Efficacy of an AS03A-adjuvanted split H5N1 influenza vaccine against an antigenically distinct low pathogenic H5N1 virus in pigs.

We used the pig model of influenza to examine the efficacy of an AS03(A)-adjuvanted split H5N1 (A/Indonesia/05/2005) vaccine against challenge with a low pathogenic (LP) H5N1 avian influenza (AI) virus (duck/Minnesota/1525/1981) with only 85% amino acid homology in its HA1. Influenza seronegative pigs were vaccinated twice intramuscularly with adjuvanted vaccine at 3 antigen doses, unadjuvanted vaccine or placebo. All pigs were challenged 4 weeks after the second vaccination and euthanized 2 days later. After 2 vaccinations, all pigs in the adjuvanted vaccine groups had high hemagglutination inhibiting (HI) antibody titers to the vaccine strain (160-640), and lower antibody titers to the A/Vietnam/1194/04 H5N1 strain and to 2 LP H5 viruses with 90-91% amino acid homology to the vaccine strain (20-160). Eight out of 12 pigs had HI titers (10-20) to the challenge virus immediately before challenge. Neuraminidase inhibiting antibodies to the challenge virus were detected in most pigs (7/12) and virus neutralizing antibodies in all pigs. There was no antigen-dose dependent effect on the antibody response among the pigs immunized with adjuvanted H5N1 vaccines. After challenge, these pigs showed a complete clinical protection, reduced lung lesions and a significant protection against virus replication in the respiratory tract. Though the challenge virus showed only moderate replication efficiency in pigs, our study suggests that AS03(A)-adjuvanted H5N1 vaccine may confer a broader protection than generally assumed. The pros and cons of the pig as an H5N1 challenge model are also discussed.

Hoover's sign is a predictor of airflow obstruction severity and is not related to hyperinflation in chronic obstructive pulmonary disease.

BACKGROUND: Several phenotypes are described in COPD. OBJECTIVES: To assess if COPD patients with Hoover's sign (HS) belong to a particular phenotype. METHODS: All consecutive COPD patients with varying degree of airflow obstruction that came for lung function testing in one university hospital were prospectively assessed, using clinical and magnetometer detection of HS, body mass index (BMI), St. George's Respiratory Questionnaire for health-related quality of life, six-minute-walk test (6MWT) with inspiratory capacity (IC) measurements and expiratory flow limitation (EFL) detection. Previous exacerbations were also reported. RESULTS: 82 patients were studied. Magnetometers confirmed HS in 56 of them, of which 79% (44/56) were detected by clinical assessment. HS (+) patients were older (64 ± 10 vs 59 ± 10 years, p=0.03), had a higher BMI (26 ± 5 vs 23 ± 4, p=0.04), a lower FEV1 (53% ± 18% vs 63% ± 18% pred, p=0.02) and a higher IC decrease at the end of 6MWT, (-19 ± 2 vs -7 ± 4% pred, p=0.003). A larger proportion of HS (+) patients also reported severe exacerbations during the past 2 years (39% vs 12% p=0.01). There was no statistical evidence that HS was related to hyperinflation and/or EFL. CONCLUSION: The very simple clinical HS allows identifying a particular population of COPD patients of older age and higher BMI with a more severe airflow obstruction, increased dynamic hyperinflation during exercise and higher exacerbation frequency. These characteristics were not linked to hyperinflation or EFL.

Adjuvant System AS03 containing α-tocopherol modulates innate immune response and leads to improved adaptive immunity.

AS03 is an Adjuvant System (AS) containing α-tocopherol and squalene in an oil-in-water (o/w) emulsion. AS03 has been considered for the development of pandemic and seasonal influenza vaccines. Key features of AS03's mode of action were investigated in vivo in mice and ex vivo in human cells. AS03's adjuvant activity was superior to that of aluminium hydroxide and required the spatio-temporal co-localisation of AS03 with the antigen. This requirement coincided with AS03 triggering a transient production of cytokines at the injection site and in the draining lymph nodes (dLNs). The nature of the cytokines produced was consistent with the enhanced recruitment of granulocytes and of antigen-loaded monocytes in the dLNs. The presence of α-tocopherol in AS03 was required for AS03 to achieve the highest antibody response. The presence of α-tocopherol also modulated the expression of some cytokines, including CCL2, CCL3, IL-6, CSF3 and CXCL1; increased the antigen loading in monocytes; and increased the recruitment of granulocytes in the dLNs. Hence, AS03's promotion of monocytes as the principal antigen-presenting cells, and its effects on granulocytes and cytokines, may all contribute to enhancing the antigen-specific adaptive immune response.

Longevity of the protective immune response induced after vaccination with one or two doses of AS03A-adjuvanted split H5N1 vaccine in ferrets.

It is crucial that a safe and effective pandemic vaccine be rapidly available to combat a new pandemic threat. In this study we investigated the magnitude and persistence of the protective efficacy induced by one or two doses (3.75 µg HA/dose) of AS03(A)-adjuvanted H5N1 A/Indonesia/5/05 split vaccine in a lethal ferret challenge model. All ferrets that received at least one dose of adjuvanted vaccine 4 weeks before homologous challenge survived and showed reduced or undetectable virus replication in the lungs and the upper airways. Ferrets receiving two doses of adjuvanted vaccine 19 and 16 weeks before the challenge also showed high level of protection from replication in the lungs and the upper airways, albeit with only 83% survival. Animals in the control groups (non-adjuvanted vaccine or saline) and animals immunized with one dose of adjuvanted vaccine administered 10 or 16 weeks before challenge showed only 17-33% survival rate after challenge. In conclusion, our observations support the possibility that a single dose of AS03(A)-adjuvanted H5N1 split vaccine can offer a rapid and short term but partial protection against disease. A second dose of the adjuvanted vaccine, which can be given with a flexible injection schedule, was shown to be essential to induce appreciable levels of antibodies and long-term protection.

Pandemic H1N1 vaccine requires the use of an adjuvant to protect against challenge in naïve ferrets.

In the context of an A/H1N1 influenza pandemic situation, this study demonstrates that heterologous vaccination with an AS03-adjuvanted 2008/2009 seasonal trivalent and pandemic H5N1 monovalent split vaccine conferred partial protection in influenza-naïve ferrets after challenge with the influenza pandemic H1N1 A/The Netherlands/602/09 virus. Further, unlike saline control and non-adjuvanted vaccine, it was shown that immunization of naïve ferrets with an AS03-adjuvanted pandemic H1N1 A/California/7/09 influenza split vaccine induced increased antibody response and enhanced protection against the challenge strain, including significant reduction in viral shedding in the upper respiratory tract and reduced lung pathology post-challenge. These results show the need for vaccination with the adjuvanted vaccine to fully protect against viral replication and influenza disease in unprimed ferrets.