Question

Vaccines act by offering attenuated forms of pathogens to be recognized by the host immune system. Once exposed, the immune system develops specific defenses (acquired response) against that pathogen, so that in the future, vaccinated individuals that get into contact with the true pathogen will already possess the necessary immune response to fight off the disease. In the case of viruses, the attenuated version of the pathogen is usually composed of viral proteins without its genetic material (in other words, the virus is incapable of replication and incapable of causing an infection).

Influenza type A viruses can cause severe illness and are responsible for influenza human pandemics. Despite its great impact in our society, no permanent vaccine has been devised so far, and new versions of the vaccine have to be developed and administrated every year. Describe the evolutionary mechanism that you think is responsible for this phenomenon?

Answer 1

Influenza virus exhibits differences in two surface proteins- Hemagglutinin HA and the neuraminidase protein NA. Based on HA and NA, there are three strains of influenza-A/HINI, A/H3N2 and type B. Seasonal Vaccination has been the strategy used to prevent influenza infection, although none of these vaccines provide long term immunity. Antigenic drift and antigenic drift are the mechanisms by which the virus protects itself during evolution.

It has been indicates that frequent vaccination may also be responsible for mutations creating new antigenic drift by applying selective pressure. HA is HA is a glycosylated integral membrane protein present on the surface of the influenza virus. It acts in both receptor binding and is also a fusion protein. It binds to sialic acid residues attached to host cell glycoproteins. NA, on the other hand is an integral membrane glycoprotein, which has a neuraminidase activity. NA cleaves sialic acid residues, which helps in release of new viruses from the host cells. PB1 is other protein that is frequently mutated. The influenza vaccines target these two proteins. Mutations that alter the amino acids in the antigenic sites on HA and NA have evolutionary advantage. They allow the virus to evade pre-existing immunity generated against the virus. These specific and selective mutations that occur in the antigenic sites on these two proteins result in antigenic drift. Mutations that resulted in H5N1 strain of the virus, was shown to be a K58I substitution in HA protein. This mutation is associated with increased replication of the virus in the upper respiratory tract. In H7N9 virus, the K581 mutation was combined with other point mutations G219S and R29K. These additional two mutations promoted drug resistance in the virus and also increased binding affinity to different sialic acid residues. Antigenic drift over a period of time may therefore lead to creation of a new virus strain. This new strain of virus would be entirely different than the original strain. Mutation E627K mutation of PB2 region causes one strain which primarily infected poultry to now infect humans. Replacement of the E627K mutation by another mutation in H1N1 at another site that caused increased infectivity of H1N1 in humans in 2009. In 1918 and 1997, the H1N1 and H5N1 virus had N66S mutation in the region PB1-F2. Thus, the antigenic drift is also responsible for increasing pathogenicity of influenza virus.

In antigenic shift, two different strains of influenza can cause formation of a new strain of influenza. Antigenic shift is mostly seen with the HA antigen. A major mechanism by which antigenic shift occurs is when a non-human strain gains the ability to infect humans. As this strain was not infecting humans previous, the new combination of HA or NA is not recognized by the immune system in humans to generate immune response. Example of such antigenic shift was the H1N1 virus. H1N1 before 2009 was only observed in avian species. However, due to antigenic shift, this virus could infect humans.

Influenza virus is composed of eight single stranded RNA segments. Each of these segments will encode for a specific viral protein. In antigenic shift, there are rearrangements of gene segments observed. It is also seen when two viruses infect the same cell causing assortment of the two viruses. The 1918 pandemic of H1N1 was due to antigenic shift from pigs to humans. This type A H1N1 was a quadruple reassortment virus containing genes from H1N1 virus of Eurasian pigs, H1N2 virus of avian swine flu and H3N2 human influenza virus. PB2 and NA was from H1N2, PB1 was from H3N2, and NA, M segments from H1N1. This new virus also had HA, NP, NS from a classic swine influenza virus.

As these reassortment causes formation of a new virus with different combination of parental RNA, they are not recognized by the immune system. Hence, the new viral strain can escape the immune response and cause enhanced infectivity.

Recombination is another evolutionary mechanism that occurs in rare cases of influenza virus. Non-homologous recombination between two different fragments and rare homologous recombination due to template switching during RNA replication are major mechanism for recombination. Homologous recombination has been observed in PB2, HA and NP has occurred between H1N1 sub-strains or H1N1 and H3N2 strains. However, recombination is not very common. Antigenic drift and shift are the major mechanism of evolution in Influenza virus.