Novel vaccines and adjuvant systems: The utility of animal models for predicting immunogenicity in humans

Abstract

as for the prevention or treatment of cancer, allergy and autoimmune disorders, lifestyle related conditions (e.g., hypertension, smoking, contraception) and miscellaneous pathological states (e.g., Alzheimer's dementia). All vaccines contain one or more antigens, that can take various forms from peptides up to whole cells, and today many vaccines also contain an adjuvant. Such adjuvants are designed to affect the biodistribution of the antigen (e.g., provide a depot effect or target the antigen to particular immune cells) and/ or enhance resulting immune responses through direct activation of specific immune cells.Antigen discovery is not a new science, and for a long time there have been plenty of novel antigen candidates that were not being developed for want of an adjuvant system more potent than alum, which was, until fairly recently, the only adjuvant in a licensed vaccine. Alum is a relatively weak adjuvant with a strong Th2 bias, hence effective mostly for induction of antibodies. Thus, the need for novel adjuvants was particularly urgent for vaccines being designed for therapeutic applications where cell-mediated immunity is required for efficacy.Development of new vaccine adjuvants has been facilitated by two interrelated factors: (1) the rapidly expanding knowledge of the immune system, in particular the mechanisms by which the immune system naturally recognizes and responds to pathogens and how this innate immune activation is translated into adaptive immunity with memory, and (2) the discovery of natural or synthetic agonists for receptors that detect pathogen-associated molecular patterns and their development as potent new generation vaccine adjuvants.Successful development of a new vaccine formulation requires that the antigen and adjuvant components in the formulation are compatible, chemically distinct and detectable for quality control purposes. As well, they need to be sufficiently stable, have scalable and cost-effective synthesis, and last but certainly not least, be effective in inducing an adequate and appropriate immune response. The risk for most of these elements can be ascertained fairly quickly, but efficacy is a huge challenge. Certainly no one would consider testing a novel vaccine in humans without having achieved encouraging immunogenicity data in animals, but how useful or meaningful is the animal data for designing human studies and predicting outcome? There is a fair degree of judgment and guesswork required, and failure to do this well can lead to protracted and costly drug development pathways. Even with ultimate testing in human clinical trials, it may not be possible to measure efficacy directly when the pathogen is rarely Animal models are essential for acquiring safety, immunogenicity and efficacy data to support the development of novel vaccines. However, extrapolating such results to designing human trials is challenging due to species-specific differences in responses to antigens, adjuvants and pathogens. As well, most early vaccine work is conducted with in-bred mous...

Anti-nicotine vaccines: Comparison of adjuvanted CRM 197 and Qb-VLP conjugate formulations for immunogenicity and function in non-human primates

“…More convincing data comes from a clinical study on subjects vaccinated with NicVAX, where single photon emission computed tomography (SPECT) was used to measure nicotine binding to β2 nicotinic receptors in the brain; the eleven subjects showed a mean reduction of only 12.5% in brain nicotine binding post-vaccination compared to baseline [48]. While animal models may be useful for screening purposes in the laboratory and for acquiring safety, immunogenicity and efficacy data to support further development, their utility in predicting immunogenicity and function in humans is limited [49]. This is particularly true for anti-nicotine vaccines since there are important psychosocial aspects to smoking, with factors beyond nicotine brain levels playing an important role.…”

Transcription Analysis of the Extracellular Adherence Protein fromStaphylococcus aureusin Authentic Human Infection and In Vitro

“…Although experimental infections are clearly of interest for analysis of in vivo gene expression compared with that in humans, fundamental differences in rodent anatomy and physiology exist, and defense mechanisms vary greatly between humans and other animals [42,43]. In fact, in rodents, induction of local immunosuppression (such as the presence of a foreign body) is necessary to generate persistent S. aureus infection [44,45].…”

Selection of Adjuvants for Enhanced Vaccine Potency

“…Therefore, MF59-adjuvanted vaccines were found to be more effective than a commercial product, such as hepatitis B virus (HBV) vaccine (containing recombinant PreS2 and S antigens) in healthy adult subjects [137]. However, the species-and antigen-dependent variation in immunogenicity enhancement by MF59 appears to be a deficiency of this adjuvant system [15,138]. MF59 does not seem to induce significant side effects compared with vaccines without MF59 in healthy adults [137,139].…”

“…Even the intensity of an immune response can make a difference. A weak immune response is generally Th2-biased and therefore, increasing the intensity of response may lead to a Th1 response [15]. The Th1 response to an intramuscular flu vaccine (Fluarix) increased when the dose was increased from 1/10th of a full dose to a full dose, with a relatively similar Th2 response [16].…”