Background:Self-testing for SARS-CoV-2 infection using lateral flow devices (LFDs) was a key component of the COVID-19 pandemic response; however, LFD performance has shown a high degree of variability. Between August 2020 and July 2023, the UK Health Security Agency (UKHSA), including predecessor organisations, undertook a three-phase SARS-CoV-2 test development and evaluation programme to independently evaluate commercially available SARS-CoV-2 LFDs, incorporating standardised laboratory assessment of test sensitivity. Here we describe results from a comparison of UKHSA laboratory assessment findings with manufacturer-reported LFD sensitivity data. Methods:The UKHSA assessed the sensitivity of LFDs, by laboratory testing of surplus clinical samples from a secondary healthcare setting. These data were compared with manufacturer-reported clinical sensitivity data and analytical sensitivity (limit of detection [LOD; 50% tissue culture infectious dose [TCID50]/mL]) from LFD instructions for use (IFU). Findings:UKHSA-determined LFD sensitivity ranged from 32 to 83%. Of 86 LFDs assessed, 73 included device sensitivity data in the manufacturers' IFU that claimed clinical sensitivity ≥85%, and 49 claimed clinical sensitivity ≥95%. No evidence of correlation was observed between manufacturer-reported test sensitivity and UKHSA determined test sensitivity, and no evidence of correlation was observed between manufacturer-reported test LOD and UKHSA-determined test sensitivity. Interpretation:Laboratory evaluation found no evidence of correlation between manufacturer-reported SARS-CoV-2 LFD sensitivity data and UKHSA laboratory-determined sensitivity, supporting previous reports of discrepancies. Our findings suggest that manufacturer-reported performance data and claims for SARS-CoV-2 LFDs should be interpreted with caution and support the need for independent monitoring and testing, and standardisation of analysis methodologies. Funding:This study was funded by UK Department of Health and Social Care; UK Health Security Agency (formerly Public Health England and the National Health Service Test and Trace); and the University of Oxford NIHR Biomedical Research Centre.

With the rapid spread and evolution of SARS-CoV-2, the ability to monitor its transmission and distinguish among viral lineages is critical for pandemic response efforts. The most commonly used software for the lineage assignment of newly isolated SARS-CoV-2 genomes is pangolin, which offers two methods of assignment, pangoLEARN and pUShER. PangoLEARN rapidly assigns lineages using a machine learning algorithm, while pUShER performs a phylogenetic placement to identify the lineage corresponding to a newly sequenced genome. In a preliminary study, we observed that pangoLEARN (decision tree model), while substantially faster than pUShER, offered less consistency across different versions of pangolin v3. Here, we expand upon this analysis to include v3 and v4 of pangolin, which moved the default algorithm for lineage assignment from pangoLEARN in v3 to pUShER in v4, and perform a thorough analysis confirming that pUShER is not only more stable across versions but also more accurate. Our findings suggest that future lineage assignment algorithms for various pathogens should consider the value of phylogenetic placement.

This protocol lists the primer bed file for a modified Artic v3 set for SARS-CoV-2 sequencing. Two primers have been added to reduce dropouts.

Population-representative estimates of SARS-CoV-2 infection prevalence and antibody levels in specific geographic areas at different time points are needed to optimise policy responses. However, even population-wide surveys are potentially impacted by biases arising from differences in participation rates across key groups. Here, we used spatio-temporal regression and post-stratification models to UK’s national COVID-19 Infection Survey (CIS) to obtain representative estimates of PCR positivity (6,496,052 tests) and antibody prevalence (1,941,333 tests) for different regions, ages and ethnicities (7-December-2020 to 4-May-2022). Not accounting for vaccination status through post-stratification led to small underestimation of PCR positivity, but more substantial overestimations of antibody levels in the population (up to 21 percentage points), particularly in groups with low vaccine uptake in the general population. There was marked variation in the relative contribution of different areas and age-groups to each wave. Future analyses of infectious disease surveys should take into account major drivers of outcomes of interest that may also influence participation, with vaccination being an important factor to consider.

The MYC oncogene is often dysregulated in human cancer, including hepatocellular carcinoma (HCC). MYC is considered undruggable to date. Here, we comprehensively identify genes essential for survival of MYC high but not MYC low cells by a CRISPR/Cas9 genome-wide screen in a MYC-conditional HCC model. Our screen uncovers novel MYC synthetic lethal (MYC-SL) interactions and identifies most MYC-SL genes described previously. In particular, the screen reveals nucleocytoplasmic transport to be a MYC-SL interaction. We show that the majority of MYC-SL nucleocytoplasmic transport genes are upregulated in MYC high murine HCC and are associated with poor survival in HCC patients. Inhibiting Exportin-1 (XPO1) in vivo induces marked tumor regression in an autochthonous MYC-transgenic HCC model and inhibits tumor growth in HCC patient-derived xenografts. XPO1 expression is associated with poor prognosis only in HCC patients with high MYC activity. We infer that MYC may generally regulate and require altered expression of nucleocytoplasmic transport genes for tumorigenesis.

BACKGROUND/OBJECTIVES:We investigated if performing two lateral flow device (LFD) tests, LFD2 immediately after LFD1, could improve diagnostic sensitivity or specificity for detecting severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) antigen. STUDY DESIGN:Individuals aged ≥16 years attending UK community testing sites (February-May 2021) performed two successive LFD tests and provided a nose-and-throat sample for a polymerase chain reaction (PCR) test. Using the PCR result as the reference diagnosis, we assessed whether improvements could be achieved in sensitivity (by counting a positive result in either LFD as a positive overall test result) or specificity (by using LFD2 as confirmatory test). RESULTS:Overall, 2231 participants were included with 159 (7 %) having a positive PCR test. Of 2223 participants who completed both LFD tests, LFD results were highly concordant both with each other and with PCR tests (>97 %). The proportion of discord LFD results decreased significantly over the study period. Combined LFD usage achieved a sensitivity of 68.6 %, versus 67.1 % for either LFD individually. The specificity increased from 99.5 % to 99.8 % when using LFD2 as confirmatory test. Observed increases in sensitivity and specificity were not statistically significant. Void results were recorded for 31 (1.4 %) LFD1s, 19 (0.9 %) LFD2s and 6 (0.3 %) combined LFD tests. CONCLUSIONS:LFD tests were highly reproducible even when they were performed by untrained users following only written instructions and without supervision. While performing two LFD tests of the same type in quick succession marginally increased sensitivity or specificity, statistically significant improvements were not detected in our study.

Following primary SARS-CoV-2 vaccination, whether boosters or breakthrough infections provide greater protection against SARS-CoV-2 infection is incompletely understood. Here we investigated SARS-CoV-2 antibody correlates of protection against new Omicron BA.4/5 (re-)infections and anti-spike IgG antibody trajectories after a third/booster vaccination or breakthrough infection following second vaccination in 154,149 adults ≥18 y from the United Kingdom general population. Higher antibody levels were associated with increased protection against Omicron BA.4/5 infection and breakthrough infections were associated with higher levels of protection at any given antibody level than boosters. Breakthrough infections generated similar antibody levels to boosters, and the subsequent antibody declines were slightly slower than after boosters. Together our findings show breakthrough infection provides longer-lasting protection against further infections than booster vaccinations. Our findings, considered alongside the risks of severe infection and long-term consequences of infection, have important implications for vaccine policy.

Cancer cells accumulate genetic mutations in coding proteins that may be presented by HLA as neoantigenic peptides (peptide HLA, pHLA). T cells scan for neoantigenic pHLA by the T-cell receptor (TCR):CD3 complex. This complex has the dual function of binding pHLA, by the TCR, and triggering T-cell activation by CD3. Checkpoint therapy activates exhausted T cells to kill cancer cells and generally work best against tumors with high neoantigen burden and in patients with neoantigenic-reactive T cells. TCR T-cell engagers (TCE) are a novel class of immuno-therapy that bypasses these two requirements by redirecting poly-clonal T cells, regardless of their native specificity, to kill a cancer cell independent of neoantigen burden. This is accomplished through deconstructing the membrane-bound TCR:CD3 complex into a soluble bispecific protein comprised of a targeting domain (TCR) and activating domain (usually anti-CD3 single-chain variable fragment). The pool of targets for TCR TCE is larger than for antibody therapeutics and includes >90% of human intra-or extracellular proteins. Most tumor-associated antigens for solid tumors are intracellular and accessible only by a TCR therapeutic. Tebentafusp, a TCR TCE directed to a peptide derived from the gp100 melanoma protein presented by HLA*A02:01, demonstrated a survival benefit in metastatic uveal melanoma (mUM). This survival benefit highlights the promise of TCR TCEs because mUM is a solid tumor with a very low neoantigen burden and has poor response to checkpoints and chemotherapy. Other TCR TCE programs are now in clinical studies for a broader range of tumors.

IntroductionThe SARS-CoV-2 pandemic represented a formidable scientific and technological challenge to public health due to its rapid spread and evolution. To meet these challenges and to characterize the virus over time, the State of California established the California SARS-CoV-2 Whole Genome Sequencing (WGS) Initiative, or “California COVIDNet”. This initiative constituted an unprecedented multi-sector collaborative effort to achieve large-scale genomic surveillance of SARS-CoV-2 across California to monitor the spread of variants within the state, to detect new and emerging variants, and to characterize outbreaks in congregate, workplace, and other settings.MethodsCalifornia COVIDNet consists of 50 laboratory partners that include public health laboratories, private clinical diagnostic laboratories, and academic sequencing facilities as well as expert advisors, scientists, consultants, and contractors. Data management, sample sourcing and processing, and computational infrastructure were major challenges that had to be resolved in the midst of the pandemic chaos in order to conduct SARS-CoV-2 genomic surveillance. Data management, storage, and analytics needs were addressed with both conventional database applications and newer cloud-based data solutions, which also fulfilled computational requirements.ResultsRepresentative and randomly selected samples were sourced from state-sponsored community testing sites. Since March of 2021, California COVIDNet partners have contributed more than 450,000 SARS-CoV-2 genomes sequenced from remnant samples from both molecular and antigen tests. Combined with genomes from CDC-contracted WGS labs, there are currently nearly 800,000 genomes from all 61 local health jurisdictions (LHJs) in California in the COVIDNet sequence database. More than 5% of all reported positive tests in the state have been sequenced, with similar rates of sequencing across 5 major geographic regions in the state.DiscussionImplementation of California COVIDNet revealed challenges and limitations in the public health system. These were overcome by engaging in novel partnerships that established a successful genomic surveillance program which provided valuable data to inform the COVID-19 public health response in California. Significantly, California COVIDNet has provided a foundational data framework and computational infrastructure needed to respond to future public health crises.

Climate change represents a global challenge and nations are increasingly looking to decarbonise their economies by developing roadmaps for reducing greenhouse gas (GHG) emissions in accordance with international treaties, such as the Paris Agreement [1]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Christer Janson reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline PLC, Novartis and Teva outside the submitted work. Conflict of interest: Alexander Wilkinson is a member of the Montreal protocol Medical and Chemical Technical Options Committee and has made unpaid contributions to publications on the carbon footprint of inhalers and respiratory treatment which were sponsored by GlaxoSmithKline and AstraZeneca. Conflict of interest: Erika Penz has received honoraria and consulting fees from AstraZeneca, GlaxoSmithKline, Sanofi Genzyme, International Centre for Evidence-Based Medicine in Canada and Boehringer Ingelheim. Conflict of interest: Alberto Papi reports grants and personal fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Menarini and Sanofi/Regeneron; personal fees from Mundipharma, Zambon, Novartis, Edmond Pharma and Roche; and grants from Fondazione Maugeri and Fondazione Chiesi. Conflict of interest: Claus F. Vogelmeier has delivered presentations at symposia and/or served on scientific advisory boards sponsored by Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Grifols, Menarini, Novartis, Nuvaira and MedUpdate. Conflict of interest: Maciej Kupczyk reports grants from AstraZeneca and personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, Lekam, Alvogen, Emma, Nexter and Berlin Chemie. Conflict of interest: Ekaterina Maslova, Nigel Budgen and John Bell are employees of AstraZeneca. Conflict of interest: Andrew Menzies-Gow has attended advisory boards for GlaxoSmithKline, Novartis, AstraZeneca, Sanofi and Teva. He has received speaker fees from Novartis, AstraZeneca, Vectura, Teva and Roche. He has also participated in research with AstraZeneca and attended international conferences with Teva. He has consultancy agreements with AstraZeneca, Vectura and Sanofi.

Given high SARS-CoV-2 incidence, coupled with slow and inequitable vaccine roll-out in many settings, there is a need for evidence to underpin optimum vaccine deployment, aiming to maximise global population immunity. We evaluate whether a single vaccination in individuals who have already been infected with SARS-CoV-2 generates similar initial and subsequent antibody responses to two vaccinations in those without prior infection. We compared anti-spike IgG antibody responses after a single vaccination with ChAdOx1, BNT162b2, or mRNA-1273 SARS-CoV-2 vaccines in the COVID-19 Infection Survey in the UK general population. In 100,849 adults median (50 (IQR: 37-63) years) receiving at least one vaccination, 13,404 (13.3%) had serological/PCR evidence of prior infection. Prior infection significantly boosted antibody responses, producing higher peak levels and/or longer half-lives after one dose of all three vaccines than those without prior infection receiving one or two vaccinations. In those with prior infection, the median time above the positivity threshold was >1 year after the first vaccination. Single-dose vaccination targeted to those previously infected may provide at least as good protection to two-dose vaccination among those without previous infection.

Antibody responses are an important part of immunity after Coronavirus Disease 2019 (COVID-19) vaccination. However, antibody trajectories and the associated duration of protection after a second vaccine dose remain unclear. In this study, we investigated anti-spike IgG antibody responses and correlates of protection after second doses of ChAdOx1 or BNT162b2 vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the United Kingdom general population. In 222,493 individuals, we found significant boosting of anti-spike IgG by the second doses of both vaccines in all ages and using different dosing intervals, including the 3-week interval for BNT162b2. After second vaccination, BNT162b2 generated higher peak levels than ChAdOX1. Older individuals and males had lower peak levels with BNT162b2 but not ChAdOx1, whereas declines were similar across ages and sexes with ChAdOX1 or BNT162b2. Prior infection significantly increased antibody peak level and half-life with both vaccines. Anti-spike IgG levels were associated with protection from infection after vaccination and, to an even greater degree, after prior infection. At least 67% protection against infection was estimated to last for 2–3 months after two ChAdOx1 doses, for 5–8 months after two BNT162b2 doses in those without prior infection and for 1–2 years for those unvaccinated after natural infection. A third booster dose might be needed, prioritized to ChAdOx1 recipients and those more clinically vulnerable.

Background. How severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectivity varies with viral load is incompletely understood. Whether rapid point-of-care antigen lateral flow devices (LFDs) detect most potential transmission sources despite imperfect clinical sensitivity is unknown. Methods. We combined SARS-CoV-2 testing and contact tracing data from England between 1 September 2020 and 28 February 2021. We used multivariable logistic regression to investigate relationships between polymerase chain reaction (PCR)-confirmed infection in contacts of community-diagnosed cases and index case viral load, S gene target failure (proxy for B.1.1.7 infection), demographics, SARS-CoV-2 incidence, social deprivation, and contact event type. We used LFD performance to simulate the proportion of cases with a PCR-positive contact expected to be detected using 1 of 4 LFDs. Results. In total, 231 498/2 474 066 (9%) contacts of 1 064 004 index cases tested PCR-positive. PCR-positive results in contacts independently increased with higher case viral loads (lower cycle threshold [Ct] values), for example, 11.7% (95% confidence interval [CI] 11.5-12.0%) at Ct = 15 and 4.5% (95% CI 4.4-4.6%) at Ct = 30. B.1.1.7 infection increased PCR-positive results by -50%, (eg, 1.55-fold, 95% CI 1.49-1.61, at Ct = 20). PCR-positive results were most common in household contacts (at Ct = 20.1, 8.7% [95% CI 8.6-8.9%]), followed by household visitors (7.1% [95% CI 6.8-7.3%]), contacts at events/activities (5.2% [95% CI 4.9-5.4%]), work/education (4.6% [95% CI 4.4-4.8%]), and least common after outdoor contact (2.9% [95% CI 2.3-3.8%]). Contacts of children were the least likely to test positive, particularly following contact outdoors or at work/education. The most and least sensitive LFDs would detect 89.5% (95% CI 89.4-89.6%) and 83.0% (95% CI 82.8-83.1%) of cases with PCR-positive contacts, respectively. Conclusions: SARS-CoV-2 infectivity varies by case viral load, contact event type, and age. Those with high viral loads are the most infectious. B.1.1.7 increased transmission by -50%. The best performing LFDs detect most infectious cases.

Autophagy is a housekeeping mechanism tasked with eliminating misfolded proteins and damaged organelles to maintain cellular homeostasis. Autophagy deficiency results in increased oxidative stress, DNA damage and chronic cellular injury. Among the core genes in the autophagy machinery, ATG7 is required for autophagy initiation and autophagosome formation. Based on the analysis of an extended pedigree of familial cholangiocarcinoma, we determined that all affected family members had a novel germline mutation (c.2000C>T p.Arg659* (p.R659*)) in ATG7. Somatic deletions of ATG7 were identified in the tumors of affected individuals. We applied linked-read sequencing to one tumor sample and demonstrated that the ATG7 somatic deletion and germline mutation were located on distinct alleles, resulting in two hits to ATG7. From a parallel population genetic study, we identified a germline polymorphism of ATG7 (c.1591C>G p.Asp522Glu (p.D522E)) associated with increased risk of cholangiocarcinoma. To characterize the impact of these germline ATG7 variants on autophagy activity, we developed an ATG7-null cell line derived from the human bile duct. The mutant p.R659* ATG7 protein lacked the ability to lipidate its LC3 substrate, leading to complete loss of autophagy and increased p62 levels. Our findings indicate that germline ATG7 variants have the potential to impact autophagy function with implications for cholangiocarcinoma development.

The COVID-19 pandemic has led to a renewed recognition of the importance of disease prevention and public health globally. The progress in COVID-19 vaccine technology is a small portion of the pipeline of new vaccines and injectable therapies that could prevent leading causes of premature death and disability. This pipeline comes from decades of investment by governments and work by pharmaceutical companies, academic researchers, and new entrants in the field. The urgent need for new COVID-19 vaccines has also accelerated developments in this pipeline. Mirroring success during the past 50 years with the Expanded Programme on Immunization for children, global life course vaccination and other preventive strategies that use these products would strengthen health systems globally and have a major impact on disease prevention. In the adult vaccine space, new products at multiple stages of preclinical and clinical development for coronaviruses, influenza, and respiratory syncytial virus (RSV) are expected to emerge in the coming months and years.1Dolgin E Pan-coronavirus vaccine pipeline takes form 2022.Nat Rev Drug Discov. 2022; 21: 324-326Crossref PubMed Scopus (33) Google Scholar, 2Wei C-J Crank MC Shiver J Graham BS Mascola JR Nabel GJ Next-generation influenza vaccines: opportunities and challenges.Nat Rev Drug Discov. 2020; 19: 239-252Crossref PubMed Scopus (138) Google Scholar, 3Abbasi J RSV vaccines, finally within reach, could prevent tens of thousands of yearly deaths.JAMA. 2022; 327: 204-206Crossref PubMed Scopus (7) Google Scholar These could become staple products for reducing adult disease burden, particularly in winter. Although the global burden of these diseases is difficult to estimate due to insufficient data in many countries, it is likely to be considerable. For example, estimates suggest that influenza causes 389 000 deaths annually, with the majority of cases in southeast Asia, the Western Pacific region, and sub-Saharan Africa, and that at least 14 000 hospital-based deaths are caused by RSV acute respiratory infection globally, although this is likely to be an underestimation of total deaths from RSV.4Paget J Spreeuwenberg P Charu V et al.Global mortality associated with seasonal influenza epidemics: new burden estimates and predictors from the GLaMOR Project.J Glob Health. 2019; 9020421Crossref PubMed Scopus (292) Google Scholar, 5Shi T Denouel A Tietjen AK et al.Global disease burden estimates of respiratory syncytial virus–associated acute respiratory infection in older adults in 2015: a systematic review and meta-analysis.J Infect Dis. 2019; 222: S577-S583Google Scholar As durability of vaccine-induced immune response is likely to remain a challenge, an annual immunisation cycle for these infectious diseases is possible and would have real population-level health benefits. If COVID-19 and influenza booster doses become the mainstay of annual adult immunisation programmes, other innovative products could be used alongside them. Vaccines in development for tuberculosis and malaria, for example, have promising phase 2 data, with efficacy of up to 50% against tuberculosis and 80% against malaria in children.6Tait DR Hatherill M Van Der Meeren O et al.Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis.New Engl J Med. 2019; 381: 2429-2439Crossref PubMed Scopus (231) Google Scholar, 7Datoo MS Natama MH Somé A et al.Efficacy and immunogenicity of R21/Matrix-M vaccine against clinical malaria after 2 years' follow-up in children in Burkina Faso: a phase 1/2b randomised controlled trial.Lancet Infect Dis. 2022; (published online Sept 7.)https://doi.org/10.1016/S1473-3099(22)00442-XSummary Full Text Full Text PDF PubMed Scopus (31) Google Scholar Although malaria burden in children is substantial, evidence suggests that its burden in adults is underestimated,8Dhingra N Jha P Sharma VP et al.Adult and child malaria mortality in India: a nationally representative mortality survey.Lancet. 2010; 376: 1768-1774Summary Full Text Full Text PDF PubMed Scopus (206) Google Scholar and a malaria vaccine with encouraging phase 2 data is now being tested in adults (NCT05252845). Existing human papilloma virus and pneumococcal vaccination programmes still do not reach all the populations they should.9Spayne J Hesketh T Estimate of global human papillomavirus vaccination coverage: analysis of country-level indicators.BMJ Open. 2021; 11e052016Crossref PubMed Scopus (20) Google Scholar, 10Ostropolets A Shoener Dunham L Johnson KD Liu J Pneumococcal vaccination coverage among adults newly diagnosed with underlying medical conditions and regional variation in the US.Vaccine. 2022; 40: 4856-4863Crossref PubMed Scopus (4) Google Scholar A vaccine for dengue fever received its first approval for use in Indonesia in August, 2022.11TakedaTakeda's QDENGA® (dengue tetravalent vaccine [live, attenuated]) approved in Indonesia for use regardless of prior dengue exposure.https://www.takeda.com/newsroom/newsreleases/2022/takedas-qdenga-dengue-tetravalent-vaccine-live-attenuated-approved-in-indonesia-for-use-regardless-of-prior-dengue-exposure/Date: Aug 22, 2022Date accessed: October 18, 2022Google Scholar Additionally, new long-acting preventive injectable therapies might be administered by health-care workers in the future—eg, small interfering RNA (siRNA) that prevents translation of PCSK9 for atherosclerotic cardiovascular disease prevention, or the siRNA anti-hypertensive that targets angiotensinogen, if its efficacy is confirmed in ongoing trials (NCT04936035).12US Food and Drug AdministrationFDA approves add-on therapy to lower cholesterol among certain high-risk adults.https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-add-therapy-lower-cholesterol-among-certain-high-risk-adultsDate: Dec 22, 2021Date accessed: October 18, 2022Google Scholar, 13Huang SA Taubel J Fiore G et al.Abstract 14387: dose-related reductions in blood pressure with a RNA interference (RNAi) therapeutic targeting angiotensinogen in hypertensive patients: interim results from a first-in-human phase 1 study of ALN-AGT01.Circulation. 2020; 142A14387-AGoogle Scholar Long-acting injectables for HIV prevention and antipsychotic treatment could similarly have the potential to become part of preventive strategies.14US Food and Drug AdministrationFDA approves first injectable treatment for HIV pre-exposure prevention.https://www.fda.gov/news-events/press-announcements/fda-approves-first-injectable-treatment-hiv-pre-exposure-preventionDate: Dec 20, 2021Date accessed: October 18, 2022Google Scholar, 15National Council for Mental WellbeingGuide to long-acting medications for clinicians and organizations.https://www.thenationalcouncil.org/wp-content/uploads/2021/12/2022.02.02_NC_Updated-Guide-To-LAMs.pdfDate: 2022Date accessed: October 18, 2022Google Scholar Administering each product individually would be challenging due to high delivery costs and prices, especially in low-income and middle-income countries (LMICs). However, bundling delivery could reduce the per unit cost of administration by using shared resources, such as supply chains and health-care workers, for multiple products, and instituting tiered pricing would make these products more affordable for countries with constrained health budgets. Governments and industry have begun building new manufacturing capacity to avoid vaccine inequity. Before the COVID-19 pandemic, the world produced and procured about 5 billion vaccine doses annually.16AirfinityCOVID-19 vaccine production.https://www.ifpma.org/wp-content/uploads/2021/03/Airfinity_global_summit_master_final.pdfDate: 2021Date accessed: October 18, 2022Google Scholar In 2022, the world has the capacity to manufacture more than 25 billion doses of approved COVID-19 vaccines, and most production is concentrated in China, the EU, India, and the USA.16AirfinityCOVID-19 vaccine production.https://www.ifpma.org/wp-content/uploads/2021/03/Airfinity_global_summit_master_final.pdfDate: 2021Date accessed: October 18, 2022Google Scholar, 17UNICEFCOVID-19 Market Dashboard.https://www.unicef.org/supply/covid-19-market-dashboardDate: 2022Date accessed: October 18, 2022Google Scholar Sustainable, scaled, and globally distributed manufacturing would improve the response to future pandemics. As new manufacturing sites are established, coordinated demand forecasts and adoption of routine vaccinations at scale could keep these factories commercially viable so that they are available for the next pathogen outbreak. The COVID-19 pandemic highlighted the role of community-based and primary care sites to deliver vaccines and to build reliable cold chains. There is potential to integrate more preventive health services into a single point of care, reducing the need for vertical systems that focus on single diseases. Indeed, in 2019, two-thirds of global health funding to LMICs focused on HIV, tuberculosis, malaria (which historically have not benefited from long-acting pharmacological preventive technologies), and reproductive, maternal, newborn, and child health.18Institute for Health Metrics and EvaluationFinancing global health. Flows of development assistance for health.https://vizhub.healthdata.org/fgh/Date: 2022Date accessed: October 18, 2022Google Scholar Addressing these patient populations is important and funding should be sustained, but there should also be increased focus on prevention strategies for other adult diseases. These strategies should consider variations in available financing, service delivery, public health infrastructure, disease burden, vaccine acceptance, and other factors across countries. The digitisation of health systems accelerated during the COVID-19 pandemic, and digital tools identified and prioritised individuals for vaccination, recruited them to sites, and in some settings linked vaccination data to health records with a unique identifier. Before the pandemic, about 60% of LMICs did not have electronic immunisation registries.19PATHDigital Square. Electronic immunization registries in low- and middle-income countries.https://static1.squarespace.com/static/59bc3457ccc5c5890fe7cacd/t/60aee1bfd163646306fb924c/1622073794356/Digital+Square+EIR+Landscape_Final.pdfDate: 2021Date accessed: October 18, 2022Google Scholar Digitisation is key to successful vaccine roll-outs, and pressure to build this infrastructure during the pandemic led to considerable progress. This infrastructure will be particularly important given the need for multiple vaccines, repeat boosters, and diagnostic tests for many vaccines or injectables. Not all high-income countries achieved this infrastructure, but those that did created some of the best datasets and real-world evidence on COVID-19 vaccine safety and efficacy.20Dagan N Barda N Kepten E et al.BNT162b2 mRNA COVID-19 vaccine in a nationwide mass vaccination setting.N Engl J Med. 2021; 384: 1412-1423Crossref PubMed Scopus (1511) Google Scholar, 21Lopez Bernal J Andrews N Gower C et al.Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on COVID-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study.BMJ. 2021; 373n1088PubMed Google Scholar Many LMICs have or are developing digital health systems that provide a powerful starting point for scaling digitally enabled primary care and public health. Global health funders and governments should require and prioritise digital infrastructure to deliver, track, and measure the impact of adult vaccines, injectables, and other interventions. This approach would enable systems to not only record clinical encounters, but also to collect longitudinal data on demographics, clinical outcomes, and side-effects (including in clinical trials) in a privacy-protected way. This digital infrastructure would facilitate the most effective use of new vaccines and injectable therapies that could transform the prevention agenda and improve pandemic preparedness. The importance of a prevention strategy that capitalises on innovations for infectious and chronic diseases and strengthens health systems is clear, as highlighted in two 2022 reports, A Global Opportunity to Combat Preventable Disease: How to Use COVID-19 Infrastructure to Transform Public Health Worldwide22Alkasir A Berry T Britto D et al.A global opportunity to combat preventable disease: how to use COVID-19 infrastructure to transform public health worldwide. Tony Blair Institute for Global Change, January, 2022https://institute.global/sites/default/files/2022-01/GHSC%2C%20A%20Global%20Opportunity%20to%20Combat%20Preventable%20Disease%2C%20January%202022.pdfDate accessed: October 18, 2022Google Scholar and One Shot to Prevent Disease and Prepare for Future Pandemics.23Agus D Bell J Blair T One shot to prevent disease and prepare for future pandemics. Global Health Security Consortium, October, 2022https://institute.global/sites/default/files/2022-10/GHSC%2C%20Introducing%20One%20Shot%20to%20Prevent%20Disease%20and%20Prepare%20for%20Future%20Pandemics%2C%20October%202022%20FINAL.pdfDate accessed: October 25, 2022Google Scholar Vaccines and preventive injectables that are available or in development could prevent 10 million deaths each year.22Alkasir A Berry T Britto D et al.A global opportunity to combat preventable disease: how to use COVID-19 infrastructure to transform public health worldwide. Tony Blair Institute for Global Change, January, 2022https://institute.global/sites/default/files/2022-01/GHSC%2C%20A%20Global%20Opportunity%20to%20Combat%20Preventable%20Disease%2C%20January%202022.pdfDate accessed: October 18, 2022Google Scholar, 23Agus D Bell J Blair T One shot to prevent disease and prepare for future pandemics. Global Health Security Consortium, October, 2022https://institute.global/sites/default/files/2022-10/GHSC%2C%20Introducing%20One%20Shot%20to%20Prevent%20Disease%20and%20Prepare%20for%20Future%20Pandemics%2C%20October%202022%20FINAL.pdfDate accessed: October 25, 2022Google Scholar A global adult disease prevention programme, supported by geographically distributed manufacturing and digitally enabled cold chain, service delivery, and recording, could have profound implications for health worldwide between disease outbreaks and also create the systems to respond to future pathogen threats. Governments, funders, the private sector, and partner organisations need to overcome siloed efforts to deliver this programme as a positive global legacy of the COVID-19 pandemic. DBA is the paid Founding Director and Chief Executive Officer of the Ellison Institute for Transformative Medicine, a public good for-profit (the Institute comprises both a for-profit entity, whose profits will be reinvested into future public health and disease research, as well as a not-for-profit research foundation), which draws collaborators from across conventional health fields, as well as from a broad range of other disciplines to study disease and potential ways to prevent, detect, and treat the disease, and is a paid faculty member of the University of Southern California. JB is a paid faculty member of Oxford University, a paid Non-Executive Director of Oxford Science Enterprises, an independent investment company that has active investments in life sciences (novel platforms, technologies, and approaches advancing the discovery of new therapeutics and vaccines), health tech (medical devices, tools, digital diagnostics, AI-powered clinical imaging, virtual reality therapy, and solutions to improve health-care delivery), and deep tech (quantum computing and enabling technologies, fusion energy, industrial heat, novel computer hardware, electrified transportation, and solutions to tackle depleting food resources), and is a paid Chair of the Bill & Melinda Gates Foundation's Global Health Scientific Advisory Board. DBA and JB are non-paid Co-Chairs of the Global Health Security Consortium, a partnership to support and guide leaders on the global health security agenda. AN is a paid Special Adviser to Gavi, the Vaccine Alliance. AAS is the paid General Administrator of Institut Pasteur de Dakar, which produces a yellow fever vaccine. We declare no other competing interests. We thank Tamsin Berry, Romina Mariano, Gabriel Seidman, and Emily Stanger Sfeile from the Global Health Security Consortium for their assistance with preparing this Comment. Successful adult vaccine drives must centre disability inclusionThe promise of a vaccine-centred future discussed by David B Agus and colleagues presents an important opportunity for disability inclusion.1 Many novel vaccine candidates target diseases that disproportionately affect people with disabilities, including COVID-19, other respiratory illnesses, and various non-communicable diseases.2 The 10–20-year gap in life expectancy for people with disabilities makes improving inclusion in future public health systems essential.2 Full-Text PDF Successful adult vaccine drives must centre disability inclusion – Authors' replyWe thank Sara Rotenberg and Matthew Downer for their thoughtful Correspondence about the importance of disability inclusion in vaccination strategies. We appreciate their efforts to highlight this topic and agree with its importance. Preventive therapies can have different benefits in different populations, and ensuring their equitable distribution and use in those populations who would benefit most is crucial to their success for the whole population. Full-Text PDF

Following primary SARS-CoV-2 vaccination, understanding the relative extent of protection against SARS-CoV-2 infection from boosters or from breakthrough infections (i.e. infection in the context of previous vaccination) has important implications for vaccine policy. In this study, we investigated correlates of protection against Omicron BA.4/5 infections and anti-spike IgG antibody trajectories after a third/booster vaccination or breakthrough infection following second vaccination in 154,149 adults ≥18y from the United Kingdom general population. We found that higher anti-spike IgG antibody levels were associated with increased protection against Omicron BA.4/5 infection and that breakthrough infections were associated with higher levels of protection at any given antibody level than booster vaccinations. Breakthrough infections generated similar antibody levels to third/booster vaccinations, and the subsequent declines in antibody levels were similar to or slightly slower than those after third/booster vaccinations. Taken together our findings show that breakthrough infection provides longer lasting protection against further infections than booster vaccinations. For example, considering antibody levels associated with 67% protection against infection, a third/booster vaccination did not provide long-lasting protection, while a Delta/Omicron BA.1 breakthrough infection could provide 5-10 months of protection against Omicron BA.4/5 reinfection. 50-60% of the vaccinated UK population with a breakthrough infection would still be protected by the end of 2022, compared to <15% of the triple-vaccinated UK population without previous infection. Although there are societal impacts and risks to some individuals associated with ongoing transmission, breakthrough infection could be an efficient immune-boosting mechanism for subgroups of the population, including younger healthy adults, who have low risks of adverse consequences from infection. ### Competing Interest Statement DWE declares lecture fees from Gilead, outside the submitted work. PCM receives GSK funding to support a PhD fellowship in her team. No other author has a conflict of interest to declare. ### Funding Statement This study is funded by the Department of Health and Social Care with in-kind support from the Welsh Government, the Department of Health on behalf of the Northern Ireland Government and the Scottish Government. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study received ethical approval from the South Central Berkshire B Research Ethics Committee (20/SC/0195). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data are still being collected for the COVID-19 Infection Survey. De-identified study data are available for access by accredited researchers in the ONS Secure Research Service (SRS) for accredited research purposes under part 5, chapter 5 of the Digital Economy Act 2017. Individuals can apply to be an accredited researcher using the short form on . Accreditation requires completion of a short free course on accessing the SRS. To request access to data in the SRS, researchers must submit a research project application for accreditation in the Research Accreditation Service (RAS). Research project applications are considered by the project team and the Research Accreditation Panel (RAP) established by the UK Statistics Authority at regular meetings. Project application example guidance and an exemplar of a research project application are available. A complete record of accredited researchers and their projects is published on the UK Statistics Authority website to ensure transparency of access to research data. For further information about accreditation, contact Research.Support{at}ons.gov.uk or visit the SRS website.

Unlike bacteria, viruses must use host cells to replicate. This has enabled us to identify the Achilles heel of many viruses. We want to exploit this knowledge for the therapeutic targeting of current major human pathogens, such as coronaviruses and influenza for which there is a great unmet need. The orally available small molecule broad-spectrum antiviral compounds we have developed over many years target the host1Alonzi DS Scott KA Dwek RA Zitzmann N Iminosugar antivirals: the therapeutic sweet spot.Biochem Soc Trans. 2017; 45: 571-582Crossref PubMed Scopus (59) Google Scholar and are thus resistant to viral mutations. Host-targeting drugs can also be employed against newly emerging viruses even before detailed information about the virus becomes available.2Dwek RA Butters TD Platt FM Zitzmann N Targeting glycosylation as a therapeutic approach.Nat Rev Drug Discov. 2002; 1: 65-75Crossref PubMed Scopus (401) Google Scholar, 3Pieren M Galli C Denzel A Molinari M The use of calnexin and calreticulin by cellular and viral glycoproteins.J Biol Chem. 2005; 280: 28265-28271Summary Full Text Full Text PDF PubMed Scopus (56) Google Scholar This will be crucial in preventing the inevitable new epidemics from turning into pandemics. Most enveloped viruses need to use a sugar-mediated pathway in the infected human host cell to form their correct three-dimensional structures, which involves adding and processing glycans on viral envelope glycoproteins.2Dwek RA Butters TD Platt FM Zitzmann N Targeting glycosylation as a therapeutic approach.Nat Rev Drug Discov. 2002; 1: 65-75Crossref PubMed Scopus (401) Google Scholar, 3Pieren M Galli C Denzel A Molinari M The use of calnexin and calreticulin by cellular and viral glycoproteins.J Biol Chem. 2005; 280: 28265-28271Summary Full Text Full Text PDF PubMed Scopus (56) Google Scholar The glycosylation process involves enzymes in the cell trimming the sugars of the viral glycoproteins for entry into this protein folding quality control pathway. Drugs that partially inhibit these enzymes prevent the virus from making proper use of this folding pathway and lead to inhibition of secretion of infectious virus.4Block TM Lu X Mehta AS et al.Treatment of chronic hepadnavirus infection in a woodchuck animal model with an inhibitor of protein folding and trafficking.Nat Med. 1998; 4: 610-614Crossref PubMed Scopus (0) Google Scholar, 5Woodhouse SD Smith C Michelet M et al.Iminosugars in combination with interferon and ribavirin permanently eradicate noncytopathic bovine viral diarrhea virus from persistently infected cells.Antimicrob Agents Chemother. 2008; 52: 1820-1828Crossref PubMed Scopus (17) Google Scholar, 6Block TM Lu X Platt FM et al.Secretion of human hepatitis B virus is inhibited by the imino sugar N-butyldeoxynojirimycin.Proc Natl Acad Sci USA. 1994; 91: 2235-2239Crossref PubMed Google Scholar, 7Warfield KL Plummer EM Sayce AC et al.Inhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by the iminosugar UV-4.Antiviral Res. 2016; 129: 93-98Crossref PubMed Scopus (40) Google Scholar, 8Warfield KL Alonzi DS Hill JC et al.Targeting endoplasmic reticulum α-glucosidase I with a single-dose iminosugar treatment protects against lethal influenza and dengue virus infections.J Med Chem. 2020; 63: 4205-4214Crossref PubMed Scopus (21) Google Scholar Over the past 25 years, we have developed a class of drugs called iminosugars—orally available sugar mimetics that are recognised by and inhibit these sugar processing enzymes that most enveloped viruses rely on.1Alonzi DS Scott KA Dwek RA Zitzmann N Iminosugar antivirals: the therapeutic sweet spot.Biochem Soc Trans. 2017; 45: 571-582Crossref PubMed Scopus (59) Google Scholar The family of iminosugars derive from the parent compound initially isolated from the leaves of the mulberry tree. Safety and efficacy data in animals accumulated over the past 20 years show that iminosugar derivatives reduce viral levels and increase survival in animal models of chronic hepatitis B infection,6Block TM Lu X Platt FM et al.Secretion of human hepatitis B virus is inhibited by the imino sugar N-butyldeoxynojirimycin.Proc Natl Acad Sci USA. 1994; 91: 2235-2239Crossref PubMed Google Scholar hepatitis C, Japanese encephalitis, influenza,9Warfield K Barnard D Enterlein S et al.The iminosugar UV-4 is a broad inhibitor of influenza A and B viruses ex vivo and in mice.Viruses. 2016; 8: 71Crossref PubMed Scopus (25) Google Scholar and dengue.7Warfield KL Plummer EM Sayce AC et al.Inhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by the iminosugar UV-4.Antiviral Res. 2016; 129: 93-98Crossref PubMed Scopus (40) Google Scholar, 8Warfield KL Alonzi DS Hill JC et al.Targeting endoplasmic reticulum α-glucosidase I with a single-dose iminosugar treatment protects against lethal influenza and dengue virus infections.J Med Chem. 2020; 63: 4205-4214Crossref PubMed Scopus (21) Google Scholar When tested in vitro against over 31 clinical HIV isolates, including HIV-1, HIV-2, and multidrug resistant strains, iminosugars are active against a diverse panel of HIV-1 from different genetic subtypes and geographical regions, and against HIV-2 isolates and mutants resistant to antiretrovirals.10Pollock S Dwek RA Burton DR Zitzmann N N-Butyldeoxynojirimycin is a broadly effective anti-HIV therapy significantly enhanced by targeted liposome delivery.AIDS. 2008; 22: 1961-1969Crossref PubMed Scopus (55) Google Scholar All HIV isolates tested were rendered non-infectious by iminosugar treatment. Similarly, we have shown that iminosugars work against all hepatitis C genotypes tested and all four main dengue serotypes in vitro.7Warfield KL Plummer EM Sayce AC et al.Inhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by the iminosugar UV-4.Antiviral Res. 2016; 129: 93-98Crossref PubMed Scopus (40) Google Scholar When in-vitro testing against SARS-CoV-2 became possible, we showed that, as predicted, iminosugars are also antiviral against this virus.11Oxford Antiviral Drug Discovery UnitSARS CoV-2 Cellular Tracker: Zitzmann lab.http://sarscov2.assaytracker.net/Date: July 9, 2021Date accessed: March 3, 2022Google Scholar, 12Franco EJ Warfield KL Brown AN UV-4B potently inhibits replication of multiple SARS-CoV-2 strains in clinically relevant human cell lines.Front Biosci (Landmark Ed). 2022; 27: 3Crossref PubMed Scopus (1) Google Scholar As the drug target is not under the genetic control of the virus, the virus cannot mutate around it as readily, or at all. The iminosugars will also be antiviral against all variants of this coronavirus, including those for which vaccines are not yet available, and any mutants that might arise naturally or in response to direct acting antiviral drugs, such as protease inhibitors (eg, Paxlovid) and polymerase inhibitors (eg, molnupiravir). We have data (NCT0269629; NCT02061358) that show that iminosugars could be administered at comparably low concentration three times daily for 7 days—ie, as long as required in an acute infection. This dosing regimen affects mainly ER glucosidase II and leads to antiviral effects. In a 2020 study, we made the discovery that a single higher dose of the iminosugar prevents death in mice infected with lethal doses of influenza or dengue virus even if administered days after infection, and that protection correlates with inhibition of ER glucosidase I.8Warfield KL Alonzi DS Hill JC et al.Targeting endoplasmic reticulum α-glucosidase I with a single-dose iminosugar treatment protects against lethal influenza and dengue virus infections.J Med Chem. 2020; 63: 4205-4214Crossref PubMed Scopus (21) Google Scholar This shifts attention to the latter enzyme as a broad-spectrum antiviral target for an oral drug that could be administered after infection in a single-dose manner. This would be particularly useful in pandemic settings, and in poorer countries. Support for using ER glucosidase I as a broad-spectrum antiviral target comes from a study13Sadat MA Moir S Chun T-W et al.Glycosylation, hypogammaglobulinemia, and resistance to viral infections.N Engl J Med. 2014; 370: 1615-1625Crossref PubMed Scopus (84) Google Scholar that identified two siblings with a deficiency of ER glucosidase l, which is targeted by the single high-dose approach. Despite significant hypogammaglobulinaemia, the children had no history of viral disease and were not able to generate immune responses to live viral vaccines. The investigators concluded that there is a strong potential benefit of using inhibitors of glucosidase l as a means of controlling viral infections, especially those that pose a threat of rapid global spreading. But there is no need for complete inhibition of glucosidase I for therapeutic benefit. We believe that the gravity of the pandemic urgently demands us to try so-called off the beaten track host-targeting antivirals rather than only the current direct acting antiviral approaches. The use of host-targeting antivirals is supported by encouraging animal and human toxicity data and could provide a broad-spectrum oral antiviral that is mutation-proof. We believe that the higher single-dose regimen (at most, two single doses) should be recommended for global ease of use. We want to initially clinically use the generically available potent iminosugar, MON-DNJ (NCT0269629), used in the above high-dose approach studies, for which some phase 1 data are available. The less potent, but generically approved, orally available iminosugar miglustat,14Fischl MA Resnick L Coombs R et al.The safety and efficacy of combination N-butyl-deoxynojirimycin (SC-48334) and zidovudine in patients with HIV-1 infection and 200-500 CD4 cells/mm3.J Acquir Immune Defic Syndr. 1994; 7: 139-147PubMed Google Scholar could be used at a single high dose to target coronaviruses and influenza as proof of principle. HIV patients have been given high doses of miglustat in a combination trial.14Fischl MA Resnick L Coombs R et al.The safety and efficacy of combination N-butyl-deoxynojirimycin (SC-48334) and zidovudine in patients with HIV-1 infection and 200-500 CD4 cells/mm3.J Acquir Immune Defic Syndr. 1994; 7: 139-147PubMed Google Scholar The safety of miglustat at lower concentrations is well documented in its routine use in Gaucher's disease for over 20 years.15Cox T Lachmann R Hollak C et al.Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis.Lancet. 2000; 355: 1481-1485Summary Full Text Full Text PDF PubMed Google Scholar All currently available data make a clinical trial of this novel concept feasible and hence an imperative for promoting public health. This could be a transformational approach. Broad-spectrum, safe orally available antivirals are desperately needed worldwide, not only to help terminate this pandemic but to prevent the next one. This approach urgently needs support to further evaluate its promise to fill a major unmet need. RAD and NZ report funding for the research from Oxford Glycobiology Endowment. JIB and MF declare no competing interests.

The effectiveness of COVID-19 vaccination in preventing new SARS-CoV-2 infections in the general community is still unclear. Here, we used the Office for National Statistics (ONS) COVID-19 Infection Survey, a large community-based survey of individuals living in randomly selected private households across the UK, to assess the effectiveness of BNT162b2 (Pfizer-BioNTech) and ChAdOx1 nCoV-19 (Oxford-AstraZeneca; ChAdOx1) vaccines against any new SARS-CoV-2 PCR-positive tests, split according to self-reported symptoms, cycle threshold value (<30 versus ≥30) as a surrogate for viral load, and gene positivity pattern (compatible with B.1.1.7 or not). Using 1,945,071 RT-PCR results from nose and throat swabs taken from 383,812 participants between 1 December 2020 and 8 May 2021, we found that vaccination with the ChAdOx1 or BNT162b2 vaccines already reduced SARS-CoV-2 infections ≥21 days after the first dose (61%, 95% CI 54 to 68% versus 66%, 95% CI 60 to 71%, respectively) with greater reductions observed after a second dose (79%, 95% CI 65 to 88% versus 80%, 95% CI 73 to 85%, respectively). Largest reductions were observed for symptomatic infections and/or infections with a higher viral burden. Overall, COVID-19 vaccination reduced the number of new SARS-CoV-2 infections, with the largest benefit received after two vaccinations and against symptomatic and high viral burden infections, and with no evidence of difference between the BNT162b2 and ChAdOx1 vaccines.