The SARS-CoV-2 pandemic: remaining uncertainties in our understanding of the epidemiology and transmission dynamics of the virus, and challenges to be overcome

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Abstract

Great progress has been made over the past 18 months in scientific understanding of the biology, epidemiology and pathogenesis of SARS-CoV-2. Extraordinary advances have been made in vaccine development and the execution of clinical trials of possible therapies. However, uncertainties remain, and this review assesses these in the context of virus transmission, epidemiology, control by social distancing measures and mass vaccination and the effect on all of these on emerging variants. We briefly review the current state of the global pandemic, focussing on what is, and what is not, well understood about the parameters that control viral transmission and make up the constituent parts of the basic reproductive number R ₀. Major areas of uncertainty include factors predisposing to asymptomatic infection, the population fraction that is asymptomatic, the infectiousness of asymptomatic compared to symptomatic individuals, the contribution of viral transmission of such individuals and what variables influence this. The duration of immunity post infection and post vaccination is also currently unknown, as is the phenotypic consequences of continual viral evolution and the emergence of many viral variants not just in one location, but globally, given the high connectivity between populations in the modern world. The pattern of spread of new variants is also examined. We review what can be learnt from contact tracing, household studies and whole-genome sequencing, regarding where people acquire infection, and how households are seeded with infection since they constitute a major location for viral transmission. We conclude by discussing the challenges to attaining herd immunity, given the uncertainty in the duration of vaccine-mediated immunity, the threat of continued evolution of the virus as demonstrated by the emergence and rapid spread of the Delta variant, and the logistics of vaccine manufacturing and delivery to achieve universal coverage worldwide. Significantly more support from higher income countries (HIC) is required in low- and middle-income countries over the coming year to ensure the creation of community-wide protection by mass vaccination is a global target, not one just for HIC. Unvaccinated populations create opportunities for viral evolution since the net rate of evolution is directly proportional to the number of cases occurring per unit of time. The unit for assessing success in achieving herd immunity is not any individual country, but the world.

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Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Fernando P Polack, Stephen J. Thomas, Nicholas R.E. Kitchin … (2023)

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. Methods In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. Results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. Conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)

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Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

Lindsey Baden, Hana El Sahly, Brandon Essink … (2020)

Abstract Background Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle–encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. Methods This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. Results The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. Conclusions The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)

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An interactive web-based dashboard to track COVID-19 in real time

Ensheng Dong, Hongru Du, Lauren Gardner (2020)

In December, 2019, a local outbreak of pneumonia of initially unknown cause was detected in Wuhan (Hubei, China), and was quickly determined to be caused by a novel coronavirus, 1 namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The outbreak has since spread to every province of mainland China as well as 27 other countries and regions, with more than 70 000 confirmed cases as of Feb 17, 2020. 2 In response to this ongoing public health emergency, we developed an online interactive dashboard, hosted by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University, Baltimore, MD, USA, to visualise and track reported cases of coronavirus disease 2019 (COVID-19) in real time. The dashboard, first shared publicly on Jan 22, illustrates the location and number of confirmed COVID-19 cases, deaths, and recoveries for all affected countries. It was developed to provide researchers, public health authorities, and the general public with a user-friendly tool to track the outbreak as it unfolds. All data collected and displayed are made freely available, initially through Google Sheets and now through a GitHub repository, along with the feature layers of the dashboard, which are now included in the Esri Living Atlas. The dashboard reports cases at the province level in China; at the city level in the USA, Australia, and Canada; and at the country level otherwise. During Jan 22–31, all data collection and processing were done manually, and updates were typically done twice a day, morning and night (US Eastern Time). As the outbreak evolved, the manual reporting process became unsustainable; therefore, on Feb 1, we adopted a semi-automated living data stream strategy. Our primary data source is DXY, an online platform run by members of the Chinese medical community, which aggregates local media and government reports to provide cumulative totals of COVID-19 cases in near real time at the province level in China and at the country level otherwise. Every 15 min, the cumulative case counts are updated from DXY for all provinces in China and for other affected countries and regions. For countries and regions outside mainland China (including Hong Kong, Macau, and Taiwan), we found DXY cumulative case counts to frequently lag behind other sources; we therefore manually update these case numbers throughout the day when new cases are identified. To identify new cases, we monitor various Twitter feeds, online news services, and direct communication sent through the dashboard. Before manually updating the dashboard, we confirm the case numbers with regional and local health departments, including the respective centres for disease control and prevention (CDC) of China, Taiwan, and Europe, the Hong Kong Department of Health, the Macau Government, and WHO, as well as city-level and state-level health authorities. For city-level case reports in the USA, Australia, and Canada, which we began reporting on Feb 1, we rely on the US CDC, the government of Canada, the Australian Government Department of Health, and various state or territory health authorities. All manual updates (for countries and regions outside mainland China) are coordinated by a team at Johns Hopkins University. The case data reported on the dashboard aligns with the daily Chinese CDC 3 and WHO situation reports 2 for within and outside of mainland China, respectively (figure ). Furthermore, the dashboard is particularly effective at capturing the timing of the first reported case of COVID-19 in new countries or regions (appendix). With the exception of Australia, Hong Kong, and Italy, the CSSE at Johns Hopkins University has reported newly infected countries ahead of WHO, with Hong Kong and Italy reported within hours of the corresponding WHO situation report. Figure Comparison of COVID-19 case reporting from different sources Daily cumulative case numbers (starting Jan 22, 2020) reported by the Johns Hopkins University Center for Systems Science and Engineering (CSSE), WHO situation reports, and the Chinese Center for Disease Control and Prevention (Chinese CDC) for within (A) and outside (B) mainland China. Given the popularity and impact of the dashboard to date, we plan to continue hosting and managing the tool throughout the entirety of the COVID-19 outbreak and to build out its capabilities to establish a standing tool to monitor and report on future outbreaks. We believe our efforts are crucial to help inform modelling efforts and control measures during the earliest stages of the outbreak.

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Author and article information

Contributors

Roy M. Anderson:

ORCID: http://orcid.org/0000-0002-9528-3175

Journal

Journal ID (nlm-ta): Interface Focus

Journal ID (iso-abbrev): Interface Focus

Journal ID (publisher-id): RSFS

Journal ID (hwp): royfocus

Title: Interface Focus

Publisher: The Royal Society

ISSN (Print): 2042-8898

ISSN (Electronic): 2042-8901

Publication date (Electronic, pub): October 12, 2021

Publication date (Electronic, collection): 6 December 2021

Publication date PMC-release: October 12, 2021

Volume: 11

Issue: 6 , Theme issue ‘COVID-19: science, history, culture and imagination’ organised by Roger Highfield

Electronic Location Identifier: 20210008

Affiliations

[ ¹ ] Department of Infectious Disease Epidemiology, Imperial College London, , London, UK

[ ² ] Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, , Oxford, UK

[ ³ ] Joint Universities Pandemic and Epidemiological Research (JUNIPER) consortium, University of Leicester, , Leicester, UK

[ ⁴ ] Department of Respiratory Sciences, University of Leicester, , Leicester, UK

Author notes

One contribution of 19 to a theme issue ‘ COVID-19: science, history, culture and imagination’.

Electronic supplementary material is available online at https://doi.org/10.6084/m9.figshare.c.5630639.

Author information

Roy M. Anderson http://orcid.org/0000-0002-9528-3175

Carolin Vegvari http://orcid.org/0000-0003-2018-011X

T. Déirdre Hollingsworth http://orcid.org/0000-0001-5962-4238

Li Pi http://orcid.org/0000-0001-7818-408X

Rosie Maddren http://orcid.org/0000-0001-9363-3103

Chi Wai Ng http://orcid.org/0000-0002-4378-2781

Rebecca F. Baggaley http://orcid.org/0000-0002-4688-3924

Article

Publisher ID: rsfs20210008

DOI: 10.1098/rsfs.2021.0008

PMC ID: 8504893

PubMed ID: 34956588

SO-VID: 8d4a2f78-b89b-454e-b0cb-7d16cb5ae7b4

License:

Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

History

Date accepted : September 14, 2021

Funding

Funded by: Wellcome Trust, http://dx.doi.org/10.13039/100004440;

Award ID: 204801/Z/16/Z

Funded by: Li Ka Shing Foundation, http://dx.doi.org/10.13039/100007421;

Award ID: MR/V028618/1

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The SARS-CoV-2 pandemic: remaining uncertainties in our understanding of the epidemiology and transmission dynamics of the virus, and challenges to be overcome

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Most cited references 123

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

An interactive web-based dashboard to track COVID-19 in real time

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