Vaccine Non-responders Research Articles

Recombinant hepatitis B vaccination in renal failure patients.

Hepatitis B (HB) in haemodialysis patients results in morbidity and mortality, through chronicity, which leads to cirrhosis and liver carcinoma, even after renal transplantation. Hepatitis B vaccination is protective against HB virus infection. Suppressed immunity in renal failure leads to low HB vaccination success rates. Uremia, inadequate dialysis, use of low biocompatibility dialysis material, hyperparathyroidism, anemia, iron overload and malnutrition are all factors contributing to depressed immunity. Renal failure, associated with chronic inflammation, leads to impaired monokine production which results in decreased immunity. This impairment could result from defective HLA-DR B7-2 expression on monocytes. Hepatitis B vaccination non-responders express increased levels of HLA class II alleles (T-cell immune response modulators) DRB1 01 (DR1) and DRB1 15 (DR15). Various methods have been used to enhance the immune response to HB vaccination such as recombinant adjuvants, thymopentine, IL-2, levamisole and GM-CSF: they have produced variable results. Better dialysis biocompatibility and adequacy have also been conducted to overcome this low immune response. Response to conventional intramuscular HB vaccination is considered an index of adequate dialysis and low inflammatory state, both associated with better cardiovascular outcome and survival. HB vaccination reinforcement techniques evolved from an initial intramuscular double/multiple-dosing regimen to more frequent intradermal smaller dose injection. This newer regimen achieves a higher and almost complete seroconversion rate, although frequent boosters shots are necessary to maintain protective levels. Experience with pre-S1/S2, third generation, vaccines is limited and they have not been proven to be more effective than intradermally administered S antigens. Recombinant HB vaccines, intradermally administered, have been shown to elicit an immune response in all renal failure patients. Additionally the use of recombinant erythropoietin treatment to correct anemia contributes to this success.

Low response to HBsAg vaccine in chronic renal failure patients is not due to intrinsic defect of B cells.

The aim of this study was to investigate whether the inability of chronic renal failure patients to mount an adequate antibody response following hepatitis B vaccination was due to an inherent defect in the antibody producing capacity of their B cells. Peripheral blood mononuclear cells of end stage renal disease (ESRD) patients, who were not on maintenance hemodialysis (CRF) and those undergoing long-term hemodialysis (HD) were stimulated in vitro with pokeweed mitogen, a B cell mitogen or hepatitis B surface antigen. The total immunoglobulin (IgG, IgM and IgA) levels and anti-HBs specific IgM and IgG were quantitiated by sandwich ELISA and levels between patients who had a good antibody response in vivo and those who failed to mount an antibody response were compared. Spontaneous IgG production was significantly higher than normals in CRF and HD group; PWM induced IgM, IgG and IgA production was comparable to normals in both groups of patients. The spontaneous IgG and PWM stimulated IgM and IgG production was significantly higher in HD patients as compared to CRF. The in vitro Ig levels in the vaccine responders and non-responders was comparable except for the spontaneous IgG which was highest in the responders. The in vitro anti-HBs production was comparable in HB vaccine responders and non-responders; the in vivo and in vitro anti-HBs titers showed a significant correlation coefficient thereby indicating that the in vitro assay reflects the in vivo functional status of B cells. Our results demonstrate that the B cells in ESRD patients are functionally normal and cannot be the cause of the compromised vaccine response in these patients.

Occupationally Acquired Infections and the Healthcare Worker *

Much of the recent research related to occupational infections in healthcare workers has focused on the evaluation of the effectiveness of preventive measures, the cost-effectiveness of such measures, and alternative approaches to preventing common occupational infections. This article reviews recent information on healthcare workers about occupationally acquired diseases and considers the risks from unusual or re-emerging pathogens. Among recent advances of note are effective post-exposure prophylaxis for HIV, approaches to achieving immunity to hepatitis B in vaccine non-responders, better diagnostic tests for hepatitis C and improved equipment for preventing blood exposure and tuberculosis.

Complex cytokine responses to hepatitis B surface antigen and tetanus toxoid in responders, nonresponders and subjects naive to hepatitis B surface antigen

Some human subjects vaccinated with hepatitis B surface antigen (HBsAg) do not produce antibodies to the vaccine (nonresponders). The mechanism for nonresponse is unknown. To understand the response and nonresponse to nominal antigens better, we determined the level and kinetics of cytokine secretion in response to HBsAg and tetanus toxoid (TT) by peripheral blood mononuclear cells (PBMC) in vitro from HBsAg vaccine responders and nonresponders and from individuals naive to HBsAg. Proliferating PBMC secreted peak levels of interleukin-2 (IL-2) at 2 days and peak levels of tumor necrosis factor-beta (TNF-β), interferon-gamma (IFN-γ), IL-4 and IL-10 at 3–6 days post-stimulation. In contrast, nonproliferating PBMC (whether from nonresponders, naive subjects or weak responders) did not produce detectable levels of TNF-β or IFN-γ, nor was IL-4 or IL-10 produced significantly, and that produced had a different kinetic profile from that of proliferating PBMC. HBsAg-specific cytokine production by PBMC from strong responders broadly paralleled their cytokine responses to TT. Cellular cytokine mRNA levels measured by reverse transcriptase-polymerase chain reaction corroborated the secreted cytokine results. The anti-HBsAg- and anti-TT-specific T cell cytokine responses were mixed Th1/2-like and donor-specific. An HBsAg-specific cytokine response, but not a TT-specific cytokine response, was completely missing in nonresponders. These data suggest that the T cell defect of HBsAg nonresponse is not due to a skewed cytokine profile.

Cellular and humoral immune responses induced by intradermal or intramuscular vaccination with the major hepatitis B surface antigen.

The vaccination route may influence the success of immunization against pathogens. The conventional intramuscular (i.m.) application of a vaccine containing the hepatitis B virus (HBV) surface antigen (HBsAg) led to protective anti-HBs antibody levels in the majority of vaccine recipients. In this study, we vaccinated healthy volunteers and a group of i.m. vaccine nonresponders via the intradermal (i.d.) route and analyzed the HBV-specific B-cell response as well as class-II- and class-I-restricted T-cell responses by (3)H-thymidine uptake, enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunospot assay (ELISPOT). The results were then compared with i.m. vaccinated controls. I.d. vaccinations were well tolerated and induced neutralizing anti-HBs antibodies in all naive vaccine recipients and, importantly, all but one former i.m. nonresponder developed protective anti-HBs serum antibody levels after 2 or 3 i.d. immunizations. On the cellular level, i.d. vaccine recipients showed significantly higher anti-HBs producing B-cell frequencies and more vigorous class-II-restricted T-helper (Th) cell responses than i.m. controls. However, although the HBsAg-specific T cells were characterized by their cytokine release as Th1-like cells in both groups, human leukocyte antigen (HLA)-A2+ individuals who received the soluble HBsAg via the i.d. route developed higher peptide-specific cytotoxic CD8+ T cell precursor (CTLp) frequencies. In conclusion, i.d. HBsAg vaccination is more effective even in former i.m. vaccine nonresponders with respect to antibody induction and specific B- and T-cell responses. The induction of virus-specific CTLp may provide the rationale to study the i.d. HBsAg vaccine in the treatment of chronic hepatitis B.

Northern region asplenia register--analysis of first two years.

OBJECTIVES: To assess the feasibility of setting up a register of patients with asplenia within a defined geographical area; to ensure that guidelines on best practice were implemented; to obtain...

Mechanism of action of vaccine therapy in murine hepatitis B virus carriers: vaccine-induced activation of antigen presenting dendritic cells

Background/Aims: Vaccine therapy in which vaccine containing hepatitis B surface antigen (HBsAg) is injected has shown therapeutic activity (vaccine therapy) in some human and murine chronic hepatitis B virus (HBV)-carriers. Using HBV-transgenic mice (HBV-Tg), an animal model of the HBV-carrier state, the mechanism underlying the antiviral and immune modulatory capacity of vaccine therapy was studied. Methods: Placebo-controlled, double-blind trials of vaccine therapy were conducted in HBV-Tg; some HBV-Tg responded to the therapy, whereas others were non-responders. The titers of HBV-markers, the functions of lymphocytes and antigen presenting dendritic cells were compared between vaccine responders and vaccine non-responders. Results: The prevaccinated titers of HBsAg, hepatitis B e antigen (HBeAg), HBV DNA and the responses of lymphocytes to polyclonal mitogens were almost unchanged between responders and non-responders, but the levels of proliferation of HBsAg-specific lymphocytes from non-responders was significantly lower than responders ( p<0.05). The capacity of dendritic cells to induce proliferation of T cells and production of antibody to HBsAg (anti-HBs) was significantly higher in responders compared with non-responders ( p<0.05). Injection with HBsAg resulted in upregulation of MHC class II and CD86 antigens ( p<0.05) on dendritic cells and increased production of IL-12, IL-2 and TNF-α in cultures ( p<0.05) in vaccine responders but not in non-responders. Conclusions: The activation of dendritic cells following injection with vaccine containing HBsAg is the vital factor underlying the therapeuticpotentiality of vaccine therapy in HBV carriers.

Occupationally acquired infections and the healthcare worker

Much of the recent research related to occupational infections in healthcare workers has focused on the evaluation of the effectiveness of preventive measures, the cost-effectiveness of such measures, and alternative approaches to preventing common occupational infections. This article reviews recent information on healthcare workers about occupationally acquired diseases and considers the risks from unusual or re-emerging pathogens. Among recent advances of note are effective post-exposure prophylaxis for HIV, approaches to achieving immunity to hepatitis B in vaccine non-responders, better diagnostic tests for hepatitis C and improved equipment for preventing blood exposure and tuberculosis.

Randomized, comparative trial of 20 μg vs 40 μg Engerix B vaccine in hepatitis B vaccine non-responders

Fifty-two adults who had previously received 4 × 20 μg doses of hepatitis B [Engerix-B] vaccine (appropriately administered into the deltoid muscle) and who had failed to develop detectable anti-HBs were randomized to receive a fifth dose of Engerix-B (either 20 μg or 40 μg) intramuscularly (deltoid). The participants were blinded as to the contents of the syringe. Anti-HBs was tested (by EIA) 3 months after the injection. Anti-HBs results from 45 non-responders were evaluable. Seven vaccinees were excluded; four of these on the basis of failure to have follow-up blood collected and three who were found to be anti-HBc positive (one HBsAg positive). Twelve of 22 (54.5%) of those receiving 20 μg of HB vaccine developed anti-HBs, whereas 10 of 23 (43.5%) who received 40 μg developed anti-HBs, showing no significant difference between the regimens. The mean geometric titres were 93 ± 50 and 86 ± 51 IU l −1, respectively. Vaccinee groups were well matched for age, sex and body mass index and the interval between injection and bleeding. Side-effects in those receiving the double (40 μg) dose were no different from those receiving the normal (20 μg) adult dose. On the basis of this study, a fifth dose of vaccine in non-responsive vaccinees is recommended. No significant advantage of 40 μg over 20 μg of vaccine was observed. Whilst smoking and obesity were common in this cohort of non-responders and probably contributed to the individuals primary non-responsive state, these factors had no unfavourable effect on response to a fifth dose of vaccine.

Polymorphisms of the TAP2 gene may influence antibody response to live measles vaccine virus

The transporter associated with antigen processing (TAP) gene products transport peptides from the cytosol to the endoplasmic reticulum for processing by the immune system. We hypothesized that polymorphisms within the TAP genes may influence measles vaccine antigen processing and hence antibody response. TAP genotypes were determined for subjects who were measles vaccine nonresponders ( n=32) and hyper-responders ( n=28). TAP1 and TAP2 alleles were determined by PCR amplification of specific alleles (PASA). Measles vaccine nonresponders were more likely to be homozygous at TAP2 position 665 than were hyper-responders (OR=5.0, P=0.016). Lastly, a trend was found in the overall distribution of all TAP2 genotype frequencies between hyper-responders and nonresponders ( P=0.08). No association was found between TAP1 polymorphisms and vaccine response. These data reveal an association between TAP2 genotype and measles vaccine antibody response which may explain one mechanism behind vaccine failure.

Randomized comparative trial of interferon-α versus placebo in hepatitis B vaccine non-responders and hyporesponders

Adults who had received 4 x 20 μg doses of hepatitis B (Engerix-B) vaccine (appropriately administered) and who had failed to develop detectable anti-HBs or who had had a minimal response ( < 10 IU 1 −1) were randomized to receive either a fifth dose of Engerix-B (20μg) plus 1 million units of interferon-α or a fifth dose of vaccine plus saline placebo intramuscularly (deltoid). Both vaccine and test material were given together in one syringe and participants were blind as to the syringe contents. Anti-HBs was tested (by enzyme immunoassay) one to three months following the injection. Anti-HBs results from the 150 non-responders (NR) and the 26 hyporesponders (HR) are reported. Of NRs receiving a fifth dose plus placebo, 41% developed anti-HBs, whilst 53% of those receiving interferon-α developed anti-HBs. The response rates did not differ significantly. Of HRs receiving vaccine plus placebo, 70% showed an increase in their anti-HBs titre, while 87.5% of those receiving interferon-α with vaccine had titre rises. Vaccinee groups were well matched for age, sex and body mass index and the interval between injection and venepuncture. Side-effects from interferon-α were of short duration and were tolerated by vaccinees seeking protection from hepatitis B infection. On the basis of this study, a fifth dose of vaccine in non- and hyporesponsive vaccinees is recommended. Interferon-α was of unproven value but it may increase the likelihood of seroconversion in NRs and its use could be considered in subjects at continued high risk of contracting hepatitis B. Anti-HBs responses were measurably higher in interferon-α recipients than in placebo recipients.

Chasing the escape mutant

Chasing the escape mutant

Increased serum HLA class I molecule levels in elderly human responders to influenza vaccination

Increased cell surface expression and serum levels of HLA class I molecules have been shown to occur in normal elderly humans. Elderly subjects (65 years and older) generally also have a poorer response to influenza vaccine than younger adults. Some 30 to 40% of elderly subjects do not respond to influenza vaccination. Sera from 20 elderly subjects with a positive response to influenza vaccine (HAI antibody titer > 40) and 20 subjects who did not respond (HAI antibody titer < 40) were randomly selected and the levels of soluble HLA class I molecules determined before and after vaccination. The subjects who responded had higher serum HLA class I levels both before and after vaccination than did non-responders. Two weeks after vaccination non-responders showed similar serum HLA class I levels (1.78 mg/ml +/- 0.62) as compared to prevaccination levels (1.73 mg/ml +/- 0.49). The responders showed significantly higher levels of soluble HLA class I molecules following vaccination (2.64 mg/ml +/- 0.99) as compared to pre-vaccination (2.08 mg/ml +/- 0.85, p = 0.00001). Our results suggest that measuring soluble HLA class I molecules in the serum may be useful in assessing the adequacy of response to influenza vaccination in the elderly population.

Measles

Measles has become epidemic over most of the world, with an important increase in the number of cases and associated morbidity and mortality in the United States since 1986. The two major factors responsible for this rise in the number of cases are, first, the increase in unvaccinated preschool-age children and, second, vaccine nonresponders (approximately 5%). The highest attack rate occurred in teenagers (15 to 19 years old) and in nine states (82% of cases). This situation has prompted revised immunization recommendations for those counties reporting more than five cases of measles among preschool-age children during each of the previous 5 years. In these counties, a first dose with monovalent measles vaccine is recommended at 9 months of age, followed by a second dose with measles, mumps, and rubella vaccine at 15 months of age, and revaccination of all children at the time of school entry. Recent publications regarding the use of vitamin A and certain antiviral agents are encouraging and are discussed in the manuscript. All cases of measles should be reported and investigated promptly. A good outbreak-control program will depend on the rapid recognition of the disease, a team approach, and prompt vaccination or IgG administration to susceptible persons.

Diminished response to recombinant hepatitis B vaccine in homosexual men with HIV antibody: An indicator of poor prognosis

Three doses of a recombinant DNA HBV vaccine (MSD) were given to healthy male homosexuals. Seventy-eight out of 104 (77.6%) participants had detectable antibody (anti-HBs) two months after the third dose. Seroconversion occurred in only 9 out of 27 subjects (33.3%) who were anti-HIV positive compared with 69 out of 77 (89.6%) who were negative (chi 2 = 30.8; P less than .001). Fifteen of the 18 anti-HIV positive who did not mount an antibody response to the hepatitis B vaccine (anti-HBs) later progressed to persistent generalised lymphadenopathy syndrome (5), AIDS-related complex (5), and AIDS (5). Only one of the nine anti-HIV positive anti-HBs responders developed PGL (chi 2 = 10.14; P less than .005). Our results show that anti-HIV positive homosexuals are poor responders to the recombinant hepatitis B vaccine and anti-HIV positive non-responders are more likely to develop clinically apparent HIV infection.

Correlation between peripheral lymphocyte subsets and antibody to hepatitis B surface antigen response in hepatitis B vaccine recipients.

Peripheral lymphocyte subsets of 14 heterosexual recipients of hepatitis B vaccine were measured by indirect immunofluorescence using specific monoclonal antibodies. 12/14 vaccine recipients developed antibody to hepatitis B surface antigen after the second injection of vaccine; however, 2 recipients remained seronegative. Prior to the vaccination, these two vaccine non-responders had been found to have a significantly reduced ratio of peripheral helper-inducer T cells to suppressor/cytotoxic T cells (1.15 +/- 0.02 vs. 1.79 +/- 0.12), and an increase in the proportion of natural killer/killer cells (25.6 +/- 1.5% vs. 13.8 +/- 1.6%) as compared to the 12 responders. Enumeration of peripheral lymphocyte subsets prior to vaccination may be useful in predicting the immune response of hepatitis B vaccine recipients.