阅读说明：本技术 疫苗接种 (Vaccination ) 是由 C.乌斯特富格斯 于 2018-04-27 设计创作，主要内容包括：本发明涉及用于保护免于带状疱疹(带状疱疹)的免疫原性组合物以及方法。(The present invention relates to immunogenic compositions and methods for protecting against herpes zoster (shingles).)

1. An immunogenic composition, e.g. a vaccine composition, comprising a Varicella Zoster Virus (VZV) gE antigen truncated to remove the carboxy terminal anchor region, in combination with an adjuvant comprising a saponin, a TLR-4 agonist and liposomes for use in a method of protecting against or preventing Herpes Zoster (HZ) and/or Post Herpetic Neuralgia (PHN) in a human subject after a step comprising administering one dose of the immunogenic composition, e.g. a vaccine composition.

2. An immunogenic composition, e.g., a vaccine composition, comprising a Varicella Zoster Virus (VZV) gE antigen truncated to remove the carboxy terminal anchor region, in combination with an adjuvant comprising a saponin, a TLR-4 agonist and liposomes, for reducing the incidence of HZ in a human subject administered a dose of the composition by 50% or more compared to a human subject not administered the composition.

3. An immunogenic composition, e.g. a vaccine composition, according to claim 1 or 2, wherein said one dose is the first dose of a multi-dose, e.g. 2-dose, immunization program.

4. An immunogenic composition, e.g. a vaccine composition, according to any of the preceding claims, wherein two doses of the immunogenic composition, e.g. the vaccine composition, are administered to the subject at an interval of between 1 month and 12 months.

5. An immunogenic composition, e.g. a vaccine composition, according to claim 3 or 4, wherein the two doses of the immunogenic composition, e.g. the vaccine composition, are administered at an interval of 2-6 months or 2-12 months.

6. An immunogenic composition, e.g. a vaccine composition, according to claim 3, wherein said two doses of immunogenic composition, e.g. vaccine composition, are administered at an interval of 2-6 months.

7. An immunogenic composition, e.g. a vaccine composition, according to claim 1 or 2, wherein a single dose of said immunogenic composition, e.g. a vaccine composition, is administered to said human subject.

8. An immunogenic composition, e.g. a vaccine composition, for use according to any of the preceding claims, wherein the efficacy of the one dose of the composition in reducing the incidence of HZ in a subject receiving the one dose of the composition is 50% or more compared to a subject not receiving the composition.

9. An immunogenic composition, e.g. a vaccine composition, for use according to any of the preceding claims, wherein the method is for reducing the incidence of HZ by 50% or more in a subject receiving said one dose of the composition compared to a subject not receiving said composition.

10. The use of an immunogenic composition, e.g. a vaccine composition, according to any of the preceding claims, wherein the human subject is 70 years of age or older.

11. An immunogenic composition, e.g. a vaccine composition, for use according to any one of claims 1-4, wherein the human subject is 50 years of age or older, and wherein the efficacy of the one dose of the composition in reducing the incidence of HZ is 80% or higher, 85% or higher, or 90% or higher.

12. The immunogenic composition, e.g. vaccine composition, for use according to any of the preceding claims, for use in an individual prior to the start of immunosuppressive therapy, e.g. one month prior to the start of immunosuppressive therapy.

13. The immunogenic, e.g. vaccine, composition for use according to any of the preceding claims for an individual who received a live attenuated VZV vaccine at least 3 years ago, at least 4 years ago, at least 5 years ago, at least 8 years ago, or at least 10 years ago.

14. An immunogenic, e.g. vaccine, composition according to any preceding claim wherein the VZV gE antigen is not in the form of a fusion protein.

15. An immunogenic, e.g. vaccine, composition according to any of the preceding claims, wherein the VZV gE antigen comprises the sequence of SEQ ID No. 1.

16. An immunogenic, e.g. vaccine, composition according to any of the preceding claims, wherein the VZV gE antigen is present in an amount of 20-100 μ g per dose, such as 25 μ g, 50 μ g or 100 μ g per dose.

17. An immunogenic, e.g. vaccine, composition according to any of the preceding claims, wherein the VZV antigen is present in an amount of 50 μ g per dose.

18. An immunogenic composition, e.g. a vaccine composition, according to any preceding claim wherein the saponin is QS 21.

19. An immunogenic composition, e.g. a vaccine composition, according to any of the preceding claims, wherein the saponin, e.g. QS21, is present in an amount of 1-100 μ g, e.g. 25 μ g or 50 μ g, per dose.

20. An immunogenic composition, e.g. a vaccine composition, according to any preceding claim, wherein the saponin, e.g. QS21, is present in an amount of 50 μ g per dose.

21. An immunogenic composition, e.g. a vaccine composition, according to any of the preceding claims, wherein the TLR-4 agonist is 3-O-deacyl-4' -monophosphoryl lipid a (3D-MPL).

22. An immunogenic composition, e.g. a vaccine composition, according to any of the preceding claims, wherein the TLR-4 agonist, e.g. 3D-MPL, is present in an amount of 25 μ g or 50 μ g per dose, e.g. 50 μ g per dose.

23. An immunogenic composition, e.g. a vaccine composition, according to any of the preceding claims, wherein the liposomes further comprise a sterol, suitably cholesterol.

24. An immunogenic composition, e.g. a vaccine composition, according to any of the preceding claims, wherein the liposomes comprise or consist of the liposomal lipid Dioleoylphosphatidylcholine (DOPC) and cholesterol.

25. An immunogenic composition, e.g. a vaccine composition, according to any of the preceding claims, which does not comprise a further VZV antigen, wherein the further VZV antigen is a live attenuated or inactivated VZV OKA strain.

26. An immunogenic, e.g. vaccine, composition according to any of the preceding claims which does not comprise an additional VZV antigen.

27. A method of protecting against or preventing Herpes Zoster (HZ) and/or post herpetic neuralgia comprising the steps of: administering to a human subject a dose of an immunogenic composition, e.g., a vaccine composition, comprising a VZV gE antigen truncated to remove the carboxy-terminal anchor region, in combination with an adjuvant comprising a saponin, a TLR-4 agonist, and a liposome.

28. The method according to claim 27, further comprising one or more of the features of the preceding claims.

29. A method of protecting against, preventing, or reducing the incidence of herpes zoster and/or post herpetic neuralgia in an individual, comprising the steps of:

a. selecting a subject from a population in need of protection against, prevention of, or reduction in incidence of, herpes zoster and/or post herpetic neuralgia for a limited period of time after administration, and

b. administering a first and second dose of an immunogenic composition, e.g., a vaccine composition, comprising a VZV gE antigen truncated to remove the carboxy-terminal anchor region, in combination with an adjuvant comprising a saponin, a TLR-4 agonist, and a liposome,

wherein the protection, prevention, or reduction in incidence of HZ and/or PHN persists for at least 4 years after administration of the second dose.

30. A method of protecting against, preventing, or reducing the incidence of herpes zoster and/or post herpetic neuralgia in an individual, comprising the steps of:

a. selecting a subject from a population in need of protection from, prevention of, or reduction in the incidence of herpes zoster and/or post herpetic neuralgia prior to immunosuppressive therapy, and

b. administering first and second doses of an immunogenic composition, e.g., a vaccine composition, comprising a VZV gE antigen truncated to remove the carboxy-terminal anchor region, in combination with an adjuvant comprising a saponin, a TLR-4 agonist, and a liposome.

31. A method of protecting against or preventing herpes zoster and/or post herpetic neuralgia in a subject receiving immunosuppressive medical therapy, comprising:

a. identifying an individual for whom immunosuppressive medical therapy is planned, and

b. administering a single dose of the vaccine composition prior to initiation of the immunosuppressive therapy,

wherein the vaccine composition comprises a VZV gE antigen truncated to remove the carboxy terminal anchor region and an adjuvant comprising a saponin, a TLR-4 agonist and a liposome.

32. A method of protecting against, preventing, or reducing the incidence of herpes zoster and/or post herpetic neuralgia in a population of individuals receiving immunosuppressive medical therapy, comprising:

a. identifying a population of individuals for whom immunosuppressive medical therapy is planned, and

b. administering to each of said individuals a single dose of a vaccine composition prior to initiation of said immunosuppressive therapy,

wherein the vaccine composition comprises a VZV gE antigen truncated to remove the carboxy terminal anchor region and an adjuvant comprising a saponin, a TLR-4 agonist and a liposome.

33. The method according to claim 31 or 32, wherein said one or more individuals are scheduled to receive chemotherapy, radiation therapy or immunosuppressive drug compounds.

34. The method according to claim 31 or 32, wherein the single dose is administered at least 30 days before the start of immunosuppressive medical therapy.

35. A method of protecting against or preventing herpes zoster and/or post herpetic neuralgia in a subject receiving immunosuppressive medical therapy, comprising:

a. identifying individuals who received a live attenuated VZV vaccine at least 3 years ago, at least 4 years ago, at least 5 years ago, at least 8 years ago, or at least 10 years ago, and

b. a single dose of the vaccine composition is administered,

wherein the vaccine composition comprises a VZV gE antigen truncated to remove the carboxy terminal anchor region and an adjuvant comprising a saponin, a TLR-4 agonist and a liposome.

36. A method of protecting against, preventing, or reducing the incidence of herpes zoster and/or post herpetic neuralgia in a population of individuals receiving immunosuppressive medical therapy, comprising:

a. identifying a population of individuals who received a live attenuated VZV vaccine at least 3 years ago, at least 4 years ago, at least 5 years ago, at least 8 years ago, or at least 10 years ago, and

b. administering to each of said individuals a single dose of a vaccine composition,

wherein the vaccine composition comprises a VZV gE antigen truncated to remove the carboxy terminal anchor region and an adjuvant comprising a saponin, a TLR-4 agonist and a liposome.

37. The method of any one of claims 31, 32, 35 and 36, wherein the vaccine efficacy is at least 50% or at least 60% as assessed after 60 days, 70 days, 80 days, or 90 days after administration of a single dose of vaccine.

Technical Field

The present invention relates to methods of inducing early protection against and preventing herpes zoster or postherpetic neuralgia, particularly in elderly and immunocompromised human patients.

Background

Herpes Zoster (HZ), also known as shingles, is a common and often debilitating disease that occurs predominantly in elderly or immunocompromised individuals. HZ results from symptomatic reactivation of latent Varicella Zoster Virus (VZV) in the dorsal root and brain ganglia. This virus is often acquired in childhood as chickenpox.

The only vaccine currently available with demonstrated efficacy against HZ or post-herpetic neuralgia (PHN) is the live attenuated vaccine of the VZV OKA strain sold as ZOSTAVAX. ZOSTAVAX decreased the incidence of HZ by 51.3% (p-value <0.001) in all populations (> 60 YOA), although its effectiveness decreased with age of the vaccinee. In particular, Vaccine Efficacy (VE) dropped to 37.6% in older people (> 70 years). ZOSTAVAX is contraindicated in persons with immune deficiencies due to malignancies, Human Immunodeficiency Virus (HIV) infection, or immunosuppressive medical therapy. (ZOSTAVAXEMA SPC 2012; Oxman et al, N Engl J Med 2005; 352: 2271-. Morrison VA et al reported a decline in potency of ZOSTAVAX, which became more and more limited for more than 5-8 years after vaccination and was no longer statistically significant for more than 8 years (Morrison et al, clin. infection. Diseases, published in advance, 11 months and 20 days 2014).

Adjuvanted subunit VZV compositions are described in WO2006/094756 (US 7939084, which is incorporated herein by reference to define immunogenic compositions). Leroux-Roels I. et al (J. feed. Diseases 2012: 2061280) -1290) reported phase I/II clinical trials of adjuvanted VZV gE subunit vaccines, with safety and immunogenicity assessed. Adjuvanted subunit VZV vaccines have been shown to provide high potency after a 2-dose regimen (Himal l. et al, 2015NEJM 372(22): 2087).

Summary of The Invention

The present invention relates to immunogenic compositions and methods for protecting against HZ after administration of a dose of the composition, and particularly within a short time frame after administration of a dose.

The present invention also relates to a method of protecting against, preventing or reducing the incidence of herpes zoster and/or post herpetic neuralgia in an individual, comprising the steps of:

a. selecting a subject from a population in need of protection against, prevention of, or reduction in incidence of, herpes zoster and/or post herpetic neuralgia for a limited period of time after administration, and

b. administering a single or first dose of an immunogenic composition (e.g., a vaccine composition) comprising a VZV gE antigen truncated to remove the carboxy-terminal anchor region in combination with an adjuvant comprising a saponin, a TLR-4 agonist, and a liposome.

The present invention also relates to a method of protecting against, preventing or reducing the incidence of herpes zoster and/or post herpetic neuralgia in an individual, comprising the steps of:

a. selecting a subject from a population in need of protection from, prevention of, or reduction in the incidence of herpes zoster and/or post herpetic neuralgia prior to immunosuppressive therapy, and

b. administering a single or first dose of an immunogenic composition (e.g., a vaccine composition) comprising a VZV gE antigen truncated to remove the carboxy-terminal anchor region in combination with an adjuvant comprising a saponin, a TLR-4 agonist, and a liposome, wherein the administration is performed prior to or concomitantly with the initiation of immunosuppressive therapy.

Drawings

FIGS. 1A-1C illustrate: adjuvanted VZV g was used in a 2-dose vaccination regimen at 0,2 months in an overall cohort of study subjects (FIG. 1A), a cohort of subjects from 60-69 years of age (FIG. 1B), and a cohort of subjects greater than or equal to 70 years of age (FIG. 1C)E (different amounts of gE per dose, i.e., 25 μ g, 50 μ g, and 100 μ g), cell-mediated immune response after a single dose of adjuvanted VZV gE (saline was administered as the first dose, then adjuvanted VZV gE100 μ g was administered as the second dose), or after use of VZV gE (100 μ g per dose) in a 0,2 month 2-dose vaccination regimen. The Y-axis being CD4²⁺T cell/10⁶ CD4⁺T cells, and the X-axis is the number of months after the initial vaccination.

FIGS. 2A-2C illustrate: in the overall cohort of study subjects (fig. 2A), the cohort of subjects from the age of 60-69 (fig. 2B), and the cohort of subjects greater than or equal to 70 (fig. 2C), VZV gE antibody levels after using adjuvanted VZV gE at a 2-dose vaccination regimen of 0,2 months, single dose adjuvanted VZV gE (each dose having different amounts of gE, i.e., 25 μ g, 50 μ g, and 100 μ g), single dose adjuvanted VZV gE (saline administered as the first dose, then adjuvanted VZV gE100 μ g administered as the second dose), or after using VZV gE (100 μ g per dose) at a 2-dose vaccination regimen of 0,2 months. The Y-axis is the Geometric Mean Concentration (GMC) of the antibody and the X-axis is the number of months after the initial vaccination.

Figures 3A-3B provide a study design of the phase III clinical vaccination trial (trial I) described in example 1.

Figure 4 provides a study design of the phase III clinical vaccination trial (trial II) described in example 2.

Figure 5 provides a study design of the phase III clinical vaccination trial described in example 3.

Figure 6 presents the immunogenicity data reported for example 3: panel a-humoral immune response to VZV gE/AS01B vaccination: anti-glycoprotein E (gE) antibody concentration as determined by enzyme-linked immunosorbent assay, reporting the geometric mean concentration (GMC [ mIU/mL)]) And error bars represent 95% Confidence Intervals (CI); panel B-cellular immune response to VZV gE/AS01B vaccination reporting expression of at least 2 activation markers (CD 4) AS determined by intracellular staining and flow cytometry^{2 +}) gE specific CD4⁺Cells (data per 10)⁶Outside of the main bodyMedian cell count of peripheral blood mononuclear cells); light bars indicate the HZ-PreVac group and dark bars indicate the HZ-NonVac group. HZ-NonVac = participants who never received a live attenuated herpes Zoster Vaccine (ZVL); HZ-PreVac = participants who received ZVL ≧ 5 years before the study began.

Fig. 7 provides a design of a clinical trial to evaluate immunogenicity and safety of HZ/su vaccines in adults with solid tumors vaccinated prior to or at the start of immunosuppressive chemotherapy (chemo).

Fig. 8 illustrates: GMC (adaptive ATP cohort for humoral immunogenicity) of anti-gE antibodies in ST subjects, wherein gE = glycoprotein E; ATP = according to protocol specification; GMC = geometric mean concentration; IU = international unit; m0 = prior to vaccination; m1 = 1 month after dose 1, M2/M6/M13 = 1, 5 and 12 months after dose 2. Error bars represent 95% confidence intervals. The first bar in each time period (M) is HZ/su PreChemo, the second bar is HZ/su OnChemo, the third bar is placebo PreChemo, and the fourth bar is placebo OnChemo.

Fig. 9 illustrates: ELISA concentration of anti-gE antibody in ST subjects humoral VRR (adaptive ATP cohort for humoral immunogenicity), wherein gE = glycoprotein E; ATP = according to protocol specification; VRR = vaccine response rate; % = percentage of responders; m1 = 1 month after dose 1, M2/M6/M13 = 1, 5 and 12 months after dose 2. VRR is defined as: (i) for subjects that were seropositive for the initial anti-gE antibody, the antibody concentration after the second vaccination was greater than or equal to 4 times the pre-vaccination level; (ii) for subjects who were seronegative for the initial anti-gE antibody, the antibody concentration after the second vaccination was > 4-fold greater than the anti-gE cut-off (97 mIU/mL). Error bars represent 95% confidence intervals. The first bar in each time period (M) is HZ/su PreChemo, the second bar is HZ/su OnChemo, the third bar is placebo PreChemo, and the fourth bar is placebo OnChemo.

Fig. 10 illustrates: gE specific CD4 in ST subjects²⁺Frequency of T cells (adaptive ATP subgroup for CMI), wherein gE = glycoprotein E; ATP = according to protocol specification; CMI = cell-mediated immunogenicity; m0 = prior to vaccination; m1 = 1 month after dose 1, M2/M13 = 1 and 12 months after dose 2; min = minimum; max = maximum; q1 = first quartile; q3 third quartile.

Fig. 11 illustrates: by gE-specific CD4 in ST subjects²⁺CMI VRR of T cell frequency (adaptive ATP subgroup to CMI), wherein CMI = cell-mediated immunogenicity. VRR = vaccine response rate; gE = glycoprotein E; ATP = according to protocol specification; % = percentage of responders; m1 = 1 month after dose 1, M2 = 1 month after dose 2; m13 = 12 months after dose 2. Vaccine response rates were defined as: (i) anti-gE CD4 prior to initial vaccination²⁺Frequency above cut-off (320/106 gE-specific CD 4)²⁺) Main body of (2), anti-gE CD4²⁺The frequency is increased by more than or equal to 2 times compared with the level before vaccination; (ii) anti-gE CD4 prior to initial vaccination²⁺Subjects with frequencies below the cut-off value, anti-gE CD4²⁺The frequency is greater than or equal to 2 times the cut-off value. Error bars represent 95% confidence intervals. The first in each time period (M) is HZ/su PreChemo and the second is placebo PreChemo.

Fig. 12 illustrates: GMC of anti-gE antibodies in RTR subjects (ATP cohort for humoral immunogenicity). The first bar at each time point was HZ/su; the second is placebo. GMC = geometric mean concentration; gE = glycoprotein E; ATP = according to protocol specification; IU = international unit; m0 = prior to vaccination; m1 = 1 month after dose 1; m2 = 1 month after dose 2; y = year of age; CIS = calcineurin inhibitor or sirolimus; CS = corticosteroid; MC = mycophenolate ester compound. Error bars represent 95% confidence intervals.

Fig. 13 illustrates: ELISA concentration of anti-gE antibody in RTR subjects humoral VRR (ATP cohort for humoral immunogenicity). The first bar at each time point was HZ/su and the second bar was placebo. VRR = vaccine response rate; % = percentage of responders; other abbreviations are the same as in fig. 12. VRR is defined as: (i) for subjects that were seropositive for the initial anti-gE antibody, the antibody concentration after the second vaccination was greater than or equal to 4 times the pre-vaccination level; (ii) for subjects who were seronegative for the initial anti-gE antibody, the antibody concentration after the second vaccination was > 4-fold greater than the anti-gE cut-off (97 mIU/mL). Error bars represent 95% confidence intervals.

Fig. 14 illustrates: gE specific CD4 in RTR subjects²⁺Frequency of T cells (ATP subgroup for CMI). CMI = cell-mediated immunogenicity; min = minimum; max = maximum; q1 = first quartile; q3 = third quartile; the other abbreviations are the same as in fig. 12 and 13.

Fig. 15 illustrates: gE-specific CD4 in RTR-through subjects²⁺CMI VRR for T cell frequency (ATP subgroup for CMI). The abbreviations are the same as in FIGS. 12-14. Vaccine response rates were defined as: (i) anti-gE CD4 prior to initial vaccination²⁺Frequency above cut-off (320/106 gE-specific CD 4)²⁺) Main body of (2), anti-gE CD4²⁺The frequency is increased by more than or equal to 2 times compared with the level before vaccination; (ii) anti-gE CD4 prior to initial vaccination²⁺Subjects with frequencies below the cut-off value, anti-gE CD4²⁺The frequency is greater than or equal to 2 times the cut-off value. Error bars represent 95% confidence intervals.

Detailed Description

The present invention relates to the unexpected discovery that effective protection from or prevention of or reduction in the severity of herpes zoster and/or PHN is achieved following a single or first dose of an immunogenic composition as described herein. Previously, supported by clinical immunization data reported by Chlibek r. et al (2014Vaccine 32:1745-1753), it was believed that the adjuvanted VZV gE subunit Vaccine required at least 2 doses of the Vaccine composition to generate an adequate immune response for effective prevention of herpes zoster and/or PHN in susceptible individuals, i.e. in a population known to be immunosenescent, such as elderly (50 Years (YOA) or older, 60 YOA or older, 70 YOA or older or 80 YOA or older), or immunocompromised human individuals (e.g. human individuals undergoing immunosuppressive therapy, individuals suffering from immunosuppressive infection (e.g. HIV)). FIGS. 1A-C and 2A-C are taken from Chlibek R. et al (2014Vaccine 32: 1745-1753). In FIGS. 1A-C and 2A-C (as shown in FIG. 1A), the study subjects received: two doses of the same adjuvanted (AS01B) VZV gE composition (comprising 25 μ g, 50 μ g, or 100 μ g VZV gE) separated by two months; two doses of unadjuvanted VZV gE two months apart (100 μ g gE/saline), or one dose of saline followed by one dose of adjuvanted VZV gE two months later (saline +100 μ g gE/AS 01B). Figures 1A-C show substantial differences in cell-mediated immune responses after adjuvanted gE (25, 50, or 100 μ g gE per dose) of a 0,2 month 2-dose regimen compared to a single dose of adjuvanted gE (100 μ g gE per dose) in a general cohort of subjects (figure 1A), a cohort of subjects from 60-69 years of age (figure 1B), and a cohort of subjects greater than or equal to 70 years of age (figure 1C). FIGS. 2A-C show similar effects on VZV gE antibody levels. The efficacy of adjuvanted VZV gE subunit vaccine compositions after a 2-dose vaccination regimen is described in WO 2016/096968.

It has now been found that herpes zoster and/or PHN in an individual can be effectively prevented or reduced in severity after one dose of an immunogenic composition as described herein. It has been found that one dose of an immunogenic composition described herein (e.g., a vaccine composition) is effective to protect against or prevent herpes zoster and/or PHN before 2 months after administration of said one dose. As shown in example 1, in a population of subjects 50 years old or older who received a single dose of immunogenic composition (i.e., a subset of study subjects for which the 2-dose regimen was not completed in the study), effective prevention against HZ was demonstrated in vaccinated subjects (compared to subjects receiving placebo) during a mean follow-up period of 76 days (see table 1). In example 2, data from subjects receiving a single dose (70 YOA or greater) was combined with data from subjects receiving only the first dose of the two dose administration regimen (70 YOA or greater). Effective protection of HZ by a single dose of the immunogenic composition was demonstrated in this pooled population (compared to placebo-vaccinated subjects) during a mean follow-up period of 85 days (see table 1).

According to one embodiment, the method comprises administering a single dose of the immunogenic composition, i.e. it is a dose in a single dose immunization program. Alternatively, the method comprises administering one dose, which is the first dose administered in a multi-dose immunization program. In another embodiment, the one dose is the first dose administered in a 2-dose immunization procedure. In yet further embodiments, the one dose is a first dose of a 2-dose immunization schedule, wherein the first dose is effective to prevent or protect against HZ prior to administration of a second dose of the 2-dose immunization schedule.

In the case of a multi-dose immunization program, the interval between administration of 2 (or more) doses of the vaccine may vary between 1 month to about one year (i.e., 12 months), or between 1 to 3 months, or between 2 to 12 months, or between 2 to 6 months. In one embodiment, the interval is 2, 6 or 12 months. In particular, the interval is 2 months. Also in particular, the interval is 12 months. Alternatively, the interval is 1 year. It will be apparent to those skilled in the art that the "1 month" interval is not limited to the administration of subsequent doses only on the day that occurs just one month later; administration on a "1 month" schedule typically occurs during a period of 30 to 48 days after the previous administration. Administration at 2 month intervals is typically within 49 to 83 days; the 12 month interval is typically within 335 days and 395 days.

In a specific embodiment, the one dose is the first dose administered in a 2-dose immunization program with an interval of 0,2 to 0,6 months.

The prophylactic or protective use or method (vaccination) according to the invention provides a high efficacy after administration of one dose of the immunogenic composition. The efficacy of one dose of the immunogenic composition to prevent or protect against HZ is expressed as a reduction in the incidence of HZ in the population after receiving only one dose of the immunogenic composition compared to placebo. The efficacy of a dose of the immunogenic composition in preventing or protecting against HZ is 50% or more, suitably 55% or more, suitably 60% or more, suitably 65% or more, suitably 70% or more, suitably 75% or more, suitably 80% or more, suitably 85% or more, or 90% or more.

Furthermore, the efficacy according to the present invention has been found to be high in a number of target populations. In contrast to the usual reduction in vaccine efficacy observed in subjects with a decline in the immune system, the efficacy of vaccination using the immunogenic composition (e.g. vaccine composition) according to the invention is abnormally high in a number of target populations, even in individuals over the age of 70 years or more, achieving substantial protection after one dose.

Specific target populations contemplated according to the present invention are human individuals aged > 50, 60, 70, 50 to 59, or 60 to 69 years old; and more specifically, subjects aged ≧ 70, such as ≧ 71, such as ≧ 72, such as ≧ 73, such as ≧ 74, such as ≧ 75, such as ≧ 80 or ≧ 81. In a specific embodiment, the target population comprises human individuals older than 70 years of age.

Thus, in a specific embodiment:

-the efficacy of one dose of the immunogenic composition to prevent or protect against HZ in an adult population of 70 years of age or older is 50% or more, suitably 55% or more, suitably 60% or more, suitably 65% or more;

-the efficacy of a dose of the immunogenic composition to prevent or protect against HZ in an adult population of 50 years of age or older is 50% or more, suitably 55% or more, suitably 60% or more, suitably 65% or more, suitably 70% or more, suitably 75% or more, suitably 80% or more, suitably 85% or more, or 90% or more;

-the efficacy of a dose of the immunogenic composition to prevent or protect against HZ in an adult population of 70 years of age or older is 50% or more, suitably 55% or more, suitably 60% or more, suitably 65% or more, as measured within two weeks, one month, six weeks, or within two months after said dose;

-the efficacy of a dose of the immunogenic composition to prevent or protect against HZ in an adult population of 50 years of age or older is 50% or more, suitably 55% or more, suitably 60% or more, suitably 65% or more, suitably 70% or more, suitably 75% or more, suitably 80% or more, suitably 85% or more, or 90% or more, as measured within two weeks, one month, six weeks, or within two months after said dose.

The dose of the immunogenic composition can be administered in a single dose regimen. As used herein, "single dose" or "single dose regimen" refers to administration of only one dose to achieve prevention or protection. Subjects undergoing a single dose regimen are not planned or instructed to obtain a second dose, for example, over a subsequent one year, two years, 18 months, three years, four years, or more. Thus, in a method comprising administering a single dose of an immunogenic composition, the method comprises a step of administering, the step of administering consisting of administering a single dose of the immunogenic composition.

Other particular populations suitable for treatment with the present invention are immunocompromised populations or individuals, such as HIV positive patients or patients with AIDS, transplant patients, such as kidney transplant patients or hematopoietic transplant patients, patients with hematological malignancies, patients with solid tumors or otherwise immunocompromised or immunocompromised patients.

Another specific population of subjects facing reduced immunity or immunosuppressive therapy that would benefit from the timely administration of one or a first dose of the immunogenic composition are patients with hematopoietic stem cell transplantation, hematologic malignancies, solid organ transplantation, end stage renal disease, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease.

Because of the early appearance of effective prevention of HZ after one dose of the immunogenic composition, the protection or prevention of HZ provided by one dose (e.g., the first dose in a multi-dose regimen) is particularly useful for registering subjects receiving immunosuppressant therapy or otherwise facing situations where innate immunity will be suppressed in the near future. Thus, the invention provides for the use of a dose of an immunogenic composition prior to or in conjunction with the initiation of immunosuppressive therapy in a subject. Thus, a particular population suitable for treatment with the present invention is one that is immunocompetent (capable of producing an immune response within the normal range) but is scheduled to receive immunosuppressive therapy or has an increased likelihood of receiving immunosuppressive therapy in the near future (e.g., one week, two weeks, three weeks, one month, six weeks, two months, three months, four months, five months, six months, or one year after administration of a dose, or one week to one month, two months, three months, five months, six months, or one year after administration of a dose, or two weeks, two months, three months, four months, five months, six months, or one year after administration of a dose). Suitable subjects include those who initiate (or enroll to receive) immunosuppressive (also known as immunosuppressive or immunosuppressive) therapy (e.g., chemotherapy, radiation therapy, or immunosuppressive drug compounds), as well as those who are scheduled to undergo organ transplantation or are enrolled in a waiting list for receiving organ transplantation.

Currently, no Herpes Zoster (HZ) vaccine is approved for immunosuppressed or immunocompromised individuals. It is estimated that individuals with Solid Tumors (ST) receiving immunosuppressive chemotherapy (chemo) have a 3-4 times higher incidence of HZ than the general population in the United states (12/1000 vs 3.2/1000 man-year) (Habel et al, Cancer epidemic Biomarkersprev, 2013;22: 82-90; Insinga et al, J Gen Intern Med 2005;20: 748-53). The incidence of shingles in individuals with Solid Organ Transplantation (SOT) is estimated to be 8-9 times that of the general population of the united states (3.2/1000 people-year).

In a further embodiment, the target population contemplated according to the invention comprises or consists of a subject previously vaccinated with a live attenuated VZV vaccine. It has been reported that protection against HZ and/or PHN diminishes rapidly following immunization with a live attenuated VZV vaccine (Tseng HF et al, J infusion Dis (2016) 213(12): 1872-5). It has now been found that the immunogenic compositions described herein can be effectively used to prevent shingles (or HZ) and/or PHN in subjects previously vaccinated with a live attenuated VZV vaccine (e.g., more than 3 years ago, 4 years ago, more than 5 years ago, more than 6 years ago, more than 7 years ago, more than 8 years ago, or more than 10 years ago).

The immunogenic compositions (e.g., vaccine compositions) according to the invention comprise a recombinant VZV gE antigen in combination with an adjuvant.

As disclosed herein, a suitable VZV gE antigen is VZV glycoprotein gE (also referred to as gp1), or an immunogenic variant thereof, truncated to remove the carboxy terminal anchor region. Davison et al (J Gen Virol, 67:1759-1816(1986)) disclose the complete Varicella Zoster Virus (VZV) nucleotide sequence. The wild type or full length gE protein consists of 623 amino acids comprising the signal peptide, the major part of the protein, the hydrophobic anchor region (residues 546-558) and the C-terminal tail. In one aspect, a VZV gE C-terminal truncate (also referred to as a truncated gE or gE truncate) is used, wherein the truncation removes from 4-20% of all amino acid residues from the carboxy terminus, e.g., the absence of residues 547-623. In an alternative embodiment, the truncated gE lacks the carboxy-terminal anchor region (e.g., an internal deletion in the C-terminal region, suitably about amino acids 547-558 of the wild-type sequence). In one embodiment, the VZV gE antigen is a truncated gE comprising or consisting of the sequence of SEQ ID number 1. In a further embodiment, the VZV gE antigen is not present in the form of a fusion protein comprising a further (non-gE) VZV protein or an immunologically active fragment thereof.

VZV gE antigens, including anchorless VZV gE antigens (which are also immunogenic variants) and their production, are described in EP0405867 (incorporated herein by reference) and references therein [ see also Vafai A. antibody binding sites on truncated forms of vacuum lla-zo viruses gpI (gE) glycoprotein Vaccine 199412: 1265-9 ]. EP0192902 also discloses gE and its production. Haumont et al (Virus Research (1996) vol 40, p 199-204; herein fully incorporated by reference) also disclose truncated gE. An adjuvanted VZV gE composition suitable for use according to the invention, i.e. a carboxy-terminally truncated VZV gE in combination with an adjuvant comprising QS21, 3D-MPL and liposomes further containing cholesterol, is disclosed in WO2006/094756 (US 7939084, which is incorporated herein by reference). Leroux-Roels I. et al (J. feed. Diseases 2012: 2061280) -1290) reported a phase I/II clinical trial that evaluated an adjuvanted VZV truncated gE subunit vaccine.

As used herein, the term "variant" refers to an antigen that is modified relative to its naturally occurring form. As disclosed herein, a suitable "variant" is an "immunogenic variant" so that it is sufficiently similar to a native antigen to retain antigenic properties and still be able to induce an immune response that is cross-reactive with the native antigen. A variant polypeptide may comprise multiple substitutions, preferably conservative substitutions, when compared to the reference sequence (i.e. the wild-type sequence), i.e. one amino acid is substituted by another amino acid with similar properties, for example the aliphatic amino acids Val, Ile, Leu, Met, or the basic amino acids Lys, Arg, His, or the aromatic amino acids Phe, Tyr, Trp (e.g. 1-50, such as 1-25, especially 1-10, or 1, 2, 3, 4, 5, 6,7, 8, 9 or 10 changes, and especially 1 amino acid residue may be altered (e.g. substituted or deleted). In particular, variants with respect to SEQ ID No.1 are contemplated. Suitably, such substitutions do not occur in the region of the major epitope (i.e. the immunologically important epitope) and therefore do not have a significant effect on the immunogenic properties of the antigen. VZV gE is known to contain B-cell and CD4+ T-cell epitopes, as described in R.E. Bergen et al (Viral Immunology, 4 (3) (1991), pp. 151-166); W.J. Fowler et al (Virology, 214 (2) (1995), pp. 531-; G.N. Malavige et al (Clin Exp Immunol,152 (3) (2008), pp. 522- & 531) and L.Wu & B. Forghani (Arch Virol, 142 (2) (1997), pp. 349- & 362). Protein variants may also include those in which additional amino acids are inserted compared to the reference sequence, for example, such insertions may occur at 1-10 positions (such as 1-5 positions, suitably 1 or 2 positions, especially 1 position), and may, for example, involve the addition of 50 or fewer amino acids (such as 20 or fewer, especially 10 or fewer, especially 5 or fewer) at each position. Suitably, such insertion does not occur in the region of the epitope and therefore has no significant effect on the immunogenic properties of the antigen. One example of an insertion includes a short stretch of histidine residues (e.g., 2-6 residues) that aids in the expression and/or purification of the antigen in question. Variants also include those in which amino acids have been deleted compared to the reference sequence, for example, such deletions may occur at 1-10 positions (such as 1-5 positions, suitably 1 or 2 positions, especially 1 position), and may, for example, involve deletions of 20 or fewer amino acids (such as 10 or fewer, especially 5 or fewer, especially 2 or fewer) at each position. Suitably, such deletions do not occur in the epitope region and therefore do not have a significant effect on the immunogenic properties of the antigen. The skilled artisan will recognize that a particular protein variant may comprise substitutions, deletions and additions (or any combination thereof). Variants preferably exhibit at least about 70% identity, more preferably at least about 80% identity, and most preferably at least about 90% identity (such as at least about 95%, at least about 98%, or at least about 99%) to the relevant reference sequence. Examples of algorithms suitable for determining sequence identity and percent sequence similarity are the BLAST and BLAST 2.0 algorithms described in Altschul et al, Nuc. Acids Res. 25:3389-3402 (1977) and Altschul et al, J. mol. biol. 215:403-410 (1990), respectively. Whether a given variant elicits such an immune response can be measured by a suitable immunological assay, such as ELISA or flow cytometry.

The amount of VZV gE antigen used to immunize a human individual against HZ or PHN is selected to be an amount that induces an immunoprotective response in a typical vaccinee without significant adverse side effects. Such amounts will vary depending on the particular antigen employed and how it is presented. In general, it is expected that each dose will contain 1-1000. mu.g of protein, for example 2-100. mu.g or 5-60. mu.g. In the case of VZV gE antigen, then 25-100. mu.g of gE may be used in humans, on the one hand, e.g. 40-100. mu.g of gE for human use, on the one hand about 25. mu.g, about 50. mu.g or about 100. mu.g of gE, suitably 25. mu.g, 50. mu.g or 100. mu.g of gE. In a preferred embodiment, the VZV gE antigen (e.g., SEQ ID number 1) is used at a dose of 50 μ g. As disclosed herein, a "dose" is an amount administered in a single administration.

As disclosed herein, suitable adjuvants comprise a TLR-4 ligand and a saponin in a liposomal formulation.

Particularly suitable saponins for use in the present invention are Quil a and derivatives thereof. Quil A is the tree Quillaja Saponaria Molina from south America (Quil)Quillaja saponariaMolina) and was first described by Dalsgaard et al in 1974 ("Saponin adjuvants", archiv. f ü r die gesamte Virusforschung, vol.44, Springer Verlag, Berlin, p243-254) Is active as an adjuvant. Purified fractions of Quil a have been isolated by HPLC which retain adjuvant activity without toxicity associated with Quil a (EP 0362278), such as QS7 and QS21 (also known as QA7 and QA 21). QS21 is a natural saponin derived from the bark of the quillaja saponaria tree that typically induces CD8+ cytotoxic T Cell (CTL), Th1 cells and predominantly IgG2a antibody responses and is the preferred saponin in the context of the present invention.

Suitably, the saponin is provided in a composition of low reactogenicity in which the saponin is quenched using an exogenous sterol. Suitable sterols include beta-sitosterol, stigmasterol, ergosterol, ergocalciferol, and cholesterol. In a particular embodiment, the adjuvant composition comprises cholesterol as a sterol. These sterols are well known in the art, for example in merck index, 11 th edition, page 341, cholesterol is disclosed as a naturally occurring sterol found in animal fat. There are several specific forms of less reactogenic compositions in which QS21 is quenched using exogenous cholesterol. The saponin/sterol is formulated in a liposome formulation structure. A process for obtaining saponins/sterols in liposomal formulations is described in WO 96/33739 (US6846489, incorporated herein by reference), particularly in example 1. The relative amount of sterol to phospholipid is 1-50% (mol/mol), suitably 20-25%.

When the active saponin fraction is QS21, QS 21: the ratio of sterols is typically in the range of 1:100 to 1:1 (w/w), suitably between 1:10 to 1:1 (w/w), and preferably 1:5 to 1:1 (w/w). Suitably an excess of sterol is present, QS 21: the ratio of sterols is at least 1:2 (w/w). In one embodiment, the QS 21: the ratio of sterols is 1:5 (w/w). The sterol is suitably cholesterol.

The adjuvant composition comprises a TLR-4 agonist. Suitable examples of TLR-4 agonists are lipopolysaccharides, suitably non-toxic derivatives of lipid A, in particular monophosphoryl lipid A, or more particularly 3-deacylated monophosphoryl lipid A (3D-MPL).

3D-MPL is sold by GlaxoSmithKline Biologicals S.A. under the name MPL and is referred to throughout as MPL or 3D-MPL. See, e.g., U.S. patent nos. 4,436,727; 4,877,611, respectively; 4,866,034 and 4,912,094 (each of which is incorporated herein by reference). 3D-MPL predominantly promoted a CD4+ T cell response with the IFN-g (Th1) phenotype. 3D-MPL may be produced according to the method disclosed in GB 2220211A. Chemically, it is a mixture of 3-deacylated monophosphoryl lipids A having 4, 5 or 6 acylated chains. In the compositions of the invention, small particle 3D-MPL may be used to prepare adjuvant compositions. The small particle 3D-MPL has a particle size such that it can be sterile filtered through a 0.22 μm filter. Such formulations are described in WO 94/21292. Preferably, powdered 3D-MPL is used to prepare the adjuvant composition of the invention.

Other TLR-4 agonists that may be used are alkyl aminoglycoside phosphates (AGPs), such as those disclosed in WO98/50399 or U.S. patent No. 6,303,347 (methods for preparing AGPs are also disclosed), suitably RC527 or RC529 as disclosed in U.S. patent No. 6,764,840, or a pharmaceutically acceptable salt of AGP. Some AGPs are TLR-4 agonists and some are TLR-4 antagonists. In the present invention, the use of TLR-4 agonists is contemplated.

Other suitable TLR-4 ligands are as described in WO2003/011223 (US20020176861) and WO2003/099195 (US 7833993), both incorporated herein by reference, e.g. compound I, compound II and compound III as disclosed on pages 4-5 of WO2003/011223 or pages 3-4 of WO2003/099195, and in particular those disclosed in WO2003/011223, such as ER803022, ER803058, ER803732, ER804053, ER804057m ER804058, ER804059, ER804442, ER804680 and ER 804764. For example, one suitable TLR-4 ligand is ER 804057.

Other TLR4 agonists that may be used in the present invention include Glucopyranosyl Lipid Adjuvants (GLA), such as described in WO2008/153541 or WO2009/143457 or in Coler RN et al, (2011) Development and catalysis of Synthetic Glucopyranosyl Lipid Adjuvant System as a vaccine Adjuvant. PLoS ONE 6(1): e16333. doi:10.1371/j ournal. port. 0016333 and Arias MA et al (2012) Glucopyranosyl Lipid Adjuvant (GLA), a Synthetic TLR4Agonist, protein potential System and Mucosanol research immunization with Vgp140. PLoS ONE 7: 7. jo 00444. 539. 1144. j ournal. 1144. with the use of such agonists. WO2008/153541 or WO2009/143457 are incorporated herein by reference for the purpose of defining TLR4 agonists that can be used in the present invention.

Adjuvant compositions comprise both a saponin and a TLR4 agonist. In a specific example, the adjuvant composition comprises QS21 and 3D-MPL.

The TLR-4 agonist (such as lipopolysaccharide, e.g. 3D-MPL) may be used in an amount of 1-100 μ g per human dose of the adjuvant composition. 3D-MPL may be used at a level of about 50 μ g, for example between 40 and 60 μ g, suitably between 45 and 55 μ g, or between 49 and 51 μ g or 50 μ g. In a further embodiment, the human dose of the adjuvant composition comprises a level of 3D-MPL of about 25 μ g, for example between 20-30 μ g, suitably between 21-29 μ g or between 22-28 μ g or between 23-27 μ g or between 24-26 μ g or 25 μ g.

Saponins (e.g., QS21) may be used in an amount of 1-100 μ g per human dose of the adjuvant composition. QS21 may be used at a level of about 50. mu.g, for example between 40-60. mu.g, suitably 45-55. mu.g, or 49-51. mu.g or 50. mu.g. In a further embodiment, a human dose of the adjuvant composition comprises QS21 at a level of about 25 μ g, for example between 20 and 30 μ g, suitably between 21-29 μ g or between 22-28 μ g or between 23-27 μ g or between 24-26 μ g or 25 μ g. The QS21 may be present at a dose of 60 μ g or less, 55 μ g or less, or 30 μ g or less per dose. QS21 may be present at a dose of greater than or equal to 20 mug, greater than or equal to 40 mug, or greater than or equal to 45 mug per dose.

The weight ratio of TLR-4 agonist to saponin is suitably between 1:5 and 5:1, suitably 1: 1. For example, where 3D-MPL is present in an amount of 50 μ g or 25 μ g then QS21 may suitably also be present in an amount of 50 μ g or 25 μ g per human dose of the adjuvant composition.

By "liposomal formulation" is meant that the saponin and the TLR-4 agonist are formulated with liposomes. Liposomes intended for use in the present invention contain a neutral lipid, such as phosphatidylcholine, which is suitably non-crystalline at room temperature, such as egg yolk phosphatidylcholine, Dioleoylphosphatidylcholine (DOPC) or dilauroylphosphatidylcholine. In a preferred embodiment, the liposomes of the invention contain DOPC. The liposomes may also contain charged lipids which increase the stability of the liposome-QS 21 structure to liposomes composed of saturated lipids. In these cases, the amount of charged lipid is suitably 1-20% w/w, preferably 5-10%.

WO2013/041572 (US20140234403, incorporated herein by reference), in particular examples 3 and 4, further discloses a method of preparing a liposome bulk formulation (bulk preparation) of DOPC liposomes further comprising cholesterol and 3D-MPL for further mixing with QS21 to obtain an adjuvant suitable for use according to the present invention.

In a particular embodiment, the immunogenic composition for use according to the invention consists essentially of a VZV gE antigen truncated to remove the carboxy terminal anchor region, or a derivative thereof, in combination with an adjuvant comprising QS21, 3D-MPL and cholesterol containing liposomes.

The compositions are typically administered by the intramuscular route, but alternative routes, such as intradermal or subcutaneous, are also contemplated.

The immunogenic composition (e.g. vaccine composition) according to the invention is used for vaccination of a human individual, i.e. to protect against or prevent Herpes Zoster (HZ), i.e. to prevent reactivation of VZV (also known as shingles), and/or Post Herpetic Neuralgia (PHN). In one embodiment, the immunogenic composition (e.g., a vaccine composition) is used to protect against or prevent the occurrence of herpes zoster. In the event that HZ does occur, the severity of shingles is suitably reduced (i.e., HZ is improved) as compared to unvaccinated individuals. Moreover, when HZ does occur, other disease syndromes may develop, such as postherpetic neuralgia.

PHN is the most common severe complication of HZ. PHN is defined as the persistent pain after the disappearance of HZ rash. Affected patients often complain of burning, cramping, intermittent severe pain, or electrocution-like pain or palpation pain. The older age is the definite risk factor for PHN. Other risk factors may include severe HZ rash and painful HZ prodromal symptoms. PHN tends to improve within a few months. Approximately 70-80% of cases resolve within 1 year, but in some people PHN persists for many years (Dworkin et al, 2007.clin. infec. dis.; 44 suppl. 1: S1-S26). PHN is generally defined as the pain 90 days after the rash has appeared. The intensity, character and duration of PHN vary widely between individuals. Therefore, a specific questionnaire aimed at assessing the pain (in terms of extent and duration) and discomfort associated with the HZ was specifically designed, called the shingles brief pain scale (ZBPI). A copy of the ZBPI questionnaire can be obtained, for example, from Coplan et al, 2004. J. pain. 5(6) 344-. Such zppis are particularly useful and are typically used in the evaluation (e.g., in clinical trials) of compounds intended to prevent or protect against HZ-associated pain, including PHN.

In a further embodiment, the invention relates to the use in protecting against or preventing postherpetic neuralgia. In the event HZ does occur, the severity of PHN is suitably reduced (i.e., PHN is improved) as compared to unvaccinated individuals. The use or method as disclosed herein will enhance the immune response typically induced by natural infection. As disclosed herein, it is understood that "preventing" or "protecting from" HZ and/or PHN occurs when the incidence of HZ and/or PHN and/or the severity of the occurrence is reduced. Prevention or protection from HZ and/or PHN can be assessed in the identified population as compared to another population, e.g., in a vaccinated population as compared to a comparable but unvaccinated population. A reduction in severity refers to a reduction in the overall disease or any clinical manifestations associated with HZ and/or PHN. For example, a reduction in severity refers to a reduction in pain associated with HZ and/or PHN, which can be suitably measured and monitored using a ZBPI questionnaire.

In a further embodiment, the use or method according to the invention is for protecting against or preventing both HZ and PHN.

Even more preferred is each of the foregoing preferred and particularly preferred embodiments, wherein the VZV gE antigen has the sequence of SEQ ID number 1 and is present at a dose of 50 μ g, and wherein QS21 and 3D-MPL are also present at a dose of 50 μ g.

A further particular embodiment is an immunogenic composition (e.g. a vaccine composition) comprising a VZV gE antigen or derivative thereof truncated to remove the carboxy terminal anchor region, in combination with an adjuvant comprising QS21, 3D-MPL and cholesterol containing liposomes for use in a method for protecting against or preventing Herpes Zoster (HZ) and/or post herpetic neuralgia in an individual 80 years of age or older, reducing the incidence of PHN by at least 60% or at least 70% for at least 5 years.

Term(s) for

As used herein, a truncated antigen or protein is an antigen or protein that lacks an amino acid region as compared to its wild-type or full-length form. A "truncated" antigen or protein may be the result of removal of the region from a wild-type or full-length molecule, or may be prepared de novo, e.g., recombinantly produced in a truncated form.

It is to be understood that "prevention of disease" does not mean prevention of disease in 100% of subjects receiving treatment.

As used herein, "immunosuppressant medical therapy" includes treatment with immunosuppressant drug compounds. Immunosuppressant drug compounds are drugs that inhibit or reduce the strength of the body's immune system. When used to reduce the risk of rejection of a transplanted organ, immunosuppressant medical therapy may be referred to as anti-rejection therapy or the use of anti-rejection pharmaceutical compounds. In addition, immunosuppressant medical therapies may be used to treat autoimmune diseases such as lupus, psoriasis and rheumatoid arthritis. Immunosuppressant drug compounds include corticosteroids, such as prednisone, budesonide, and prednisolone; calcineurin inhibitors, such as cyclosporine, tacrolimus; mTor inhibitors such as sirolimus, everolimus; IMDH (inosine monophosphate dehydrogenase) inhibitors, such as azathioprine, leflunomide, mycophenolate mofetil; and biologicals, such as monoclonal antibodies.

The invention is illustrated by the following non-limiting examples.

Example 1: vaccine efficacy against HZ in adults 50 years of age and older