Rationally-designed vaccine adjuvants: separating efficacy from toxicity.

Adjuvants, substances included in many vaccines in order to improve immune responses, are challenging to develop and license because adjuvant compounds that stimulate strong protective immunity also frequently induce significant toxicity. Adjuvant design and development has until recently been largely empirical; but with the current knowledge that most adjuvants act via receptors of the innate immune system, molecular-based approaches are rapidly advancing the field. Data support the concept that proinflammatory pathways induced by innate immune receptor triggering underlie many of the observed toxic effects. Importantly, the cellular signaling pathways that lead to inflammation are known, for a number of innate immune receptors, to be distinct from those that are involved in the costimulation of protective adaptive immune responses, leading to approaches for attenuating inflammatory signaling that should lead to safer and more effective vaccine adjuvants. This article addresses whether there is a clear rationale for the separation of toxicity from efficacy in the function of adjuvants based upon innate immune receptor ligands.

Working group consultation: alloimmunity as a vaccine approach against HIV/AIDS: National Institutes of Health Meeting Report, May 24, 2012.

Alloimmunization vaccine strategies propose to avoid the problem of the extreme antigenic variability of human immunodeficiency virus (HIV) by instead focusing on the cellular antigens incorporated into HIV virions as they bud from infected cells. This report summarizes a Consultation meeting convened by the National Institute of Allergy and Infectious Diseases, National Institutes of Health on May 24, 2012. The objectives of the meeting were to (1) reach a consensus on the essential questions surrounding alloimmunization as a strategy for vaccine design against HIV, and (2) determine the experimental elements that might be needed for addressing these questions in an optimized pilot framework nonhuman primate (NHP) protocol for allogeneic immunization. The Consultation revisited the rationale and concerns of vaccination to induce allogeneic immunity, one of the most potent natural immune responses. The panelists' consensus was that a carefully designed skin graft transplant pilot experiment, in major histocompatibility complex (MHC) disparate male Mauritian cynomolgus macaques (MCM; Macaca fascicularis), would be useful for initially evaluating if alloimmunization results in an effective or even a partially effective safe AIDS vaccine. A successful NHP study for allogeneic immunization would provide further opportunities to explore vaccine-elicited immune and genetic correlates of protection against the acquisition of viral infection.

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.

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

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.

Addressing parents' concerns: do vaccines cause allergic or autoimmune diseases?

Anecdotal case reports and uncontrolled observational studies in the medical literature claim that vaccines cause chronic diseases such as asthma, multiple sclerosis, chronic arthritis, and diabetes. Several biological mechanisms have been proposed to explain how vaccines might cause allergic or autoimmune diseases. For example, allergic diseases might be caused by prevention of early childhood infections (the "hygiene hypothesis"), causing a prolongation of immunoglobulin E-promoting T-helper cell type 2-type responses. However, vaccines do not prevent most common childhood infections, and large well-controlled epidemiologic studies do not support the hypothesis that vaccines cause allergies. Autoimmune diseases might occur after immunization because proteins on microbial pathogens are similar to human proteins ("molecular mimicry") and could induce immune responses that damage human cells. However, wild-type viruses and bacteria are much better adapted to growth in humans than vaccines and much more likely to stimulate potentially damaging self-reactive lymphocytes. Consistent with critical differences between natural infection and immunization, well-controlled epidemiologic studies do not support the hypothesis that vaccines cause autoimmunity. Flaws in proposed biological mechanisms that explain how vaccines might cause chronic diseases are consistent with the findings of many well-controlled large epidemiologic studies that fail to show a causal relationship.

Addressing parents' concerns: do multiple vaccines overwhelm or weaken the infant's immune system?

Recent surveys found that an increasing number of parents are concerned that infants receive too many vaccines. Implicit in this concern is that the infant's immune system is inadequately developed to handle vaccines safely or that multiple vaccines may overwhelm the immune system. In this review, we will examine the following: 1) the ontogeny of the active immune response and the ability of neonates and young infants to respond to vaccines; 2) the theoretic capacity of an infant's immune system; 3) data that demonstrate that mild or moderate illness does not interfere with an infant's ability to generate protective immune responses to vaccines; 4) how infants respond to vaccines given in combination compared with the same vaccines given separately; 5) data showing that vaccinated children are not more likely to develop infections with other pathogens than unvaccinated children; and 6) the fact that infants actually encounter fewer antigens in vaccines today than they did 40 or 100 years ago.