
mechanism. It is therefore important to analyze the desired goals for each vaccine being developed and to devise a rational approach using one or more adjuvants by analysis of adjuvant mechanisms. Reconstitution of membrane-associated antigens with adjuvants or carriers can result in different types of immunological presentation. Soluble antigens may be presented to lymphocytes, dendritic cells, and macrophages, while paniculate antigen formulations may be presented only to phagocytic cells, such as macrophages. The intracellular processing of antigen by APCs can determine whether antibody production or cytotoxic T lymphocytes (CTLs) will be the induced. Generally, antigens that are present in the cytoplasm, (e.g., viral and tumor antigens) have a capability of inducing CTLs, while exogenous extracellular antigens such as bacteria may have a capability of inducing antibodies but not CTLs. Liposomes can stimulate both production of antibodies and CTLs, and it is thought that liposomes can cause both major histocompatibility complex (MHC) class 1-dependent and class Il-dependent immune responses. Immune stimulatory complexes (ISCOMS) also have the ability to induce CTLs. In considering the possibility of developing a vaccine for individuals who are HIV + it was felt that the first vaccine injection would actually consist of a boosting immunization since the individuals are already primed. In this case cellmediated immunity, particularly induction of CTLs, may be more important than antibody production. It was pointed out that although polio is an example of a vaccine that relies on humoral immunity, an HIV vaccine would need an adjuvant that induces both humoral and cellular immunity.
nicity IFA has been withdrawn as a candidate for widespread use as a general adjuvant for human use, but it does have potential applicability for use in HIV individuals. One exercise that was attempted by the workship participants was to identify a long list of potential adjuvants. These adjuvants were identified by panel and audience members based on previous animal and human studies (Table 1). Extension of the list was constrained by the time available for compilation and the list is not meant to be comprehensive. Nevertheless, this list underscores the diversity of the numerous adjuvant approaches that might be possible. MECHANISMS OF ADJUVANT ACTIONS
Downloaded by Gothenburg University Library from www.liebertpub.com at 01/24/19. For personal use only.
The mechanisms of adjuvant action •
•
are numerous, some are:
Depot effect for slow release of antigen Effects on antigen-presenting cells (APCs) Targeting to APCs Activation of APCs Recruitment of APCs (including helper and suppressor
lymphocytes)
• •
,
Reconstitution of antigen and exposure of new Induction of cytokines
epitopes
A useful strategy in developing a vaccine formulation would be not to rely on a single adjuvant and not to be dependent on a single underlying mechanism of adjuvant action. Combinations of adjuvants could take advantage of more than one adjuvant
Table 1. Partial List
of
Possible Adjuvants (shown proposed by
in the order that they were
participants)
Alum
Incomplete Freund's adjuvant (IFA) Liposomes Liposomes (containing MPL) + Alum Monophosphoryl lipid A (MPL) Muramyl tripeptide-phosphatidylethanolamine (MTP-PE) (Biocine) Muramyl dipeptide (MDP) M DP + IFA
Threonyl MDP + oil + pluronic block polymer (Syntex adjuvant formulation, SAF) Keyhole limpet hemocyanin (KLH) + alum MPL + oil + cell walls (Detox) (Ribi ImmunoChem
Research)
Interferon—alpha Interferon—gamma Glycoprotein of Klebsiella pneumoniae Immunostimulating complexes (ISCOMS) Liposomes (containing MTP-PE) QS-21 (saponin-like component from Quil A) (Cambridge Biotech) Interleukin 1 (IL-1) Nonionic block polymer (L 180) (CytRx) Aluminum + human growth factor Guanosine analogues Cholera toxin Lipospheres (fat core with surface-imbedded Cholesterol derivatives Virus envelope proteins Tween
phospholipids) (Nova Pharmaceutical)
ADJUVANTS/CLINICAL TRIALS WORKING GROUP The question arose as to the importance of the half-life of the antibody and the rapidity of the immune response desired. A considerable time may be rquired for induction of effective memory cells. Memory response after injection of polio vaccine may require 6 to 12 months. Adjuvants can drive modulation of accessory T cells, or may change the relative balance of helper and suppressor T cells and this can greatly influence the time course of the immune response. Monophosphoryl lipid A has the capability of overcoming suppressor T-cell activity.
Downloaded by Gothenburg University Library from www.liebertpub.com at 01/24/19. For personal use only.
SAFETY AND TOXICITY OF ADJUVANTS As noted earlier, various adjuvants may be associated with local reactogenicity, mainly at the site of injection. Systemic effects can also occur, mainly due to stimulation of cytokines, such as interleukin 1 (IL-1). Lipid A is an example of an adjuvant that has considerable ability to cause systemic toxicities. The most effective way to monitor the toxicities of adjuvants containing lipid A is through pyrogenicity testing in rabbits. Adjuvants that pass pyrogenicity testing are much less likely to be toxic in humans. For monitoring endotoxic reactions pyrogenicity testing (but not merely Limulus lysate assay) should be sufficient as a quality control test for a vaccine; however, IL-6 secretion can be useful for following toxic effects in humans. It was also pointed out that tolerable reactogenicity of adjuvants may differ considerably for HIV+ and HIV~ individuals. For this reason, different adjuvants may be required for different vaccinated populations. There was some disagreement among the panel members as to whether reactogenicity should be ignored as an important factor at this time because of the urgency of the AIDS epidemic. On the one hand, the reasoning was put forth that for a killed vaccine in disease-free people safety would be a more important issue than efficacy, but for development of an HIV vaccine, efficacy was more important than safety, particularly for HIV+ individuals. Those who pursued this line of reasoning concluded that immediate testing in humans should not have to wait for extensive scientific inquiries into adjuvant mechanisms and toxicities. On the other hand, a representative of the pharmaceutical industry disagreed with this approach and pointed out that pharmaceutical companies will always be very sensitive to potential liability issues. Cooperation by pharmaceutical companies will be critical in the development of HIV vaccines, and regardless of the efficacy of a given vaccine the enthusiasm for development of vaccines containing toxic adjuvants will be greatly limited. Overall the feeling was expressed that companies would not be willing to take on the responsibilities of liability even if scientists and the population as a whole would wish them to do so.
IMPACT OF REGULATORY ISSUES ON ADJUVANT DEVELOPMENT It was pointed out that, from a regulatory standpoint, the mandate of the U.S. Food and Drug Administration is to protect the public from the harmful side effects of products, rather than to actively develop drugs or vaccines. However, there was
1429
general accord that the FDA would be willing to take whatever measures might be possible to facilitate adjuvant development. It was also pointed out that the investigational new drug application (IND) and the final license application are very different regulatory processes. Both safety and adjuvant activity
in the form of immunostimulation must be documented in order license. A question arose concerning the potential for the development of generic adjuvants that could be widely used with different antigens. However, a possible drawback of this approach may be the lack of benefits to volunteers injected with adjuvants alone, and this might limit the licensing of adjuvants in the absence of a specific vaccine. In addition, the adjuvant might or might not work in a formulation with a given antigen, again limiting the development of an adjuvant by itself. to obtain a
CURRENT REPERTOIRE OF ADJUVANTS
Adjuvant formulations that have gained current popularity for human vaccine trials include the following (those that were discussed are listed below, along with some brief comments that arose in the discussion): • •
Alum IFA: It
felt that this should be used as an adjuvant in HIV for immunotherapy. As a result of this, data would be obtained at the same time on the effectiveness of IFA as an adjuvant for prophylactic immunization. Monophosphoryl lipid A (MPL) (partially detoxified lipid A): This adjuvant has been used intramuscularly with oil (Detox formulation) or water. The Detox formulation has produced both humoral and cell-mediated immunity in cancer patients, and also has been used in malaria vaccine trials. was
séropositives
•
•
•
•
Muramyl tripeptide-phosphatidylethanolamine (MTP-PE).
This adjuvant is reactogenic. However, it is an active adjuvant that increases antibody responses when compared with alum. Liposomes (containing MPL) + alum: In a malaria vaccine trial in humans this adjuvant gave high antibody titers against a poorly immunogenic synthetic antigen. It had low reactogenicity and was well tolerated. When used in mice the liposomal formulation induced CTLs. Muramyl dipeptide (MDP): This adjuvant has been tested in the United States. It apparently had no significant side effects. It stimulated humoral activity, but studies on cell-mediated
immunity were not performed. DIRECTIONS FOR THE FUTURE AND DISCUSSION OF THE ROLE OF THE NATIONAL INSTITUTES OF HEALTH
Although vaccinology is flowering, one must focus on the immediate issues required by the crisis of the AIDS epidemic. The panel members agreed that there is a variety of avenues to pursue in the selection of an appropriate adjuvant(s) for use in an HIV vaccine. An effective and safe adjuvanted HIV vaccine should be one which induces comprehensive and long-lasting immunity, including mucosal immunity. However, there was
ALVING ET AL.
1430 among the group that the end point for an in an HIV vaccine should be prevention of disease rather than prevention of infection. Over the years the Vaccine Research & Development Branch (VRDB), Division of AIDS, National Institute of Allergy and Infectious Diseases has had a strong commitment to adjuvant research. To that end, they have focused their efforts on identifying new and novel adjuvants and expanding the understanding of the mechanisms of adjuvant action. Recently, a large comparative adjuvant study also was set up for systematic, direct comparison of potentially promising adjuvants in the SIV model. Finally, the VRDB currently is sponsoring Phase I clinical trials of selected adjuvants in humans. It is anticipated that insights gleaned from this workshop will help to encourage ongoing strategies of the VRDB as well as to provide new suggestions that will help to expedite the identification of effective adjuvants that will be used in an HIV vaccine.
also
a consensus
Downloaded by Gothenburg University Library from www.liebertpub.com at 01/24/19. For personal use only.
adjuvant
ADJUVANT WORKSHOP PARTICIPANTS Organizer: Dr. Barbara Detrick; Chair: Dr. Carl R. Alving; Participants: Dr. Abram Benenson, Dr. David Chernoff, Dr.
Barbara Detrick, Dr. Michel DeWilde, Dr. Diño Dina, Dr. Raphael Dolin, Dr. Friedrich Dorner, Dr. Robert Edelman, Dr. Robert Hunter, Dr. Raphael Mannino, Dr. Thomas Merigan, Dr. Mark Newman, Dr. Abe Osterhaus, Dr. Jon Rudbach, Dr. Jonas Salk, and Dr. Gayle Smith
Address
reprint requests
to:
Carl R. Alving Department of Membrane Biochemistry Walter Reed Army Institute of Research Washington. DC 20307-5100
