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Matrix M H5N1 Vaccine Induces Cross-H5 Clade Humoral Immune Responses in a Randomized Clinical Trial and Provides Protection from Highly Pathogenic Influenza Challenge in Ferrets.

Cox RJ, Major D, Pedersen G, Pathirana RD, Hoschler K, Guilfoyle K, Roseby S, Bredholt G, Assmus J, Breakwell L, Campitelli L, Sjursen H - PLoS ONE (2015)

Bottom Line: Highly pathogenic avian influenza (HPAI) viruses constitute a pandemic threat and the development of effective vaccines is a global priority.The NIBRG-14-specific seroprotection rates fell significantly by six months and were low against cross-reactive strains although the adjuvant appeared to prolong the longevity of the protective responses in some subjects.In a HPAI ferret challenge model, the vaccine protected the animals from febrile responses, severe weight loss and local and systemic spread of the virus.

View Article: PubMed Central - PubMed

Affiliation: Influenza Centre, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Research and Development, Haukeland University Hospital, Bergen, Norway; Jebsen Centre for Influenza Vaccine Research, University of Bergen, Bergen, Norway.

ABSTRACT

Background and methods: Highly pathogenic avian influenza (HPAI) viruses constitute a pandemic threat and the development of effective vaccines is a global priority. Sixty adults were recruited into a randomized clinical trial and were intramuscularly immunized with two virosomal vaccine H5N1 (NIBRG-14) doses (21 days apart) of 30 μg HA alone or 1.5, 7.5 or 30 μg HA adjuvanted with Matrix M. The kinetics and longevity of the serological responses against NIBRG-14 were determined by haemagglutination inhibition (HI), single radial haemolysis (SRH), microneutralization (MN) and ELISA assays. The cross-H5 clade responses in sera were determined by HI and the antibody-secreting (ASC) cell ELISPOT assays. The protective efficacy of the vaccine against homologous HPAI challenge was evaluated in ferrets.

Results: The serological responses against the homologous and cross-reactive strains generally peaked one week after the second dose, and formulation with Matrix M augmented the responses. The NIBRG-14-specific seroprotection rates fell significantly by six months and were low against cross-reactive strains although the adjuvant appeared to prolong the longevity of the protective responses in some subjects. By 12 months post-vaccination, nearly all vaccinees had NIBRG-14-specific antibody titres below the protective thresholds. The Matrix M adjuvant was shown to greatly improve ASC and serum IgG responses following vaccination. In a HPAI ferret challenge model, the vaccine protected the animals from febrile responses, severe weight loss and local and systemic spread of the virus.

Conclusion: Our findings show that the Matrix M-adjuvanted virosomal H5N1 vaccine is a promising pre-pandemic vaccine candidate.

Trial registration: ClinicalTrials.gov NCT00868218.

No MeSH data available.


Related in: MedlinePlus

The kinetics and long-term single radial haemolysis antibody response induced after vaccination.The kinetics (A) and long-term (B) single radial haemolysis response to the homologous vaccine strain A/Vietnam/1194/2004 (NIBRG-14) after vaccination with two doses (21 ±1 days apart) of inactivated virosomal H5N1 vaccine alone (30μg HA, blue) or 1.5 (red), 7.5 (green) or 30 μg HA (black) adjuvanted with Matrix-M (50μg). The sampling day after vaccination is shown on the x-axis. Each symbol represents the geometric mean lysis zone area (mm2) for one individual participant, with the group geometric mean and 95% confidence interval presented. The dotted line shows the seroprotective SRH Zone area of ≥25mm2.
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pone.0131652.g003: The kinetics and long-term single radial haemolysis antibody response induced after vaccination.The kinetics (A) and long-term (B) single radial haemolysis response to the homologous vaccine strain A/Vietnam/1194/2004 (NIBRG-14) after vaccination with two doses (21 ±1 days apart) of inactivated virosomal H5N1 vaccine alone (30μg HA, blue) or 1.5 (red), 7.5 (green) or 30 μg HA (black) adjuvanted with Matrix-M (50μg). The sampling day after vaccination is shown on the x-axis. Each symbol represents the geometric mean lysis zone area (mm2) for one individual participant, with the group geometric mean and 95% confidence interval presented. The dotted line shows the seroprotective SRH Zone area of ≥25mm2.

Mentions: Fig 3A shows the kinetics of the SRH response to the homologous vaccine strain NIBRG-14. A seroprotective SRH response was defined as a SRH zone area ≥25mm2. No SRH antibodies were detected pre vaccination apart from two volunteers in the 7.5 μg HA adjuvanted group who had very low SRH zone areas of 6 and 9mm2. The SRH responses started to increase from day 7 post-first vaccination with 3 out of 15 subjects in the 30μg HA adjuvanted group having SRH zone areas ≥25 mm2. The SRH titres continued to increase by day 14-post first vaccination, with 4 subjects in the 30μg HA adjuvanted group and 1–2 subjects in other groups having SRH zone areas ≥25 mm2. By day 21, 7 of 15 subjects (47%) in the adjuvanted 30μg HA group had SRH zone areas ≥25 mm2, whereas only 2 to 4 vaccinees had protective antibody titres in the other vaccine groups. The second immunization augmented the SRH titres in all of the vaccine and by day 28, all of the subjects in the adjuvanted 7.5μg HA and 30 μg HA groups had SRH zone areas ≥25 mm2, whilst high SRH titres were also detected in the adjuvanted 1.5μg HA (85% protected) and virosomal alone groups (54% protected). When considering only the responding subjects, the adjuvanted 7.5μg HA and 30 μg HA groups had significantly higher GMT zone areas compared with the non-adjuvanted group at day 28. Similarly at day 35, the 7.5μg HA group had significantly higher SRH zone areas compared with the non-adjuvanted group. Among the volunteers that received an adjuvanted vaccine, between 0% and 13% failed to elicit a SRH response at day 42, whilst the number of non-responders was 43% in the non-adjuvanted group.


Matrix M H5N1 Vaccine Induces Cross-H5 Clade Humoral Immune Responses in a Randomized Clinical Trial and Provides Protection from Highly Pathogenic Influenza Challenge in Ferrets.

Cox RJ, Major D, Pedersen G, Pathirana RD, Hoschler K, Guilfoyle K, Roseby S, Bredholt G, Assmus J, Breakwell L, Campitelli L, Sjursen H - PLoS ONE (2015)

The kinetics and long-term single radial haemolysis antibody response induced after vaccination.The kinetics (A) and long-term (B) single radial haemolysis response to the homologous vaccine strain A/Vietnam/1194/2004 (NIBRG-14) after vaccination with two doses (21 ±1 days apart) of inactivated virosomal H5N1 vaccine alone (30μg HA, blue) or 1.5 (red), 7.5 (green) or 30 μg HA (black) adjuvanted with Matrix-M (50μg). The sampling day after vaccination is shown on the x-axis. Each symbol represents the geometric mean lysis zone area (mm2) for one individual participant, with the group geometric mean and 95% confidence interval presented. The dotted line shows the seroprotective SRH Zone area of ≥25mm2.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493055&req=5

pone.0131652.g003: The kinetics and long-term single radial haemolysis antibody response induced after vaccination.The kinetics (A) and long-term (B) single radial haemolysis response to the homologous vaccine strain A/Vietnam/1194/2004 (NIBRG-14) after vaccination with two doses (21 ±1 days apart) of inactivated virosomal H5N1 vaccine alone (30μg HA, blue) or 1.5 (red), 7.5 (green) or 30 μg HA (black) adjuvanted with Matrix-M (50μg). The sampling day after vaccination is shown on the x-axis. Each symbol represents the geometric mean lysis zone area (mm2) for one individual participant, with the group geometric mean and 95% confidence interval presented. The dotted line shows the seroprotective SRH Zone area of ≥25mm2.
Mentions: Fig 3A shows the kinetics of the SRH response to the homologous vaccine strain NIBRG-14. A seroprotective SRH response was defined as a SRH zone area ≥25mm2. No SRH antibodies were detected pre vaccination apart from two volunteers in the 7.5 μg HA adjuvanted group who had very low SRH zone areas of 6 and 9mm2. The SRH responses started to increase from day 7 post-first vaccination with 3 out of 15 subjects in the 30μg HA adjuvanted group having SRH zone areas ≥25 mm2. The SRH titres continued to increase by day 14-post first vaccination, with 4 subjects in the 30μg HA adjuvanted group and 1–2 subjects in other groups having SRH zone areas ≥25 mm2. By day 21, 7 of 15 subjects (47%) in the adjuvanted 30μg HA group had SRH zone areas ≥25 mm2, whereas only 2 to 4 vaccinees had protective antibody titres in the other vaccine groups. The second immunization augmented the SRH titres in all of the vaccine and by day 28, all of the subjects in the adjuvanted 7.5μg HA and 30 μg HA groups had SRH zone areas ≥25 mm2, whilst high SRH titres were also detected in the adjuvanted 1.5μg HA (85% protected) and virosomal alone groups (54% protected). When considering only the responding subjects, the adjuvanted 7.5μg HA and 30 μg HA groups had significantly higher GMT zone areas compared with the non-adjuvanted group at day 28. Similarly at day 35, the 7.5μg HA group had significantly higher SRH zone areas compared with the non-adjuvanted group. Among the volunteers that received an adjuvanted vaccine, between 0% and 13% failed to elicit a SRH response at day 42, whilst the number of non-responders was 43% in the non-adjuvanted group.

Bottom Line: Highly pathogenic avian influenza (HPAI) viruses constitute a pandemic threat and the development of effective vaccines is a global priority.The NIBRG-14-specific seroprotection rates fell significantly by six months and were low against cross-reactive strains although the adjuvant appeared to prolong the longevity of the protective responses in some subjects.In a HPAI ferret challenge model, the vaccine protected the animals from febrile responses, severe weight loss and local and systemic spread of the virus.

View Article: PubMed Central - PubMed

Affiliation: Influenza Centre, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Research and Development, Haukeland University Hospital, Bergen, Norway; Jebsen Centre for Influenza Vaccine Research, University of Bergen, Bergen, Norway.

ABSTRACT

Background and methods: Highly pathogenic avian influenza (HPAI) viruses constitute a pandemic threat and the development of effective vaccines is a global priority. Sixty adults were recruited into a randomized clinical trial and were intramuscularly immunized with two virosomal vaccine H5N1 (NIBRG-14) doses (21 days apart) of 30 μg HA alone or 1.5, 7.5 or 30 μg HA adjuvanted with Matrix M. The kinetics and longevity of the serological responses against NIBRG-14 were determined by haemagglutination inhibition (HI), single radial haemolysis (SRH), microneutralization (MN) and ELISA assays. The cross-H5 clade responses in sera were determined by HI and the antibody-secreting (ASC) cell ELISPOT assays. The protective efficacy of the vaccine against homologous HPAI challenge was evaluated in ferrets.

Results: The serological responses against the homologous and cross-reactive strains generally peaked one week after the second dose, and formulation with Matrix M augmented the responses. The NIBRG-14-specific seroprotection rates fell significantly by six months and were low against cross-reactive strains although the adjuvant appeared to prolong the longevity of the protective responses in some subjects. By 12 months post-vaccination, nearly all vaccinees had NIBRG-14-specific antibody titres below the protective thresholds. The Matrix M adjuvant was shown to greatly improve ASC and serum IgG responses following vaccination. In a HPAI ferret challenge model, the vaccine protected the animals from febrile responses, severe weight loss and local and systemic spread of the virus.

Conclusion: Our findings show that the Matrix M-adjuvanted virosomal H5N1 vaccine is a promising pre-pandemic vaccine candidate.

Trial registration: ClinicalTrials.gov NCT00868218.

No MeSH data available.


Related in: MedlinePlus