462 29 APRIL 2022 • VOL 376 ISSUE 6592 science.org SCIENCEBy Nimalan Arinaminpathy1,2,
Chadi M. Saad-Roy^3 , Qiqi Yang^4 , Isa Ahmad1,2,
Prashant Yadav5,6, Bryan Grenfell4,7T
he rapid development of vaccines
against COVID-19 raises questions
about what could be achieved in vac-
cines to other major diseases. Influ-
enza presents an important case study;
it is one of the few infections that
causes substantial public health burden in
its endemic form while also having proven
pandemic potential. We offer a first step in
bringing together the value proposition of
future influenza vaccines considering two
key characteristics: the breadth of protec-
tion that vaccines offer (against individual
strains, all strains within a subtype, multiple
subtypes, or all subtypes) and the duration
for which protection remains effective (see
the figure). We examine implications of these
characteristics, from both epidemiologic and
economic perspectives, and discuss how a fu-
ture market for influenza vaccines might best
align public health and economic incentives.
Although many of these factors are specific
to influenza, we consider comparisons with
other major infections, such as tuberculosis
and COVID-19.
Current influenza vaccines, mainly tar-
geting the variable region of the haemag-
glutinin surface glycoprotein of the virus
( 1 ), cannot be used to protect a population
in advance of a pandemic and are only de-
ployed in routine immunization against
specific variants of seasonal influenza. By
contrast, through offering broad protec-
tion, new vaccines could mitigate equally
against both seasonal and pandemic in-
fluenza. Such vaccines would be distinct
among immunization programs by having
value in both routine and strategic modes
of deployment. Moreover, current influ-
enza vaccines are mostly still produced by
using the same egg-based methods that
have been used for roughly the past 70years. New vaccines would transform these
production methods. For example, both
mRNA and viral vector technology bypass
the need for candidate vaccine viruses to
initiate the production process, requiring
only the genetic sequence of the target an-
tigens. Although such vaccines will depend
on new technologies for their manufacture,
the unprecedented pace and scale of rollout
of COVID-19 vaccines have shown that such
hurdles can be overcome.EPIDEMIOLOGICAL IMPLICATIONS
The basic reproduction number for seasonal
and pandemic influenza (R 0 )—the expected
number of secondary cases produced by a
typical infectious individual in a fully sus-
ceptible population—is typically less than 2,
meaning that even partial vaccination cov-
erage and efficacy can have strong effects
in reducing the burden of influenza. It is
likely that a future influenza vaccine would
offer less than lifelong protection, necessi-
tating repeated vaccination over a lifetime.
Depending on the duration of immunity,
repeat vaccination may not need to be as
frequent as every year. If the vaccine targets
“conserved” antigens that do not evolve as
rapidly as the variable region of haemag-
glutinin (the target of current vaccines), the
antigenic formulation of the vaccine may
need not be updated as often as with cur-
rent seasonal vaccines.
Previous modeling work has illustrated
that if the duration of immunity and the fre-
quency of immunization are sufficiently high
that population immunity is allowed to accu-
mulate over time, a future influenza vaccine
could exert greater reductions in seasonal
influenza burden than that of a conventional
vaccine with the same coverage and efficacy
( 2 ). Multiyear cohort studies of vaccinated
versus unvaccinated individuals would pro-
vide valuable data on the duration of vaccine-
induced protection that will be important in
planning future vaccination programs.On breadth, although an ideal vaccine
would be effective against all subtypes of
influenza A, in practice it has proven chal-
lenging to achieve such universal breadth of
protection. Previous work has shown how
infection-induced, T cell–mediated hetero-
subtypic immunity could protect against
severe disease from pandemic influenza
in humans ( 3 ). Several vaccine candidates
aim to raise T cell immunity against targets
such as the nucleoprotein and the matrix
protein [for example, ( 4 )], which are con-
served across influenza subtypes.
On the other hand, recent work has fo-
cused on antibody-mediated immunity
against the haemagglutinin stalk, which,
being critical for the stability of the overall
haemagglutinin molecule, shows far less
variability than the “head” region [for ex-
ample, ( 5 )]. However, stalk-based immunity
is not universal: Because H1 and H3, the two
subtypes of influenza A currently causing
seasonal influenza in humans, belong to dif-
ferent clades, stalk-reactive antibodies to H1
may offer only limited cross-protection to H3,
and vice versa. Vaccinating against H3 may
therefore open an ecological niche, allowing
greater epidemics of H1 than currently occur,
and vice versa. Analogous effects have been
observed for pneumococcus, in which wide-
spread vaccination uptake against a limited
set of serotypes has typically been followed
by an increase in carriage of nonvaccine sero-
types (although not necessarily accompanied
by increases in disease) ( 6 ).
Overall, for any future influenza vaccine
offering less-than-universal protection, it
will be critical to adopt complementary vac-
cination strategies to close the “protection
gap” (see the figure). For example, a future
vaccination program could combine a stalk-
based H3 vaccine with a conventional H1
vaccine, or a combination of stalk-based H1
and H3 vaccines.ECONOMIC IMPLICATIONS
Although improved breadth and duration of
protection both have positive implications
for epidemiological impact, they could act
in opposing directions in the context of
manufacturing and distribution (see the fig-
ure). A future influenza vaccine that offers
broad protection could have higher global
demand than that of current influenza vac-
cines, giving rise to a substantially expanded
market for manufacturers to serve. If such
a vaccine does not need to be updated as
frequently as current vaccines, as a result
of targeting more conserved influenza anti-INSIGHTS(^1) MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, London, UK. (^2) Abdul Latif Jameel Institute
for Disease and Emergency Analytics, School of Public Health, Imperial College London, London, UK.^3 Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
(^4) Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ, USA. (^5) Technology and Operations Management, INSEAD, Fontainebleau, France. (^6) Center for Global
Development, Washington, DC, USA.^7 Princeton School of Public and International Affairs, Princeton University, Princeton, NJ, USA. Email: [email protected]
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