Perhaps one of the most incredibly effective vaccines ever used, against smallpox, has completely eradicated a terribly nasty human disease. Yet the way in which vaccinia virus, the live poxvirus contained in the smallpox vaccine, actually orchestrates a protective immune response is still mostly unknown. The live virus component is a major reason why the smallpox vaccine is so good – instead of having some crusty bit of dried up dead protein in there, there is a real virus that looks a bit like smallpox and properly challenges the immune system.

Once the smallpox vaccine is administered, vaccinia begins replicating in the human body, causing a mild infection, and soon begins to exist in two different forms: one lives outside the cells of the body, milling about and spreading to infect new cells, while the other hides out inside the cells of the body and spawns lots of new viruses. The one that lives on the outside of cells is typically exposed to and controlled by the immune system, and is made up of five major surface protein components (A33, A34, A36, A56 and B5), as well as a lipid membrane that surrounds the entire virus particle, all of which can be targeted by immune cells.

Researcher’s have been trying to understand how one part of the immune system, the antibodies, drive protection against vaccinia virus – and thus against smallpox. Typically, if enough antibodies bind to enough important virus proteins, this blocks virus accessibility and shuts down infection. Yet this does not seem to be the case with vaccinia. One team in California recruited nine people who had previously received the smallpox vaccine and looked at antibody responses in their blood. In all nine individuals, antibodies recognising vaccinia struggled to inactivate the virus on their own, only working properly to suppress viral infection in the presence of another immune system component, complement. Complement is a series of proteins in the blood, which help antibodies by attracting other immune cells to neutralise foreign material. Four individuals controlled the virus almost exclusively through neutralising antibodies targeted against the virus protein B5, while other donors had a minimal contribution (15-28%) from B5 antibodies; their protection, instead, was supplemented by antibodies against a second virus protein, A33. The only effective antibodies against either B5 or A33 were the ones that bound vaccinia virus very tightly, in a destructive huggy embrace.

This suggests that, contrary to current theories in vaccine development, antibodies don’t have to be able to work alone to bring about viral destruction in order to effectively control disease. While antibodies are important in establishing immunity against smallpox, multiple parts of the immune system work together to protect against such pathogens.

Benhnia MR, Maybeno M, Blum D, Aguilar-Sino R, Matho M, Meng X, Head S, Felgner PL, Zajonc DM, Koriazova L, Kato S, Burton DR, Xiang Y, Crowe JE Jr, Peters B, & Crotty S (2013). Unusual features of vaccinia virus extracellular virion form neutralization resistance revealed in human antibody responses to the smallpox vaccine. Journal of virology, 87 (3), 1569-85 PMID: 23152530