T cell-based HIV vaccine candidate demonstrates positive results

November 10, 2008

Study demonstrates proof-of-concept for vaccine model

BOSTON -- The question of whether or not to continue to pursue the development of T-cell-based HIV-1 vaccines has been a source of controversy following last year's widely publicized failure of the field's most promising candidate, a vaccine developed by Merck known as V520.

Now a study led by investigators at Beth Israel Deaconess Medical Center (BIDMC) provides the proof-of-concept that a T-cell-based strategy remains a viable course to follow.

Described in today's dvance On-line Publication of Nature, the study showed that an improved regimen using two distinct adenovirus vectors - rAd26 prime/rAd5 boost - and expressing the simian immunodeficiency virus (SIV) Gag protein, resulted in potent T-cell immune responses leading to long-term immune control of an SIV challenge in monkeys. The findings demonstrate for the first time using this stringent animal model that such a vaccine may be effective in the fight against AIDS.

"This is a controversial field right now," says the study's lead scientist Dan Barouch, MD, PhD, Principal Investigator of the NIH-sponsored Integrated Preclinical/Clinical AIDS Vaccine Development (IPCAVD) program, who is working to develop new HIV-1 vaccine candidates. "Despite the disappointing setbacks in HIV-1 vaccine development this past year, our findings suggest that we're not at the end of the road when it comes to T-cell vaccines. Our data show that T-cell vaccines that elicit greater magnitude, breadth, and quality of immune responses as compared with the Merck vaccine can result in improved protection in the rhesus monkey model of AIDS."

The induction of the immune system's "killer" T-cells as a means of protecting against HIV-1 is designed to overcome a number of unique obstacles that make the virus impervious to traditional vaccine strategies, which typically work by producing antibodies to eliminate the invading virus. Instead, T-cell generated immunity works by selectively targeting and destroying any cells that have already been infected by the virus.

"Although our vaccine regimen did not prevent acquisition of SIV infection, it substantially reduced the levels of virus in the blood of these animals and prevented the development of AIDS," says Barouch, who is also an Associate Professor of Medicine at Harvard Medical School.

Barouch and his colleagues in the Division of Viral Pathogenesis at BIDMC, in collaboration with the biotechnology company Crucell Holland BV, have spent the past three years developing new rare serotype adenoviral vectors, which deliver HIV antigens and are the basis for one strategy of HIV-1 vaccine development. Viral vector vaccines are made by deleting one or more genes from a harmless or attenuated virus, in this case, adenovirus. Segments of DNA-encoding HIV-1 proteins are inserted in place of the deleted genes and thereby transfer the proteins into human cells to stimulate an immune response to the HIV-1 virus.

Last year's Merck trial used as its vector adenovirus serotype 5 (rAd5) which is a virus responsible for the common cold. "Because Ad5 is encountered frequently in the environment," explains Barouch, "many individuals harbor preexisting immunity to this virus." As a result, following vaccination, this vector often proves ineffective in delivering its "cargo" to induce an immune response to HIV.

In the new study, Barouch's laboratory used an rAd26 viral vector as its means of transport. Ad26 is rarely encountered in the human population and has the ability to induce a potent immune response, providing protective efficacy against SIV.

Also distinct from the Merck study, the authors made use of a heterologous "prime-boost" system to enhance the vaccine's immunogenicity. "In most cases, the immune response induced by a single dose of a vaccine isn't strong enough or sustainable enough to provide effective protection," explains Barouch. By administering a second "boost" the antigen's immune response can be enhanced. In this case, the scientists successively administered the same antigen in two separate vectors: The first rAd26 vector "primed" the animals' immune responses; re-exposure to the same antigen in a second rAd5 vector provided the "boost."

Their results showed that when challenged with a lethal dose of SIV, the vaccinated animals were able to reduce viral replication and to remain healthy for more than 500 days following infection, indicating that the vaccine had sparked a powerful immune response.

"This is an extremely important study because it shows that there is still hope for vaccines currently in the pipeline," says Bruce Walker, MD, Director of the Harvard University Center for AIDS Research (CFAR). "It also gives the first clear indication of the level and type of immunity that will likely be needed for an AIDS vaccine to work."

More than 25 years after the discovery of HIV-1, AIDS remains one of the world's most devastating health problems. An estimated 33.2 million people currently live with HIV/AIDS while 2.5 million new infections were reported in 2007 alone.

Beth Israel Deaconess Medical Center

Primer to the Immune Response: Academic Cell Update Edition
by Tak W. Mak (Author), Mary Saunders (Author)

Now available with the most current and relevant research from Cell Press, Mak's Primer to the Immune Response, Academic Cell Update Edition, gives readers both the concepts and the applications students need to know to fully grasp Immunology. Mak introduces basic concepts and then follows with specific applications in research today. This book is further enhanced by its inclusion in the Academic Cell collaboration, providing it with links to current and recently published research.Now with an online study guide with the most current, relevant research from Cell PressFull supplements including test bank, powerpoint and online self quizzingColor illustrations enhance key topics and concepts

The Immune Response to Infection
by Stefan H. E. Kaufmann (Editor), Barry T. Rouse (Editor), David L. Sacks (Editor)

This new volume both combines two previous ASM Press books (Immunology of Infectious Diseases and The Innate Immune Response to Infection), integrating the innate immune response and the adaptive immune response to infection into a synthetic narrative, and bring everything up to date, incorporating the numerous important developments that have occurred in this most dynamic sub-discipline of microbiology.

Retroviral Immunology: Immune Response and Restoration (Infectious Disease)
by Giuseppe Pantaleo (Editor), Bruce D. Walker (Editor)

World-renowned authorities address the most important aspects of the immunology of retroviruses, namely immune response, genetic and virologic factors modulating the response, and the HIV-specific humoral and cell-mediated responses. In addition to the basic concepts of immune restoration, key topics covered include immune restoration after antiviral therapy and vaccine-induced immune response. Up-to-date and authoritative, Retroviral Immunology: Immune Response and Restoration provides a much-needed critical synthesis of both the experimental and clinical aspects of retroviral infections, and lays the groundwork for developing effective restoration strategies for the many immune-compromised HIV and AIDS patients who suffer fatal opportunistic infections.

Innate Immune Response to Pathogens and Recent Advances in Microbiology Researches

An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own healthy cells and tissues in order to function properly. Detection is complicated as pathogens can evolve rapidly, and adapt to avoid the immune system and allow the pathogens to successfully infect their hosts.
To survive this challenge, multiple mechanisms evolved that recognize and neutralize pathogens. Even simple unicellular organisms such as bacteria possess enzyme systems that protect against viral infections. Other basic immune mechanisms evolved in ancient eukaryotes and remain in...

Nutrition and Immune Function (Frontiers in Nutritional Science)
by Philip C Calder (Author), Catherine J Field (Author), Harsharnjit S Gill (Author)

This book provides a review of the roles of specific nutrients in maintaining the immune response and host protection against infection. It also considers the influence of various factors, such as exercise and ageing, on the interaction between nutrition and immune function. The main emphasis is on humans, but comparative mammalian data are also presented.The contents include methods for studying nutrient-immune function interactions, the impact of undernutrition on immune function and infection, the influences of fatty acids, amino acids, antioxidant vitamins, and various minerals on immunity, immunological effects of changes throughout the life cycle, and public health policy implications.

Primer to The Immune Response
by Tak W. Mak (Author), Mary Saunders (Author)

Primer to The Immune Response is an invaluable resource for college students, university undergraduates and students in medicine and other health professions who need a concise but complete and understandable introduction to immunology.
This book is written in the same engaging conversational style as the published reference book The Immune Response: Basic and Clinical Principles and conveys the same fascinating appeal of immunology. The authors bring clarity, readability and continuity of voice to an audience that requires only a brief survey of the most fundamental concepts in basic and clinical immunology. Primer to The Immune Response is beautifully illustrated with over 200 superb figures and 36 full color plates, and further enhanced by the inclusion of 60 tables and 6...

Control of Innate and Adaptive Immune Responses during Infectious Diseases
by Julio Aliberti (Editor)

Upon infection the host needs to mount vigorous immune response against pathogen in order to successfully control its replication. However, once the infectious agent is controlled or eliminated, host cells need to signal the immune system to slow or cease its activities. While vast knowledge has been accumulated through the years on the mechanisms involved in the initiation and effector phases of the immune responses, the pathways triggered in order to modulate or end innate and acquired immunity are becoming more evident as evidence for its relevance comes to surface. Due to its biological power, evidence has surfaced indicating that eventually pathogens may take advantage of such regulatory pathways in order to escape effector mechanisms and progress to persistence. This book will...

Cellular Signaling and Innate Immune Responses to RNA Virus Infections
by Allan R. Brasier (Editor), Adolfo Garc¡a-Sastre (Editor)

Infections with RNA viruses represent a significant cause of morbidity and mortality in vertebrates. This volume is written with the belief that a careful examination of the early host responses to these RNA virus infections, as well as of the mechanisms adopted by these viruses to evade early host antiviral responses, will provide a platform of knowledge on which we will be able to develop new and more effective methods for controlling the spread of RNA viruses or modifying their disease course.

Specialization and Complementation of Humoral Immune Responses to Infection (Current Topics in Microbiology and Immunology)
by Tim Manser (Editor)

The importance of specific antibodies for the clearance of and long-term resistance to many infectious pathogens has long been appreciated. In the last five years, data from these areas of research has coalesced, resulting in the emergence of a new and more complete understanding of how antibody-mediated resistance to pathogens is elaborated. This volume will highlight this new perspective on antibody responses to infection and convey its practical implications.

Bacterial Evasion of Host Immune Responses (Advances in Molecular and Cellular Microbiology)
by Brian Henderson (Editor), Petra C. F. Oyston (Editor)

Over the past fifty years cells and mediators involved in our immune defences have been painstakingly identified. However, it is only relatively recently that the ability of microorganisms to evade immunity has been recognized and investigated. This volume introduces the mechanisms used by bacteria to evade both humoral and cellular immune responses, using systems ranging in complexity from the simple quorum sensing molecules (acyl homoserine lactones) to the supramolecular syringe-like devices of type III secretion systems.