Part 1:Quarantine And Testing Strategies To Ameliorate Transmission Due To Travel During The COVID-19 Pandemic: A Modelling Study

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Chad R. Wells, a,# Abhishek Pandey, a,# Meagan C. Fitzpatrick, a,b William S. Crystal, a Burton H. Singer,c Seyed M. Moghadas,d Alison P. Galvani, a,e and Jeffrey P. Townsend,e,f,g,h*

a Center for Infectious Disease Modeling and Analysis (CIDMA), Yale School of Public Health, New Haven, Connecticut, 06520, USA

b Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA

c Emerging Pathogens Institute, University of Florida, P.O. Box 100009, Gainesville, FL, 32610, USA

d Agent-Based Modelling Laboratory, York University, Toronto, Ontario, Canada

e Department of Ecology and Evolutionary Biology, Yale University, New Haven, Connecticut, 06525, USA f Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, 06510, USA

g Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, 06511, USA h Program in Microbiology, Yale University, New Haven, Connecticut, 06511, USA

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Summary

Background Numerous countries have imposed strict travel restrictions during the COVID-19 pandemic, contributing to a large socioeconomic burden. The long quarantines that have been applied to contacts of cases may be excessive for travel policy.

Methods We developed an approach to evaluate imminent countrywide COVID-19 infections after 0−14-day quarantine and testing. We identiﬁed the minimum travel quarantine duration such that the infection rate within the destination country did not increase compared to a travel ban, deﬁning this minimum quarantine as “sufﬁcient.”

Findings We present a generalized analytical framework and a speciﬁc case study of the epidemic situation on November 21, 2021, for application to 26 European countries. For most origin-destination country pairs, a three-day or shorter quarantine with RT-PCR or antigen testing on exit sufﬁces. Adaptation to the European Union trafﬁc-light risk stratiﬁcation provided a simpliﬁed policy tool. Our analytical approach provides guidance for travel policy during all phases of pandemic diseases.

Interpretation For nearly half of the origin-destination country pairs analyzed, travel can be permitted in the absence of quarantine and testing. For the majority of pairs requiring controls, a short quarantine with testing could be as effective as a complete travel ban. The estimated travel quarantine durations are substantially shorter than those speciﬁed for traced contacts.

Funding EasyJet (JPT and APG), the Elihu endowment (JPT), the Burnett and Stender families’ endowment (APG), the Notsew Orm Sands Foundation (JPT and APG), the National Institutes of Health (MCF), Canadian Institutes of Health Research (SMM) and Natural Sciences and Engineering Research Council of Canada EIDM-MfPH (SMM).

Keywords: SARS CoV-2; RT-PCR test; antigen test; tourism; COVID-19; Variant of concern; European Union; epi- demic; pandemic; travel; quarantine; disease transmission; prevalence; imminent infection; duration; incidence; policy

Evidence before this study

Evidence from early in the pandemic indicates that border closures at the epicenter slowed global dissemination of COVID-19. As community transmission became established in many nations, studies have suggested that the beneﬁt of strict border closures in mitigating the transmission of disease from travelers diminished. Research for community settings has shown that testing later during quarantine, rather than upon entry into quarantine, can substantially shorten the duration of quarantine needed to reduce post-quarantine transmission. In particular, for international air travelers, a 14- day quarantine can effectively be shortened to ﬁve or seven days. The number of infectious COVID-19 cases that escape from these quarantines depends on the prevalence of disease in the country from which travel is originating as well as the travel volume into the country.

Added-value of this study

We developed a framework to identify quarantine and testing strategies that enable travel from speciﬁc origins without increasing infection rates per capita within destinations. No prior study has evaluated the appropriate duration of quarantine necessary to prevent any rise in infection rates per capita in the destination countries as a result of travel. By accounting for prevalence, daily incidence, vaccine coverage, immunity, age demographics, and travel ﬂow between countries, we quantify- ﬁed the contribution of travel towards imminent infections in the destination country under different quarantine and testing strategies. For travel between 26 European countries, our results for the pandemic situation observed on November 21, 2021, demonstrate that there are often less burdensome quarantine and testing strategies that can serve as effective alternatives to the strict border closure. These estimated sufﬁcient quarantine durations are especially dependent on COVID-19 prevalence and immunity within the two countries. We also found that asymmetry in the travel ﬂow, just not the volume of travel ﬂow, can also inﬂuence the estimated sufﬁcient quarantine durations. Using data on variants of concern, including Omicron, we found that the adequacy of a border control strategy to limit variant spread depends strongly on the geographical distribution of the variant. While our results pertain to European countries, we also provide an interactive spreadsheet that can be used to determine appropriate quarantine durations between any two countries. Moreover, our framework can also be applied at any spatial or population scale within which movement restrictions could feasibly be implemented.

Implications of all available evidence without risking a short-term increase in infection rates. As long as community transmission is occurring, the long-term epidemic trend within the destination country is more apt to be determined by other disease control measures, e.g., contact tracing, vaccination, and non-pharmaceutical interventions. Together, travel quarantine and other related control measures can mitigate the risk of transmission between countries, limiting the threat of variants of concern.

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Introduction

Quarantine of travelers to prevent the importation of dis-ease has been a cornerstone of efforts to prevent infectious disease since at least the fourteenth century.1 Ongoing effort to limit the importation and global dissemination of COVID-19 cases have included the imposition of strict national border control measures, typically mandating an extensive quarantine.2 These restrictions were aimed at slowing or mitigating the spread of SARS- CoV-2 to heretofore unafﬂicted nations.3 However, border closures at the epicenter only minimally delayed global spread.4 Moreover, border restrictions and extended quarantines have had diminishing effects as the pandemic has progressed.5−7 While regions that implemented inter-national travel controls early experienced a delay in the time of the initial peak—compared with regions that waited8—imported cases have had little impact on the epidemic trajectory where community transmission was well established.9 Furthermore, these interventions carry a large socioeconomic burden. A policy that enables safe travel between countries and shortens travel quarantine without increasing the country-speciﬁc infection rate would aid in the rejuvenation of the international economy.

Quarantine duration has traditionally been set with the objective of ensuring prevention of post-quarantine transmission with or without testing.10 Such a goal is reasonable for those entering a country experiencing zero or near-zero prevalence of disease,11 or for a traced contact with a high chance of being infected. For example, the World Health Organization recommends a 14-day quarantine of exposed individuals to mitigate onward transmission from COVID-19 cases who have extended incubation periods.12,13 However, travelers are typically far less likely to have been infected than traced contacts; if disease prevalence in their origin country is not substantially elevated in comparison to their destination, then their risk of transmitting is presumably equivalent to residents of the destination country who are following the same country-speciﬁc public health precautions. Because international travel is generally considered a desirable activity for diverse socioeconomic reasons, it would be reasonable for border controls in these global pandemic scenarios to have the objective not of preventing any transmission of pandemic disease by travelers—which, after all, is typically exchangeable in impact with transmission by residents—but instead ensuring that travel does not cause a net increase in dis-ease compared to border closure or complete ban of travel. Because sufﬁcient quarantine and testing at the border can decrease within-country post-quarantine transmission to arbitrarily low levels,10,14−16 and infected individuals departing the country diminish within-country transmission, such a balance should be determinable.

Questions regarding the efﬁcacy of travel quarantine and testing have recently been brought to the fore by the emergence of variants of concern of SARS CoV-2 (VOCs). Some VOCs are more transmissible than previous strains,17 and there is uncertainty regarding the extent of protection provided by natural and vaccine-acquired immunity against each VOC.18−20 VOC emergence has spurred the renewal of border closures, long quarantines, and extensive COVID-19 testing to prevent VOCs from establishing in unaffected countries.5 Impeding the establishment of VOCs with an appropriate travel quarantine strategy could provide time for vaccine coverage to be scaled up, limiting overall transmission.21 However, it is unclear what minimal travel quarantine and testing strategies are sufﬁcient to reduce the seeding of new VOC cases. Therefore, knowledge of the potential suppressive effects of travel quarantine and testing on the prevalence of known VOCs is important to limit the resurgence of the disease and should be considered in the speciﬁcation of country-speciﬁc and individualized travel quarantine strategies.

Here we integrate analytical approaches for the calculation of post-quarantine transmission10 with a model of country-speciﬁc imminent infections (i.e., the infections that will be generated from currently infected individuals) to develop a generalized analytical framework to identify travel quarantine and testing strategies such that infections will not increase in the destination country when compared to a strategy of the complete border closure. To quantify the minimum sufﬁcient duration of travel quarantine among each origin-destination pair of 26 countries in Europe, we incorporate the travel ﬂow between countries and country-speciﬁc age structure, while accounting for natural immunity, vaccine coverage, and disease burden observed on November 21, 2021, across Europe. We also generalized the analysis to provide quarantine and testing strategies based on Euro-pean Union (EU) trafﬁc-light stratiﬁcation of COVID-19 risk instead of country-speciﬁc strategies.

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Methods

Sufﬁcient travel quarantine

To identify travel quarantine and testing strategies that do not elevate a country’s case burden when travel is resumed with another country, we evaluated the extent

of transmission in a country when travel is allowed, compared to the transmission occurring under a travel ban (Fig. I, Table r). Our measure of transmission was the daily new within-country imminent infections(generated over infected individuals remaining disease time course). When considering travel between countries, we assume long-term stays such that prevalence in travelers rises to the prevalence in the country visited by the time of return. The assumption of long-term stays instead of short-term stays simplifies the calculations of imminent infections when allowing travel between two countries, and provides a conservative estimate of the minimum sufficient quarantine duration (Supplementary material: Sufficient travel quarantine). We do not specifically model inflight transmission in our calculations, as the risk of inflight transmission with appropriate precautions is low.22

No travel. Daily new within-country imminent infection in country A(destination country) with no travel between country A and country B is NETCARE(I-9A), where NT is the total population of country A, CA is the average daily incidence per capita (over the last two weeks) within country A, RE。is the effective reproduction number accounting for self-isolation upon symptom onset, and g Ais the percent of country A that is immune. The term eg can be decomposed into the fraction who are currently infected plus the fraction that has either recovered from infection and remains immune or has been vaccinated and remains immune.

Travel between countries A and B. Country-specific imminent infection in country A with long-term travel is composed of non-travelers and travelers. The contribution to daily new within-country imminent infection of non-travelers is NACARE,(I-A), where NA is the number of non-traveling and non-quarantined country-A residents. At steady-state with respect to travel, the contribution to daily new within-country imminent infection of returning travelers is nABpgRo。y(I-9A), where nAB is the daily number of country-A residents returning from a long-term visit to country B, pg is the prevalence of non-isolated infections in country B, and Ro,y is the average left-over imminent infection in country A of an infected visitor who underwent the quarantine-and-testing regimen QA. Similarly, daily new within-country imminent infections are increased by the arrival of infected travelers from country B, whose contribution is nBAgRo.v(r-9A), where nB.A is the daily number of long-term visitors from country B to country A. Country-specific imminent infection in country A is also increased by travelers from country B who become infected in country A; their contribution towards daily new within-country imminent infection is ng CA(=aa)RE,(r-9A), where ng is the number of residents of the country B abroad in country A, and 5n is the infection risk ratio for individuals who are not immune to infection at frequency I-Qg while in country A with its frequency of susceptibility I-9A

Figure 1. The model schematic diagram for daily new within-country imminent infections and travel quarantine. With travel between country A (red) and country B (blue), the travel quarantine speciﬁed by country A is dependent on the intensity of infection in both country A and B, the number of residents leaving country A for country B, the number of travelers entering country A from country B, the number of residents returning to country A, and the number of travelers from country B returning to country B. In the most general instantiation of our model, the minimum duration of travel quarantine is dependent on the number of daily travelers from country A to country B, nAB, the number of daily travelers from country B to country A, NBA, the country- speciﬁc prevalence of non-isolated infections r, country-speciﬁc immunity ’, the number of travelers from country B abroad in country A, nB, the number of citizens of A who are non-travelers and not quarantined, NA, daily incidence per capita, c. The amount of remaining transmission (RE, RV, RQ, V) is calculable based on virus- or variant-speciﬁc properties and the temporal infectivity and test sensitivity.10

For a speciﬁed testing strategy, the minimum quarantine duration that satisﬁes this condition is deﬁned as a sufﬁcient travel quarantine.

Effective reproduction numbers

To determine the effective reproduction numbers (Supplementary material: Effective reproduction number), we ﬁrst constructed average temporal infectivity pro- ﬁle for an infected individual23,24 using a reproduction number of 3 and an incubation period of 5¢72 days (Supplementary material: Infectivity proﬁle and Fig. S9).10,25-27 Accounting for the proportion of infections that remain asymptomatic after the incubation period,28 we calculate an effective reproduction

number for non-travelers using the average infectivity profile while assuming individuals self-isolate upon symptom onset. For travelers, we also discount the periods in the average temporal infectivity profile when they can not transmit (e.g. isolation, quarantine, or travel abroad).

Travel quarantine strategies

For each origin-destination country pair, we evaluated a travel quarantine strategy of o-I4 days quarantine duration with an RT-PCR test conducted on exit. If quarantine durations up to I4 days were not sufficient, then we indicated a travel ban. A delay of 24 h was assumed in obtaining results for an RT-PCR test (e.g.an exit RT-PCR test is conducted 24 h before exiting from quarantine); we specified no delay in obtaining antigen test results. We considered three alternative quarantine strategies: i)no testing,ii) antigen testing on exit from quarantine, and ii) antigen testing on entry to and exit from quarantine.

Diagnostic sensitivity

To determine the temporal diagnostic sensitivity of the RT-PCR assay over the course of the disease, we fit a time-dependent function (represented by a log-Normal prob-ability density function)to the results from serial test-ing,29 with the sensitivity of the rapid antigen test also dependent on the percent positive agreement of the BD Veritor rapid antigen test (Supplementary material: Temporal diagnostic sensitivity and Fig. S8).30

Country-paired analysis

We applied our modeling framework to 26 European countries, using country-specific vaccine coverage, natural immunity, estimated daily incidence,

prevalence,age demographics,i and 2or9 country pair-wise travel flow (Table Sr).To calculate the level of vac-cine-acquired immunity, we used age-and dose-specific effectiveness in the reduction of documented infection, specifying age- and country-specific vaccination coverage. Natural immunity is inferred from the estimated number of cumulative infections in the country, which accounts for the under-reporting of cases. We specify prevalence to be infections that are active and not isolated based on estimated daily incidence. To quantify the country's pairwise travel fow data, annual arrivals for all forms of paid accommodation were utilized for the majority of countries (Table Sr). Using this annual data, we calculated the average number of daily travelers between the countries. The use of arrivals for all forms of paid accommodation reflects the multitude of travel routes (e.g., automobile, train, or airplane)into a country and does not limit it to just airline travel.

A generalized approach based on the European Union traffic-light system

We also conducted a generalized implementation of our modeling framework aligned to the EU traffic-light system to contrast the results with our country-specific analysis. Unlike the country-specific analysis that is highly parameterized, we applied our approach for the EU traffic-light model based on differences in incidence and prevalence alone, otherwise specifying the average traits of European countries (Supplementary material: Generalised approach using EU traffic-light system). The EU traffic-light system for COVID-Ig travel restrictions stratifies the epidemic status of a country based on caseload over the preceding two weeks:i)< 25 cases (Green); ii)25-I5o cases(Amber); ii)15o-5oo cases (Red); and iv)>5oo cases (Dark Red), per Ioo,ooo residents. We considered four categories of countries stratified by their risk status: 25/roo,ooo (Green status), I5o/1roo,ooo(Amber status),5oo/too,ooo(Red status),and r,ooo/too,ooo (Dark Red). Assuming sym-metric travel fow for the resulting 16 combinations, we calculated the minimum sufficient travel quarantine for each origin-destination pair.

Variants of concern

In our base-case scenario, we evaluated the goal of eliminating the impact of travel on all within-country imminent infections without distinguishing among genetic variants or their characteristics. To quantify quarantine durations that can prevent variants of concern from seeding or increasing the extent of its transmission in a destination country, we evaluated travel quarantine strategies based on i) daily new within-country imminent infections emanating from a particular VOC and ii) daily new within-country imminent infections from multiple variants. We determined the minimum sufficient quarantine when considering multiple VOCs by calculating the minimum duration of travel quarantine that satisfies the daily new within-country imminent infection inequality for all variants considered(Fig.). We considered two known and prevalent VOCs, Delta G/478K.VI and Omicron B.1.I.529+BA.4°We character ised the VOCs with increased transmission relative to the general transmission, Ioo% cross-immunity, and no reduction in vaccine effectiveness. Using the estimate that the Delta G/478K.VI VOCis 6o%more transmissible within households than the Alpha 2o2o2/or GRY VOC,142 we assumed that the Delta G/478K.Vr VOC is Igr-2% more transmissible relative to general transmission. Based on early estimates that the odds of household transmission of Omicron B.1.1.529+BA relative to Delta G/478K.VI is 3.2,43we assumed that Omi-cron B.1.I.529+BA is 4I31% more transmissible relative to general transmission (ie.,76.2 % more transmissible than Delta).

Sensitivity and scenario analysis

By assessing the change in sufficient quarantine durations as a result of the perturbations in each parameter, we identified how the parameters influence our estimates. To conduct this one-way sensitivity analysis, we calculated sufficient quarantines after iteratively altering the value of each parameter by one standard deviation towards the median from the 26 countries, while retaining all other parameters fixed (Supplementary material: Sensitivity analysis).

To evaluate the impact of the different assumptions on the duration of the minimum sufficient quarantine, we conducted scenario analyses that computed the sufficient quarantine durations associated with r) alternative duration of the incubation period, 2)reduced adherence to quarantine or self-isolation upon symptom onset,3)serial dates of analysis, and 4) an alternative measure of travel flow (airline passenger data). For different values of the incubation period, we examined a longer reported incubation period of 8.29 days+4 and an extended incubation period of nr-66 days (based on the gsth percentile of the reported distribution).45 When varying the adherence to self-isolation, we only vary it for individuals who are not in quarantine, as isolation is mandatory in quarantine. Lack of adherence to quarantine was parameterized as complete; transmission for those not adhering to quarantine was specified as equivalent to the scenario of a zero-day quarantine with no test. To perform a scenario analysis examining the differences in outcome across serial dates of analysis, we quantified the minimum duration of quarantine at weekly intervals between October 3,2o2I and November 2I,2o2I and then compared these durations to those estimated for October 3, 2o2I. To calculate imminent infections based on an alternative source of travel fow data, annual air passenger transport between countries was used.46