Contributors (in alphabetical order): Samuel Clifford, Rosalind Eggo, Julia Gog, Bryan Grenfell,
Deirdre Hollingsworth, Petra Klepac, Jessica Metcalf, Billy Quilty, and Robin Thompson.
Source: GOV UK
This paper summarises the current scientific consensus and hypothesis on the role of global
vaccination in emergence and importation of new variants, and identifies key areas of uncertainty for
making future projections and policies. We highlight key considerations for future policymaking, and
where that could be guided by new evidence. Some aspects relate to medium–term decisions (~3
months) and others to long–term issues (~12 months) as travel and behaviour returns to baseline.
● The biggest threat to the UK’s health security and response to the SARS–CoV–2 pandemic is
the emergence (and establishment within the UK) of variants that either have increased
transmissibility, increased disease severity, escape prior immunity, or a combination of these
characteristics [high confidence]
● Substantial global circulation of SARS–CoV–2 will lead to the evolution of new variants and
continued risk of importation to the UK [medium confidence].
● Increased international vaccination by donation/sharing of purchased doses, or supporting
increased manufacture, has the potential to reduce the appearance and establishment of
variants internationally, as well as the risk of their importation to the UK [medium confidence].
● It is unknown how levels of vaccination change the relative risk of the appearance and
establishment of an immune escape variant. Most current variants of concern emerged before
mass vaccination or high population immunity from infection [medium confidence]. Any level
of population immunity may increase selection pressure for immune escape variants but there
is no evidence to suggest this pressure would be greater for vaccine–induced immunity than
immunity driven by infection [medium confidence].
● At the individual level, partial immunity may create conditions that favour onward
transmission of variants with immune escape–associated mutations [low confidence].
However, it is not yet clear how different vaccines, dosing regimes, or immunity from previous
infection may intersect with different variants and individual host characteristics to influence
the emergence of immune escape variants [medium–high confidence].
● If immunocompromised or populations otherwise vulnerable to chronic infections are shown
to be a significant source of new variants with concerning characteristics, then focussing
global vaccination efforts to these populations (and their contacts) may reduce the risk of new
variants of concern emerging [medium–high confidence].
Risk of importation of novel variants
● As the number of travellers to the UK increases so will the risk of importation of variants and
the burden on genomic surveillance systems [high confidence]. The number of importations
that would result in the establishment of local transmission of a new variant is difficult to
predict due to overdispersion and the unpredictability of variant characteristics such as
transmissibility [high confidence]. Border measures are likely to delay but not prevent
introduction [high confidence].
● If vaccination continues to protect against infection, and reduce onward transmission, then
requiring travellers to be vaccinated is likely to reduce the risk of importation but may
exacerbate inequalities if international vaccination coverage remains low and heterogenous
● Imported cases are less likely to lead to outbreaks and established community transmission in
the UK if transmission in the UK is controlled, by population immunity or non–pharmaceutical
interventions [high confidence].
● It is unclear which domestic communities may be at higher risk from imported variants.
Increasing domestic vaccination in all groups or those with higher exposure to international
travellers is likely to reduce the probability of establishment of transmission after importation
Benefits of international vaccination
● A successful domestic strategy hinges on achieving low numbers of infections globally to
reduce the emergence of novel variants of concern [medium–high confidence].
● Establishing the optimal priority or targeting of international vaccination efforts is
complicated by biological uncertainties and logistical complexities (e.g. distribution, vaccine
hesitancy, regional stability, etc). In the short term, prioritisation of countries with higher
volumes of travellers coming to or from the UK (or for whom more open borders are
economically desirable) could be considered [low confidence].
● Multilateral cooperation and a commitment to increasing global vaccination rates, in part by
sharing resources such as doses, is highly likely to have the biggest impact on the incidence of
infections globally and thus the biggest impact on the risk of the emergence of new variants
The biggest threat to the UK’s health security and response to the SARS–CoV–2 pandemic in the
medium to long term is the emergence (and establishment within the UK) of variants which have
any of the properties of:
a. increased transmissibility (or faster growth through any means)
b. higher severity (causing worse health outcomes)
c. escape prior immunity (from previous infection or vaccine)
d. any combinations of the above.
The steps on the pathway from international emergence to establishment of domestic transmission
in the UK on which interventions can act:
a. A variant first appears through mutation in the unknown source location
b. The variant establishes transmission in that location
note: (emergence: both a and b together)
c. The variant is imported to the UK
d. Establishment of transmission of the variant in the UK.
Increased international vaccination by donation or sharing of doses or supporting manufacture, has
the potential to reduce the risks of the first three steps, hence reducing the threat to the UK.
In this paper, we explore the evolutionary arguments for the effects of vaccination, consider in more
detail international importation routes, and combine these to draw out consequences for a successful
strategy for the UK for international vaccination. Finally we highlight the key unknowns, and areas
where further work is urgently needed.
2. Evolutionary considerations of vaccination effects on novel variants
Increasing international vaccination will reduce the number of cases in which new variants can appear
(lower prevalence at source), the probability of local establishment (lower reproduction ratio at
source) and the probability of importation to the UK (lower prevalence at source). A possible
counterargument is that vaccination may directly affect appearance and selection for immune escape
variants (infection– or vaccine–induced). Overall, we argue that increasing international vaccine
coverage is very likely to help prevent the emergence of variants.
Mutations that affect one of transmissibility, severity, or immune escape can affect other properties,
and it is not clear how these are interlinked in terms of their underlying biology or in terms of selection
(1). For example, transmissibility and immune escape may be linked for SARS–CoV–2: the spike (S)
glycoprotein is both the main target of neutralizing antibodies (2) and houses the receptor binding
domain (RBD) that binds to the human ACE2 cellular receptor and modulates transmissibility (3).
Further, it is not currently possible to predict the limits of transmissibility or severity for potential
At the scale of individuals, partially–immune hosts may create conditions that favour onward
transmission of variants associated with immune escape. If there is no immunity, mutations associated
with immune escape will not have a selective advantage (4), whereas if immunity (infection– or
vaccine–induced) is complete, such that these mutations cannot achieve onward transmission, they
will not spread either. However, the exact characteristics of such partially–immune hosts, and how
particular vaccines, dosing regimes, or variants may intersect to create conditions that favour
appearance of immune escape variants remains unclear.
Partially immunized individuals (i.e. in receipt of a single dose for a two–dose vaccine) have also been
suggested as creating a context allowing selection for such variants (5; 6; 7). Expansions of sequencing
and surveillance worldwide, including sequencing of any breakthrough cases in vaccinated individuals
(and their contacts) are required to establish the nature of this risk, and will also inform our
understanding of the degree to which immune escape co–varies with transmissibility and health
Characteristics of infected individuals may also matter for variant emergence. Immunocompromised
hosts and chronic infections have been suggested as a source of variants (8; 9; 10; 11). If
immunocompromised or populations otherwise vulnerable to chronic infections are shown to be a
significant source of new variants with concerning characteristics, focussing global vaccination efforts
to these populations (and their contacts) may reduce the risk of new variants of concern emerging.
To date, emergence has occurred in the context of little or no vaccination (12); thus variants, including
variants with a degree of immune escape, can clearly arise as a result of the infection of unvaccinated
populations. Any level of population immunity may increase selection pressure for immune escape
variants but there is no evidence to suggest this pressure would be greater for vaccine–induced
immunity than immunity driven by infections.
Moving to the scale of populations, the relative risk of selection for immune escape in vaccinated
versus unvaccinated populations is unknown. However, increasing numbers of cases provide more
opportunities for escape mutations to appear (13). If immune escape is more likely to appear in
vaccinated individuals than unvaccinated, then at the population level this will cause risk of immune
escape to be greatest for a partially vaccinated population: when there is an appreciable proportion
vaccinated yet prevalence can still run high (14). Currently however, many countries already have
some level of partial vaccination coverage and remain at risk of high future SARS–CoV–2 prevalence –
here any assistance to reduce prevalence will help mitigate the appearance and establishment of
3. Risk of importation and establishment of transmission of novel variants
The simplest estimation of the risk of importing a novel variant to the UK is the prevalence of a variant
in a given location multiplied by the volume of travel from that location to the UK. Reducing either or
both of these factors may lower this risk, as would isolating and detecting infected and infectious
arrivals through quarantine and/or testing of travellers. Increased international vaccination is likely to
affect the former (both through appearance and establishment as described above), and decrease the
risk of importation and need for border controls. Maintaining long term border controls or reduced
travel is likely to be expensive, and only delay rather than prevent importation.
Prevalence estimates in source locations may be under–ascertained and lagged due to limited
surveillance and delays in reporting (15). The surveillance of variants is limited further by genomic
sequencing capacity which is mostly concentrated in high–income countries. Variants may only be
detected after importation into a country with established testing and sequencing, at which point the
variant may be well established in the origin location and seeded widely elsewhere through
The number of international travellers arriving/returning to the UK remains significantly lower than
before the pandemic1, but is likely to increase over time. This will increase both the risk of importation
and the burden on border surveillance. Travel volumes to some locations may change rapidly if new
border restrictions (domestic or international) are introduced. Travellers may also pass through
intermediate countries before reaching the UK subject to different regulations, or to avoid border
Modelling has shown that interventions such as testing prior to the flight or upon arrival (repeatedly
or in combination with quarantine) may reduce both the number of imported infections, and also the
potential for onward transmission, but has also highlighted important limitations (16; 17; 18; 19; 20;
21). The effectiveness of such interventions will largely be dependent on the degree of participation
and adherence, voluntary or otherwise, to the specified strategy and the volume of cases.
Both modelling and real–world assessment of stringent border measures, e.g. as in Australia and New
Zealand, indicate that border interventions may delay and reduce the frequency of, but not prevent,
case importation due to the accumulation of small risks over time (22). The number of importations
that result in a high chance of established local transmission is difficult to predict due to large variation
in the secondary case distribution of SARS–CoV–2 (overdispersion, or “superspreading”) (23; 24), but
variants with higher R are likely to establish local transmission after fewer introductions. Delaying
establishment of community transmission gives an opportunity to implement domestic interventions
which limit the extent of community transmission. Maintaining stringent restrictions on travel over
the long–term carries significant economic and social costs which must be weighed against the benefits
of reducing the frequency of importation.
Requiring travellers to be vaccinated may also reduce the risk of importation if vaccination continues
to protect against infection. As such, increased international vaccination may reduce the risk of
importation and thus allow for increased travel from a greater number of countries. However, this
may exacerbate inequalities if international vaccination coverage remains low or heterogeneous. In
the long term, genomic surveillance and testing of incoming vaccinated travellers is likely to be needed
but would decrease the risk of importing vaccine–escape strains only if coupled with interventions
limiting onward transmission.
If infected travellers are arriving into a country where the effective reproduction number, R, of the
variant is low or below 1, either due to the impact of contact rate reducing NPIs or population
immunity (either from vaccination or previous infection), then imported cases will be less likely to
spark outbreaks and establish community transmission (25). If vaccination coverage is low,
heterogeneous, or ineffective against variants, there is potential for extensive community
transmission within susceptible subpopulations. It is unclear what factors drive emergence of variants,
therefore which locations they may occur, and thus which domestic communities may be at–risk for
importation. Domestic vaccination campaigns should prioritise increasing vaccination coverage,
including in hard–to–reach groups and those with higher exposure to all international travellers, to
reduce the probability that importations lead to establishment of transmission.
4. Potential domestic benefits from international vaccination
Taking into account the importation and evolutionary considerations above, a successful domestic
strategy hinges on achieving low numbers of infections globally to prevent the emergence of novel
variants. In the short term, a domestic focus for vaccination combined with import controls may have
utility, but in the medium to long term and COVID–19 endemicity (26), cooperating to drive global
mass vaccination is likely to be better for the UK, for two reasons:
1. Substantial global infection prevalence will lead to evolutionary pressure and likely emergence
of variants. The presence of variants internationally may require prolonged maintenance of
border measures and additional local interventions to delay/prevent establishment of new
variants, entailing significant economic costs.
2. Medium–term strategies to achieve local control of transmission depend on the reproduction
number and immune escape of circulating variants. Given the history of the pandemic, we
cannot exclude the evolution of more transmissible, more severe, and less vaccine–susceptible
variants (27). Importation and establishment (as border measures are unlikely to be infallible)
of such variants of concern in the UK would decrease the feasibility of local control.
International coordination to raise global vaccination coverage, for example by dose–sharing, will
enable most effective leveraging of available doses. Establishing the optimal priority or targeting of
international vaccination efforts is complicated by biological uncertainties and logistical
complexities (e.g. distribution, vaccine hesitancy, regional stability, etc). In the short term,
prioritisation of countries with higher volumes of travellers coming to or from the UK (or for whom
more open borders are economically desirable) could be considered.
Regional and global control of infection requires an ambitious programme of mass (ideally regional)
manufacture and global dissemination of vaccines. This demands multilateral cooperation and
commitment but is likely to result in domestic and global benefits by controlling transmission,
reducing the spectre of evolution, and improving the capacity to develop and manufacture booster
doses as the evolutionary goalposts shift. These outcomes are likely to generate considerable returns
on the substantial required investment.
Multilateral cooperation and a commitment to increasing global vaccination rates, in part by sharing
resources such as doses, is highly likely to have the biggest impact on the incidence of infections
globally and thus the biggest impact on the risk of the emergence of new variants (26). There are
circumstances where considerable impact can be achieved by a single country sharing resources with
others. For example, during the smallpox eradication effort the US financed smallpox elimination in
India with $100 million USD, the rest covered by India. This altruistic move was also strongly in US self–
interest as it could not stop its domestic smallpox vaccination campaign until the virus was eradicated
elsewhere in the world. There was also a strong economic case for resource sharing, since the US saves
its entire contribution on smallpox eradication every 26 days (massive return on investment). We
cannot predict where novel variants will emerge, so a unilateral targeted approach is likely to only
have a limited effect. While there is high prevalence of COVID–19 in many different areas of the world
with different levels of surveillance capacity, domestic intervention and border measures are needed
to lower the risk to the UK from new variants. As such, reducing the probability of emergence of new
variants globally is in the UK’s local interest. This can be best achieved in a coordinated multilateral
effort of resource sharing and supporting development, manufacture and global deployment of
vaccine and booster doses (28).
5. Key uncertainties and future needs
While the principle that decreasing global prevalence by increasing international vaccination is critical
to decreasing the risk posed by new variants to the UK, there are a number of key areas of uncertainty
which make prediction and precise strategy design extremely challenging. Here we note the major
areas of uncertainty underlying the conclusions above, which require further research:
5.1 Duration of infection– and vaccine–induced immunity:
Although the current consensus is that adaptive immune responses following natural SARS–CoV–2
infection are fairly robust and long lasting (29; 30), the picture is less clear in the face of emerging
variants (31; 32; 33), particularly the delta strain (34; 35; 36; 37). The expected duration of both
infection– and vaccine–induced immunity is unclear. If and why immunity wanes and the time–scale
over which this occurs will impact the level of community immunity (38; 39; 40; 41) and the probability
of establishment of new variants (5). Waning immunity allows more breakthrough infections,
especially if prevalence remains high, but the effect on probability of generating new variants is
unknown. New evidence on the duration of immunity could require altered vaccination strategies,
including for booster vaccinations. However, as always through this: if total global prevalence is lower
then the total risk is lower.
5.2 Immunocompromised people and chronic infections as higher risk for variant emergence:
Infection of immunocompromised individuals has been linked with viral evolution and the emergence
of variants (8; 42). More evidence is urgently needed if infection of these individuals increases risk of
creation of variants. Global vaccination, genomic surveillance, diagnostic testing for SARS–CoV–2, and
mitigation measures could be targeted to these groups and their contacts, although the global
distribution and their prevalence is unknown. For example, data on HIV/SARS–CoV–2 co–infection are
still scarce, particularly in terms of within–host viral evolution in coinfected hosts. In the absence of
targeted measures, global reduction of prevalence remains a leading tool in minimising opportunities
for variant emergence.
5.3 Probability of variant emergence in vaccinated vs unvaccinated groups:
It is not known whether variant emergence is more likely in fully– or partially–immunised groups, or
those with infection–induced immunity. Vaccine–induced immunity appears strong, and major variants
so far have emerged in the context of little vaccination.
5.4 Feasibility of targeted border restrictions as an approach:
Targeting of border restrictions to countries with evidence of new variants will be very challenging
• We currently cannot predict the likely context of emergence and therefore likely locations.
• Weaker surveillance systems (especially in genomic surveillance) in emergence locations and
potential de–prioritisation of COVID–19 surveillance means we may not get an early signal even
of increased transmission in a particular location. Therefore domestic UK or border
surveillance (or that of other nations) may be the earliest signal of a new variant (as observed
for gamma variant). Building or maintaining international surveillance could also benefit the
• By the time a variant is identified there is likely to already be international seeding, including
to the UK. The UK has high travel volumes so has consistently received exogenous variants
early. Therefore, targeted restrictions are challenging, especially if there is effort to
circumvent them via alternate travel routes.
• Once a variant appears and establishes, the speed of reaching dominance and increasing cases
has been extremely rapid (for example, alpha and delta variants). Therefore the timescale on
which targeted interventions must be enacted is very short, especially for variants with
5.5 Vaccine dose and efficacy
Optimal strategy will depend on the details of vaccine action, in particular:
● Dose fractionalisation could increase the number of doses available, as long as immunity
achieved by fractional doses is equivalent to full dose (6; 43).
● There is increasing evidence of variable efficacy between vaccine types, and higher efficacy is
much better in terms of minimising risk of emergence as it decreases the number of partially
immune hosts. Similarly single–dose vaccines avoid a period of partial immunity seen for 2–
dose vaccines, however total achieved efficacy needs to be equivalent. A vaccine which
prevented severe disease but had little effect on transmission would be concerning for escape.
● New evidence on efficacy or immune responses to mixed–dose strategies could ease vaccine
deployment logistics by removing the need for homologous doses and verification of first–
1. Assessing the risk of vaccine–driven virulence evolution in SARS–CoV–2. Miller, Ian F. et al.
2. Robust neutralizing antibodies to SARS–CoV–2 infection persist for months. Wajnberg, Ania et al.
3. SARS–CoV–2 RBD in vitro evolution follows contagious mutation spread, yet generates an able
infection inhibitor. Zahradnik, Jiri et al.
4. Unifying the Epidemiological and Evolutionary Dynamics of Pathogens. Grenfell, Bryan T, et al.
5. Epidemiological and evolutionary considerations of SARS–CoV–2 vaccine dosing regimes. Saad–Roy,
Chadi M, et al. https://science.sciencemag.org/content/372/6540/363.
6. Concerns about SARS–CoV–2 evolution should not hold back efforts to expand vaccination. Cobey,
Sarah, et al. https://pubmed.ncbi.nlm.nih.gov/33795856/.
7. Targeted vaccination and the speed of SARS–CoV–2 adaptation. Gandon, Sylvain, et al.
8. Persistence and Evolution of SARS–CoV–2 in an Immunocompromised Host. Choi, Bina, et al.
9. SARS–CoV–2 evolution during treatment of chronic infection. Kemp, Steven A, et al. Persistence
and Evolution of SARS–CoV–2 in an Immunocompromised Host.
10. Case Study: Prolonged Infectious SARS–CoV–2 Shedding from an Asymptomatic
Immunocompromised Individual with Cancer. Avanzato, Victoria A, et al.
11. Recurrent deletions in the SARS–CoV–2 spike glycoprotein drive antibody escape. McCarthy, Kevin
R, et al. https://science.sciencemag.org/content/371/6534/1139.
12. COVID–19, the first pandemic in the post–genomic era. Van Dorp, Lucy, et al.
13. SARS–CoV–2 incidence and vaccine escape. Thompson, Robin N, et al.
14. Vaccine escape in a heterogeneous population: insights for SARS–CoV–2 from a simple model.
Gog, Julia R, et al. https://doi.org/10.1098/rsos.210530.
15. Reconstructing the early global dynamics of under–ascertained COVID–19 cases and infections.
Russell, Timothy W, et al. https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916–020–
16. Estimated effectiveness of symptom and risk screening to prevent the spread of COVID–19.
Gostic, Katelyn, et al. https://elifesciences.org/articles/55570.
17. Strategies to reduce the risk of SARS–CoV–2 re–introduction from international travellers. Clifford,
Samuel, et al. https://doi.org/10.1101/2020.07.24.20161281.
18. Quarantine and testing strategies to reduce transmission risk from imported SARS–CoV–2
infections: a global modelling study. Quilty, Billy J, et al.
19. Quantifying the impact of quarantine duration on COVID–19 transmission. Ashcroft, Peter, et al.
20. Optimal COVID–19 quarantine and testing strategies. Wells, Chad R, et al.
21. Routine asymptomatic testing strategies for airline travel during the COVID–19 pandemic: a
simulation study. Kiang, Mathew V, et al. https://doi.org/10.1016/S1473–3099(21)00134–1.
22. Estimating the Failure Risk of Quarantine Systems for Preventing COVID–19 Outbreaks in
Australia and New Zealand. Grout, Leah, et al. https://doi.org/10.1101/2021.02.17.21251946.
23. Estimating the overdispersion in COVID–19 transmission using outbreak sizes outside China.
Endo, Akira, et al. https://pubmed.ncbi.nlm.nih.gov/32685698/.
24. Introducing the Outbreak Threshold in Epidemiology. Hartfield, Matthew, et al.
25. Effectiveness of interventions targeting air travellers for delaying local outbreaks of SARS–CoV–2.
Clifford, Samuel, et al. https://doi.org/10.1093/jtm/taaa068.
26. Vaccine nationalism and the dynamics and control of SARS–CoV–2. Wagner, Caroline E, et al.
27. The origins and potential future of SARS–CoV–2 variants of concern in the evolving COVID–19
pandemic. Otto, Sarah P, et al. https://www.cell.com/current–biology/fulltext/S0960–
28. Self–enforcing regional vaccination agreements. Klepac, Petra, et al.
29. Immunological memory to SARS–CoV–2 assessed for up to 8 months after infection. Dan, Jennifer
M, et al. https://science.sciencemag.org/content/371/6529/eabf4063.
30. Longitudinal analysis of humoral immunity against SARS–CoV–2 Spike in convalescent individuals
up to 8 months post–symptom onset. Anand, Sai Priya, et al.
31. Efficacy of NVX–CoV2373 Covid–19 Vaccine against the B.1.351 Variant. Shinde, Vivek, et al.
32. Reinfection by the SARS–CoV–2 P.1 variant in blood donors in Manaus, Brazil. Prete Jr, Carlos A, et
33. Prior SARS–CoV–2 infection rescues B and T cell responses to variants after first vaccine dose.
Reynolds, Catherine J, et al. https://science.sciencemag.org/content/372/6549/1418.
34. Effectiveness of COVID–19 vaccines against the B.1.617.2 variant. Lopez Bernal, Jamie.
35. Effectiveness of COVID–19 vaccines against hospital admission with. Stowe, Julia, et al.
36. Effectiveness of COVID–19 vaccines against variants of concern, Canada. Nasreen, Sharifa.
37. Lieber, Dov. Pfizer Vaccine Less Effective Against Delta Infections but Prevents Severe Illness,
Israeli Data Show. [Online] https://www.wsj.com/articles/pfizers–covid–19–vaccine–is–less–effective–
38. Projecting the transmission dynamics of SARS–CoV–2 through the postpandemic period. Kissler,
Stephen M, et al. https://science.sciencemag.org/content/368/6493/860.
39. Trajectory of individual immunity and vaccination required for SARS–CoV–2 community immunity:
a conceptual investigation. Saad–Roy, Chadi M, et al. https://doi.org/10.1098/rsif.2020.0683.
40. Dynamics of SARS–CoV–2 with waning immunity in the UK population. Crellen, Thomas, et al.
41. Challenges in creating herd immunity to SARS–CoV–2 infection by mass vaccination. Anderson,
Roy M, et al. https://doi.org/10.1016/S0140–6736(20)32318–7.
42. Within–host evolution of SARS–CoV–2 in an immunosuppressed COVID–19 patient: a source of
immune escape variants. Weigang, Sebastian, et al. https://doi.org/10.1101/2021.04.30.21256244.
43. Fractionation of COVID–19 vaccine doses could extend limited supplies and reduce mortality.
Cowling, Benjamin J, et al. https://www.nature.com/articles/s41591–021–01440–4.
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