B cells, antibodies, and vaccination

Antibodies co-evolve with pathogens

B cells determine antibody diversity

Structure of a B cell receptor

Origins of B cell receptor diversity

VDJ recombination

Affinity maturation

VDJ loci

VDJ recombination

Selection on naive repertoire

Stability

Autoreactivity

Germinal centers

Affinity maturation

Dynamics in one GC

Ab feedback may diversify the repertoire

GC B cells evolve

AID induces somatic hypermutation

Mutation rate varies over the variable region

GCs produce plasma and memory cells

In humans, memory cells evolve further

Evidence from sampling lymph nodes

Clones can be long-lived

Broadly neutralizing antibodies are often highly diverged

Broadly neutralizing antibodies to flu elusive

Why do some people develop more bnAbs?

Can we induce high levels in everyone?

How can we guarantee they will dominate?

"Restricted" responses to epitopes

Genotype affects response to H5N1 vaccination

Allele copy number affects clone frequency

Ethnic differences in copy number

Genetics might matter, but what else?

A story about a sample of people born between 1965 and 1979...

In 2013, H1N1 acquired K166Q

Uneven recognition

Homology with childhood strain

Recapitulation in ferrets

Strain phenotypes depend on host

"Antigenic seniority"

Broad cohort-specific effects

What's so special about early infections?

A general model of sin

Early infections affect vaccine response

Response to 2009 H1N1 vaccine

Stalk responses can fade

Stalk antibodies bind with lower avidity

Stalk antibodies are more polyreactive

What determines Ab immunodominance?

Host genotype

Order (Age?) of infection

Immunogenicity

Autoreactivity

In U.S., flu vaccine coverage is high(-ish)

In RCT, vaccine provides indirect protection

Influenza vaccine effectiveness is low

H3N2: 33% (95% CI: 26-39)

B: 54% (46-61)

pH1N1: 61% (57-65)

H1N1: 67% (29-85)

What's going on?

Poor strain selection (antigenic mismatch)

Egg adaptations (antigenic mismatch)

Interaction with pre-existing immune responses

Sin diminishes egg effects in 2012-2013?

Ferrets recognize egg adaptations, but humans don't

Vaccine effectiveness tracks cohorts

Another curiosity: low VE in repeat vaccinees