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For patients age 16 and older with advanced chronic kidney disease (CKD), including those undergoing hemodialysis, we recommend a higher dose of hepatitis B virus (HBV) vaccine, more doses, or both. Vaccination with a higher dose may improve the immune response. The hepatitis B surface antibody (anti-HBs) titer should be monitored 1 to 2 months after completion of the vaccination schedule and annually thereafter, with a target titer of 10 IU/mL or greater. For patients who do not develop a protective antibody titer after completing the initial vaccination schedule, the vaccination schedule should be repeated.
RECOMMENDED DOSES AND SCHEDULES
Recommendation 1
Give higher vaccine doses, increase the number of doses, or both.
Recommendation 2
A 4-dose regimen may provide a better antibody response than a 3-dose regimen. (Note: This recommendation applies only to Engerix-B; 4 doses of Recombivax-HB would be an off-label use.)
Rationale. The US Centers for Disease Control and Prevention reported that after completion of a 3-dose vaccination schedule, the median proportion of patients developing a protective antibody response was 64% (range 34%–88%) vs a median of 86% (range 40%–98%) after a 4-dose schedule.3
Lacson et al5 compared antibody response rates after 3 doses of Recombivax-HB and after 4 doses of Engerix-B and found a better response rate with the 4-dose schedule. The rate of persistent protective anti-HBs titer after 1 year was 77% for Engerix-B vs 53% for Recombivax-HB.
Agarwal et al6 evaluated response rates in patients who had mild CKD (serum creatinine levels 1.5–3.0 mg/dL), moderate CKD (creatinine 3.0–6.0 mg/dL), and severe CKD (creatinine > 6.0 mg/dL). The seroconversion rates after 3 doses of 40-μg HBV vaccine were 87.5% in those with mild CKD, 66.6% in those with moderate CKD, and 35.7% in those with severe disease. After a fourth dose, rates improved significantly to 100%, 77%, and 36.4%, respectively.
Recommendation 3
In patients with CKD, vaccination should be done early, before they become dependent on hemodialysis.
Rationale. Patients with advanced CKD may have a lower seroconversion rate. Fraser et al7 found that after a 4-dose series, the seroprotection rate in adult prehemodialysis patients with serum creatinine levels of 4 mg/dL or less was 86%, compared with 37% in patients with serum creatinine levels above 4 mg/dL, of whom 88% were on hemodialysis.7
In a 2003 prospective cohort study by DaRoza et al,8 patients with higher levels of kidney function were more likely to respond to HBV vaccination, and the level of kidney function was found to be an independent predictor of seroconversion.8
A 2012 prospective study by Ghadiani et al9 compared seroconversion rates in patients with stage 3 or 4 CKD vs patients on hemodialysis, with medical staff as controls. The authors reported seroprotection rates of 26.1% in patients on hemodialysis, 55.2% in patients with stage 3 or 4 CKD, and 96.2% in controls. They concluded that vaccination is more likely to induce seroconversion in earlier stages of kidney disease.9
MONITORING THE RESPONSE TO VACCINATION AND REVACCINATION
Testing after vaccination is recommended to determine response. Testing should be done 1 to 2 months after the last dose of the vaccination schedule.1–3 Anti-HBs levels 10 IU/mL and greater are considered protective.10
Revaccination with a full vaccination series is recommended for patients who do not develop adequate levels of protective antibodies after completion of the vaccination schedule.2 Reported response rates to revaccination have varied from 40% to 50% after 2 or 3 additional intramuscular doses of 40 µg, to 64% after 4 additional intramuscular doses of 10 µg.3 Serologic testing should be repeated after the last dose of the vaccination series, as serologic testing after only 1 or 2 additional doses appears to be no more cost-effective.2,3
To the best of our knowledge, no data exist to indicate that in nonresponders, further doses given after completion of 2 full vaccination schedules would induce an antibody response.
ANTIBODY PERSISTENCE AND BOOSTER DOSES
Antibody levels fall with time in patients on hemodialysis. Limited data suggest that in patients who respond to the primary vaccination series, antibodies remain detectable for 6 months in 80% to 100% (median 100%) of patients and for 12 months in 58% to 100% (median 70%) of patients.3 The need for booster doses should be assessed by annual monitoring.2,11 Booster doses should be given when the anti-HBs titer declines to below 10 IU/mL. Limited data indicate that nearly all such patients would respond to a booster dose.3
OTHER WAYS TO IMPROVE VACCINE RESPONSE
Other strategies to improve vaccine response, such as the addition of adjuvants or immunostimulants, have shown variable success.12 Intradermal HBV vaccination in patients on chronic hemodialysis has also been proposed. The efficacy of intradermal vaccination may be related to the dense network of immunologic dendritic cells within the dermis. After intradermal administration, the antigen is taken up by dendritic cells residing in the dermis, which mature and travel to the regional lymph node where further immunostimulation takes place.13
In a systematic review of four prospective trials with a total of 204 hemodialysis patients,13 a significantly higher proportion of patients achieved seroconversion with intradermal HBV vaccine administration than with intramuscular administration. The authors concluded that the intradermal route in primary nonresponders undergoing hemodialysis provides an effective alternative to the intramuscular route to protect against HBV infection in this highly susceptible population.
Additional well-designed, double-blinded, randomized trials are needed to establish clear guidelines on intradermal HBV vaccine dosing and vaccination schedules.
- Grzegorzewska AE. Hepatitis B vaccination in chronic kidney disease: review of evidence in non-dialyzed patients. Hepat Mon 2012; 12:e7359.
- Chi C, Patel P, Pilishvili T, Moore M, Murphy T, Strikas R. Guidelines for vaccinating kidney dialysis patients and patients with chronic kidney disease. www.cdc.gov/dialysis/PDFs/Vaccinating_Dialysis_Patients_and_Patients_dec2012.pdf. Accessed September 6, 2017.
- Recommendations for preventing transmission of infections among chronic hemodialysis patients. MMWR Recomm Rep 2001; 50:1–43.
- Kim DK, Riley LE, Harriman KH, Hunter P, Bridges CB; Advisory Committee on Immunization Practices. Recommended immunization schedule for adults aged 19 years or older, United States, 2017. Ann Intern Med 2017; 166:209–219.
- Lacson E, Teng M, Ong J, Vienneau L, Ofsthun N, Lazarus JM. Antibody response to Engerix-B and Recombivax-HB hepatitis B vaccination in end-stage renal disease. Hemodialysis international. Hemodial Int 2005; 9:367–375.
- Agarwal SK, Irshad M, Dash SC. Comparison of two schedules of hepatitis B vaccination in patients with mild, moderate and severe renal failure. J Assoc Physicians India 1999; 47:183–185.
- Fraser GM, Ochana N, Fenyves D, et al. Increasing serum creatinine and age reduce the response to hepatitis B vaccine in renal failure patients. J Hepatol 1994; 21:450–454.
- DaRoza G, Loewen A, Djurdjev O, et al. Stage of chronic kidney disease predicts seroconversion after hepatitis B immunization: earlier is better. Am J Kidney Dis 2003; 42:1184–1192.
- Ghadiani MH, Besharati S, Mousavinasab N, Jalalzadeh M. Response rates to HB vaccine in CKD stages 3-4 and hemodialysis patients. J Res Med Sci 2012; 17:527–533.
- Jack AD, Hall AJ, Maine N, Mendy M, Whittle HC. What level of hepatitis B antibody is protective? J Infect Dis 1999; 179:489–492.
- Guidelines for vaccination in patients with chronic kidney disease. Indian J Nephrol 2016; 26(suppl 1):S15–S18.
- Somi MH, Hajipour B. Improving hepatitis B vaccine efficacy in end-stage renal diseases patients and role of adjuvants. ISRN Gastroenterol 2012; 2012:960413.
- Yousaf F, Gandham S, Galler M, Spinowitz B, Charytan C. Systematic review of the efficacy and safety of intradermal versus intramuscular hepatitis B vaccination in end-stage renal disease population unresponsive to primary vaccination series. Ren Fail 2015; 37:1080–1088.
For patients age 16 and older with advanced chronic kidney disease (CKD), including those undergoing hemodialysis, we recommend a higher dose of hepatitis B virus (HBV) vaccine, more doses, or both. Vaccination with a higher dose may improve the immune response. The hepatitis B surface antibody (anti-HBs) titer should be monitored 1 to 2 months after completion of the vaccination schedule and annually thereafter, with a target titer of 10 IU/mL or greater. For patients who do not develop a protective antibody titer after completing the initial vaccination schedule, the vaccination schedule should be repeated.
RECOMMENDED DOSES AND SCHEDULES
Recommendation 1
Give higher vaccine doses, increase the number of doses, or both.
Recommendation 2
A 4-dose regimen may provide a better antibody response than a 3-dose regimen. (Note: This recommendation applies only to Engerix-B; 4 doses of Recombivax-HB would be an off-label use.)
Rationale. The US Centers for Disease Control and Prevention reported that after completion of a 3-dose vaccination schedule, the median proportion of patients developing a protective antibody response was 64% (range 34%–88%) vs a median of 86% (range 40%–98%) after a 4-dose schedule.3
Lacson et al5 compared antibody response rates after 3 doses of Recombivax-HB and after 4 doses of Engerix-B and found a better response rate with the 4-dose schedule. The rate of persistent protective anti-HBs titer after 1 year was 77% for Engerix-B vs 53% for Recombivax-HB.
Agarwal et al6 evaluated response rates in patients who had mild CKD (serum creatinine levels 1.5–3.0 mg/dL), moderate CKD (creatinine 3.0–6.0 mg/dL), and severe CKD (creatinine > 6.0 mg/dL). The seroconversion rates after 3 doses of 40-μg HBV vaccine were 87.5% in those with mild CKD, 66.6% in those with moderate CKD, and 35.7% in those with severe disease. After a fourth dose, rates improved significantly to 100%, 77%, and 36.4%, respectively.
Recommendation 3
In patients with CKD, vaccination should be done early, before they become dependent on hemodialysis.
Rationale. Patients with advanced CKD may have a lower seroconversion rate. Fraser et al7 found that after a 4-dose series, the seroprotection rate in adult prehemodialysis patients with serum creatinine levels of 4 mg/dL or less was 86%, compared with 37% in patients with serum creatinine levels above 4 mg/dL, of whom 88% were on hemodialysis.7
In a 2003 prospective cohort study by DaRoza et al,8 patients with higher levels of kidney function were more likely to respond to HBV vaccination, and the level of kidney function was found to be an independent predictor of seroconversion.8
A 2012 prospective study by Ghadiani et al9 compared seroconversion rates in patients with stage 3 or 4 CKD vs patients on hemodialysis, with medical staff as controls. The authors reported seroprotection rates of 26.1% in patients on hemodialysis, 55.2% in patients with stage 3 or 4 CKD, and 96.2% in controls. They concluded that vaccination is more likely to induce seroconversion in earlier stages of kidney disease.9
MONITORING THE RESPONSE TO VACCINATION AND REVACCINATION
Testing after vaccination is recommended to determine response. Testing should be done 1 to 2 months after the last dose of the vaccination schedule.1–3 Anti-HBs levels 10 IU/mL and greater are considered protective.10
Revaccination with a full vaccination series is recommended for patients who do not develop adequate levels of protective antibodies after completion of the vaccination schedule.2 Reported response rates to revaccination have varied from 40% to 50% after 2 or 3 additional intramuscular doses of 40 µg, to 64% after 4 additional intramuscular doses of 10 µg.3 Serologic testing should be repeated after the last dose of the vaccination series, as serologic testing after only 1 or 2 additional doses appears to be no more cost-effective.2,3
To the best of our knowledge, no data exist to indicate that in nonresponders, further doses given after completion of 2 full vaccination schedules would induce an antibody response.
ANTIBODY PERSISTENCE AND BOOSTER DOSES
Antibody levels fall with time in patients on hemodialysis. Limited data suggest that in patients who respond to the primary vaccination series, antibodies remain detectable for 6 months in 80% to 100% (median 100%) of patients and for 12 months in 58% to 100% (median 70%) of patients.3 The need for booster doses should be assessed by annual monitoring.2,11 Booster doses should be given when the anti-HBs titer declines to below 10 IU/mL. Limited data indicate that nearly all such patients would respond to a booster dose.3
OTHER WAYS TO IMPROVE VACCINE RESPONSE
Other strategies to improve vaccine response, such as the addition of adjuvants or immunostimulants, have shown variable success.12 Intradermal HBV vaccination in patients on chronic hemodialysis has also been proposed. The efficacy of intradermal vaccination may be related to the dense network of immunologic dendritic cells within the dermis. After intradermal administration, the antigen is taken up by dendritic cells residing in the dermis, which mature and travel to the regional lymph node where further immunostimulation takes place.13
In a systematic review of four prospective trials with a total of 204 hemodialysis patients,13 a significantly higher proportion of patients achieved seroconversion with intradermal HBV vaccine administration than with intramuscular administration. The authors concluded that the intradermal route in primary nonresponders undergoing hemodialysis provides an effective alternative to the intramuscular route to protect against HBV infection in this highly susceptible population.
Additional well-designed, double-blinded, randomized trials are needed to establish clear guidelines on intradermal HBV vaccine dosing and vaccination schedules.
For patients age 16 and older with advanced chronic kidney disease (CKD), including those undergoing hemodialysis, we recommend a higher dose of hepatitis B virus (HBV) vaccine, more doses, or both. Vaccination with a higher dose may improve the immune response. The hepatitis B surface antibody (anti-HBs) titer should be monitored 1 to 2 months after completion of the vaccination schedule and annually thereafter, with a target titer of 10 IU/mL or greater. For patients who do not develop a protective antibody titer after completing the initial vaccination schedule, the vaccination schedule should be repeated.
RECOMMENDED DOSES AND SCHEDULES
Recommendation 1
Give higher vaccine doses, increase the number of doses, or both.
Recommendation 2
A 4-dose regimen may provide a better antibody response than a 3-dose regimen. (Note: This recommendation applies only to Engerix-B; 4 doses of Recombivax-HB would be an off-label use.)
Rationale. The US Centers for Disease Control and Prevention reported that after completion of a 3-dose vaccination schedule, the median proportion of patients developing a protective antibody response was 64% (range 34%–88%) vs a median of 86% (range 40%–98%) after a 4-dose schedule.3
Lacson et al5 compared antibody response rates after 3 doses of Recombivax-HB and after 4 doses of Engerix-B and found a better response rate with the 4-dose schedule. The rate of persistent protective anti-HBs titer after 1 year was 77% for Engerix-B vs 53% for Recombivax-HB.
Agarwal et al6 evaluated response rates in patients who had mild CKD (serum creatinine levels 1.5–3.0 mg/dL), moderate CKD (creatinine 3.0–6.0 mg/dL), and severe CKD (creatinine > 6.0 mg/dL). The seroconversion rates after 3 doses of 40-μg HBV vaccine were 87.5% in those with mild CKD, 66.6% in those with moderate CKD, and 35.7% in those with severe disease. After a fourth dose, rates improved significantly to 100%, 77%, and 36.4%, respectively.
Recommendation 3
In patients with CKD, vaccination should be done early, before they become dependent on hemodialysis.
Rationale. Patients with advanced CKD may have a lower seroconversion rate. Fraser et al7 found that after a 4-dose series, the seroprotection rate in adult prehemodialysis patients with serum creatinine levels of 4 mg/dL or less was 86%, compared with 37% in patients with serum creatinine levels above 4 mg/dL, of whom 88% were on hemodialysis.7
In a 2003 prospective cohort study by DaRoza et al,8 patients with higher levels of kidney function were more likely to respond to HBV vaccination, and the level of kidney function was found to be an independent predictor of seroconversion.8
A 2012 prospective study by Ghadiani et al9 compared seroconversion rates in patients with stage 3 or 4 CKD vs patients on hemodialysis, with medical staff as controls. The authors reported seroprotection rates of 26.1% in patients on hemodialysis, 55.2% in patients with stage 3 or 4 CKD, and 96.2% in controls. They concluded that vaccination is more likely to induce seroconversion in earlier stages of kidney disease.9
MONITORING THE RESPONSE TO VACCINATION AND REVACCINATION
Testing after vaccination is recommended to determine response. Testing should be done 1 to 2 months after the last dose of the vaccination schedule.1–3 Anti-HBs levels 10 IU/mL and greater are considered protective.10
Revaccination with a full vaccination series is recommended for patients who do not develop adequate levels of protective antibodies after completion of the vaccination schedule.2 Reported response rates to revaccination have varied from 40% to 50% after 2 or 3 additional intramuscular doses of 40 µg, to 64% after 4 additional intramuscular doses of 10 µg.3 Serologic testing should be repeated after the last dose of the vaccination series, as serologic testing after only 1 or 2 additional doses appears to be no more cost-effective.2,3
To the best of our knowledge, no data exist to indicate that in nonresponders, further doses given after completion of 2 full vaccination schedules would induce an antibody response.
ANTIBODY PERSISTENCE AND BOOSTER DOSES
Antibody levels fall with time in patients on hemodialysis. Limited data suggest that in patients who respond to the primary vaccination series, antibodies remain detectable for 6 months in 80% to 100% (median 100%) of patients and for 12 months in 58% to 100% (median 70%) of patients.3 The need for booster doses should be assessed by annual monitoring.2,11 Booster doses should be given when the anti-HBs titer declines to below 10 IU/mL. Limited data indicate that nearly all such patients would respond to a booster dose.3
OTHER WAYS TO IMPROVE VACCINE RESPONSE
Other strategies to improve vaccine response, such as the addition of adjuvants or immunostimulants, have shown variable success.12 Intradermal HBV vaccination in patients on chronic hemodialysis has also been proposed. The efficacy of intradermal vaccination may be related to the dense network of immunologic dendritic cells within the dermis. After intradermal administration, the antigen is taken up by dendritic cells residing in the dermis, which mature and travel to the regional lymph node where further immunostimulation takes place.13
In a systematic review of four prospective trials with a total of 204 hemodialysis patients,13 a significantly higher proportion of patients achieved seroconversion with intradermal HBV vaccine administration than with intramuscular administration. The authors concluded that the intradermal route in primary nonresponders undergoing hemodialysis provides an effective alternative to the intramuscular route to protect against HBV infection in this highly susceptible population.
Additional well-designed, double-blinded, randomized trials are needed to establish clear guidelines on intradermal HBV vaccine dosing and vaccination schedules.
- Grzegorzewska AE. Hepatitis B vaccination in chronic kidney disease: review of evidence in non-dialyzed patients. Hepat Mon 2012; 12:e7359.
- Chi C, Patel P, Pilishvili T, Moore M, Murphy T, Strikas R. Guidelines for vaccinating kidney dialysis patients and patients with chronic kidney disease. www.cdc.gov/dialysis/PDFs/Vaccinating_Dialysis_Patients_and_Patients_dec2012.pdf. Accessed September 6, 2017.
- Recommendations for preventing transmission of infections among chronic hemodialysis patients. MMWR Recomm Rep 2001; 50:1–43.
- Kim DK, Riley LE, Harriman KH, Hunter P, Bridges CB; Advisory Committee on Immunization Practices. Recommended immunization schedule for adults aged 19 years or older, United States, 2017. Ann Intern Med 2017; 166:209–219.
- Lacson E, Teng M, Ong J, Vienneau L, Ofsthun N, Lazarus JM. Antibody response to Engerix-B and Recombivax-HB hepatitis B vaccination in end-stage renal disease. Hemodialysis international. Hemodial Int 2005; 9:367–375.
- Agarwal SK, Irshad M, Dash SC. Comparison of two schedules of hepatitis B vaccination in patients with mild, moderate and severe renal failure. J Assoc Physicians India 1999; 47:183–185.
- Fraser GM, Ochana N, Fenyves D, et al. Increasing serum creatinine and age reduce the response to hepatitis B vaccine in renal failure patients. J Hepatol 1994; 21:450–454.
- DaRoza G, Loewen A, Djurdjev O, et al. Stage of chronic kidney disease predicts seroconversion after hepatitis B immunization: earlier is better. Am J Kidney Dis 2003; 42:1184–1192.
- Ghadiani MH, Besharati S, Mousavinasab N, Jalalzadeh M. Response rates to HB vaccine in CKD stages 3-4 and hemodialysis patients. J Res Med Sci 2012; 17:527–533.
- Jack AD, Hall AJ, Maine N, Mendy M, Whittle HC. What level of hepatitis B antibody is protective? J Infect Dis 1999; 179:489–492.
- Guidelines for vaccination in patients with chronic kidney disease. Indian J Nephrol 2016; 26(suppl 1):S15–S18.
- Somi MH, Hajipour B. Improving hepatitis B vaccine efficacy in end-stage renal diseases patients and role of adjuvants. ISRN Gastroenterol 2012; 2012:960413.
- Yousaf F, Gandham S, Galler M, Spinowitz B, Charytan C. Systematic review of the efficacy and safety of intradermal versus intramuscular hepatitis B vaccination in end-stage renal disease population unresponsive to primary vaccination series. Ren Fail 2015; 37:1080–1088.
- Grzegorzewska AE. Hepatitis B vaccination in chronic kidney disease: review of evidence in non-dialyzed patients. Hepat Mon 2012; 12:e7359.
- Chi C, Patel P, Pilishvili T, Moore M, Murphy T, Strikas R. Guidelines for vaccinating kidney dialysis patients and patients with chronic kidney disease. www.cdc.gov/dialysis/PDFs/Vaccinating_Dialysis_Patients_and_Patients_dec2012.pdf. Accessed September 6, 2017.
- Recommendations for preventing transmission of infections among chronic hemodialysis patients. MMWR Recomm Rep 2001; 50:1–43.
- Kim DK, Riley LE, Harriman KH, Hunter P, Bridges CB; Advisory Committee on Immunization Practices. Recommended immunization schedule for adults aged 19 years or older, United States, 2017. Ann Intern Med 2017; 166:209–219.
- Lacson E, Teng M, Ong J, Vienneau L, Ofsthun N, Lazarus JM. Antibody response to Engerix-B and Recombivax-HB hepatitis B vaccination in end-stage renal disease. Hemodialysis international. Hemodial Int 2005; 9:367–375.
- Agarwal SK, Irshad M, Dash SC. Comparison of two schedules of hepatitis B vaccination in patients with mild, moderate and severe renal failure. J Assoc Physicians India 1999; 47:183–185.
- Fraser GM, Ochana N, Fenyves D, et al. Increasing serum creatinine and age reduce the response to hepatitis B vaccine in renal failure patients. J Hepatol 1994; 21:450–454.
- DaRoza G, Loewen A, Djurdjev O, et al. Stage of chronic kidney disease predicts seroconversion after hepatitis B immunization: earlier is better. Am J Kidney Dis 2003; 42:1184–1192.
- Ghadiani MH, Besharati S, Mousavinasab N, Jalalzadeh M. Response rates to HB vaccine in CKD stages 3-4 and hemodialysis patients. J Res Med Sci 2012; 17:527–533.
- Jack AD, Hall AJ, Maine N, Mendy M, Whittle HC. What level of hepatitis B antibody is protective? J Infect Dis 1999; 179:489–492.
- Guidelines for vaccination in patients with chronic kidney disease. Indian J Nephrol 2016; 26(suppl 1):S15–S18.
- Somi MH, Hajipour B. Improving hepatitis B vaccine efficacy in end-stage renal diseases patients and role of adjuvants. ISRN Gastroenterol 2012; 2012:960413.
- Yousaf F, Gandham S, Galler M, Spinowitz B, Charytan C. Systematic review of the efficacy and safety of intradermal versus intramuscular hepatitis B vaccination in end-stage renal disease population unresponsive to primary vaccination series. Ren Fail 2015; 37:1080–1088.
