Chronic Kidney Disease
Classic Vaccination Schedules and Protection Rates
The standard HBV vaccination schedule in healthy adults ranges from 10 to 20µg per dose in a three- or four-vaccination-step schedule, given intramuscularly at zero, one and six months or zero, one, two and 12 months. Seroprotection rates are approximately 95% in healthy adults.27
In elderly people, the obese, heavy smokers
or immunocompromised individuals, including those suffering from CKD28
or infected with HIV, HBV vaccination is less effective. This is
demonstrated by the lower conversion rates present in CKD patients, lower antibody titres and rapid decline of antibody levels.29 They therefore require higher doses of vaccine and more injections (i.e. at zero, one, two and six months). There are several HBV vaccines available for patients suffering from CKD, in particular for pre-dialysis and dialysis patients. Recombivax HB® and Engerix® are the best known for HBV vaccination of CKD patients.1,30,31
Recombivax
HB (Merck, Sharp&Dhome; or HBVAX PRO) contains 40µg/ml per dose and CKD patients receive three doses at zero, one and six months. Engerix-B (SmithKline Beecham) is used as two doses of 1ml containing 20µg/ml HBsAg each per vaccination step and vaccination is performed using four time-points of vaccination, i.e. zero, one, two and six months. Fendrix® (GlaxoSmithKline), licensed as of 2004 in Europe, is dosed as 20µg/0.5ml and has the new adjuvant AS04 in addition to alum, and four time-points are used for vaccination.32
Response rates ranged from 67 to 86%, but data of 48.5 and 30% have also been reported – the first in a clinical controlled trial and the second in an uncontrolled setting.33
Usually, a rapid loss of anti-HBs
levels is observed in CKD patients; titres below 10IU/l require a booster vaccination followed by serology testing.34
The current HBV vaccination protocol for patients suffering from CKD in North American and European dialysis centres consists of the use of a reinforced vaccination series of four inoculations of Engerix B (40µg),30
three doses of Recombivax HB or four doses of Fendrix
(20µg). More research (randomised clinical trials) is warranted before a definitive recommendation can be made with respect to HBV vaccination of CKD patients.
Is Serology Adequate to Monitor Hepatitis B Virus Vaccination Response?
Serology is often used as readout for assessing adequate protection upon vaccination.35
Adequate protection is defined as having an anti-
HBs titre >10IU/l. Based on serology, a division can be made into non- responders, with titres <10IU/l, and responders, with titres ≥10IU/l; in Europe a subdivision is made in the responder population, i.e. weak responders, having a titre of 10–100IU/l, and strong responders, with anti-HBs titres >100IU/l.
Is serology the gold standard for determining vaccination efficacy? Evidence exists that individuals that have lost antibodies to HBsAg usually show an anamnestic response upon receiving a booster vaccination or exposure to HBV, demonstrating that immunological memory (i.e. antigen-specific T/B cells) can outlast the anti-HBs detection and thus provide protection against acute disease or chronic carrier state.36,37
However, this generally holds true for
immunocompetent individuals, while for the immunocompromised regular testing and booster administrations when anti-HBs levels fall below 10IU/l are needed.38
16
Protection against T-cell-dependent antigens also depends on development of an adequate antigen-specific T-cell response upon vaccination,39
which requires the presence of efficient APCs.
Patients with end-stage renal disease (ESRD) show clinical signs of an immune defect characterised by an increased susceptibility for infections and a decreased serological response to T-cell-dependent antigens.40
The contribution of specific T-cell subsets to this immune
deficiency is not known. Progressive loss of renal function is accompanied by significant changes in T-cell subsets with a selective depletion of naïve T-cells.41
a detailed analysis of HBV-vaccination-induced antigen-specific T-cell responses within recently defined memory T-cell subsets and comparing ESRD patients with age-/sex-matched healthy donors.42
Results revealed
different kinetics of antigen-specific T-cell development, with a delayed development of central memory T-lymphocytes that are able to home to secondary lymph nodes and aberrant or defective development of effector memory CD4+ T-lymphocytes able to migrate to the periphery.42 In particular, IL-2-producing HBsAg-specific effector memory CD4+ T cells are poorly generated. These cells are closely related to lowered HBsAg-specific proliferation and anti-HBsAg immunoglobulin G (IgG) titres. Forty per cent of the ESRD patient population did not reach adequate antibody titre, whereas all of the healthy donors did. Higher protection rates may be achieved by improving adjuvants, but the route of administration and site of injection are also very important in achieving an optimal response.43
Alternative Application Modes
It has long been known that the way the vaccine is applied matters in terms of vaccination efficacy. The classic route for intramuscular vaccines used to be into the gluteus muscle. However, injection into the deltoid muscle was found to be superior in healthcare workers.44 This led to the recommendation for patients with renal failure to exclusively use the deltoid muscle for injection. However, this may still not be the optimal route of application. Vaccines injected into the muscle address local lymph nodes as the major place of antigen presentation and T-cell activation. The skin has access to a large capacity of antigen presentation via its dendritic cells. These might be more efficient for T-lymphocyte activation than lymph node and blood APCs. With this hypothesis in mind, several studies tried to overcome vaccination resistance in chronic renal failure patients by fractionated intradermal injection of hepatitis B vaccine. The vaccine was applied strictly intradermally, since subcutaneous injection did not induce a sufficient immune response.44
The results of smaller
studies were mixed. A 2006 meta-analysis concluded, based on results in 640 patients from 12 studies, that intradermal vaccination resulted in a higher primary vaccination response rate than intramuscular application in chronic renal failure.45
However, this
benefit did not last over the follow-up periods. Due to the relative effort of the intradermal vaccination procedure (in many studies 16 injections of 5µg of vaccine over a period of 32 weeks), this application route did not become widely established.
Fifty-nine chronic dialysis patients who did not reach a minimum of 10mIU/ml anti-HBs after three intramuscular injections of 40µg of hepatitis B vaccine at months zero, one and six were randomised to receive either two further intramuscular injections of 40µg Engerix-B eight weeks apart or two intradermal injections per
Intradermal hepatitis B vaccination might be a useful tool in previous non-responders, as suggested by a recent randomised controlled trial.46
EUROPEAN NEPHROLOGY
The current authors were the first to perform
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100