Science - USA (2022-06-10)

INSIGHTS | PERSPECTIVES

GRAPHIC: KELLIE HOLOSKI/

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protection from immune escape variants
will depend on specific host and viral prop-
erties, including susceptibility to reinfec-
tion and transmission from breakthrough
infection. Additionally, global movement
seeds new SARS-CoV-2 outbreaks, poten-
tially in regions with vastly different levels
of preexisting infection-induced or vaccinal
immunity and other epidemiological fac-
tors. Depending upon this immune land-
scape, population-level selection may favor
variants with either higher transmissibility
or increased immune escape. Inequitable
vaccine coverage increases global infection
levels, which increases the likelihood for
variants with either of these characteristics.
To untangle the effects of immunity on
transmission, it will be crucial to quantify
the cross-scale impact of host immune re-
sponses on epidemiology and viral evolu-
tion. Although several studies have made
progress in this general direction ( 8 , 10 ),

there remain important gaps that need to
be addressed. In particular, epidemiologi-
cal studies that simultaneously quantify
immunity and transmission across popula-
tions and at different biological scales are
necessary, along with the development of
cross-scale modeling approaches. There are
a number of study designs and associated
measurements that could address these
gaps and determine the impact of immu-
nity on cross-scale phylodynamics (see the
figure). Long-term longitudinal studies
that monitor immunity across cohorts and
ages, in addition to measuring viral loads,
sequence variation, and household trans-
mission, are essential. Using these data in
cross-scale modeling frameworks could elu-
cidate the impact of immunity on transmis-
sion and viral variation.
The phylodynamics of the COVID-19 pan-
demic have provided many—often nasty—

surprises compared to expectations honed

by the dynamics of other viruses, notably

influenza virus. For example, the observa-

tion that some hosts sicken with COVID-19,

but do not then strongly seroconvert ( 12 ),

complicates interpretation of measuring

antibody titers for dissecting the impact

of population immunity. Assuming these

immunologically “cryptic” individuals are

capable of virus transmission, do they con-

tribute to net evolution of the virus (e.g.,

owing to the presence of unmeasured im-

munity)? It is also unclear how host im-

mune responses besides neutralizing anti-

bodies (such as T cell immunity, which is

harder to measure) affect evolutionary tra-

jectories. Moreover, whether existing popu-

lation immunity to endemic viruses creates

a cross-protective firewall against emergent

pathogen spillover, and how this might oc-

cur, needs further investigation (as does

the potential impact of animal reservoirs).

Perhaps the central question for future

SARS-CoV-2 variants is the relationship be-

tween transmission rate, immune escape,

and clinical severity. Specifically, is there a

“worst case” viral genotype that combines

high transmission, immune escape, and se-

verity? This will depend in a complex way

on—still partially understood—cross-scale

viral and immune dynamics. Unfortunately,

the virus is likely to explore these phylody-

namics before they can be predicted, espe-

cially given continued transmission arising

from global inequities in vaccine supply.

One general strategy for exploring these

complexities is to generate phylodynamic

case law by broadening studies to explore

the phylodynamics of multiple pathogens

using recently developed multiplex immu-

nological methods ( 13 ) with viral sequenc-

ing. Analyzing immunity against multiple

pathogens and variants will also address

issues such as antigenic imprinting (the im-

munity conferred after recovery from the

first infection) in influenza, the potential

contribution of immunologically cryptic

individuals to pathogen evolution, serotype

interactions in dengue, and the polymicro-

bial impact of nonpharmaceutical interven-

tions used to mitigate COVID-19.

New phylodynamic models and data

structures should be developed to answer

these questions. For example, studies have

pioneered statistical methods to determine

transmission patterns and evolutionary

history from sequence data ( 14 ), and a fit-

ness-based model to predict future inci-

dence of influenza clades ( 15 ). Combining

either approach with models that account

for within-host kinetics and immuno-

epidemiology may be a particularly fruit-

ful avenue to unravel the impact of host

immunity on pathogen eco-evolutionary

dynamics. For SARS-CoV-2 specifically,

it is important to quantify immune land-

scapes at all spatial scales (local, regional,

and global). Crucially, this quantification

will enable the development of tools and

infrastructure that will aid in predicting

future epidemic and evolutionary trajec-

tories. These suggested approaches echo

proposals for a Global Immunological

Observatory (i.e., regular mass blood sam-

pling to monitor immunological signa-

tures) ( 13 ), but with an important evolu-

tionary focus to elucidate the cross-scale

impacts of immunity on pathogen dynam-

ics. More generally, such immuno-epidemi-

ology and viral discovery could help eluci-

date the phylodynamics and vaccinology of

a much wider range of pathogens. j

REFERENCES AND NOTES

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4. K. Koelle et al., Science 314 , 1898 (2006).


5. R. T. Eguia et al., PLOS Pathog. 17 , e1009453 (2021).


6. J. Zahradník et al., Nat. Microbiol. 6 , 1188 (2021).


7. K. P. Y. Hui et al., Nature 603 , 715 (2022).


8. D. H. Morris et al., eLife 9 , e62105 (2020).


9. D. Planas et al., Nature 602 , 671 (2022).


10. K. S. Xue et al., eLife 6 , e26875 (2017).


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ACKNOWLEDGMENTS

The authors thank A. Spaulding, D. Douek, and A. McDermott

for discussions. The authors are funded by the Natural

Sciences and Engineering Research Council of Canada

through a Postgraduate Doctoral Scholarship (C.M.S.-R.) ; a

Charlotte Elizabeth Procter Fellowship of Princeton University

(C.M.S.-R); the US Centers for Disease Control and Prevention

(B.T.G.); and the Flu Lab (B.T.G.).

10.1126/science.abn9410

Monitoring across

ages and degree of

immune competence

Infection Recovery

Waning

immunity

Estimate transmission

impact of immune

status on viral variant

Reinfection

t 1 t 2 t 3 t 4 t 5

Household

transmission

Household

transmission

Viral load,

sequences

Vaccination Serology

Studying immuno-epidemiology
Cohort studies are needed to understand the impact of immunity on phylodynamic evolutionary patterns.
There are two classes of unknowns: the impact of vaccination for individuals with different degrees of immunity,
and the impact of vaccination on subsequent susceptibility to and transmissibility of breakthrough infections.

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