Hepatitis b immunisation regimen and compositions

Abstract

There is provided a method of treating chronic hepatitis B infection (CHB) in a human, comprising the steps of: a) administering to the human a composition comprising a replication-defective chimpanzee adenoviral (ChAd) vector comprising a polynucleotide encoding a hepatitis B surface antigen (HBs) and a nucleic acid encoding a hepatitis B virus core antigen (HBc); b) administering to the human acomposition comprising a Modified Vaccinia Virus Ankara (MVA) vector comprising a polynucleotide encoding a hepatitis B surface antigen (HBs) and a nucleic acid encoding a hepatitis B virus core antigen (HBc); and c) administering to the human a composition comprising a recombinant hepatitis B surface antigen (HBs), recombinant hepatitis B virus core antigen (HBc) and an adjuvant.

Description

[0001] field of invention

[0002] The present invention relates to immunization regimens particularly suited for the treatment of chronic hepatitis B, methods for treating chronic hepatitis B and compositions for use in such regimens and methods. The protocols and methods involve administering a composition comprising a vehicle for delivery of a hepatitis B antigen and a composition comprising a recombinant hepatitis B antigen protein.

[0003] Background of the invention

[0004] Hepatitis B virus (HBV) infection is a major public health problem. Approximately 257 million people worldwide are infected with HBV [WHO, 2017]. The clinical course and outcome of HBV infection are largely dependent on the age at infection and the complex interplay between viral and host immune responses [Ott, 2012; Maini, 2016]. Thus, exposure to HBV may lead to acute hepatitis, which resolves itself or may progress to various forms of chronic infection, including inactive hepatitis B surface ant...

Examples

Embodiment 1

[0280] Example 1 - Evaluation of ChAd155-HBV (with and without hIi) priming in the HLA.A2 / DR1 transgenic mouse model and MVA-HBV enhanced

[0281] Target

[0282] The primary objective of this experiment was to determine whether priming with a dose of ChAd155-HBV (with or without hIi), followed by a booster dose of MVA-HBV, could induce the expression of a new gene in HLA.A2 / DR1 mice transgenic for human MHC-I / II molecules. Induces strong CD8 against HBc + T cell response. In addition, a head-to-head comparison between ChAd155-HBV with and without hli was performed to investigate that the hli sequence further increases HBc-specific CD8 + Potential for T-cell responses, as previously reported for other antigens [Spencer, 2014; Capone, 2014]. HBs-specific CD8 was also assessed + T-cell responses and HBc- and HBs-specific CD4 + T-cell and antibody responses.

[0283] Research design

[0284] HLA.A2 / DR1 mice (11 mice per group) were treated with 10 intramuscularly o...

Embodiment 2

[0302] Example 2 - HBc-HBs / AS01 in inbred mice (CB6F1) B-4 Immunogenicity studies

[0303] Target

[0304] The main objective of this immunogenicity study was to determine when in AS01 B-4 Whether HBc and HBs proteins can induce HBc- and HBs-specific humoral and T-cell responses when co-formulated in .

[0305] Research design

[0306] 6- to 8-week-old CB6F1 mice (30 mice per group) were treated with 50 µl AS01 on days 0, 14 and 28 B-4 The HBc, HBs or HBc-HBs (listed in the following table 2) prepared in the Chinese medicine were immunized intramuscularly three times. HBc- and HBs-specific T cell responses were measured on fresh PBL 7 days after the second and third dose, and anti-HBs and anti-HBc antibodies were measured 14 days after the second and third dose answer.

[0307] Table 2: Treatment Groups

[0308] Group antigen 1 1 µg HBc / AS01 B-4 (HBc / AS01 B-4 )

2 1 µg HBs / AS01 B-4 (HBs / AS01 B-4 )

3 1µg HBc + 1µg HBs / AS01 B-4...

Embodiment 3

[0319] Example 3 - Comparative Adjuvant Experiments in Inbred Mice (CB6F1)

[0320] Target

[0321] The main purpose of this experiment was to compare the 4:1 ratio with different adjuvants (alum, AS01 B-4 or AS01 E-4 ) HBc and HBs antigens formulated together or without adjuvant induced strong CD4 against both antigens + Capacity for T-cell and humoral responses.

[0322] Research design

[0323] CB6F1 mice aged 6 to 8 weeks (35 mice for groups 1-4 and 25 mice for group 5) were treated with alum, AS01 B-4 or AS01 E-4 The prepared HBc-HBs antigen (4µg-1µg) (listed in Table 3 below) was immunized intramuscularly three times. with AS01 B-4 Compared to AS01 E-4 The adjuvant system contains half the amount of immune enhancers QS-21 and MPL. HBc- and HBs-specific T cell responses were measured on fresh PBL 7 days after the second and third doses, after ex vivo restimulation with the pool of peptides for 6 hours, and after the second and third doses Anti-HBs and anti-HB...

[0001] field of invention

[0002] The present invention relates to immunization regimens particularly suited for the treatment of chronic hepatitis B, methods for treating chronic hepatitis B and compositions for use in such regimens and methods. The protocols and methods involve administering a composition comprising a vehicle for delivery of a hepatitis B antigen and a composition comprising a recombinant hepatitis B antigen protein.

[0003] Background of the invention

[0004] Hepatitis B virus (HBV) infection is a major public health problem. Approximately 257 million people worldwide are infected with HBV [WHO, 2017]. The clinical course and outcome of HBV infection are largely dependent on the age at infection and the complex interplay between viral and host immune responses [Ott, 2012; Maini, 2016]. Thus, exposure to HBV may lead to acute hepatitis, which resolves itself or may progress to various forms of chronic infection, including inactive hepatitis B surface ant...

Examples

Embodiment 1

[0280] Example 1 - Evaluation of ChAd155-HBV (with and without hIi) priming in the HLA.A2 / DR1 transgenic mouse model and MVA-HBV enhanced

[0281] Target

[0282] The primary objective of this experiment was to determine whether priming with a dose of ChAd155-HBV (with or without hIi), followed by a booster dose of MVA-HBV, could induce the expression of a new gene in HLA.A2 / DR1 mice transgenic for human MHC-I / II molecules. Induces strong CD8 against HBc + T cell response. In addition, a head-to-head comparison between ChAd155-HBV with and without hli was performed to investigate that the hli sequence further increases HBc-specific CD8 + Potential for T-cell responses, as previously reported for other antigens [Spencer, 2014; Capone, 2014]. HBs-specific CD8 was also assessed + T-cell responses and HBc- and HBs-specific CD4 + T-cell and antibody responses.

[0283] Research design

[0284] HLA.A2 / DR1 mice (11 mice per group) were treated with 10 intramuscularly o...

Embodiment 2

[0302] Example 2 - HBc-HBs / AS01 in inbred mice (CB6F1) B-4 Immunogenicity studies

[0303] Target

[0304] The main objective of this immunogenicity study was to determine when in AS01 B-4 Whether HBc and HBs proteins can induce HBc- and HBs-specific humoral and T-cell responses when co-formulated in .

[0305] Research design

[0306] 6- to 8-week-old CB6F1 mice (30 mice per group) were treated with 50 µl AS01 on days 0, 14 and 28 B-4 The HBc, HBs or HBc-HBs (listed in the following table 2) prepared in the Chinese medicine were immunized intramuscularly three times. HBc- and HBs-specific T cell responses were measured on fresh PBL 7 days after the second and third dose, and anti-HBs and anti-HBc antibodies were measured 14 days after the second and third dose answer.

[0307] Table 2: Treatment Groups

[0308] Group antigen 1 1 µg HBc / AS01 B-4 (HBc / AS01 B-4 )

2 1 µg HBs / AS01 B-4 (HBs / AS01 B-4 )

3 1µg HBc + 1µg HBs / AS01 B-4...

Embodiment 3

[0319] Example 3 - Comparative Adjuvant Experiments in Inbred Mice (CB6F1)

[0320] Target

[0321] The main purpose of this experiment was to compare the 4:1 ratio with different adjuvants (alum, AS01 B-4 or AS01 E-4 ) HBc and HBs antigens formulated together or without adjuvant induced strong CD4 against both antigens + Capacity for T-cell and humoral responses.

[0322] Research design

[0323] CB6F1 mice aged 6 to 8 weeks (35 mice for groups 1-4 and 25 mice for group 5) were treated with alum, AS01 B-4 or AS01 E-4 The prepared HBc-HBs antigen (4µg-1µg) (listed in Table 3 below) was immunized intramuscularly three times. with AS01 B-4 Compared to AS01 E-4 The adjuvant system contains half the amount of immune enhancers QS-21 and MPL. HBc- and HBs-specific T cell responses were measured on fresh PBL 7 days after the second and third doses, after ex vivo restimulation with the pool of peptides for 6 hours, and after the second and third doses Anti-HBs and anti-HB...

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