(C) PLOS One This story was originally published by PLOS One and is unaltered. . . . . . . . . . . A spatial vaccination strategy to reduce the risk of vaccine-resistant variants [1] ['Xiyun Zhang', 'Department Of Physics', 'Jinan University', 'Guangzhou', 'Gabriela Lobinska', 'Department Of Molecular Genetics', 'Weizmann Institute Of Science', 'Michal Feldman', 'School Of Computer Science', 'Center For Combating Pandemics'] Date: 2022-08 The COVID-19 pandemic demonstrated that the process of global vaccination against a novel virus can be a prolonged one. Social distancing measures, that are initially adopted to control the pandemic, are gradually relaxed as vaccination progresses and population immunity increases. The result is a prolonged period of high disease prevalence combined with a fitness advantage for vaccine-resistant variants, which together lead to a considerably increased probability for vaccine escape. A spatial vaccination strategy is proposed that has the potential to dramatically reduce this risk. Rather than dispersing the vaccination effort evenly throughout a country, distinct geographic regions of the country are sequentially vaccinated, quickly bringing each to effective herd immunity. Regions with high vaccination rates will then have low infection rates and vice versa. Since people primarily interact within their own region, spatial vaccination reduces the number of encounters between infected individuals (the source of mutations) and vaccinated individuals (who facilitate the spread of vaccine-resistant strains). Thus, spatial vaccination may help mitigate the global risk of vaccine-resistant variants. The COVID-19 pandemic demonstrated that the process of global vaccination against a novel virus can be a prolonged one. During the period of vaccination, the level of infection remains high, and each infection has a small chance to mutate into a vaccine-resistant variant. Moreover, the fact that large numbers of people are being vaccinated generates an evolutionary advantage to vaccine resistance, such that even one infection with a resistant variant will likely spread within the population and become the dominant variant. Thus, a prolonged vaccination campaign can result in vaccine escape. To reduce this risk, we propose a spatial vaccination strategy. Rather than dispersing the vaccination effort evenly throughout a country, distinct geographic regions of the country are sequentially vaccinated, quickly bringing each to effective herd immunity. Regions with high vaccination rates will then have low infection rates and vice versa. Since people primarily interact within their own region, spatial vaccination reduces the number of encounters between infected individuals (the source of mutations) and vaccinated individuals (who facilitate the spread of vaccine-resistant strains). Thus, even if a global vaccination campaign requires a prolonged period of time, the risk of vaccine escape is reduced when using a spatial strategy. Funding: X.Z. was supported by the NNSF of China under Grant No. 12105117, the Fundamental Research Funds for the Central Universities (Grant No. 21621007), Guangdong Basic and Applied Basic Research Foundation (Grant No. 2022A1515010523), the Science and Technology Planning Project of Guangzhou (Grant No. 202201010360), and E.D. was supported by NSF grant SES-1919494. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2022 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 1. Introduction A prime goal of vaccination during an ongoing pandemic is the rapid attainment of herd immunity, a state in which the proportion of immunized individuals is large enough to block the spread of the virus. The literature has focused on optimization strategies for efficient vaccination campaigns of large populations during a pandemic. These strategies are often designed to exploit the structure of social networks, based on the idea that the transmission dynamics are strongly intertwined with the network’s intrinsic connectivity patterns [1]. Thus, for example, network heterogeneity motivates the prioritized vaccination of “super-spreaders” [2]. At the mesoscopic scale, it was found that pandemic intervention strategies that target local network structures significantly outperform those that solely focus on the entire network structure simultaneously [3]. In addition to rapid eradication of the current pathogenic strain, an important aim of a vaccination campaign should be to minimize the chance of emergence, due to mutation, of a next strain, and in particular a vaccine-resistant strain that may undermine the entire campaign [4–17]. Indeed, if a vaccine-resistant variant appears by spontaneous mutation during a vaccination campaign it may have a clear advantage over the original strain, against which vaccines were targeted, since it can infect both vaccinated and unvaccinated individuals. Recent mathematical modeling has, in fact, shown that averting such escape scenarios is only possible under a combination of rapid vaccination and strict social distancing [18], a situation which the current campaign has shown to be unfeasible. Given the relatively slow pace of vaccination, is it possible to mitigate the risk that vaccine resistance will emerge? The solution proposed here is based on spatial vaccination, a new vaccination strategy that has the potential to dramatically reduce the probability of this undesired evolutionary development. We focus on the current COVID-19 pandemic as a case study and in particular on the period preceding the appearance of the highly contagious though less severe Omicron variant. Since the initial COVID-19 strains (namely, Wuhan and Alpha) were relatively severe, and since no vaccine existed at the time, strict social distancing measures were employed to keep the pandemic under control and prevent it from proliferating. These measures were both imposed by the authorities and also driven by individuals’ independent response to the spread. The result was an ongoing adaptive behavior that reacted to the severity of the spread, thus maintaining the effective reproduction number R at around unity (Fig 1) [19]. In particular, social distancing measures were gradually relaxed as vaccination progressed and population immunity increased. Such a combination of vaccination and adaptive social distancing may have crucial implications for vaccine escape. Indeed, we depart from the canonical SIR models and explicitly take into account adaptive social distancing. PPT PowerPoint slide PNG larger image TIFF original image Download: Fig 1. The global reproduction rate (R) during the period 2/20 to 8/21 [ The global reproduction rate (R) during the period 2/20 to 8/21 [ 20 21 ]. As a result of adaptive social distancing, society converges to a state in which R is maintained in the vicinity of unity (dashed line). It can therefore be expected that as vaccination progresses and population immunity is gradually acquired, social distancing practices will be relaxed, thus maintaining R at about 1. https://doi.org/10.1371/journal.pcbi.1010391.g001 To understand the effect of adaptive social distancing more clearly, consider the gradual buildup of population immunity as vaccination gains prevalence. Instead of consistently pushing R to below 1, the increase in population immunity is offset by a relaxation of social distancing, keeping R around 1 and maintaining a significant rate of infection, a rate that will likely persist until vaccination prevalence approaches herd immunity levels [20]. Indeed, such a pattern has can be observed in countries such as the UK and the US (Fig 2). PPT PowerPoint slide PNG larger image TIFF original image Download: Fig 2. Actual vs. predicted pandemic status in the UK and US during the vaccination campaign. As the fraction of the (first-dose) vaccinated (green line) increases, the extrapolated R (dotted blue line) declines. This extrapolation assumes that factors such as the social distancing restrictions, variant composition, weather, etc. remain unchanged from the start of the vaccination campaign. The empirically measured R (solid blue line) has remained in the vicinity of unity (with a temporary jump to 1.5 just after the introduction of the more infectious delta variant). Furthermore, the extrapolated number of infections (dotted red line) declines much faster than the actual number (solid red line). These trends indeed confirm that adaptive social behavior leads to a relaxation in prophylactic measures, in response to the accumulation of population immunity. https://doi.org/10.1371/journal.pcbi.1010391.g002 These conditions create a potentially fertile breeding ground for vaccine escape [22]. Once a significant share of the population is vaccinated, a vaccine-resistant variant, which can potentially infect anyone, whether vaccinated or not, has a selective advantage relative to the wild-type strain, as the latter can only infect unvaccinated individuals. Since the wild type’s R is maintained around 1, this relative advantage translates into an absolute positive growth rate of R>1 for the resistant variant, allowing it–if it occurs by a random mutation–to quickly spread throughout the population. This, together with the large number of infections expected during the slow vaccination process, might create a high probability that a mutation will occur and take over the population. Such a mechanism for vaccine escape is, indeed, unique to situations in which mitigation involves both vaccination and social distancing, with the latter being relaxed in response to the progress of the former [19,20,22,23]. The straightforward solution is to avoid the extended period in which high vaccination prevalence coexists alongside a high rate of infection. Ideally, this would dictate a policy to vaccinate the entire population within a short period of time. Such a solution, however, ignores the main bottleneck to vaccine rollout, namely the inherent limitations on vaccination capacity. To overcome this obstacle, we propose a spatial vaccination strategy which will be shown to dramatically reduce the risk of vaccine escape, even under the existing constraints on the vaccination rate. The proposed spatial strategy takes advantage of the geographic segregation that often characterizes the population distribution, and the fact that people mainly interact within the region they reside in. We propose to divide each country (or possibly a smaller geographic unit such as a state) into smaller regions that are sufficiently disconnected in terms of social interactions and then sequentially vaccinate one region at a time, thus concentrating the entire country’s vaccination capacity in order to quickly bring that region towards herd immunity. Such partitioning would replace the gradual accumulation of nationwide herd immunity. The obvious advantage is that the rapid achievement of herd immunity in each individual region should avoid the prolonged period of interaction between infected individuals and the vaccinated population. Thus, the dangerous combination of high infection rates (the source of mutations) and high vaccination rates (which provide an advantage to resistant strains) is dramatically reduced. Since the majority of infectious interactions are local in nature [24], namely they occur within a single region; cross-infection between regions is rare. Therefore, vaccinating all regions one by one may be able to facilitate a safe and rapid accumulation of local herd immunity in each region, until it is finally achieved for the entire population. The result will be to reach country-level immunity in roughly the same amount of time, but with a significantly lower risk of an escaping variant. Other considerations may also be important in devising an effective vaccination strategy, and in particular the prioritization of the vulnerable population. We therefore also examine the application of spatial vaccination only after a uniform vaccination of up to 15% of the population (i.e. the most vulnerable groups). As we demonstrate, this has limited impact on the outcome of the proposed spatial vaccination strategy. The reason for this is that most of the additional risk of vaccine escape due to uniform vaccination occurs only once the vaccine coverage is well above 15%–prior to that the resistant variant’s selective advantage is small. Spatial vaccination allows for additional (relatively low-cost) measures that further reduce the risk of vaccine escape and are not applicable or are too costly under a uniform vaccination regime. First, an effort can be made to identify and isolate infections by the resistant variant in the vaccinated areas. Such variant contact tracing is likely to be successful since in vaccinated areas, which are clear of wild-type infections, every short infection chain is highly likely to originate from the resistant variant. This measure is difficult to apply under the current vaccination regime, in which resistant variant infections may be hidden among the predominant wild-type infections. Second, the authorities can impose limitations on population movement between the vaccinated and unvaccinated regions. Such limitations would not be overly burdensome if the order of vaccination is wisely planned, with the goal of keeping the vaccinated and unvaccinated areas geographically contiguous, with one (moving) border between them. Third, the authorities may impose a short, moving lockdown that is applied in each region during or just prior to vaccination. Such a localized and brief lockdown can be more easily enforced relative to prolonged countrywide lockdowns, which impose a devastating individual and societal burden. Finally, the spatial strategy is effective not only in mitigating vaccine escape, but also in reducing the overall number of infections. This is because, as vaccination progresses, the infections in regions that reach herd immunity will cease much earlier than under uniform vaccination. In fact, if the number of regions is sufficiently large, the total number of infections is reduced by close to 50%, since the infections in a region will on average end after half of the nationwide vaccination time. Looking to the future, spatial vaccination may be useful if humanity will face a virus with two crucial properties. First, it is sufficiently harmful that–until vaccination can control it–social distancing must be imposed until a vaccine is developed. This is because it is the relaxation of social distancing following vaccination that generates the increased risk of resistant variants. Second, that R 0 is not sufficiently high to prevent the vaccination from achieving herd immunity. The ability to quickly bring each specific region to herd immunity, so that infections cease there, is at the core of spatial vaccination. A future pandemic with these two properties may involve a completely new virus or a new variant of COVID-19 which escapes the immunity conferred by infection with the current strains or by vaccination, yet has a much lower R 0 (Note than an escape variant can proliferate even if it is deficient relative to the current strain). [END] --- [1] Url: https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1010391 Published and (C) by PLOS One Content appears here under this condition or license: Creative Commons - Attribution BY 4.0. via Magical.Fish Gopher News Feeds: gopher://magical.fish/1/feeds/news/plosone/