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Recombinant Hepatitis B Surface Antigen and Vaccine Containing It

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Recombinant Hepatitis B Surface Antigen and Vaccine Containing It Europaisches Patentamt 291 586 J European Patent Office CO Publication number: 0 A2 Office europeen des brevets EUROPEAN PATENT APPLICATION © Application number: 87202618.2 © Intel* C12N 15/00 , C12P 21/02 , A61K 39/29 © Date of filing: 26.08.82 Claims for the following Contracting State: AT. © Applicant: GENENTECH, INC. 460 Point San Bruno Boulevard South San Francisco California 94080(US) © Priority: 31.08.81 US 298235 03.12.81 US 326980 @ Inventor: Levinson, Arthur D. 3690 Ralston Avenue @ Date of publication of application: Hillsborough California 9401 0(US) 23.11.88 Bulletin 88/47 Inventor: Yansura, Daniel G. 330 Carmel Avenue ® Publication number of the earlier application in Pacifica California 94044(US) accordance with Art.76 EPC: 0 073 656 Inventor: Liu, Chung-Cheng 709 Bahama Lane © Designated Contracting States: Foster City California 94404(US) AT BE CH DE FR GB IT LI LU NL SE © Representative: Armitage, Ian Michael et al MEWBURN ELLIS & CO. 2/3 Cursitor Street London EC4A1BQ(GB) © Recombinant hepatitis B surface antigen and vaccine containing it © Hepatitis B surface antigen is expressed in a transformant vertebrate ce! ulture, producing 22nm particles of mature HBsAg acking HBsAg precursor protein, but nevertheless immunogenic and having vaccine potential. CO 00 ID CD CM CL LLJ Xerox Copy Centre 0 291 586 RECOMBINANT HEPATITIS B SURFACE ANTIGEN AND VACCINE CONTAINING IT This invention relates to the production of the disease pandemically. virus vector (hepatitis B hepatitis B surface antigen (HBsAg) by recom- Hepatitis is cause by a state - the so- binant DNA technology, and to its use as a vac- virus or HBV) which in its whole the virion and cine. The application is divided out of EP 73656 called Dane particle - represents 27 nucleocapsid enclosing a DNA (the parent application), which is directed to the 5 consists of a nm surrounding the expression of polypeptides in vertebrate cell cul- molecule and an envelope associated with the virion ture. nucleocapsid. Proteins a DNA poly- The present invention is directed to means and include the core antigen (HBcAg), whic has methods of producing in vertebrate cell culture, merase and the surface antigen (HBsAG) of infected and carrier hu- hepatitis B surface antigen (HBsAg) in discrete w been found in serum HBsAG have also been found particle form comprising immunogenic determinant- mans. Antibodies to HBV infected It is believed that (s) of hepatitis B virus (HBV). The HBsAg hereof is in serum people. induce im- secreted into the cell culture medium in discrete HBsAG is the HBV antigen than can of antibody (anti-HBs) and particle form, devoid of any additional, fused poly- munogenic production the in an HBV vaccine. peptide artifact, whether enclosed by another por- 75 thus it would be principle directed to: Dane et aL, Lancet 1970 tion of the HBV genome or by DNA homologous to Attention is J. Immunology 107, the vector employed. This invention contemplates <£, 695 (1970); Hollinger et a]., J. Immunology 109, 834 the use of the thus produced HBsAg for the prep- 1099 (1971); Ling et al., Science"*! Peterson aration of vaccines useful to confer immunogenicity (1972); Blumberg, 97 17 (1977); Sci 74, 1530 (1977) to HBV in susceptible humans, to such vaccines 20 et al., Proc. Nat. Acad. (USA) Assessment of and to the method of using them to inoculate and and Viral Hepatitis, A Contemporary and Preven- confer immunogenicity to HBV in susceptible hu- Etiology, Epidemiology, Pathogenesis Franklin Institute Press, mans. tion. (Vyas et al., eds.) which is hereby incor- Thus, in one aspect the present invention pro- Philadelphia, 1978, each of reference to further illustrate the vides a method for making hepatitis B surface 25 porated by this this invention. antigen which comprises expressing in a transfor- background of infected predomi- mant vertebrate cell culture a DNA sequence en- HBsAg is present in plasma of particles having coding said antigen but lacking any sequences nantly in the form spherical about 16 to 25nm - the so- encoding the hepatitis B surface antigen precursor diameters ranging from ir22nm These are thought to repre- sequence. 30 called particle." Because anti- In another aspect the invention provides the sent a noninfectious viral envelope. protective against HBV use of 22 nm particles consisting of mature hepati- bodies against HBsAg are effec- tis B surface antigen having no hepatitis B surface infection, these non-infectious particles can vaccine. antigen precursor sequence in the preparation of a tively be used as a B virus has not been vaccine for conferring immunogenicity to hepatitis 35 Inasmuch as the hepatitis and only be obtained B virus in a susceptible human. infectious in cell culture can means In a further aspect the invention provides a from infected humans or higher primates, and maintain- vaccine comprising a pharmaceutically acceptable have not been available for obtaining HBV for in producing vehicle and hepatitis B surface antigen particles ing sufficient supplies of use immunization HBV. having a diameter of about 22 nm and consisting of 40 antigen for against Publication No. mature hepatitis B surface antigen and lacking any In British Patent Application 2034323A and European Patent Applications Pub- precursor sequence thereof. lication Nos. 13828 and 20251 are respectively described the isolation and cloning of the HBV 45 genome, the expression of HBV core antigen and the production in E.coH of a fusion protein purpor- of HBsAg. Proc. Natl. Hepatitis B (serum hepatitis) virus is transmit- tedly containing a portion Acad. Sci. (USA) 77, 4549 (1980) reports the in- ted among humans and manifests as chronically chromosome by transformation debilitating infection which can result progressively tegration of mouse with tandem cloned hepatitis B in severe liver damage, primary carcinoma and 50 of mouse cells death. In most cases, complete recovery from genomes. in Proc. Natl. Acad. Sci. (USA) hepatitis B infections can be expected; however, Moriarty et al., described the construction of a large segments of the population, especially in 78, 2606 (1981), simian virus 40 (SV40) recombinant carrying a frag- many African and Asian countries, are chronic car- of kidney cells riers with the dangerous potential of transmitting ment of HBV-DNA. Cultures monkey 0 291 586 were infected with the viral recombinant and pro- added following transfection, and the medium as- duced a 22nm particle purportedly characteristic of sayed at various times for HBsAg expression fol- those found in sera of hepatitis B infected patients. lowing 24 hours accumulation. HBsAg expression The Moriarty et al. recombinant vector contained a is expressed as counts per minute (cpm) in 0.2 ml large segment of the HBV genome harboring the 5 undiluted medium, as assayed by RIA (Abbott HBsAg sequence and included DNA sequences Labs.) encoding SV40 tumor proteins and possibly other Figure 6 depicts immunogenicity of HBsAg HBV proteins. derived from monkey cells. Medium from 20 15-cm Further, their construction incorporated the dishes of Cos cells transfected with pHBs348-L HBsAg DNA in frame with the VP-2 protein coding 70 was harvested and HbsAg purified as described sequence of SV40 virus. It is not clear whether above for electron microscopic examination. Three mature HBsAg was expressed. groups of five mice were immunized with 2.8 ug, Some preferred embodiments of the invention 0.6 ug, or 0.006 ug of purified HBsAg in the will now be described with reference to the accom- presence of complete Freund's adjuvant. Control panying drawings, in which: 75 mice were immunized with similar amounts of au- Figure 1 depicts the construction of plasmid thentic HBsAg derived from human serum (North pSVR containing SV40 DNA with a deletion of the American Biologicals Inc.) Mice were tail bled at coding region for the VP-1 protein. various times following immunization, anti-HBsAg Figure 2 depicts the construction of plasmid antibody quantitated by RIA (Abbott Labs), and the pHS94 harboring HBsAg DNA. 20 results expressed as the average titer per mouse. Figure 3 depicts the construction of plasmid Mice immunized with HBsAg derived from tissue pSVHBSA containing HBsAg DNA and sequences culture developed titers identical to mice immu- of DNA derived from SV40 and pBR322. In part B, nized with HBsAg derived from human serum. the DNA sequence surrounding the ATG initiation Figure 7 demonstrates the presence of HBV codon of VP-1 protein (boxed in top line) is com- 25 sequences replicating as part of SV40. pared with that of HBsAg created in the recom- Figure 8A depicts a sucrose gradient sedi- binant (boxed ATG in bottomline). The hind III site mentation of HBsAg synthesized via the recom- which was converted to an EcoRI site is underlined. binant vector hereof. Figure 8B is a corresponding Figure 4 depicts the replication of plasmid CsCI gradient centrifugation thereof. DNA in monkey cells. Monolayers of Cos cells 30 Figure 9 depicts an electron micrograph of were grown to 50-60 percent confluency in 6-cm HBsAg synthesized as a 22nm particle in accor- plastic dishes. The cells were washed with Dul- dance with this invention. becco's modified medium, and 2ml of medium containing 1 ug of plasmid DNA and DEAE-dextran at 200 ug was applied for 12 hours at 37°. The 35 CeN Culture Systems/Cell Culture Vectors DNA solution was removed, the cells washed once with medium, and 5ml of medium containing 10 Propagation of vertebrate cells in culture percent fetal calf serum was added and the cells (tissue culture) has become a routine procedure in incubated at 37° for either one or three days prior recent years (see Tissue Culture, Academic Press, to DNA extraction. At these times, small super- 40 Kruse and Patterson eds, 1973). Employed herein coiled plasmid DNA was isolated according to the was the CV-1 line of monkey kidney fibroblasts as method of Hirt (14).
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