Because of an increase in the number of reports of Guillian-Barre syndrome (GBS) following A/New Jersey influenza vaccination, the National Influenza Immunization Program was suspended December 16, 1976 and nationwide surveillance for GBS was begun. This surveillance uncovered a total of 1098 patients with onset of GBS from October 1, 1976, to January 31, 1977, from all 50 states, District of Columbia, and Puerto Rico. A total of 532 patients had recently received an A/New Jersey influenza vaccination prior to their onset of GBS (vaccinated cases), and 15 patients received a vaccination after their onset of GBS. Five hundred forty-three patients had not been recently vaccinated with A/New Jersey influenza vaccine and the vaccination status for 8 was unknown. Epidemiologic evidence indicated that many cases of GBS were related to vaccination. When compared to the unvaccinated population, the vaccinated population had a significantly elevated attack rate in every adult age group. The estimated attributable risk of vaccine-related GBS in the adult population was just under one case per 100,000 vaccinations. The period of increased risk was concentrated primarily within the 5-week period after vaccination, although it lasted for approximately 9 or 10 weeks.

IDX184 is a nucleotide prodrug designed to enhance formation in the liver of the active triphosphate of 2-methylguanosine (2-MeG), a potent and specific polymerase inhibitor of the hepatitis C virus (HCV). In the present study, single ascending oral doses of 5, 10, 25, 50, 75, and 100 mg IDX184 were administered sequentially to cohorts of 8 healthy subjects, randomized 6:2, active/placebo. Plasma and urine pharmacokinetic sampling was performed over a period of 120 h after dosing. Upon absorption, IDX184 rapidly disappeared from plasma, with a mean half-life (t 1/2 ) of approximately 1 h, while plasma concentrations of 2-MeG gradually increased. Consistent with a liver-targeting approach, plasma exposure of IDX184 and 2-MeG was low and was also dose related: the mean maximum concentrations ranged from 1.1 to 17 ng/ml for IDX184 and 1.7 to 19 ng/ml for 2-MeG, and the respective mean total area under the curve ranged from 1.2 to 22.7 and 17.3 to 334 ng ⅐ h/ml. Mean 2-MeG plasma concentrations 24 h after dosing were 0.6 to 3 ng/ml for the 25-to 100-mg doses. Mean 2-MeG t 1/2 values ranged from 18 to 43 h for doses of 25 mg and above. Mean cumulative urine excretion was 0.2% and 12 to 20% of administered doses for the unchanged IDX184 and 2-MeG, respectively. IDX184 was safe and well tolerated; no serious adverse events (SAEs), dose-dependent adverse events (AEs), or dose-limiting toxicities were observed. The incidence of AEs and laboratory abnormalities was low and was similar among subjects receiving IDX184 or a placebo. All AEs were mild to moderate and resolved at the end of study. The favorable safety and pharmacokinetic profiles support further clinical evaluation of IDX184 in HCV-infected patients.Hepatitis C virus (HCV) infection is a global public health problem. The global prevalence of hepatitis C infection is estimated to average 3%, resulting in approximately 170 million HCV-infected persons worldwide (8).The current standard of care for patients with chronic hepatitis C and compensated liver disease is the combination of parenterally administered pegylated interferon and orally administered ribavirin. However, sustained virologic response rates are less than 50% in treatment-naive patients with genotype 1 infection (2, 4). In addition, many patients are not good candidates for treatment with these agents due to advanced liver disease or concurrent medical conditions, and many patients show poor tolerance of these treatments. Therefore, there is a need for new anti-HCV therapies, particularly for patients with genotype 1 HCV or those who have failed to respond to the available treatment options.While nucleoside HCV polymerase inhibitors have a higher genetic barrier to resistance and have demonstrated clinical anti-HCV activity, early nucleoside analogs have wide systemic exposure and inefficient phosphorylation of their 5Ј-monophosphate (MP) metabolite, resulting in limited formation of the active 5Ј-triphosphate (TP) in the liver, the site of HCV replication (1,3,5). In that context, IDX184 (Fig. 1) ...

Disrupting transmission of Borrelia burgdorferi (B. burgdorferi ) from infected ticks to humans is one strategy to prevent the significant morbidity from Lyme disease. We have previously shown that an anti-OspA human monoclonal antibody, 2217, prevents transmission of B. burgdorferi from infected ticks in animal models. Maintenance of a protective plasma concentration of a human monoclonal antibody for tick season presents a significant challenge for a pre-exposure prophylaxis strategy. Here, we describe the optimization of 2217 by amino acid substitutions (LS, M428L and N434S) into the Fc domain. The LS mutation led to a twofold-increase in half-life in cynomolgus monkeys.In a rhesus macaque model, 2217LS protected animals from tick transmission of spirochetes at a dose of 3 mg/kg. Crystallographic analysis of Fab in complex with OspA reveals that 2217 binds a novel epitope that is highly conserved among the B. burgdorferi, B. garinii, and B. afzelii species. Unlike most vaccines that may require boosters to achieve protection, our work supports the development of 2217LS as an effective pre-exposure prophylaxis in Lyme-endemic regions with a single dose at the beginning of tick season offering immediate protection that remains for the duration of exposure risk.

This prospective, parallel‐group, randomized, double‐blind, multicenter study compared the efficacy and safety of FV‐100 with valacyclovir for reducing pain associated with acute herpes zoster (HZ). Patients, ≥50 years of age, diagnosed with HZ within 72 h of lesion appearance who had HZ‐associated pain, were randomized 1:1:1 to a 7‐day course of either FV‐100 200 mg QD (n = 117), FV‐100 400 mg QD (n = 116), or valacyclovir 1000 mg TID (n =117). Efficacy was evaluated on the basis of the burden of illness (BOI; Zoster Brief Pain Inventory scores); incidence and duration of clinically significant pain (CSP); pain scores; incidence and severity of post‐herpetic neuralgia (PHN); and times to full lesion crusting and to lesion healing. Safety was evaluated on the basis of adverse event (AE)/SAE profiles, changes in laboratory and vital signs values, and results of electrocardiograms. The burden of illness scores for pain through 30 days were 114.5, 110.3, and 118.0 for FV‐100 200 mg, FV‐100 400 mg, and valacyclovir 3000 mg, respectively. The incidences of PHN at 90 days for FV‐100 200 mg, FV‐100 400 mg, and valacyclovir 3000 mg were 17.8%, 12.4%, and 20.2%, respectively. Adverse event and SAE profiles of the two FV‐100 and the valacyclovir groups were similar and no untoward signals or trends were evident. These results demonstrate a potential for FV‐100 as an antiviral for the treatment of shingles that could both reduce the pain burden of the acute episode and reduce the incidence of PHN compared with available treatments.

e IDX184 is a liver-targeted prodrug of 2=-methylguanosine (2=-MeG) monophosphate. This study investigated the safety, tolerability, antiviral activity, and pharmacokinetics of IDX184 as a single agent in treatment-naïve patients with genotype-1 chronic hepatitis C virus (HCV) infection. Forty-one patients with baseline HCV RNA > 5 log 10 IU/ml, alanine aminotransferase (ALT) < 2.5؋ the upper limit of normal, and compensated liver disease were dosed. Sequential cohorts of 10 patients, randomized 8:2 (active:placebo), received 25, 50, 75, and 100 mg of IDX184 once daily for 3 days, with a 14-day follow-up. There were no safety-related treatment discontinuations or serious adverse events. The adverse events and laboratory abnormalities observed for IDX184-and placebo-treated patients were similar. At the end of the 3-day treatment period, changes from baseline in HCV RNA levels (means ؎ standard deviations) were ؊0.5 ؎ 0.6, ؊0.7 ؎ 0.2, ؊0.6 ؎ 0.3, and ؊0.7 ؎ 0.5 log 10 for the 25-, 50-, 75-, and 100-mg doses, respectively, while viral load remained unchanged for the pooled placebo patients (؊0.05 ؎ 0.3 log 10 ). Patients with genotype-1a and patients with genotype-1b responded similarly. Serum ALT levels decreased, especially at daily doses > 75 mg. During the posttreatment period, plasma viremia and serum aminotransferase levels returned to near pretreatment levels. No resistance mutations associated with IDX184 were detected. Plasma exposure of IDX184 and its nucleoside metabolite 2=-MeG was dose related and low. Changes in plasma viral load correlated with plasma exposure of 2=-MeG. In conclusion, the results from this proof-of-concept study show that small doses of the liver-targeted prodrug IDX184 were able to deliver significant antiviral activity and support further clinical evaluation of the drug candidate. There are an estimated 170 million people worldwide with chronic hepatitis C virus (HCV) infection, representing a global prevalence of approximately 3%. The annual rate of new infections remains high (about 3 to 4 million/year). Most of those infected develop persistent, chronic infection, and an estimated 20% to 50% of patients are at risk for developing long-term complications, including cirrhosis and hepatocellular carcinoma (HCC) (18).The most widely available treatment option for patients with chronic HCV infection is the combination of parenterally administered pegylated interferon and orally administered ribavirin (pegIFN/RBV). Rates of cure, indicated by sustained virologic response (SVR), with this regimen are less than 50% in treatmentnaïve patients with the hard-to-treat genotype-1 infection (5, 7). Both pegIFN and RBV have poor tolerability and are not suitable for patients with advanced liver diseases or concurrent medical conditions. Over the past decade, major efforts have been devoted to developing direct-acting antivirals (DAAs) blocking specific steps in the HCV replication cycle. The addition of HCV NS3/4A protease inhibitors to pegIFN/RBV has shortened the treatment duration for man...