Source: https://patents.google.com/patent/US9226957B2/en
Timestamp: 2018-06-18 16:28:17
Document Index: 39577068

Matched Legal Cases: ['Application No. 60', 'Application No. 07842706', 'Application No. 0784276', 'Application No. 07842706', 'Application No. 14173324', 'Application No. 2009018599', 'Application No. 200780037288', 'Application No. 12165985', 'Application No. 1', 'Application No. 2009018599', 'Application No. 2009018599']

US9226957B2 - Compositions and methods of enhancing immune responses - Google Patents
US9226957B2
US9226957B2 US14100957 US201314100957A US9226957B2 US 9226957 B2 US9226957 B2 US 9226957B2 US 14100957 US14100957 US 14100957 US 201314100957 A US201314100957 A US 201314100957A US 9226957 B2 US9226957 B2 US 9226957B2
US14100957
US20140093534A1 (en )
Provided herein are Salmonella enteritidis 13A strains and compositions comprising these strains. Also provided are methods of enhancing an immune response against Influenza A and methods of reducing morbidity associated with an Influenza A infection. Methods of enhancing an immune response to a vaccine vector by expressing a polypeptide of CD154 capable of binding CD40 are also disclosed. Methods of developing a bacterial vaccine vector are disclosed. Methods of generating scarless site-specific mutations in a bacterium are also disclosed.
This application is a continuation of U.S. Pat. No. 8,604,178, issued Dec. 10, 2013, which is a national stage filing under 35 U.S.C. 371 of International Application No. PCT/US2007/078785, filed Sep. 18, 2007, which claims priority to U.S. Provisional Patent Application No. 60/825,983, filed Sep. 18, 2006, all of which are incorporated herein by reference in their entirety.
This invention was made with United States government support awarded by National Institutes of Health grant R21 AI063137. The United States may have certain rights in this invention.
EXAMPLES Example 1 Construction of M2e and M2e/CD154 Inserts
All primers used for PCR are listed in Table 1. Typically, PCR was performed using approximately 0.1 μg of purified genomic, plasmid or PCR-generated DNA (Qiagen, Valencia, Calif., USA), 1× cloned Pfu polymerase buffer, 5U Pfu polymerase (Stratagene La Jolla, Calif., USA), 1 mM dNTPs (GE Healthcare Bio-Sciences Corp., Piscataway, N.J.), and 1.2 μM of each primer in a total volume of 50 μL. The DNA engine thermal cycler (Bio-Rad, Hercules, Calif., USA) was used with the following amplification conditions: 94° C. for 2 minutes; 30 cycles of 94° C. sec for 30 sec, 58° C. for 60 sec, 72° C. for 90 sec per 1 kb; and 72° C. for 10 minutes for final extension. Each PCR product was gel purified (Qiagen, Valencia, Calif., USA) and either eluted in 25 μL EB buffer for preparation of templates used in overlapping extension PCR or in 504, EB buffer, ethanol precipitated and suspended in 5 μL of ddH2O for electroporation into S. enteritidis.
Iam-up-f loop 9 up 5′TGTACAAGTGGACGCCAATC 3′ (SEQ ID NO: 10)
Iam-up-r 5′GTTATCGCCGTCTTTGATATAGCC 3′ (SEQ ID NO: 11)
Iam-dn-f looop 9 dn 5′ATTTCCCGTTATGCCGCAGC 3′ (SEQ ID NO: 12)
Iam-dn-r 5′GTTAAACAGAGGGCGACGAG 3′ (SEQ ID NO: 13)
Km-f I-SceI/Kmr gene 5′GCTATATCAAAGACGGCGATAAC TAACTATAACGGTCCTAAGGTAGCGAAT (SEQ ID NO: 14)
TCCGGGGATCCGTCGA 3′
Km-r 5′GCTGCGGCATAACGGGAAATTGTAGGCTGGAGCTGCTTCG 3′ (SEQ ID NO: 15)
Kan4f inside Kmr gene: 5′CAAAAGCGCTCTGAAGTTCC 3′ (SEQ ID NO: 31)
Kan4r sequencing 5′GCGTGAGGGGATCTTGAAGT 3′ (SEQ ID NO: 32)
Iam-i1 M2e/loop 9 dn 5′GCTATATCAAAGACGGCGATAAC GAAGTTGAAACCCCGATTCGTAAC ATTTCC (SEQ ID NO: 16)
CGTTATGCCGCAGCG 3′
Iam-i2 CD154s/loop 9 dn 5′GCTATATCAAAGACGGCGATAAC TGGGCAGAAAAAGGTTATTATACCATGTCT (SEQ ID NO: 17)
ATTTCCCGTTATGCCGCAGC 3′
i2-i1h-f CD154s-(Gly)3-LM2- 5′TGGGCAGAAAAAGGTTATTATACCATGTCTGGTGGTGGTGAAGTTGAAACCC (SEQ ID NO: 33)
(Gly)3-loop 9 dn CGATTCGTAACGGTGGTGGT ATTTCCCGTTATGCCGCAGC 3′
i2-i1-r CD154s-(Gly)3- 5′AGACATGGTATAATAACCTTTTTCTGCCCAACCACCACC GTTATCGCCGTCTT (SEQ ID NO: 34)
loop 9 up TGATATAGCC 3′
TJ1-f CD154-(Ser)4-LM2- 5′TGGGCAGAAAAAGGTTATTATACCATGTCTTCCTCCTCCTCCGAAGTTGAAA (SEQ ID NO: 35)
(Ser)4-LM2-(Ser)4- CCCCGATTCGTAACTCCTCCTCCTCCGAAGTTGAAACCCCGATTCGTAACTCCT
loop 9 dn CCTCCTCC ATTTCCCGTTATGCCGCAGC 3′
TJ1-r CD154-(Ser)4-M2eA- 5′AGACATGGTATAATAACCTTTTTCTGCCCAGGAGGAGGAGGAGTTACGGGTC (SEQ ID NO: 36)
(Ser)4-M2eA- GGGGTTTCAACTTCGGAGGAGGAGGAGTTACGGGTCGGGGTTTCAACTTCGGA
(Ser)4-loop 9 up GGAGGAGGA GTTATCGCCGTCTTTGATATAGCC 3′
Iam 3f outer regions  5′GCCATCTCGCTTGGTGATAA 3′ (SEQ ID NO: 18)
of loop 9:
Iam 3r sequencing 5′CGCTGGTATTTTGCGGTACA 3′ (SEQ ID NO: 19)
Transformation of pKD46 into S. enteritidis was the first step carried out so that Red recombinase enzymes could be used for mediating recombination of subsequent mutations. Plasmid pKD46 was harvested from E. coli BW25113 (Datsenko and Wanner, PNAS 2000, 97:6640-6645) using a plasmid preparation kit (Qiagen Valencia, Calif., USA). Then 0.5 μL of pKD46 DNA was used for transformation into S. enteritidis 13A which had been prepared for electroporation. (Datsenko and Wanner, PNAS 2000, 97:6640-6645). Briefly, cells were inoculated into 10-15 mL of 2×YT broth and grown at 37° C. overnight. Then 100 μL of overnight culture was re-inoculated into 10 mL fresh 2×YT broth at 37° C. for 3-4 hours. Cells to be transformed with pKD46 plasmid were heated at 50° C. for 25 minutes to help inactivate host restriction. Cells were washed five times in ddH2O water and resuspended in 60 μL of 10% glycerol. Cells were then pulsed at 2400-2450 kV for 1-6 ms, incubated in SOC for 2-3 hours at 30° C. and plated on LB media with appropriate antibiotics. S. enteritidis transformants with pKD46 were maintained at 30° C. When these transformants were prepared for additional electroporation reactions, all steps were the same except that 15% arabinose was added to induce Red recombinase enzymes one hour prior to washing, and cells did not undergo the 50° C. heat step.
Loop 9 Up—I-SceI/Kmr—Loop 9 Down Construct
Introduction of 1-SceI enzyme recognition site along with the Kmr gene into loop 9 of the lamB gene was done by combining the Red recombinase system (Datsenko and Wanner, PNAS 2000, 97:6640-6645, which is incorporated herein by reference in its entirety) and overlapping PCR (Horton et al., BioTechniques 1990, 8:528-535, which is incorporated herein by reference in its entirety). The insertion site corresponds to nucleotide 1257 of the lamB gene using Salmonella typhimurium LT2 (S. typhimurium) as an annotated reference genome. First, the upstream and downstream regions immediately flanking the loop 9 insertion site (loop 9 up and loop 9 down, respectively) were amplified separately. Primers used were lam-up-f and lam-up-r for loop 9 up and lam-dn-f and lam-dn-r for loop 9 down. Then the Kmr gene from pKD13 plasmid was amplified using primers Km-f and Km-r. Here, the 1-SceI enzyme site was synthetically added to the 5′ end of Km-f primer then preceded by a region complimentary to the loop-up-r primer. Likewise, a region complimentary to the loop-dn-f primer was added to the 5′ end of Km-r primer. The complimentary regions allow all 3 PCR products to anneal when used as templates in one PCR reaction. FIG. 2A represents this design scheme. PCR fragments consisting of loop 9 up-I-SceI/Kmr loop 9 down sequence (PCR-A) were electroporated into S. enteritidis cells, which harbored pKD46 and were induced by arabinose, and then plated on LB with Km plates. To verify the correct sequence orientation of the mutation, we performed colony PCR with primer pairs Kan4F/lam3f and Kan4R/lam3r, where Kan4F and Kan4R are Kmr gene-specific primers and lam3f and lam3r are primers located outside the lamB loop 9 region. These PCR fragments were gel purified (Qiagen, Valencia, Calif., USA) and used for DNA sequencing.
Loop 9 Up—LM2 or CD154s or Combination Sequence—Loop 9 Down Construct
The final overlapping PCR fragment, PCR-B, contained the added LM2 (or CD154s or combination sequences flanked by loop 9 up and down regions (FIG. 2B). Combination sequences consisted of LM2 or an alternate M2e epitope associated with avian species (M2eA) and CD154 along with spacers such as Glycine (Gly) or Serine (Ser) residues. Inserted sequences were as follows: LM2 (SEQ ID NO:37); M2eA (SEQ ID NO:38); combination sequence no. 1 (Gly)3-CD154s-(Gly)3-LM2-(Gly)3 (SEQ ID NO:39); and combination sequence no. 2 (Ser)4-M2eA-(Ser)4-M2eA-(Ser)4-CD154-(Ser)-LM2-(Ser)4-LM2-(Ser)4 (SEQ ID NO:40).
PCR-B products were electroporated into S. enteritidis cells along with plasmid pBC-I-SceI at a molar ratio of approximately 40:1 (Kang et al., J Bacteriol 2004, 186:4921-4930, which is incorporated herein by reference in its entirety). Clones for each PCR-B recombination mutation were chosen according to the ability to grow on Cm plates but not on Km plates, due to the replacement of PCR-B for the Kmr encoding PCR-A sequence. Modified regions in the selected clones were PCR-amplified, and DNA sequences were determined using primers lam3f and lam3r located outside the loop 9 down and up amplified regions.
The second mutation step required constructing a PCR fragment, referred to as PCR-B and shown in FIG. 2B, consisting of the final insertion sequence, LM2 or CD154 or combination sequences, flanked by lamB homologous fragments. PCR-B amplicons have no selection marker and must be counter-selected after replacement for the previous I-SceI site/Kmr mutation in SE164. Plasmid pBC-I-SceI encodes the Cmr gene and the I-SceI enzyme, which will cut the genome at the 1-SceI site of SE164. Therefore, pBC-I-SceI was electroporated into SE164 along with PCR-B. After recombination of PCR-B to replace PCR-A, positive clones were chosen based on the ability to grow on Cm but not on Km. After DNA sequencing of mutants to confirm successful recombination of PCR-B, the strains were designated SE172, SE173, SE180, and SE189 for insert sequences LM2, CD154s, (Gly)3-CD154s-(Gly)3-LM2-(Gly)3 (SEQ ID NO: 39), and (Ser)4-M2eA-(Ser)4-M2eA-(Ser)4-CD154-(Ser)4-LM2-(Ser)4-LM2-(Ser)4 (SEQ ID NO: 40), respectively. Ten random clones for each the LM2 and CD154 insertion were used for PCR with lam 3f and lam 3r then digested using unique restriction enzymes sites for each insertion sequence and 100% of clones tested by digestion were positive for the desired mutation sequence. Sequencing results demonstrated that the insertion of LM2 or CD154s or combination sequences was exactly into the loop 9 region without the addition of extraneous nucleotides.
SE13A-M2E-
SE13A SE13A-M2E SE13A-CD154 CD154
CD154 − Not tested + +
Colonization (Ceca Tonsils) Invasion (Liver/Spleen)
Treatment Groups D 7 D 14 D 21 D 28 D 7 D 14 D 21 D 28
S ⁢ / ⁢ P ⁢ ⁢ ratio ⁢ ⁢ calculation ⁢ ⁢ : ⁢ ⁢ sample ⁢ ⁢ mean - negative ⁢ ⁢ control ⁢ ⁢ mean positive ⁢ ⁢ control ⁢ ⁢ mean - negative ⁢ ⁢ control ⁢ ⁢ mean
The calculated SIP ratios for each group are shown in FIGS. 3 and 4. As is shown, M2e-specific antibody levels for each group expressing M2e-CD154 produced an ELISA signal that was on average over 30% higher when compared with their respective group that only expresses M2e. The data demonstrate that SE13A-M2e and SE13A-M2e-CD154 are both capable of eliciting a robust antibody response to M2e. This response was clearly augmented by addition of the CD154 peptide. In addition, similar responses were generated when either the aroA or htrA auxotrophic SE13A strains were utilized. These strains may provide vaccine vectors with higher safety for clinical use without sacrificing generation of a robust immune response.
Example 7 Challenge Study
The influenza viruses used in these studies were A/Turkey/Virginia/158512/2002 (TV/02) H7N2 LP Avain Influenza (LPAI H7N2) and A/Egret/Hong Kong/757.2/2002 (Eg/02) H5N1 HP avian influenza (HPAI H5N1). Viruses were grown and titered in 9-11 day old embryonated SPF (specific pathogen free) chicken eggs as previously described (Suarez et al., J. Virol. 1998 August; 72(8):6678-88.).
Hemagglutination inhibition test was performed with BPL-inactivated homologous H5N1 antigen with sera collected at day 0 in Expt. I and Day 0 and 14 in Expt. II as previously described (Suarez et al., 1998). Titers greater ≧3 (log2) were considered positive. Virus isolation from oral and cloacal swabs on days 2 and 4 post-challenge was performed in 9-11 day of embryonation SPF chicken eggs as previously described (Tumpey et al., Avian Dis. 2004 January-March; 48(1):167-76). Briefly, swabs were collected into 2 ml brain-heart infusion (BHI) broth with antibiotics (1000 units/ml penicillin G, 200 μg/ml gentamicin sulfate, and 4 μg/ml amphotericin B; Sigma Chemical Company, St. Louis, Mo.) from each bird on day 0, 2, 4, days post challenge for virus isolation.
Purified AIV proteins from whole virus (H5N1 and H7N2) were separated by SDS-PAGE in a 10% polyacrylamide gel and transferred as previously described (Kapczynski and Tumpey, Avian Dis. 2003 July-September; 47(3):578-87). Briefly, anti-M2e serum from birds previously immunized with ΔSE M2e-HM (1:1000) was incubated with the membrane containing AIV antigen for 1 hour at room temperature. Following three washes in PBS-Tween 20 (0.05%) the membrane was reacted with horseradish peroxidase-labeled goat anti-chicken IgG secondary antibody (Southern Biotech Associates, Inc, Birmingham, Ala.) at a 1:2000 dilution for 1 hour. After washing as above, the membrane was reacted with ECL Western Blotting Detection Reagents (Amersham Biosciences, Piscataway, N.J.) according to the manufacturers' recommendations, and exposed to Hyperfilm ECL (Amersham Biosciences). The film was developed using Kodak GBX developing reagents (Eastman Kodak Company) according to the manufacturers' recommendations.
Experiment I CHALLENGE with LPAI H7N2
Experiment II Challenge with HPAI H5N1
1. A vaccine vector comprising at least two antigenic polynucleotides, wherein a first antigenic polynucleotide encodes SEQ ID NO: 5 and a second antigenic polynucleotide encodes SEQ ID NO: 20, and wherein the first antigenic polynucleotide is inserted in the same reading frame into a first transmembrane polynucleotide encoding an external portion of a transmembrane protein and the second antigenic polynucleotide is inserted in the same reading frame into a second transmembrane polynucleotide encoding an external portions of a transmembrane protein.
2. The vaccine vector of claim 1, wherein the vaccine vector enhances the immune response of a subject to Influenza A.
3. The vaccine vector of claim 1, further comprising a third antigenic polynucleotide encoding a hemagglutinin polypeptide.
4. The vaccine vector of claim 3, wherein the hemagglutinin polypeptide is selected from SEQ ID NO: 21, SEQ ID NO: 22 or a combination thereof.
5. The vaccine vector of claim 1, further comprising at least one polynucleotide encoding a polypeptide selected from the group consisting of SEQ ID NO: 23, SEQ ID NO: 24 or combinations thereof.
6. The vaccine vector of claim 1, wherein the first antigenic polynucleotide and the second antigenic polynucleotides are inserted in frame into one transmembrane polynucleotide such that SEQ ID NO: 5 and SEQ ID NO: 20 are expressed within the same external portion of the transmembrane protein.
7. The vaccine vector of claim 6, wherein SEQ ID NO: 5 and SEQ ID NO:20 are separated by amino acid spacers.
8. The vaccine vector of claim 7, wherein the spacers are Serine or Glycine amino acids.
9. The vaccine vector of claim 1, wherein the vaccine vector is a bacterial vector and the bacterial vector is a member of the Enterobecteraciae family.
10. The vaccine vector of claim 1, farther comprising a CD154 polynucleotide sequence encoding a CD154 polypeptide having fewer than 50 amino acids and comprising amino acids 140-149 of SEQ ID NO: 26 or a homolog thereof.
11. The vaccine vector of claim 10, wherein the CD154 homolog is selected from SEQ ID NOs: 6, 7, 27, 28 and 29.
12. The vaccine vector of claim 10, wherein the CD154 polynucleotide is inserted into a bacterial polynucleotide encoding an external portion of a transmembrane protein.
13. A method of enhancing an immune response against Influenza in a subject comprising administering to the subject the vaccine vector of claim 1 in an amount effective to enhance the immune response of the subject to Influenza in response to vaccination.
14. A vaccine vector comprising a first polynucleotide encoding a polypeptide of SEQ ID NO: 8 or SEQ ID NO: 9, wherein the polynucleotide is inserted into a second polynucleotide in the vaccine vector encoding an external portion of a transmembrane protein in the same reading frame as the polynucleotide encoding the transmembrane protein.
15. A method of enhancing an immune response against Influenza in a subject comprising administering to the subject the vaccine vector of claim 14 in an amount effective to enhance the immune response of the subject to Influenza in response to vaccination.
16. A vaccine vector comprising at least two antigenic polynucleotides, wherein a first antigenic polynucleotide encodes an M2e polypeptide, and a second antigenic polynucleotide encodes a hemagglutinin polypeptide, wherein the first antigenic polynucleotide is inserted in the same reading frame into a first transmembrane polynucleotide sequence encoding an external portion of a transmembrane protein and the second antigenic polynucleotides are inserted in the same reading frame into a second transmembrane polynucleotide sequences encoding an external portion of a transmembrane protein, and wherein the vaccine vector enhances the immune response of a subject to Influenza A.
17. The vaccine vector of claim 16, wherein the M2e polypeptide is selected from SEQ ID NOs: 1, 2, 3, 4, 5 and 20; and wherein the hemagglutinin polypeptide is selected from SEQ ID NOs: 21 and 22.
18. The vaccine vector of claim 16, wherein the first antigenic polynucleotides and the second antigenic polynucleotide are inserted in frame into one transmembrane polynucleotide sequence such that the M2e polypeptides and the hemagglutinin polypeptide are expressed within the same external portion of the transmembrane protein.
19. A method of enhancing an immune response against Influenza in a subject comprising administering to the subject the vaccine vector of claim 16 in an amount effective to enhance the immune response of the subject to Influenza in response to vaccination.
20. A vaccine vector comprising a CD154 polynucleotide sequence encoding a CD154 polypeptide having fewer than 50 amino acids and comprising amino acids 140-149 of SEQ ID NO: 26 or a homolog thereof, wherein the CD154 polynucleotide is inserted into a polynucleotide encoding an external portion of a transmembrane protein in the same reading frame as the polynucleotide encoding the transmembrane protein and the CD154 polypeptide is expressed on the surface of the vaccine vector.
21. The vaccine vector of claim 1, wherein the first transmembrane protein and the second transmembrane protein are the same transmembrane protein.
22. The vaccine vector of claim 1, wherein the first transmembrane protein and the second transmembrane protein are separate transmembrane proteins.
23. The vaccine vector of claim 16, wherein the first transmembrane protein and the second transmembrane protein are the same transmembrane protein.
24. The vaccine vector of claim 16, wherein the first transmembrane protein and the second transmembrane protein are separate transmembrane proteins.
US14100957 2006-09-18 2013-12-09 Compositions and methods of enhancing immune responses Active US9226957B2 (en)
US44185110 true 2010-09-28 2010-09-28
US14100957 US9226957B2 (en) 2006-09-18 2013-12-09 Compositions and methods of enhancing immune responses
US14971704 US20160114025A1 (en) 2006-09-18 2015-12-16 Compositions and methods of enhancing immune responses
US12441851 Continuation US8604178B2 (en) 2006-09-18 2007-09-18 Compositions and methods of enhancing immune responses
PCT/US2007/078785 Continuation WO2008036675A8 (en) 2006-09-18 2007-09-18 Compositions and methods of enhancing immune responses
US44185110 Continuation 2010-09-28 2010-09-28
US14971704 Continuation US20160114025A1 (en) 2006-09-18 2015-12-16 Compositions and methods of enhancing immune responses
US20140093534A1 true US20140093534A1 (en) 2014-04-03
US9226957B2 true US9226957B2 (en) 2016-01-05
US14971704 Pending US20160114025A1 (en) 2006-09-18 2015-12-16 Compositions and methods of enhancing immune responses
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