CDC Recommendation for Hepatitis B Vaccination among Adults with Diabetes: 

Grading of Scientific Evidence in Support of Key Recommendations 

GRADE Tables: Hepatitis B Vaccination Among Persons with Diabetes Referenced in MMWR Dec 

23, 2011 / Vol 60(50);1709-11 

Methods for Grading of Recommendations Assessment, Development, and Evaluation 

(GRADE) According to ACIP Guidelines 

Evidence of benefits, harms, values and preferences, and cost effectiveness were reviewed in 

accordance with GRADE methods to determine the recommendation category (Ahmed F, 

Temte JL, Campos-Outcalt D, Schünemann HJ; for the ACIP Evidence Based Recommendations 

Work Group (EBRWG). Methods for developing evidence-based recommendations by the 

Advisory Committee on Immunization Practices (ACIP) of the U.S. Centers for Disease Control 

and Prevention (CDC). Vaccine 29(49):9171-6, 2011). Pooled data from 6 placebo-controlled 

randomized trials (5798 subjects) indicated a relative risk for hepatitis B infection events of 0.37 

(95% CI 0.29, 0.48) among vaccinated subjects, although evidence type was downgraded for 

indirectness as trials did not focus on subjects with diabetes. Pooled data from 5 observational 

studies (285 subjects with diabetes) indicated 91.6% of subjects with diabetes achieved 

seroprotection, although evidence type was downgraded for imprecision due to small numbers. 

No serious vaccine-related adverse events were reported in any study. The Institute of 

Medicine found evidence supporting a causal relationship between hepatitis B vaccination and 

anaphylaxis in yeast-sensitive individuals; the risk of anaphylaxis following hepatitis B vaccine is 

estimated at 1.1 per million doses. [IOM (Institute of Medicine). 2011. Adverse Effects of 

Vaccines: Evidence and Causality. Washington, DC: The National Academies Press; Bohlke K, 

Davis RL, Marcy SM, Braun MM, DeStefano F, Black SB, Mullooly JP, Thompson RS; Vaccine 

Safety Datalink Team. Risk of anaphylaxis after vaccination of children and adolescents, 

Pediatrics 2003;112:815-20]. 

June 13, 2014

https://www.cdc.gov/vaccines/acip/recs/grade/hepb-vac-adults-diabetes.pdf
 

 

 


 


 


 


 

a Table 1: Benefits and Harms of Hepatitis B Vaccination Among Persons with Diabetes 

Outcome No. of Incidence in Incidence in Relative risk (95% Seroprotection Risk difference per Number 

subjects (# controls vaccinated CI) of hepatitis B proportion among 1000 (95% CI), needed 

studies) infection events subjects with vaccinated versus to 

among vaccinated diabetes (95% CI) not vaccinated vaccinate 

(NNV) 

BENEFITS 

Hepatitis B infection b b b c d 5798 (6 RCTs) 10.7% 4.1% 0.37 (0.29, 0.48) -- -67 (-76, -56) 261 events
 

Seroprotection 91.6% (87.6%,
 285 (5 Obs) -- -- -- -- -­ 94.4%) 

HARMS 

Serious adverse 6251 (6 RCTs e e 

0.0% 0.0% -- -- -- -­ events and 3 Obs)
 

Anaphylaxis 6251 (6 RCTs e e
 0.0% 0.0% -- -- -- -­ and 3 Obs) 

a 

Some studies include persons with and without diabetes 

b 

Follow-up ranged from 12-29 months; figures do not account for person-time of follow-up for all studies; relative risk and 95% CI calculated 

from RevMan software version 5.1 

c 

Calculated from GRADE profiler software version 3.6 assuming fixed effects 

d 

Number needed to treat (number needed to vaccinate) calculated from modeling analysis of adults with diabetes ages ≥20 years (lifetime 

perspective) 

e 

No serious events reported. Study sizes not sufficient to detect rare serious adverse events 
 

 

 

 

a Table 2: Type of Evidence for Hepatitis B Vaccination Benefits and Harms among Persons with Diabetes 

Outcome Design (# Risk of bias Inconsistency Indirectness Imprecision Other Evidence type 

studies) considerations 

Benefits 

Hepatitis B infection events b RCT (6) No serious No serious Yes (-1) No serious No serious 2 

c Seroprotection Obs (5) No serious No serious No serious Yes (-1) No serious 4 

Harms 

Serious adverse events RCT (6) b d No serious No serious Yes (-1) No serious No serious 2 Obs (3) 

Anaphylaxis RCT (6) b d No serious No serious Yes (-1) No serious No serious 2 Obs (3) 

a 

Some studies include persons with and without diabetes 

b 

Subjects with diabetes not focus of RCT studies; one RCT used 3 mcg dose on 0,1,2 month schedule; one study used 5 mcg dose on 0,1,2 month 

schedule with subcutaneous administration 

c 

Total number of events <300, 95% CI 0.88, 0.94 

d Study sizes not sufficient to detect rare adverse events: rate of anaphylaxis estimated 1.1 per million doses (95% CI 0.1, 3.9 per million doses); 

(Bohlke K. et al. Pediatrics 2003;112:815-20). Widespread vaccine use for 30 years has not revealed other serious adverse events (IOM (Institute 

of Medicine). 2011. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press) 
 

 

 

 

a Table 3: Summary of Evidence for Benefits and Harms of Hepatitis B Vaccination among Adults with Diabetes 

Comparison Outcome Study design Findings Evidence type Overall evidence type 

(# studies) 

Hepatitis B vaccination vs. Hepatitis B RCT (6) Decreased risk among 2 2 

no vaccination infection events vaccinated 

Seroprotection Obs (5) Seroprotection among 4 

subjects with diabetes 

similar to that among 

subjects without diabetes 

Serious adverse RCT (6) No serious vaccine-related 2 

b 

events Obs (3) adverse events 

Anaphylaxis RCT (6) No serious vaccine-related 2 

b 

Obs (3) adverse events 

a 

Some studies include persons with and without diabetes 

b 

Study sizes not sufficient to detect rare adverse events 
 

 

 

 

 

Table 4. Considerations for Formulating 

Recommendations: Hepatitis B Vaccine for Adults with 

Diabetes 

Key factors Comments 

Balance between benefits 

and harms 

Evidence type for benefits 

and harms 

Values 

Cost-effectiveness 

Benefits are greater than 

potential harms 

Benefits: Evidence type 2 

Harms: Approximately 30 

year hepatitis B vaccine 

history indicates serious 

adverse events and 

anaphylaxis extremely rare 

High values on preventable 

a 

outcomes for persons <60 

years and moderate to high 

values for persons >60 years 

assigned by ACIP Hepatitis 

Work Group 

Vaccination is most cost 

effective for adults with 

diabetes for ages <60 years a

Preventable outcomes consist of acute hepatitis, fulminant 

hepatitis, chronic hepatitis, cirrhosis, hepatocellular carcinoma, 

liver transplantation, death 

Summary: Benefits are greater than potential harms; overall 

evidence is type 2. High values were placed on prevention of the 

morbidity and mortality of hepatitis B virus infection among 

adults with diabetes. 
 

 

 

 

 

 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

Study References 

1.	 Arslanoglu I, Cetin B, Isguven P, Karavus M. Anti-HBs response to standard hepatitis B vaccination in children and adolescents with 

diabetes mellitus. Journal of Pediatric Endocrinology & Metabolism 2002;15(4):389-95. 

2.	 Bouter KP, Diepersloot RJ, Wismans PJ, et al. Humoral immune response to a yeast-derived hepatitis B vaccine in patients with type 1 

diabetes mellitus. Diabet Med 1992 Jan-Feb;9(1):66-9. 

3.	 Douvin C, Simon D, Charles MA, et al. Hepatitis B vaccination in diabetic patients. Randomized trial comparing recombinant vaccines 

containing and not containing pre-S2 antigen. Diabetes Care 1997 Feb;20(2):148-51. 

4.	 Li Volti S, Caruso-Nicoletti M, Biazzo F, et al. Hyporesponsiveness to intradermal administration of hepatitis B vaccine in insulin 

dependent diabetes mellitus. Archives of Disease in Childhood 1998;78(1):54-7. 

5.	 Marseglia GL, Scaramuzza A, dAnnunzio G, Comolli G, Gatti M, Lorini R. Successful immune response to a recombinant hepatitis B vaccine 

in young patients with insulin-dependent diabetes mellitus. Diabetic Medicine 1996;13(7):630-3. 

6.	 Dienstag JL, Werner BG, Polk BF, et al. Hepatitis B vaccine in health care personnel: safety, immunogenicity, and indicators of efficacy. 

Ann Intern Med 1984 Jul;101(1):34-40. 

7.	 Szmuness W, Stevens CE, Harley EJ, et al. Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk 

population in the United States. N Engl J Med 1980 Oct 9;303(15):833-41. 

8.	 Francis DP, Hadler SC, Thompson SE, et al. The prevention of hepatitis B with vaccine. Report of the centers for disease control multicenter efficacy trial among homosexual men. Ann Intern Med 1982 Sep;97(3):362-6. 

9.	 Szmuness W, Stevens CE, Harley EJ, et al. Hepatitis B vaccine in medical staff of hemodialysis units: efficacy and subtype cross-protection. 

N Engl J Med 1982 Dec 9;307(24):1481-6. 

10.	 Crosnier J, Jungers P, Courouce AM, et al. Randomised placebo-controlled trial of hepatitis B surface antigen vaccine in French 

haemodialysis units: I, Medical staff. Lancet 1981 Feb 28;1(8218):455-9. 

11.	 Coutinho RA, Lelie N, Albrecht-Van Lent P, et al. Efficacy of a heat inactivated hepatitis B vaccine in male homosexuals: outcome of a 

placebo controlled double blind trial. Br Med J (Clin Res Ed) 1983 Apr 23;286(6374):1305-8.