Immunogenicity achieved by the intradermal hepatitis B vaccination programme for US Army soldiers in Korea

Immunogenicity achieved by the intradermal hepatitis B vaccination programme for US Army soldiers in Korea R.H. Ronish *'~, B.M. Diniega*, P.W. Kelley*, M.H. Sjogren*, D.R. Arday*, N.E. Aronson ~, C.H. HokeTand B.P. Petruccelli ~ Hepatitis B virus (HBV) infections are a significant threat to the 30 000 US Army soldiers stationed in South Korea. Hepatitis B surface antigen carrier rates in some Korean populations may run as high as 15%, and H B V incidence estimates for US soldiers in Korea have ranged from 0.6 to 6% per year. In response to this threat, on 1 October 1986 the US Army instituted a mandatory three-dose (0, 30-60, and 60+ days), 0.1 ml per dose, intradermal (i.d.) immunization regimen for all soldiers bound for permanent assignments in Korea. Although shown to be immunogenic in experimental studies, the i.d. route had never been attempted on as large a scale as in this operational setting. During September 1987, an evaluation o f programme compliance and immune response was conducted. For those who received three doses according to schedule, antibody response was similar to that reported by previous controlled trials that used the i.d. approach. The three-dose i.d. series appeared to provide protective antibody levels in at least 67% of soldiers, but, consistent with previous trials, antibody levels were approximately one-half those obtained jollowing intramuscular vaccination. We conclude that, as a cdst-reduction strategy, wide-scale use of intradermal hepatitis B vaccine may be useful in situations characterized by short-term increased H B V infection risk. Keywords:Hepatitis B; intradermal vaccination; immunogenicity; military

INTRODUCTION The incidence of acute hepatitis B in the US in 1986 was 11.2 cases/100 000 people 1. The chronic HBV carrier state can be identified in 0.1-0.5% of the US population. Identified risk groups for hepatitis B, acquired in this country, include intravenous drug abusers, homosexual men, institutionalized persons, and health care workers. Among American solidiers in Korea, however, annual HBV infection rates have been estimated to range from 0.6 to 6%, based upon hospital admission rates and upon a cross-sectional HBV core antibody (anti-HBc) prevalence survey of volunteers for a gonorrhoea vaccine trial. In several studies of US soldiers in Korea, heterosexual contact with the indigenous population, *Epidemiology Consultant Service, Division of Preventive Medicine, Walter Reed Army Institute of Research, Washington, DC, USA; tDepartment of Virus Diseases, Walter Reed

Army Institute of Research, Washington, DC, USA; *+Department of Medicine, Walter Reed Army Medical Center, Washington, DC, USA; ~Division Surgeon's Office, 2nd Infantry Division, Tongduchon, Korea. ']To whom correspondence should be addressed at: 621 Meadows Drive South, Richland, WA 99352, USA. Address for reprints: Division of Preventive Medicine, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA 0264-410X/91/050364~)5 ,~ 1991 Butterworth-HeinemannLtd 364

Vaccine, Vol. 9, May 1991

among whom HBV carrier rates may run as high as 15%, has been found to be a significant risk behaviour 2"3. In 1984, concern over the HBV threat to US troops in Korea led the Armed Forces Epidemiology Board (AFEB) to recommend that all Army personnel bound for permanent assignment in Korea be immunized against hepatitis B. There are, however, approximately 30000 troops in Korea at any given time. In addition, the average length of time in Korea is brief (1.1 years), so protection need not necessarily be long-lived. Typical soldiers have only about 90 days notice before being transferred to Korea and, therefore, need a more rapid immunization schedule than the 6-month regimen customarily employed. Finally, the usual intramuscular route of adminstration costs more than $100 per person, a significant expense in light of the rapid turnover of troops. Following demonstration that rabies vaccine could be effective by the intradermal route, several small studies of plasma-derived HBV vaccine administered intradermally (i.d.) demonstrated that seroconversion rates are similar to those following intramuscular (i.m.) administration, •even though the i.d. dose was only one-tenth of the usual i.m. dose 4-9. Although these studies showed peak antibody titres by the i.d. route to be about one-half of those by the i.m. route and even though the duration of protective titres is known to be proportional to peak

Intradermal hepatitis B vaccination: R.H. Ronish et al.

antibody response, titres were sufficiently high to suggest that i.d. immunization could be expected to provide protection for at least 13 months 8'1°-14. These facts led the AFEB to support the option that troops bound for Korea be immunized against HBV with three intradermal doses of vaccine given over a 2-month period of time. We report here our evaluation of the levels of immunity achieved in this first large scale use of intradermally administered hepatitis B vaccine. MATERIALS AND METHODS

The intradermal vaccination programme In accordance with policy set by the Army Surgeon General, beginning on 1 October 1986 all US soldiers placed on orders for a permanent assignment to Korea were required to be vaccinated against hepatitis B virus infection by the intradermal route. This was accomplished using plasma-derived vaccine (Heptavax-B: Merck Sharp, and Dohme) in a three-dose regimen. Each dose consisted of 2#g of hepatitis B surface antigen (HBsAg) (0.1 ml), with doses given in the upper, outer arm on day 0, between days 30 and 60, and between days 60 and 180 (60 days was recommended). The immunizations provided under this policy were administered by immunization clinic personnel located at over 60 Army medical treatment facilities throughout the world. Educational posters and other instructional guidance were disseminated to these immunization stations as a means of enhancing the likelihood of good intradermal administration technique. Soldiers who were unable to complete the series before departure for Korea were to complete the series after arrival. Although soldiers already on station in Korea as of 1 October 1986 were not required to receive the vaccine, it was made available to them. Failure to meet the scheduled dose intervals necessitated restarting the series; consequently, some soldiers ultimately received a total of four vaccinations.

Study population For the evaluation, Eighth US Army, the headquarters organization in Seoul, arranged access to approximately 2000 soldiers from three battalions assigned to the 2rid Infantry Division. It was estimated that three battalions would yield a sample size sufficient to calculate levels of immunity with enough precision to be useful in making programme decisions. Since this was an operational evaluation of an ongoing programme, all members of these units were directed to participate in this serosurvey, but, for reasons such as leave and temporary duty away from the primary duty location, battalion participation rates ranged from 70% to 90%. Ultimately, a total of 1682 soldiers provided sera and other data.

Data collection Data collection was conducted between 26 August and 6 September 1987 and involved several components. A questionnaire was administered to gather personal data, including demographic information and information on hepatitis B immunization history. Along with the 'questionnaire, the immunization records of all participants were reviewed and pertinent data on the dose, route of adminstration, and dates of hepatitis B immunizations were abstracted. Each soldier had blood drawn for

measurement of serological markers of HBV infection. The blood was centrifuged, and the sera were then aliquoted into labelled tubes. The specimens were immediately frozen at approximately - 100°F and were subsequently shipped in dry ice to the Walter Reed Army Institute of Research for testing.

Laboratory methods Sera were tested for antibody to HBV surface antigen (anti-HBsAg) and for antibody to HBV core antigen (anti-HBc) by radioimmunoassay (AUSAB, CORAB: Abbott Laboratories; Chicago). The presence of antiHBsAg without anti-HBc was taken to indicate a successful immunization. All sera with detectable antiHBc were tested for IgM anti-HBc (CORAB-M: Abbott Laboratories) to distinguish between recent and distant infection. Finally, sera positive for anti-HBc and negative for anti-HBs were tested for hepatitis B surface antigen (HBsAg: AUSRIA II, Abbott Laboratories). Using AUSAB, a ratio of sample counts per minute to mean negative control counts per minute (S/N ratio) was calculated. The S/N ratio has been variously termed the P/N ratio or Sample Ratio Unit (SRU). An SRU/> 2.1 defines seropositivity, according to the instructions provided by the manufacturer. The Centers for Disease Control define a protective antibody level 15 as SRU ~>10. In the CORAB assay, specimens with blocking greater than or equal to 50% were called positive, as recommended by the manufacturer. RESULTS Of the 1682 troops queried and bled, 101 lacked medical record documentation for all or part of the hepatitis B immunizations claimed by the soldier; these individuals were excluded from subsequent analyses of antibody response to vaccine. The remaining group of 1581 soldiers was further subdivided. Of these soldiers 268 had some or all hepatitis B immunizations documented as being by a route other than i.d.; these were also excluded from analyses of immunogenicity. Of the remaining 1313 troops (who were documented as having received either no HBV immunizations or all doses by the intradermal route), 97 were positive for anti-HBc, indicating prior infection with hepatitis B virus and were eliminated from further analyses. It is within the remaining group of 1216 that the presence of anti-HBs can be reasonably attributed to the vaccine. Of these 1216 soldiers, however, 182 received vaccinations at other than the prescribed intervals, leaving a total of 1034 soldiers (hereafter referred to as the 'analysis subgroup') for the study of immunogenicity. Within the analysis subgroup, 437 soldiers had no history of hepatitis B immunization, often because they had arrived in Korea before implementation of the programme. Two of the original 1682 soldiers did not contribute sufficient sera for laboratory evaluation. Results of serological testing for the 1680 soldiers, from whom adequate quantities of sera were obtained, demonstrated that 921 soldiers (54.8%) were positive for anti-HBs, and 125 (7.4%) were positive for anti-HBc. Only one of those positive for anti-HBc had the IgM class of the antibody to core antigen. A total of 26 soldiers were both anti-HBc positive and anti-HBs negative and were, therefore, potential carriers; 12 of these tested positive for HBsAg.

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Intradermal hepatitis B vaccination: R.H. Ronish et al. Table 1 Comparison of the demographic characteristics of four sub-populations surveyed during the September 1987 evaluation: the total group; the analysis subgroup (see text for definition); those positive for core antibody; and those positive for surface antigen

Mean age Proportion male Race/ethnic group: White; Non-hispanic Black; Non-hispanic Hispanic Asian/Pacific Islander Native American Mean time in Korea

Total (n = 1682)

Analysis (n = 1034)

Anti-HBc + (n = 125)

HBsAg + (n = 12)

25.1 96%

24.4 97%

28.8 93%

30.8 100%

64% 24% 6% 3% 2% 9.0 months

67% 22% 5% 2% 2% 9.3 months

38% 37% 5% 14% 2% 10.7 months

33% 25% 0 17% 17% 10.5 months

1OO -

n=166

9 ~

~> o o

' 4C

n=530 =

~.

a_

1

2

:3

Totol number of shots received Figure 1 Distribution of anti-HBs levels (SRUs) in the subgroup which was negative for anti-HBc and which had received either no doses or all doses by the intradermal route at the prescribed intervals examined by the total number of hepatitis B vaccinations received. SRU range: t-l, 2.1-9.9; [ ] 10-49; [ ] 50-99; • i> 10

Demographically, the analysis subgroup was not noticeably different from the total study population (n = 1682), nor were any of the vaccinated subgroups (i.e. those who had received a total of one, two, or three doses of vaccine) of the analysis subgroup different from the total study population. Those who had received no immunizations for hepatitis B, however, had averaged significantly more time in Korea (12.5 months). Members of the anti-HBc positive subgroup and of the probable carrier subgroup tended to be older and also to have spent more time in Korea (Table 1). A larger proportion of the subgroup positive for anti-HBc was black or Asian/Pacific Islander, and a larger proportion of the presumed carriers was Asian/Pacific Islander or Native American. The remainder of the analysis of antibody response was confined to members of the analysis subgroup: i.e. those who had received doses at the prescribed intervals (n= 1034). There was a clear relationship between the number of doses received and the level of antibody to HBsAg (Figure I). The mode of the interval between the first and second doses was 30 days, while that between the second and third doses was 32 days (> 70% of the intervals were between 25 and 60 days). Among those who had received at least three doses, 89% were seropositive (SRU >~2.1) at the time of the survey, and 67% had protective levels (SRU>~10) of anti-HBs.

366

n=4

60.

40'

0 0. o

n=~91

0

n=9

80.

60 C.)

n=1:3

100.

n=14.7

V a c c i n e , Vol. 9, M a y 1991

20.

O'

:3

4

5

6

7

8

9

10

11

12

Time (months) Figure 2 Distribution over time of anti-HBs levels (SRUs) in the subgroup which was anti-HBc negative and which had received three hepatitis B immunizations at the prescribed intervals - time measured from the date of the first dose in the series. SRU range: [ ] 2.1-9.9; [] 10-49; [ ] 50-99; • range /> 100

Approximately 14% of these individuals had titres from 50 to 99 SRU, and 18% had levels greater than or equal to 100 SRU. In order to estimate the duration of antibody persistence after vaccination, those soldiers who had completed the intradermal series at the proper intervals (for a total of three doses) were divided into groups based upon the elapsed time since the initial vaccination (Figure 2). Note that the antibody levels indicated for 3 and 4 months represent measurements in close proximity to the third shot and, thus, may not reflect the full boosting effect of the third shot. For the remaining months after the first dose in the series, levels of anti-HBs appeared relatively stable, with the possible exception of a decrease, at the 12-month mark, in the proportion of soldiers with the highest titres.

DISCUSSION This study suggests that immunization clinic personnel, with varying degrees of experience and stationed around the world, can skilfully administer hepatitis B vaccine via the technically demanding intradermal route. Use of the ID approach has the potential to allow substantial cost-savings, while producing levels of antibody which are protective for the necessary duration. Some admini-

Intradermal hepatitis B vaccination: R.H. Ronish et al. Table 2 Comparison of the antibody response (i.e. proportion seropositive for anti-HBs) in various studies which used plasma-derived hepatitis B vaccine in adults Seropositive (%)" after given dose Reference

n

Mean age (years)

Dose (#g)

Timing (months)

Miller e t al. 6 Zoulek e t a l . ?

14 9

34.4 27.3

Redfieid e t a l . 8 Halsey e t a l ? Current study

25 19 c

26.9 24.4

2 2 x 4~ 5 2 2 2

0, 0 1, 0, 0, 0,

1

2

3

1, 6

25

42

83

6 1, 6 1, 4 1, 2 +

0 16 11 36

67 72 75

100 96 100 89

aSRU~>2.1; "four doses of 2/~g each - one dose in each extremity; Cn=330, 166, 147 for 1, 2, 3 shots, respectively

1OO 90

~ ~

60

~' ~ o

3o 20

50

o

I 2

3

I

2

0

3

Current study (i.d.) Miller6(i.d.)

I

2

0

3

Redfield 8(i.d.)

I 2

o

3

RedfieldS(i.m.)

Rgure 3 Comparison of the distributions of anti-HBs levels (SRUs) in two controlled trials with those in the current study. Redfield's i.m. group is comparable to other studies that used i.m. plasma-derived hepatitis B vaccine and is included for comparison. Levels are examined at various points in the vaccination series: after the first dose (1); after the second dose (2); after the third dose (3); and immediately before the third dose (a). See text for the timing of measurement of antibody titres after a given dose. SRU range: [ ] 2.1-9.9; [] 10-49; [ ] 50-99; • / > 100

strative difficulties with the programme, however, were clearly evident. As illustrated in Table 2, when implemented as prescribed, this programme achieved a proportion of seropositivity (SRU>~2.1) comparable to previous controlled studies. Examination of antibody titres, however, allows further judgements on the technical implementation of the programme, the level of protection achievable, and the duration of that protection. Figure 3 displays the magnitude of antibody response in the current study and compares it with responses obtained in other studies of i.m. and i.d. administration. This is done on the basis of the distribution of SRUs for each of the three doses. In the previous studies antibody titres were measured 1 month after each dose and immediately before the third dose; for the current study, however, various amounts of time elapsed from a given dose to the measurement 0f antibody titre. Antibody titres for Redfield's i.m. group are similar to those found in other studies of i.m. plasma-derived HBV vaccine1 o-12. It can be seen that, for one and two doses, the distribution of titres obtained under this operational Army programme compare favourably with those obtained in the previous studies. The distribution discovered after the third dose, on the other hand, more closely resembles that measured at 6 months (i.e. immediately before the third dose) in the previous studies. The levels, measured 1 month after the third dose in these prior studies, were significantly higher than those measured

after the third dose in the current study. Because the current study is a cross-sectional design with varying time intervals marked from the last dose of a series, it is not surprising that previous studies, which presumably documented antibody response near its peak after a given dose, yielded higher titres. On the other hand, it is also conceivable that the timing for the third dose in the Army programme for soldiers in Korea was less than optimal: it may not have had the booster effect of the 6-month dose in the usual i.m. programme16,17. This possibility is further suggested by the pattern of the antibody response. Administration of the vaccine (either i.d. or i.m.) at the usual 0, 1, and 6 months resulted in no change in the proportion of vaccinees seroconverting after the third dose, compared with the second; the third dose did, however, increase the proportion of vaccinees with high titres. In the present study, both the proportion seroconverting and the proportion with high titres increased after the third dose, suggesting the need for a longer interval between doses two and three. Similar to previous studies of i.d. immunization for hepatitis B, the antibody levels achieved by the Army programme for soldiers in Korea were lower than those obtained with i.m. vaccination. This has some implications for antibody persistence. Several studies have demonstrated that antibody persistence is a function of peak antibody titre: the greater the peak level, the longer protective levels persist ~2 14. Therefore, it may be expected that antibody persistence, in intradermally vaccinated persons, will be shorter than that following i.m. vaccination. Hadler indicates, however, that persons who have a good initial antibody response and who subsequently develop titres below 10 SRU, continue to maintain some form of protection against clinically significant disease and against the chronic carrier state 12. It is worth noting that, although antibody levels in this evaluation appeared constant over time, they were not measured beyond 12 months from the first dose and that any extrapolation beyond 12 months is speculative. There is the suggestion of a trend toward lower levels developing in the later months, but small numbers of subjects do not permit firm conclusions about the implications of this observation. In comparison with mher i.d. studies, the lower than expected proportion of soldiers with protective titres has several programme implications. As suggested above, perhaps the immunization series should be administered with a longer interval between the second and third doses, possibly making more advantageous use of the third dose.

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I n t r a d e r m a l hepatitis B vaccination: R.H. Ronish et al.

On the other hand, it may be necessary to consider routine boosters at some time beyond one year, particularly for those soldiers who extend their tour in Korea. It is not yet clear, however, whether boosting antibody titres is truly necessary for those whose titres have fallen below 10 SRU, but whose initial response was adequate 12. For the specific requirements of the US soldier in Korea, the i.d. administration of HBV vaccine appears a useful alternative to the usual i.m. approach: adequate levels of protection can be achieved, and the duration of protection is usually sufficient for the typical length of tour in Korea. As noted, however, the duration of protection beyond 1 year remains speculative. It must also be kept in mind that hepatitis B vaccines are not generic: i.d. administration of a plasma-derived vaccine prepared by one manufacturer may be more or less immunogenic than that prepared by another, and yeast recombinant vaccines may be different when compared with one another or to plasma-derived vaccines. Furthermore, blindly to extend the use of intradermal HBV vaccine to most other populations requiring protection from HBV infection would be premature. In the meantime, it is prudent to recommend that traditional risk groups for HBV infection continue to be vaccinated intramuscularly. ACKNOWLEDGEMENTS We wish to thank LTC Howard Wiener, SP 4 Carolyn McLain, S P 4 Lionel Lyde, members of the 5th Preventive Medicine Unit, and the medical staff of the 2nd Infantry Division for invaluable assistance with administrative, clinical, logistic, and laboratory support in Korea. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as necessarily reflecting the views of the Department of the Army or the Department of Defense. REFERENCES 1 Summary of Notifiable Diseases. MMWR 1987, 35, 52 2 Lemon, S.M., Lednar, W.M., Bancroft, W.H., Cannon,

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3 4

5

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8

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12

13 14

15 16

17 H.G.,

Benenson, M., Churchill, F.E. et al. Etiology of viral hepatitis in American soldiers. Am. J. Epidemiol. 1987, 116, 438 Aronson, N.E. and Palmer, B.F. Acute hepatitis in American soldiers assigned to Korea. South. Med. J. 1988, 81,949 Bernard, K.W., Roberts, M.A., Sumner, J.W., Winkler, W.G., Mallonee, J., Baer, G.M. and Chaney, R. Human diploid cell rabies vaccine: effectiveness of immunization with small intradermal or subcutaneous doses. J. Am. Med. Assoc. 1982, 247, 1138 Burridge, M.J., Baer, G.M., Sumner, J.W. and Sussman, O. Intradermal immunization with human diploid cell rabies vaccine. J. Am. Med. Assoc. 1982, 248, 1611 Miller, K.D., Gibbs, R.D., Mulligan, M.M, Nutman, T.B. and Francis, D.P. Intradermal hepatitis B virus vaccine: immunogenicity and side-effects in adults. Lancet 1983, ii, 1454 Zoulek, G., Lorbeer, B., Jilg, W. and Deinhardt, F. Evaluation of a reduced dose of hepatitis B vaccine administered intradermally. J. Med. Virol. 1984, 14, 27 Redfield, R.R., Innis, B.L., Scott, RM., Cannon, H.G. and Bancroft, W.H. Clinical evaluation of low-dose intradermally administered hepatitis B virus vaccine: a cost reduction strategy. J. Am. Med. Assoc. 1985, 254, 3203 Halsey, N.A., Reppert, E.J., Margolis, H.S., Francis, D.P. and Fields, H.A. Intradermal hepatitis B vaccination in an abbreviated schedule. Vaccine 1986, 4, 228 Szmuness, W., Stevens, C.E., Zang, E.A., Harley, E.J. and Kellner, A. A controlled clinical trial of the efficacy of the hepatitis B vaccine (Heptavax B): a final report. Hepatology 1981, 1,377 Francis, D.P., Hadler, S.C., Thompson, S.E., Maynard, J.E., Ostrow, D.G., Altman, N.L. 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 Hadler, S.C., Francis, D.P., Maynard, J.E., Thompson, S.E., Judson, F.N., Echenberg, D.F. et al. Long-term immunogenicity and efficacy of hepatitis B vaccine in homosexual men. N. Engl. J. Med. 1986, 315, 209 Jilg, W., Schmidt, M., Deinhardt, F. and Zachoval, R. Hepatitis B vaccination: how long does protection last?. Lancet 1984, ii, 2458 Ambrosch, F., Frisch-Niggemeyer, W., Kremsner, P., Kunz, C., Andre, F., Salary, A. and Wiedermann, G. Persistence of vaccine-induced antibodies to hepatitis B surface antigen and the need for booster vaccination in adult subjects. Postgrad. Med. J. 1987, 63 (Suppl. 2), 129 Recommendations of the Immunization Practices Advisory Committee: update on hepatitis B prevention. MMWR 1987, 36, 353 Hollinger, F.B., Adam, E., Heiberg, D. and Melnick, J.L. Response to hepatitis B vaccine in a young adult population. In: Vira/Hepatitis: 1981 /nternational Symposium (Eds Szmuness, W., Alter, H.J. and Maynard, J.E.) Franklin Institute Press, Philadelphia, 1982, pp. 451-66 Hadler, S.C., deMonzon, M.A., Lugo, D.R. and Perez, M. Effect of timing of hepatitis B vaccine doses on response to vaccine in Yucpa Indians. Vaccine 1989, 7, 106