抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Mutation of the Maturase Lipoprotein Attenuates the Virulence of Streptococcus equi to a Greater Extent than Does Loss of General Lipoprotein Lipidation Andrea Hamilton,†‡ Carl Robinson,† Iain C. Sutcliffe, Josh Slater, Duncan J. Maskell, Nick Davis-Poynter, Ken Smith, Andrew Waller, and Dean J. Harrington* University of Sunderland, SR1 3SD Tyne and Wear, United Kingdom; Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk CB8 7UU, United Kingdom; Northumbria University, Newcastle upon Tyne NE1 8ST, United Kingdom; Royal Veterinary College, Hertfordshire AL9 7TA, United Kingdom; Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, United Kingdom; and University of Bradford, West Yorkshire BD7 1DP, United Kingdom

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Infection and immunity

Vaccination has had a major impact on the control of infectious diseases. However, there are still many infectious diseases for which the development of an effective vaccine has been elusive. In many cases the failure to devise vaccines is a consequence of the inability of vaccine candidates to evoke appropriate immune responses. This is especially true where cellular immunity is required for protective immunity and this problem is compounded by the move toward devising sub-unit vaccines. Over the past decade nanoscale size (<1000 nm) materials such as virus-like particles, liposomes, ISCOMs, polymeric, and non-degradable nanospheres have received attention as potential delivery vehicles for vaccine antigens which can both stabilize vaccine antigens and act as adjuvants. Importantly, some of these nanoparticles (NPs) are able to enter antigen-presenting cells by different pathways, thereby modulating the immune response to the antigen. This may be critical for the induction of protective Th1-type immune responses to intracellular pathogens. Their properties also make them suitable for the delivery of antigens at mucosal surfaces and for intradermal administration. In this review we compare the utilities of different NP systems for the delivery of sub-unit vaccines and evaluate the potential of these delivery systems for the development of new vaccines against a range of pathogens.

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Vaccine delivery using nanoparticles

Aluminum-containing adjuvants are widely used in preventive vaccines against infectious diseases and in preparations for allergy immunotherapy. The mechanism by which they enhance the immune response remains poorly understood. Aluminum adjuvants selectively stimulate a Th2 immune response upon injection of mice and a mixed response in human beings. They support activation of CD8 T cells, but these cells do not undergo terminal differentiation to cytotoxic T cells. Adsorption of antigens to aluminum adjuvants enhances the immune response by facilitating phagocytosis and slowing the diffusion of antigens from the injection site which allows time for inflammatory cells to accumulate. The adsorptive strength is important as high affinity interactions interfere with the immune response. Adsorption can also affect the physical and chemical stability of antigens. Aluminum adjuvants activate dendritic cells via direct and indirect mechanisms. Phagocytosis of aluminum adjuvants followed by disruption of the phagolysosome activates NLRP3-inflammasomes resulting in the release of active IL-1β and IL-18. Aluminum adjuvants also activate dendritic cells by binding to membrane lipid rafts. Injection of aluminum-adjuvanted vaccines causes the release of uric acid, DNA and ATP from damaged cells which in turn activate dendritic cells. The use of aluminum adjuvant is limited by weak stimulation of cell-mediated immunity. This can be enhanced by addition of other immunomodulatory molecules. Adsorption of these molecules is determined by the same mechanisms that control adsorption of antigens and can affect the efficacy of such combination adjuvants. The widespread use of aluminum adjuvants can be attributed in part to the excellent safety record based on a 70-year history of use. They cause local inflammation at the injection site, but also reduce the severity of systemic and local reactions by binding biologically active molecules in vaccines.

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Mechanism of immunopotentiation and safety of aluminum adjuvants

The Gram-negative bacterial outer membrane (GNB-OM) is asymmetric in its lipid composition with a phospholipid-rich inner leaflet and an outer leaflet predominantly composed of lipopolysaccharides (LPS). LPS are polyanionic molecules, with numerous phosphate groups present in the lipid A and core oligosaccharide regions. The repulsive forces due to accumulation of the negative charges are screened and bridged by the divalent cations (Mg2+ and Ca2+) that are known to be crucial for the integrity of the bacterial OM. Indeed, chelation of divalent cations is a well-established method to permeabilize Gram-negative bacteria such as Escherichia coli. Here, we use X-ray and neutron reflectivity (XRR and NR, respectively) techniques to examine the role of calcium ions in the stability of a model GNB-OM. Using XRR we show that Ca2+ binds to the core region of the rough mutant LPS (RaLPS) films, producing more ordered structures in comparison to divalent cation free monolayers. Using recently developed solid-suppor...

Effect of Divalent Cation Removal on the Structure of Gram-Negative Bacterial Outer Membrane Models

In vitro fibrillogenesis of collagen type I in varying ionic and pH conditions

Alhydrogel® adjuvant, ultrasonic dispersion and protein binding: a TEM and analytical study.

Aluminum salts are the most widely used vaccine adjuvants, and phosphate is known to modulate antigen-adjuvant interactions. Here we report an unexpected role for phosphate buffer in an anthrax vaccine (SparVax) containing recombinant protective antigen (rPA) and aluminum oxyhydroxide (AlOH) adjuvant (Alhydrogel). Phosphate ions bind to AlOH to produce an aluminum phosphate surface with a reduced rPA adsorption coefficient and binding capacity. However, these effects continued to increase as the free phosphate concentration increased, and the binding of rPA changed from endothermic to exothermic. Crucially, phosphate restored the thermostability of bound rPA so that it resembled the soluble form, even though it remained tightly bound to the surface. Batches of vaccine with either 0.25 mM (subsaturated) or 4 mM (saturated) phosphate were tested in a disease model at batch release, which showed that the latter was significantly more potent. Both formulations retained their potency for 3 years. The strongest aluminum adjuvant effects are thus likely to be via weakly attached or easily released native-state antigen proteins.

Increasing the Potency of an Alhydrogel-Formulated Anthrax Vaccine by Minimizing Antigen-Adjuvant Interactions

The structure of Yersinia pestis Caf1 polymer in free and adjuvant bound states.

Yersina pestis, the bubonic plague bacterium, is coated with a polymeric protein hydrogel for protection from host defences. The protein, which is robust and non-stick, resembles structures found in many eukaryotic extracellular-matrix proteins. Cells grown on the natural polymer cannot adhere and grow poorly; however, when cell-adhesion motifs are inserted into the protein, the cells proliferate.

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Andrei Soliakov

Papers

In vitro fibrillogenesis of collagen type I in varying ionic and pH conditions

Alhydrogel® adjuvant, ultrasonic dispersion and protein binding: a TEM and analytical study.

Increasing the Potency of an Alhydrogel-Formulated Anthrax Vaccine by Minimizing Antigen-Adjuvant Interactions

The structure of Yersinia pestis Caf1 polymer in free and adjuvant bound states.

Reversible non-stick behaviour of a bacterial protein polymer provides a tuneable molecular mimic for cell and tissue engineering.