Antigenic evolution of seasonal influenza viruses


Richard Neher
Biozentrum, University of Basel


slides at neherlab.org/201710_PCCMI.html

Human seasonal influenza viruses

slide by Trevor Bedford


  • Influenza viruses evolve to avoid human immunity
  • Vaccines need frequent updates

nextflu.org

joint work with Trevor Bedford & his lab

code at github.com/blab/nextflu

Hemagglutination Inhibition assays

Slide by Trevor Bedford

HI data sets

  • Long list of distances between sera and viruses
  • Tables are sparse, only close by pairs
  • Structure of space is not immediately clear
  • MDS in 2 or 3 dimensions
Smith et al, Science 2002
Slide by Trevor Bedford

Integrating antigenic and molecular evolution

  • $H_{a\beta} = v_a + p_\beta + \sum_{i\in (a,b)} d_i$
  • each branch contributes $d_i$ to antigenic distance
  • sparse solution for $d_i$ through $l_1$ regularization
  • related model where $d_i$ are associated with substitutions
RN et al, PNAS, 2016

Integrating antigenic and molecular evolution

  • MDS: $(d+1)$ parameters per virus
  • Tree model: $2$ parameters per virus
  • Sparse solution
    → identify branches or substitutions that cause titer drop
RN et al, PNAS, 2016

Are antigenic distances tree-like?

Rate of antigenic evolution

  • Cumulative antigenic evolution since the root: $\sum_i d_i$
  • A/H3N2 evolves faster antigenically
  • A/H3N2 has a more rapid population turn-over
  • Proportion of children is high in B vs A/H3N2 infections

How many sites are involved?


Mutationeffect
K158N/N189K 3.64
K158R 2.31
K189N 2.18
S157L 1.29
V186G 1.25
S193F 1.2
K140I 1.1
F159Y 1.08
K144D 1.08
K145N 0.91
S159Y 0.89
I25V 0.88
Q1L 0.85
K145S 0.85
K144N 0.85
N145S 0.85
N8D 0.73
T212S 0.69
N188D 0.65

Predicting successful influenza clades

Predicting successful influenza clades

HI distances on the phylogenetic tree

Shortcomings of ferret HI data

  • ferrets are naive -- no complicated history of exposure
  • H1N1pdm experienced three recent rapid amino acid replacements
  • age specific immuno-dominance caused problems in the 2013-2014 influenza season

Linderman .... Hensley, PNAS 2014

  • ABs in people born between 1960 and 1979 target an epitope containing 163K
  • Young people target a different epitope -- like ferrets
  • The 163K epitope in H1N1pdm is similar to H1N1 viruses circulating 1976-1986
  • The vaccine virus was 163K, likely boosted the old response
Figure from Linderman et al

Human seasonal influenza viruses

slide by Trevor Bedford

Shortcomings of ferret HI data

Figure from Linderman et al

Linderman .... Hensley, PNAS 2014

  • People born between 1960 and 1979 target an epitope containing 163K
  • Young people target a different epitope -- like ferrets
  • The 163K epitope in H1N1pdm is similar to H1N1 viruses circulating 1976-1986
  • The vaccine virus was 163K, likely boosted the old response
  • After 1986, 163K was shielded by glycosylation
  • People born later had no old ABs targeting 166K

Conclusions and Questions

  • We need to complement ferrets with systematic human serology
  • How do we move away from egg based vaccines?
  • How important is the history of exposure to vaccine efficacy?
  • What mediates the competition between distant influenza lineages?
  • Universal vaccines?

Influenza and Theory acknowledgments

  • Boris Shraiman
  • Colin Russell
  • Trevor Bedford
  • Oskar Hallatschek

  • All the NICs and WHO CCs that provide influenza sequence data
  • The WHO CCs in London and Atlanta for providing titer data

nextflu.org

  • Trevor Bedford
  • Colin Megill
  • Pavel Sagulenko
  • Sidney Bell
  • James Hadfield