Field evaluation of a hepatitis A vaccine in a Norwegian contingent to the United Nations Interim Force in Lebanon Per Aarhaug

The Norwegian population is" basically seronegative regarding anti-hepatitis A antibodies. For this' reason the), are particularly vulnerable when exposed to hepatitis' A virus when staying in h~ghly endemic' areas. Norwegian UN-personnel have so far been protected with serum immunoglobulins (Ig). Two studies are reported, one followed a vaccination schedule o f O, 1 and 2 months with a booster at month 12, while the otherJ'ollowed a s'chedule o[ day 0 and 14 with a booster at month 7. Both wereJield trials" evaluating the new hepatitis A vaccine, from SmithKline Beecham Biological, in Norwegian UN soldiers serving in Lebanon. Both trials showed 100% seroconversion /ollowing the initial vaccination course, with low reactogenicity and no clinical or subclinical sign o f hepatitis. The new vacccine has decisive advantages over immunoglobulins on medical, practical and economic grounds, Keywords: Hepatitis A: lield trial: military

INTRODUCTION Hepatitis A has a very low incidence in Norway today. Sera with antibody to hepatitis A virus (anti-HAV) are only found in middle-aged or elderly people, in travellers and among foreign workers. The Norwegian population is basically seronegative regarding anti-HAV. Norwegians follow the patterns of other Europeans in having extensive travel activity both for leisure and business. This means that Norwegians are a high risk group wherever they are exposed to hepatitis A infection, particularly if the exposure is extended. At an early stage of the United Nations Interim Force in Lebanon (UNIFIL), the Norwegian Field Hospital was instrumental in designing a policy for an immunization programme against hepatitis A. The programme was based on experience and extensive trials in the United Nations Emergency Force (UNEF) in Gaza between 1956-1961 as well as in U N I F I L 1978 1980. In the U N E F operations 243 cases of fulminant clinical hepatitis A were recorded in 40 074 men, i.e. 5.6 cases per thousand. The Scandinavian contingents (Danes, Swedes and Norwegians) accounted for the vast majority of these cases. Different policies were used regarding prophylaxis with serum immunoglobulins (Ig). The disease occurred in the unprotected groups (Table l)l. In the first years of the U N I F I L operations (1978-80), 143 cases of fulminant clinical hepatitis A were recorded, of which 115 cases in 1500 men were accounted for in one year by the French contingent. They were not inoculated

University of Oslo, School of Medicine, Postboks 39, Gaustad Sykehus, N-0320 Oslo, Norway

with Ig according to standing recommendations. When the French later conformed with the lg prophylaxis policy, the incidence of hepatitis A dropped to levels comparable to that of other contingents (Table 2) 2 This clearly supports the view that the Middle East is a highly endemic area for hepatitis A, that Europeans are particularly vulnerable and that hepatitis A is an important operational threat to UN missions in this area. Extensive studies on Ig prophylaxis was performed on 10 000 men in the U N E F operation, indicating a protective efficacy of 91%, using 2.8 ml 16% Ig (KABI) every three months 3. Similarly, 15 000 men and women in U N I F I L were given 2 ml 16% Ig (KABI) every three months, to achieve a protective efficacy of 97% 2. These and other studies are the basis for the present policy regarding hepatitis A prophylaxis in UNIFIL; namely 2 ml 16% Ig every three months (Table 3). In both the U N E F and U N I F I L operations, since 1978 and throughout the operation Norwegian troops serving in Lebanon have been subject to these guidelines and have suffered no significant problems with hepatitis A. MATERIALS AND METHODS However, given the alternative of active immunization using the recently developed inactivated hepatitis A vaccine (SmithKline Beecham Biologicals), several constraints connected with the use of passive immunization with Ig in UN personnel need to be examined. It became attractive to test the use of the new vaccine in dealing with UN personnel. Based on the works of Just and Mfiller 4 6 the properties, i.e. the kinetics, reactogenicity and immunogenicity, of the new vaccine seemed very 0264-410X/92/100S 156-03

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Vaccine, Vol. 10, Suppl. 1, 1992

© 1992Butterworth-HeinemannLtd

Hepatitis A vaccine in Norwegian UN Force: P. Aarhaug Table I

Viral hepatitis 1957-1982. Total number of cases and repatriations by year and contingent

Contingent

1957

Brazilian Danor (Danish) Bn (Norwegian) Hospital (Norwegian) Sum of Danish and Norwegian contingents Canadian

Total Repat Total Total Total

1958

6 0 3 1 1

1959

14 1 13 14 14

1980

0 2 2 7 0

7 2 19 13 10

1961

1 0 9 4 3

Sum

Total strength

Per cent incidence

28 5 46 39"{

3037

0.92

67

( Sum }. Repat

5 2

41 4

9 3

42 0

16 6

28 ) 113 15

Total Repat Total Repat Total Repat Total Repat Total

7 0 7 1 1 1 23 0 9

1 1 2 0 1 1 1 8 3

1 0 2 0 0 0 1 0 NR

8 9 3 0 1 0 2 0 NR

5 6 3 0 1 1 0 0 NR

Total Repat Total

58 4 10

63 15 2

13 5 4

63 11 3

26 13 1

Total

68

65

17

Indian Yugoslavian Swedish Columbian/Finnish/ Indonesian All contingents Civilian Staff UNEF

6050 4770 /

0.76 0.82 /

6532 1755

Note cases reported 1962 1 1 1 0

1.26 1.59

12582

0.90

22 16 17 1 4 3 27 8 12

4853

0.44

5636

0.30

6946

0.05

4990

0.54

1853

0.64

223 48 20 243

40097 a 40097,

0.56 1.2

0 1 1 8 8 0 0 0 0 0 0 NR 10 10 2 12

27

Notified cases in whole of UNEF 1957-1962: 225. Reproduced from Rev. Int. Serv. Sant. Armees 1963, supp. 5, pp. 33 with permission. Repat, repatriated cases; Danor, Danish Norwegian field hospital; Bn, batallion. . Recapitulants included

Table 2

Infectious hepatitis in UNIFIL 1978--1980 by year and national contingent Contingent

Average strength per year

Canada Fiji France Ghana Iran Ireland Italy Nepal Netherlands Nigeria Norway Senegal

120 5OO 1200-600 350-850 600 700 50 650 800 700 1000 600

Total

1978

0 0 99 0 0 0 5 3 2. 0 109

1979

1980

Total

1 16 5 0 1 1 0 1 4

0 0 3 0 2 0 0 0

0 1 115 8 0 0 0 6 3 3 3 4

29

5

143

Repatriations

1 72 3

1 2 2 83

Reproduced from Rev. Int. Serv. Sant. Armees 1982, 55, p. 69 with permission, a One case detected after return to home country. -, Not represented in UNIFIL

promising. A trial was designed for Norwegian troops in UNIFIL, using a vaccine dose of 720 ELISA units (El.U) for the primary vaccination course of months 1, 2, 3 and a booster at month 12. The first trial was subject to serious logistical, administrative and formal constraints, making it impossible to complete the study with the desired number of participants. However, valuable experience was gained as well as some important conclusions. The results compared well with other studies, i.e. low reactogenicity, high seroconversion rates following the second dose (98.8%) and no signs of hepatitis A infection 4.5. A shorter primary vaccination course seems adequate in producing protective levels of anti-HAV antibody titres. This led to a further trial conducted on the XXVI Norwegian contingent to UNIFIL, from May to November 1991. Two doses of 720 EI.U was to be given at day 0 and day 14 with a booster at month 7.

A total of 549 soldiers were enrolled conforming with the usual inclusion/exclusion criteria. For logistical reasons, 73 subjects received only one dose. They were given Ig to conform with the Armed Forces' requirements and hence excluded from the study. The remaining 476 soldiers, 446 males and 10 females with an average age of 28.8 years (range 19-55 years), completed the primary vaccination course and received the booster at month 9 after their return to Norway. The booster dose was temporarily delayed 2 months by the National Drug Administration in case bovine serum from the UK had been used in the manufacture of the vaccine. Bovine spongioform encephalitis (BSE) in the UK was in focus at that time. It was documented that lot VHA 007 A4 used in study contained no UK bovine serum and the study was completed with this vaccine. Following each injection, local and general symptoms were recorded for three days on symptom sheets. Serum samples were collected before the primary vaccination course and at month 1, 2, 3, 7 and 10. The first set of samples were screened with hepatitis A virus antibody radioimmunoassay (HAVABRIA, Abbot, USA) for any sign of previous exposure to hepatitis A infection. The rest were analysed with a sensitive enzyme-linked immunosorbent assay (ELISA, SmithKline Beecham) for vaccine-induced anti-HAV antibody titres. A 5-year followup on antibody titres is planned to determine duration of protective antibody titre levels. Sera were also tested for liver enzymes, aspartate and alanine aminotransferases (AST and ALT), before vaccination and at month 7 and 10. RESULTS The vaccine was well tolerated, with only mild to moderate symptoms reported. However, at the time of the first vaccination the subjects were also vaccinated to U N I F I L standards with diphtheria-tetanus, polio, typhoid, cholera and BCG. Some groups also received hepatitis B

V a c c i n e , Vol. 10, S u p p l . 1, 1992

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Hepatitis A vaccine in Norwegian UN Force. P. Aarhaug Table 3

Prophylaxis in military personnel. Survey of investigations in the Middle East area

Reference Published by

Force

Theatre

No. of inoculated subjects

Period

Protection rate (%)

Ig dosage

Gellis et al. 1945 Kluge 1963

US UNEF I

Mediterranean Sinai/Gaza

1 700 10 080

1944 1956-62

84 91

Kark 1980

tDF

Israel

16 000

1977-79

88

10 ml 2.8 ml 3 months 5 ml 6 months

French battery/ UNIFIL

South Lebanon

1000

1978-79

98

UNIFIL

South Lebanon

15 O00

1978-80

97

Demarchi et al. 1980 Kluge 1981

5 ml 3 months 2 ml

Reproduced from Rissa 1982, 55, pp. 71, with permission

DISCUSSION

o~O

100 •-

/ I000 /;

80

m L

6o

~ c

4o

~

2o

IIIII/I 1

""

t

I

I

I

I

1

2

3

7

9

~ ~" E

~J--

"C_ E

I0

Time (months)

1 Seroconversion rate (--) and geometric mean titre (---) induced by inactivated hepatitis A vaccine. Arrows show time of vaccination. Blood samples were taken at 1 month (n = 378, Seroconversion 83.1%, GMT 197, range 22-958), 2 months (n - 40, Seroconversion 100%, GMT 303, range 28-1541), 9 months (n = 321, Seroconversion 100%, GMT 147, range 23-648), 10 months (n = 291, Seroconversion 100%, GMT 1010, range 87-7886) Figure

vaccine. These vaccinations may have influenced the symptoms reported following the first dose. The number of subjects reporting symptoms at this time were considerably higher (54.4%) than in the first trial (39.0%), but not very different from other studies. However, the overall number of subjects reporting symptoms were fairly constant in the two studies: 37.0% versus 39.7% for the first and second studies, respectively. Our medical staff', based on extensive experience with Ig, subjectively reported significantly less complaints with the hepatitis A vaccine compared to Ig. Soreness (10%), swelling (8.9%), redness (7.1%) and induration at the site of injection (5.5%), were the most frequently reported local symptoms. Malaise (18.8%) and headache (13.4%) were the most common general symptoms. Onset of symptoms were early and they lasted < 24 h. No serious adverse reactions were reported. No pathological elevation in liver enzymes, indicating damage to liver cells, were recorded either induced by the vaccine or by hepatitis A infection. Figure 1 shows the immunogenicity, seroconversion rates and geometric mean titres. The seroconversion rate is somewhat lower following the primary vaccination course than that obtained in other studies ~, but generally it shows the same pattern. A different timing in blood sampling would have been desirable in evaluating the results, but this was difficult due to logistical constraints. The compliance for the study was 53.4%, as 293 of the initial 549 subjects enrolled returned for the final blood sampling at month 10. No clinical cases of hepatitis A were recorded during the trial, nor were any serological evidences of infection observed in the 321 subjects tested at the end of their mission in Lebanon, indicating protective efficacy of the hepatitis A vaccine.

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Vaccine, Vol. 10, Suppl. 1, 1992

The results from the two trials show that the inactivated hepatitis A vaccine induced low reactogenicity and resulted in seroconversion in all subjects following the primary vaccination course. The new vaccine is indeed an effective alternative to Ig and offers several advantages over Ig. From a medical point of view the principle of active immunization is clearly preferable to passive immunization. It gives long-term protection with the possibility of better control. The low reactogenicity also makes it more acceptable than Ig. Logistically and economically, the vaccine provides many advantages although these have not yet been evaluated in the context of the UN. Ethical questions are regularly raised in Scandinavia concerning the acquisition of sera from countries in the developing world for Ig production and other purposes. With the hepatitis A vaccine there will no longer be moral constraint to providing protection against hepatitis A . In the future it is hoped that a cheaper, single-dose vaccine, preferably in combination with hepatitis B vaccine will become available. In the meantime we will continue to use the new inactivated hepatitis A vaccine and prefer this to passive immunization with Ig.

REFERENCES 1

2

3 4 5

6 7

8

9

Kluge, T. Gammaglobulin in the prevention of viral hepatitis. A study on the effect of medium size doses. Rev. Int. Serv. Sant. A r m i e s 1963, suppl. 5, 59-63 Kluge, T. Infectious hepatitis in UNIFIL International review of the Army, Navy and Air Force Medical Services. Rev. Int. Serv. Sant. A r m i e s 1982, 55, 69-74 Kluge, T. Hepatitis. Rev. Int. Serv. Sant. Armees 1963, suppl. 5, 31-34 Just, M. Study report HAV-001, data on file MLiller, R., Chriske, H., Deinhardt, F., Jilg, J., Theilmann, L, Hess, G, Hofmann, F., Hopf, U., Stickl, H., Maiwald, M., Bienzle, U., Sch6feld, C., Zimmermann, H., Dietrich, M., May, B., Bock, H E , Clemens, R. and Boaerts, H. Hepatitis A vaccination: schedule for accelerated immunization. Vaccine 1992, 10 (Suppl. 1), $124-125 Just, M. Study Report HAV-048, data on file Gellis, S., Stokes, J., Brother, G.M., Hall, W.M., Gilmore, H.R., Beyer, E. and Morrissey, R.A. The use of human serum globulin (gamma globulin) in infectious (epidemic) hepatitis in the Mediterranean theatre of operations. J. Am. Med. Asoc., 1945, 128, 1062-1063 Kark, J.D. Pre-exposure prophylaxis with immune serum globulin for prevention of viral hepatitis (HAV): a controlled field trial in Israel Defence Forces Recruits. Proc. 23rd Int. Congr. Mil. Med. PharmacoL, Santiago, Chile, 5/6 December 1980 Demarchi, J., Laverdant, C., Dutertre, J., Hainaut, J. Prophylaxie de I'hepatite virale de type A par les immuno-globulines polyvalentes. R6sultats obtenus darts les armees. Med. Armees 1980, 8, 496-508

Field evaluation of a hepatitis A vaccine in a Norwegian contingent to the United Nations Interim Force in Lebanon.

The Norwegian population is basically seronegative regarding anti-hepatitis A antibodies. For this reason they are particularly vulnerable when expose...
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