Charles J. Hackett

Innate immune activation as a broad-spectrum biodefense strategy: Prospects and research challenges

Abstract Biodefense strategies require protection against a broad and largely unforeseen spectrum of pathogens—the forte of innate immune system defenses—that have evolved over millennia to function within moments of encountering either ancient or newly emerging pathogens. Although constitutive, the innate immune system is activated by the presence of microbes or their products, providing a rationale for a potential biodefense strategy. Both prophylactic and postexposure strategies involving innate immune stimulation have been shown to be plausible to prevent or ameliorate infections in animal models. Innate immune-activating compounds based on conserved microbial components recognized by toll-like molecules and other receptors could be synthesized and delivered like drugs by using an entirely different strategy from conventional vaccination. However, important theoretic and practical questions emerge about developing and deploying innate immune protective strategies for biodefense. This rostrum discusses prospects and problems in the overall approach itself. Important topics include microbe-specific issues about innate immune system effectiveness against highly virulent pathogens and general questions, such as whether innate immune responses will be safe and effective if used in a diverse human population of different age groups and with different genetic makeups.

Alloimmunization as a Strategy for Vaccine Design against HIV/AIDS

AO NE-D AY W O RK SH OP organized by Thomas Lehner and Gene Shearer and cosponsored by the National Institute of Allergy and Infectious Diseases (NIAID), NIH, and the NIH Office of AIDS Research (OAR) was held at the NIH (Bethesda, MD) on May 6, 1999. With the current worldwide rate of HIV infection estimated to be 16,000 per day, new approaches for the prevention of HIV infection and disease need to be considered. The primary objective of this workshop was to review the published data from HIV-1 exposure and infection, as well as from the SIV–macaque model, to assess whether further consideration should be given to the possibility of immunization against HLA alloantigens as an alternative strategy for an AIDS vaccine. Furthermore, because more than 33 million persons are now infected worldwide, and the incidence of failure of highly active antiretroviral therapy (HAART) is increasing, a secondary objective was to consider alloimmunization as a strategy for immune-based therapy in HIV-infected patients. The rationale of using alloimmunizati on for protection against HIV/AIDS was presented more than 6 years ago,1 and has been reconsidered on the basis of additional new findings. 2 This brief review of the workshop considers alloim munization first as a prophylactic AIDS vaccine, and second as an approach for immune-based therapy. It should be noted that the data suggesting the use of alloimmunizat ion for prophylactic and therapeutic immunization are distinct, and that the strategies for using alloimmunizat ion to achieve vaccine and therapeutic end points may not necessarily be the same.

Immunology research: challenges and opportunities in a time of budgetary constraint.

There have been enormous advances in the field of immunology over the past 3 decades, and those advances have had a positive effect on many subspecialties of medicine. Opportunities for even more notable advances remain. However, present and projected budget constraints for the National Institutes of Health have created formidable challenges. This commentary addresses the opportunities and challenges for the field of immunology during a period of restricted budgets.

Immunologic tolerance for immune system-mediated diseases.

Induction of long-term, antigen-specific immunologic unresponsiveness holds great promise for the treatment of many immune system-mediated diseases, including asthma, allergies, autoimmune diseases, and transplant rejection. Unlike current immunosuppressive treatments, immunologic tolerance therapies would affect only the undesired immune responses, leaving protective immunity intact. A variety of approaches to immunologic tolerance induction are being taken, reflecting the molecular and cellular complexity of immune system activation and regulation. The presentations summarized in this report represent promising strategies, some of which are being evaluated in advanced animal models and human clinical trials. Approaches presented include the following: interference with costimulatory signals in T-cell induction, T-cell receptor antagonism by altered peptides, exploitation of antigen-induced apoptosis to eliminate undesired T cells, opposition of inflammation by the induction of regulatory cytokines, induction of transplant tolerance by mixed chimerism, and deviation from deleterious allergic antibody responses by use of immunostimulatory DNA sequences. These multifaceted approaches are strongly supported by knowledge of basic immune mechanisms, which should facilitate the rational development of these therapies for controlling immune-mediated diseases.

Integrating Safety and Efficacy Evaluation Throughout Vaccine Research and Development

Vaccines have led to some of the greatest public health achievements in history, including the worldwide eradication of naturally occurring smallpox and the near eradication of polio. In addition, vaccines have contributed to significant reduction in the disease burden imposed by measles, mumps, hepatitis, influenza, diphtheria, and many other infections. The science of vaccinology is dynamic; it unfolds as technology enables scientists to continue to create safer and more effective vaccines. Safety evaluation is integrated into every step of the vaccine research and development process. The National Institute of Allergy and Infectious Diseases (NIAID) is the lead institute at the National Institutes of Health (NIH) for research and development of vaccines against emerging and reemerging infectious diseases (Text Box 1). Together with partners throughout the federal government, in academia, and in the public and private sectors, NIAID-supported scientists have helped develop many important life-saving vaccines against diseases such as invasive Haemophilus influenzae type b (Hib), pneumococcal pneumonia, meningitis, pertussis, influenza, chickenpox, and hepatitis A and B. Use of these and other vaccines worldwide has made significant contributions to public health by reducing the morbidity and mortality associated with many dreaded infectious diseases (Text Box 2). Discovery, development, and evaluation of vaccines are performed in multiple stages as promising ideas are developed into potential vaccine candidates. Developing a vaccine usually involves collaboration between federal agencies, academia, and industry. The NIAIDs role in vaccine development and testing extends from basic research through clinical evaluation (Fig 1). FIGURE 1 Stages of vaccine research, development, and evaluation. Safety evaluation is integral to every stage of the product-development pathway. This pathway begins with basic research, which involves understanding the pathogens mechanism of action, the interaction between pathogen and host, and the host response. Target identification entails studying the biological plausibility of particular strategies for creating … Address correspondence to Richard L. Gorman, MD, Associate Director for Clinical Research, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, 6610 Rockledge Dr, MSC 6604, Bethesda, MD 20892-6604. E-mail: gormanr{at}niaid.nih.gov