Unmet Needs and New Promises in Hepatitis B Vaccination for CKD Patients
shares the 226 aa of the p24 region at the C-terminus and has an extra 55-aa residue at the N-terminus, termed pre-S2, corresponding to gp33 and gp36. The large HBs protein (LHBs) contains, in addition to the S and pre-S2 domain, the pre-S1 domain of 119 aa (p39, gp42). In the native envelope, these different proteins are covalently linked to one another and a relatively high portion of the LHBs will result in the formation of filamentous HBsAg. In the envelope of the complete wild-type HBV particle, the composition is similar to that of the secreted HBsAg filaments, with a high proportion of LHBs. Thus, a vaccine containing HBsAg filaments should be able to induce an immune response to all three envelope antigen components.
The surface protein of HBV is the first identified blood marker for active HBV infection and has become the most important antigen for developing HBV vaccines.10,11
The first available vaccines were
generated by harvesting HBsAg from plasma samples of chronic HBV carriers. Inactivation (and prevention of possible transmission of blood-borne pathogens) of these preparations was accomplished with a combination of urea, pepsin, formaldehyde and heat. These plasma-derived vaccines were developed in France and the US and brought onto the market between 1981 and 1982.12
Upon development of recombinant DNA technology, several vaccine manufacturers applied this technique to express HBsAg by HBV- transfected yeasts (i.e. Saccharomyces cerevisiae). These so-called ‘second-generation’ recombinant DNA hepatitis B vaccines13
became
commercially available from 1986 and are now mostly used to vaccinate against hepatitis B. The small envelope S protein is released from the HBV-transfected yeast and purified to eliminate yeast components using, for example, filtration or chromatography.
During the 1990s, the so-called ‘third-generation’ vaccines were manufactured by transfecting mammalian cells with HBV. These express and secrete the small S and the mid pre-S2 proteins or all three envelope proteins – S, pre-S2 and the large pre-S1 protein.9,14,15 Pre-S antigens, in particular pre-S1, express highly immunogenic T- and B-cell epitopes, and the first antibodies to occur following natural infection are directed against the pre-S antigens.
Both the new pre-S/S HBV vaccines and some new adjuvants have been proved to enhance immunogenicity in immunocompromised individuals as well as in non-responders to the conventional vaccines.
Immune Deficiency in Chronic Renal Failure
The immune system is strongly influenced by failing kidney function. The alterations involve unspecific mechanisms such as phagocytosis as well as highly antigen-specific T-cell activation. The latter is particularly relevant for vaccination responses, at least against the typical viral antigens. Uraemic intoxication alters the capability of antigen-presenting cells (APCs) to activate T-lymphocytes. This activation process physiologically requires a primary antigen-specific signal that selects T cells based on their T-cell-receptor specificity. In addition, modulating secondary signals are needed to direct the mode of activation of the selected T-cell clone. APCs of patients with chronic renal failure provide impaired secondary signals in the T-cell activation process. In particular, the expression of the co-stimulatory molecule CD86 on the surface of APCs is reduced in chronic renal failure.16
The
signal transmitted by CD86 is important for the production of the major T-cell activation factor interleukin-2 (IL-2), which is required
EUROPEAN NEPHROLOGY
for clonal expansion. Such expansion is needed both for cellular effector function and for helper function towards B cells in the process of antibody formation.
The CD86 signal is most relevant during primary T-cell responses to antigens the patient has never been in contact with before. Memory responses can be initiated even in the absence of this signalling. Consequently, primary immune responses involving T-cell-dependent antigens are diminished in chronic renal failure, while memory responses are not. Reduced expression of CD86 on circulating monocytes of the patients is closely associated with hepatitis B vaccine non-response.16
In addition to mechanisms involving APC surface molecules, the pattern of soluble immune mediators is deviated in chronic renal failure as well. A hallmark of kidney dysfunction is the overproduction of pro-inflammatory cytokines by monocytes.17
modify immune responses in several ways. High levels of IL-1018 IL-1219
These cytokines and
seem to be of major relevance for patients with CKD. IL-10 is a
counter-regulator of inflammation and high levels of this cytokine limit cytokine excesses, thereby supporting physiological T- and B- lymphocyte function. A highly prevalent genetic polymorphism that leads to elevated production of IL-10 during inflammatory responses is associated with hepatitis B vaccination response in dialysis patients.20
While IL-10 influences the probability and magnitude of a
serological immune response to viral antigens, IL-12 is an important regulatory cytokine that modulates T-cell differentiation. Chronic renal failure patients mostly have high production of this substance, which results in deviation of T-cell responses from B-cell help (T-helper cell type 2 [Th2] response) towards a cytotoxic T-cell effector function (Th1 response).19
Consequently, high levels of IL-12 are associated with serological non-response upon vaccination.
The experimental data leading to our current understanding of the immune defect in chronic renal failure were collected some 10–15 years ago. Since then, dialysis technology and intensity have improved. The immune defect seems to be less intense nowadays but, nevertheless, the main mechanisms are still in place.
Immune dysfunction is caused by the retention of toxic metabolic products that are physiologically cleared through the kidneys. Many different substances are involved, mostly in the molecular weight range between 500 and 5,000Da. Among them are toxic phenol derivates as well as immunoactive proteins; the latter are particularly interesting since they may directly influence immune functions. The kidneys have clearance function for many cytokines and immune proteins with a molecular weight below 50kDa. Due to this molecular mass they are glomerularly filtered and subsequently metabolised by the tubular system. With failing kidney function the clearance of such proteins is decreased and plasma concentrations rise. This has been shown for cytokines (IL-1,21 cytokine receptors (IL-1RA,23 factor-alpha [TNF-α] or IL-624 endotoxin receptor sCD14.25
interferons [IFNs]22 ),
soluble receptors for tumour necrosis ) or other proteins such as the soluble In addition, uraemia alters several
metabolic pathways and leads to a pro-oxidant state with reduced antioxidative capacity and enhanced production of advanced oxidated or glycated proteins.26
These alterations all contribute to
the syndrome of impaired immune functions in uraemic patients and contribute to the impaired vaccination response rates commonly seen in these individuals.
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