Biology Reference
In-Depth Information
vaccine, a good choice for a first detailed study of vacci-
nation, as the vaccine is extremely effective (over 90% of
vaccinees are protected), and because it is known to elicit
neutralizing antibodies that last more than three decades.
Blood samples were taken from cohorts of individuals on
the day of the vaccination (time 0) and at several time
points afterwards, until 60 days after vaccination and
including days 3
was commonly induced by both YF-17D and LAIV but not
TIV. Thus, different vaccines and different vaccine types
appear to activate distinct immune mechanisms.
The new insights into the mechanisms of vaccine
response can help to develop improved vaccines. For
instance, Pulendran and colleagues vaccinated mice with
synthetic nanoparticles that contained antigens plus ligands
that signal through TLR4 and TLR7, and showed that they
induced synergistic increases in antigen-specific neutral-
izing antibodies, compared to immunization with single
TLR ligands
[48]
. Such coupling between systems analyses
and targeted combinatorial vaccine design heralds a new era
of highly targeted and personalized vaccination strategies.
7, which covers the initial innate
response. Both studies showed a strong change in gene
expression following vaccination, which could be detected
as early as day 3 and which peaked by day 7. Gene set
functional enrichment analysis showed that the changes in
gene expression corresponded not only to factors directly
related to antibody production, but also to other effectors of
the immune response, most prominently activation of virus-
dependent innate immunity
[46,47]
and the proliferation of
antigen-specific cytotoxic T cells, whose numbers varied
significantly between individuals
[47]
. The strong innate
response upon vaccination was unexpected because the
formation of neutralizing antibodies is primarily an adap-
tive immunity-dependent process. This suggests that there
is a strong dependence of the adaptive arm of the immune
response on the innate arm. Using gene expression data
from the earlier time points (days 0
e
Antibody and TCR Repertoire Diversity
The adaptive arm of immunity tailors responses for any
encountered antigen. To do so, B and T cells need to
generate an enormous repertoire of structural diversity in
antigen-recognizing proteins, including antibodies (also
known as immunoglobulins) and T-cell receptors (TCR),
so that they may be able to recognize and eliminate the
large range of possible foreign invaders and cancerous
cells. The immune system generates structural diversity
through the recombination of three separate and highly
variable gene segments loci, termed variable (V), diversity
(D) and joining (J) to form a very large number of poly-
peptides (heavy and light chains of antibodies and
a
,
b
,
g
and
d
of T-cell receptors) that can combine to form het-
erodimeric antigen-recognition domains. An allelic
exclusion mechanism generally allows only a single VDJ
combination to be expressed in a given cell, despite the
additional chromosomal copies, and a separate mechanism
activated following antigen recognition assures high
specificity of the receptor/antibody to the antigen through
hyper-mutation and selection.
VDJ recombination can create as many as 10
8
different
combinations. With an estimated cell count of 10
11
different B and T cells in an individual human being, it is
assumed that this mechanism generates a sufficiently large
repertoire for immune system antigen recognition.
However, until recently, surveying even a small fraction of
an individual's repertoire was considered an impossible
task. As a consequence, even basic questions related to the
structure and dynamics of the repertoire had gone unan-
swered for decades. Next-generation DNA sequencing now
offers an opportunity to start exploring the basic principles
of repertoire selection, as well as its relation to disease.
An individual zebrafish maintains at any one time an
average of 300 000 B cells, five orders of magnitudes less
than a human, and up to 975 unique VDJ combinations.
Seizing on this lower complexity, Quake and colleagues
used next-generation DNA sequencing to sequence heavy
chain V regions (V
H
),
7), Pulendran and
colleagues could predict the magnitude of the later adaptive
response of antigen-specific cytotoxic T-cell proliferation.
Close examination of the set of predictor genes implicated
that the stress response shuts down protein translation as
part of the immune mechanisms of vaccination unappre-
ciated
[47]
. Thus, such studies can serve both for the
identification of predictive biomarkers and as a stepping
stone for the exploration of immune mechanisms involved
in vaccination.
In a follow-up publication, Nakaya et al., in a similar
longitudinal experimental design, analyzed influenza
response over a 3-year period. As noted above, the effect of
influenza vaccination is suboptimal, and individuals are
exposed to a variant of virus and/or receive vaccinations on
an annual basis. All adults have been previously exposed to
at least some flu strains, which greatly confounds analysis
because prior exposure has primed memory responses
which may activate in some individuals based on virus
strain similarity, and because it is unclear what the base
response is. Furthermore, for influenza, two different
vaccines are in common use: a live attenuated virus given to
individuals under the age of 65 (LAIV) and a killed virus
(TIV) usually given to at-risk groups. The two vaccines do
not elicit an antibody response of the same magnitude, and
although a common gene signature is observed, the genes
induced by the two vaccines are for the most part quite
different. Comparing the gene expression signature of YF-
17D-vaccinated individuals to those vaccinated with
influenza showed a distinct vaccine-specific signature for
both vaccines, although a common interferon-related gene
e
from 14 different animals to
