Influenza Virus Polymerase: A Key to Viral Pathogenesis & Vaccine Development

The influenza A virus (IAV) RNA polymerase complex plays a key role in viral pathogenesis and host adaptation. This is exemplified by the fact that the current live-attenuated influenza vaccine (LAIV) is derived from a cold-adapted virus that has attenuating mutations in the genes that encode the viral polymerase complex.

The current LAIV is a highly attractive vaccine because it can be delivered via a mucosal route (nasally), without use of needles. Moreover, data suggest that LAIV is more effective than inactivated influenza vaccine (IIV) in young children. However, LAIV is not licensed for use in infants and the youngest children (<2 years of age) because of a risk of wheezing and asthma. We have recently identified novel polymerase mutations which may further attenuate the current LAIV, preventing it from replicating at the elevated temperatures encountered in the febrile lower airway - and thereby potentially making it safe enough for use in infants and children under the age of 2. In collaboration with the lab of Dr. Martínez-Sobrido, we are presently examining the replication properties and temperature sensitivity of this modified LAIV, both in vitro and in vivo.

Finally, we are also conducting experiments aimed at uncovering novel mechanisms that may contribute to the adaptation of avian influenza viruses to mammalian hosts. We have identified a unique avian influenza virus RNA polymerase that functions efficiently in mammalian cells at 37oC, but which lacks the previously defined mutations that contribute to the adaptation of other avian influenza virus RNA polymerases to human cells. We are presently conducting experiments to identify the mutations that may account for this unexpected polymerase phenotype.

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