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48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)/46th Infectious Disease Society of America Annual Meeting (IDSA)

Washington, DC / October 25-28, 2008

After primary infection and resolution, the varicella-zoster virus (VZV) remains latent in the sensory ganglia of cranial nerves and the spinal dorsal root ganglia. Reactivation of VZV and virus replication can occur after many decades of latency, causing herpes zoster (HZ) and debilitating pain in the form of post-herpetic neuralgia (PHN).

A strategy to vaccinate adults aged <u>></u>60 years with a live, attenuated HZ vaccine in the double-blind, placebo-controlled SPS (Shingles Prevention Study) was successful in reducing the burden of illness due to HZ, the incidence of HZ and the incidence of PHN through four years of follow-up (Oxman et al. N Engl J Med 2005;352(22):2271-84). The frequency, severity and duration of the infection were reduced by >60% in vaccine recipients in this study of 38,546 subjects. Efficacy of the vaccine was demonstrated regardless of age.

Based on these results, the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention recommended HZ vaccine for universal vaccine of immunocompetent persons aged <u>></u>60 years (Harpaz et al. MMWR Recomm Rep 2008;57(RR-5):1-30).

Vaccine Efficacy Persists to Seven Years

A substudy of the SPS shows that the efficacy of the vaccine persists to seven years’ post-vaccination, reported Dr. Kenneth Schmader, Duke University, Durham VA Medical Center, North Carolina. In the extended study, 14,270 of the original cohort of over 38,000 consented to follow-up from 3.5 years to seven years’ post-vaccination. “The vaccine maintained efficacy even out to year 7 and it also maintained efficacy against pain measures, specifically, the burden-of-illness score that measures pain severity by duration, and the incidence of PHN,” he told delegates.

When analyzed yearly, vaccine efficacy persisted on all three outcomes measures—incidence of HZ, incidence of PHN and HZ-related burden of illness:

• The reduction in the incidence of HZ was 44.6% in the vaccine group compared with placebo in year 4 post-vaccination and remained as high as 54.8% in year 7.

• The rate of PHN in vaccine recipients was reduced by 60.7% vs. placebo in year 4, by 73.8% in year 5, by 32.0% in year 6 and by 58.5% in year 7. Dr. Schmader noted that because of the few number of cases of PHN after year 2, the advantage of the vaccine on this measure lost statistical significance (wide confidence intervals) after this time.

• Burden of illness was reduced by 66.9% in year 4 in patients randomized to the vaccine, by 74.9% in year 5, by 23.6% in year 6 and by 80.1% in year 7.

Cumulative data from years 3.5 to 7 showed that patients randomized to the vaccine had reductions in the rates of HZ, PHN and HZ-related burden of illness of 39.6%, 60.1% and 50.1%, respectively, compared with placebo (not significant for PHN because of the few number of cases). For the entire study period (years 0 to 7), vaccine efficacy on these outcomes measures was 48.7%, 64.9% and 58.6%, respectively (all significant). The duration of vaccine efficacy is as yet unknown and will require further follow-up, noted Dr. Schmader. “It is going to take a little longer to decide whether or not the patients need a booster.” The vaccine efficacy will continue to be assessed for years 7 to 10.

Safety and Immunogenicity

In adults <u>></u>50 years with a history of HZ, administration of a single dose of a live attenuated HZ vaccine was well tolerated and resulted in higher VZV antibody titres compared with a similarly aged group that received a placebo vaccine, reported Dr. Richard Mills, Palmetto Medical Research, Mount Pleasant, South Carolina. “Data in persons with a known history of HZ will support the ACIP recommendation for universal vaccination in those 60 or older, and will act as a surrogate to help address questions regarding administration of the vaccine to persons whose history of HZ is not clear,” he told delegates.

One hundred subjects with a history of HZ five or more years previously were included in the analysis. The groups were randomized to receive the live attenuated vaccine or placebo and then crossed over to the opposite group at week 4. The groups were stratified according to the number of years since their HZ episode (five to nine years, <u>></u>10 years). “As far as serious side effects, there weren’t any,” remarked Dr. Mills. “There were statistically significant side effects with respect to injection-site reactions that were attributed to the vaccine, such as warmth, redness and erythema.”

Within 28 days following the vaccination, 45.9% receiving the vaccine had injection-site reactions compared with 4% of placebo. A similar proportion in each group reported systemic clinical adverse events (15% of the vaccine group vs. 14% of the placebo group). “The antibody titres had a bump in both groups based on the time since their HZ episode; there wasn’t a statistically significant difference between the group that had shingles five to nine years ago and the ones that had it 10 years ago or longer,” he added.

The geometric mean fold-rise (GMFR) from pre-vaccination to week 4 was 2.1 after administration of the zoster vaccine and 1.0 after placebo. The GMFR responses were higher in subjects aged 50 to 59 years than in those aged <u>></u>60.

“The main thing this study was answering was [whether] adults older than 50 who had a prior episode of shingles up to nine years or 10 or more years ago could safely tolerate the vaccine without any side effects in the short term. They did that very well, and we found favourable antibody responses,” stated Dr. Mills. “It is more evidence to support vaccinating patients if they say they have a history of shingles more than five years ago. We did not have an arm that had shingles one to five years previously, and it would have been interesting to see the results in this group.”

Immune Responses Correlate with Severity

According to Dr. Adriana Weinberg, Medical Director, Clinical Virology Laboratory, University of Colorado Hospital, Denver, VZV-specific immune responses were similar after HZ or HZ vaccine administration in patients enrolled into an immunology substudy of the SPS. The immunology substudy was conducted in 1395 subjects in whom blood samples were obtained prior to vaccination, at six weeks after vaccination, and were tested at one, two and three years after vaccination for VZV-specific cell-mediated immunity (VZV-CMI) and for VZV antibody by glycoprotein ELISA.

Immune responses to HZ were compared between those of 682 vaccine recipients and 680 placebo recipients who did not develop HZ; an analysis of HZ severity and immune responses was limited to placebo recipients who developed HZ.

HZ increased anti-VZV antibodies and numbers of effector and memory cells from fourfold to 15-fold. VZV-specific immune responses after HZ onset followed similar trends in the vaccine and placebo groups. The magnitude of the VZV-effector CMI response was higher at six weeks after HZ compared to the response after vaccination, but were similar at one year and thereafter.

A higher VZV-CMI in the first week of HZ was associated with a reduced severity of HZ, whereas higher levels of anti-VZV antibodies were associated with more severe HZ and an increased risk of PHN. The HZ vaccine and HZ itself induced similar levels of VZV T-cell memory.