Enhanced immunogenicity, mortality protection, and reduced viral brain invasion by alum adjuvant with an H5N1 split-virion vaccine in the ferret.

Abstract

BACKGROUND:

Pre-pandemic development of an inactivated, split-virion avian influenza vaccine is challenged by the lack of pre-existing immunity and the reduced immunogenicity of some H5 hemagglutinins compared to that of seasonal influenza vaccines. Identification of an acceptable effective adjuvant is needed to improve immunogenicity of a split-virion avian influenza vaccine.

METHODS AND FINDINGS:

Ferrets (N = 118) were vaccinated twice with a split-virion vaccine preparation of A/Vietnam/1203/2004 or saline either 21 days apart (unadjuvanted: 1.9 µg, 7.5 µg, 30 µg, or saline), or 28 days apart (unadjuvanted: 22.5 µg, or alum-adjuvanted: 22.5 or 7.5 µg). Vaccinated animals were challenged intranasally 21 or 28 days later with 10(6) EID(50) of the homologous strain. Immunogenicity was measured by hemagglutination inhibition and neutralization assays. Morbidity was assessed by observed behavior, weight loss, temperature, cytopenias, histopathology, and viral load. No serum antibodies were detected after vaccination with unadjuvanted vaccine, whereas alum-adjuvanted vaccination induced a robust antibody response. Survival after unadjuvanted dose regimens of 30 µg, 7.5 µg and 1.9 µg (21-day intervals) was 64%, 43%, and 43%, respectively, yet survivors experienced weight loss, fever and thrombocytopenia. Survival after unadjuvanted dose regimen of 22.5 µg (28-day intervals) was 0%, suggesting important differences in intervals in this model. In contrast to unadjuvanted survivors, either dose of alum-adjuvanted vaccine resulted in 93% survival with minimal morbidity and without fever or weight loss. The rarity of brain inflammation in alum-adjuvanted survivors, compared to high levels in unadjuvanted vaccine survivors, suggested that improved protection associated with the alum adjuvant was due to markedly reduced early viral invasion of the ferret brain.

CONCLUSION:

Alum adjuvant significantly improves efficacy of an H5N1 split-virion vaccine in the ferret model as measured by immunogenicity, mortality, morbidity, and brain invasion.

• Authors: Robert Colby Layton, Andrew Gigliotti, Penny Armijo, Leslie Myers, Jennifer Knight, Nathaniel Donart, John Pyles, Sarah Vaughan, Jennifer Plourde, Ndingsa Fomukong, Kevin S Harrod, Peng Gao, Frederick Koster
• Journal: PloS one (PLoS One) Vol. 6 Issue 6 Pg. e20641 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21687736 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adjuvants, Immunologic
• Alum Compounds
• Viral Vaccines

Topics

• Adjuvants, Immunologic (pharmacology)
• Alum Compounds (pharmacology)
• Animals
• Antibody Formation
• Brain (drug effects, immunology, virology)
• Ferrets
• Hematologic Tests
• Influenza A Virus, H5N1 Subtype (drug effects, immunology, physiology)
• Survival Analysis
• Time Factors
• Vaccination
• Viral Load (drug effects, immunology)
• Viral Vaccines (immunology)
• Virion (immunology)