This modelling study looks at the conditions which increase the risk of the emergence and establishment of a vaccine resistant variant.  One of the key results is that the risk is highest when a large fraction of the population has been vaccinated, but transmission is also high.  This is the situation we find ourselves in at the moment.  It has to be remembered that this is a modelling study.  The real world is always much more complex than can be represented in a model and chance will always play a key role.  Nevertheless, studies like this can highlight threats and help us work through potential risk-mitigation strategies.

In this peer-reviewed modelling study, the authors use a model with SARS-CoV-2 like parameters to assess the potential emergence of vaccine-resistant variants, and the role of the impact of the rate of vaccination and non-pharmaceutical interventions to reduce the probability of the establishment of vaccine-resistant variants in the population.

As stressed by the authors, the mechanism to adjust the transmission rate reflects the strengthening or relaxation of a package of non-pharmaceutical interventions.  The model in the study does not attribute the effect of individual intervention measures on virus transmission rates.

One of the authors’ conclusions is that a global vaccination effort is necessary to reduce the chances of a global spread of a resistant strain, which corroborates other modelling work presented in a preprint1 (not yet peer-reviewed) suggesting vaccine sharing between nations could be a powerful tool to decrease the potential for antigenic evolution.  Therefore, there could be additional benefits to pursuing an equitable vaccine distribution worldwide beyond the protection provided by the vaccines to those receiving it.

Models of infectious disease transmission are one tool, as part of a collective response, that can assess the impact of options seeking to control a disease outbreak.  To achieve robust public health outcomes requires an interdisciplinary approach, with multiple sectors communicating and working together.

Whilst the modelling can provide general principles (under stated model and parameter assumptions) for a vaccine-resistant variant having an increased chance of emerging and becoming established, the model can not precisely tell us when such an event may happen or where it may happen.

Therefore, it is crucial we have situational awareness of how the virus is mutating and identifying variants that are of concern; whether that concern be due to the variant being more transmissible, causing a rise in severity, immunity derived from vaccines or infection by another variant offering less protection against the new variant, or a combination of these. The World Health Organization advocates strengthening surveillance and sequencing capacity, and a systematic approach to provide a representative indication of the extent of transmission of SARS-CoV-2 variants.  Another potential benefit of having fewer infections is a higher proportion of overall infections can then be sequenced, enhancing the chance of earlier identification of emergent variants that are of concern.

Vaccination remains a crucial tool in protecting us from COVID-19 illness and severe outcomes.  As the vaccine rollout advances, it is important to continually monitor in the population (through observational studies using surveillance data) the impact of vaccination on epidemiological outcomes such as preventing infection, symptomatic disease, hospitalisation, death and onward transmission.  Also, obtaining high vaccine uptake in all regions and eligible demographic groups is key to lessen the chances of there being parts of the population that have less immunity, reducing the potential for outbreaks to spread and lowering the chance of the emergence and establishment of a vaccine-resistant variant.

With SARS-CoV-2 being a relatively novel virus, there is still uncertainty in its epidemiological, virological and immunological characteristics. As we accumulate new information over time our ideas and understanding will develop.

1 Wagner et al. (2021) Vaccine nationalism and the dynamics and control of SARS-CoV-2. medRxiv 2021.06.02.21258229. https://doi.org/10.1101/2021.06.02.21258229

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Modelling studies of pathogen evolution, such as this one from Rella and colleagues, can help us to tease out how certain aspects of policy decisions might impact, in relative terms, upon the risk of a new SARS-CoV-2 variant emerging.  Rella and colleagues find here that, when vaccine coverage is high, the risk of a vaccine strain emerging increases when the prevalence of infection is also high.  This makes sense, since the probability of a vaccine-resistant strain emerging depends upon two factors: one, the strength of natural selection for a vaccine-resistant strain, which is stronger when the frequency of vaccinated individuals is higher in a given population; and two, the rate at which potential vaccine-resistant mutations may emerge, which of course depends upon how many active infections there are in the first place, as each additional infection represents an additional opportunity for random mutation to produce a vaccine-resistant strain.  Additionally, a vaccine-resistant strain is less likely to randomly die out during a period in which transmission is higher.

The qualitative result—basically, that the risk of a vaccine-escape mutant emerging will be lower if we keep cases down as much as possible—certainly makes sense.  However, I don’t think we really know enough about the fundamental processes of SARS-CoV-2 mutation and selection to make solid quantitative predictions—i.e., about how much any specific policy increases the risk of a vaccine mutant emerging and spreading, in absolute terms.  With regard to UK policy, one could make the argument that by releasing restrictions now as opposed to in a few months’ time, the probability of a vaccine escape mutant emerging in the UK might actually be lower, because seasonal factors and school closures will help to dampen transmission and lessen the probability of an escape mutant spreading widely.

Every country should do their part to avoid creating fertile grounds for viral evolution where possible, which, thankfully, is a goal largely in alignment with public health and economic goals, as they all involve controlling transmission.  But ultimately, dealing with the emergence of a vaccine escape strain is really a global issue, not a national one; as soon as a vaccine escape mutant emerges somewhere, it becomes everybody’s problem.  So I would think that the most important decisions for policy makers in the UK to minimise the risk of a vaccine escape strain involve: strengthening global genomic surveillance; having an effective plan for border surveillance and controls when needed; continuing to contribute to the scientific work of monitoring the properties of new variants, regardless of where they emerge, to look for early evidence of immune escape; and helping to build the global capacity for manufacturing and deploying both existing and updated vaccines quickly and equitably.

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There has been a lot of discussion about what the consequences of lifting “non-pharmaceutical interventions” – restrictions on mixing and measures such as mask-wearing and improved ventilation – intended to reduce the transmission of Covid-19.

This paper uses mathematical modelling to predict the consequences; in particular, the likelihood that a vaccine resistant strain of the virus will emerge.

There is a saying that “All models are wrong, but some are useful”.  Modelling an issue like this is highly complex, and often a small change to the assumptions used can make a dramatic difference to the outcome of a model.

Nevertheless, the assumptions made in this model appear robust.

Furthermore, there is intuitive validity to its conclusions: “…we found that a fast rate of vaccination decreases the probability of emergence of a resistant strain. Counterintuitively, when a relaxation of non-pharmaceutical interventions happened at a time when most individuals of the population have already been vaccinated the probability of emergence of a resistant strain was greatly increased. Consequently, we show that a period of transmission reduction close to the end of the vaccination campaign can substantially reduce the probability of resistant strain establishment. Our results suggest that policymakers and individuals should consider maintaining non-pharmaceutical interventions and transmission reducing behaviours throughout the entire vaccination period.”

You would expect that as more people are vaccinated, and if the vaccines are effective at preventing infection and transmission (which they are1), there will be less transmission of the virus.

The more transmission there is, the more likely it is that significant “variants of concern”, including vaccine escape variants, will arise.

Yet it is also the case that in a relatively unvaccinated population, vaccine escape variants will have little competitive advantage, and are unlikely to become prevalent.  In moderately- or highly-vaccinated populations, however, variants that can still be transmitted to and by fully vaccinated people will have a considerable competitive advantage.

So there is intuitive validity in the idea that using all means to minimise transmission, when a high proportion of the population is vaccinated, is important.  Allowing high rates of transmission at this time means that fully vaccinated people are more likely to be infected; and this means that vaccine escape variants are more likely to arise and spread, undermining the value of the vaccination programme (at least until a “tweaked” vaccine that is effective against the variant can be rolled out).

Modelling studies such as this should always be viewed with caution; but the findings from this one are highly consistent with other ways of looking at the same question, and thus provide useful support for them.

1. Public Health England. COVID-19 vaccine surveillance report: 22 July 2021 (week 29). COVID-19 vaccine surveillance reports 2021; Updated 22 Jul 2021; Accessed: 2021 (29 Jul): (https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1002580/Vaccine_surveillance_report_-_week_28.pdf or via https://www.gov.uk/government/publications/covid-19-vaccine-surveillance-report).

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