| 要約: | <p>Influenza A continues to impose a considerable burden on humans and animals, including farmed poultry and pigs. Current vaccination approaches successfully protect certain populations against specific strains, but none are effective at consistently inducing broad and long-lasting protection to the diversity of circulating strains. </p>
<p>Single cycle viruses may offer a promising solution as they are able to safely present a wide array of viral antigens in the respiratory tract by undergoing just one round of cell infection in their host. This is thought to be advantageous for stimulating broadly protective resident memory T-cell responses in the lung as well as mucosal antibody responses.</p>
<p>This thesis describes the design and evaluation of a candidate vaccine platform called CLEARFLU, building on the previously described single cycle virus S-Flu designed by Alain Townsend. CLEARFLU viruses are unable to replicate in vivo due to the introduction of several independently inactivating mutations into the hemagglutinin protein, blocking the cell entry step of infection. They can however be propagated in cell culture by providing complementing hemagglutinin in trans. </p>
<p>We demonstrate that CLEARFLU viruses do not cause disease in mice or pigs, even when administered to the respiratory tract. They induce a strong T-cell response in the lung, including to the highly conserved viral component nucleoprotein which is known to be associated with broad protection. CLEARFLU viruses also stimulate both systemic and local strain-specific antibody to neuraminidase and neutralising antibody to hemagglutinin in mice. This neutralising response to hemagglutinin is a notable advantage over other hemagglutinin-inactivated single cycle viruses like S-Flu which do not induce such responses and can thus limit but not prevent future infection. </p>
<p>Together with investigations into their genomic stability, we demonstrate that CLEARFLU viruses show promise as vaccine candidates able to generate both non-neutralising protection against a broad range of strains and neutralising protection against strain-matched challenge.</p>
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