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Editorial overview: Vaccines: Vaccines for cancer and infectious diseases
Available online at www.sciencedirect.com
ScienceDirect Editorial overview: Vaccines: Vaccines for cancer and infectious diseases John R Mascola and Rafi Ahmed Current Opinion in Immunology 2015, 35:v–vii For a complete overview see the Issue Available online 11th August 2015 http://dx.doi.org/10.1016/j.coi.2015.07.009 0952-7915/Published by Elsevier Ltd.
John R Mascola
Vaccine Research Center, NIAID, NIH, USA e-mail: [email protected] John R Mascola, M.D., is the director of the Vaccine Research Center (VRC) of the National Institutes of Allergy and Infectious Diseases (NIAID), NIH. His research interests include virology, humoral immunity and vaccine development. His laboratory focuses on understanding antibody-mediated protective immune responses via studies of both the plasma antibody compartment and the B-cell compartment.
Rafi Ahmed
Introduction Over that past 100 years, vaccines to prevent illness by infectious diseases have had an enormous impact on global public health. Together with the eradication of small pox in 1980, vaccines for diseases such as polio, measles, mumps and diphtheria have dramatically reduced rates of infection, and in many regions of the world, rendered these infections to be uncommon. Yet, major challenges remain and vaccines are needed for several infections of global importance. Human immunodeficiency virus (HIV), tuberculosis (TB) and malaria claim more than four million deaths per year, but effective vaccines have not yet been developed despite decades of research [1]. Respiratory syncytial virus (RSV), a major killer of children, has evaded numerous attempts at vaccine development. In some cases, we have suboptimal vaccines, such as for pertussis, where more durable immunity is needed. And there are existing or emerging diseases for which vaccines are needed, as for hepatitis C virus (HCV) and Ebola virus, described in these pages. Fortunately, the science of vaccinology has evolved substantially, and together with improved vaccine technologies, there are new opportunities to develop needed vaccines. In addition, recent advances in our understanding of innate and adaptive immunity and the awareness that the immune system can eliminate cancers, are beginning to translate into the arena of vaccine therapy for some infections and for treatment of cancers. Thus, we are probably at the beginning of a new era of vaccinology — one where we hope to tackle some old nemesis, and begin to harness the immune system to treat chronic disease.
Therapeutic vaccines for cancer
Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA e-mail: [email protected] Dr. Rafi Ahmed is the Georgia Research Alliance professor of Microbiology and Immunology, and director of the Emory
www.sciencedirect.com
A major bridge between vaccines for infectious diseases and vaccines for cancer was built upon our understanding that some chronic viral infections, including hepatitis B virus, Epstein bar virus and human papilloma virus (HPV) are associated with the development of malignant tumors. Among these, the etiological link between specific serotypes of HPV and cervical cancer is particularly strong — and most cases of cervical cancer are thought to be the result of HPV infection. With the recent development of highly effective vaccines to prevent HPV infection, attention is now focused on treatment of already established HPV infection by therapeutic vaccination. As discussed by van der Sluis et al., a crucial aspect of therapeutic immunization for HPV probably involves the use of appropriate viral antigens, together with breaking local immune regulation to enhance CD8 T-cell responses against these antigens. Such modalities include depletion or inhibition of immunosuppressive T-regulatory cells or blockade of Current Opinion in Immunology 2015, 35:v–vii
vi Vaccines
Vaccine Center at Emory University School of Medicine in Atlanta, GA. He earned his undergraduate degree from Osmania University, India and his Ph.D. from Harvard University in Cambridge, Massachusetts. After completing his postdoctoral training in the Department of Immunology at Scripps Clinic and Research Foundation in La Jolla, CA, he joined the Department of Microbiology and Immunology at the UCLA School of Medicine. He was at UCLA from 1984 to 1995 and moved to Emory University in 1995. His research efforts are directed towards: first, understanding the mechanisms of immunological memory and using this knowledge to develop new and more effective vaccines; second, defining the mechanisms of T cell exhaustion during chronic viral infections and cancer and developing strategies for restoring function in exhausted T cells. He is a member of the National Academy of Sciences and the Institute of Medicine.
inhibitory pathways mediated by PD-1 or CTLA-4. These principles can be broadened to modulate the immune systems response to numerous other tumor antigens, whether of viral or tumor origin. Kissick and Sanda review the status of current clinical trials of active vaccination as cancer immunotherapy. They note the first groundbreaking results reported in 2010, showing that the use of a monoclonal antibody targeting CTLA-4 was associated with improved survival in patients with metastatic melanoma. Recently, striking results have been seen with PD-1 directed immune therapy that shows not only significantly better response rates in melanoma, but is also effective in several other cancers such as lung, bladder, lymphoma, kidney and head/neck. In addition to these immune checkpoint inhibitors, efforts are aimed at boosting CD8 T-cell mediated cytotoxic killing of antigen expressing tumor cells. A major area of clinical investigation involves adoptive transfer of CD8 T-cells, or more recently, of T-cells genetically modified to express chimeric antigen receptors (CAR) that are able to directly recognize surface antigens on the tumor, and thus bring cytotoxic T-cells in close proximity to tumor cells. Kissick and Sandra also review the specific use of vaccines delivering tumor antigens, often with adjuvants or immune modulating agents, to expand the population of tumor antigen specific T-cells. Current clinical trials include vaccine therapy for melanoma, lung, kidney, prostate and breast cancer.
Vaccines to prevent and treat chronic viral infection (HIV and HCV) Chronic viral infections pose a particular challenge to both therapeutic and preventive vaccination. In particular, both HIV and HCV persist at high levels and display considerable antigenic diversity and the ability to evade host immune responses. As noted by Walker and Grakoui, HCV has recently become a curable infection by the development of highly effective anti-viral drugs, but such antiviral treatment is expensive and not widely available. Thus, the prevalence and devastating liver disease associated with this virus are unlikely to diminish without an effective preventative vaccine. Since the body is able to eradicate HCV infection in about 30% of cases, the goal of HCV vaccination in not necessarily to prevent infection (sterilizing immunity), but rather to augment the immune response to prevent chronic infection and liver disease. Currently, clinical trials are in progress with vaccines that elicit neutralizing antibodies to HCV surface proteins, or with gene-based vector vaccines aimed at inducing CD8 T-cells to internal viral proteins. The story for HIV has similarities but also marked differences to HCV. It is widely believed that an effective HIV vaccine will need to prevent infection, since natural immunity or control of HIV infection is rare. As reviewed by Haynes, a major area of focus includes the elicitation neutralizing antibodies to the viral envelope glycoprotein (Env), which have been shown to protect in non-human primate models. Over the past 5–6 years, highly potent and broadly reactive neutralizing antibodies have been isolated from some HIV-1 infected donors. This has led to renewed interest in eliciting such antibodies with a vaccine. In this regard, advances in our understanding of the Env structure and major neutralization epitopes, along with recent studies describing how antibodies evolve and affinity mature to gain effective neutralization, have provided new insights in vaccine strategies. While full sterilizing immunity is preferred, there has been a recent resurgence of the concept that unusually robust CD8 T-cell responses may be able to fully control viral replication. Here, using the simian immunodeficiency virus (SIV) model in monkeys, an attenuated rhesus CMV vector induced broad CD8 T-cell responses that could control SIV replication after Current Opinion in Immunology 2015, 35:v–vii
www.sciencedirect.com
Editorial overview Mascola and Ahmed vii
viral challenge in about half of the monkeys. These finding provided a bridge back to the field of therapeutic vaccination for HIV. As reviewed by Mylvaganam et al., antiretroviral therapy (ART) effectively controls viral replication but does not eliminate the viral reservoir and also does not rescue the profound immune dysfunction associated with chronic HIV infection. Thus, a major goal of therapeutic vaccination is to enhance immune mediated viral suppression, ideally such that ART is no longer needed. To achieve this level of functional cure, it is believed that therapeutic immunization will need to be combined with PD-1 blockade, cytokine therapies, and/or latency reversing agents that stimulate latent cells do divide and express antigen — and thus be recognized and killed by HIV specific CD8 T cells.
Vaccines for TB, malaria, pertussis Along with HIV, TB and malaria account for a major portion of the global infectious diseases morbidity and mortality. Vaccines for both diseases have proven to be major scientific challenges. Neonatal BCG vaccination has been used for decades in highly endemic regions and has modest efficacy in preventing clinical tuberculosis. As reviewed by Andersen and Urdahl, TB vaccine strategies include pre-exposure vaccination, generally of infants prior to TB infection, and post exposure vaccines, targeting adolescents and adults with latent TB infection. In addition, therapeutic vaccination could be used along with conventional chemotherapy, to shorten the treatment or to prevent recurrence of disease. Promising research on mechanism of protective immunity, including the role of robust T-cell responses in the lung, the site of TB infection, has led to clinical trials with several novel antigens and vaccine approaches. Protection against severe clinical malaria has been the long sought goal for this parasitic infection, which is estimated to infect almost 200 million persons per year and cause more than 500,000 deaths each year. Moreno and Joyner nicely review the challenges imposed by the complex life cycle of the parasite and categorize current malaria vaccine efforts by the stage of the life cycle that is targeted by the vaccine: pre-erythrocytic, erythrocytic and transmission blocking vaccines. The most advanced vaccine is the circumsporozoite protein from the pre-erythrocytic stage, fused to the surface antigen of hepatitis B, which has shown modest efficacy against severe malarial disease in children. However, various additional vaccine antigens and vaccine approaches are advancing into clinical trials, including protein and gene-based vector vaccines. A different category of needed vaccines includes the disease pertussis, caused by the bacterium Bordetella
www.sciencedirect.com
pertussis. The disease is most severe in children and the release and use of a whole-cell pertussis vaccine in the 1940s was associated with a dramatic decline in cases, especially severe cases and deaths. Because of side effects associated with the whole cell vaccine, the current licensed vaccines are acellular, and are combined with diphtheria and tetanus to formulate the DTaP vaccine. Warfel and Edwards review data on the recent reemergence of pertussis infections, and review vaccine and epidemiologic studies of the efficacy and durability of the current DTaP vaccine. They highlight limitations in protective immune response by the current vaccine and propose animal model studies that could be used to test potentially improved vaccines.
Vaccines for acute viral infections: RSV and Ebola Interest in the development of an Ebola vaccine has been greatly spurred by the recent wide-spread outbreak of Ebola virus infection in several countries in West Africa. This outbreak has killed over 10,000 people and continues to fester nearly a year after it started. There are currently several candidate Ebola vaccines in human clinical trials with the two lead approaches using either vesicular stomatitis virus (VSV) based vectors, or a chimpanzee adenovirus vectors, expressing Ebola virus glycoproteins. Zhou and Sullivan review the progress of the chimpanzee adenovirus (ChAd) vaccine platform, including data with boosting by Modified Vaccinia Ankara (MVA) Ebola vector, and discuss the correlates of protective immunity against Ebola. Recently published data from a ring vaccination study using the VSV vaccine in Guinea, west Africa, provide the first human data indicating that an Ebola vaccine may be possible [2]. Finally, Graham et al. review recent exciting progress in the development of new vaccine immunogens for RSV, based on the viral surface glycoprotein F. They highlight how the atomic level crystal structure of the RSV F glycoprotein provided insights into mutations that could stabilize the protein in its pre-fusion form (Pre-F). The ability to now express this antigen in a stable conformation for future clinical testing and an excellent example a structure-based approach to vaccine development.
References 1.
Nabel GJ: Designing tomorrow’s vaccines. N Engl J Med 2013, 368:551-560.
2.
Henao-Restrepo AM, Longini IM, Egger M, Dean NE, Edmunds WJ, Camacho A, Carroll MW, Doumbia M, Draguez B, Duraffour S et al.: Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial. Lancet. In press. http://dx.doi.org/10.1016/S0140-6736(15)61117-5.
Current Opinion in Immunology 2015, 35:v–vii
ScienceDirect Editorial overview: Vaccines: Vaccines for cancer and infectious diseases John R Mascola and Rafi Ahmed Current Opinion in Immunology 2015, 35:v–vii For a complete overview see the Issue Available online 11th August 2015 http://dx.doi.org/10.1016/j.coi.2015.07.009 0952-7915/Published by Elsevier Ltd.
John R Mascola
Vaccine Research Center, NIAID, NIH, USA e-mail: [email protected] John R Mascola, M.D., is the director of the Vaccine Research Center (VRC) of the National Institutes of Allergy and Infectious Diseases (NIAID), NIH. His research interests include virology, humoral immunity and vaccine development. His laboratory focuses on understanding antibody-mediated protective immune responses via studies of both the plasma antibody compartment and the B-cell compartment.
Rafi Ahmed
Introduction Over that past 100 years, vaccines to prevent illness by infectious diseases have had an enormous impact on global public health. Together with the eradication of small pox in 1980, vaccines for diseases such as polio, measles, mumps and diphtheria have dramatically reduced rates of infection, and in many regions of the world, rendered these infections to be uncommon. Yet, major challenges remain and vaccines are needed for several infections of global importance. Human immunodeficiency virus (HIV), tuberculosis (TB) and malaria claim more than four million deaths per year, but effective vaccines have not yet been developed despite decades of research [1]. Respiratory syncytial virus (RSV), a major killer of children, has evaded numerous attempts at vaccine development. In some cases, we have suboptimal vaccines, such as for pertussis, where more durable immunity is needed. And there are existing or emerging diseases for which vaccines are needed, as for hepatitis C virus (HCV) and Ebola virus, described in these pages. Fortunately, the science of vaccinology has evolved substantially, and together with improved vaccine technologies, there are new opportunities to develop needed vaccines. In addition, recent advances in our understanding of innate and adaptive immunity and the awareness that the immune system can eliminate cancers, are beginning to translate into the arena of vaccine therapy for some infections and for treatment of cancers. Thus, we are probably at the beginning of a new era of vaccinology — one where we hope to tackle some old nemesis, and begin to harness the immune system to treat chronic disease.
Therapeutic vaccines for cancer
Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA e-mail: [email protected] Dr. Rafi Ahmed is the Georgia Research Alliance professor of Microbiology and Immunology, and director of the Emory
www.sciencedirect.com
A major bridge between vaccines for infectious diseases and vaccines for cancer was built upon our understanding that some chronic viral infections, including hepatitis B virus, Epstein bar virus and human papilloma virus (HPV) are associated with the development of malignant tumors. Among these, the etiological link between specific serotypes of HPV and cervical cancer is particularly strong — and most cases of cervical cancer are thought to be the result of HPV infection. With the recent development of highly effective vaccines to prevent HPV infection, attention is now focused on treatment of already established HPV infection by therapeutic vaccination. As discussed by van der Sluis et al., a crucial aspect of therapeutic immunization for HPV probably involves the use of appropriate viral antigens, together with breaking local immune regulation to enhance CD8 T-cell responses against these antigens. Such modalities include depletion or inhibition of immunosuppressive T-regulatory cells or blockade of Current Opinion in Immunology 2015, 35:v–vii
vi Vaccines
Vaccine Center at Emory University School of Medicine in Atlanta, GA. He earned his undergraduate degree from Osmania University, India and his Ph.D. from Harvard University in Cambridge, Massachusetts. After completing his postdoctoral training in the Department of Immunology at Scripps Clinic and Research Foundation in La Jolla, CA, he joined the Department of Microbiology and Immunology at the UCLA School of Medicine. He was at UCLA from 1984 to 1995 and moved to Emory University in 1995. His research efforts are directed towards: first, understanding the mechanisms of immunological memory and using this knowledge to develop new and more effective vaccines; second, defining the mechanisms of T cell exhaustion during chronic viral infections and cancer and developing strategies for restoring function in exhausted T cells. He is a member of the National Academy of Sciences and the Institute of Medicine.
inhibitory pathways mediated by PD-1 or CTLA-4. These principles can be broadened to modulate the immune systems response to numerous other tumor antigens, whether of viral or tumor origin. Kissick and Sanda review the status of current clinical trials of active vaccination as cancer immunotherapy. They note the first groundbreaking results reported in 2010, showing that the use of a monoclonal antibody targeting CTLA-4 was associated with improved survival in patients with metastatic melanoma. Recently, striking results have been seen with PD-1 directed immune therapy that shows not only significantly better response rates in melanoma, but is also effective in several other cancers such as lung, bladder, lymphoma, kidney and head/neck. In addition to these immune checkpoint inhibitors, efforts are aimed at boosting CD8 T-cell mediated cytotoxic killing of antigen expressing tumor cells. A major area of clinical investigation involves adoptive transfer of CD8 T-cells, or more recently, of T-cells genetically modified to express chimeric antigen receptors (CAR) that are able to directly recognize surface antigens on the tumor, and thus bring cytotoxic T-cells in close proximity to tumor cells. Kissick and Sandra also review the specific use of vaccines delivering tumor antigens, often with adjuvants or immune modulating agents, to expand the population of tumor antigen specific T-cells. Current clinical trials include vaccine therapy for melanoma, lung, kidney, prostate and breast cancer.
Vaccines to prevent and treat chronic viral infection (HIV and HCV) Chronic viral infections pose a particular challenge to both therapeutic and preventive vaccination. In particular, both HIV and HCV persist at high levels and display considerable antigenic diversity and the ability to evade host immune responses. As noted by Walker and Grakoui, HCV has recently become a curable infection by the development of highly effective anti-viral drugs, but such antiviral treatment is expensive and not widely available. Thus, the prevalence and devastating liver disease associated with this virus are unlikely to diminish without an effective preventative vaccine. Since the body is able to eradicate HCV infection in about 30% of cases, the goal of HCV vaccination in not necessarily to prevent infection (sterilizing immunity), but rather to augment the immune response to prevent chronic infection and liver disease. Currently, clinical trials are in progress with vaccines that elicit neutralizing antibodies to HCV surface proteins, or with gene-based vector vaccines aimed at inducing CD8 T-cells to internal viral proteins. The story for HIV has similarities but also marked differences to HCV. It is widely believed that an effective HIV vaccine will need to prevent infection, since natural immunity or control of HIV infection is rare. As reviewed by Haynes, a major area of focus includes the elicitation neutralizing antibodies to the viral envelope glycoprotein (Env), which have been shown to protect in non-human primate models. Over the past 5–6 years, highly potent and broadly reactive neutralizing antibodies have been isolated from some HIV-1 infected donors. This has led to renewed interest in eliciting such antibodies with a vaccine. In this regard, advances in our understanding of the Env structure and major neutralization epitopes, along with recent studies describing how antibodies evolve and affinity mature to gain effective neutralization, have provided new insights in vaccine strategies. While full sterilizing immunity is preferred, there has been a recent resurgence of the concept that unusually robust CD8 T-cell responses may be able to fully control viral replication. Here, using the simian immunodeficiency virus (SIV) model in monkeys, an attenuated rhesus CMV vector induced broad CD8 T-cell responses that could control SIV replication after Current Opinion in Immunology 2015, 35:v–vii
www.sciencedirect.com
Editorial overview Mascola and Ahmed vii
viral challenge in about half of the monkeys. These finding provided a bridge back to the field of therapeutic vaccination for HIV. As reviewed by Mylvaganam et al., antiretroviral therapy (ART) effectively controls viral replication but does not eliminate the viral reservoir and also does not rescue the profound immune dysfunction associated with chronic HIV infection. Thus, a major goal of therapeutic vaccination is to enhance immune mediated viral suppression, ideally such that ART is no longer needed. To achieve this level of functional cure, it is believed that therapeutic immunization will need to be combined with PD-1 blockade, cytokine therapies, and/or latency reversing agents that stimulate latent cells do divide and express antigen — and thus be recognized and killed by HIV specific CD8 T cells.
Vaccines for TB, malaria, pertussis Along with HIV, TB and malaria account for a major portion of the global infectious diseases morbidity and mortality. Vaccines for both diseases have proven to be major scientific challenges. Neonatal BCG vaccination has been used for decades in highly endemic regions and has modest efficacy in preventing clinical tuberculosis. As reviewed by Andersen and Urdahl, TB vaccine strategies include pre-exposure vaccination, generally of infants prior to TB infection, and post exposure vaccines, targeting adolescents and adults with latent TB infection. In addition, therapeutic vaccination could be used along with conventional chemotherapy, to shorten the treatment or to prevent recurrence of disease. Promising research on mechanism of protective immunity, including the role of robust T-cell responses in the lung, the site of TB infection, has led to clinical trials with several novel antigens and vaccine approaches. Protection against severe clinical malaria has been the long sought goal for this parasitic infection, which is estimated to infect almost 200 million persons per year and cause more than 500,000 deaths each year. Moreno and Joyner nicely review the challenges imposed by the complex life cycle of the parasite and categorize current malaria vaccine efforts by the stage of the life cycle that is targeted by the vaccine: pre-erythrocytic, erythrocytic and transmission blocking vaccines. The most advanced vaccine is the circumsporozoite protein from the pre-erythrocytic stage, fused to the surface antigen of hepatitis B, which has shown modest efficacy against severe malarial disease in children. However, various additional vaccine antigens and vaccine approaches are advancing into clinical trials, including protein and gene-based vector vaccines. A different category of needed vaccines includes the disease pertussis, caused by the bacterium Bordetella
www.sciencedirect.com
pertussis. The disease is most severe in children and the release and use of a whole-cell pertussis vaccine in the 1940s was associated with a dramatic decline in cases, especially severe cases and deaths. Because of side effects associated with the whole cell vaccine, the current licensed vaccines are acellular, and are combined with diphtheria and tetanus to formulate the DTaP vaccine. Warfel and Edwards review data on the recent reemergence of pertussis infections, and review vaccine and epidemiologic studies of the efficacy and durability of the current DTaP vaccine. They highlight limitations in protective immune response by the current vaccine and propose animal model studies that could be used to test potentially improved vaccines.
Vaccines for acute viral infections: RSV and Ebola Interest in the development of an Ebola vaccine has been greatly spurred by the recent wide-spread outbreak of Ebola virus infection in several countries in West Africa. This outbreak has killed over 10,000 people and continues to fester nearly a year after it started. There are currently several candidate Ebola vaccines in human clinical trials with the two lead approaches using either vesicular stomatitis virus (VSV) based vectors, or a chimpanzee adenovirus vectors, expressing Ebola virus glycoproteins. Zhou and Sullivan review the progress of the chimpanzee adenovirus (ChAd) vaccine platform, including data with boosting by Modified Vaccinia Ankara (MVA) Ebola vector, and discuss the correlates of protective immunity against Ebola. Recently published data from a ring vaccination study using the VSV vaccine in Guinea, west Africa, provide the first human data indicating that an Ebola vaccine may be possible [2]. Finally, Graham et al. review recent exciting progress in the development of new vaccine immunogens for RSV, based on the viral surface glycoprotein F. They highlight how the atomic level crystal structure of the RSV F glycoprotein provided insights into mutations that could stabilize the protein in its pre-fusion form (Pre-F). The ability to now express this antigen in a stable conformation for future clinical testing and an excellent example a structure-based approach to vaccine development.
References 1.
Nabel GJ: Designing tomorrow’s vaccines. N Engl J Med 2013, 368:551-560.
2.
Henao-Restrepo AM, Longini IM, Egger M, Dean NE, Edmunds WJ, Camacho A, Carroll MW, Doumbia M, Draguez B, Duraffour S et al.: Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial. Lancet. In press. http://dx.doi.org/10.1016/S0140-6736(15)61117-5.
Current Opinion in Immunology 2015, 35:v–vii