Trevor Bedford and Sidney Bell

6 Nov 2018

SMBE Satellite Workshop on Genome Evolution in Pathogen Transmission and Disease

Kyoto, Japan

Project to provide a real-time view of the evolving influenza population

in collaboration with Richard Neher

- Download all recent HA sequences from GISAID
- Filter to remove outliers
- Subsample across time and space
- Align sequences
- Build tree
- Estimate clade frequencies
- Infer antigenic phenotypes
- Export for visualization

*
with John Huddleston and Richard Neher
*

"The future is here, it's just not evenly distributed yet"

— William Gibson

Clade frequencies $X$ derive from the fitnesses $f$ and frequencies $x$ of constituent viruses, such that

$$\hat{X}_v(t+\Delta t) = \sum_{i:v} x_i(t) \, \mathrm{exp}(f_i \, \Delta t)$$

This captures clonal interference between competing lineages

The fitness $f$ of virus $i$ is estimated as

$$\hat{f}_i = \beta^\mathrm{A} \, f_i^\mathrm{A} + \beta^\mathrm{B} \, f_i^\mathrm{B} + \ldots$$

where *A*, *B*, etc... are different standardized viral attributes

We learn $\beta$ coefficients from most recent 12 years of H3N2 evolution

Optimal $\beta$ coefficients minimize sum of squared errors between observed clade frequencies and frequency estimated in a 1-year look ahead

Fit to a subset of non-nested clades

Model | $\beta$ coefficient | Growth correlation | Growth accuracy |
---|---|---|---|

Antigenic drift based on HI model (cTiterSub) |
0.33 | 0.29 | 69% |

Cross-immunity based on epitope mutations (ep_x) |
0.50 | 0.18 | 60% |

Protein function based on deep mutational scanning (dms) |
0.20 | 0.01 | 57% |

Clade growth based on local branching index (lbi) |
0.39 | 0.30 | 61% |

Dengue (serotype 2)

Flu (H3N2)

DENV4-I associated with adverse events

dengue case outcomes

dengue case outcomes

are poorly understood

Serotypes are genetically distinct

Serotypes are antigenically distinct

Clades are genetically distinct

**Are clades antigenically distinct?**

dengue evolve

antigenically?

Interserotype hypothesis

Full tree hypothesis

PRNT50 titers from monovalent vaccine trials + nonhuman primates

Interserotype model

Full tree model

distinct antigenic phenotypes

Dengue

Flu (H3N2)

Clade frequencies $X$ derive from the clade fitness $f_i$, such that

$$\hat{X}_i(t+\Delta t) = X_i(t) \, \mathrm{exp}(f_i \, \Delta t)$$

Estimate fitness as frequency-weighted antigenic distance*

from recently circulating clades

* estimated from the interserotype or full tree antigenic model.

standing population immunity

Circulating clades:

Population immunity:

Population susceptibility:

Clade growth:

drive

drive

Interserotype model

Full tree model

**Dengue serotype flux**

62% of variation explained

5 year windows

**Flu clade turnover**

53% of variation explained

1 year windows

Similar models of antigenic evolution are effective

for pathogens with very different evolutionary dynamics

Prospective modeling can reveal relative contributions to viral fitness

**Bedford Lab**:
Alli Black,
Sidney Bell,
John Huddleston,
Barney Potter,

James Hadfield,
Louise Moncla,
Tom Sibley,
Maya Lewinsohn

**Influenza**: WHO Global Influenza Surveillance Network, GISAID, Richard Neher, John Huddleston,
Barney Potter, James Hadfield, Rod Daniels, Boris Shraiman, Colin Russell, Andrew Rambaut, Dave Wentworth, Becky Garten, Jackie Katz,
Marta Łuksza, Michael Lässig, Richard Reeve

**Dengue**: Leah Katzelnick, Molly O'hainle, Richard Neher, Paul Edlefsen, Michal Juraska