The pandemic 2009 (H1N1) swine influenza virus is mild compared to the pandemic 1918 (H1N1) virus because of a proline-to-serine substitution in the receptor-binding site of its hemagglutinin - a hypothesis.

The relative mildness of the pandemic 2009 (H1N1) swine influenza virus compared to the 1918 pandemic (H1N1) virus may be due to a variety of possible causes, including the existence of effective immunity in the host, the lessened ability of the virus to bind to target cells or to replicate in them, a diminished secretion of molecules that could cause further complications like pneumonia, etc. A comparison of the hemagglutinin sequences from the pandemic 2009 (H1N1) viruses with that of the 1918 (H1N1) virus reveals a difference in the residues occupying position 200, which has been shown to be involved in receptor binding. In all the pandemic 2009 (H1N1) hemagglutinin sequences available in the NCBI database, position 200 is occupied by serine. In the hemagglutinin of the 1918 (H1N1) virus, position 200 is occupied by proline. A proline-to-serine substitution could introduce a significant structural change in the receptor-binding site of the hemagglutinin, which could reduce the receptor-binding ability of the 2009 (H1N1) virus. It is proposed that this substitution is the cause of the relative avirulence of the 2009 (H1N1) virus compared to the 1918 (H1N1) virus.