Dr. Amish Patel, Senior Director, Product Development, Emergent BioSolutions
Vaccination remains the most effective means to protect human from infectious deceasesby stimulating pathogen-specific immune responses and establishing long-term immunologic memory. Since many recombinant and synthetic antigens have low immunogenicity, adjuvants are added to the formulation to boost the immunogenicity and reduce the antigen doses needed for protective immunity. In the past decades,the manipulation of materials at nanoscale has led to significant breakthroughs in biomedical applications.Impressively, nanomaterials have shown their capability in improving vaccineefficacy as potent adjuvants.
In general, nanomaterials refer to particulate materials having a length scale of 1-100 nm in at least one dimension. The versatility of those materials come from their unique physicochemical properties that are distinctive from bulk materials. Their properties can be easily engineered with varied size, shape, surface chemistry, charge, and roughness to be suitable for myriad of biomedical applications including drug delivery, vaccines, imaging, and medical devices.
Vaccine adjuvants are used to amplify the antigen-specific immunogenicity. To date, there have been nearly 100 different types of adjuvants that are commercially available or under development. Among these adjuvants, Aluminum salts remain the most widely licensed adjuvant in the US and Europe. However, Alum has limited capacity to stimulate cellular immune responses and low adjuvant effect on polysaccharide antigens. Asthere has been a significant expansion in clinically approved nanomedicines, it opens new venue to explore the adjuvant capability of nanomaterials.
To develop the ideal adjuvant, nanomaterials are of great potential due to its delivery capacity and immunoregulatory property. Antigens loaded into nanocarriers are less affected by the degradation of proteolytic degradation of antigens in vivo. This may allow for delivery of lower dose of antigen or fewer numbers of immunizations. In addition, nanocarriers have been shown to exhibit a prolonged release profile in circulation and/or within the intracellular components. Moreover, antigen loaded in nanocarriers has shown enhanced antigen-presenting cell (APC) targeting and internalization as particulates, as compared to soluble forms.
Nanocarriers composed of lipids, proteins, metals or polymers have already been used to attain some of these attributes.
Dr. Yuchen Wang, Scientist, Product Development, Emergent BioSolutions
MF59, a nano-sized adjuvant approved for influenza vaccine (Fluad®), consists of anoil-in- water emulsion of ~250 nm droplet. Use of this adjuvant has shown significant increase in antibody titers through direct simulation of cytokine production. At development stage, liposomes, which are spherical particles composed of phospholipid double-layer shell can enhance both humoral and cellular immunity to protein and polysaccharide antigens. Poly(lactic-co-glycolic acid) (PLGA) nanospheres have shown enhanced targeting to human dendritic cells (DCs). Although highly biocompatible, the rapid degradation of PLGA nanoparticles (NPs) limits its half-life in vivo. Non-degradable nanomaterials, including gold and silver NPs, have been used to deliver viral and bacterial antigens, inducing robust immune responses against influenza and tuberculosis in mice. The major advantages of inorganic NPs include low production cost, reproducibility and safety in application.
Vaccine adjuvants are used to amplify the antigen-specific immunogenicity. To date, there have been nearly 100 different types of adjuvants that are commercially available or under development
In addition to the delivery capability, nanomaterials themselves have intrinsic immunomodulatory activity that makes them excellent vaccine adjuvants. Their particulate structure and nanoscale sizelead to inflammasome activation, recruitment of immune cells and complementsystem activation. An excellent example is virus-like particles (VLPs) which are non-infective viruses consisting of viral envelop proteins without genetic material. Its particulate structure and similarity to infective virus lead to stimulation of both cellular and humoral immunity. The most recently approved VLP vaccine is Gardasil® for immunization against human papillomavirus (HPV).
Nanocarriers are also highly versatile since they can be engineered with desired physicochemical properties. Throughintroduction of positive surface charges, nanocarriers can improve cellular uptake significantly as cell membrane is negatively charged. For example, uptake and immunogenicity of polyethyleneimine (PEI)-coated mesoporous silica NPs were considerably enhanced compared withpolyethylene glycol (PEG) coated unmodifiedparticles(neutral charge). NPs modified with pH-responsive surface entities can undergo structural deformation or degradation under acidic pH.Once taken up , they can disrupt the endosomal membrane and enable cytosolic release, which has shown to be critical in increasingmajor histocompatibility complex (MHC) class I presentation and cytotoxic T lymphocytes (CTL) activation. In addition, hydrophobic moieties of NPs can be recognized by immune cells therefore inducing more cytokines and co-stimulatory molecules than hydrophilic polymeric NPs.
Although promising, safety is a major concern when it comes to adjuvant approval for human use. The biological fate of nanomaterials remainsunclear.The accumulation of non-degradable or slowly degradable nanomaterials in the human body might cause toxicity. Nevertheless, the short exposure of human to the nanomaterial in the case of vaccine therapeutics reduces the risk of causing severe side effects. Looking forward, we as an industry should learn more about adjuvant mechanisms, which will guide us to more supplicated vaccine design using nanotechnology platforms and tools to better serve human health services.