On May 22, 2009, World Health Organization (WHO) Director-General Dr. Margaret Chan said that the Pandemic (H1N1) 2009 virus must be closely monitored in the southern hemisphere, as it could mix with ordinary seasonal influenza and change in unpredictable ways. Experts writing in the July issue of The New England Journal of Medicine note that historically, pandemic viruses have evolved between seasons, and the current strain may become more severe or transmissible in the coming months. They therefore stress the importance of international cooperation to engage in proper surveillance to help monitor changes in the virus's behavior, which will aid in both "vaccine targeting" and interpreting illness patterns in the fall of 2009.

Other experts are also concerned that the new virus strain could mutate over the coming months. Guan Yi, a leading virologist from the University of Hong Kong, for instance, described the new H1N1 influenza virus as "very unstable", meaning it could mix and swap genetic material (reassortment) when exposed to other viruses. During an interview he said "Both H1N1 and H5N1 are unstable so the chances of them exchanging genetic material are higher, whereas a stable (seasonal flu) virus is less likely to take on genetic material." The H5N1 virus is mostly limited to birds, but in rare cases when it infects humans it has a mortality rate of between 60% to 70%. Experts worry about the emergence of a hybrid of the more virulent Asian-lineage HPAI (highly pathogenic avian influenza) A/H5N1 strain (media labeled "bird flu") with more human-transmissible Influenza A strains such as this novel 2009 swine-origin A/H1N1 strain (media labeled "swine flu"), especially since the H5N1 strain is and has been for years endemic in birds in countries like China, Indonesia, Vietnam and Egypt.

Other studies conclude that the virus is likely well adapted to humans, has a clear biological advantage over seasonal flu strains and that reassortment is unlikely at this time due to its current ease in replication and transmission. However, Federal health officials in the U.S. noted that the horrific 1918 flu epidemic, which killed hundreds of thousands in the United States alone, was preceded by a mild "herald" wave of cases in the spring, followed by devastating waves of illness in the autumn.

As of October 2009, a research done by Taubenberger showed that the evolution of A (H1N1) is relatively slow since 1918 and the structure of the 2009 virus is similar to that of 1918 flu pandemic. A study from Hokkaido University predicted that these similar Hemagglutinin antigen residues will soon be targeted by antibody-mediated selection pressure in humans and and whether the antigenic changes similar to seasonal influenza should be the main focus of monitoring.