Granulocyte Macrophage Colony Stimulating Factor (Gm-Csf) Induced Sero-Protection in End Stage Renal Failure Patients to Hepatitis B in Vaccine Non-Responders

Abstract

Hepatitis B (HB) virus infection is a major health problem in dialysis dependent end stage renal failure (ESRF) patients. The sero-conversion rate after recombinant HB vaccine in ESRF patients is poor. Adjuvants like Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) have been found to improve response rate to vaccines. This study was conducted to evaluate the efficacy of GM-CSF as an adjuvant to HB vaccine in ESRF patients who were non-responders to the usual three double dose vaccinations (primary non-responders). Fifty consecutive HBsAg negative and anti-HBs negative ESRF patients on hemodialysis over thirty months were prospectively included (Jan. 96-June 98). All received 40 microg of recombinant HB vaccine at 0, 1, 2 month interval. Anti-HBs titres were subsequently tested after four weeks of the third dose. There were 19 (38%) primary non-responders (antiHBs negative). Twelve (Group I) of primary non-responders were given an additional dose of HB vaccine with 300 microg (5-6 microg/kg) of GM-CSF (Leucomax) and the remaining seven (Group II) received only an additional dose of HB vaccine. Anti-HBs was determined by Abbott's ELISA kit, and titre above 10 mIU/mL was considered as protective. In Group I, sero-protective titres were obtained in 11 out of 12 (91.6%) patients, whereas in Group II none of the patients achieved sero-protection (p < 0.001). The sero-conversion rate improved from initial 62% (31/50) to overall 84% (42/150) after the use of GM-CSF. There were no adverse events noted with the use of GM-CSF. At one year, 24 out of 32 (75%) who were sero-protected earlier continued to remain sero-protected. This study indicates that GM-CSF is a potent HB vaccine adjuvant for sero-conversion in primary non-responders.

Hydrogel-Delivered GM-CSF Overcomes Nonresponsiveness to Hepatitis B Vaccine through the Recruitment and Activation of Dendritic Cells

“…Several previous clinical studies attempted to use GM-CSF as a bolus injection to improve the efficacy of HBsAg vaccine in healthy nonresponders (22) and in hemodialysis patients (23)(24)(25)(26)(27)(28)(29). However, in general, the improvement in vaccine efficacy was not impressive, which might be due to the short serum half-life of GM-CSF (41) and the low local GM-CSF concentration at the point where the immune response was taking place.…”

“…As a result, GM-CSF, in the form of a recombinant protein or a gene product encoded by plasmid DNA or viral vectors, has been codelivered as an adjuvant and has proved effective in enhancing immune responses to a number of vaccines (20,21). In terms of HBV vaccines, systemic administration of rGM-CSF was investigated as an adjuvant in healthy nonresponders (22) and in hemodialysis patients (23)(24)(25)(26)(27)(28)(29). However, in these studies, GM-CSF showed no effect or only moderately increased the seroconversion rate and anti-HBs titers.…”

Lower peripheral blood CD14+ monocyte frequency and higher CD34+ progenitor cell frequency are associated with HBV vaccine induced response in HIV infected individuals

“…However, the complex milieu of immune defects associated with HIV infection create unique challenges in formulating appropriate vaccine enhancing adjuvants. GM-CSF, when administered as a vaccine adjuvant, has been observed to improve HBV vaccine efficacy in the setting of renal failure [10, 11] and in the setting of HIV infection[12]. In AIDS Clinical Trials Group (ACTG) study A5220, GM-CSF administration was not found to improve HBV vaccine responses[13].…”

Non-conventional expression systems for the production of vaccine proteins and immunotherapeutic molecules

“…In 2002, P. pastoris was approved in 2002 by the World Health Organization (WHO) for the production of an HBV vaccine biosimilar by Shantha Biotechnologies (a Sanofi company), and this biosimilar has recently been shown to be potentially more effective than vaccines produced in S. cerevisiae in particular patient groups. 33,34 Hyper-mannosylation, a well-known limitation of conventional yeast systems, is weaker in P. pastoris, which has been engineered to produce human-like glycosylation of recombinant proteins by knocking out 4 glycosylationassociated genes and introducing more than 14 heterologous genes. 35,36 In 2004, this technique resulted in the development of Glycoswitch Ò from Merck, a technology allowing for uniform Man5 N-glycosylation and development of a set of vectors to express glycan-modifying enzymes in yeast strains not limited to P. pastoris.…”

“…It shows low viscosity morphology, allowing easy, large-scale, high-cell-density growth in fermenters using inexpensive substrates. Furthermore, this fungus supports broad ranges of pH (4.5-7.0) and temperature (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44) C) for growth. A C1 genetic toolbox is available, and the 3eight megabase pair genome has been sequenced, enabling the development of various gene expression strategies.…”