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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 of the haemagglutination inhibition antibody response induced after vaccination.The kinetics of the haemagglutination inhibition (HI) antibody response to the homologous vaccine strain (A) A/Vietnam/1194/2004 (NIBRG-14) and the cross-H5 clade HI responses to (B) A/Cambodia/R0405050/2007 (NIBRG-88), (C) A/Indonesia/5/2005 (RG2) and (D) A/turkey/Turkey/1/2005 (NIBRG-23) strains were measured by the HI assay. Subjects were vaccinated 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. The HI titres were measured by the modified HI test using horse erythrocytes. Each symbol represents the geometric HI titre for one individual, with the group geometric mean and 95% confidence interval presented. The dotted line shows the protective HI titre of 32.
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pone.0131652.g004: The kinetics of the haemagglutination inhibition antibody response induced after vaccination.The kinetics of the haemagglutination inhibition (HI) antibody response to the homologous vaccine strain (A) A/Vietnam/1194/2004 (NIBRG-14) and the cross-H5 clade HI responses to (B) A/Cambodia/R0405050/2007 (NIBRG-88), (C) A/Indonesia/5/2005 (RG2) and (D) A/turkey/Turkey/1/2005 (NIBRG-23) strains were measured by the HI assay. Subjects were vaccinated 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. The HI titres were measured by the modified HI test using horse erythrocytes. Each symbol represents the geometric HI titre for one individual, with the group geometric mean and 95% confidence interval presented. The dotted line shows the protective HI titre of 32.

Mentions: The kinetics of the HI response against the homologous vaccine strain (NIBRG-14) following vaccination is shown in Fig 4A. A seroprotective response was defined as an HI titre ≥32. No pre vaccination HI antibody titres were detected in any of the volunteers. The NIBRG-14-specific HI antibody titres started to increase at 7 days post vaccination in all groups, except the lowest adjuvanted dose. By day 14, an increase in the NIBRG-14-specific HI response was detected in all vaccine groups and the titres continued to increase up to day 21. On day 21, a majority of subjects (66%) in the 30μg HA adjuvanted group (GMT = 34) were seroprotected. The second vaccine dose enhanced the NIBRG-14-specific HI responses in all vaccine groups. Among the responding subjects, significantly higher HI GMTs were observed in the adjuvanted 30μg HA group compared with the non-adjuvanted group at days 28 and 42 post-vaccination. A majority of subjects immunized with one of the adjuvanted vaccines (75% to 93%) had seroprotective HI response after the second vaccination (between days 28 and 35), whilst during the same period, between 54% and 64% in the vaccine alone group were seroprotected. By day 42, similar GMTs were observed in the 1.5μg (GMT = 56) and 7.5μg (GMT = 53) HA adjuvanted groups showing the potential of Matrix M adjuvant to dose spare.


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 of the haemagglutination inhibition antibody response induced after vaccination.The kinetics of the haemagglutination inhibition (HI) antibody response to the homologous vaccine strain (A) A/Vietnam/1194/2004 (NIBRG-14) and the cross-H5 clade HI responses to (B) A/Cambodia/R0405050/2007 (NIBRG-88), (C) A/Indonesia/5/2005 (RG2) and (D) A/turkey/Turkey/1/2005 (NIBRG-23) strains were measured by the HI assay. Subjects were vaccinated 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. The HI titres were measured by the modified HI test using horse erythrocytes. Each symbol represents the geometric HI titre for one individual, with the group geometric mean and 95% confidence interval presented. The dotted line shows the protective HI titre of 32.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4493055&req=5

pone.0131652.g004: The kinetics of the haemagglutination inhibition antibody response induced after vaccination.The kinetics of the haemagglutination inhibition (HI) antibody response to the homologous vaccine strain (A) A/Vietnam/1194/2004 (NIBRG-14) and the cross-H5 clade HI responses to (B) A/Cambodia/R0405050/2007 (NIBRG-88), (C) A/Indonesia/5/2005 (RG2) and (D) A/turkey/Turkey/1/2005 (NIBRG-23) strains were measured by the HI assay. Subjects were vaccinated 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. The HI titres were measured by the modified HI test using horse erythrocytes. Each symbol represents the geometric HI titre for one individual, with the group geometric mean and 95% confidence interval presented. The dotted line shows the protective HI titre of 32.
Mentions: The kinetics of the HI response against the homologous vaccine strain (NIBRG-14) following vaccination is shown in Fig 4A. A seroprotective response was defined as an HI titre ≥32. No pre vaccination HI antibody titres were detected in any of the volunteers. The NIBRG-14-specific HI antibody titres started to increase at 7 days post vaccination in all groups, except the lowest adjuvanted dose. By day 14, an increase in the NIBRG-14-specific HI response was detected in all vaccine groups and the titres continued to increase up to day 21. On day 21, a majority of subjects (66%) in the 30μg HA adjuvanted group (GMT = 34) were seroprotected. The second vaccine dose enhanced the NIBRG-14-specific HI responses in all vaccine groups. Among the responding subjects, significantly higher HI GMTs were observed in the adjuvanted 30μg HA group compared with the non-adjuvanted group at days 28 and 42 post-vaccination. A majority of subjects immunized with one of the adjuvanted vaccines (75% to 93%) had seroprotective HI response after the second vaccination (between days 28 and 35), whilst during the same period, between 54% and 64% in the vaccine alone group were seroprotected. By day 42, similar GMTs were observed in the 1.5μg (GMT = 56) and 7.5μg (GMT = 53) HA adjuvanted groups showing the potential of Matrix M adjuvant to dose spare.

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