WO2020210628A1

WO2020210628A1 - Compositions and methods for improving vaccination of hyporesponsive individuals

Info

Publication number: WO2020210628A1
Application number: PCT/US2020/027675
Authority: WO
Inventors: Johnson Yiu-Nam Lau; Ivan Fan Ngai HUNG; Kai Wang Kelvin TO; Kwok Yung YEUN
Original assignee: Emv Enhance (Hk) Limited; Versitech Limited
Priority date: 2019-04-10
Filing date: 2020-04-10
Publication date: 2020-10-15

Abstract

Compositions and methods are provided that enhance the ability of low- or non-responding individuals undergoing renal replacement therapy to develop a protective antibody response following immunization. A toll-like receptor agonist is applied at or near the vaccination site and left in place for a period of time following vaccination, for example with a Hepatitis B vaccine.

Description

COMPOSITIONS AND METHODS FOR IMPROVING VACCINATION OF

HYPORESPONSIVE INDIVIDUALS

[0001] This application claims the benefit of United States Provisional Patent Application No. 62/832,193 filed on April 10, 2019. This and all other referenced extrinsic materials are incorporated herein by reference in their entirety. Where a definition or use of a term in a reference that is incorporated by reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein is deemed to be controlling.

Field of the Invention

[0002] The field of the invention is preparations for enhancing the effectiveness of vaccines, particularly in individuals undergoing renal replacement therapy.

Background

[0003] The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0004] Individuals with kidney disease are frequently immunocompromised, resulting in a higher risk of bacterial and viral infections than the general population. The etiology of this is unclear. Infectious disease is a leading cause of death in patients with chronic kidney disease. Compounding this problem is the relatively high rate of exposure of individuals with kidney disease to pathogens, due to their frequent exposure to hospital environments and the invasive nature of some treatments (e.g. hemodialysis). In particular, hepatitis B virus (HBV) infection remains an important clinical issue among patients on renal replacement therapy (RRT). Chronic hepatitis B infection results in increased risk for HBV complications including hepatic cirrhosis and hepatocellular carcinoma. At this time hepatitis B vaccination (HBVv) remains the best strategy for prevention of HBV infection.

[0005] Unimmunized patients on RRT, especially those on hemodialysis, are at high risk of HBV infection and subsequently development of complications including cirrhosis and hepatocellular carcinoma. Nevertheless, immunogenicity and antibody persistence in this group of patients to the conventional intramuscular hepatitis B vaccination have been remarkably poor. Typically such patients fail to respond despite receiving repeated and multiple dose regimen of hepatitis B virus vaccine (HBVv). This is thought to be a result of chronic renal disease, which affects both innate and adaptive immune responses, along with the presence of uremic toxins and nutritional deficiencies that accompany it. Other factors associated with inadequate anti- HBs response include advanced age, diabetes mellitus, obesity, acquired immunity disturbances, malnutrition, altered hemoglobin levels; mode of dialysis (hemodialysis vs. chronic ambulatory peritoneal dialysis), and adequacy of dialysis. Vaccine- associated factors include the route of delivery, adjuvant and dosage given, and concomitant immunosuppression. Various methods including intradermal, high dose intramuscular and the 3^rd generation PreS/S HBVv vaccine formulation alone or together with the adjuvanted vaccines (including the Toll-like receptor 9 agonist) and AS04 adjuvanted HBVv have been attempted with mixed success.

[0006] It has been found that topical application of the toll-like receptor 7 (TLR7) agonist imiquimod before intradermal seasonal influenza vaccination was able to augment and the immunogenicity of influenza vaccination among the elderly with immunosenescence and patients with chronic illness. Such individuals, however, typically did not have underlying renal disease and the accompanying characteristic immune dysfunction.

[0007] Thus, there is still a need for a safe and effective means of improving immune response to immunization in individuals undergoing renal replacement therapy.

Summary of The Invention

[0008] The inventive subject matter provides apparatus, systems and methods that improve immune response to vaccination for individuals that are immunocompromised due to renal replacement therapy. Topical application of a toll-like receptor agonist at the vaccination site prior to or at the time of vaccination was found to facilitate development of an effective immune response in individuals undergoing renal replacement therapy and that are immunocompromised, including non-responders.

[0009] Embodiments of the inventive concept include method of improving immune response to a vaccine composition in an immunocompromised individual by identifying an individual that is immunocompromised as a result or renal replacement therapy, topically applying a topical pharmaceutical preparation that includes a toll-like receptor 7 agonist to the individual’s skin, intradermally injecting the vaccine composition through the skin where the topical

pharmaceutical preparation has been applied, and maintaining the topical pharmaceutical preparation on the skin surface for at least one hour to at least eight hours after injecting the vaccine composition (such as a hepatitis or pneumococcus vaccine). Suitable toll-like receptor agonists include imiquimod, resiquimod, gardiquimod, isotoribine, loxoribine, bropirimine, 852A, GS-9620, SZU-101, S-27609, guanine nucleoside analogs, imidoazoquinoline-based compounds, and/or stabilized immunomodulatory RNA. An identified individual can be hypo- responsive or even non-responsive to immunization without topical application of the topical pharmaceutical preparation.

[0010] The topical pharmaceutical preparation can be formulated to provide a seroprotection rate of greater than 75% at four weeks post-immunization, provide a seroprotection rate of greater than 90% at twelve weeks post-immunization, provide a seroprotection rate of greater than 90% at 78 weeks post-immunization, provide a seroprotection rate of greater than 89% at four weeks post-immunization in non-responsive individuals, and/or provide a seroprotection rate of greater than 90% at 78 weeks post-immunization in non-responsive individuals.

[0011] Another embodiment of the inventive concept is a kit for immunizing an individual that has a reduced immune response due to undergoing renal replacement therapy. Such a kit includes a topical pharmaceutical preparation that includes a toll-like receptor 7 agonist and a vaccine preparation (such as a hepatitis and/or pneumococcal vaccine). The toll-like receptor 7 agonist is provided in an amount sufficient to produce an effective immune response when the individual undergoing renal replacement therapy is non-responsive to immunization with the vaccine preparation without the topical pharmaceutical preparation. Such a kit can also include an occlusive dressing and/or instructions for use. Such instructions can include direction to apply the topical pharmaceutical preparation prior to a vaccination site prior to vaccination with the vaccine preparation, and can also include direction to maintain the topical pharmaceutical preparation at the vaccination site for at least one hour following vaccination. [0012] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments, along with the accompanying drawing figures in which like numerals represent like components.

Brief Description of The Drawings

[0013] FIG. 1: FIG. 1 depicts a recruitment flow-chart for patients enrolled in an study directed to an exemplary embodiment of the inventive concept. IMQ_ID: imiquimod ointment + intradermal vaccine; AQ_ID: aqueous cream + intradermal vaccine; AQ_IM: aqueous cream + intramuscular vaccine.

[0014] FIG. 2: FIG. 2 shows results of seroprotection rate (anti-HBs >10 mlU/mL) in patients on renal replacement therapy by treatment groups (mITT population). IMQ_ID: imiquimod ointment + intradermal vaccine; AQ_ID: aqueous cream + intradermal vaccine; AQ_IM:

aqueous cream + intramuscular vaccine.

[0015] FIG. 3: FIG. 3 shows geometric mean concentrations of anti-HBs in patients on renal replacement therapy by treatment groups. Error bars represent 95% confidence intervals; GMC: geometric mean concentration; mITT: modified intent-to -treat; IMQ_ID: imiquimod ointment + intradermal vaccine; AQ_ID: aqueous cream + intradermal vaccine; AQ_IM: aqueous cream + intramuscular vaccine.

Detailed Description

[0016] The inventive subject matter provides compositions and methods that improve the efficacy of vaccination in populations that are hyporesponsive to conventional vaccine preparation (for example vaccines directed to hepatitis, pneumococcus, and/or a coronavirus), in particular patients undergoing renal replacement therapy (such as hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration, and/or kidney transplant). In methods of the inventive concept this is accomplished by topical application of a pharmaceutically acceptable formulation that includes a toll-like receptor 7 agonist, such as imiquimod, at the vaccination site. [0017] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments, along with the accompanying drawing figures in which like numerals represent like components.

[0018] One should appreciate that the disclosed techniques provide many advantageous technical effects including providing immunization protection for communicable diseases to a highly vulnerable patient population.

[0019] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.

[0020] In one embodiment of the inventive concept a toll-like receptor agonist is applied topically to skin overlying an immunization site prior to immunization, at about the same time as immunization (e.g. within 5 minutes), or after immunization (e.g. within one hour of

immunization) of an individual with renal disease leading to immunocompromise. The toll-like receptor agonist can be topically applied using any suitable vehicle or mechanism. Suitable vehicles or mechanism include application as a mist or spray, as a cream, as an ointment, as a gel, as a foam, as a formulation applied and/or held in a porous or fibrous media (such as a wipe, swab, or pad), as part of an occlusive dressing, and/or as part of an appliable device (such as a microneedle device).

[0021] A formulation containing a toll-like receptor agonist can be applied to the skin surface at or near (e.g. within 5 mm, 1 cm, 1,5 cm, 2 cm, 3 cm, 5 cm, or 10 cm) the vaccination site. The skin surface to which the formulation is applied can have a mean diameter of 1 cm, 2 cm, 3 cm, 5 cm, 7 cm, 10 cm, 15 cm, or 20 cm).

[0022] Such a formulation, and can be applied prior, at about the same time (e.g. within 1 minutes, 2 minutes, 3 minutes, four minutes or five minutes), or soon after (e.g. within one hour) of a vaccinating injection. In some embodiments the topical formulation can be applied simultaneously with the vaccination, for example using a microneedle device that incorporates both the toll-like receptor agonist and the vaccine. In some embodiments the topical formulation containing the toll-like receptor agonist remains on the skin surface for at least 5 minutes, 10 minutes, 15 minutes, 30 minutes, one hour, two hours, four hours, six hours, eight hours, twelve hours, sixteen hours, twenty four hours, thirty six hours, or up to 48 hours following vaccination.

[0023] Suitable vaccinating formulations can be applied by intradermal injection, subdermal injection, and/or intramuscular injection. Vaccinating formulations can include vaccines directed to viral or bacterial pathogens, Suitable vaccinating species can be directed to cholera, dengue, diphtheria, hepatitis A, hepatitis B, hepatitis E, Haemophilus influenza type b, human papilloma virus, influenza (monovalent or multivalent), Japanese encephalitis, malaria, measles, meningococcal meningitis, mumps, pertussis, pneumococcal pneumonia, poliomyelitis, rabies, rotavirus, rubella, tetanus, tick-borne encephalitis, tuberculosis, typhoid, varicella, yellow fever, pneumococcus , and coronaviruses (e.g. SARS, MERS, Covid-19, etc.).

[0024] As noted above, compositions and methods of the inventive concept can incorporate one or more toll-like receptor agonists. In a preferred embodiment the toll-like receptor agonist is a toll-like receptor 7 agonist. Such a toll-like receptor agonist can be a low molecular weight compound ( i.e . less than 500 D) or a high molecular weight compound (e.g. greater than 500 D), and can be soluble or miscible in aqueous solvents, organic solvents (e.g. ethanol, DMSO, etc,), or mixed solvents that include both aqueous and organic solvent components. Examples of suitable toll-like receptor agonists include, but are not limited to, imiquimod, resiquimod, gardiquimod, isotoribine, loxoribine, bropirimine, 852A, GS-9620, SZU-101, S-27609, guanine nucleoside analogs, imidoazoquinoline-based compounds, and/or stabilized immunomodulatory RNA.

[0025] In an example of the inventive concept, a double-blind, randomized-controlled trial was performed using compositions and methods of the inventive concept, adult individuals identified as being on renal replacement therapy (RRT) (undergoing either hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD)) were immunized against hepatitis B.

Patients were randomly allocated (1:1:1) into one of the following treatment groups: (1) treatment with a topical imiquimod-cream followed by intradermal hepatitis B vaccine (HBVv) and designated IMQ_ID, (2) topical treatment with an aqueous cream formulation followed by intradermal HBVv and designated AQ_ID, and (3) topical treatment with an aqueous cream formulation followed by intramuscular HBVv (designated AQ_IM). Both patients and investigators were blinded to the type of topical treatment and the route of vaccine delivery. The HBVv used was a Sci-B-Vac™ vaccine containing 3 antigens (the S, Pre-Si and Pre-S2 antigens). The intradermal needle used was the MicronJet600™ needle. The primary endpoint of the study was the seroprotection rate ( i.e . having an anti-HBs >10mIU/mL) of the HBVv at 52 weeks after the first vaccination. Secondary end-points were the seroprotection rate of HBVv and the geometric mean antibody concentration (GMC) of the anti-HBs at 4, 12, 26 and 78 weeks after the first vaccination. Adverse reactions were also assessed up to 4 weeks after vaccination. A total of 94 patients on RRT were enrolled, among which of whom 54 patients (57.4%) were non-responders to conventional hepatitis b vaccination. The baseline

demographics of all three groups were well matched. All recruited had been on stable dialysis for at least 3 months before recruitment. Participants with history of allergy to components of the vaccine were excluded.

[0026] As noted above the HBVv used in the exemplary study, Sci-B-Vac™ (Bio-Hep-B®) 10pg/ mL, is a recombinant vaccine containing S, Pre-Si and Pre-S2 protein components of HBsAg, and is manufactured by BioTechnology General Ltd., Rehovot, Israel, with good safety record (7). Safety of intradermal HBVv has been demonstrated in large clinical trials previously (8-12). All intradermal vaccinations were delivered using the MicronJet™ needle (Nanopass). Patients were randomly assigned by a computer program into the three test groups described above by simple randomization with no stratification, an experimental group (IMQ_ID) and two control groups (AQ_ID and AQ_IM respectively). All patients received a 4-doses regimen of the HBVv, Sci-B-Vac™ (Bio-Hep-B®), each time receiving the same dosage of lmL (10pg) at 0, 1, 3 and 6 months.

[0027] At each vaccination, a 16cm² square was marked on the deltoid region of both arms of all patients. In the IMQ_ID group the contents of one sachet of Aldara™ 5% cream (iNova Pharmaceuticals™, Hong Kong; 12.5 mg imiquimod in 250 mg cream) was applied to the marked surface on the skin 5 minutes prior to vaccination. In the AQ_ID and the AQ_IM group an aqueous cream (B.P.™; FT Pharmaceuticals™, New Zealand) was applied to the marked skin surface. Patients in the IMQ_ID and AQ_ID received 0.5mL of intradermal Sci-B-Vac™ at each deltoid, totally lmL of Sci-B-Vac™. For the AQ_IM group, patients received 0.5mL of intramuscular Sci-B-Vac™ at each deltoid, totaling lmL of Sci-B-Vac™. The vaccine was injected in the approximate center of the marked area after the cream was absorbed. The imiquimod or aqueous cream B.P. was removed by the participant using tap water 8 hours after vaccination. To maintain blinding, each participant was assigned a serial number, and the randomization list linked each serial number with the 3 study groups. Only the study nurse had such knowledge. Both participants and investigators remained blinded to the type of topical treatment applied and the route of delivery during the follow-up period until the completion of the study.

[0028] Safety was evaluated by asking participants to remain on the clinic premises for 30 minutes for post-immunization observation. An immediate adverse event checklist was completed prior to discharge, covering the period of time associated with the development of severe anaphylactic reactions. Diaries were provided to the participants to document symptoms of local and systemic adverse events that presented within the 7 days following vaccination. Systemic symptoms included fever (body temperature >37.5° C), headache, lethargy, runny nose, sore throat, and severe adverse events. Local symptoms (including pain, swelling, induration, and ecchymosis) were documented as solicited events. Swelling and induration were graded based on size (grade 1 <20mm, grade 2 >20mm). Pain was graded accordingly (grade 1 = pain on touch, grade 2 = pain when arm was moved). The diaries were collected upon follow-up on day 28 after vaccination.

[0029] In order to measure immunogenicity blood was taken from participants at baseline, 4, 12, 26, 52 and 78 weeks after vaccination for antibody assay. Hepatitis B serology, including anti- HBs, anti-HBc, HBsAg, anti-HCV, and anti-HIV, were tested on an ARCHITECT™ system (Abbott Diagnostics™, Wiesbaden, Germany) using Architect anti-HBs, anti-HBc, HBsAg, anti- HCV, and HIV Ag/Ab Combo assays respectively. The Architect assay is a chemiluminescent microparticle immunoassay (CMIA) for qualitative and quantitative determination of antibody in blood samples. Briefly, sera were collected after centrifugation of clotted blood samples at 1,500 x g for 10 minutes and were stored at -20° C until use. Serum samples and assay reagents, calibrator and controls were loaded on the Architect System according to the manufacturer’s instructions. An anti-HBs concentration > 10 mlU/ml is regarded as being protective against Hepatitis B viral infection. Appropriate dilution of the sample with Architect anti-HBs specimen diluent was performed if the anti-HBs value exceed 1,000 mlU/ml. Samples with cut-off values (S/Co) < 1 were considered nonreactive and those with S/Co > 1 were considered reactive for anti-HCV and HIV Ag/Ab, as recommended by the manufacturer. As noted above, the primary endpoint is the seroprotection rate (anti-HBs >10mIU/mL) of the HBVv at 52 weeks after the first vaccination. The secondary endpoints were the seroprotection rate of HBVv and the GMC of the anti-HBs at 4, 12, 26 and 78 weeks after the first vaccination. Adverse reactions were also assessed up to 4 weeks after vaccination.

[0030] The week 52 seroprotection rates of the IMQ_ID and the control AQ-IM were estimated to be 80% and 40% respectively. With a power of 80% and a two-sided type 1 error of 5%, 30 participants would be needed for each group allowing a 20% loss to follow-up rate. For immunogenicity analyses, the GMC and 95% confidence intervals (C.I.s) were log-transformed and compared by one-way analysis of variance. A Chi-squared test was used to compare the demographic parameters and seroprotection rate among the four different groups. IBM SPSS Statistics 21.0. Armonk, New York: IBM corp. was used for statistical computation. A P-value <0.05 was considered to represent a significant difference.

[0031] Overall a total of 116 patients on RRT were screened, of which 94 patients underwent randomization (see FIG. 1); 92 patients completed the study. One patient from each of the IMQ_ID and the AQ_IM succumbed before 52 weeks after the first vaccination. Both patients succumbed from community acquired pneumonia which was not related to the HBVv. Thirty- two patients were randomized to the IMQ_ID group, and 31 patients were randomized to AQ_ID and AQ_IM respectively. Overall, 28.7% and 71.3% of the patients were on HD and CAPD respectively (see Table 1). A majority of 54 patients (57.4%) had received previous HBVv with no response. The median age was 60.5 (53.5-67.5) years and 59.5% of the patients were male. Past medical history, cause of renal failure and baseline laboratory findings were well matched among the three groups.

IMQ_ID: imiquimod ointment + intradermal vaccine; AQ_ID: aqueous cream + intradermal vaccine; AQ_IM: aqueous cream + intramuscular vaccine

Table 1

[0032] No serious adverse events related to vaccination were reported (see Table 2). The incidence of local or systemic adverse events was infrequent and self-limiting. Although grade 1 pain, swelling, induration, and hyperpigmentation were more commonly found in IMQ_ID and the AQ_ID groups, there were no differences among the three groups. None of the subjects had visible vaccine leakage from the injection site.

Fever: body temperature >37.5°C. Swelling and induration were graded based on size: grade 1, <20mm; grade 2, 20- 50mm; grade 3, >50mm (none of the participants developed >2 skin reaction. Pain was graded as follows: grade 1, pain on touch; grade 2, pain when arm is moved.

Table 2

[0033] The primary outcome by modified intention to treat (mITT) of seroprotection rate was significantly better at week 52 for the treatment group (IMQ_ID), with a 96.9% seroprotection rate, compared to 74.2% and 48.4% for the AQ_ID and AQ_IM groups respectively (p<0.001) (see Table 3 and FIG. 2). The GMC was also significantly higher at week 52 for the IMQ_ID group at 1,135 mlU/mL (95% C.I. 579.4-2,218.2 mlU/mL), compared to only 86.9 mlU/mL (95% C.I. 18.5-409.3 mlU/mL) and 7.2 mlU/mL (2.0-26.5mIU/mL) for the AQ_ID and AQ_IM groups respectively (p<0.001) (see Table 3 and FIG. 3). The seroprotection rate and GMC measured at all five time points were significantly better for the IMQ_ID group (p<0.001) than the control groups. The seroprotection rate remained at 96.9% with a very high GMC 631 mlU/mL (95% C.I. 312.6-1,273.5 mlU/mL) at 78 weeks. [0020] Multivariate analysis demonstrated that IMQ_ID vaccination [Odds ratio (O.R.) 3.70 (95% C.I. 1.16-11.81; p=0.027) was the only factor independently associated with higher seroprotection rate at 52 weeks. (Tables 4 and 5).

IMQ_ID: imiquimod ointment + intradermal vaccine; AQ_ID: aqueous cream + intradermal vaccine; AQ_IM: aqueous cream + intramuscular vaccine.

Seroprotection rate (anti-HBs >10 mlU/mL); GMC: geometric mean concentrations of anti-HBs [Significant P- values in bold]

Table 3

Table 4

Table 5

[0034] A subgroup analysis of the 54 non-responders demonstrated a similar pattern (see Table 6). The seroprotection rate and GMC measured at all five time points were significantly better for the IMQ_ID group (p<0.01 and p<0.001 respectively) than the control groups. The peak GMC of the non-responders IMQ_ID group at 52 weeks and 78 weeks was even higher when compared to the IMQ_ID group as a whole [1,721.9 (95% C.I. 826-3,581) mlU/mL and 984 (95% C.I. 533.3-1,811.3) mlU/mL vs. 1,135 (95% C.I. 579.4-2218.2) mlU/mL and 631 (95% C.I. 312.6-1,273.5) mlU/mL]

IMQ_ID: imiquimod ointment + intradermal vaccine; AQ_ID: aqueous cream + intradermal vaccine; AQ_IM: aqueous cream + intramuscular vaccine. Seroprotection rate (anti-HBs >10 mlU/mL); GMC: geometric mean concentrations of anti-HBs [Significant P- values in bold]

Table 6

[0035] In regard to the safety and practical concerns of topical application of TLR7 agonist and intradermal injection of the aluminum hydroxide containing Sci-B-Vac™, it is apparent that such a strategy is safe. Although the local side effects of grade 1 swelling, induration, and

pigmentation were more common via the intradermal route such local side effects were self- limiting and showed no significant difference among the three groups. The results were comparable to the dermatological side effects typically found in intradermal HBVv in dialysis patients. Systemic side effects were infrequent in all three groups. The findings were similar to a recent systematic review on intradermal hepatitis B vaccination in patients with end-stage renal disease unresponsive to primary vaccination.

[0036] Although the examples provided above utilized topical treatment with imiquimod, the Inventors believe that other toll-like receptor agonists will also prove effective. Suitable toll-like receptors agonists include resiquimod, gardiquimod, isotoribine, loxoribine, bropirimine, 852A, GS-9620, SZU-101, S-27609, guanine nucleoside analogs, imidoazoquinoline-based compounds, and stabilized immunomodulatory RNAs. The Inventors also contemplate that prodrugs of toll like receptors agonists (such as R07020531) can be effective in compositions and methods of the inventive subject matter.

[0037] It should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the spirit of the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms “comprises” and“comprising” should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced. Where the specification claims refer to at least one of something selected from the group consisting of A, B, C .... and N, the text should be interpreted as requiring only one element from the group, not A plus N, or B plus N, etc.

Claims

What is claimed is:

1. A method of improving immune response to a vaccine composition in an

immunocompromised individual, comprising:

identifying an individual that is immunocompromised as a result or renal replacement therapy;

topically applying a topical pharmaceutical preparation comprising a toll-like receptor 7 agonist to a skin surface of the individual;

intradermally injecting the vaccine composition through the skin surface; and

maintaining the topical pharmaceutical preparation on the skin surface for at least one hour after injecting the vaccine composition.

2. The method of claim 1, wherein the toll-like receptor agonist is selected from the group consisting of imiquimod, resiquimod, gardiquimod, isotoribine, loxoribine, bropirimine, 852A, GS-9620, SZU-101, S-27609, guanine nucleoside analogs, imidoazoquinoline-based compounds, and a stabilized immunomodulatory RNA.

3. The method of claim 1 or 2, comprising identifying the individual as hypo-responsive to immunization without topical application of the topical pharmaceutical preparation.

4. The method of one of claims 1 to 3, comprising identifying the individual as a non- responsive individual.

5. The method of one of claims 1 to 4, wherein the vaccine composition comprises a hepatitis vaccine.

6. The method of claim 5, wherein the hepatitis vaccine is a hepatitis B vaccine.

7. The method of one of claims 1 to 6, wherein the topical pharmaceutical preparation is retained on the skin surface for at least 8 hours following vaccination.

8. The method of one of claims 1 to 7, wherein the topical pharmaceutical preparation is formulated to provide a seroprotection rate of greater than 75% at four weeks post-immunization.

9. The method of one of claims 1 to 8, wherein the topical pharmaceutical preparation is formulated to provide a seroprotection rate of greater than 90% at twelve weeks post

immunization.

10. The method of one of claims 1 to 9, wherein the topical pharmaceutical preparation is formulated to provide a seroprotection rate of greater than 90% at 78 weeks post-immunization.

11. The method of one of claims 1 to 10, wherein the topical pharmaceutical preparation is formulated to provide a seroprotection rate of greater than 89% at four weeks post-immunization in non-responsive individuals.

12. The method of one of claims 1 to 11, wherein the topical pharmaceutical preparation is formulated to provide a seroprotection rate of greater than 90% at 78 weeks post-immunization in non-responsive individuals.

13. A kit for immunizing an individual undergoing renal replacement therapy, comprising: a topical pharmaceutical preparation comprising a toll-like receptor 7 agonist; and a vaccine preparation,

wherein the toll-like receptor 7 agonist is provided in an amount sufficient to produce an effective immune response when the individual undergoing renal replacement therapy is non-responsive to immunization with the vaccine preparation without the topical pharmaceutical preparation.

14. The kit of claim 13, further comprising an occlusive dressing.

15. The kit of claim 13 or 14, comprising directions for application of the topical pharmaceutical preparation prior to a vaccination site prior to vaccination with the vaccine preparation.

16. The kit of one of claims 13 to 15, comprising directions for maintenance of the topical pharmaceutical preparation at the vaccination site for at least one hour following vaccination.

17. The kit of one of claims 13 to 16, wherein the vaccine preparation comprises a hepatitis B vaccine.

18. The kit of one of claims 13 to 17, wherein the toll-like receptor agonist is selected from the group consisting of imiquimod, resiquimod, gardiquimod, isotoribine, loxoribine, bropirimine, 852A, GS-9620, SZU-101, S-27609, guanine nucleoside analogs, imidoazoquinoline-based compounds, and a stabilized immunomodulatory RNA.