Induction of heterosubtypic cross-protection against influenza by a whole inactivated virus vaccine: the role of viral membrane fusion activity.
BACKGROUND
The inability of seasonal influenza vaccines to effectively protect against infection with antigenically drifted viruses or newly emerging pandemic viruses underlines the need for development of cross-reactive influenza vaccines that induce immunity against a variety of virus subtypes. Therefore, potential cross-protective vaccines, e.g., whole inactivated virus (WIV) vaccine, that can target conserved internal antigens such as the nucleoprotein (NP) and/or matrix protein (M1) need to be explored.


RESULTS
In the current study we show that a WIV vaccine, through induction of cross-protective cytotoxic T lymphocytes (CTLs), protects mice from heterosubtypic infection. This protection was abrogated after depletion of CD8+ cells in vaccinated mice, indicating that CTLs were the primary mediators of protection. Previously, we have shown that different procedures used for virus inactivation influence optimal activation of CTLs by WIV, most likely by affecting the membrane fusion properties of the virus. Specifically, inactivation with formalin (FA) severely compromises fusion activity of the virus, while inactivation with β-propiolactone (BPL) preserves fusion activity. Here, we demonstrate that vaccination of mice with BPL-inactivated H5N1 WIV vaccine induces solid protection from lethal heterosubtypic H1N1 challenge. By contrast, vaccination with FA-inactivated WIV, while preventing death after lethal challenge, failed to protect against development of disease and severe body weight loss. Vaccination with BPL-inactivated WIV, compared to FA-inactivated WIV, induced higher levels of specific CD8+ T cells in blood, spleen and lungs, and a higher production of granzyme B in the lungs upon H1N1 virus challenge.


CONCLUSIONS
The results underline the potential use of WIV as a cross-protective influenza vaccine candidate. However, careful choice of the virus inactivation procedure is important to retain membrane fusion activity and full immunogenicity of the vaccine.
Department of Medical Microbiology, Molecular Virology Section, University Medical Center of Groningen, Groningen, The Netherlands.
Natalija
N
Budimir
Anke
A
Huckriede
Tjarko
T
Meijerhof
Louis
L
Boon
Emma
E
Gostick
David A
DA
Price
Jan
J
Wilschut
Aalzen
A
de Haan
D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D001835:Body Weight / Q000187:drug effects; D056738:Cross Protection / Q000187:drug effects / Q000276:immunology*; D005557:Formaldehyde / Q000494:pharmacology; D006385:Hemagglutination Inhibition Tests; D006801:Humans; D007106:Immune Sera / Q000187:drug effects / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000276:immunology; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects / Q000276:immunology; D007252:Influenza Vaccines / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology* / Q000517:prevention & control* / Q000821:virology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology / Q000821:virology; D051379:Mice; D009698:Nucleoproteins / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D011420:Propiolactone / Q000494:pharmacology; D013045:Species Specificity; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D014611:Vaccination; D015164:Vaccines, Inactivated / Q000276:immunology*; D019562:Viral Load / Q000187:drug effects / Q000276:immunology; D038301:Virus Inactivation / Q000187:drug effects; D053586:Virus Internalization / Q000187:drug effects
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D007106:Immune Sera; D007252:Influenza Vaccines; D009698:Nucleoproteins; D015164:Vaccines, Inactivated; D005557:Formaldehyde; D011420:Propiolactone