Broadly protective antibodies against influenza A virus

Mirte Pascha

Antibodies acquired through natural infection or by vaccination play a key role in protection against influenza A virus (IAV). Protective antibodies target epitopes that are exposed on the surface of viruses or infected cells. IAV particles contain receptor-binding hemagglutinin (HA, H1-16) and receptor-destroying neuraminidase (NA, N1-N9), which are main targets of the host immune system. Traditionally, the main focus of vaccine developers has been on the HA protein, as antibodies inhibiting hemagglutination and virus infection are an established correlate of protection. The immunodominant part of the HA protein recognized by such antibodies is however a very variable region. Therefore, current vaccines targeting human H1N1 and H3N2 viruses require regular updates and do not protect against animal viruses. This has led to the development of so-called prototype universal vaccines focused on the conserved HA stem region. While promising results have been obtained, induction of broadly protective antibodies still requires improvement. The NA protein has long been ignored by vaccine developers, even while we and others have demonstrated the protective efficacy of anti-NA immune responses. This is in part because antibodies against NA have little neutralizing activity in routinely used infection assays. This attitude is currently changing, also because of observations that also NA protein may be targeted by broadly reactive antibodies. However, little is known about the epitopes targeted by these broadly reactive antibodies. In the current project, we will identify broadly-reactive/protective anti/nanobodies that specifically bind to rare conserved epitopes on multiple HA and NA subtypes. The novel anti/nanobodies that bind to conserved epitopes on HA and NA, can be used for diagnosis and therapy, but also for the design for novel broadly-protective vaccine antigens.