Putative failures of recombinant DNA hepatitis B vaccines

Letter Putative failures of recombinant D N A hepatitis B vaccines Sir, The efforts to assess the effect of 1-week exposure of a recombinant hepatitis B vaccine (Engerix-B, Smith Kline Biologicals) to 37"C on its reactogenicity and immunogenicity 1 would, a priori, appear to be very commendable. Immunization of 58 healthy young adults with a vaccine lot stored continuously at 4 °C or a lot kept at 37°C for 1 week, was not associated with a significant difference in incidence, type or severity of symptoms attributable to a hepatitis B vaccine. The storage at 37°C for a week was not accompanied by any significant difference in the GMT for the anti-HBs titres, 1 month after the third dose of the respective vaccine lots. Unfortunately the encouraging results on reactogenicity and immunogenicity' cannot be extrapolated towards utility of recombinant hepatitis B vaccines in vast areas in Asia, Africa and Latin America where ambient temperatures far exceeding 40 °C are a rule rather than exception, and there is marked diurnal variation in sunlight, humidity and drought. Moreover, different permutations and combinations of adverse environmental factors in these areas have been incriminated for the local continued failures of otherwise efficient immunobiologicals2. To avoid catastrophies of the sort associated with other immunobiologicals in such areas, it is essential that studies on reactogenicity and immunogenicity of recombinant hepatitis B vaccines are carried out only with the vaccine lots that had been exposed to every possible rigour of temperature, drought, humidity and sunlight in an environment closely simulating the inadequate transport and storage facilities in developing countries I. Extrapolation of the apparently meritorious result ~ universally could be delusive and fallacious, like the report, during early 1960s, on thermal stabilization of polioviruses with a high cation concentration. Under precisely con0264-410X/89/020164-01 $03.00 O 1989 Butterworth & Co. (Publishers) Ltd

164 Vaccine, Vol. 7, April 1989

trolled conditions, M g 2+ did stabilize polioviruses to temperatures ranging from 4 to 50°C 3, but that stabilization did introduce a complacency, albeit pseudo, about field stability of oral poliovirus vaccine in developing countries 4. The recombinant vaccine would appear not to have coped with the problem of a non-response or hyporesponse associated with plasmaderived vaccines. In a private community hospital at Pasadena, 25 fulltime employees who had failed to produce adequate anti-HBs response with plasma-derived vaccine have been immunized with three doses of a recombinant vaccine containing 10 lag of HBsAg with alum adjuvant (Recombivab-HB, lot 978/C-K563; Merck, Sharp and Dohme). Among these 9 men and 16 women, both the initial and subsequent anti-HBs responses have been dismal% Even immunization of 58 healthy young adults with recombinant vaccine (Energer, Smith-Kline Biologicals) has failed to elicit an anti-HBs response in one vaccine 1. The inadequate anti-HBs response has been speculated to be due to a genetic influence on the host immune system that results in a significant alteration in different subsets of immunologically competent cells, or by altered production of the class II glycoprotein antigen, DR 5. Though the role of DR antigen in non-responsiveness to recombinant vaccines could be defined through extended haplotypes for histocompatibility antigens, the non-responders could best be tested for quantitative changes in their T-cell subsets in peripheral blood using a dual-colour fluorescence analysis. The dual-colour fluorescence analysis of T-cells in peripheral blood has efficiently divided the peripheral T-cells into four subsets o f L e u - 2 a + 1 5 +, L e u - 2 a + 1 5 -, Leu-3a÷8 + and Leu-3a+8 -. In patients with fulminant hepatic failures, there is a significant elevation of Leu-2a+15 - and r e d u c t i o n of

Leu-2a +15 +, with no significant difference in patients with acute hepatitis or chronic hepatitis 6. The contribution by various functional subsets in non-responders to various hepatitis B vaccines merits critical evaluation by dual-colour fluorescence analysis with fluorescein isothiocyanate and phycoerythrin. The role of pre-S antigen is not all that explicit in terms of its safety, immunogenicity and protection. Incorporation of pre-S polypeptides into hepatitis B vaccines has been speculated to be the most feasible way of dealing with non-respondersT. Both pre-S1 and pre-S2 antibody response are elicited earlier than antiHBs response and a heightened humeral response to both of them occurs early in the course of fulminant hepatitis and is responsible for hepatic damage and rapid clearance of virus s. Nevertheless, during immunization of 354 infants with a Pasteur vaccine (Hevac B) containing 2-5 IxgHBsAg and 1-2% pre-S2 genecoded protein, anti-pre-S2 activity was confined only to anti-HBs positive sera. The non-responders to pre-S2 antigen have been hyporesponders or non-responders to S antigen, while a good pre-S2 response is associated with a similar response to S antigen 9. Recently, improved lots of the recombinant vaccine have been obtained with an improved process for a new master seed of yeast cells producing HBsAg. A comparison of the immunogenicity of the earlier recombinant lots and two new recombinant vaccine lots has been made in 90 serenegative health workers with 10tag doses (Merck, Sharp and Dohme). With the latest recombinant vaccine lots, the anti-HBs developed earlier and the GMT have been significantly higher 10. Further investigations with recombinant vaccine lots from new master seed of yeast cells incorporating various pre-S polypeptides would be desirable to eliminate hypo- and nonresponders to hepatitis B vaccines.

S.C. Arya Centre for Logistical Research and Innovation, M-I22 (of part 2) Greater Kailash-H, New Delhi 110048, India

Book Review 5 Weissman, J.Y., Tsuchiyose, M.M., Tong, M.J.

References 1 Just, M. and Burger, R. Immunogenicity of a heat-treated recombinant DNA hepatitis B vaccine. Vaccine 1988,6, 399 2 Arya, S.C. Can the new polio vaccines take the

heat? Nature1988,332, 789 3 Wallis, C. and Melnick, J.L. Cationic stabilization--a new property of enteroviruses. Virology 1962, 18, 504 4 Arya, B.C. Continuing global poliomyelitis morbidity and lacunae of trivalent poliovirus vaccines. Vaccine 1988,6, 213

etal. Lackof response to recombinant hepatitis B in non-responders to the plasma vaccine.

Am. Med.Assoc.1988,260, 1734 6 Hasegawa, K., Yamauchi, K., Furukawa,T. and Obata, H. Dual color fluorescence of peripheral T-cell subsets in hepatitis B virus-induced liver disease. Hepatology1988,8, 1134 7 Stephenne, J. Recombinant versus plasmaderived hepatitis B vaccines: issues of safety,

8 Ise, I., Tsuda, F., Aihara, S. etaL Antibodies to translation products of the pre-S~ and pre-S2 regions of the envelope gene of hepatitis B in fulminant hepatitis B. Hepatology1988,8, 1089

9 Coursaget, P., Adamowicz, P., Bourdil, C. etaL Anti-pre-S2 antibodies in natural hepatitis B virus infection and after immunization. Vaccine

1988, 6, 357 10 Gibas,A.L., Watkins, E., Cody, H. and Dienstag,

immunogenicity and cost-effectiveness. Vaccine

J.L. Improved immunogenicity of new masterseed lots of recombinant yeast derived hepatitis

1988, 6, 299

B vaccine (abstract). Hepatology1988, 8, 1276

Book Review Viral Hepatitis and Liver Disease Editor, A.J. Zuckerman, Alan $350.00, ISBN 0-8451-4247-X

R. L i s s , I n c . , N e w Y o r k ,

This ll36-page tome, that covers the proceedings of the International Symposium, can truly be considered to be the present and future Bible for viral infections of the liver. The 278 individual articles cover all aspects of viral infections of the liver caused by hepatitis A virus, enteric and parenterally transmitted nonA, non-B hepatitis viruses of presently unknown or unestablished aetiology, hepatitis B virus, and the defective hepatitis D (Delta agent) virus. The scope of the book is broad and covers present knowledge of aetiology, molecular biology, pathogenesis, diagnostics, epidemiology, immunology, clinical aspects, treatment and prophylaxis for each of the entities. To paraphrase a ly~Ticfrom 'My Fair Lady', all that shouldbe there is there! Greatest attention is given to hepatitis B, for which there is the largest body of knowledge. Of special interest to the contemporary period, perhaps, is the information relating to the comparative biology and biochemistry of the hepadnavirus that causes hepatitis B, and the retrolentiviruses that cause acquired immune deficiency disease, or AIDS. Agents of the two virus groups share a similar gene organization and important gene and polypeptide sequences, suggesting a distant common ancestry. Both agents produce a reverse transcriptase

0264-410X/89/020165-01 $03.00 (~ 1989 Butterworth & Co. (Publishers) Ltd

1988, 1 1 6 0 p p . ,

that provides for alternate RNA-DNA encoding in their life cycle and makes possible the integration of their DNA into the host cell genome. Integration is mandatory for the replicative cycle of the retroviruses, but not for hepadnaviruses that can also replicate episomally. The retroviruses and the hepadnaviruses may be closely related in the evolutionary sense and the viruses of hepatitis B and AIDS share a common mode of transmission by blood, sex and mother-to-foetus. For hepatitis B, there are highly safe and effective vaccines that provide a means for eliminating new viral infections and the sequelae of chronicactive hepatitis and cirrhosis and cancer of the liver. Unlike hepatitis B, the reverse transcriptase of AIDS virus is remarkably error-prone, causing hypervariability in the principal neutralizing epitope of the viral outer envelope glycoprotein. Moreover, the retrolentivirus causing AIDS may be transmitted by infected cells of the monocyte/macrophage series that bear few cell surface markers of viral infection that would permit immunologic detection and cell destruction. What was once considered the obvious route to an AIDS virus vaccine, simply by copying that for hepatitis B, has proved disappointingly untrue and AIDS stands distinct as one of the most difficult targets for contem-

porary vaccine development. The progress toward a hepatitis A vaccine, made possible by the original cell culture propagation of the virus in 1979, was reviewed. Even though the technical feasibility and approach to both live and killed virus vaccines has been evident for more than a decade, progress has been remarkably slow. A more fruitful era of development may now be in progress. Non-A, non-B hepatitis control by vaccines must await more precise definition of the viral aetiologies and the development of reliable means for propagation or, at least, production of the immunologically important antigens. Hepatitis D agent, because of its requirement for hepatitis B virus surface antigen for its outer coat, and because of its dependence on acute hepatitis B infection or latency, is controllable by vaccination against hepatitis B. This extremely valuable and timely book will serve as a source of encyclopaedic information on the principal but not all the agents that cause hepatitis. Its nearly eight pounds in weight of condensed information preclude its use for light reading while travelling; it does not come in a vest pocket edition! Instead, it will serve as a 'Pilgrim's guide' to serious study of all things hepatitic!

Maurice

R. Hilleman

Merck Institute for Therapeutic Research, West Point, P e n n s y l v a n i a 19486

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