Broadly neutralizing antibodies against influenza virus and prospects for universal therapies
Highlights
► Broadly neutralizing antibodies to influenza virus. ► Three major protective epitopes on influenza hemagglutinin. ► Design of novel immunogens. ► Therapeutic antibodies and small proteins.
Section snippets
Evasion of host antibody responses
Because antibodies play a central role in the recognition and elimination of invading microbes, many pathogens have developed strategies to evade the humoral immune response. Many viral pathogens, such as influenza and HIV, have evolved low-fidelity polymerases that result in high mutation rates [1]. While this process leads to a large number of deleterious mutations that inactivate or attenuate individual virus particles, the large diversity of the resulting virus quasispecies allows these
Broadly neutralizing antibodies
Broadly neutralizing antibodies (bnAbs) against a number of highly variable viruses have been reported, including hepatitis C [2, 3, 4], dengue [5], RSV [6], and influenza [7, 8•, 9••, 10••, 11••, 12•, 13••, 14•, 15••, 16•], but they have been explored most fruitfully and most abundantly so far in the case of HIV. Neutralizing antibodies against HIV target the Env protein (gp120/gp41), which is functionally and perhaps even distantly related evolutionarily to influenza HA [17]. A number of
Early work on bnAbs against influenza
In contrast to the relatively large number of broadly neutralizing antibodies known for HIV, until recently only one such cross-protective antibody against influenza had been identified. Antibody C179 was isolated many years ago from a mouse that had been immunized with H2N2 virus, but was later found to cross-neutralize H1, H2, H5, H6, and H9 subtypes [7, 18, 19]. All of these subtypes are members of the group 1 hemagglutinins, one of the two major subdivisions of the influenza A viruses (
Human antibodies with broad activity specific for group 1 viruses
The next major advance in the field came ∼15 years later, with the discovery of a novel class of human antibodies encoded by the VH1-69 gene [9••, 10••, 11••, 12•]. CR6261 [9••, 10••] and F10 [11••] are the best studied among the antibodies from this family. These antibodies were all isolated by phage display, are remarkably similar to one another at the sequence level and have a relatively small number of mutations from the germline antibody sequence. Further, these antibodies have very
Human antibodies with broad activity specific for group 2 viruses
In contrast to the now relatively large number of VH1-69 antibodies that have been identified against group 1 HAs, few antibodies thus far been reported with broad activity against group 2 HAs. As the latter viruses are no more antigenically diverse than the group 1 subtypes, it is unclear whether the dearth of antibodies specific to group 2 HAs represents a unique obstacle to the neutralization of this lineage, limitations in the technologies used to screen large numbers of antibodies, or
Human antibodies against both group 1 and 2 viruses
HAs from human influenza viruses that have caused pandemics come from group 1 (H1 and H2) and group 2 (H3). Further, zoonotic subtypes with the potential to trigger future pandemics are also found in both groups (H5 and H9 from group 1, H7 from group 2). A universal therapy for influenza will need to be effective against both groups (as well as influenza B), and consequently, there is increasing interest in antibodies that can span these two phylogenetic lineages.
Perhaps the first antibody that
Future outlook
Over the past few years, our understanding of the antibody response against influenza HA expanded in ways that may have been unimaginable even 5 years ago. In 1996, we knew that cross-reactive murine antibodies like C179 could exist [7], yet little progress had been made in the 13 subsequent years towards understanding how this antibody worked and its implications for human health. Until very recently, it was unclear whether humans could even generate such a broadly neutralizing antibody
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Funding from NIH grant P01 AI058113 (I.A.W.); a predoctoral fellowship from the Achievement Rewards for College Scientists Foundation (D.C.E.); grant GM080209 from the NIH Molecular Evolution Training Program (D.C.E.); and the Skaggs Institute (I.A.W.) are acknowledged. We thank Gira Bhabha for assistance in figure preparation.
References (32)
- et al.
Measurement of the mutation rates of animal viruses: influenza A virus and poliovirus type 1
J Virol
(1986) - et al.
Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge
Nat Med
(2008) - et al.
Monoclonal antibody AP33 defines a broadly neutralizing epitope on the hepatitis C virus E2 envelope glycoprotein
J Virol
(2005) - et al.
Broadly neutralizing human monoclonal antibodies to the hepatitis C virus E2 glycoprotein
J Gen Virol
(2008) - et al.
A broadly flavivirus cross-neutralizing monoclonal antibody that recognizes a novel epitope within the fusion loop of E protein
PLoS ONE
(2011) - et al.
Isolation of a second recombinant human respiratory syncytial virus monoclonal antibody fragment (Fab RSVF2-5) that exhibits therapeutic efficacy in vivo
J Infect Dis
(1998) - et al.
A common neutralizing epitope conserved between the hemagglutinins of influenza A virus H1 and H2 strains
J Virol
(1993) - et al.
Cross-protective potential of a novel monoclonal antibody directed against antigenic site B of the hemagglutinin of influenza A viruses
PLoS Pathog
(2009) - et al.
Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells
PLoS ONE
(2008) - et al.
Antibody recognition of a highly conserved influenza virus epitope
Science
(2009)