A novel combination adjuvant platform for human and animal vaccines
Introduction
Vaccines provide significant public health benefits by reducing the burden of infectious diseases. Live vaccines generate effective immune responses, but have been associated with a number of safety concerns, including improper attenuation, the occasional presence of adventitious agents and reverting back to virulence. Non-replicating vaccines i.e. whole, inactivated viruses and specifically recombinant or highly purified subunit antigens are often weakly immunogenic and need to be formulated with adjuvants to enhance their immunogenicity and induce robust antibody and effector T cell responses to prevent infections. Adjuvants are an essential part of vaccines, usually used to stimulate faster, stronger, and long-lasting immune responses to vaccines and thus can be used for enhancing immune responses to vaccine antigens, providing faster onset of immunity, improving immune responses to immunization in infant or elderly populations, whose immune system are immature or waning, reducing the immunization schedule and dose sparing, which implies reducing the quantity of antigen required in the vaccine preparation [1]. Adjuvants are often required in subunit vaccines due to the poor immunogenicity of such antigens.
There is no single adjuvant that can include all the vaccine requirements. Using a single adjuvant has a number of limitations, including induction of weak, improper, and short-lived immune responses. For example, alum and MF59 [2] are the universally approved adjuvants for human vaccines. Both normally induce Th2-biased immune responses but only weak cytotoxic immune responses, as required for protection against intracellular pathogens such as viruses, invasive bacteria and protozoa. In contrast, when multiple adjuvants are used in combination they can act synergistically by stimulating and activating various types of immune cells such as dendritic cells, macrophages, lymphocytes etc. A combination adjuvant platform is promising and beneficial for suboptimal vaccines and particularly advantageous for vaccines against specific and more susceptible populations, such as neonates and the older adults. In some respects the neonatal immune system is similar to that of the elderly since they both are having diminished anti-microbial activity by immune cells, reduced antigen-uptake and -presentation by antigen presenting cells and compromised adaptive immune responses [3]. Combination adjuvants may therefore provide an approach to boost immune responses in both neonates and the elderly. Often these combinations are comprised of a delivery system and an immunostimulatory adjuvant, especially combinations with toll-like receptor (TLR) agonists and monophosphoryl lipid A (MPL). Combination adjuvants such as Montanides, ISCOMs, Liposomes etc. formulated with or without other adjuvants have been tested in humans and animals and have generated promising result [4], [5], [6], [7], [8], [9], [10]. Recently, we developed a novel combination adjuvant platform (TriAdj) that is highly effective with a wide range of animal and human antigens.
Section snippets
Combination adjuvant platform for animal vaccines
Veterinary vaccines have been used for several years and play an important role in promoting animal health, welfare, food production, and public health. They are a cost-effective method to protect animals from disease, improve food production, and reduce the need for antibiotics in food and companion animals. Furthermore, vaccines are essential in preventing transmission of zoonotic disease to humans. Interestingly, there are unique challenges with respect to animal vaccines including the need
Combination adjuvant platform for human vaccines
Several combination adjuvants consisting of a variety of immunomodulators such as Immune Stimulating Complexes (ISCOMs), montanides, nanoemulsions, and adjuvant systems have been developed in recent years and are currently being tested with human vaccines in preclinical and clinical trials. The novel adjuvant platform, TriAdj, was co-formulated with various human vaccine antigens and tested in animal models including mice, cotton rats, pigs and sheep. This adjuvant platform is highly effective
Mechanisms of action of the combination adjuvant
Various mechanisms of action were identified for this novel combination adjuvant. For example, TriAdj used as a mucosal (intranasal) adjuvant increased antigen uptake by dendritic cells, improved dendritic cell maturation, and more efficiently transported the antigen to local draining lymph nodes to present it to T cells [17]. TriAdj-formulated antigen promoted the production of chemokines, cytokines and inflammatory cytokines, followed by recruitment and activation of several immune cell
Future perspectives
As our understanding of the immune system develops, and in particular its linkages between innate and adaptive immunity, combination adjuvants will continue to emerge that include multiple danger signals resulting in sophisticated and tailor-made responses that are based on stimulation of multiple receptors and signalling pathways in a multitude of immune cells. In particular, with the advent of precision medicine and the role of the microbiome in shaping the immune response to vaccination,
Acknowledgments
Research in the authors’ laboratories is supported from a variety of funding agencies including the Krembil Foundation – Canada, the Bill and Melinda Gates Foundation – United States, the Canadian Institutes of Health Research (CIHR), the National Science and Engineering Research Council (NSERC), the Saskatchewan Health Research Foundation (SHRF), the Alberta Livestock and Meat Agency (ALMA), the Saskatchewan Agriculture Development Fund (ADF), and the Pan-Provincial Vaccine Enterprise. The
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