Characterization of breakthrough hemolysis events observed in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria.

Eculizumab is first-line treatment for paroxysmal nocturnal hemoglobinuria (PNH); however, approximately 11%-27% of patients may experience breakthrough hemolysis (BTH) on approved doses of eculizumab. Ravulizumab, a new long-acting C5 inhibitor with a four-times longer mean half-life than eculizumab, provides immediate, complete, and sustained C5 inhibition over 8-week dosing intervals. In two phase 3 studies, ravulizumab was noninferior to eculizumab (Pinf ≤0.0004) for the BTH endpoint; fewer patients experienced BTH with ravulizumab versus eculizumab in both studies (301 [complement inhibitor-naive patients], 4.0% vs 10.7%; 302 [patients stabilized on eculizumab at baseline], 0% vs 5.1%). In the current analysis, patient-level data were evaluated to assess causes and clinical parameters associated with incidents of BTH reported during the 26-week treatment periods in the ravulizumab phase 3 PNH studies. Of the five BTH events occurring in ravulizumab-treated patients across the studies, none were temporally associated with suboptimal C5 inhibition (free C5 ≥0.5 µg/mL); four (80.0%) were temporally associated with complement-amplifying conditions (CACs). Of the 22 events occurring in eculizumab-treated patients, eleven were temporally associated with suboptimal C5 inhibition, including three events also associated with concomitant infection. Six events were associated with CACs only. Five events were unrelated to free C5 elevation or reported CACs. These results suggest that the immediate, complete, and sustained C5 inhibition achieved through weight-based dosing of ravulizumab reduces the risk of BTH by eliminating BTH associated with suboptimal C5 inhibition in patients with PNH. Clinicaltrials.gov identifiers: Study 301, NCT02946463; Study 302, NCT03056040.

One-year efficacy and safety of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria naïve to complement inhibitor therapy: open-label extension of a randomized study.

BACKGROUND: Ravulizumab, the only long-acting complement C5 inhibitor for adults with paroxysmal nocturnal hemoglobinuria (PNH), demonstrated non-inferiority to eculizumab after 26 weeks of treatment in complement inhibitor-naïve patients during a phase III randomized controlled trial. We present open-label extension results with up to 52 weeks of treatment. METHODS: Patients assigned to ravulizumab every 8 weeks (q8w) or eculizumab every 2 weeks during the randomized primary evaluation period received ravulizumab q8w during the 26-week extension. Efficacy endpoints were lactate dehydrogenase (LDH) normalization, transfusion avoidance, breakthrough hemolysis (BTH), LDH levels, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and stabilized hemoglobin. Serum free C5 levels and safety were assessed. Outcomes as of the data cut-off (4 September 2018) were summarized using descriptive statistics. RESULTS: Overall, 124 patients continued ravulizumab, and 119 switched from eculizumab to ravulizumab. During the extension, 43.5% and 40.3% of patients in the ravulizumab-ravulizumab and eculizumab-ravulizumab arms, respectively, achieved LDH normalization; 76.6% and 67.2% avoided transfusion. BTH decreased in the eculizumab-ravulizumab arm; no events were associated with free C5 ⩾0.5 µg/mL while receiving ravulizumab. Overall, 73.4% and 65.5% of patients in the ravulizumab-ravulizumab and eculizumab-ravulizumab arms, respectively, achieved stabilized hemoglobin. Similar proportions of patients achieved ⩾3-point improvement in FACIT-Fatigue at week 52 (ravulizumab-ravulizumab, 64.5%; eculizumab-ravulizumab, 57.1%). All patients maintained free C5 <0.5 µg/mL during the ravulizumab extension, including those who experienced C5 excursions ⩾0.5 µg/mL while receiving eculizumab during the primary evaluation period. Adverse events were comparable between groups and decreased over time. CONCLUSION: In adult, complement inhibitor-naïve patients with PNH, ravulizumab q8w for up to 52 weeks demonstrated durable efficacy and was well tolerated, with complete and sustained free C5 inhibition and a decreased incidence of BTH with no events associated with loss of free C5 control. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02946463.

Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: results of two phase 3 randomised, multicentre studies.

Ravulizumab, a novel long-acting complement component 5 (C5) inhibitor administered every 8 weeks (q8w), was non-inferior to eculizumab for all efficacy outcomes in two randomised, open-label, phase 3 trials in C5 inhibitor-naïve (Study 301) and eculizumab-experienced (Study 302) adult patients with paroxysmal nocturnal haemoglobinuria (PNH). This pre-specified analysis characterised ravulizumab pharmacokinetics (PK), pharmacodynamics (PD; free C5 levels), and PD differences between medications (Study 301, n = 246; Study 302, n = 195). Ravulizumab PK parameters were determined using non-compartmental analysis. Serum free C5 was quantified with a Gyros-based fluorescence assay (ravulizumab) and an electrochemiluminescence ligand-binding assay (eculizumab). Ravulizumab PK parameters were numerically comparable in both studies; the median time to maximum concentrations ranged from 2·3 to 2·8 and 2·3 to 2·6 h in studies 301 and 302, respectively. Ravulizumab steady-state serum concentrations were achieved immediately after the first dose and sustained throughout treatment. For ravulizumab, the mean (SD) post hoc terminal elimination half-life was 49·7 (8·9) days. Serum free C5 concentrations <0·5 µg/ml were achieved after the first ravulizumab dose and sustained throughout treatment in both studies. In a minority of patients, free C5 concentrations <0·5 µg/ml were not consistently achieved with eculizumab in either study. Ravulizumab q8w was more consistent in providing immediate, complete, sustained C5 inhibition than eculizumab every-2-weeks in patients with PNH.

Assessing Preferences for Rare Disease Treatment: Qualitative Development of the Paroxysmal Nocturnal Hemoglobinuria Patient Preference Questionnaire (PNH-PPQ©).

PURPOSE: To develop a patient preference questionnaire (PPQ) assessing eculizumab and ravulizumab treatment for paroxysmal nocturnal hemoglobinuria (PNH). PATIENTS AND METHODS: The development of the PNH-PPQ© was consistent with Food and Drug Administration guidelines for patient-reported outcome measure development, and included 1) a targeted literature review; 2) PNH expert clinician input on treatment preferences; 3) review of existing qualitative data on the PNH treatment and disease experience; 4) concept elicitation interviews with 8 PNH patients who received eculizumab and/or ravulizumab; 5) translatability review; and 6) cognitive debriefing with 5 patients. Interview participants were recruited through a United Kingdom PNH patient advocacy group and a Canadian clinical site involved in clinical trial ALXN1210-PNH-302. RESULTS: Six themes were identified as most relevant to the PNH treatment experience from the concept elicitation interviews: disease symptoms (n=8/8); treatment frequency (n=7/8); quality of life impact of treatment/disease (n=7/8); treatment burden (n=7/8); treatment efficacy (n=5/8); and treatment side effects (n=5/8). An initial list of 88 preference questions was reduced to 11 highly relevant and non-redundant questions reflecting the 6 themes. Cognitive interview participants unanimously agreed that the PNH-PPQ instructions were clear; response options were understandable, easy to use, and provided enough choices; and the questions captured the factors that inform treatment preferences. DISCUSSION: When new drugs have similar efficacy to existing medications, documenting patient preferences is important for confirming patient benefit from the new medication. Understanding what matters most to patients is essential for delivering patient-centered care and may play a particularly significant role in treatment decision making. The availability of such a tool may be especially important as new orphan drugs are developed and patients with rare diseases have more than one treatment option to consider. CONCLUSION: The PNH-PPQ provides a patient-centered approach for evaluating preferences for the treatment of PNH. The PNH-PPQ has subsequently assessed patient preference in the clinical trial sub-study ALXN1210-PNH-302s.

Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study.

Ravulizumab, a new complement component C5 inhibitor administered every 8 weeks, was noninferior to eculizumab administered every 2 weeks in complement-inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH). This study assessed noninferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy. In this phase 3, open-label, multicenter study, 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for >6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). Primary efficacy end point was percentage change in lactate dehydrogenase (LDH) from baseline to day 183. Key secondary end points included proportion of patients with breakthrough hemolysis, change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, transfusion avoidance, and stabilized hemoglobin. In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizumab (P inf < .0006 for all end points), including percentage change in LDH (difference, 9.21% [95% confidence interval (CI), -0.42 to 18.84], P = .058 for superiority), breakthrough hemolysis (difference, 5.1 [95% CI, -8.89 to 18.99]), change in FACIT-Fatigue score (difference, 1.47 [95% CI, -0.21 to 3.15]), transfusion avoidance (difference, 5.5 [95% CI, -4.27 to 15.68]), and stabilized hemoglobin (difference, 1.4 [95% CI, -10.41 to 13.31]). The most frequently reported adverse event was headache (26.8%, ravulizumab; 17.3%, eculizumab). No meningococcal infections or discontinuations due to adverse events occurred. Patients with PNH may be safely and effectively switched from labeled-dose eculizumab administered every 2 weeks to ravulizumab administered every 8 weeks. This trial was funded by Alexion Pharmaceuticals, Inc., and is registered at www.clinicaltrials.gov as #NCT03056040.

Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study.

Ravulizumab (ALXN1210), a new complement C5 inhibitor, provides immediate, complete, and sustained C5 inhibition. This phase 3, open-label study assessed the noninferiority of ravulizumab to eculizumab in complement inhibitor-naive adults with paroxysmal nocturnal hemoglobinuria (PNH). Patients with lactate dehydrogenase (LDH) ≥1.5 times the upper limit of normal and at least 1 PNH symptom were randomized 1:1 to receive ravulizumab or eculizumab for 183 days (N = 246). Coprimary efficacy end points were proportion of patients remaining transfusion-free and LDH normalization. Secondary end points were percent change from baseline in LDH, change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, proportion of patients with breakthrough hemolysis, stabilized hemoglobin, and change in serum free C5. Ravulizumab was noninferior to eculizumab for both coprimary and all key secondary end points (Pinf < .0001): transfusion avoidance (73.6% vs 66.1%; difference of 6.8% [95% confidence interval (CI), -4.66, 18.14]), LDH normalization (53.6% vs 49.4%; odds ratio, 1.19 [0.80, 1.77]), percent reduction in LDH (-76.8% vs -76.0%; difference [95% CI], -0.83% [-5.21, 3.56]), change in FACIT-Fatigue score (7.07 vs 6.40; difference [95% CI], 0.67 [-1.21, 2.55]), breakthrough hemolysis (4.0% vs 10.7%; difference [95% CI], -6.7% [-14.21, 0.18]), and stabilized hemoglobin (68.0% vs 64.5%; difference [95% CI], 2.9 [-8.80, 14.64]). The safety and tolerability of ravulizumab and eculizumab were similar; no meningococcal infections occurred. In conclusion, ravulizumab given every 8 weeks achieved noninferiority compared with eculizumab given every 2 weeks for all efficacy end points, with a similar safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02946463.

Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies.

Ravulizumab (ALXN1210), a humanized monoclonal antibody to complement component C5, was engineered from eculizumab to have a substantially longer terminal half-life, permitting longer dosing intervals for paroxysmal nocturnal hemoglobinuria (PNH) treatment. Two phase 1b/2 multicenter open-label studies evaluated efficacy and safety of multiple doses and regimens of ravulizumab in PNH patients naive to complement-inhibitor treatment. Patients in study 103 (n = 13) received ravulizumab 900 mg (lower trough exposure) or 1800 mg every 4 weeks (higher trough exposure); those in study 201 (n = 26) received 1000 mg every 4, 1600 mg every 6, 2400 mg every 8, or 5400 mg every 12 weeks. Trough exposure levels with study 201 dosing regimens were similar to the study 103 900-mg every-4-weeks regimen. Rapid sustained reduction of plasma lactate dehydrogenase (LDH) occurred across all cohorts (73%-90% at end point vs baseline). A greater proportion of patients had normalized LDH (<234 U/L) at least once from days 29 to 253 in the higher- (85.7%) vs lower-trough-exposure (50.0%-83.3%) cohorts; the weighted average of the proportion of instances of LDH normalization from days 29 to 253 was highest in higher- vs lower-trough-exposure cohorts (62.3% vs 31.4%-54.5%). No patients in the higher-trough-exposure cohort, but 1 to 2 patients in all lower-trough-exposure cohorts, experienced breakthrough hemolysis. Ravulizumab improved quality of life (QoL) measures in all cohorts. Two patients experienced meningococcal infections; both recovered and continued in the study. In summary, ravulizumab provided rapid and sustained reduction in complement-mediated hemolysis and improved QoL at dosing intervals up to 12 weeks. This trial was registered at www.clinicaltrials.gov as #NCT02598583 (study 103) and NCT02605993 (study 201).

T-cell-mediated immune response to pneumococcal conjugate vaccine (PCV-13) and tetanus toxoid vaccine in patients with moderate-to-severe psoriasis during tofacitinib treatment.

BACKGROUND: Psoriasis is often treated with immunomodulatory therapies that can affect the immune response to common antigens. Tofacitinib is an oral Janus kinase inhibitor. OBJECTIVE: To characterize the effect of long-term exposure to tofacitinib 10 mg twice daily on T-cell function in psoriasis patients. METHODS: Patients completing at least 3 months' continuous treatment with tofacitinib 10 mg twice daily were vaccinated with T-cell-dependent vaccines (monovalent tetanus toxoid and 13-valent pneumococcal conjugate [PCV-13]). Patients were assessed at baseline (before vaccination) and then again 4 weeks after vaccination. For PCV-13, we evaluated serotype-specific, opsonophagocytic antibody responses, and for tetanus toxoid, we evaluated humoral responses. RESULTS: Among 60 patients who completed the study, the geometric mean fold rise from baseline for the 13 PCV serotypes at 4 weeks postvaccination varied from 8.3 (serotype 3) to 101.9 (serotype 6A). Similar results were observed for patients with and without lymphopenia at baseline. For tetanus toxoid, 51 (88%) patients had ≥2-fold and 35 (60%) patients had ≥4-fold rise in antibody concentration. LIMITATIONS: There was no placebo control. CONCLUSION: Most psoriasis patients who receive tofacitinib can mount satisfactory T-cell-dependent responses to PCV-13 and tetanus vaccines.

Herpes zoster in psoriasis patients treated with tofacitinib.

BACKGROUND: Tofacitinib is an oral Janus kinase (JAK) inhibitor. Immunomodulatory therapies can increase the risk for herpes zoster (HZ) in patients with psoriasis. OBJECTIVE: To evaluate the relationship between tofacitinib use and HZ risk. METHODS: We used phases 2 and 3 and long-term extension (LTE) data from the tofacitinib development program in psoriasis to calculate HZ incidence rates (IR; events per 100 patient-years); potential HZ risk factors were evaluated using Cox-proportional hazard models. RESULTS: One hundred thirty (3.6%) patients on tofacitinib (IR 2.55), no patients on placebo, and 2 using etanercept (IR 2.68) developed HZ. Nine patients (7%) were hospitalized, and 8 (6%) had multidermatomal HZ; no encephalitis, visceral involvement, or deaths occurred. In total, 121 (93%) patients on tofacitinib continued or resumed use after HZ. HZ risk factors included Asian descent (hazard ratio [HR] 2.92), using tofacitinib 10 mg twice daily (vs 5 mg twice daily; HR 1.72), prior use of biologics (HR 1.72), and older age (HR 1.30). LIMITATIONS: Generalizability to other psoriasis populations might be limited. The effect of HZ vaccination was not studied. CONCLUSION: Tofacitinib is associated with increased HZ risk relative to placebo. Asian race, increasing age, higher dose, and prior biologic exposure are associated with heightened risk.

Tofacitinib attenuates pathologic immune pathways in patients with psoriasis: A randomized phase 2 study.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. OBJECTIVE: We sought to elucidate the molecular mechanisms underlying the clinical efficacy of tofacitinib in patients with psoriasis. METHODS: Twelve patients with plaque psoriasis were randomized (3:1) to receive 10 mg of tofacitinib or placebo twice daily for 12 weeks. Biopsy specimens were taken from nonlesional (baseline) and lesional (baseline, days 1 and 3, and weeks 1, 2, 4, and 12) skin. Biopsy specimens were examined for psoriatic epidermal features (thickness, Ki67(+) keratinocytes and keratin 16 [KRT16] mRNA expression, and phosphorylated signal transducer and activator of transcription [pSTAT](+) nuclei) and T-cell and dendritic cell (DC) subsets by using immunohistochemistry, and mRNA transcripts were quantified by using a microarray. RESULTS: In lesional skin keratinocyte pSTAT1 and pSTAT3 staining was increased at baseline but reduced after 1 day of tofacitinib (baseline, median of 1290 pSTAT1(+) cells/µm(2); day 1, median of 332 pSTAT1(+) cells/µm(2); and nonlesional, median of 155 pSTAT1(+) cells/µm(2)). Epidermal thickness and KRT16 mRNA expression were significantly and progressively reduced after days 1 and 3 of tofacitinib administration, respectively (eg, KRT16 decreased 2.74-fold, day 3 vs baseline, P = .016). Decreases in DC and T-cell numbers were observed after weeks 1 and 2, respectively. At week 4, significant decreases in IL-23/TH17 pathways were observed that persisted through week 12. Improvements in clinical and histologic features were strongly associated with changes in expression of psoriasis-related genes and reduction in IL-17 gene expression. CONCLUSIONS: Tofacitinib has a multitiered response in patients with psoriasis: (1) rapid attenuation of keratinocyte Janus kinase/STAT signaling; (2) removal of keratinocyte-induced cytokine signaling, leading to reductions in pathologic DC and T-cell numbers to nonlesional levels; and (3) inhibition of the IL-23/TH17 pathway.

Clinical response and mortality in tigecycline complicated intra-abdominal infection and complicated skin and soft-tissue infection trials.

An imbalance in all-cause mortality was noted in tigecycline phase 3 and 4 comparative clinical trials across all studied indications. We investigated clinical failure and mortality in phase 3 and 4 complicated skin and soft-tissue infection (cSSTI) and complicated intra-abdominal infection (cIAI) tigecycline trials using descriptive analyses of a blinded adjudication of mortality and multivariate regression analyses. Attributable mortality analyses of cSSTI revealed death due to infection in 0.1% of each treatment group (P=1.000). In cIAI, there were no significant differences between tigecycline (1.2%) and comparator (0.7%) subjects who died due to infection (P=0.243). For cIAI clinical failure, treatment interaction with organ dysfunction was observed with no difference observed between clinical cure for tigecycline (85.4%) and comparator (76.7%) treatment groups (odds ratio=0.58, 95% confidence interval 0.28-1.19). Tigecycline-treated subjects had more adverse events of secondary pneumonias (2.1% vs. 1.2%) and more adverse events of secondary pneumonias with an outcome of death (0.5% vs. 0.1%). These analyses do not suggest that tigecycline is a factor either for failure (cSSTI and cIAI studies) or for death (cIAI studies).

Combination antifungal therapy for invasive aspergillosis: a randomized trial.

BACKGROUND: Invasive aspergillosis (IA) is associated with poor outcomes in patients with hematologic malignancies (HMs) and hematopoietic cell transplantation (HCT). Small studies suggest a role for combination antifungal therapy. OBJECTIVE: To assess the safety and efficacy of voriconazole and anidulafungin compared with voriconazole monotherapy for treatment of IA. DESIGN: Randomized, double-blind, placebo-controlled multicenter trial. (ClinicalTrials.gov: NCT00531479). SETTING: 93 international sites. PATIENTS: 454 patients with HM or HCT and suspected or documented IA were randomly assigned to treatment with voriconazole and anidulafungin or placebo. Primary analysis was done in the modified intention-to-treat population of 277 patients in whom IA was confirmed. MEASUREMENTS: The primary outcome was 6-week mortality; secondary outcomes included 12-week mortality, mortality in major subgroups, and safety measures. RESULTS: Mortality rates at 6 weeks were 19.3% (26 of 135) for combination therapy and 27.5% (39 of 142) for monotherapy (difference, -8.2 percentage points [95% CI, -19.0 to 1.5]; P  = 0.087). Secondary mortality outcomes favored combination therapy. Multivariable regression analysis suggested that maximum galactomannan value, Karnofsky score, and baseline platelet count had prognostic significance. Most patients (218 of 277 [78.7%]) had IA diagnosis established by radiographic findings and maximum galactomannan positivity. In a post hoc analysis of this dominant subgroup, 6-week mortality was lower in combination therapy than monotherapy (15.7% [17 of 108] vs. 27.3% [30 of 110]; difference, -11.5 percentage points [CI, -22.7 to -0.4]; P = 0.037). Safety measures, including hepatotoxicity, were not different. LIMITATIONS: Mortality at 6 weeks was higher than expected, and the difference in mortality was lower than expected, which reduced power to detect a treatment effect. Enrollment was restricted to patients with HM or HCT, which limited generalizability. CONCLUSION: Compared with voriconazole monotherapy, combination therapy with anidulafungin led to higher survival in subgroups of patients with IA. Limitations in power preclude definitive conclusions about superiority. PRIMARY FUNDING SOURCE: Pfizer.

HIV-1(89.6) Gag expressed from a replication competent HSV-1 vector elicits persistent cellular immune responses in mice.

We have constructed a replication competent, gamma(1)34.5-deleted herpes simplex virus type-1 (HSV-1) vector (J200) that expresses the gag gene from human immunodeficiency virus type-1, primary isolate 89.6 (HIV-1(89.6)), as a candidate vaccine for HIV-1. J200 replicates in vitro, resulting in abundant Gag protein production and accumulation in the extracellular media. Immunization of Balb/c mice with a single intraperitoneal injection of J200 elicited strong Gag-specific CD8 responses, as measured by intracellular IFN-gamma staining and flow cytometry analysis. Responses were highest between 6 weeks and 4 months, but persisted at 9 months post-immunization, the last time-point evaluated. These data highlight the potential utility of neuroattenuated, replication competent HSV-1 vectors for delivery of HIV-1 immunogens.

Current non-AIDS antiviral chemotherapy.

The evolution of antiviral therapy began with developments in the management of influenza and herpes simplex keratitis in the 1960s and early 1970s. However, the field exploded with the successful treatment of herpes simplex encephalitis, herpes zoster and genital herpes simplex virus infections, all occurring in the late 1970s and early 1980s. These advances have contributed to the development of therapies for HIV that have transformed the lives of infected patients in recent years. The clinical fruit of all of these research advances has been an armamentarium of drugs that can be used to successfully treat a variety of viral illnesses. In addition to HIV/AIDS, current antiviral therapy focuses primarily on herpesviruses, hepatitis viruses and influenza. Notably, considerable progress remains to be made in these areas. Moreover, a variety of additional viral diseases currently require the development of specific therapies.

Hepatitis B DNA vaccine induces protective antibody responses in human non-responders to conventional vaccination.

A novel DNA vaccine against hepatitis B virus was administered intraepidermally by particle-mediated epidermal delivery (PMED) to 16 human subjects who demonstrated absent or non-sustainable responses to conventional hepatitis B vaccination. Eleven subjects received three doses of vaccine at 56-day intervals, and five subjects received only a single vaccination. Each dose of vaccine contained 4 microg of plasmid DNA encoding the hepatitis B surface antigen (HBsAg). The vaccine was safe and well tolerated. Remarkably, the DNA vaccine elicited antibody responses in 12 of the 16 subjects after a licensed subunit vaccine failed to induce a lasting response after >/=3 vaccinations. This study provides evidence in humans for protective immunogenicity of a particle-mediated DNA vaccine in subjects who have responded suboptimally to conventional vaccination.