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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

Correlation between serological responses to the homologous and cross-reactive H5N1 strains at days 21, 42 and 180 after vaccination.The correlation between A/Vietnam/1194/2004 (NIBRG-14)-specific HI, SRH, MN and IgG responses and the HI responses against A/turkey/Turkey/1/2005 (NIBRG-23), A/Cambodia/R0405050/2007 (NIBRG-88) and A/Indonesia/5/2005 (RG2) at 21, 42 and 180 days after vaccination. Volunteers were divided into four vaccine groups and were vaccinated with two doses (21 ±1 days apart) of inactivated virosomal H5N1 vaccine alone (30μg HA) or 1.5, 7.5 or 30μg HA adjuvanted with Matrix-M (50μg). Data from the four vaccine groups were combined to calculate the Spearman rank correlation coefficient (r) value (adjusted for multiple comparisons) for each association between the homologous and cross-H5 clade serological response. Abbreviations: p, Two-tailed p value (95% confidence interval); NS, no significant correlation.
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pone.0131652.g007: Correlation between serological responses to the homologous and cross-reactive H5N1 strains at days 21, 42 and 180 after vaccination.The correlation between A/Vietnam/1194/2004 (NIBRG-14)-specific HI, SRH, MN and IgG responses and the HI responses against A/turkey/Turkey/1/2005 (NIBRG-23), A/Cambodia/R0405050/2007 (NIBRG-88) and A/Indonesia/5/2005 (RG2) at 21, 42 and 180 days after vaccination. Volunteers were divided into four vaccine groups and were vaccinated with two doses (21 ±1 days apart) of inactivated virosomal H5N1 vaccine alone (30μg HA) or 1.5, 7.5 or 30μg HA adjuvanted with Matrix-M (50μg). Data from the four vaccine groups were combined to calculate the Spearman rank correlation coefficient (r) value (adjusted for multiple comparisons) for each association between the homologous and cross-H5 clade serological response. Abbreviations: p, Two-tailed p value (95% confidence interval); NS, no significant correlation.

Mentions: To test whether subjects who had high NIBRG-14-specific serological responses (HI, SRH, MN and serum IgG) also had good cross-H5 clade HI responses, we performed Spearman rank correlation coefficient (r) analysis at 21, 42 and 180 days post-vaccination (Fig 7). Subjects that had higher NIBRG-14-specific HI, SRH, MN and IgG responses also had good HI responses to NIBRG-23 and NIBRG-88 strains with Spearman r values ranging between 0.36 and 0.7. The correlation between the homologous serological responses and HI responses to the RG2 strain were less robust. On day 21, the RG2-specific HI response showed a significant correlation with the homologous HI response (r = 0.49, p<0.0001) but not with the SRH, MN or IgG responses. However, by day 42, a significant correlation was observed between the NIBRG-14-specific HI, SRH, MN and IgG responses and the RG2-specific HI responses, with Spearman r values ranging between 0.38 and 0.48. At six months post-vaccination, the NIBRG-14-specific HI responses showed significant correlation with the NIBRG-23 and NIBRG-88-specific HI responses, but not with RG2-specific HI titres.


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)

Correlation between serological responses to the homologous and cross-reactive H5N1 strains at days 21, 42 and 180 after vaccination.The correlation between A/Vietnam/1194/2004 (NIBRG-14)-specific HI, SRH, MN and IgG responses and the HI responses against A/turkey/Turkey/1/2005 (NIBRG-23), A/Cambodia/R0405050/2007 (NIBRG-88) and A/Indonesia/5/2005 (RG2) at 21, 42 and 180 days after vaccination. Volunteers were divided into four vaccine groups and were vaccinated with two doses (21 ±1 days apart) of inactivated virosomal H5N1 vaccine alone (30μg HA) or 1.5, 7.5 or 30μg HA adjuvanted with Matrix-M (50μg). Data from the four vaccine groups were combined to calculate the Spearman rank correlation coefficient (r) value (adjusted for multiple comparisons) for each association between the homologous and cross-H5 clade serological response. Abbreviations: p, Two-tailed p value (95% confidence interval); NS, no significant correlation.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131652.g007: Correlation between serological responses to the homologous and cross-reactive H5N1 strains at days 21, 42 and 180 after vaccination.The correlation between A/Vietnam/1194/2004 (NIBRG-14)-specific HI, SRH, MN and IgG responses and the HI responses against A/turkey/Turkey/1/2005 (NIBRG-23), A/Cambodia/R0405050/2007 (NIBRG-88) and A/Indonesia/5/2005 (RG2) at 21, 42 and 180 days after vaccination. Volunteers were divided into four vaccine groups and were vaccinated with two doses (21 ±1 days apart) of inactivated virosomal H5N1 vaccine alone (30μg HA) or 1.5, 7.5 or 30μg HA adjuvanted with Matrix-M (50μg). Data from the four vaccine groups were combined to calculate the Spearman rank correlation coefficient (r) value (adjusted for multiple comparisons) for each association between the homologous and cross-H5 clade serological response. Abbreviations: p, Two-tailed p value (95% confidence interval); NS, no significant correlation.
Mentions: To test whether subjects who had high NIBRG-14-specific serological responses (HI, SRH, MN and serum IgG) also had good cross-H5 clade HI responses, we performed Spearman rank correlation coefficient (r) analysis at 21, 42 and 180 days post-vaccination (Fig 7). Subjects that had higher NIBRG-14-specific HI, SRH, MN and IgG responses also had good HI responses to NIBRG-23 and NIBRG-88 strains with Spearman r values ranging between 0.36 and 0.7. The correlation between the homologous serological responses and HI responses to the RG2 strain were less robust. On day 21, the RG2-specific HI response showed a significant correlation with the homologous HI response (r = 0.49, p<0.0001) but not with the SRH, MN or IgG responses. However, by day 42, a significant correlation was observed between the NIBRG-14-specific HI, SRH, MN and IgG responses and the RG2-specific HI responses, with Spearman r values ranging between 0.38 and 0.48. At six months post-vaccination, the NIBRG-14-specific HI responses showed significant correlation with the NIBRG-23 and NIBRG-88-specific HI responses, but not with RG2-specific HI titres.

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