AT ECCMID 2017
VIENNA (FRONTLINE MEDICAL NEWS) – Topical imiquimod appeared to enhance the immunogenicity of an intradermal hepatitis B vaccine in patients on renal replacement therapy.
Patients on hemodialysis or peritoneal dialysis who got the combination developed significantly higher seroprotection and antibody levels than those who got either the typical intramuscular vaccination or an intradermal vaccination on unprepared skin, Ivan Fan-Ngai Hung, MD , said at the European Conference on Clinical Microbiology and Infectious Diseases. By 1 year, the protection and titers did begin to fall, but they still remained significantly higher than in the two comparator groups, said Dr. Hung, a clinical professor at the University of Hong Kong.
“Hepatitis B is a very important viral infection in patients on renal replacement therapy, and their response to the conventional intramuscular vaccines has been suboptimal,” he said in an interview. “We find that this strategy of vaccination is safe and highly effective and overcomes that hyporesponsiveness. We should also consider this in immunocompromised patients, [in] those getting immunosuppressants, and in transplant patients.”
Dr. Hung and his colleagues have been investigating imiquimod’s immunogenicity-boosting potential for several years. Their initial murine work with an H1N1 influenza virus appeared in 2014 (Clin Vaccine Immunol. 2014 Apr;21[4]: 570-9). The investigators intraperitoneally immunized mice with a monovalent A(H1N1) vaccine combined with imiquimod (VIC) then intranasally inoculated them with a lethal dose of the virus. When compared with mice who received only vaccine, only imiquimod, or only placebo, the VIC group showed significantly greater and significantly longer survival. Virus-specific serum immunoglobulin M, IgG, and neutralizing antibodies were all significantly higher.
The investigators theorized that imiquimod, a Toll-like receptor 7 agonist, plays several key roles in boosting immune response, including inducing the differentiation and migration of dendritic cells, enhancing B cell differentiation, and increasing long-term B cell memory.
Within the past 2 years, the group has advanced to human influenza trials in healthy young adults and elders with comorbidities.
Both studies employed a 5% imiquimod cream delivering 250 mg of the drug. It was applied at the injection site 5 minutes before vaccination. In the elder study, 90% of the 91 subjects who got the combination achieved seroconversion, compared with 13% of those who got an intramuscular injection and 39% of those who got an intradermal injection plus placebo cream. The geometric mean titers went up faster and stayed elevated longer. The better immunogenicity was associated with fewer hospitalizations for influenza or pneumonia (Clin Infect Dis. 2014;59[9]:1246-55).
The immunogenicity findings were similar in the study of 160 healthy young people. This study had a surprising twist too, Dr. Hung said in his talk. Not only did the combination significantly improve immunogenicity against the vaccine influenza strains, it increased immunogenicity against the nonvaccine strains, especially the antigenically drifted H3N2 strain of 2015, which was not included in the 2013-2014 recommended vaccine (Lancet Inf Dis. 2016 Feb;16(2):209-18 ).
The study Dr. Hung presented in Vienna was an interim analysis of the first to apply this technique to a hepatitis B vaccine. It enrolled 69 patients (51 on peritoneal dialysis and 18 on hemodialysis). They were a mean 65 years old. All received 10 mcg of the Sci-B-Vac at baseline, 1 month, and 6 months. Vaccine was delivered in a trineedle unit designed for shallow intradermal penetration (MicronJet600; NanoPass Technologies ) Group IQ received topical imiquimod along with the intradermal vaccine. Group ID received a placebo cream and the intradermal vaccine. Group IM received a placebo cream and an intramuscular vaccination.
Anti–hepatitis B titers were measured at baseline and at 1, 3, 6, and 12 months. The primary outcome was seroprotection at 1 month. The secondary outcomes were seroprotection at 3, 6, and 12 months; anti–hepatitis B antibody titer; and safety.
By 1 month, seroprotection was already significantly higher in the IQ group than in the ID and IM groups (60% vs. 50% and 38%, respectively).
By 3 months, the seroprotection rate in group IQ had risen to 85%. It remained elevated there at 6 months then tailed off to about 70% by 12 months. The ID and IM groups followed this same rising and falling curve but remained significantly lower at all time points. At 12 months, seroprotection was similar in both these groups – about 40%.
The anti–hepatitis B antibody titers told a similar story. Titers in the IQ group rose more rapidly and sharply, to 544 mIU/mL at 6 months and 566 mIU/mL at 12 months. The ID group also experienced a strong response, rising to 489 mIU/mL at 6 months. However, by 12 months, titer levels had dropped to 170 mIU/mL.
Titers in the IM group barely moved at all during the entire follow-up period, never rising above 21 mIU/mL.
There were no differences in systemic reactions among the three groups, but those who got the intradermal vaccines reported slightly more swelling and induration at the injection site.
“Since this is an interim analysis, we cannot determine long-term protection or antibody titers,” Dr. Hung cautioned. “However, we are starting a similar study in elderly patients and also one for those who are on low-dose immunosuppressants. We believe this regimen will also work for them.”
Dr. Hung has been on advisory boards for Pfizer and Gilead Sciences.
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