Inactivated hepatitis A vaccine: active and passive immunoprophylaxis in chimpanzees Robert H. Purcell *+, Erik D'Hondt¢, Richard Bradbury~, Suzanne U. Emerson*, Sugantha Govindarajan' and Leonard Binn' Studies q/" active and passive inmmnoprot)h.t'Mxis were carried out it, chimpanzees to determine whether a candidate hepatitis A virus (HA V) vaccine could stimulate antibody m HA V (anti-HA 17) that was qualitatively shTfilar to anti-HA V sth~lulated by natural iJ?/Eelion. Normal immune globulin ( I,g ) was prepared.fi'om plasma obtained./kom human vohmteers be/are and after vaccination with the HA V vaccine, and these preparations or commereia/h' prepared I,~ were administered to chimpanzees. Protective q~ca > <
7800 _>4000

47 ( ) 40 ( ) 346 ( + ) 113 ( + )

_> 120

_> 1600

51 ( - )

±

_>131

_>1600

80(±)

+

-

+

_>209

_>3200

29 ( - )

-

+ + -

± -

_>322 ->440 _>323 _>2612 _>2702

_>3200 _> 1000 _>2000 _>8000 _>8000

66 ( ) 9 ( ) 48 ( ) 835(+) 103 ( + )

+ -

+

NT + +

alncrease in amount of anti-HAV (measured as mlU for total or reciprocal titre for IgM) between time of challenge and peak level following challenge expressed as fold. NT, Not tested (chimpanzee could not be biopsied for medical reasons). See text for definitions

table virus between weeks 1 and 3 post-challenge. The sensitivity of this assay was ~ 105.s infectious doses of HAV as determined with a standard pool of cell-culture derived virus.

Immunofluorescence Liver biopsies from only two of the chimpanzees were positive for HAV antigen by immunofluorescence. A single biopsy (week 4) from one of the two chimpanzees that received pre-vaccination Ig and one biopsy (week 6) from one chimpanzee that received the higher volume of postvaccination Ig were positive.

Protection against hepatitis As seen in Table l, only the chimpanzees that received experimental Ig prepared from the plasma of vaccinees before vaccination and the chimpanzees that received nothing (positive controls) developed consistent liver enzyme elevations and histopathological changes indicative of hepatitis. In contrast, chimpanzees that were passively immunized with Ig containing anti-HAV were partially or completely protected against hepatitis A following challenge. Thus, all chimpanzees that had detectable anti-HAV prior to challenge, regardless of its source (vaccination or Ig from vaccinated or convalescent humans) were protected against hepatitis A, and all chimpanzees that lacked detectable anti-HAV developed hepatitis A. The lowest virus-neutralizing titre of passively acquired anti-HAV that was protective in chimpanzees was 1:10.

CONCLUSIONS Inactivated hepatitis A vaccine protected chimpanzees against intravenous challenge with virulent HAV as demonstrated by virological, biochemical, histological and serological criteria. Anti-HAV stimulated by vaccination with inactivated HAV vaccine is capable of preventing hepatitis A when administered passively. In this

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respect, it mimics commercial Ig containing anti-HAV stimulated by natural infection with HAV. Although both preparations prevented hepatitis A, neither preparation prevented infection with HAV when exposure was by the intravenous route. In contrast, Ig prepared from human vaccinees before vaccination failed to protect against either illness or infection, thus validating the specificy of the passive protection with the Ig preparations. Thus, anti-HAV stimulated by vaccination of volunteers with inactivated HAV vaccine was capable of passive immunoprophylaxis against hepatitis A when administered to chimpanzees. The reason why passively acquired anti-HAV protected only against hepatitis but not infection, whereas vaccine apparently protected against both, is not known but may simply reflect the higher titres of anti-HAV stimulated by the vaccine. Alternatively, cell-mediated immune respones may have been involved, but the excellent protective effect of traces of passively-acquired antiHAV suggests that cell-mediated responses are not essential and may not be important. It is surprising but gratifying that such a small amount of anti-HAV is protective. It suggests that the titre of anti-HAV present in commercial normal Ig is still adequate to prevent hepatitis A and is likely to be sufficient in the future, even if average levels continue to fall. It is also gratifying to know that anti-HAV stimulated by vaccination is protective when passively administered. This indicates that vaccination with hepatitis A vaccine can be used as a means of stimulating a high titre of anti-HAV in plasmapheresis donors for the purpose of preparing hepatitis A Ig. Active immunoprophylaxis with hepatitis A vaccine is preferable to passive immunoprophylaxis in almost all instances, and such vaccines should largely replace the administration of Ig for the prevention of hepatitis A in the future. The rapid appearance of anti-HAV following only one dose of vaccine suggests that protection is afforded by vaccination within days of administration of the vaccine, making vaccination an attractive alternative to Ig, even in situations where exposure may occur prior to administration of booster doses of vaccine. Further

Protective efficacy o f hepatitis A vaccine: R. H. Purcell et al.

more, the extremely high level of anti-HAV stimulated by vaccine, compared to Ig, makes it likely that vaccination in the community will also prevent not only hepatitis but infection with HAV. Such prevention of infection will minimize spread of HAV more effectively than passive immunoprophylaxis. Finally, the high level of antiHAV stimulated by HAV vaccines promises long-term immunity, a distinct advantage over Ig, which must be administered repeatedly to sustain protection. Future studies will determine how often booster doses of vaccine must be administered and whether subsequent exposure of vaccinees to HAV will stimulate a protective anamnestic anti-HAV response in vaccinees who have lost detectable anti-HAV over time. ACKNOWLEDGEMENT © US Government.

REFERENCES 1 Stapleton, J., Jansen, R. and Lemon, S. Neutralizing antibody to hepatitis A virus in immune serum globulin and in the sera of human recipients of immune serum globulin. Gastroenterology 1985, 89, 637-642 MacGregor, A., Kornitschuk, M., Hurrell, J.G.R., Lehmann, N.I., Coulepis, A.G., Locarnini, S.A. etaL Monoclonal antibodies against hepatitis A virus. J. Clin. Microbiol. 1983, 18, 1237-1243 Anderson, D.A., Coulepis, A.G., Chenoweth, M.P. and Gust, I.D. Indirect immunofluorescense assay for the detection of hepatitis A virusspecific serum immunoglobulins. J. Clin. Microbiol. 1986, 24, 163-165 Lemon, S.M. and Binn, L.N. Serum neutralizing antibody response to hepatitis A virus. J. Infect. Dis. 1983, 148, 1033-1039 Andre, F.E., Hepburn A. and D'Hondt, E. Inactivated candidate vaccines for hepatitis A. Prog. Med. ViroL 1990, 37, 72-95 Gust, I.D., Lehmann, N.I., Crowe, S., McCrorie, M., Locarnini, S.A. and Lucas, C.R. The origin of the HM175 strain of hepatitis A virus. J. Infect. Dis. 1985, 151,365-367 Emerson, S.U., McRill, C., Rosenblum, B., Feinstone, S. and Purcell, R.H. Mutations responsible for adaptation of hepatitis A virus to efficient growth in cell culture. J. Virol. 1991, 65, 4882-4886

Vaccine, Vol. 10, Suppl. 1, 1992

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Inactivated hepatitis A vaccine: active and passive immunoprophylaxis in chimpanzees.

Studies of active and passive immunoprophylaxis were carried out in chimpanzees to determine whether a candidate hepatitis A virus (HAV) vaccine could...
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