Increased vaccine tolerability and protection via NF-κB modulation.

Improving adjuvant responses is a promising pathway to develop vaccines against some pathogens (e.g., HIV or dengue). One challenge in adjuvant development is modulating the inflammatory response, which can cause excess side effects, while maintaining immune activation and protection. No approved adjuvants yet have the capability to independently modulate inflammation and protection. Here, we demonstrate a method to limit inflammation while retaining and often increasing the protective responses. To accomplish this goal, we combined a partial selective nuclear factor kappa B (NF-kB) inhibitor with several current adjuvants. The resulting vaccines reduce systemic inflammation and boost protective responses. In an influenza challenge model, we demonstrate that this approach enhances protection. This method was tested across a broad range of adjuvants and antigens. We anticipate these studies will lead to an alternative approach to vaccine formulation design that may prove broadly applicable to a wide range of adjuvants and vaccines.

Antiviral effect of a derivative of isonicotinic acid enisamium iodide (FAV00A) against influenza virus.

With only a single class of antiviral drugs existing for treatment of influenza (neuraminidase inhibitors), the search for novel effective compounds is urgently needed. We evaluated a low molecular mass compound, enisamium iodide (FAV00A), against influenza virus infections in primary differentiated normal human bronchial epithelial (NHBE) cells, and in ferrets. FAV00A (500 µg/ml) markedly inhibited influenza virus replication and reduced viral M-gene expression in NHBE cells. Treatment of ferrets with FAV00A (200 mg/kg once daily for 7 days) initiated 24 h after inoculation with 105 TCID50 of influenza A/Wisconsin/67/2005 (H3N2) virus resulted in a significant decrease in virus titers in the upper respiratory tract. Our data show that FAV00A exhibits an antiviral effect against influenza virus in NHBE cells and provides some benefits in a ferret model. Thus, further Keywords: antiviral agents; enisamium iodide; influenza virus; MDCK cells; NHBE cells; ferrets.

Peramivir and its use in H1N1 influenza.

A novel H1N1 influenza virus of swine origin has emerged, causing the first pandemic of the 21st century. Infections with 2009 pandemic influenza A (H1N1) are typically moderate. However, in rare cases, respiratory distress, neurological complications and death have been reported. To alleviate complications associated with 2009 H1N1 influenza infection, the neuraminidase (NA) inhibitors oseltamivir (oral) and zanamivir (inhaled) are recommended. Hospitalized patients with severe complications may not respond to these drugs or be able to receive oral antiviral therapy, and therefore, parenteral formulations that would allow rapid delivery at high concentrations are being pursued. Peramivir is a novel potent NA inhibitor currently in clinical trials for intravenous (i.v.) administration. In clinical trials, i.v. peramivir was shown to be safe and well tolerated, with a pharmacokinetic profile that supports once-daily dosing. Based on the safety and efficacy of i.v. peramivir in clinical trials and the need for a parenteral antiviral, the U.S. Food and Drug Administration issued an Emergency Use Authorization (EUA) for the use of peramivir for the treatment of hospitalized patients with known or suspected 2009 H1N1 influenza infection. In Japan, peramivir has been licensed under the name Rapiacta. The development of peramivir leading to the issuance of the EUA and approval in Japan will be discussed.

Vaccination against the avian infectious bronchitis virus affects sperm concentration, sperm quality and blood testosterone concentrations in cockerels.

1. It was previously found that cockerels vaccinated with live attenuated avian infectious bronchitis virus (AIBV) have decreased serum testosterone concentrations, epididymal stones and reduced fertility. The objectives of this study were twofold: to determine if reduced fertility following vaccination with live attenuated virus was the result of reduced sperm concentration or reduced sperm quality and to determine if vaccination with a killed strain of virus caused a similar reduction in sperm function in vivo. 2. Specific-pathogen-free Single Comb White Leghorn cockerels were divided into three treatment groups: no vaccination (NONVAC), vaccination with killed AIBV virus (KVAC) or vaccination with live attenuated AIBV virus (LVAC). Semen was collected daily from 17 to 27 weeks of age, and semen quality was assessed frequently by analysing sperm concentration, viability, motility, and ability to reach and interact with the ovum in vivo. Blood plasma was assayed for testosterone concentration. 3. Differences in sperm analysis among treatment groups were limited. Sperm viability was increased in NONVAC during week 20 which then decreased in week 22 when compared to vaccinated cockerels. Acrosome damage was increased in vaccinated cockerels in week 22, and decreased in weeks 25 and 27 when compared to controls, which correlate to the period of epididymal stone development. Plasma testosterone concentrations and sperm concentrations among treatment groups were different only at 16 and 19 weeks of age, respectively. There were no differences across treatment groups in sperm mobility through Accudenz or in numbers of sperm holes in perivitelline membranes of eggs following insemination with semen from 27-week-old cockerels. No differences were observed in viability or acrosome integrity between cockerels with and without epididymal stones within treatment groups. 4. In conclusion, pre-pubertal vaccination against AIBV and subsequent epididymal stone formation had a limited effect on sperm concentration, sperm quality and plasma testosterone concentrations. Vaccination with killed AIBV vaccine did not diminish effects on sperm function in vivo.