Broadly neutralizing antibodies against influenza virus and prospects for universal therapies

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Vaccines are the gold standard for the control and prevention of infectious diseases, but a number of important human diseases remain challenging targets for vaccine development. An influenza vaccine that confers broad spectrum, long-term protection remains elusive. Several broadly neutralizing antibodies have been identified that protect against multiple subtypes of influenza A viruses, and crystal structures of several neutralizing antibodies in complex with the major influenza surface antigen, hemagglutinin, have revealed at least 3 highly conserved epitopes. Our understanding of the molecular details of these antibody–antigen interactions has suggested new strategies for the rational design of improved influenza vaccines, and has inspired the development of new antivirals for the treatment of influenza infections.

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.

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