Limited initial supply of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine raises the question of how to prioritize available doses. We used a mathematical model to compare five age-stratified prioritization strategies. A highly effective transmission-blocking vaccine prioritized to adults ages 20 to 49 years minimized cumulative incidence, but mortality and years of life lost were minimized in most scenarios when the vaccine was prioritized to adults greater than 60 years old. Use of individual-level serological tests to redirect doses to seronegative individuals improved the marginal impact of each dose while potentially reducing existing inequities in COVID-19 impact. Although maximum impact prioritization strategies were broadly consistent across countries, transmission rates, vaccination rollout speeds, and estimates of naturally acquired immunity, this framework can be used to compare impacts of prioritization strategies across contexts.

https://science.sciencemag.org/content/sci/early/2021/01/21/science.abe6959.full.pdf

Model-informed COVID-19 vaccine prioritization strategies by age and serostatus.

Since its emergence in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused hundreds of millions of cases and continues to circulate globally. To establish a novel SARS-CoV-2 human challenge model that enables controlled investigation of pathogenesis, correlates of protection and efficacy testing of forthcoming interventions, 36 volunteers aged 18–29 years without evidence of previous infection or vaccination were inoculated with 10 TCID50 of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally in an open-label, non-randomized study (ClinicalTrials.gov identifier NCT04865237 ; funder, UK Vaccine Taskforce). After inoculation, participants were housed in a high-containment quarantine unit, with 24-hour close medical monitoring and full access to higher-level clinical care. The study’s primary objective was to identify an inoculum dose that induced well-tolerated infection in more than 50% of participants, with secondary objectives to assess virus and symptom kinetics during infection. All pre-specified primary and secondary objectives were met. Two participants were excluded from the per-protocol analysis owing to seroconversion between screening and inoculation, identified post hoc. Eighteen (~53%) participants became infected, with viral load (VL) rising steeply and peaking at ~5 days after inoculation. Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log10 copies per milliliter (median, 95% confidence interval (8.41, 9.53)). Viable virus was recoverable from the nose up to ~10 days after inoculation, on average. There were no serious adverse events. Mild-to-moderate symptoms were reported by 16 (89%) infected participants, beginning 2–4 days after inoculation, whereas two (11%) participants remained asymptomatic (no reportable symptoms). Anosmia or dysosmia developed more slowly in 15 (83%) participants. No quantitative correlation was noted between VL and symptoms, with high VLs present even in asymptomatic infection. All infected individuals developed serum spike-specific IgG and neutralizing antibodies. Results from lateral flow tests were strongly associated with viable virus, and modeling showed that twice-weekly rapid antigen tests could diagnose infection before 70–80% of viable virus had been generated. Thus, with detailed characterization and safety analysis of this first SARS-CoV-2 human challenge study in young adults, viral kinetics over the course of primary infection with SARS-CoV-2 were established, with implications for public health recommendations and strategies to affect SARS-CoV-2 transmission. Future studies will identify the immune factors associated with protection in those participants who did not develop infection or symptoms and define the effect of prior immunity and viral variation on clinical outcome. In the first SARS-CoV-2 challenge study in humans, 36 young, healthy adult participants were intranasally inoculated with virus and monitored for productive infection, symptoms, virus kinetics, antibody response and safety in a controlled setting. 

/pdf/safety-tolerability-and-viral-kinetics-during-sars-cov-2-9k1xij2p.pdf

Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults

Limited initial supply of SARS-CoV-2 vaccine raises the question of how to prioritize available doses. Here, we used a mathematical model to compare five age-stratified prioritization strategies. A highly effective transmission-blocking vaccine prioritized to adults ages 20-49 years minimized cumulative incidence, but mortality and years of life lost were minimized in most scenarios when the vaccine was prioritized to adults over 60 years old. Use of individual-level serological tests to redirect doses to seronegative individuals improved the marginal impact of each dose while partially addressing existing inequities in COVID-19 impact. While maximum impact prioritization strategies were broadly consistent across countries, transmission rates, vaccination rollout speeds, and estimates of naturally acquired immunity, this framework can be used to compare impacts of prioritization strategies across contexts.

https://www.medrxiv.org/content/medrxiv/early/2020/12/07/2020.09.08.20190629.full.pdf

Model-informed COVID-19 vaccine prioritization strategies by age and serostatus

Background: When estimating health state utility values (HSUV) for multiple health conditions, the alternative models used to combine these data can produce very different values. Results generated using a baseline of perfect health are not comparable with those generated using a baseline adjusted for not having the health condition taking into account age and gender. Despite this, there is no guidance on the preferred techniques that should be used and very little research describing the effect on cost per QALY results. Methods: Using a cardiovascular disease (CVD) model and cost per QALY thresholds, we assess the consequence of using different baseline health state utility profiles (perfect health, individuals with no history of CVD, general population) in conjunction with three models (minimum, additive, multiplicative) frequently used to estimate proxy scores for multiple health conditions. Results: Assuming a baseline of perfect health ignores the natural decline in quality of life associated with co-morbidities, over-estimating the benefits of treatment to such an extent it could potentially influence a threshold policy decision. The minimum model biases results in favour of younger aged cohorts, while the additive and multiplicative technique produces similar results. Although further research in additional health conditions is required to support our findings, this pilot study highlights the urgent need for analysts to conform to an agreed reference case and provides initial recommendations for better practice. We demonstrate that in CVD, if data are not available from individuals without the health condition, HSUVs from the general population provide a reasonable approximation.

Populating an economic model with health state utility values: moving towards better practice

Alex Crozier and colleagues look at how new technologies can be most appropriately used to support different testing strategies and examine the benefits and risks

https://www.bmj.com/content/bmj/372/bmj.n208.full.pdf

Put to the test: use of rapid testing technologies for covid-19.

BACKGROUND: In most countries, contacts of confirmed COVID-19 cases are asked to quarantine for 14 days after exposure to limit asymptomatic onward transmission. While theoretically effective, this policy places a substantial social and economic burden on both the individual and wider society, which might result in low adherence and reduced policy effectiveness. We aimed to assess the merit of testing contacts to avert onward transmission and to replace or reduce the length of quarantine for uninfected contacts. METHODS: We used an agent-based model to simulate the viral load dynamics of exposed contacts, and their potential for onward transmission in different quarantine and testing strategies. We compared the performance of quarantines of differing durations, testing with either PCR or lateral flow antigen (LFA) tests at the end of quarantine, and daily LFA testing without quarantine, against the current 14-day quarantine strategy. We also investigated the effect of contact tracing delays and adherence to both quarantine and self-isolation on the effectiveness of each strategy. FINDINGS: Assuming moderate levels of adherence to quarantine and self-isolation, self-isolation on symptom onset alone can prevent 37% (95% uncertainty interval [UI] 12-56) of onward transmission potential from secondary cases. 14 days of post-exposure quarantine reduces transmission by 59% (95% UI 28-79). Quarantine with release after a negative PCR test 7 days after exposure might avert a similar proportion (54%, 95% UI 31-81; risk ratio [RR] 0·94, 95% UI 0·62-1·24) to that of the 14-day quarantine period, as would quarantine with a negative LFA test 7 days after exposure (50%, 95% UI 28-77; RR 0·88, 0·66-1·11) or daily testing without quarantine for 5 days after tracing (50%, 95% UI 23-81; RR 0·88, 0·60-1·43) if all tests are returned negative. A stronger effect might be possible if individuals isolate more strictly after a positive test and if contacts can be notified faster. INTERPRETATION: Testing might allow for a substantial reduction in the length of, or replacement of, quarantine with a small excess in transmission risk. Decreasing test and trace delays and increasing adherence will further increase the effectiveness of these strategies. Further research is required to empirically evaluate the potential costs (increased transmission risk, false reassurance) and benefits (reduction in the burden of quarantine, increased adherence) of such strategies before adoption as policy. FUNDING: National Institute for Health Research, UK Research and Innovation, Wellcome Trust, EU Horizon 2021, and the Bill & Melinda Gates Foundation.

Quarantine and testing strategies in contact tracing for SARS-CoV-2: a modelling study.

BACKGROUND: In response to the COVID-19 pandemic, the UK first adopted physical distancing measures in March, 2020. Vaccines against SARS-CoV-2 became available in December, 2020. We explored the health and economic value of introducing SARS-CoV-2 immunisation alongside physical distancing in the UK to gain insights about possible future scenarios in a post-vaccination era. METHODS: We used an age-structured dynamic transmission and economic model to explore different scenarios of UK mass immunisation programmes over 10 years. We compared vaccinating 75% of individuals aged 15 years or older (and annually revaccinating 50% of individuals aged 15-64 years and 75% of individuals aged 65 years or older) to no vaccination. We assumed either 50% vaccine efficacy against disease and 45-week protection (worst-case scenario) or 95% vaccine efficacy against infection and 3-year protection (best-case scenario). Natural immunity was assumed to wane within 45 weeks. We also explored the additional impact of physical distancing on vaccination by assuming either an initial lockdown followed by voluntary physical distancing, or an initial lockdown followed by increased physical distancing mandated above a certain threshold of incident daily infections. We considered benefits in terms of quality-adjusted life-years (QALYs) and costs, both to the health-care payer and the national economy. We discounted future costs and QALYs at 3·5% annually and assumed a monetary value per QALY of £20 000 and a conservative long-run cost per vaccine dose of £15. We explored and varied these parameters in sensitivity analyses. We expressed the health and economic benefits of each scenario with the net monetary value: QALYs × (monetary value per QALY) - costs. FINDINGS: Without the initial lockdown, vaccination, and increased physical distancing, we estimated 148·0 million (95% uncertainty interval 48·5-198·8) COVID-19 cases and 3·1 million (0·84-4·5) deaths would occur in the UK over 10 years. In the best-case scenario, vaccination minimises community transmission without future periods of increased physical distancing, whereas SARS-CoV-2 becomes endemic with biannual epidemics in the worst-case scenario. Ongoing transmission is also expected in intermediate scenarios with vaccine efficacy similar to published clinical trial data. From a health-care perspective, introducing vaccination leads to incremental net monetary values ranging from £12·0 billion to £334·7 billion in the best-case scenario and from -£1·1 billion to £56·9 billion in the worst-case scenario. Incremental net monetary values of increased physical distancing might be negative from a societal perspective if national economy losses are persistent and large. INTERPRETATION: Our model findings highlight the substantial health and economic value of introducing SARS-CoV-2 vaccination. Smaller outbreaks could continue even with vaccines, but population-wide implementation of increased physical distancing might no longer be justifiable. Our study provides early insights about possible future post-vaccination scenarios from an economic and epidemiological perspective. FUNDING: National Institute for Health Research, European Commission, Bill & Melinda Gates Foundation.

The potential health and economic value of SARS-CoV-2 vaccination alongside physical distancing in the UK: a transmission model-based future scenario analysis and economic evaluation.

Jack Williams

Papers

Quarantine and testing strategies in contact tracing for SARS-CoV-2: a modelling study.

The potential health and economic value of SARS-CoV-2 vaccination alongside physical distancing in the UK: a transmission model-based future scenario analysis and economic evaluation.