Within-host SARS-CoV-2 viral kinetics informed by complex life course exposures reveals different intrinsic properties of Omicron and Delta variants (preprint)

The emergence of successive SARS-CoV-2 variants of concern (VOC) during 2020-22, each exhibiting increased epidemic growth relative to earlier circulating variants, has created a need to understand the drivers of such growth. However, both pathogen biology and changing host characteristics - such as varying levels of immunity - can combine to influence replication and transmission of SARS-CoV-2 within and between hosts. Disentangling the role of variant and host in individual-level viral shedding of VOCs is essential to inform COVID-19 planning and response, and interpret past epidemic trends. Using data from a prospective observational cohort study of healthy adult volunteers undergoing weekly occupational health PCR screening, we developed a Bayesian hierarchical model to reconstruct individual-level viral kinetics and estimate how different factors shaped viral dynamics, measured by PCR cycle threshold (Ct) values over time. Jointly accounting for both inter-individual variation in Ct values and complex host characteristics - such as vaccination status, exposure history and age - we found that age and number of prior exposures had a strong influence on peak viral replication. Older individuals and those who had at least five prior antigen exposures to vaccination and/or infection typically had much lower levels of shedding. Moreover, we found evidence of a correlation between the speed of early shedding and duration of incubation period when comparing different VOCs and age groups. Our findings illustrate the value of linking information on participant characteristics, symptom profile and infecting variant with prospective PCR sampling, and the importance of accounting for increasingly complex population exposure landscapes when analysing the viral kinetics of VOCs.

Natural and hybrid immunity following four COVID-19 waves in a South African cohort (preprint)

Background: More than half the global population has been exposed to SARS-CoV-2. Naturally induced immunity influences the outcome of subsequent exposure to variants and vaccine responses. We measured anti-spike IgG responses to explore the basis for this enhanced immunity. Methods: A prospective cohort study in a South African community through the ancestral/beta/delta/omicron SARS-CoV-2 waves. Health seeking behaviour/illness were recorded and post-wave serum samples probed for IgG to Spike (CoV2-S-IgG). To estimate protective CoV2-S-IgG threshold levels, logistic functions were fit to describe the correlation of CoV2-S-IgG measured before a wave and the probability for seroconversion/boosting thereafter for unvaccinated and vaccinated adults. Findings: Despite little disease, 176/339 (51.9%) participants were seropositive following wave 1, rising to 74%, 89.8% and 97.3% after waves 2, 3 and 4 respectively. CoV2-S-IgG induced by natural exposure protected against subsequent SARS-CoV-2 infection with the greatest protection for beta and the least for omicron. Vaccination induced higher CoV2-SIgG in seropositive compared to naive vaccinees. Amongst seropositive participants, proportions above the 50% protection against infection threshold were 69% (95% CrI: 62, 72) following 1 vaccine dose, 63% (95% CrI: 63, 75) following 2 doses and only 11% (95% CrI:7, 14) in unvaccinated during the omicron wave. Interpretation: Naturally induced CoV2-S-IgG do not achieve high enough levels to prevent omicron infection in most exposed individuals but are substantially boosted by vaccination leading to significant protection. A single vaccination in those with prior immunity is more immunogenic than 2 doses in a naive vaccinee and thus may provide adequate protection.

Public perceptions and interactions with UK COVID-19 Test, Trace and Isolate policies, and implications for pandemic infectious disease modelling (preprint)

The efforts to contain SARS-CoV-2 and reduce the impact of COVID-19 have been supported by Test, Trace and Isolate (TTI) systems in many settings, including the United Kingdom. The mathematical models underlying policy decisions about TTI make assumptions about behaviour in the context of a rapidly unfolding and changeable emergency. This study investigates the reported behaviours of UK citizens in July 2021, assesses them against how a set of TTI processes are conceptualised and represented in models and then interprets the findings with modellers who have been contributing evidence to TTI policy. We report on testing practices, including the uses of and trust in different types of testing, and the challenges of testing and isolating faced by different demographic groups. The study demonstrates the potential of input from members of the public to benefit the modelling process, from guiding the choice of research questions, influencing choice of model structure, informing parameter ranges and validating or challenging assumptions, to highlighting where model assumptions are reasonable or where their poor reflection of practice might lead to uninformative results. We conclude that deeper engagement with members of the public should be integrated at regular stages of public health intervention modelling.

Test to release from isolation after testing positive for SARS-CoV-2 (preprint)

The rapid spread and high transmissibility of the Omicron variant of SARS-CoV-2 is likely to lead to a significant number of key workers testing positive simultaneously. Under a policy of self-isolation after testing positive, this may lead to extreme staffing shortfalls at the same time as e.g. hospital admissions are peaking. Using a model of individual infectiousness and testing with lateral flow tests (LFT), we evaluate test-to-release policies against conventional fixed-duration isolation policies in terms of excess days of infectiousness, days saved, and tests used. We find that the number of infectious days in the community can be reduced to almost zero by requiring at least 2 consecutive days of negative tests, regardless of the number of days' wait until testing again after initially testing positive. On average, a policy of fewer days' wait until initiating testing (e.g 3 or 5 days) results in more days saved vs. a 10-day isolation period, but also requires a greater number of tests. Due to a lack of specific data on viral load progression, infectivity, and likelihood of testing positive by LFT over the course of an Omicron infection, we assume the same parameters as for pre-Omicron variants and explore the impact of a possible shorter proliferation phase.

Comparing human and model-based forecasts of COVID-19 in Germany and Poland (preprint)

Forecasts based on epidemiological modelling have played an important role in shaping public policy throughout the COVID-19 pandemic. This modelling combines knowledge about infectious disease dynamics with the subjective opinion of the researcher who develops and refines the model and often also adjusts model outputs. Developing a forecast model is difficult, resource- and time-consuming. It is therefore worth asking what modelling is able to add beyond the subjective opinion of the researcher alone. To investigate this, we analysed different real-time forecasts of cases of and deaths from COVID-19 in Germany and Poland over a 1-4 week horizon submitted to the German and Polish Forecast Hub. We compared crowd forecasts elicited from researchers and volunteers, against a) forecasts from two semi-mechanistic models based on common epidemiological assumptions and b) the ensemble of all other models submitted to the Forecast Hub. We found crowd forecasts, despite being overconfident, to outperform all other methods across all forecast horizons when forecasting cases (weighted interval score relative to the Hub ensemble 2 weeks ahead: 0.89). Forecasts based on computational models performed comparably better when predicting deaths (rel. WIS 1.26), suggesting that epidemiological modelling and human judgement can complement each other in important ways.

Quarantine and testing strategies to reduce transmission risk from imported SARS-CoV-2 infections: a global modelling study (preprint)

Background Many countries require incoming air travellers to quarantine on arrival and/or undergo testing to limit importation of SARS-CoV-2. Methods We developed mathematical models of SARS-CoV-2 viral load trajectories over the course of infection to assess the effectiveness of quarantine and testing strategies. We consider the use of Polymerase Chain Reaction (PCR) and lateral flow testing (LFT) both pre-flight, to reduce the number of infectious arrivals and when exiting quarantine, and daily testing of arrivals with LFTs. We also estimate the effect of each strategy relative to domestic incidence, and limits of achievable risk reduction, for 99 countries where flight data and case numbers are estimated. Results We find that immediately pre-flight LFTs are more effective than PCR tests 3 days before departure in decreasing the number of departing infectious travellers. Pre-flight LFTs and post-flight quarantines, with tests to release, may prevent the majority of transmission from infectious arrivals while reducing the required duration of quarantine; a pre-flight LFT followed by 5 days in quarantine with a test to release would reduce the expected number of secondary cases generated by an infected traveller compared to symptomatic self-isolation alone, Rs, by 85% (95% UI: 74%, 96%) for PCR and 85% (95% UI: 70%, 96%) for LFT, even assuming imperfect adherence to quarantine (28% of individuals) and self-isolation following a positive test (86%). Under the same adherence assumptions, 5 days of daily LFT testing would reduce Rs by 91% (95% UI: 75%, 98%). Conclusions Strategies aimed at reducing the risk of imported cases should be considered with respect to: domestic incidence, transmission, and susceptibility; measures in place to support quarantining travellers; and incidence of new variants of concern in travellers' origin countries. Daily testing with LFTs for 5 days is comparable to 5 days of quarantine with a test on exit or 14 days with no test.

Quarantine and testing strategies in contact tracing for SARS-CoV-2 (preprint)

Previous work has indicated that contact tracing and isolation of index case and quarantine of potential secondary cases can, in concert with physical distancing measures, be an effective strategy for reducing transmission of SARS-CoV-2 (1). Currently, contacts traced manually through the NHS Test and Trace scheme in the UK are asked to self-isolate for 14 days from the day they were exposed to the index case, which represents the upper bound for the incubation period (2). However, following previous work on screening strategies for air travellers (3,4) it may be possible that this quarantine period could be reduced if combined with PCR testing. Adapting the simulation model for contact tracing, we find that quarantine periods of at least 10 days combined with a PCR test on day 9 may largely emulate the results from a 14-day quarantine period in terms of the averted transmission potential from secondary cases (72% (95%UI: 3%, 100%) vs 75% (4%, 100%), respectively). These results assume the delays from testing index cases and tracing their contacts are minimised (no longer than 4.5 days on average). If secondary cases are traced and quarantined 1 day earlier on average, shorter quarantine periods of 8 days with a test on day 7 (76% (7%, 100%)) approach parity with the 14 day quarantine period with a 1 day longer delay to the index cases test. However, the risk of false-negative PCR tests early in a traced cases infectious period likely prevents the use of testing to reduce quarantine periods further than this, and testing immediately upon tracing, with release if negative, will avert just 17% of transmission potential on average. In conclusion, the use of PCR testing is an effective strategy for reducing quarantine periods for secondary cases, while still reducing transmission of SARS-CoV-2, especially if delays in the test and trace system can be reduced, and may improve quarantine compliance rates.

Strategies to reduce the risk of SARS-CoV-2 re-introduction from international travellers (preprint)

To mitigate SARS-CoV-2 transmission risks from international travellers, many countries currently use a combination of up to 14 days of self-quarantine on arrival and testing for active infection. We used a simulation model of air travellers arriving to the UK from the EU or the USA and the timing of their stages of infection to evaluate the ability of these strategies to reduce the risk of seeding community transmission. We find that a quarantine period of 8 days on arrival with a PCR test on day 7 (with a 1-day delay for test results) can reduce the number of infectious arrivals released into the community by a median 94% compared to a no quarantine, no test scenario. This reduction is similar to that achieved by a 14-day quarantine period (median 99% reduction). Shorter quarantine periods still can prevent a substantial amount of transmission; all strategies in which travellers spend at least 5 days (the mean incubation period) in quarantine and have at least one negative test before release are highly effective (e.g. a test on day 5 with release on day 6 results in a median 88% reduction in transmission potential). Without intervention, the current high prevalence in the US (40 per 10,000) results in a higher expected number of infectious arrivals per week (up to 23) compared to the EU (up to 12), despite an estimated 8 times lower volume of travel in July 2020. Requiring a 14-day quarantine period likely results in less than 1 infectious traveller each entering the UK per week from the EU and the USA (97.5th percentile). We also find that on arrival the transmission risk is highest from pre-symptomatic travellers; quarantine policies will shift this risk increasingly towards asymptomatic infections if eventually-symptomatic individuals self-isolate after the onset of symptoms. As passenger numbers recover, strategies to reduce the risk of re-introduction should be evaluated in the context of domestic SARS-CoV-2 incidence, preparedness to manage new outbreaks, and the economic and psychological impacts of quarantine.

Changing travel patterns in China during the early stages of the COVID-19 pandemic (preprint)

Understanding changes in human mobility in the early stages of the COVID-19 pandemic is crucial for assessing the impacts of travel restrictions designed to reduce disease spread. Here, relying on data from mainland China, we investigated the spatio-temporal characteristics of human mobility between 1st January and 1st March 2020 and discussed their public health implications. An outbound travel surge from Wuhan before travel restrictions were implemented was also observed across China due to the Lunar New Year, indicating that holiday travel may have played a larger role in mobility changes compared to impending travel restrictions. Holiday travel also shifted healthcare pressure related to COVID-19 towards locations with lower access to care. Network analyses showed no sign of major changes in the transportation network after Lunar New Year. Changes observed were temporary and have not yet led to structural reorganisation of the transportation network at the time of this study. One sentence summaryUnderstanding travel before, during, and after the introduction of travel restrictions in China in response to the COVID-19 Pandemic.

The effect of inter-city travel restrictions on geographical spread of COVID-19: Evidence from Wuhan, China (preprint)

Background: To contain the spread of COVID-19, a cordon sanitaire was put in place in Wuhan prior to the Lunar New Year, on 23 January 2020, restricting travel to other parts of China. We assess the efficacy of the cordon sanitaire to delay the introduction and onset of local transmission of COVID-19 in other major cities in mainland China. Methods: We estimated the number of infected travellers from Wuhan to other major cities in mainland China from November 2019 to March 2020 using previously estimated COVID-19 prevalence in Wuhan and publicly available mobility data. We focused on Beijing, Chongqing, Hangzhou, and Shenzhen as four representative major cities to identify the potential independent contribution of the cordon sanitaire and holiday travel. To do this, we simulated outbreaks generated by infected arrivals in these destination cities using stochastic branching processes. We also modelled the effect of the cordon sanitaire in combination with reduced transmissibility scenarios representing the effect of local non-pharmaceutical interventions. Findings: In the four cities, given the potentially high prevalence of COVID-19 in Wuhan between Dec 2019 and early Jan 2020, local transmission may have been seeded as early as 2 - 8 January 2020. By the time the cordon sanitaire was imposed, simulated case counts were likely in the hundreds. The cordon sanitaire alone did not substantially affect the epidemic progression in these cities, although it may have had some effect in smaller cities. Interpretation: Our results indicate that the cordon sanitaire may not have prevented COVID-19 spread in major Chinese cities; local non-pharmaceutical interventions were likely more important for this.

Interventions targeting air travellers early in the pandemic may delay local outbreaks of SARS-CoV-2 (preprint)

Background: We evaluated if interventions aimed at air travellers can delay local SARS-CoV-2 community transmission in a previously unaffected country. Methods: We simulated infected air travellers arriving into countries with no sustained SARS-CoV-2 transmission or other introduction routes from affected regions. We assessed the effectiveness of syndromic screening at departure and/or arrival & traveller sensitisation to the COVID-2019-like symptoms with the aim to trigger rapid self-isolation and reporting on symptom onset to enable contact tracing. We assumed that syndromic screening would reduce the number of infected arrivals and that traveller sensitisation reduces the average number of secondary cases. We use stochastic simulations to account for uncertainty in both arrival and secondary infections rates, and present sensitivity analyses on arrival rates of infected travellers and the effectiveness of traveller sensitisation. We report the median expected delay achievable in each scenario and an inner 50% interval. Results: Under baseline assumptions, introducing exit and entry screening in combination with traveller sensitisation can delay a local SARS-CoV-2 outbreak by 8 days (50% interval: 3-14 days) when the rate of importation is 1 infected traveller per week at time of introduction. The additional benefit of entry screening is small if exit screening is effective: the combination of only exit screening and traveller sensitisation can delay an outbreak by 7 days (50% interval: 2-13 days). In the absence of screening, with less effective sensitisation, or a higher rate of importation, these delays shrink rapidly to less than 4 days. Conclusion: Syndromic screening and traveller sensitisation in combination may have marginally delayed SARS-CoV-2 outbreaks in unaffected countries.