Wednesday, April 24, 2013

An Emerging Influenza Vaccine

            Throughout history, the influenza virus has proven to be highly problematic for human beings.  Various epidemics have spread across the globe and taken many lives, including the recent avian flu (H5N1) and swine flu (H1N1).  While the virus itself does cause a lot of harm, it is often pneumonia caused by Staphylococcus aureus (S. aureus), which results from the influenza infection, that often proves to be fatal (1).  Virologists have been looking for a vaccine that would help not only to prevent influenza infection, but also to deter S. aureus infection.  In their journal article, Dai et al. explain how they found a conserved section of the protein HA which can be made into a vaccine and coupled with the bacterial antigen Ag85A to do just that.

            The HA protein in Influenza A Virus (IAV) holds domains necessary for viral attachment to host cells.  To activate this protein, the virus cleaves it into two domains: HA1 and HA2.  The host often deploys an immune response that targets antibodies to the HA protein, which prevents IAV virions from attaching to the host cells (2).  While this is temporarily affective, IAV tends to evolve very rapidly, so vaccines geared towards the HA protein become outdated very quickly (3).  However, the HA2 domain has been seen to remain highly conserved over virus generations, and the majority of the mutations can be attributed to the HA1 region.  Therefore, it seems reasonable that if antibodies were made to target the HA2 region specifically, then they would be able to be effective for longer periods of time (4).

            Ag85A is an antigen secreted by the bacteria Mycobacterium tuberculosis (M. tuberculosis).  As a vaccine, Ag85A was known to increase the production of T helper 1 (TH1) cytokine responses to M. tuberculosis (5), which in turn lead to an increase in the expression of toll-like receptor 2 (TLR2).  TLR2 recognizes molecules specific to Staphylococcus species and activates immune responses to them (6).  Therefore, Ag85A could act as a vaccine for S. aureus.  Dai et al. hypothesized that combining the HA2 domain of the HA protein and Ag85A into a single vaccine would create both an effective antibody response to IAV and antibacterial response to S. aureus, preventing both influenza and the potentially lethal pneumonia that tends to follow.

            To create the vaccine, the researchers put the genes for HA and Ag85A onto one plasmid, and inserted it into cells.  Both genes were successfully expressed in these cells. Once they confirmed that the two genes could be expressed, they tested the vaccine’s effect on mice.  Compared to mice without any vaccination, mice that had the vaccine produced many more HA neutralizing antibodies.  There were also much higher levels of cytokines and TLR2 produced in these mice after they were infected with S. Aureus.  Overall, the vaccinated mice exhibited much less weight loss and had a higher survival rate when introduced to IAV and S. aureus than those that were not vaccinated.

An interesting secondary discovery found by Dai et al. was that there were more antibodies for HA produced in mice vaccinated with both HA and Ag85A than those that were vaccinated with just HA.  This suggests that Ag85A may have an antiviral effect on IAV.  This possibility should be the subject of future studies.

The creation of this vaccine could prove to be a large step in preventing future influenza epidemics.  Because this vaccine acts on a highly conserved influenza protein, it may be able to work against novel influenza strains that evolve or jump the species barrier.  Also, annual or seasonal flu shots may no longer be necessary, as the vaccine will be able to remain effective for longer periods of time.  Not only does this provide extra convenience, but it makes influenza treatments easier, as people will only have to pay for one shot instead of many.  This will allow those who may not normally be able to afford flu shots to receive vaccinations, leading to increased human health across the world.

Primary Source:
Dai J, Pei D, Wang B, Kuang Y, Ren L, Cao K, Zuo B, Shao J, Li S, Jiang Z, Li H, Li M: “A novel DNA vaccine expressing the Ag85A-HA2 fusion protein provides protection against influenza A virus and Staphylococcus aureus.” Virology Journal 2013, 10:40.

Supporting Articles:
(1) Tsigrelis C, Mohammad M, Fraimow HS, Dellinger RP, Marchesani D, Reboli AC:
“Secondary bacterial pneumonia due to Staphylococcus aureus complicating 2009
influenza A (H1N1) viral infection.” Infection 2010, 38(3):237–239.

(2) Chandran SS, Verhoeven D, Teijaro JR, Fenton MJ, Farber DL: “TLR2 engagement on
dendritic cells promotes high frequency effector and memory CD4 T cell responses.” J
Immunol 2009, 183(12):7832–7841.

(3) Kim JH, Skountzou I, Compans R, Jacob J: “Original antigenic sin responses to influenza
viruses.” J Immunol 2009, 183(5):3294–3301.

(4) Sui J, Hwang WC, Perez S, et al: “Structural and functional bases for broad-spectrum
neutralization of avian and human influenza a viruses.” Nat Struct Mol Biol 2009,

(5) Romano M, Roupie V, Hamard M, Huygen K: “Evaluation of the immunogenicity of
pBudCE4.1 plasmids encoding mycolyl-transferase Ag85A and phosphate transport
receptor PstS-3 from Mycobacterium tuberculosis.” Vaccine 2006, 24(21):4640–4643.

(6) Holley MM, Zhang Y, Lehrmann E, Wood WH, Becker KG, Kielian T: “Toll-like receptor
2 (TLR2)-TLR9 crosstalk dictates IL-12 family cytokine production in microglia.” Glia
2011, doi:10.1002.

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