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Safety and immunogenicity of a live attenuated varicella vaccine in VZV-seropositive HIV-infected adults

Safety and immunogenicity of a live attenuated varicella vaccine in VZV-seropositive HIV-infected... Rese ReseAR ARc cH H p p A Ape peR R Human Vaccines 6:4, 318-321; April 2010; © 2010 Landes Bioscience safety and immunogenicity of a live attenuated varicella vaccine in VZV-seropositive HIV-infected adults 1, 1 2 Adriana Weinberg, * Myron J. Levin and Rob Roy MacGregor 1 2 University of Colorado Denver School of Medicine; Aurora, CO USA; Division of Infectious Diseases; Department of Medicine; University of Pennsylvania School of Medicine; Philadelphia, PA USA Key words: varicella zoster virus vaccine, HIV, HA ART, cell-mediated immunity, herpes zoster Background: Herpes-zoster is common in HIV-infected patients in spite of antiretroviral therapy. We evaluated the safety and immunogenicity of a live attenuated varicella-zoster virus (VZV) vaccine as a candidate for protecting HIV- infected adults against herpes-zoster. Results: s ixty-seven HIV-infected and 15 uninfected subjects, 18 to 65 years old, were enrolled. Adverse events were nd minor and similar in HIV-infected vaccine and placebo recipients. At 12 weeks after the 2 dose of vaccine the magnitude of each measure of VZV CMI increased significantly in healthy controls. In HIV-infected vaccinees, VZV RCF significantly increased and ELISPOT showed a positive trend. None of VZV CMI measures significantly increased in HIV-infected pla - cebo recipients. The immunogenicity of the vaccine did not correlate with the nadir c D4 cells of HIV-infected subjects. Methods: HIV-infected adults with c D4 ≥400 cells/μL and plasma HIV RNA <1,000/mL were randomly assigned to receive two doses of VZV vaccine or placebo 12 weeks apart. HIV-uninfected age-matched controls also received two doses of vaccine. VZV-specific cell-mediated immunity (CMI) was measured at baseline and after vaccination using responder cell frequency (RCF), lymphocyte proliferation, and IFNγ eLIsp OT. Conclusions: Two doses of varicella vaccine were safe in HIV-infected subjects with c D4 ≥400 cells/μL, but were only modestly immunogenic. Introduction Boosting VZV-specic fi cell-mediated immunity (CMI) with a live-attenuated VZV vaccine has the potential to prevent or attenu- 14-19 Herpes zoster (HZ) was a common complication of HIV infection ate HZ in immune compromised patients. A study in immune 1-3 before the advent of highly active antiretroviral therapy (H A A RT) competent older adults demonstrated that vaccination with high- and was often complicated by prolonged duration of HZ rash and potency live attenuated VZV vaccine reduces the frequency of HZ an increased incidence of post-herpetic neuralgia, encephalitis and by half and its morbidity by two-thirds. We report the safety and 4-6 TM retinal necrosis. The introduction of HA ART markedly reduced immunogenicity of a live-attenuated varicella vaccine (Varivax ) the incidence and morbidity of HZ in HIV-infected subjects, but in HIV-infected adults. even with HA ART, HZ remains more common in HIV-infected 8-10 individuals compared with the general population. These data Results suggest that an alternative intervention will be necessary to reduce the threat of HZ in the HIV-infected host. Demographic characteristics. Eighty-two subjects were enrolled: There are several antivirals effective against varicella-zoster 36 in HIV-infected Cohort 1 (19 vaccine and 17 placebo recipi- virus (VZV). However, successful treatment of HZ requires early ents); 31 in HIV-infected Cohort 2 (14 vaccine and 17 placebo 11,12 recognition and initiation of antivirals. Even under ideal cir- recipients); and 15 healthy adults (Table 1). All subjects were VZV- cumstances, antivirals do not prevent the development of post-her- seropositive at entry. One subject from each cohort withdrew for petic neuralgia, the most important complication of HZ. A more personal reasons. effective approach would be prevention of HZ. This was achieved Safety. Most adverse events (AEs) were grade 1 or 2. They in high-risk transplant recipients with antiviral suppressive therapy were equally common in both HIV-infected Cohorts and did not during the first year after transplantation. However, this approach differ statistically between vaccine and placebo recipients (Table is not practical for HIV-infected individuals in whom the timing 2). Reactions to the second injection were less common than of HZ is not predictable, and in whom the increased incidence of after the first injection both in vaccine and placebo recipients. HZ is likely to persist in spite of many years of HA ART. One subject in the vaccine group had an asymptomatic, transient *Correspondence to: Adriana Weinberg; Email: Adriana.Weinberg@ucdenver.edu Submitted: 07/14/09; Revised: 11/04/09; Accepted: 11/15/09 Previously published online: www.landesbioscience.com/journals/vaccines/ar ticle/10654 318 Human Vaccines Volume 6 Issue 4 ReseARcH p ApeR ReseARcH pApeR Table 1. Baseline demographic characteristics of study participants by cohort Healthy HIV-infected HIV-infected HIV-infected HIV-infected controls vaccine cohort 1 placebo cohort 1 vaccine cohort 2 placebo cohort 2 N = 15 N = 19 N = 17 N = 14 N = 17 Mean age (years) 45.7 43.8 46.3 43.6 46.4 Female 6 (40%) 7 (37%) 6 (35%) 5 (36%) 5 (31%) Black 3 (20%) 10 (53%) 10 (59%) 12 (86%) 11 (69%) White 12 (80%) 9 (47%) 6 (36%) 2 (14%) 3 (1%) Latino 0 0 1 (7%) 0 2 (13%) na 650 (478 –1,283) 742 (490 –1,550) 608 (419–1,063) 496 (397–1,324) Median c D4 cells/μL (range) Median HIV RNA copies/mL (range) na <50 (<50 –731) <50 (<50 –231) <50 (<50 – 480) <75 (<75–380) Table 2. c linical and laboratory adverse events after administration of varicella vaccine or placebo to HIV-infected subjects on HAART N (%) Vaccine N (%) Placebo Parameter Dose 1 (N = 33) Dose 2 (N = 31) Dose 1 (N = 33) Dose 2 (N = 33) Injections site tenderness 5 (15) 3 (10) 3 (9) 1 (3) Injection site inflammation 3 (9) 1 (3) 1 (3) 1 (3) s ystemic rash (non-zosteriform) 1 (3) 1 (3) 2 (6) 1 (3) pruritis 1 (3) 0 2 (6) 1 (3) Fever 0 0 0 1 Adenopathy 0 0 1 (3) 0 Nose bleed 0 1 (3) 0 0 Headache, dizziness, irritability 2 (6) 0 2 (6) 1 (3) Influenza-like illness 3 (9) 0 2 (6) 1 (3) Nausea, vomiting, diarrhea 4 (12) 0 3 (9) 1 (3) c hest pain 0 0 1 (3) 0 Liver enzyme elevation 0 2 (6) 0 1 (3) Table 3. c D4 cells and plasma HIV RNA determinations in HIV-infected subjects on HAART who received varicella vaccine or placebo Weeks after vaccination Median CD4 cells/μl (range) Median plasma HIV RNA copies/ml (range) Vaccine Placebo Vaccine Placebo Before 629 (419–1283) 619 (397–1550) <50 (<50 –731) <50 (<50 –380) 6 post-dose 1 666 (363–1122) 669 (358 –1518) <50 (<50 –1102) <50 (<50 –2057) 6 post-dose 2 621 (272–1627) 789 (346 –1431) <50 (<50 – 83523) <50 (<50 –308) Grade 4 increase in ALT at week 18, which was time-associated Immunogenicity. All values of VZV-specific CMI as mea - nd with an alcohol binge and decreased to <2X the upper limit of sured by RCF, LPA and ELISPOT at 12 weeks after the 2 normal one week later. Two other subjects (one vaccine and one immunization of uninfected control vaccinees were signifi - placebo recipient) experienced transient asymptomatic, grade cantly increased [p of 0.003, 0.002 and 0.02 for RCF, LPA and 1–2 ALT elevations at week 18. AEs of HIV-uninfected controls ELISPOT, respectively (Table 4)]. In HIV-infected subjects nd were unremarkable. at 12 weeks after the 2 dose of vaccine there was a signifi - CD4 lymphocyte counts remained stable in both vaccine and cant increase in RCF values (p = 0.02) and a trend towards an placebo recipients in both of the HIV-infected Cohorts (Table increase in ELISPOT results (p = 0.08), but not in LPA (Table 3). One vaccine, whose baseline and 6 week VLs had been 413 4). The differences between baseline and post-vaccination did and 387 copies/ml, respectively, had a VL at week 18 of 83,500 not reach statistical significance in the individual cohorts of copies/mL that was associated with poor ART compliance. One HIV-infected subjects, probably because of the limited number placebo recipient whose baseline VL was <50 copies/mL had a of subjects in each cohort. There were no statistically signifi - VL rise to 1,421 copies/mL at week 6. cant differences between the two HIV-infected cohorts by age www.landesbioscience.com Human Vaccines 319 nd Table 4. Quantitative c MI responses at 12 weeks after the 2 dose of VZV vaccine Mean (SE) RCF Mean (SE) LPA Mean (SE) ELISPOT Subjects Entry PI p Entry PI p Entry PI p c ohort 1 Nadir c D4 >400 placebo 2.15 (0.5) 2.53 (0.5) 0.6 11.4 (6.1) 26.8 (14.3) 0.1 2.76 (0.7) 3.93 (0.8) 0.09 Active 0.89 (0.3) 1.78 (0.5) 0.1 16.6 (5.1) 21.1 (7.1) 0.9 1.74 (0.5) 2.65 (0.5) 0.07 c ohort 2 Nadir c D4 <200 placebo 2.85 (0.5) 2.40 (0.5) 0.4 35.7 (14.7) 44.6 (22.1) 0.6 1.15 (0.4) 1.29 (0.4) 0.71 Active 4.02 (1.2) 9.49 (4.7) 0.06 46.0 (22.5) 122.7 (35.1) 0.2 3.36 (0.8) 4.27 (0.9) 0.48 HIV All placebo 2.50 (0.6) 2.46 (0.8) 0.8 23.2 (11.1) 35.4 (18.4) 0.5 2.01 (0.5) 2.65 (0.6) 0.20 Active 2.26 (0.6) 5.26 (2.4) 0.02 28.9 (12.6) 67.0 (21.5) 0.4 2.49 (0.7) 3.43 (0.7) 0.08 Healthy controls Active 1.52 (0.4) 9.35 (2.4) 0.003 8.5 (3.8) 56.1 (17.3) 0.002 3.90 (1.1) 11.72 (2 .8) 0.02 nd Abbreviations used in this table: se , standard error; pI, post-immunization (12 weeks after the 2 dose of vaccine). or ethnicity of the subjects. In placebo recipients, none of the Overall, the immunogenicity of the varicella vaccine used in measures of CMI showed significant increases ( Table 4). this study was disappointingly low in HIV-infected subjects. A formulation of live attenuated VZV vaccine with an average of 14 Discussion times more virus than was present in the vaccine used in this study, specic fi ally developed for prevention of HZ and its complications, TM The live-attenuated VZV vaccine (Varivax ) used in this study had was demonstrated to be safe and effective in elderly individuals a relatively low potency (1,350 pfu/dose at expiry). This VZV vac- that had a signic fi ant age-related, rather than HIV-related, decline cine was safe and well tolerated by VZV-seropositive HIV-infected in VZV-specic fi CMI. A study of safety and immunogenicity of adults with CD4 >400 cells/μL and VL <1,000 RNA copies/mL, this vaccine in HIV-infected adults is in progress. regardless of their CD4 nadir. Local and systemic adverse events considered probably or possibly related to the vaccine were mild Methods (grade 1 or 2) and were equally frequent among vaccine and pla- cebo recipients, underscoring the safety of the vaccine. There were Study population and design. Two HIV-infected cohorts were no signic fi ant increases in HIV plasma RNA levels or decreases in recruited: Subjects in Cohort 1 had CD4 counts that never declined CD4 counts following administration of VZV vaccine. These data below 400 cells/μL and had been on stable treatment management are in agreement with other studies that showed an excellent safety (either therapy or none) for >3 months. Subjects in Cohort 2 had profile of this VZV vaccine in both VZV-seronegative and VZV- CD4 counts that had once been <200 cells/μL, but were >400 8,15,21 seropositive HIV-infected children. cells/μL at study entry in response to ≥12 months of HA ART. In The CMI responses to two doses of the VZV vaccine in addition, a cohort of healthy age-matched HIV-negative controls HIV-infected subjects were lower and less consistent than that was recruited. The enrollment target was ≥15 subjects per group, of HIV-uninfected age-matched controls, illustrating the per- which gave this study 87% power to detect a 30% rate of side sistent immunologic defect of HIV-infected individuals with or effects and 78% power to detect a 40% rate of immunologic boost. without HA ART. Age and ethnicity, which may play a role in The inclusion of the placebo recipients gave the study ≥80% power 22,23 responses to vaccines, did not affect the responses of HIV- to detect a 50% RCF-measured response in vaccinees. infected subjects to the vaccine. Neither did the nadir CD4 All subjects were ≥18 years of age, had anti-VZV antibodies count, which is an important observation, because previous detected by a commercial ELISA (Diamedix) and no history of studies generated conflicting results on the effect of the nadir HZ. HIV-infected subjects were required to have stable HIV RNA CD4 numbers on the immunogenicity of vaccines in HIV- <1,000 copies/mL for >3 months for Cohort 1 or >12 months for 15,24-27 infected individuals. Cohort 2. Exclusion criteria were fever within 72 hours of study Compared with placebo recipients, the two doses of VZV vac- entry, liver or renal disease, neutropenia, hemoglobin <10 gm/ cine significantly increased VZV-specific RCF values and tended dL, exposure to chickenpox or HZ, or immunosuppressive ther- to increase the ELISPOT values of HIV-infected vaccinees. apy within 4 weeks of study entry. Immune globulins or blood However, there was no appreciable change in LPA. Although, products were not permitted within 5 months of study entry, live RCF and LPA are both proliferation-based assays, the biologic or inactivated vaccines were not permitted within 4 or 2 weeks, variability of RCF is much lower compared to LPA due to the respectively, of study entry. inclusion of a limiting dilution step. Hence, differences are more Subjects from each HIV-infected cohort were randomized to TM readily appreciated in RCF. receive 2 doses of Varivax (Oka; Merck) or placebo in a blocked 320 Human Vaccines Volume 6 Issue 4 stratie fi d design matched on age and sex in a blinded fashion. wells. The RCF, defined as the cell concentration at which 37% of Injections were administered at weeks 0 and 12. The HIV-negative VZV antigen-stimulated wells are nonresponders, is expressed in controls received active vaccine at the same interval. responders/10 PBMC. 14,30 All adverse events occurring within 42 days of vaccination were LPA. LPA was performed as previously described. Results recorded and graded according to the Division of AIDS Toxicity are expressed as stimulation indices (SI). Table for Grading Severity of Adverse Experiences (http://www3. ELISPOT. ELISPOT was performed as previously described. niaid.nih.gov/research/resources/DAIDSClinRsrch/Safety.htm). The results are expressed in spot-forming cells (SFC)/10 PBMC. CD4 cell counts and plasma HIV RNA (VL) were measured at 6 Statistical analysis. Descriptive analysis was utilized for the weeks after each dose of vaccine. VZV-specic fi CMI was measured safety evaluation. The proportion of subjects in the treated groups by responder cell frequency (RCF), lymphocyte proliferation assay experiencing an adverse event was determined. Due to the small (LPA), and ELISPOT at weeks 0, 12 and 24 weeks. sample size, Fisher’s exact test and Wilcoxon rank-sum test were 28,29 RCF. RCF was performed as previously described. Replicate used for comparisons among the vaccine and placebo groups. A p cultures were stimulated with VZV antigen and mock-infected value ≤0.05 was used to define statistical significance. control for 8 days at 37°C and 5% CO , pulsed with H-thymidine, Acknowledgements harvested and counted with a beta counter (Perkin Elmer). Responder wells were defined as VZV-stimulated wells with We thank Dr. Kathleen Brady and Ms. Renee Jesser for their con- counts per minute (cpm) >mean +3 SD cpm in control-stimulated tributions to this study. 24. Valdez H, Connick E, Smith KY, Lederman MM, 13. Erard V, Guthrie KA, Varley C, Heugel J, Wald References A, Flowers ME, et al. One-year acyclovir prophy- Bosch RJ, Kim RS, et al. Limited immune restora- 1. Buchbinder SP, Katz MH, Hessol NA, Liu JY, O’Malley tion after 3 years’ suppression of HIV-1 replication in laxis for preventing varicella-zoster virus disease after PM, Underwood R, et al. Herpes zoster and human hematopoietic cell transplantation: no evidence of patients with moderately advanced disease. Aids 2002; immunodeficiency virus infection. J Infect Dis 1992; 16:1859-66. rebound varicella-zoster virus disease after drug discon- 166:1153-6. tinuation. Blood 2007; 110:3071-7. 25. Abzug MJ, Pelton SI, Song LY, Fenton T, Levin MJ, 2. Donahue JG, Choo PW, Manson JE, Platt R. The Nachman SA, et al. Immunogenicity, safety and predic- 14. Levin MJ, Gershon AA, Weinberg A, Blanchard S, incidence of herpes zoster. Arch Intern Med 1995; Nowak B, Palumbo P, et al. Immunization of HIV- tors of response after a pneumococcal conjugate and 155:1605-9. pneumococcal polysaccharide vaccine series in human infected children with varicella vaccine. J Pediatr 2001; 3. Glesby MJ, Moore RD, Chaisson RE. Herpes zoster 139:305-10. immunodeficiency virus-infected children receiving in patients with advanced human immunodeficiency highly active antiretroviral therapy. Pediatr Infect Dis J 15. Levin MJ, Gershon AA, Weinberg A, Song LY, Fentin virus infection treated with zidovudine. Zidovudine 2006; 25:920-9. T, Nowak B. Administration of live varicella vaccine Epidemiology Study Group. J Infect Dis 1993; 26. Levin MJ, Song LY, Fenton T, Nachman S, Patterson to HIV-infected children with current or past signifi- 168:1264-8. cant depression of CD4(+) T cells. J Infect Dis 2006; J, Walker R, et al. Shedding of live vaccine virus, 4. Glesby MJ, Moore RD, Chaisson RE. Clinical spectrum 194:247-55. comparative safety and influenza-specific antibody of herpes zoster in adults infected with human immu- responses after administration of live attenuated and 16. Gershon AA, Steinberg SP, Gelb L, Galasso G, nodeficiency virus. Clin Infect Dis 1995; 21:370-5. inactivated trivalent influenza vaccines to HIV-infected Borkowsky W, LaRussa P, et al. Live attenuated vari- 5. Hoppenjans WB, Bibler MR, Orme RL, Solinger children. Vaccine 2008; 26:4210-7. cella vaccine. Efficacy for children with leukemia in AM. Prolonged cutaneous herpes zoster in acquired remission. Jama 1984; 252:355-62. 27. Weinberg A, Gona P, Nachman SA, Defechereux P, immunodeficiency syndrome. Arch Dermatol 1990; Yogev R, Hughes W, et al. Antibody responses to 17. Hata A, Asanuma H, Rinki M, Sharp M, Wong RM, 126:1048-50. hepatitis A virus vaccine in HIV-infected children with Blume K, et al. Use of an inactivated varicella vaccine 6. Jacobson MA, Berger TG, Fikrig S, Becherer P, Moohr evidence of immunologic reconstitution while receiving in recipients of hematopoietic-cell transplants. N Engl highly active antiretroviral therapy. J Infect Dis 2006; JW, Stanat SC, et al. Acyclovir-resistant varicella zoster J Med 2002; 347:26-34. virus infection after chronic oral acyclovir therapy in 193:302-11. 18. LaRussa P, Steinberg S, Gershon AA. Varicella vaccine patients with the acquired immunodeficiency syn- 28. Weinberg A, Wiznia AA, LaFleur BJ, Shah S, Levin MJ. for immunocompromised children: results of collabora- drome (AIDS). Ann Intern Med 1990; 112:187-91. Varicella-Zoster virus-specific cell-mediated immunity tive studies in the United States and Canada. J Infect in HIV-infected children receiving highly active anti- 7. Palella FJ Jr, Delaney KM, Moorman AC, Loveless Dis 1996; 174:320-3. MO, Fuhrer J, Satten GA, et al. Declining morbidity retroviral therapy. J Infect Dis 2004; 190:267-70. 19. Hardy I, Gershon AA, Steinberg SP, LaRussa P. The and mortality among patients with advanced human 29. Levin MJ, Oxman MN, Zhang JH, Johnson GR, incidence of zoster after immunization with live attenu- immunodeficiency virus infection. HIV Outpatient Stanley H, Hayward AR, et al. VZV-specific immune ated varicella vaccine. A study in children with leuke- Study Investigators. N Engl J Med 1998; 338:853-60. responses in elderly recipients of a herpes zoster vaccine. mia. Varicella Vaccine Collaborative Study Group. N 8. Levin MJ, Anderson JP, Seage GR, 3rd, Williams PL. J Infect Dis 2008; 197:825-35. Engl J Med 1991; 325:1545-50. Short-term and long-term effects of highly active anti- 30. Weinberg A, Betensky RA, Zhang L, Ray G. Effect of 20. Oxman MN, Levin MJ, Johnson GR, Schmader KE, retroviral therapy on the incidence of herpes zoster in shipment, storage, anticoagulant and cell separation Straus SE, Gelb LD, et al. A vaccine to prevent herpes HIV-infected children. J Acquir Immune Defic Syndr on lymphocyte proliferation assays for human immu- zoster and postherpetic neuralgia in older adults. N 2009; 50:182-91. nodeficiency virus-infected patients. Clin Diagn Lab Engl J Med 2005; 352:2271-84. Immunol 1998; 5:804-7. 9. Vanhems P, Voisin L, Gayet-Ageron A, Trepo C, Cotte 21. Gershon AA, Levin MJ, Weinberg A, Song LY, Larussa L, Peyramond D, et al. The incidence of herpes zoster 31. Smith JG, Levin M, Vessey R, Chan IS, Hayward AR, PS, Steinberg SP, et al. A Phase I-Ii Study of Live is less likely than other opportunistic infections to be Liu X, et al. Measurement of cell-mediated immunity Attenuated Varicella-Zoster Virus Vaccine to Boost reduced by highly active antiretroviral therapy. J Acquir with a Varicella-Zoster Virus-specific interferon-gamma Immunity in Human Immunodeficiency Virus-Infected Immune Defic Syndr 2005; 38:111-3. ELISPOT assay: responses in an elderly population Children with Previous Varicella. Pediatr Infect Dis J 10. Martinez E, Gatell J, Moran Y, Aznar E, Buira E, receiving a booster immunization. Journal of medical 2009; 28:653-5. virology 2003; 70:38-41. Guelar A, et al. High incidence of herpes zoster in 22. Levin MJ, Oxman MN, Zhang JH, Johnson GR, patients with AIDS soon after therapy with protease Stanley H, Hayward AR, et al. Varicella-zoster virus- inhibitors. Clin Infect Dis 1998; 27:1510-3. specific immune responses in elderly recipients of a 11. Wood MJ, Kay R, Dworkin RH, Soong SJ, Whitley herpes zoster vaccine. J Infect Dis 2008; 197:825-35. RJ. Oral acyclovir therapy accelerates pain resolution in 23. McMahon BJ, Williams J, Bulkow L, Snowball M, patients with herpes zoster: a meta-analysis of placebo- Wainwright R, Kennedy M, et al. Immunogenicity controlled trials. Clin Infect Dis 1996; 22:341-7. of an inactivated hepatitis A vaccine in Alaska Native 12. Beutner KR, Friedman DJ, Forszpaniak C, Andersen children and Native and non-Native adults. J Infect Dis PL, Wood MJ. Valaciclovir compared with acyclovir 1995; 171:676-9. for improved therapy for herpes zoster in immunocom- petent adults. Antimicrob Agents Chemother 1995; 39:1546-53. www.landesbioscience.com Human Vaccines 321 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Human Vaccines Taylor & Francis

Safety and immunogenicity of a live attenuated varicella vaccine in VZV-seropositive HIV-infected adults

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Taylor & Francis
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Copyright © 2010 Landes Bioscience
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1554-8600
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10.4161/hv.6.4.10654
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Abstract

Rese ReseAR ARc cH H p p A Ape peR R Human Vaccines 6:4, 318-321; April 2010; © 2010 Landes Bioscience safety and immunogenicity of a live attenuated varicella vaccine in VZV-seropositive HIV-infected adults 1, 1 2 Adriana Weinberg, * Myron J. Levin and Rob Roy MacGregor 1 2 University of Colorado Denver School of Medicine; Aurora, CO USA; Division of Infectious Diseases; Department of Medicine; University of Pennsylvania School of Medicine; Philadelphia, PA USA Key words: varicella zoster virus vaccine, HIV, HA ART, cell-mediated immunity, herpes zoster Background: Herpes-zoster is common in HIV-infected patients in spite of antiretroviral therapy. We evaluated the safety and immunogenicity of a live attenuated varicella-zoster virus (VZV) vaccine as a candidate for protecting HIV- infected adults against herpes-zoster. Results: s ixty-seven HIV-infected and 15 uninfected subjects, 18 to 65 years old, were enrolled. Adverse events were nd minor and similar in HIV-infected vaccine and placebo recipients. At 12 weeks after the 2 dose of vaccine the magnitude of each measure of VZV CMI increased significantly in healthy controls. In HIV-infected vaccinees, VZV RCF significantly increased and ELISPOT showed a positive trend. None of VZV CMI measures significantly increased in HIV-infected pla - cebo recipients. The immunogenicity of the vaccine did not correlate with the nadir c D4 cells of HIV-infected subjects. Methods: HIV-infected adults with c D4 ≥400 cells/μL and plasma HIV RNA <1,000/mL were randomly assigned to receive two doses of VZV vaccine or placebo 12 weeks apart. HIV-uninfected age-matched controls also received two doses of vaccine. VZV-specific cell-mediated immunity (CMI) was measured at baseline and after vaccination using responder cell frequency (RCF), lymphocyte proliferation, and IFNγ eLIsp OT. Conclusions: Two doses of varicella vaccine were safe in HIV-infected subjects with c D4 ≥400 cells/μL, but were only modestly immunogenic. Introduction Boosting VZV-specic fi cell-mediated immunity (CMI) with a live-attenuated VZV vaccine has the potential to prevent or attenu- 14-19 Herpes zoster (HZ) was a common complication of HIV infection ate HZ in immune compromised patients. A study in immune 1-3 before the advent of highly active antiretroviral therapy (H A A RT) competent older adults demonstrated that vaccination with high- and was often complicated by prolonged duration of HZ rash and potency live attenuated VZV vaccine reduces the frequency of HZ an increased incidence of post-herpetic neuralgia, encephalitis and by half and its morbidity by two-thirds. We report the safety and 4-6 TM retinal necrosis. The introduction of HA ART markedly reduced immunogenicity of a live-attenuated varicella vaccine (Varivax ) the incidence and morbidity of HZ in HIV-infected subjects, but in HIV-infected adults. even with HA ART, HZ remains more common in HIV-infected 8-10 individuals compared with the general population. These data Results suggest that an alternative intervention will be necessary to reduce the threat of HZ in the HIV-infected host. Demographic characteristics. Eighty-two subjects were enrolled: There are several antivirals effective against varicella-zoster 36 in HIV-infected Cohort 1 (19 vaccine and 17 placebo recipi- virus (VZV). However, successful treatment of HZ requires early ents); 31 in HIV-infected Cohort 2 (14 vaccine and 17 placebo 11,12 recognition and initiation of antivirals. Even under ideal cir- recipients); and 15 healthy adults (Table 1). All subjects were VZV- cumstances, antivirals do not prevent the development of post-her- seropositive at entry. One subject from each cohort withdrew for petic neuralgia, the most important complication of HZ. A more personal reasons. effective approach would be prevention of HZ. This was achieved Safety. Most adverse events (AEs) were grade 1 or 2. They in high-risk transplant recipients with antiviral suppressive therapy were equally common in both HIV-infected Cohorts and did not during the first year after transplantation. However, this approach differ statistically between vaccine and placebo recipients (Table is not practical for HIV-infected individuals in whom the timing 2). Reactions to the second injection were less common than of HZ is not predictable, and in whom the increased incidence of after the first injection both in vaccine and placebo recipients. HZ is likely to persist in spite of many years of HA ART. One subject in the vaccine group had an asymptomatic, transient *Correspondence to: Adriana Weinberg; Email: Adriana.Weinberg@ucdenver.edu Submitted: 07/14/09; Revised: 11/04/09; Accepted: 11/15/09 Previously published online: www.landesbioscience.com/journals/vaccines/ar ticle/10654 318 Human Vaccines Volume 6 Issue 4 ReseARcH p ApeR ReseARcH pApeR Table 1. Baseline demographic characteristics of study participants by cohort Healthy HIV-infected HIV-infected HIV-infected HIV-infected controls vaccine cohort 1 placebo cohort 1 vaccine cohort 2 placebo cohort 2 N = 15 N = 19 N = 17 N = 14 N = 17 Mean age (years) 45.7 43.8 46.3 43.6 46.4 Female 6 (40%) 7 (37%) 6 (35%) 5 (36%) 5 (31%) Black 3 (20%) 10 (53%) 10 (59%) 12 (86%) 11 (69%) White 12 (80%) 9 (47%) 6 (36%) 2 (14%) 3 (1%) Latino 0 0 1 (7%) 0 2 (13%) na 650 (478 –1,283) 742 (490 –1,550) 608 (419–1,063) 496 (397–1,324) Median c D4 cells/μL (range) Median HIV RNA copies/mL (range) na <50 (<50 –731) <50 (<50 –231) <50 (<50 – 480) <75 (<75–380) Table 2. c linical and laboratory adverse events after administration of varicella vaccine or placebo to HIV-infected subjects on HAART N (%) Vaccine N (%) Placebo Parameter Dose 1 (N = 33) Dose 2 (N = 31) Dose 1 (N = 33) Dose 2 (N = 33) Injections site tenderness 5 (15) 3 (10) 3 (9) 1 (3) Injection site inflammation 3 (9) 1 (3) 1 (3) 1 (3) s ystemic rash (non-zosteriform) 1 (3) 1 (3) 2 (6) 1 (3) pruritis 1 (3) 0 2 (6) 1 (3) Fever 0 0 0 1 Adenopathy 0 0 1 (3) 0 Nose bleed 0 1 (3) 0 0 Headache, dizziness, irritability 2 (6) 0 2 (6) 1 (3) Influenza-like illness 3 (9) 0 2 (6) 1 (3) Nausea, vomiting, diarrhea 4 (12) 0 3 (9) 1 (3) c hest pain 0 0 1 (3) 0 Liver enzyme elevation 0 2 (6) 0 1 (3) Table 3. c D4 cells and plasma HIV RNA determinations in HIV-infected subjects on HAART who received varicella vaccine or placebo Weeks after vaccination Median CD4 cells/μl (range) Median plasma HIV RNA copies/ml (range) Vaccine Placebo Vaccine Placebo Before 629 (419–1283) 619 (397–1550) <50 (<50 –731) <50 (<50 –380) 6 post-dose 1 666 (363–1122) 669 (358 –1518) <50 (<50 –1102) <50 (<50 –2057) 6 post-dose 2 621 (272–1627) 789 (346 –1431) <50 (<50 – 83523) <50 (<50 –308) Grade 4 increase in ALT at week 18, which was time-associated Immunogenicity. All values of VZV-specific CMI as mea - nd with an alcohol binge and decreased to <2X the upper limit of sured by RCF, LPA and ELISPOT at 12 weeks after the 2 normal one week later. Two other subjects (one vaccine and one immunization of uninfected control vaccinees were signifi - placebo recipient) experienced transient asymptomatic, grade cantly increased [p of 0.003, 0.002 and 0.02 for RCF, LPA and 1–2 ALT elevations at week 18. AEs of HIV-uninfected controls ELISPOT, respectively (Table 4)]. In HIV-infected subjects nd were unremarkable. at 12 weeks after the 2 dose of vaccine there was a signifi - CD4 lymphocyte counts remained stable in both vaccine and cant increase in RCF values (p = 0.02) and a trend towards an placebo recipients in both of the HIV-infected Cohorts (Table increase in ELISPOT results (p = 0.08), but not in LPA (Table 3). One vaccine, whose baseline and 6 week VLs had been 413 4). The differences between baseline and post-vaccination did and 387 copies/ml, respectively, had a VL at week 18 of 83,500 not reach statistical significance in the individual cohorts of copies/mL that was associated with poor ART compliance. One HIV-infected subjects, probably because of the limited number placebo recipient whose baseline VL was <50 copies/mL had a of subjects in each cohort. There were no statistically signifi - VL rise to 1,421 copies/mL at week 6. cant differences between the two HIV-infected cohorts by age www.landesbioscience.com Human Vaccines 319 nd Table 4. Quantitative c MI responses at 12 weeks after the 2 dose of VZV vaccine Mean (SE) RCF Mean (SE) LPA Mean (SE) ELISPOT Subjects Entry PI p Entry PI p Entry PI p c ohort 1 Nadir c D4 >400 placebo 2.15 (0.5) 2.53 (0.5) 0.6 11.4 (6.1) 26.8 (14.3) 0.1 2.76 (0.7) 3.93 (0.8) 0.09 Active 0.89 (0.3) 1.78 (0.5) 0.1 16.6 (5.1) 21.1 (7.1) 0.9 1.74 (0.5) 2.65 (0.5) 0.07 c ohort 2 Nadir c D4 <200 placebo 2.85 (0.5) 2.40 (0.5) 0.4 35.7 (14.7) 44.6 (22.1) 0.6 1.15 (0.4) 1.29 (0.4) 0.71 Active 4.02 (1.2) 9.49 (4.7) 0.06 46.0 (22.5) 122.7 (35.1) 0.2 3.36 (0.8) 4.27 (0.9) 0.48 HIV All placebo 2.50 (0.6) 2.46 (0.8) 0.8 23.2 (11.1) 35.4 (18.4) 0.5 2.01 (0.5) 2.65 (0.6) 0.20 Active 2.26 (0.6) 5.26 (2.4) 0.02 28.9 (12.6) 67.0 (21.5) 0.4 2.49 (0.7) 3.43 (0.7) 0.08 Healthy controls Active 1.52 (0.4) 9.35 (2.4) 0.003 8.5 (3.8) 56.1 (17.3) 0.002 3.90 (1.1) 11.72 (2 .8) 0.02 nd Abbreviations used in this table: se , standard error; pI, post-immunization (12 weeks after the 2 dose of vaccine). or ethnicity of the subjects. In placebo recipients, none of the Overall, the immunogenicity of the varicella vaccine used in measures of CMI showed significant increases ( Table 4). this study was disappointingly low in HIV-infected subjects. A formulation of live attenuated VZV vaccine with an average of 14 Discussion times more virus than was present in the vaccine used in this study, specic fi ally developed for prevention of HZ and its complications, TM The live-attenuated VZV vaccine (Varivax ) used in this study had was demonstrated to be safe and effective in elderly individuals a relatively low potency (1,350 pfu/dose at expiry). This VZV vac- that had a signic fi ant age-related, rather than HIV-related, decline cine was safe and well tolerated by VZV-seropositive HIV-infected in VZV-specic fi CMI. A study of safety and immunogenicity of adults with CD4 >400 cells/μL and VL <1,000 RNA copies/mL, this vaccine in HIV-infected adults is in progress. regardless of their CD4 nadir. Local and systemic adverse events considered probably or possibly related to the vaccine were mild Methods (grade 1 or 2) and were equally frequent among vaccine and pla- cebo recipients, underscoring the safety of the vaccine. There were Study population and design. Two HIV-infected cohorts were no signic fi ant increases in HIV plasma RNA levels or decreases in recruited: Subjects in Cohort 1 had CD4 counts that never declined CD4 counts following administration of VZV vaccine. These data below 400 cells/μL and had been on stable treatment management are in agreement with other studies that showed an excellent safety (either therapy or none) for >3 months. Subjects in Cohort 2 had profile of this VZV vaccine in both VZV-seronegative and VZV- CD4 counts that had once been <200 cells/μL, but were >400 8,15,21 seropositive HIV-infected children. cells/μL at study entry in response to ≥12 months of HA ART. In The CMI responses to two doses of the VZV vaccine in addition, a cohort of healthy age-matched HIV-negative controls HIV-infected subjects were lower and less consistent than that was recruited. The enrollment target was ≥15 subjects per group, of HIV-uninfected age-matched controls, illustrating the per- which gave this study 87% power to detect a 30% rate of side sistent immunologic defect of HIV-infected individuals with or effects and 78% power to detect a 40% rate of immunologic boost. without HA ART. Age and ethnicity, which may play a role in The inclusion of the placebo recipients gave the study ≥80% power 22,23 responses to vaccines, did not affect the responses of HIV- to detect a 50% RCF-measured response in vaccinees. infected subjects to the vaccine. Neither did the nadir CD4 All subjects were ≥18 years of age, had anti-VZV antibodies count, which is an important observation, because previous detected by a commercial ELISA (Diamedix) and no history of studies generated conflicting results on the effect of the nadir HZ. HIV-infected subjects were required to have stable HIV RNA CD4 numbers on the immunogenicity of vaccines in HIV- <1,000 copies/mL for >3 months for Cohort 1 or >12 months for 15,24-27 infected individuals. Cohort 2. Exclusion criteria were fever within 72 hours of study Compared with placebo recipients, the two doses of VZV vac- entry, liver or renal disease, neutropenia, hemoglobin <10 gm/ cine significantly increased VZV-specific RCF values and tended dL, exposure to chickenpox or HZ, or immunosuppressive ther- to increase the ELISPOT values of HIV-infected vaccinees. apy within 4 weeks of study entry. Immune globulins or blood However, there was no appreciable change in LPA. Although, products were not permitted within 5 months of study entry, live RCF and LPA are both proliferation-based assays, the biologic or inactivated vaccines were not permitted within 4 or 2 weeks, variability of RCF is much lower compared to LPA due to the respectively, of study entry. inclusion of a limiting dilution step. Hence, differences are more Subjects from each HIV-infected cohort were randomized to TM readily appreciated in RCF. receive 2 doses of Varivax (Oka; Merck) or placebo in a blocked 320 Human Vaccines Volume 6 Issue 4 stratie fi d design matched on age and sex in a blinded fashion. wells. The RCF, defined as the cell concentration at which 37% of Injections were administered at weeks 0 and 12. The HIV-negative VZV antigen-stimulated wells are nonresponders, is expressed in controls received active vaccine at the same interval. responders/10 PBMC. 14,30 All adverse events occurring within 42 days of vaccination were LPA. LPA was performed as previously described. Results recorded and graded according to the Division of AIDS Toxicity are expressed as stimulation indices (SI). Table for Grading Severity of Adverse Experiences (http://www3. ELISPOT. ELISPOT was performed as previously described. niaid.nih.gov/research/resources/DAIDSClinRsrch/Safety.htm). The results are expressed in spot-forming cells (SFC)/10 PBMC. CD4 cell counts and plasma HIV RNA (VL) were measured at 6 Statistical analysis. Descriptive analysis was utilized for the weeks after each dose of vaccine. VZV-specic fi CMI was measured safety evaluation. The proportion of subjects in the treated groups by responder cell frequency (RCF), lymphocyte proliferation assay experiencing an adverse event was determined. Due to the small (LPA), and ELISPOT at weeks 0, 12 and 24 weeks. sample size, Fisher’s exact test and Wilcoxon rank-sum test were 28,29 RCF. RCF was performed as previously described. Replicate used for comparisons among the vaccine and placebo groups. A p cultures were stimulated with VZV antigen and mock-infected value ≤0.05 was used to define statistical significance. control for 8 days at 37°C and 5% CO , pulsed with H-thymidine, Acknowledgements harvested and counted with a beta counter (Perkin Elmer). Responder wells were defined as VZV-stimulated wells with We thank Dr. Kathleen Brady and Ms. Renee Jesser for their con- counts per minute (cpm) >mean +3 SD cpm in control-stimulated tributions to this study. 24. Valdez H, Connick E, Smith KY, Lederman MM, 13. Erard V, Guthrie KA, Varley C, Heugel J, Wald References A, Flowers ME, et al. One-year acyclovir prophy- Bosch RJ, Kim RS, et al. Limited immune restora- 1. Buchbinder SP, Katz MH, Hessol NA, Liu JY, O’Malley tion after 3 years’ suppression of HIV-1 replication in laxis for preventing varicella-zoster virus disease after PM, Underwood R, et al. Herpes zoster and human hematopoietic cell transplantation: no evidence of patients with moderately advanced disease. Aids 2002; immunodeficiency virus infection. J Infect Dis 1992; 16:1859-66. rebound varicella-zoster virus disease after drug discon- 166:1153-6. tinuation. Blood 2007; 110:3071-7. 25. Abzug MJ, Pelton SI, Song LY, Fenton T, Levin MJ, 2. Donahue JG, Choo PW, Manson JE, Platt R. The Nachman SA, et al. Immunogenicity, safety and predic- 14. Levin MJ, Gershon AA, Weinberg A, Blanchard S, incidence of herpes zoster. Arch Intern Med 1995; Nowak B, Palumbo P, et al. Immunization of HIV- tors of response after a pneumococcal conjugate and 155:1605-9. pneumococcal polysaccharide vaccine series in human infected children with varicella vaccine. J Pediatr 2001; 3. Glesby MJ, Moore RD, Chaisson RE. Herpes zoster 139:305-10. immunodeficiency virus-infected children receiving in patients with advanced human immunodeficiency highly active antiretroviral therapy. Pediatr Infect Dis J 15. Levin MJ, Gershon AA, Weinberg A, Song LY, Fentin virus infection treated with zidovudine. Zidovudine 2006; 25:920-9. T, Nowak B. Administration of live varicella vaccine Epidemiology Study Group. J Infect Dis 1993; 26. Levin MJ, Song LY, Fenton T, Nachman S, Patterson to HIV-infected children with current or past signifi- 168:1264-8. cant depression of CD4(+) T cells. J Infect Dis 2006; J, Walker R, et al. Shedding of live vaccine virus, 4. Glesby MJ, Moore RD, Chaisson RE. Clinical spectrum 194:247-55. comparative safety and influenza-specific antibody of herpes zoster in adults infected with human immu- responses after administration of live attenuated and 16. Gershon AA, Steinberg SP, Gelb L, Galasso G, nodeficiency virus. Clin Infect Dis 1995; 21:370-5. inactivated trivalent influenza vaccines to HIV-infected Borkowsky W, LaRussa P, et al. Live attenuated vari- 5. Hoppenjans WB, Bibler MR, Orme RL, Solinger children. Vaccine 2008; 26:4210-7. cella vaccine. Efficacy for children with leukemia in AM. Prolonged cutaneous herpes zoster in acquired remission. Jama 1984; 252:355-62. 27. Weinberg A, Gona P, Nachman SA, Defechereux P, immunodeficiency syndrome. Arch Dermatol 1990; Yogev R, Hughes W, et al. Antibody responses to 17. Hata A, Asanuma H, Rinki M, Sharp M, Wong RM, 126:1048-50. hepatitis A virus vaccine in HIV-infected children with Blume K, et al. Use of an inactivated varicella vaccine 6. Jacobson MA, Berger TG, Fikrig S, Becherer P, Moohr evidence of immunologic reconstitution while receiving in recipients of hematopoietic-cell transplants. N Engl highly active antiretroviral therapy. J Infect Dis 2006; JW, Stanat SC, et al. Acyclovir-resistant varicella zoster J Med 2002; 347:26-34. virus infection after chronic oral acyclovir therapy in 193:302-11. 18. LaRussa P, Steinberg S, Gershon AA. Varicella vaccine patients with the acquired immunodeficiency syn- 28. Weinberg A, Wiznia AA, LaFleur BJ, Shah S, Levin MJ. for immunocompromised children: results of collabora- drome (AIDS). Ann Intern Med 1990; 112:187-91. Varicella-Zoster virus-specific cell-mediated immunity tive studies in the United States and Canada. J Infect in HIV-infected children receiving highly active anti- 7. Palella FJ Jr, Delaney KM, Moorman AC, Loveless Dis 1996; 174:320-3. MO, Fuhrer J, Satten GA, et al. Declining morbidity retroviral therapy. J Infect Dis 2004; 190:267-70. 19. Hardy I, Gershon AA, Steinberg SP, LaRussa P. The and mortality among patients with advanced human 29. Levin MJ, Oxman MN, Zhang JH, Johnson GR, incidence of zoster after immunization with live attenu- immunodeficiency virus infection. HIV Outpatient Stanley H, Hayward AR, et al. VZV-specific immune ated varicella vaccine. A study in children with leuke- Study Investigators. N Engl J Med 1998; 338:853-60. responses in elderly recipients of a herpes zoster vaccine. mia. Varicella Vaccine Collaborative Study Group. N 8. Levin MJ, Anderson JP, Seage GR, 3rd, Williams PL. J Infect Dis 2008; 197:825-35. Engl J Med 1991; 325:1545-50. Short-term and long-term effects of highly active anti- 30. Weinberg A, Betensky RA, Zhang L, Ray G. Effect of 20. Oxman MN, Levin MJ, Johnson GR, Schmader KE, retroviral therapy on the incidence of herpes zoster in shipment, storage, anticoagulant and cell separation Straus SE, Gelb LD, et al. A vaccine to prevent herpes HIV-infected children. J Acquir Immune Defic Syndr on lymphocyte proliferation assays for human immu- zoster and postherpetic neuralgia in older adults. N 2009; 50:182-91. nodeficiency virus-infected patients. Clin Diagn Lab Engl J Med 2005; 352:2271-84. Immunol 1998; 5:804-7. 9. Vanhems P, Voisin L, Gayet-Ageron A, Trepo C, Cotte 21. Gershon AA, Levin MJ, Weinberg A, Song LY, Larussa L, Peyramond D, et al. The incidence of herpes zoster 31. Smith JG, Levin M, Vessey R, Chan IS, Hayward AR, PS, Steinberg SP, et al. A Phase I-Ii Study of Live is less likely than other opportunistic infections to be Liu X, et al. Measurement of cell-mediated immunity Attenuated Varicella-Zoster Virus Vaccine to Boost reduced by highly active antiretroviral therapy. J Acquir with a Varicella-Zoster Virus-specific interferon-gamma Immunity in Human Immunodeficiency Virus-Infected Immune Defic Syndr 2005; 38:111-3. ELISPOT assay: responses in an elderly population Children with Previous Varicella. Pediatr Infect Dis J 10. Martinez E, Gatell J, Moran Y, Aznar E, Buira E, receiving a booster immunization. Journal of medical 2009; 28:653-5. virology 2003; 70:38-41. Guelar A, et al. High incidence of herpes zoster in 22. Levin MJ, Oxman MN, Zhang JH, Johnson GR, patients with AIDS soon after therapy with protease Stanley H, Hayward AR, et al. Varicella-zoster virus- inhibitors. Clin Infect Dis 1998; 27:1510-3. specific immune responses in elderly recipients of a 11. Wood MJ, Kay R, Dworkin RH, Soong SJ, Whitley herpes zoster vaccine. J Infect Dis 2008; 197:825-35. RJ. Oral acyclovir therapy accelerates pain resolution in 23. McMahon BJ, Williams J, Bulkow L, Snowball M, patients with herpes zoster: a meta-analysis of placebo- Wainwright R, Kennedy M, et al. Immunogenicity controlled trials. Clin Infect Dis 1996; 22:341-7. of an inactivated hepatitis A vaccine in Alaska Native 12. Beutner KR, Friedman DJ, Forszpaniak C, Andersen children and Native and non-Native adults. J Infect Dis PL, Wood MJ. Valaciclovir compared with acyclovir 1995; 171:676-9. for improved therapy for herpes zoster in immunocom- petent adults. Antimicrob Agents Chemother 1995; 39:1546-53. www.landesbioscience.com Human Vaccines 321

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