Introduction to Antigenic Evolution

Sidney M. Bell, PhD (@sidneymbell)

Chan Zuckerberg Initiative

Mini workshop: California Departments of Public Health

June 10, 2021

Outline

• How do viruses evolve to escape the immune system?
   
• What does this mean for vaccine escape?
   
• How does genomic surveillance help with vaccine updates?
   
• Discussion and questions

Grubaugh, Nature Micro, 2019

Viruses acquire mutations as they replicate and transmit from person to person.

SARS-CoV-2
(~7 day serial interval, ~25 subs/year)

ACTG

ACTT

AGTT

Genetic

variation

A very small minority of mutations may change the way the virus "looks" to the immune system

Antigenic variation is usually caused by a mutation in a "surface protein"

For some viruses, antigenic variation can help them escape from pre-existing immunity

Measles

Antigenically uniform

Lifelong protection

What does this mean for vaccine updates?

Influenza & SARS-CoV-2

Previously circulating:

Population

immunity:

Population immunity can influence viral evolution

Population immunity drives flu evolution, necessitating a vaccine update every ~2 years

Influenza & SARS-CoV-2 have a similar number of substitutions per year in surface proteins

Bedford, 2/2021

BUT! Need to consider...

• Rate differences
  SARS-CoV-2 spike S1 gene is ~2x as long as Flu's HA1 gene
   
• Is the last year typical for SARS-CoV-2?
  Not enough data to define "normal" for SARS-CoV-2
   
• "Scariants are innocent until proven guilty"
  How much does each of these mutations actually
  matter for immune escape

Measuring antigenic change

+

Replication

Neutralizing flu requires about 2x as much serum after ~1 year's worth of antigenic change

+

Replication

Virus A

Antibodies from patient recovered from virus A

Four reasons why we're not panicking about vaccine escape yet

1. Immunity is broader after vaccination than after natural infection, especially for mRNA vaccines
    
2. Antibodies aren't the whole story / immunity is a multi-layer defense system
    
3. Usually requires a cluster of mutations to enable immune escape
    
4. This has been a weird year for everyone -- host and virus alike
   • Adapting to a new host species
     (selective pressure for replication and transmission)
   • Totally naive population
     (selective pressure for immune escape is a new thing)

But, we will need to update the vaccines at some point

• Likely a similar or slightly lower frequency than flu vaccine updates
   
• Likely a simpler and faster process to update
  SARS-CoV-2 mRNA vaccines than to update the egg-grown flu vaccine

How genomic surveillance can inform eventual vaccine updates

So, which mutations matter? 

Starr et al, Cell Reports, 2021

Sequencing vaccine breakthrough cases helps us identify which [combinations of] mutations are important for vaccine escape, in the real world

Values from Juraska et al, PNAS 2018

Which clades / "variants" should we
vaccinate against?

Representative sampling helps us model and predict which clades ("variants") will become more common

John Huddleston

Takehomes

• SARS-CoV-2 will change antigenically, and we'll need to update our vaccines at some point, but we're not panicking
   
• Individual mutations don't usually cause antigenic change on their own
   
• Genomic surveillance is one of the best ways to ensure we're ready to update the vaccines when the time comes
   
• SARS-CoV-2 is here to stay, but it won't ever sweep through a totally naive global population like this again. We're still learning what antigenic evolution "normally" looks like in this virus.