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(12) Patent Application Publication (10) Pub. No.: US 2011/0159031 A1 Falkner Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/0159031 A1 Falkner Et Al US 2011 O159031A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0159031 A1 Falkner et al. (43) Pub. Date: Jun. 30, 2011 (54) VACCNE TO INFLUENZA AVIRUS Related U.S. Application Data (60) Provisional application No. 61/289.309, filed on Dec. (75) Inventors: Falko G. Falkner, Orth/Donau 22, 2009. (AT); Otfried Kistner, Vienna (AT); Annett Hessel, Orth/Donau Publication Classification (AT); P. Noel Barrett, (51) Int. Cl. Klosterneuburg/Weidling (AT); A 6LX 39/285 (2006.01) Hartmut Ehrlich, Vienna (AT); CI2N 15/63 (2006.01) Georg Holzer, Wiener Neudorf CI2N 5/863 (2006.01) (AT) CI2N 7/01 (2006.01) A6IP37/04 (2006.01) A6IP3 L/16 (2006.01) (73) Assignees: BAXTER INTERNATIONAL INC., Deerfield, IL (US); BAXTER (52) U.S. Cl. ................. 424/199.1; 435/320.1; 435/235.1 HEALTHCARE S.A., Glattpark (57) ABSTRACT (Opfikon) (CH) The present invention relates, in general, to compositions and methods for administering a vaccine against influenza to a (21) Appl. No.: 12/976,145 Subject, the vaccine comprising a vaccinia virus vector and a hemagglutinin and neuraminidase gene, separate or in com (22) Filed: Dec. 22, 2010 bination, from an influenza A virus. Patent Application Publication Jun. 30, 2011 Sheet 1 of 9 US 2011/O159031 A1 Figure 1. A) kDa 2 3 4 5 6 7 8 9 kDa 25 20 Patent Application Publication Jun. 30, 2011 Sheet 2 of 9 US 2011/O159031 A1 Figure 2. 3. & is as 3 C QP { {3 M W 2------------------------------ ims ims N. NB N N Red N. N. 3 g g &g : - - - - a- - - 2- Y - s x.3 &w w& &w 3. E. a. s s: s s& s &axs s Figure 3. A) 8 & 3 Mis--a g 'fi....Ca 40 8 if A Ni -- E3 2 4 3 8 2 & 32224: 83.83332 83 2 3 838 & 2 22:38 283 time after challenge (days) time after challenge (days) Patent Application Publication Jun. 30, 2011 Sheet 3 of 9 US 2011/O159031 A1 Figure 4. 00 & Fig. 4 Figure 5. [[] ×× Fig. 5 Patent Application Publication Jun. 30, 2011 Sheet 4 of 9 US 2011/O159031 A1 Figure 6. e O-or O 25 30 35 40 45 25 30 35 40 45 days days 4. O C 2 O 25 30 35 40 45 25 30 35 40 45 days days -o- Lung, H17CA PP -- Lung, N1/CA PP -e- Spleen, H17CA PP -A- Spleen, N1/CA PP Patent Application Publication Jun. 30, 2011 Sheet 6 of 9 US 2011/O159031 A1 Figure 9. VALYSELF AVRGOECI GYANNSTEK WERNW WHAKE) EE THINGKECKN GPEEEGIC SAGWE, GNP ECRLSWE WSY EVEKENP RGCY GS NOYEEKE, SSWKHFEKVK ELPKDRWTOH TTTGGSRACA WSCNPSFFRN WWTKKGSN YEWAKGSYNN TSGEOMLI:W GVHHPNDETE ORTY (NVGT YVSV GTSTN KRSTPC ATR PKWNGCSRM EFSWTEMW NEES ON EAPEY GE'KI SKRGSSGMK 8, GENCE KCQ PGAIN TTLPFHNVHP ET GECPKYV KSEKLYIATG I, RNVPCIQSR ERRRKKRGLF GAAGFEGG WOGMVDGWYG YHHSNCCGSG YAADKESTOK AFIGITNKVN SVIEKMNT OF EAVGKEFSNL ERRENINKK MEDGFLOVW YNAELVME NERTIF HOS NWKN YOKVR MOE, RINVKEI. GNCCFE FY HK CEECMNSWK NGTYYKYE EESKNRNEI KGVKSSVGV YO3. L.A.IYA:W AGSISLAMM AGSEN, CSN GS3...QCRICI* (SEQ ID NO : 5) Figure 10. mHS promoter Sg|P promoter *A, Ca DSR sWA- H1--Ca Figure 11. dark NP lark -------- I -------- - -------... MW, DA, RSR intergei regio Patent Application Publication Jun. 30, 2011 Sheet 7 of 9 US 2011/O159031 A1 Figure 12. -A A. HA2 Figure 13. O O i 106 10-5 104 MVA wt PBS VVA--N1 Ca US 2011/O 159031 A1 Jun. 30, 2011 VACCNE TO INFLUENZA AVIRUS newly identified H1N1 strain. Efficient induction of antibod ies and surprisingly high levels of CD8 T cells were induced CROSS REFERENCE TO RELATED against both antigens. APPLICATIONS SUMMARY OF THE INVENTION 0001. This application claims the priority benefit of U.S. Provisional Patent Application No. 61/289.309, filed Dec. 22, 0007. The present invention relates to the preparation and 2009, hereby incorporated by reference in its entirety. use of an antigenic composition or recombinant virus com prising a vaccinia virus vector and polynucleotides encoding FIELD OF THE INVENTION influenza A genes that are relevant in producing an immune response and influenza infection. The antigenic composition 0002 The present invention relates, in general, to compo and recombinant virus are useful as a vaccine to induce an sitions and methods for administering a vaccine against influ immune response in a Subject against the heterologous influ enza to a subject, the vaccine comprising a vaccinia virus enza genes expressed by the virus. vectorandahemagglutinin and neuraminidase gene, separate 0008. In one aspect, the invention provides an antigenic composition comprising a vaccinia virus vector comprising a or in combination, from an influenza A virus. polynucleotide encoding a hemagglutinin protein (HA) from influenza A and a polynucleotide encoding a neuraminidase BACKGROUND OF THE INVENTION protein (NA) from an influenza A virus, wherein the HA is of subtype selected from the group consisting of H1, H2, H3, 0003. The emergence and global spread of the new H1N1 H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, and influenza Subtype in humans has made the development of H16, and wherein the NA is of a subtype selected from the vaccines against pandemic influenza viruses a global health group consisting of N1, N2, N3, N4, N5, N6, N7, N8 and N9. priority. Several strategies are currently followed to produce pandemic vaccines, such as the development of inactivated whole virus vaccines, Subunit vaccines, recombinant viral proteins and live vaccines. Vaccines based on inactivated influenza virus are usually derived from embryonated hens eggs or, more recently, from permanent cell cultures. Protec tive immunity elicited by these vaccines is mainly based on neutralizing antibodies directed against the hemagglutinin gene (HA) (20, 21). 0004 Abroader immune response including efficientanti bodies against the influenza Surface proteins and induction of CD8 T cells, as induced by live vaccines, would be desirable. Attenuated live vaccines based on cold-adapted influenza strains (1,10) or on nonreplicating, NS-1 gene-deleted influ enza virus (12, 18) presumably have these advantages. Intra nasal application of Such pre-pandemic live vaccines, how ever, might result in new reassortant strains by co-infections in the respiratory tract with wild-type influenza strains raising safety concerns. In certain instances, influenza reassortants of the cold-adapted internal gene backbone with avian strains seem to have incompatible gene segments and induce only Subpotent immune responses (6). Only the re-introduction of the polybasic cleavage site into the HA (previously deleted to attenuate the live virus) restored infectivity and immunoge nicity (17). In another case, passaging of the live vaccine in host cells was required to achieve acceptable growth. Passag ing, however, may result in reduced immunogenicity requir 0010. In one embodiment, the polynucleotide encoding ing screening of adequate reassortants (6). Further, the long the HA and the polynucleotide encoding the NA are derived term effect of repeated intranasal administration of high doses from the same virus strain. In another embodiment, the poly of live vaccines on the olfactory system is largely unknown. nucleotide encoding the HA and the polynucleotide encoding 0005 Live vaccines based on poxviral vectors, such as the NA are derived from different virus strains. In a related vaccinia virus vectors, including the highly inactivated modi embodiment, the HA is derived from subtype H1 and the NA fied vaccinia Ankara Vector, are alternatives to prior vaccines derived from subtype N1. In a further embodiment, the HA as these vectors have a long safety record, induce T cell and NA are derived from influenza A strain virus A/Califor responses and are usually administered by demonstrated Sub nia/07/2009. cutaneous or intramuscular routes. 0011. In some embodiments, the H1 HA protein encoded 0006. The purpose of this study was to evaluate the by the polynucleotide is set out in FIG. 8 (SEQID NO: 14) or immune response and the protective potential of vaccinia FIG. 14A (SEQID NO: 16). In a related embodiment, the N1 based influenza vaccines expressing the protective antigens NA protein encoded by the polynucleotide is set out in FIG. hemagglutinin and neuraminidase, as exemplified against a 14B (SEQID NO: 17). US 2011/O 159031 A1 Jun. 30, 2011 0012. In certain embodiments, the HA is of subtype H2. In derived from subtype N1. In a further embodiment, the HA one embodiment, the amino acid sequence of the H2 protein and NA are derived from influenza A strain virus A/Califor is set out in FIG.9 (SEQID NO: 15) or FIG.15 (SEQID NO: nia/07/2009. 19). 0023. In some embodiments, the H1 HA protein encoded 0013. It is further contemplated that the antigenic compo by the polynucleotide is set out in FIG. 8 (SEQID NO: 14) or sition described herein optionally comprises a polynucleotide FIG. 14A (SEQID NO: 16). In a related embodiment, the N1 encoding an influenza A nucleoprotein (NP) protein. In one NA protein encoded by the polynucleotide is set out in FIG. 14B (SEQID NO: 17). embodiment the amino acid sequence of the NP is set out FIG. 0024. In certain embodiments, the HA is of subtype H2. In 14C (SEQID NO: 18). one embodiment, the amino acid sequence of the H2 protein 0014. In some embodiments, the HA, NA and NP are is set out in FIG.9 (SEQID NO: 15) or FIG.15 (SEQID NO: derived from the same influenza strain or from different influ 19). enza A strains. For example, in Some embodiments the anti 0025. It is further contemplated that the antigenic compo genic composition comprises an HA, NA and NP from one or sition described herein optionally comprises a polynucleotide more of an H1N1, H2N1, H3N2 or H5N1 influenza virus.
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