Sensitivity of the Test for Antibody to Hepatitis B Surface Antigen -- United States

Beginning in March 1986, some test kits for antibody to hepatitis B surface antigen (anti-HBs) were modified to increase sensitivity, and new anti-HBs tests were introduced with increased sensitivity for detecting anti-HBs. To assess the impact of this increased sensitivity on the interpretation of hepatitis B postvaccination testing results, the Food and Drug Administration (FDA) conducted a study of currently distributed anti-HBs test kits to determine the lower limits of their sensitivity relative to the World Health Organization (WHO) Anti-HBs Reference Preparation. In addition, CDC conducted a study among a group of vaccinated public safety workers to determine the positive predictive values of the current anti-HBs tests when used to evaluate immunity after hepatitis B vaccination. This report provides background to and summarizes the results of these two studies.

One of the uses for the test for anti-HBs is to evaluate the immune response in persons who have received hepatitis B vaccine. In its initial recommendations, the Immunization Practices Advisory Committee (ACIP) defined an adequate (protective) antibody response as greater than or equal to 10 sample ratio units (SRU {sample signal divided by the test kit negative control mean}) by radioimmunoassay (RIA) (1). This level was based on results of routine screening and hepatitis B vaccine-efficacy studies conducted in the early 1980s (2-5). Subsequently, the determination of anti-HBs levels was standardized by expressing anti-HBs concentrations in milli-international units per milliliter (mIU/mL) using the WHO Anti-HBs Reference Preparation (6), and an anti-HBs level of greater than or equal to 10 mIU/mL was recommended by ACIP as the standard for demonstrating postvaccination protection against hepatitis B (7). Because the value of 10 SRU by RIA and the manufacturers' recommended positive threshold for enzyme immunoassays (EIA) were similar to 10 mIU/mL, ACIP recommendations issued in 1987 defined the protective level of anti-HBs as greater than or equal to 10 mIU/mL, approximately equivalent to 10 SRU by RIA or positive by EIA (7).

To determine the lower limits of the sensitivity of currently distributed anti-HBs test kits relative to the WHO Anti-HBs Reference Preparation, in 1991, FDA made a single quantitative determination of anti-HBs for each of the kits licensed in the United States and for each of the different testing procedures (i.e., short and long incubation). The lower limits of detection were estimated at less than 5 mIU/mL using all assays and all procedures, suggesting that in some hepatitis B vaccine recipients tested 1-6 months after their last dose of vaccine, an anti-HBs test result of greater than or equal to 10 SRU by RIA or positive by EIA determined after March 1986 may not be indicative of immunity because the quantity of anti-HBs may be less than 10 mIU/mL.

To determine the positive predictive values of current anti-HBs tests, CDC compared anti-HBs results by RIA and by EIA with titers expressed in mIU/mL in serum samples from a group of public safety workers vaccinated 1-6 months before testing (Table_1). Of 363 vaccine recipients who had responses of greater than or equal to 10 SRU by RIA, three (0.8% {95% confidence interval (CI)=0.2%-2.6%}) had titers less than 10 mIU/mL. Of 378 recipients who were positive by EIA, nine (2.4% {95% CI=1.2%-4.6%}) had titers less than 10 mIU/mL. On the basis of these results, the positive predictive values of currently available RIA and EIA tests in predicting an anti-HBs titer of greater than or equal to 10 mIU/mL are 99.2% and 97.6%, respectively. Reported by: Laboratory of Hepatitis, Div of Transfusion Transmitted Diseases, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration. Hepatitis Br, Div of Viral and Rickettsial Diseases, National Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: ACIP recommends that a protective level of anti-HBs be defined as greater than or equal to 10 mIU/mL (9). To avoid misinterpretation of positive anti-HBs test results, anti-HBs test-kit manufacturers are planning to revise their test kits to include a 10 mIU/mL standard reagent referenced to the WHO anti-HBs standard. This kit labeling and design change does not affect the use of the test kits for diagnosis and monitoring of hepatitis B virus infection.

ACIP recommendations for management of vaccinated persons exposed to blood that contains or might contain hepatitis B surface antigen (HBsAg) vary depending on whether the exposed person is known to be a primary hepatitis B vaccine responder (9). The increased sensitivity of the anti-HBs tests may have resulted in a small number of persons who were incorrectly considered to have protective anti-HBs levels after vaccination if they were tested since March 1986, and their test results were based on values of greater than or equal to 10 SRU by RIA or positivity by EIA. If such persons are exposed to an HBsAg-positive source and have not had a quantitative determination of anti-HBs (based on values of greater than or equal to 10 mIU/mL) following vaccination, CDC recommends that they be considered as having an unknown response to hepatitis B vaccine when following postexposure prophylaxis guidelines (9).

Although the sensitivity of both the RIA and EIA anti-HBs tests has increased since March 1986, this increase has not substantially affected the ability of these assays to determine whether vaccinated persons have protective antibody levels. In addition, no cases of hepatitis B have been reported in persons considered to be hepatitis B vaccine responders. Therefore, retesting of persons in whom postvaccination testing was done who do not have an exposure to an HBsAg-positive source is not recommended.

Although the findings of the CDC study are not directly related to the use of anti-HBs testing for prevaccination serologic screening, such screening is recommended only in populations in which the prevalence of prior infection is expected to be high and screening is cost effective. Because few false positives would be expected in such populations even with the more sensitive anti-HBs test kits, retesting of persons who have had prevaccination anti-HBs testing since March 1986 is not recommended.

References

1. CDC. Inactivated hepatitis B virus vaccine. MMWR 1982;31:317- 22,327-8.

2. Francis DP, Hadler SC, Thompson SE, et al. The prevention of hepatitis B with vaccine: report of the Centers for Disease Control multi-center efficacy trial among homosexual men. Ann Intern Med 1982;97:362-6.

3. Hadler SC, Murphy BL, Schable CA, Heyward WL, Francis DP, Kane MA. Epidemiological analysis of the significance of low-positive test results for antibody to hepatitis B and core antigens. J Clin Microbiol 1984;19:521-5.

4. Werner BG, Dienstag JL, Kuter BJ, et al. Isolated antibody to hepatitis B surface antigen and response to hepatitis B vaccination. Ann Intern Med 1985;103:201-5.

5. Kessler HA, Harris AA, Payne JA, Hudson E, Potkin B, Levin S. Antibodies to hepatitis B surface antigen as the sole hepatitis B marker in hospital personnel. Ann Intern Med 1985;103:21-6.

6. Hollinger FB, Adam E, Heiberg D, Melnick JL. Response to hepatitis B vaccine in a young adult population. In: Szmuness W, Alter HJ, Maynard JE, eds. Viral hepatitis 1981 international symposium. Philadelphia: Franklin Institute Press, 1982:451-66.

7. CDC. Update on hepatitis B prevention. MMWR 1987;36:354-60,366.

8. Hadler SC, Margolis HS. Hepatitis B immunization: vaccine types, efficacy, and indications for immunization. In: Remington JS, Schwarz MN, eds. Current clinical topics in infectious diseases. Boston: Blackwell Scientific Publications, 1992:282-308.

9. CDC. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination -- recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991;40(RR-13).

Table_1
Note: To print large tables and graphs users may have to change their printer settings to landscape and use a small font size.

TABLE 1. Comparison of antibody to hepatitis B surface antigen (anti-HBs) test results,
by radioimmunoassay (RIA) and enzyme immunoassay (EIA) with titers expressed in
milli-international units (mIU) per mL in serum samples from 437 public safety workers
1-6 months after receiving hepatitis B vaccine
===================================================================================================
                                                          Positive predictive value
                                        Titers       ------------------------------------
                      Positive*       <10 mIU/mL
Anti-HBs   Total    -------------    ------------      No.      No. with titers
  test     tested   No.     (%)      No.     (%)     positive     >=10 mIU/mL       (%)
-------------------------------------------------------------------------------------------------
RIA         437     363    (83.1)     3     (0.8)      363            360          (99.2)
EIA         437     378    (86.5)     9     (2.4)      378            369          (97.6)
--------------------------------------------------------------------------------------------------
* >=10 sample ratio units by RIA or positive by EIA. The overall anti-HBs response to hepatitis B
  vaccine was lower than expected because this population included a large proportion of
  persons who were aged >40 years, overweight, and/or smokers, factors associated with non-
  response to hepatitis B vaccine (8).
===================================================================================================

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