Systemic Bioavailability of Sublingual Atropine Ophthalmic Solution: a Phase I Study in Healthy Volunteers with Implications for Use as a Contingency Medical Countermeasure.

INTRODUCTION: Atropine sulfate is an FDA-approved medical countermeasure (MCM) for the treatment of organophosphorus nerve agent and organophosphate pesticide toxicity. Sufficient MCM supplies must be available in an incident involving a mass human exposure either from an accidental chemical release or a terrorist attack. METHODS: We performed a randomized, 3-sequence, 3-period phase I crossover study to assess the bioavailability and pharmacokinetics (PK) of a single dose (0.5 mg and 1.0 mg) of 1% ophthalmic atropine sulfate solution administered sublingually to 15 healthy adult volunteers. The primary endpoint was evaluation of the bioavailability of each of the two sublingual doses against a 1.0 mg reference intravenous (IV) atropine dose. Secondary endpoints included the safety and tolerability (xerostomia scale) of atropine sulfate administered sublingually. RESULTS: Sublingual atropine was safe (no severe AEs or SAEs were reported with either dose) and well tolerated, with a single subject reaching maximum xerostomia on a single dosing day. The geometric mean AUC∞ was 286.40, 493.81, and 816.47 min*ng/mL for the 0.5 mg and 1.0 mg sublingual doses, and the 1.0 mg IV dose, respectively. Compared to IV administration, the 1.0 mg sublingual dose produced 0.60 (90% CI: 0.55-0.66) of the overall concentration of atropine over time (AUC∞). CONCLUSION: Sublingual atropine sulfate 1% ophthalmic solution may be an alternative formulation and route of administration combination which expands the capacity and dosing options of atropine as a nerve agent MCM.

Adjuvanted recombinant hemagglutinin H7 vaccine to highly pathogenic influenza A(H7N9) elicits high and sustained antibody responses in healthy adults.

An unprecedented number of human infections with avian influenza A(H7N9) in the fifth epidemic wave during the winter of 2016-2017 in China and their antigenic divergence from the viruses that emerged in 2013 prompted development of updated vaccines for pandemic preparedness. We report on the findings of a clinical study in healthy adults designed to evaluate the safety and immunogenicity of three dose levels of recombinant influenza vaccine derived from highly pathogenic A/Guangdong/17SF003/2016 (H7N9) virus adjuvanted with AS03 or MF59 oil-in water emulsions. Most of the six study groups meet the FDA CBER-specified vaccine licensure criterion of 70% seroprotection rate (SPR) for hemagglutination inhibition antibodies to the homologous virus. A substantial proportion of subjects show high cross-reactivity to antigenically distinct heterologous A(H7N9) viruses from the first epidemic wave of 2013. These results provide critical information to develop a pandemic response strategy and support regulatory requirements for vaccination under Emergency Use Authorization.

Evaluation of BioThrax® and AV7909 anthrax vaccines in adults 66 years of age or older.

BACKGROUND: Multiple Anthrax vaccines are licensed or in development for post-exposure prophylaxis in individuals 18 to 65 years of age. No information exists on anthrax vaccines in populations over the age of 65. It is critical that we assess the capacity of anthrax vaccines to generate a protective immune response in older individuals. In this study, we compared BioThrax® to a formulation containing a CpG adjuvant (AV7909). METHODS: We conducted a Phase 2 clinical study to evaluate safety and immunogenicity of three vaccination schedules of the AV7909 vaccine candidate and one vaccination schedule of BioThrax® vaccine in adults over 65 years of age. A total of 305 subjects were enrolled to assess safety and immunogenicity by seroprotection rates, toxin neutralizing antibody titers, and anti-Protective Antigen ELISA titers. RESULTS: Compared to BioThrax, AV7909 elicited a more robust immune response in older subjects, especially with three doses of AV7909 at Days 1, 15, and 29, or two doses at Days 1 and 29. These trends were true with both seroprotection rates as defined by the percentage of subjects with 50 percent neutralization factors greater than 0.56, and geometric mean antibody titers. The responses to both AV7909 and BioThax were lower in older subjects compared to those aged 18-50. CONCLUSION: The immunogenicity data suggest that the CpG adjuvant in the AV7909 vaccine helps to elicit a more robust immune response in subjects over the age of 65. Alternative dosing strategies may be considered in this population given the high seroprotection rates with Day 1 and 29, or Day 1, 15, and 29 regimens. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT03518125.

Efficacy and safety of oral solithromycin versus oral moxifloxacin for treatment of community-acquired bacterial pneumonia: a global, double-blind, multicentre, randomised, active-controlled, non-inferiority trial (SOLITAIRE-ORAL).

BACKGROUND: Community-acquired bacterial pneumonia (CABP) is a leading cause of morbidity and mortality, and treatment recommendations, each with specific limitations, vary globally. We aimed to compare the efficacy and safety of solithromycin, a novel macrolide, with moxifloxacin for treatment of CABP. METHODS: We did this global, double-blind, double-dummy, randomised, active-controlled, non-inferiority trial at 114 centres in North America, Latin America, Europe, and South Africa. Patients (aged ≥18 years) with clinically and radiographically confirmed pneumonia of Pneumonia Outcomes Research Team (PORT) risk class II, III, or IV were randomly assigned (1:1), via an internet-based central block randomisation procedure (block size of four), to receive either oral solithromycin (800 mg on day 1, 400 mg on days 2-5, placebo on days 6-7) or oral moxifloxacin (400 mg on days 1-7). Randomisation was stratified by geographical region, PORT risk class (II vs III or IV), and medical history of asthma or chronic obstructive pulmonary disease. The study sponsor, investigators, staff, and patients were masked to group allocation. The primary outcome was early clinical response, defined as an improvement in at least two of four symptoms (cough, chest pain, sputum production, dyspnoea) with no worsening in any symptom at 72 h after the first dose of study drug, with a 10% non-inferiority margin. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT-01756339. FINDINGS: Between Jan 3, 2013, and Sept 24, 2014, we randomly assigned 860 patients to receive solithromycin (n=426) or moxifloxacin (n=434). Patients were followed up to days 28-35 after first dose. Solithromycin was non-inferior to moxifloxacin in achievement of early clinical response: 333 (78·2%) patients had an early clinical response in the solithromycin group versus 338 (77·9%) patients in the moxifloxacin group (difference 0·29, 95% CI -5·5 to 6·1). Both drugs had a similar safety profile. 43 (10%) of 155 treatment-emergent adverse events in the solithromycin group and 54 (13%) of 154 such events in the moxifloxacin group were deemed to be related to study drug. The most common adverse events, mostly of mild severity, were gastrointestinal disorders, including diarrhoea (18 [4%] patients in the solithromycin group vs 28 [6%] patients in the moxifloxacin group), nausea (15 [4%] vs 17 [4%] patients) and vomiting (ten [2%] patients in each group); and nervous system disorders, including headache (19 [4%] vs 11 [3%] patients) and dizziness (nine [2%] vs seven [2%] patients). INTERPRETATION: Oral solithromycin was non-inferior to oral moxifloxacin for treatment of patients with CABP, showing the potential to restore macrolide monotherapy for this indication. FUNDING: Cempra.

Early phase evaluation of SQ109 alone and in combination with rifampicin in pulmonary TB patients.

OBJECTIVES: SQ109, an asymmetrical diamine, is a novel anti-TB drug candidate. This first study in patients was done to determine safety, tolerability, pharmacokinetics and bacteriological effect of different doses of SQ109 alone and in combination with rifampicin when administered over 14 days. PATIENTS AND METHODS: Smear-positive pulmonary TB patients were randomized into six groups of 15 to receive once-daily oral treatment with 75, 150 or 300 mg of SQ109, rifampicin (10 mg/kg body weight), rifampicin plus 150 mg of SQ109, or rifampicin plus 300 mg of SQ109 for 14 days. Patients were hospitalized for supervised treatment, regular clinical, biochemical and electrocardiographic safety assessments, pharmacokinetic profiling and daily overnight sputum collection. RESULTS: SQ109 was safe and generally well tolerated. Mild to moderate dose-dependent gastrointestinal complaints were the most frequent adverse events. No relevant QT prolongation was noted. Maximum SQ109 plasma concentrations were lower than MICs. Exposure to SQ109 (AUC0-24) increased by drug accumulation upon repeated administration in the SQ109 monotherapy groups. Co-administration of SQ109 150 mg with rifampicin resulted in decreasing SQ109 exposures from day 1 to day 14. A higher (300 mg) dose of SQ109 largely outweighed the evolving inductive effect of rifampicin. The daily fall in log cfu/mL of sputum (95% CI) was 0.093 (0.126-0.059) with rifampicin, 0.133 (0.166-0.100) with rifampicin plus 150 mg of SQ109 and 0.089 (0.121-0.057) with rifampicin plus 300 mg of SQ109. Treatments with SQ109 alone showed no significant activity. CONCLUSIONS: SQ109 alone or with rifampicin was safe over 14 days. Upon co-administration with rifampicin, 300 mg of SQ109 yielded a higher exposure than the 150 mg dose. SQ109 did not appear to be active alone or to enhance the activity of rifampicin during the 14 days of treatment.

The immunogenicity and safety of a nicotine vaccine in smokers and nonsmokers: results of a randomized, placebo-controlled phase 1/2 trial.

This randomized, placebo-controlled phase 1/2 trial evaluated the safety and immunogenicity of four doses of a nicotine vaccine in smokers and nonsmokers. Subjects were 21 smokers and 9 nonsmokers in good physical and mental health. They were aged 24-60 years, were recruited from the general public using newspaper advertisements, and were evaluated at University Hospital Maastricht. Each volunteer received four spaced intramuscular injections of 100 microg of purified 3'-aminomethylnicotine conjugated to detoxified Pseudomonas aeruginosa r-exoprotein A or placebo both adsorbed to 800 microg aluminum into the deltoid muscle of alternating arms. Clinical safety was determined by vital signs, reactogenicity, and adverse events, and immunogenicity was measured by enzyme-linked immunosorbent assay. Intensive follow-up for 266 days revealed the vaccine to be well tolerated. We found no significant differences in adverse events between the vaccine and placebo groups. Significant increases in the geometric mean titer (GMT) levels of nicotine-specific antibodies were observed from 7 days after the second vaccination (day 21), reaching nicotine-specific antibody levels of at least 8 microg/ml in half of the subjects (50%) at day 49. A fourth dose administered at day 182 significantly boosted waning antibody levels to a GMT of 10.8 microg/ml at day 217 (95% CI 6.0-19.3). Results showed that the immunogenicity of the vaccine was not impeded by the presence of nicotine. These observations provide evidence in humans that the vaccine we used may represent a feasible strategy for evoking type-specific antibodies against nicotine.

Protective antibody levels and dose requirements for IV 5% Nabi Hepatitis B immune globulin combined with lamivudine in liver transplantation for hepatitis B-induced end stage liver disease.

Lamivudine combined with Hepatitis B immune globulin (HBIg) prevents post liver transplant (LT) HBV recurrence. The study was designed to assess the impact of lamivudine on hepatitis B antibody (anti-HBs) and dosage requirements of intravenous 5% HBIg (Nabi-HB) in the first 36 weeks post LT. Adults undergoing LT for chronic HBV received lamivudine prior to or at LT, and IV HBIg 20,000 IU on day of LT, 10,000 on days 1-7, weeks 4 and 8, and 5,000 every 4 weeks thereafter. Replicative status based on serum HBV DNA (> 5 pg/mL = replicator (R) or < or = 5 pg/mL = nonreplicator (N) was determined at initiation of lamivudine (R or N) and within 2 weeks of LT (r or n), resulting in 3 groups: Nn, Rn, and Rr. Between December 1999 and May 2001, 30 patients (10 Nn, 13 Rn, 6 Rr, and 1 unknown), mean age of 52 years underwent LT. HBsAg neutralization was achieved with anti-HBs > 300 IU/L during week 1 and > 200 IU/L during weeks 2-12. All but one patient were HBsAg-negative on last follow-up. Pre-LT suppression of HBV replication resulted in similar dose requirements and pK in the Rn and Nn groups within 1 week after LT. Comparatively, the Rr group had greater HBIg requirements during weeks 1-12 due to greater anti-HBs clearance and shortened t(1/2) during the entire 36-week follow-up. In conclusion, this study provides a rationale for the use of lower HBIg doses in HBV patients with suppressed replication undergoing LT.

Safety and immunogenicity of a nicotine conjugate vaccine in current smokers.

Immunotherapy is a novel potential treatment for nicotine addiction. The aim of this study was to assess the safety and immunogenicity of a nicotine conjugate vaccine, NicVAX, and its effects on smoking behavior. Smokers (N = 68) were recruited for a noncessation treatment study and assigned to 1 of 3 doses of the nicotine vaccine (50, 100, or 200 microg) or placebo. They were injected on days 0, 28, 56, and 182 and monitored for a period of 38 weeks. Results showed that the nicotine vaccine was safe and well tolerated. Vaccine immunogenicity was dose-related (P < .001), with the highest dose eliciting antibody concentrations within the anticipated range of efficacy. There was no evidence of compensatory smoking or precipitation of nicotine withdrawal with the nicotine vaccine. The 30-day abstinence rate was significantly different across the 4 doses (P = .02), with the highest rate of abstinence occurring with 200 microg. The nicotine vaccine appears to be a promising medication for tobacco dependence.

Safety and immunogenicity of a booster dose of Staphylococcus aureus types 5 and 8 capsular polysaccharide conjugate vaccine (StaphVAX) in hemodialysis patients.

StaphVAX, an unadjuvanted, bivalent vaccine composed of Staphylococcus aureus (S. aureus) capsular polysaccharides (CPS) types 5 and 8 bound to the mutant non-toxic recombinant Pseudomonas aeruginosa exotoxin A (rEPA) conferred approximately 60% protection for 10 months against bacteremia caused by this pathogen in hemodialysis patients. A protective level of 80 microg/ml was estimated based upon geometric mean (GM) antibody levels at the end of the efficacy period. To extend the duration of protection conferred by StaphVAX in hemodialysis patients, recipients of the vaccine were reinjected in a randomized double-blinded, placebo-controlled study. Vaccinees received StaphVAX and a saline placebo injection 14 days apart according to the randomization schedule. The booster dose of StaphVAX was administered an average of 958 days (753-1167 days) after the first injection. There were no serious adverse reactions. Antibody levels at day 14, 28, 92, and 182 post-injection were measured by ELISA. Maximal levels of IgG anti-CPS were observed at the 28-day interval. For type 5, GM antibody levels increased from 73 microg/ml at day 0 to 162 microg/ml (P < 0.001) and for type 8 from 59 microg/ml to 133 microg/ml (P < 0.001). Anti-CPS antibody levels of approximately 80 microg/ml to type 5 and type 8 were achieved in 72.4 and 74.3% of vaccinees, respectively. There was excellent correlation between the level of anti-CPS and opsonic titer (r = 0.93). Moreover, the decline of anti-CPS antibody levels at six months was significantly less rapid than that observed from the first immunization (P < 0.001). We conclude that a booster immunization to maintain protective levels of specific antibodies for an extended period of time is feasible for patients at continuous risk for S. aureus bacteremia.

Staphylococcus aureus types 5 and 8 capsular polysaccharide-protein conjugate vaccines.

BACKGROUND: Staphylococcus aureus, the first or second most common pathogen isolated from patients, is capsulated; there are at least 12 capsular types, and types 5 and 8 comprise approximately 85% of blood. Types 5 and 8, composed of a trisaccharide repeat unit including a mannose uronic acid and 2 fucoses, are non-immunogenic. As protein conjugates, they induce opsonophagocytic antibodies that confer type-specific active and passive protection in mice. METHODS: A phase II study of patients with end-stage renal disease showed that these conjugates induced approximately one third of the immunoglobulin G antibody of healthy individuals. Increasing the dose to 100 microg of polysaccharide induced levels similar to that in healthy individuals injected with 25 microg. RESULTS: In a double-blinded randomized and controlled study of patients undergoing renal dialysis, the conjugates induced statistically significant protection against bacteremia for as long as 10 months after immunization. The estimated protective level was 80 microg Ab/mL. At re-injection approximately 2 years later, 83 of 83 recipients responded with protective levels. CONCLUSIONS: Conjugate vaccine-induced antibodies to the types 5 and 8 capsular polysaccharide antibodies of S aureus prevent bacteremia caused by this pathogen. The extent and duration of conjugate-induced immunity can be extended by re-immunization approximately 1 year later. Studies of patients undergoing cardiovascular surgery who would be immunized with the staphylococcus conjugates when they are immunologically intact are planned.

Development of StaphVAX, a polysaccharide conjugate vaccine against S. aureus infection: from the lab bench to phase III clinical trials.

Staphylococcus aureus is the most common nosocomial pathogen and is responsible for approximately one-third of hospital-acquired bacteremias. The emergence of strains with multidrug resistance, including resistance to vancomycin, the antibiotic of last resort, presents the medical community with a major public health problem. Alternative therapies, including immunotherapy, have been in development for several decades. The discovery of S. aureus capsular polysaccharides from clinical isolates, and their importance to pathogenicity via antiphagocytic activity, opened a new window of opportunity for development of vaccines and immunotherapy against this pathogen. A conjugate vaccine, StaphVAX that includes the two most prevalent capsular polysaccharides, types 5 and 8, coupled to a carrier protein efficient in promoting a Th2 response, was developed. In a recent phase III clinical study in hemodialysis patients, StaphVAX was shown to prevent S. aureus bacteremia for up to 10 months following a single immunization. The history, epidemiology, serology, and development of StaphVAX, including preclinical and clinical studies demonstrating efficacy are described in this review.

Use of a Staphylococcus aureus conjugate vaccine in patients receiving hemodialysis.

BACKGROUND: In patients with decreased resistance to infection, Staphylococcus aureus is a major cause of bacteremia and its complications. The capsular polysaccharides are essential for the pathogenesis of and immunity to S. aureus infection and are targets for vaccines. METHODS: In a double-blind trial involving patients with end-stage renal disease who were receiving hemodialysis, we evaluated the safety, immunogenicity, and efficacy of a vaccine with S. aureus type 5 and 8 capsular polysaccharides conjugated to nontoxic recombinant Pseudomonas aeruginosa exotoxin A. Between April 1998 and August 1999, 1804 adult patients at 73 hemodialysis centers were randomly assigned to receive a single intramuscular injection of either vaccine or saline. IgG antibodies to S. aureus type 5 and 8 capsular polysaccharides were measured for up to two years, and episodes of S. aureus bacteremia were recorded. Efficacy was estimated by comparing the incidence of S. aureus bacteremia in the patients who received the vaccine with the incidence in the control patients. RESULTS: Reactions to the vaccine were generally mild to moderate, and most resolved within two days. The capsular polysaccharides elicited an antibody response of at least 80 microg per milliliter (the estimated minimal level conferring protection) in 80 percent of patients for type 5 and in 75 percent of patients for type 8. The efficacy during weeks 3 to 54 was only 26 percent (P=0.23). However, between weeks 3 and 40 after vaccination, S. aureus bacteremia developed in 11 of 892 patients in the vaccine group who could be evaluated for bacteremia, as compared with 26 of 906 patients in the control group (estimate of efficacy, 57 percent; 95 percent confidence interval, 10 to 81 percent; nominal P=0.02). CONCLUSIONS: In patients receiving hemodialysis, a conjugate vaccine can confer partial immunity against S. aureus bacteremia for approximately 40 weeks, after which protection wanes as antibody levels decrease.