Pharmacokinetics and tolerability of ABX464, a novel first-in-class compound to treat HIV infection, in healthy HIV-uninfected subjects.

Background: An anti-HIV compound (ABX464) has been developed with a novel mechanism of activity in that it blocks viral gene expression in cells that are already infected. Objectives: A first-in-man study was conducted to determine the pharmacokinetic and safety profiles of ABX464. This was carried out as an open label, parallel group, single ascending dose, exploratory study. Methods: Twenty-four male subjects in good health without HIV infection, aged from 18 to 55 years old, with BMIs of 18-27 kg/m 2 were included. A single oral dose of ABX464 (50, 100, 150 or 200 mg) was administered on the morning of day 0 after overnight fasting, with follow-up for 45 days. Safety assessments consisted of vital signs, electrocardiogram, physical examination, laboratory tests and urinalysis. Pharmacokinetic parameters were calculated for ABX464 and its main metabolite ABX-464- N -glucuronide (ABX464-NGlc). The study was registered at https://www.clinicaltrials (trial number NCT02792686). Results: ABX464 was well tolerated; the most frequent related treatment-emergent adverse events were headaches, nausea and vomiting; they were not considered as treatment-limiting effects. ABX464's C max was observed approximately 2 h after administration in all groups. ABX464 was rapidly and substantially metabolized into ABX464-NGlc. The C max of ABX464-NGlc was observed approximately 4 h post-dose and was about 160-fold higher than that of the parent with a much longer t 1/2 (90-110 h). The ratio of metabolite to parent drug was consistent across the complete dose range. Conclusions: These studies confirmed that ABX464 is well tolerated and rapidly and substantially metabolized into ABX464-NGlc in human subjects.

An inactivated West Nile Virus vaccine derived from a chemically synthesized cDNA system.

A cDNA comprising the complete genome of West Nile Virus (WNV) was generated by chemical synthesis using published sequence data, independent of any preformed viral components. The synthetic WNV, produced by transfection of in vitro transcribed RNA into cell culture, exhibited undistinguishable biological properties compared to the corresponding animal-derived wild-type virus. No differences were found concerning viral growth in mammalian and insect cell lines and concerning expression of viral proteins in cells. There were also no significant differences in virulence in mice following intranasal challenge. After immunizations of mice with experimental vaccines derived from the synthetic and wild-type viruses, protection from lethal challenge was achieved with similar amounts of antigen. Both vaccine preparations also induced comparable levels of neutralizing antibodies in mice. In addition, the synthetic approach turned out to be very accurate, since the rescued WNV genome contained no undesired mutations. Thus, the first flavivirus based on chemical gene synthesis was indistinguishable from the parent virus. This demonstrates that virus isolates from animal sources are dispensable to derive seed viruses for vaccine production or research.

Seasonal influenza vaccine elicits heterosubtypic immunity against H5N1 that can be further boosted by H5N1 vaccination.

Recent findings indicate that seasonal influenza vaccination or infection of healthy humans may contribute to heterosubtypic immunity against new influenza A subtypes, such as H5N1. Here, we investigated whether seasonal influenza vaccination in a mouse model could induce any immunity against the H5N1 subtype. It could be demonstrated that, largely due to the H1N1 component strain A/NewCaledonia/20/99, parenteral immunization of mice with a trivalent seasonal influenza vaccine elicited heterosubtype H5-reactive antibodies able to confer partial protection against H5N1 influenza virus infection. Furthermore, the trivalent seasonal influenza vaccine was found to be compatible with a whole virus H5N1 vaccine in a heterologous prime-boost immunization regimen, achieving superior efficacy compared to a single immunization with an equivalent low-dose of the H5N1 vaccine.

A cell culture (Vero)-derived H5N1 whole-virus vaccine induces cross-reactive memory responses.

Novel strategies are required to provide rapid vaccine coverage in the event of an influenza pandemic. A phase I/II dose finding/formulation study was performed with a whole-virus H5N1 clade 1 A/Vietnam vaccine (2-dose priming regimen) to evaluate safety and immunogenicity. Seventy-seven of 141 subjects in this study received a booster (12-17 months after priming) with a 7.5-microg dose of a clade 2.1 A/Indonesia vaccine. The prime-boost regimen resulted in antibody responses against clade 1, 2.1, 2.2, and 2.3 viruses that were significantly higher than those after the priming regimen. These findings demonstrate that a prime-boost regimen may alleviate vaccine supply constraints in a pandemic.