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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 microneutralization response after vaccination.The kinetics (A) and long-term (B) microneutralization (MN) antibody 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 30μg HA (black) adjuvanted with Matrix-M (50μg). The sampling day after vaccination is shown on the x-axis. Each symbol represents the geometric mean MN titre for one individual participant, with the group geometric mean titre and 95% confidence interval presented. The dotted line indicates the protective MN titre of 80.
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pone.0131652.g002: The kinetics and long-term microneutralization response after vaccination.The kinetics (A) and long-term (B) microneutralization (MN) antibody 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 30μg HA (black) adjuvanted with Matrix-M (50μg). The sampling day after vaccination is shown on the x-axis. Each symbol represents the geometric mean MN titre for one individual participant, with the group geometric mean titre and 95% confidence interval presented. The dotted line indicates the protective MN titre of 80.

Mentions: Fig 2 shows the kinetics (Fig 2A) and long-term (Fig 2B) MN responses in humans after vaccination. A seroprotective MN response was defined as a MN titre ≥80 [17]. No pre-vaccination neutralizing antibodies were detected in any of the subjects. MN responses were detectable by day 7 in all groups (except the adjuvanted 1.5μg HA group) with one subject each from the adjuvanted 7.5μg and 30μg HA groups having a protective antibody response. At day 14, higher MN geometric mean titres (GTMT) were observed in the adjuvanted 30μg HA (GMT = 25) and 7.5μg HA (GMT = 13) groups compared with the virosomal alone group (GMT = 9), however, when considering only the responding subjects, the differences were not statistically significant. The response plateaued to day 21 with at least one subject from each vaccine group having protective neutralizing responses. The second immunization augmented the MN response in all vaccine groups. On day 28, 38% of vaccinees in the 1.5μg HA group and 64% in the adjuvanted 30μg HA group had MN titres ≥80. In comparison, only 15% of volunteers in the virosomal alone group had protective MN titres at day 28. By day 35, an increase in the MN GMTs was observed in the adjuvanted 1.5μg HA (GMT = 95, 58% seroprotected) and 30μg HA (GMT = 163, 85% seroprotected) groups while titres slightly decreased in the other two vaccine groups. When considering only the responding subjects, the adjuvanted 30μg HA group had significantly higher GMTs compared with the non-adjuvanted group at days 28, 35 and 42 post-vaccination. On day 42, a dose-dependent response was observed in the adjuvant groups with between 46% and 60% of subjects having protective neutralizing antibody titres, whilst only 14% in the virosomal alone group were seroprotected.


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 microneutralization response after vaccination.The kinetics (A) and long-term (B) microneutralization (MN) antibody 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 30μg HA (black) adjuvanted with Matrix-M (50μg). The sampling day after vaccination is shown on the x-axis. Each symbol represents the geometric mean MN titre for one individual participant, with the group geometric mean titre and 95% confidence interval presented. The dotted line indicates the protective MN titre of 80.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131652.g002: The kinetics and long-term microneutralization response after vaccination.The kinetics (A) and long-term (B) microneutralization (MN) antibody 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 30μg HA (black) adjuvanted with Matrix-M (50μg). The sampling day after vaccination is shown on the x-axis. Each symbol represents the geometric mean MN titre for one individual participant, with the group geometric mean titre and 95% confidence interval presented. The dotted line indicates the protective MN titre of 80.
Mentions: Fig 2 shows the kinetics (Fig 2A) and long-term (Fig 2B) MN responses in humans after vaccination. A seroprotective MN response was defined as a MN titre ≥80 [17]. No pre-vaccination neutralizing antibodies were detected in any of the subjects. MN responses were detectable by day 7 in all groups (except the adjuvanted 1.5μg HA group) with one subject each from the adjuvanted 7.5μg and 30μg HA groups having a protective antibody response. At day 14, higher MN geometric mean titres (GTMT) were observed in the adjuvanted 30μg HA (GMT = 25) and 7.5μg HA (GMT = 13) groups compared with the virosomal alone group (GMT = 9), however, when considering only the responding subjects, the differences were not statistically significant. The response plateaued to day 21 with at least one subject from each vaccine group having protective neutralizing responses. The second immunization augmented the MN response in all vaccine groups. On day 28, 38% of vaccinees in the 1.5μg HA group and 64% in the adjuvanted 30μg HA group had MN titres ≥80. In comparison, only 15% of volunteers in the virosomal alone group had protective MN titres at day 28. By day 35, an increase in the MN GMTs was observed in the adjuvanted 1.5μg HA (GMT = 95, 58% seroprotected) and 30μg HA (GMT = 163, 85% seroprotected) groups while titres slightly decreased in the other two vaccine groups. When considering only the responding subjects, the adjuvanted 30μg HA group had significantly higher GMTs compared with the non-adjuvanted group at days 28, 35 and 42 post-vaccination. On day 42, a dose-dependent response was observed in the adjuvant groups with between 46% and 60% of subjects having protective neutralizing antibody titres, whilst only 14% in the virosomal alone group were seroprotected.

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