Long term vaccination strategies to mitigate the impact of SARS-CoV-2 transmission: a modelling study (preprint)

Background Vaccines have reduced severe disease and death from COVID-19. However, with evidence of waning efficacy coupled with continued evolution of the virus, health programmes need to evaluate the requirement for regular booster doses, considering their impact and cost-effectiveness in the face of ongoing transmission and substantial infection-induced immunity. Methods and findings We developed a combined immunological-transmission model parameterised with data on transmissibility, severity, and vaccine effectiveness. We simulated SARS-CoV-2 transmission and vaccine rollout in characteristic global settings with different population age-structures, contact patterns, health system capacities, prior transmission, and vaccine uptake. We quantified the impact of future vaccine booster dose strategies with both original and variant-adapted vaccine products, in the presence of both continuing transmission of Omicron subvariants and considering the potential future emergence of new variants with modified transmission, immune escape, and severity properties. We found that regular boosting of the oldest age group (75+) is the most efficient strategy, although large numbers of hospitalisations and deaths can be averted by extending vaccination to younger age groups. In countries with low vaccine coverage and high infection-derived immunity, boosting older at-risk groups is more effective than continuing primary vaccination into younger ages. These findings hold if even if virus drift results in a gradual reduction in vaccine effectiveness over time due to immune escape. In a worst-case scenario where a new variant emerges that is 10% more transmissible, as severe as Delta, and exhibits substantial further immune escape, demand on health services could be similar to that experienced during 2020. Conclusions Regular boosting of the high-risk population remains an important tool to reduce morbidity and mortality from current and future SARS-CoV-2 variants. The cost-effectiveness of boosting is difficult to assess given the ongoing uncertainty in the likelihood of future variants and their properties but focusing vaccination in the highest-risk cohorts remains the most efficient strategy to reduce morbidity and mortality.

Alternative epidemic indicators for COVID-19: a model-based assessment of COVID-19 mortality ascertainment in three settings with incomplete death registration systems (preprint)

Not all COVID-19 deaths are officially reported and, particularly in low-income and humanitarian settings the magnitude of such reporting gaps remain sparsely characterised. Alternative data sources, including burial site worker reports, satellite imagery of cemeteries and social-media-conducted surveys of infection, may offer solutions. By merging these data with independently conducted, representative serological studies within a mathematical modelling framework, we aim to better understand the range of under-reporting using the example of three major cities: Addis Ababa (Ethiopia), Aden (Yemen) and Khartoum (Sudan) during 2020. We estimate 69% - 100%, 0.8% - 8.0% and 3.0% - 6.0% of COVID-19 deaths were reported in these three settings, respectively. In future epidemics, and in settings where vital registrations systems are absent or limited, using multiple alternative data sources could provide critically-needed, improved estimates of epidemic impact. However, ultimately, functioning vital registration systems are needed to ensure that, in contrast to COVID-19, the impact of future pandemics or other drivers of mortality are reported and understood worldwide.

Quantifying the impact of delaying the second COVID-19 vaccine dose in England: a mathematical modelling study (preprint)

Background: The UK was the first country to start national COVID-19 vaccination programmes, initially administering doses 3-weeks apart. However, early evidence of high vaccine effectiveness after the first dose and the emergence of the Alpha variant prompted the UK to extend the interval between doses to 12-weeks. In this study, we quantify the impact of delaying the second vaccine dose on the epidemic in England. Methods: We used a previously described model of SARS-CoV-2 transmission and calibrated the model to English surveillance data including hospital admissions, hospital occupancy, seroprevalence data, and population-level PCR testing data using a Bayesian evidence synthesis framework. We modelled and compared the epidemic trajectory assuming that vaccine doses were administered 3-weeks apart against the real vaccine roll-out schedule. We estimated and compared the resulting number of daily infections, hospital admissions, and deaths. A range of scenarios spanning a range of vaccine effectiveness and waning assumptions were investigated. Findings: We estimate that delaying the interval between the first and second COVID-19 vaccine doses from 3- to 12-weeks prevented an average 64,000 COVID-19 hospital admissions and 9,400 deaths between 8th December 2020 and 13th September 2021. Similarly, we estimate that the 3-week strategy would have resulted in more infections and deaths compared to the 12-week strategy. Across all sensitivity analyses the 3-week strategy resulted in a greater number of hospital admissions. Interpretation: England's delayed second dose vaccination strategy was informed by early real-world vaccine effectiveness data and a careful assessment of the trade-offs in the context of limited vaccine supplies in a growing epidemic. Our study shows that rapidly providing partial vaccine-induced protection to a larger proportion of the population was successful in reducing the burden of COVID-19 hospitalisations and deaths. There is benefit in carefully considering and adapting guidelines in light of new emerging evidence and the population in question. Funding: National Institute for Health Research, UK Medical Research Council, Jameel Institute, Wellcome Trust, and UK Foreign, Commonwealth and Development Office, National Health and Medical Research Council.

Non-pharmaceutical interventions, vaccination and the Delta variant: epidemiological insights from modelling England's COVID-19 roadmap out of lockdown (preprint)

BackgroundEnglands COVID-19 "roadmap out of lockdown" set out the timeline and conditions for the stepwise lifting of non-pharmaceutical interventions (NPIs) as vaccination roll-out continued. Here we assess the roadmap, the impact of the Delta variant, and potential future epidemic trajectories. MethodsWe extended a model of SARS-CoV-2 transmission to incorporate vaccination and multi-strain dynamics to explicitly capture the emergence of the Delta variant. We calibrated the model to English surveillance data using a Bayesian evidence synthesis framework, then modelled the potential trajectory of the epidemic for a range of different schedules for relaxing NPIs. FindingsThe roadmap was successful in offsetting the increased transmission resulting from lifting NPIs with increasing population immunity through vaccination. However due to the emergence of Delta, with an estimated transmission advantage of 73% (95%CrI: 68-79) over Alpha, fully lifting NPIs on 21 June 2021 as originally planned may have led to 3,400 (95%CrI: 1,300-4,400) peak daily hospital admissions under our central parameter scenario. Delaying until 19 July reduced peak hospitalisations by three-fold to 1,400 (95%CrI: 700-1,500) per day. There was substantial uncertainty in the epidemic trajectory, with particular sensitivity to estimates of vaccine effectiveness and the intrinsic transmissibility of Delta. InterpretationOur findings show that the risk of a large wave of COVID hospitalisations resulting from lifting NPIs can be substantially mitigated if the timing of NPI relaxation is carefully balanced against vaccination coverage. However, with Delta, it may not be possible to fully lift NPIs without a third wave of hospitalisations and deaths, even if vaccination coverage is high. Variants of concern, their transmissibility, vaccine uptake, and vaccine effectiveness must be carefully monitored as countries relax pandemic control measures. FundingNational Institute for Health Research, UK Medical Research Council, Wellcome Trust, UK Foreign, Commonwealth & Development Office. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed up to 23 July 2021 with no language restrictions using the search terms: (COVID-19 or SARS-CoV-2 or 2019-nCoV or "novel coronavirus") AND (vaccine or vaccination) AND ("non pharmaceutical interventions" OR "non-pharmaceutical interventions) AND (model*). We found nine studies that analysed the relaxation of controls with vaccination roll-out. However, none explicitly analysed real-world evidence balancing lifting of interventions, vaccination, and emergence of the Delta variant. Added value of this studyOur data synthesis approach combines real-world evidence from multiple data sources to retrospectively evaluate how relaxation of COVID-19 measures have been balanced with vaccination roll-out. We explicitly capture the emergence of the Delta variant, its transmissibility over Alpha, and quantify its impact on the roadmap. We show the benefits of maintaining NPIs whilst vaccine coverage continues to increase and capture key uncertainties in the epidemic trajectory after NPIs are lifted. Implications of all the available evidenceOur study shows that lifting interventions must be balanced carefully and cautiously with vaccine roll-out. In the presence of a new, highly transmissible variant, vaccination alone may not be enough to control COVID-19. Careful monitoring of vaccine uptake, effectiveness, variants, and changes in contact patterns as restrictions are lifted will be critical in any exit strategy.

Within-country age-based prioritisation, global allocation, and public health impact of a vaccine against SARS-CoV-2: a mathematical modelling analysis (preprint)

The worldwide endeavour to develop safe and effective COVID-19 vaccines has been extraordinary, and vaccination is now underway in many countries. However, the doses available in 2021 are likely to be limited. We extended a mathematical model of SARS-CoV-2 transmission across different country settings to evaluate the public health impact of potential vaccines using WHO-developed target product profiles. We identified optimal vaccine allocation strategies within- and between-countries to maximise averted deaths under constraints on dose supply. We found that the health impact of SARS-CoV-2 vaccination depends on the cumulative population-level infection incidence when vaccination begins, the duration of natural immunity, the trajectory of the epidemic prior to vaccination, and the level of healthcare available to effectively treat those with disease. Within a country we find that for a limited supply (doses for <20% of the population) the optimal strategy is to target the elderly. However, with a larger supply, if vaccination can occur while other interventions are maintained, the optimal strategy switches to targeting key transmitters to indirectly protect the vulnerable. As supply increases, vaccines that reduce or block infection have a greater impact than those that prevent disease alone due to the indirect protection provided to high-risk groups. Given a 2 billion global dose supply in 2021, we find that a strategy in which doses are allocated to countries proportional to population size is close to optimal in averting deaths and aligns with the ethical principles agreed in pandemic preparedness planning. HighlightsO_LIThe global dose supply of COVID-19 vaccines will be constrained in 2021 C_LIO_LIWithin a country, prioritising doses to protect those at highest mortality risk is efficient C_LIO_LIFor a 2 billion dose supply in 2021, allocating to countries according to population size is efficient and equitable C_LI

Quantifying the dynamics of COVID-19 burden and impact of interventions in Java, Indonesia (preprint)

Measuring COVID-19 spread remains challenging in many countries due to testing limitations. In Java, reported cases and deaths increased throughout 2020 despite intensive control measures, particularly within Jakarta and during Ramadan. However, underlying trends are likely obscured by variations in case ascertainment. COVID-19 protocol funerals in Jakarta provide alternative data indicating a substantially higher burden than observed within confirmed deaths. Transmission estimates using this metric follow mobility trends, suggesting earlier and more sustained intervention impact than observed in routine data. Modelling suggests interventions have lessened spread to rural, older communities with weaker healthcare systems, though predict healthcare capacity will soon be exceeded in much of Java without further control. Our results highlight the important role syndrome-based measures of mortality can play in understanding COVID-19 transmission and burden.

The projected impact of mitigation and suppression strategies on the COVID-19 epidemic in Senegal: A modelling study (preprint)

Background: Physical distancing measures that reduce social contacts have formed a key part of national COVID-19 containment and mitigation strategies. Many Sub-Saharan African nations are now facing increasing numbers of cases of COVID-19 and there is a need to understand what levels of measures may be required to successfully reduce transmission. Methods: We collated epidemiological data along with information on key COVID-19 specific response policies and health system capacity estimates for services needed to treat COVID-19 patients in Senegal. We calibrated an age-structured SEIR model to these data to capture transmission dynamics accounting for demography, contact patterns, hospital capacity and disease severity. We simulated the impact of mitigation and suppression strategies focussed on reducing social contact rates. Results: Senegal acted promptly to contain the spread of SARS-CoV-2 and as a result has reduced the reproduction number from 1.9 (95% CI 1.7-2.2) to 1.3 (95% CI 1.2-1.5), which has slowed but not fully interrupted transmission. We estimate that continued spread is likely to peak in October, and to overwhelm the healthcare system with an estimated 77,400 deaths(95% CI 55,270-100,700). Further reductions in contact rates to suppress transmission (Rt<1) could significantly reduce this burden on healthcare services and improve overall health outcomes. Conclusions: Our results demonstrate that Senegal has already significantly reduced transmission. Enhanced physical distancing measures and rapid scale up of hospital capacity is likely to be needed to reduce mortality and protect healthcare infrastructure from high levels of demand.