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Nejmsr 2105280
Nejmsr 2105280
Spe ci a l R e p or t
transmission
ants of concern, and evaluation of the effect of
Increase
P681
H
variants on diagnostic tests, therapeutic agents,
R
and vaccines, will assist in global decision mak-
ing regarding changes in vaccines that may be
necessary.
transmission
G
G
R
decreases in Covid-19 case counts that occurred
in many countries earlier this year.2 The B.1.1.7
(or alpha) variant of concern increases viral
transmission
Y
Y
Q
K
* Single letter codes of amino acid changes at specified positions for the listed variants are shown.
N/T
Δ69–70
Increase transmission
Increase transmission
Phenotypic Change
decrease neutral‑
Increase transmis‑
sion, decrease
sion, decrease
and virulence,
neutralization
and virulence
virulence
features of interest on vaccine efficacy. With the example, the magnitude of the immune re-
use of such approaches (i.e., “sieve analyses”14) sponse against one or more variants of concern
in trials or in studies conducted after vaccine after a person has received a modified vaccine
deployment, important insights could be gleaned could be compared with that against the proto-
about the relevance of particular viral features, type virus after a person has received the origi-
and these insights may lead to improved strain nal vaccine that is known to be effective. Assess-
selection in the formulation of modified vaccines. ment of neutralizing responses against several
How reliably any immune biomarker can variants of concern and against the prototype
serve as a “correlate of protection” is not yet virus may help to determine whether more than
known. The effects of vaccination on such bio- one vaccine (or, ultimately, a polyvalent vaccine)
markers (as surrogate end points) — if those is needed.
biomarkers prove to be reliably predictive of the There has been consensus in recent regula-
effects of vaccine on the incidence or outcome of tory discussions15 and in WHO guidance that
breakthrough infections — could provide sup- conventional, large, clinical end-point trials are
port for regulatory action regarding new candi- probably not necessary in order to introduce
date vaccines. However, caveats include the modified vaccines against variants of concern.
potential dependence of immune correlates of Because differences among assays of immune
protection on vaccine-specific factors, viral strain, responses may complicate direct comparisons,
and the choice of Covid-19 study end points the Food and Drug Administration (but not the
(i.e., any infection vs. symptomatic infection vs. European Medicines Agency) has proposed that
severe disease). animal models16 could be used to provide fur-
ther support for the effectiveness of modified
vaccines against variants of concern.
E valuating Ne w or Modified
Vaccine s ag ains t Variant s Even with the deployment of some safe and
effective vaccines, more will be needed to ad-
Although there will be reluctance to deploy vac- dress the international pandemic. New vaccines
cines that are based on new sequences before may be more effective than previous vaccines
there is clear evidence that the original vaccines against emerging viral variants, and they may be
are failing, there will also be reluctance to allow administered in a single dose, be noninjectable,
prolonged circulation of vaccine-resistant vari- avoid cold-chain constraints, or have improved
ants while new vaccines or modified vaccines are manufacturing scalability. The design of modified
being developed, if this can be avoided. Now is vaccines or of completely new vaccines should
the time to plan for the development of modi- leverage international recommendations regard-
fied vaccines that could protect against vaccine- ing antigenic composition.
resistant variants, because such variants may well Trials of new vaccines can still yield reliable
emerge. Planning should include the effect of and interpretable results in an efficient manner
vaccine modification on timelines for vaccine by using randomization, by evaluating effects not
supply and rollout. only on immunologic but also on clinical end
Studies of modified vaccines (i.e., vaccines in points, and by using placebo controls when ethi-
which a new antigen is delivered through a vac- cally appropriate,17,18 perhaps in communities
cine that has already been shown to be effective where vaccine supply is very limited or in sub-
against previously circulating viral variants) should populations (e.g., young adults) in which even if
address the ability of these vaccines to elicit re- infection occurs, the probability of progression
sponses in persons who have not previously had to serious disease is very low.19,20 Randomized
an immunologic response against SARS-CoV-2 trials require additional planning, but when
and in previously vaccinated persons. Changes in practicable they prevent unidentified trial de-
the in vitro neutralization of circulating strains sign–related differences from confounding the
by vaccine-induced antibodies may not imply study results.21 Viral genotyping in persons with
waning effectiveness. Although neutralizing re- breakthrough infection (during or after trials)
sponses may not be reliably predictive of vaccine can support multiple analyses, including assess-
efficacy, striking differences may well provide ment of the influence of viral variants on vaccine
sufficient support for regulatory decisions. For efficacy. In randomized, controlled studies, such
* Sieve analysis is a statistical method that is used to infer the way in which vaccine efficacy varies with viral variants or
genotypes.14
genotyping also yields unbiased information abouttive advantage generally favoring more transmis-
variant-specific efficacy. Countries that participate
sible variants. Variants of concern with resistance
in such trials may assess vaccine efficacy against
against natural or vaccine-induced immunity
locally prevalent viral strains and should receive
would probably supplant previously circulating
priority access to trial vaccines if they have been
strains only if this immune evasion capability
shown to have an acceptable safety profile and resulted in increased fitness, including transmis-
to be efficacious (Table 3). In areas where place-
sibility. Given the emergence of immunity-evad-
bo-controlled trials of new vaccines are not ap- ing variants even before vaccines were broadly
propriate, the use of an active comparator could deployed, it is hard to implicate vaccines or vac-
still yield important results.22 However, the valid-
cine deployment strategies as the major drivers
ity of a noninferiority trial in which an active of immune evasion.
comparator vaccine is used as the control is de- However, prolonged viral replication in the
pendent on the ability of the previous studies ofpresence of partial immunity in immunocompro-
the active comparator to provide investigators with
mised persons or circumstances in which rapid
reliable insights about the efficacy of the active
transmission of high titers of virus occurs (e.g.,
comparator vaccine against viral variants that crowded living conditions23) could have contrib-
are currently present in communities engaged in uted to the development of variants that can at
the trial. least partially escape human immune responses.
Once modified vaccines or completely new vac-The use of antibody-based treatments (e.g., mono-
cines that address new variants have been intro- clonal antibodies or convalescent plasma) in cir-
duced, the cycle can begin anew with monitoring cumstances in which they are of limited or un-
for even newer variants that might necessitate demonstrated efficacy may further contribute to
further changes in the vaccine antigen sequence. the evolution of variants of concern that could
Development and deployment strategies should evade not only these but also other antibody re-
account for the possibility that multiple variants
sponses.24 Partially effective interventions may
may circulate in the same area. Studies in which therefore encourage viral evolution. In addition,
one vaccine is boosted with a later dose of an- the larger the number of infected persons, the
other would also be valuable. greater the chance that new variants of concern
will arise. Hence, effective public health strate-
gies such as social distancing, the use of masks,
Red ucing the Risk That Variant s
of Concern Will Emer ge and the targeted use of effective vaccines that
reduce both infection and transmission can help
Variants of concern have been evolving since the to limit viral evolution. Limiting transmission in
beginning of the Covid-19 pandemic, with selec- the general population is extremely important
for slowing the emergence of additional variants ployment should be viewed as international en-
of concern. terprises, with international coordination by the
Globally, vaccines are being rolled out slowly, WHO helping benefits to accrue throughout the
partly because of limitations on production ca- world.
pacity and “vaccine nationalism,”25 and in many Coordination is essential in assessing the
countries supplies will probably be limited even need for new or modified vaccines, in evaluating
in late 2021. Currently, the main strategy is to them, and in facilitating scientific understand-
protect critical services, persons in whom severe ing of the risk posed by novel variants and of the
disease is most likely to develop (e.g., older adults), relationships between genetic variation and anti-
and persons who are likely to transmit the virus genic escape. Open and frequent scientific dis-
to vulnerable populations (e.g., health care, front- cussion is necessary to identify which variants of
line, and essential workers), and to contain the concern require attention. Criteria are needed to
spread of the virus in the general population. The assess the appropriateness of given vaccines and
balance between using vaccines to protect per- the likely effect of emerging variants on vac-
sons from disease and using vaccines to target cines, as well as to support recommendations on
prevention of spread involves a strategic decision the development and evaluation of modified vac-
that should be informed by reliable epidemio- cines and new vaccines and the timing of their
logic information. deployment. This process can build on the global
In some epidemics, complete disease elimina- framework used periodically by the WHO to
tion has been achieved efficiently by using an coordinate the selection of antigens in influenza
epidemiologic understanding of transmission to vaccines (Fig. 2).
target the deployment of vaccines (e.g., vaccinat- Decision making about which antigens should
ing “rings” of contacts and contacts of contacts be included in vaccines against SARS-CoV-2 will
around cases of smallpox or Ebola26-28). Together need to involve epidemiologic data, data from
with other public health measures, targeting vac- evolutionary biology, and clinical, animal, and
cination to persons in certain areas or to demo- in vitro data that are pertinent to immune re-
graphic groups with a high incidence of infec- sponses and to continued vaccine efficacy in the
tion rather than focusing only on persons at high face of changing viral sequences and the possi-
risk for serious disease could slow transmission ble waning of vaccine-induced immunity. Meet-
and reduce the risk of development of additional ing these challenges efficiently will require en-
variants of concern, although no strategy can hanced surveillance with continued sharing of
work if adequate vaccine supplies are unavail- data (including viral sequences and correspond-
able. Targeted approaches are now being inves- ing antigens that are linked to clinical and epi-
tigated. For example, in certain areas, the de- demiologic information) and samples (including
ployment of some vaccines in a modified ring new viral variant isolates and serum samples
vaccination strategy has been suggested.29 Stud- obtained from vaccinated persons). It will also
ies of the effectiveness of such targeted strate- require the use of standardized reference reagents
gies could be of global relevance, especially if and models to evaluate viruses and modified vac-
groups or areas with consistently high and low cines. With collaborative, open discussion of re-
rates of transmission can be identified. sults, this data sharing will help foster consistent
and thoughtful public communications about
Co ordinating the Worldwide new variants and help maintain appropriate con-
Re sp onse fidence in vaccines and in the processes used to
develop, test, and deploy them.
New variants of concern may emerge in any cor- Although Covid-19 continues to present pub-
ner of the world and spread quickly, and conver- lic health challenges, including the emergence
gent changes have been noted in variants of of new variants, great progress has been made
concern identified in various parts of the world. in understanding this disease and how to pro-
The modification of sequences targeted by a vac- tect against it. Even though existing vaccines are
cine to meet the needs of one country could have helping to bring the pandemic under control in
repercussions elsewhere. Therefore, vaccine de- some locations, it is also necessary to plan for
velopment, vaccine modification, and vaccine de- unsatisfactory outcomes. As this planning con-
Evaluate efficacy of
modified vaccines against
variants of concern
tinues, international coordination by the WHO This article was published on June 23, 2021, at NEJM.org.
of research efforts and sharing of data and
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