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Scientific Advisor & Emeritus director at Valladolid NIC (National Influenza Centre) Spain, School of Medicine, Avd Ramón y Cajal s/n 47005 Valladolid, Spain
European Society for Clinical Microbiology and Infectious Diseases, Basel, SwitzerlandDepartment of Molecular Medicine, The University of Pavia, Pavia, ItalyDepartment of Clinical, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
Previous pandemic experience informs COVID-19 vaccine development
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Vaccines using different platforms have been developed at unprecedented speed
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In a new emergency, vaccine backbones might be used swiftly with a novel antigen
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Active surveillance for emerging variants or new pathogens is essential
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Production of sufficient vaccine for all countries and ages remains a challenge
Abstract
Pandemic dynamics and health care responses are markedly different during the COVID-19 pandemic than in earlier outbreaks. Compared with established infectious disease such as influenza, we currently know relatively little about the origin, reservoir, cross-species transmission and evolution of SARS-CoV-2. Health care services, drug availability, laboratory testing, research capacity and global governance are more advanced than during 20th century pandemics, although COVID-19 has highlighted significant gaps. The risk of zoonotic transmission and an associated new pandemic is rising substantially. COVID-19 vaccine development has been done at unprecedented speed, with the usual sequential steps done in parallel. The pandemic has illustrated the feasibility of this approach and the benefits of a globally coordinated response and infrastructure. Some of the COVID-19 vaccines recently developed or currently in development might offer flexibility or sufficiently broad protection to swiftly respond to antigenic drift or emergence of new coronaviruses. Yet many challenges remain, including the large-scale production of sufficient quantity of vaccines, delivery of vaccines to all countries and ensuring vaccination of relevant age groups. This wide vaccine technology approach will be best employed in tandem with active surveillance for emerging variants or new pathogens using antigen mapping, metagenomics and next generation sequencing.
). This trend is expected to rise because of increased human–animal contact, climate change, land use changes, global population growth, and increased global interconnectedness (
Pandemics and epidemics have increased in frequency since the Middle Ages: bubonic plague (started 1347), smallpox (early 1500s), influenza 'Great Pandemic' (1833), cholera (1881), Spanish influenza (1918), Asian influenza (1957), hepatitis C (1960s), Hong Kong influenza (1968), Russian influenza (1977), human immunodeficiency virus (HIV, 1981), severe acute respiratory syndrome coronavirus (SARS-CoV-1, 2003), swine influenza (2009), Middle East respiratory syndrome coronavirus (MERS-CoV, 2012), West Africa Ebola virus (2013), chikungunya virus (2013), Zika virus (2015) and coronavirus disease 2019 (COVID-19) (SARS-CoV-2, 2019). Although the World Health Organization (WHO) includes coronavirus as a priority pathogen, until the COVID-19 pandemic, influenza was considered to be the most likely causal pathogen of the next significant pandemic, and modelling suggested an annual 1% chance of an influenza pandemic that would result in 6 million global deaths (Madhav et al., 2018).
The first difficulty in drawing lessons from previous influenza A pandemics is that the COVID-19 outbreak is the first and only pandemic caused by a coronavirus during the scientific era (
). The term pandemic has been used for approximately 40 years and was not widely adopted during the pandemic events of 1957 and 1968. It is more than 50 years since the occurrence of a pandemic with similar severity and extent to the current COVID-19 pandemic. Mortality in the 1957 Asian and 1968 Hong Kong influenza pandemics was comparable to that of COVID-19 so far (
), there is nothing similar for the surveillance of other diseases. In the current COVID-19 pandemic, surveillance has been implemented with the same tools used for influenza surveillance (
National Academies of Sciences, Engineering, Medicine Exploring lessons learned from a century of outbreaks: readiness for 2030: proceedings of a workshop.
National Academies Press (US),
Washington (DC)2019
). War-related factors might have promoted high transmission levels and hampered efforts to contain the pandemic (National Academies of Sciences et al., 2019). In the US, it was illegal to be critical of the government during the war (
National Academies of Sciences, Engineering, Medicine Exploring lessons learned from a century of outbreaks: readiness for 2030: proceedings of a workshop.
National Academies Press (US),
Washington (DC)2019
). The causal agent is now known to be influenza A/H1N1. Influenza A virus was first isolated only in 1933 by Smith, Andrewes and Laidlaw, followed by influenza B virus by Francis in 1936 (
In February 1957, a new reassorting A/H2N2 influenza strain (Asian influenza pandemic) emerged in the Yunnan Province of China, and rapidly spread globally (
First reported in July 1968, a new A/H3N2 pandemic strain (a reassortment of the Asian influenza strain with an avian influenza H3 subtype) resulted in the Hong Kong influenza pandemic (
). It was caused by an influenza A/H1N1 virus that had circulated worldwide during the 1950s, and mainly affected individuals younger than 25 years of age (
), a triple reassortment virus containing genes from classic swine influenza A viruses, North American lineage avian influenza viruses and human influenza A viruses (
). The Spanish influenza pandemic infected approximately 500 million people, roughly one-third of the world's population at the time, with mortality estimates of 20–100 million deaths worldwide (
National Academies of Sciences, Engineering, Medicine Exploring lessons learned from a century of outbreaks: readiness for 2030: proceedings of a workshop.
National Academies Press (US),
Washington (DC)2019
), but with wide differences; for example, mortality was high where populations were naive to influenza such as islands in Oceania (e.g. 22% in Western Samoa)(
). Age-specific death rates followed a W-shaped curve, with high death rates in the very young and the elderly (as observed with seasonal influenza), but with the addition of a third peak of deaths in adults 20–40 years of age (
), with most deaths occurring in people >65 years of age (CDC, 2019b). All-cause mortality rose by between 3.6% in Canada to 13.0% in England and Wales (
Global respiratory deaths from the 2009 A/H1N1 pandemic have been estimated at 123,000–203,000, approximately 10 times as high as the WHO's laboratory-confirmed count (
Pandemic responses: non-pharmaceutical interventions, treatments and vaccination
Mitigation efforts in the 1918 pandemic relied upon non-pharmaceutical interventions (NPI) such as wearing face masks, quarantines, restriction of activities and gatherings, closures of schools and churches (
National Academies of Sciences, Engineering, Medicine Exploring lessons learned from a century of outbreaks: readiness for 2030: proceedings of a workshop.
National Academies Press (US),
Washington (DC)2019
). Concurrent school closures and public gathering bans were the most commonly implemented interventions and resulted in a statistically significant reduction in excess pneumonia and influenza deaths (
The 1957 influenza pandemic was the first in which a previous vaccine was available; however, it took 6 months before it could be rolled out because the developers needed to adjust its formulation with the new pandemic strain. Only 30 million vaccine doses were distributed globally and inadequate coverage meant that vaccination had little impact on the pandemic (
School closures and other NPIs were implemented swiftly in Mexico after the outbreak of the 2009 A/H1N1 pandemic, followed by similar measures in many other countries (
World Health Organization. Report of the WHO pandemic influenza A(H1N1) vaccine deployment initiative. 2012. Available at: https://apps.who.int/iris/handle/10665/44795 (accessed March 2021).
). A month later, the WHO identified that the amount of vaccine that could be produced within a year would be substantially less than the 4.9 billion doses previously estimated (
World Health Organization. Report of the WHO pandemic influenza A(H1N1) vaccine deployment initiative. 2012. Available at: https://apps.who.int/iris/handle/10665/44795 (accessed March 2021).
Centers for Disease Control and Prevention Interim results: state-specific influenza A (H1N1) 2009 monovalent vaccination coverage – United States, October 2009–January 2010.
). The WHO Pandemic Influenza A(H1N1) Vaccine Deployment Initiative facilitated access to the pandemic vaccine in developing countries. However, demand from countries varied considerably and sufficient vaccine was delivered to provide coverage ranging from 0.4% to >100% of the population, with a median coverage of 9.9% (
World Health Organization. Report of the WHO pandemic influenza A(H1N1) vaccine deployment initiative. 2012. Available at: https://apps.who.int/iris/handle/10665/44795 (accessed March 2021).
It has been estimated that the Spanish influenza pandemic reduced per capita Gross Domestic Product (GDP) by 6% compared with an 8% reduction resulting from World War 1 (
The coronavirus and the great influenza epidemic: lessons from the “Spanish Flu” for the coronavirus’ potential effects on mortality and economic activity.
). An analysis of the post-1940 US population showed that unborn children at the time of the pandemic had lower educational attainment, income and socioeconomic status compared with other birth cohorts (
). A systematic review of the cost effectiveness of pandemic interventions concluded that, at a threshold of $45,000 per disability-adjusted life-year (DALY), hospital quarantine and vaccination were cost-effective options, but school closures and social distancing were not (
). Cost-effectiveness ratios for antivirals ranged from $350 to $3500 per DALY or quality-adjusted life-year (QALY) in lethal epidemics but were as high as $40,000 to $250,000 for less severe infections (
). There are four endemic coronaviruses that circulate widely in humans. These cause mainly upper and mild respiratory infections such as the common cold, but also less frequently result in more severe respiratory syndromes including pneumonia in vulnerable and immunocompromised hosts (
). There are a further two epidemic coronaviruses: MERS-CoV that produces epidemic outbreaks with short chains of transmission and without clear adaptation to spread widely in humans, and SARS-CoV-1 which has been eradicated by control measures. Both are Betacoronavirus, with MERS-CoV belonging to lineage C (subgenus merbecovirus from etymology “MER” “BEta” “COronavirus”) and SARS-CoV-1 belonging to lineage B (subgenus sarbecovirus “SARs” “BEta” “COronavirus”)(
). Bats or rodents are believed to be the original, natural hosts of all seven human coronaviruses, with cattle, camels, civets and mink implicated as probable intermediate hosts (
Hul V, Karlsson EA, Hassanin A, et al. A novel SARS-CoV-2 related coronavirus in bats from Cambodia. 2021. bioRxiv preprint doi: https://doi.org/10.1101/2021.01.26.428212
SARS-CoV-1 first emerged in China in November 2002 and spread to 26 countries, although most cases were concentrated in China, Taiwan, Hong Kong, Singapore and Toronto (Canada) (
). The outbreak was short-lived and was brought under control by July 2003, by which time it had resulted in 8098 cases and 774 deaths (case fatality rate 9.5%) (
). MERS-CoV emerged in 2012 in Saudi Arabia, but was never defined as having pandemic potential. So far, it has resulted in 2562 laboratory-confirmed cases and 881 deaths (case fatality rate 34.4%) (
World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV). MERS monthly summary, November 2019. Available at: https://www.who.int/emergencies/mers-cov/en/ (accessed October 2020).
). SARS-CoV-2 was first identified in Wuhan, China in December 2019 and has rapidly spread throughout the world. As of 21 March 2021, more than 123 million cases and 2.7 million deaths had been reported globally (Johns Hopkins University, 2020). The death rate per 100,000 population reported varies enormously over time and in different countries, probably because of different testing and reporting policies (Johns Hopkins University, 2020). A systematic review including data up to June 2020 has estimated the infection fatality rate of SARS-CoV-2 at 0.68% (range 0.09–1.60) (
Individual and community-based NPIs such as isolation, physical distancing, mask use, and closure of public places were widely implemented during the SARS 2003 outbreak, as were hospital isolation facilities and widespread use of personal protective equipment (
). SARS-CoV-1 viral loads in the lungs peaked at 6–11 days after the onset of illness and the number of secondary cases was substantially reduced if an infected individual could be isolated within four days of symptom appearance (
). New Zealand banned entry from China and mandated a strict quarantine for visitors very early, followed by a stringent national lockdown and extensive testing (
). A study concluded that the most effective measures were closure or restriction of places where people gather, including businesses, educational institutions, bars, restaurants, etc (
SARS-CoV-2 has spread at a massively higher rate than SARS-CoV-1. Several factors might account for this. Firstly, there was pre-epidemic circulation in the months before the initial outbreak, and the first major outbreak occurred at the time of a Chinese holiday in a city of over 11 million people that is also a large transport hub, facilitating early spread (
). Secondly, there is a marked difference in virus shedding between SARS-CoV-1 and MERS-CoV versus SARS-CoV-2. In the former two, the virus primarily replicates in the lower airways, but more in the upper airways in the latter (
). Peak viral loads in nasopharyngeal aspirates of SARS-CoV-1 occur 6–11 days after symptom onset; in contrast, viral loads of SARS-CoV-2 peak during the first few days of infection, including before the patient becomes symptomatic.(
Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study.
). The “serial interval” provides an estimate of the time from symptom onset in a primary case to symptom onset in a secondary case. This has been estimated at 8.4 days for SARS-CoV-1, but only 4.0 days for SARS-CoV-2 (
). A third factor is the very high transmissibility of SARS-CoV-2. The basic reproduction number, R0, of SARS-CoV-2 was estimated in the European Union at 0.91–6.33 at the beginning of the outbreak, with a mean of 4.22 (
Linka K, Peirlinck M, Kuhl E. The reproduction number of COVID-19 and its correlation with public health interventions. medRxiv: the preprint server for health sciences 2020. doi: 10.1101/2020.05.01.20088047.
). In contrast, the R0 values for MERS-CoV and SARS-CoV-1 were estimated at 0.6–0.7 and 2–4, respectively, before mitigation measures were put in place (
World Health Organization. Consensus document on the epidemiology of severe acute respiratory syndrome (SARS). 2003. Available at: https://www.who.int/csr/sars/WHOconsensus.pdf?ua=1 (accessed October 2020).
The present situation differs significantly from that of 1918. In 2021, we have substantially improved health care and no intense combat or world war. We also have in place the WHO, other international governance mechanisms and the Global Health Security Agenda (GHSA) (
National Academies of Sciences, Engineering, Medicine Exploring lessons learned from a century of outbreaks: readiness for 2030: proceedings of a workshop.
National Academies Press (US),
Washington (DC)2019
). In this section, we review the current situation with regard to likely pandemic dynamics and health care responses. We discuss the role of new vaccine technology later in the paper.
Risk of zoonotic transmission
The COVID-19 pandemic has led to increasingly urgent calls to change how humans impact on the environment (
Settele J, Diaz S, Brondizio E, et al. COVID-19 stimulus measures must save lives, protect livelihoods, and safeguard nature to reduce the risk of future pandemics. IBPES Expert Guest Article, 2020. Available at: https://ipbes.net/covid19stimulus (accessed October 2020).
). Land use change, climate change, mining, urbanisation, population growth, wild animal markets and modern human-animal interactions, travel and globalisation all act to bring humans into closer contact both with each other and with animals that host novel pathogens (
Settele J, Diaz S, Brondizio E, et al. COVID-19 stimulus measures must save lives, protect livelihoods, and safeguard nature to reduce the risk of future pandemics. IBPES Expert Guest Article, 2020. Available at: https://ipbes.net/covid19stimulus (accessed October 2020).
). A study of EIDs between 1940 and 2004 showed that human population density was an independent predictor of zoonotic EIDs and wildlife host species richness was an additional predictor of zoonotic EIDs of wildlife origin (
). Another study showed that in areas with substantial human activity, wildlife that hosts pathogens shared with humans comprised a higher proportion of local species compared with nearby undisturbed areas (
The One Health initiative is a collaborative, transdisciplinary approach with focus on the interconnection between people, animals, plants and their shared environment (Figure 1) (
). PREDICT, part of USAID's Emerging Pandemic Threats programme, was established in 2009 to conduct and build capacity for surveillance for zoonotic pathogens with pandemic potential (
). The related Global Virome Project has the ambitious goal of detecting the majority of zoonotic viral threats to human health and food security within 10 years (
) but it is too early to predict whether regular reformulation of COVID vaccines will be necessary. The recent emergence and rapid spread in different parts of the world of SARS-CoV-2 virus variants that harbour point mutations in the spike protein is a matter of concern (
Tegally H, Wilkinson E, Giovanetti M, et al. Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. 2021. Available at: https://www.medrxiv.org/content/10.1101/2020.12.21.20248640v1 (accessed February 2021).
Greaney A, Loes A, Crawford K, et al. Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies. bioRxiv: the preprint server for biology 2021. doi: 10.1101/2020.12.31.425021.
). Vaccination will progressively increase the population's immunity against the virus but might also contribute to the selection of some specific escape mutants (
Centers for Disease Control and Prevention Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1) – United States, May–August 2009.
). A recent systematic review of patients with confirmed COVID-19 found that bacterial co-infection was identified in 3.5% of patients and secondary bacterial infection in 14.3%; however, 71.9% received treatment with antibiotics (
). The WHO considers antimicrobial resistance as one of the top 10 threats to global health (World Health Organization).
Antivirals are likely to be of significant benefit in reducing morbidity and mortality and are the only specific intervention available before a vaccine is developed, however supplies are limited (
). Traditional antivirals used in influenza infection are the adamantane derivatives, amantadine and rimantadine, and the neuraminidase inhibitors, oseltamivir, zanamivir, peramivir and laninamivir (
). A Cochrane review and meta-analysis found that oseltamivir reduced the time to symptom alleviation, although it was not possible to determine whether serious influenza complications such as pneumonia were reduced (
Baloxavir marboxil is a new drug against influenza virus targeting the endonuclease function of the viral PA polymerase subunit. It has been licensed in Japan and the US since 2018 and acts by inhibiting viral replication without cytotoxicity (
). It has been shown to be as effective as oseltamivir at alleviating symptoms of uncomplicated influenza and is also effective at preventing influenza infection among household contacts (
Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial.
Several monoclonal antibodies against the conserved stalk region of the influenza A haemagglutinin (HA) protein are in development and have demonstrated antiviral activity in phase 2 trials (
Safety and efficacy of monoclonal antibody VIS410 in adults with uncomplicated influenza A infection: results from a randomized, double-blind, phase-2, placebo-controlled study.
Phase 2 randomized trial of the safety and efficacy of MHAA4549A, a broadly neutralizing monoclonal antibody, in a human influenza A virus challenge model.
The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis.
Numerous drugs are being evaluated for the treatment of COVID-19. As of March 2021, the Milken Institute listed over 300 new or repurposed drugs being investigated (
). The WHO SOLIDARITY trial evaluated four repurposed drugs: remdesivir, hydroxychloroquine, lopinavir-ritonavir fixed dose combination and interferon-β1a in patients hospitalised for COVID-19 (
). The CoDEX randomised trial showed a significant increase in the number of ventilator-free days with dexamethasone compared with standard care, although there was no significant difference in all-cause mortality (
Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial.
). The RECOVERY trial showed a significant mortality benefit with dexamethasone versus standard care in patients receiving ventilator support or oxygen, but not in patients receiving no respiratory support (
). A number of neutralising monoclonal antibodies are in development for the treatment of patients with mild to moderate disease who are at high risk of progression to severe disease, with promising results (
National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2021. Available from: https://www.covid19treatmentguidelines.nih.gov/ (accessed 31 August). Accessed September 2021.
National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2021. Available from: https://www.covid19treatmentguidelines.nih.gov/ (accessed 31 August). Accessed September 2021.
). Dexamethasone or other systemic corticosteroids are widely recommended in hospitalised patients receiving supplemental oxygen or mechanical ventilation, with the possible additional of remdesivir, baricitinib or tocilizumab (
National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2021. Available from: https://www.covid19treatmentguidelines.nih.gov/ (accessed 31 August). Accessed September 2021.
National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. 2021. Available from: https://www.covid19treatmentguidelines.nih.gov/ (accessed 31 August). Accessed September 2021.
Even though effective vaccines against COVID-19 are now available, it is still unclear how widely accepted they will be by the public. Vaccine hesitancy has become a significant barrier to uptake (
), often fuelled by social media. The Mott Poll Report in the US reported that only 68% of parents intended to have their children vaccinated against influenza in the 2020–21 season (
Multi-country studies of likely acceptance of COVID-19 vaccines have shown variation between countries. In a survey of 12 countries, likely vaccine acceptance ranged from 86% in China to 63% in the US and Sweden (
). A systematic review of survey studies from 33 countries found likely acceptance rates of over 90% in Ecuador, Malaysia, Indonesia and China, while the lowest acceptance rates were found in France (59%), US (57%), Poland (56%), Russia (55%), Italy (54%), Jordan (28%) and Kuwait (24%) (
). Another study found higher COVID-19 vaccine acceptance in 10 low- and middle-income countries in Asia, Africa and South America (80.3%) compared with Russia (30.4%) and the US (64.6%) (
). Among the low- and middle-income countries, vaccine acceptance ranged from 66.5% in Pakistan and Burkina Faso to 96.6% in Nepal.
Tracking pandemic death rates
Although there are multiple sources of data on the number of deaths caused by COVID-19, the true number is unknown. The statistics available from different countries can be substantially influenced by different definitions used; for example, some countries include only laboratory-confirmed COVID-19-related deaths, whilst others also include suspected deaths. Limited testing capacity in some countries, particularly in the developing world, can lead to considerable underestimation of the death rate. These issues can be avoided, at least to a degree, by calculation of the number of excess deaths, defined as the increase in all-cause mortality over the expected mortality based on historical data. This method has been used to estimate mortality in previous pandemics and seasonal influenza epidemics. Although it does not provide the exact mortality associated with the pandemic or epidemic, it is considered to provide an objective indicator (
The excess mortality resulting from the COVID-19 pandemic is being tracked by several groups. Data from the World Mortality Dataset, which tracks mortality in 103 countries, found the highest excess mortality per 100,000 population in Latin American and Eastern European countries: Peru (590), Bulgaria (460), North Macedonia (420), Serbia (400), Mexico (360), Ecuador (350), Lithuania (350) and Russia (340) (
). Some countries, including Uruguay, Australia and New Zealand, had negative excess mortality i.e. fewer deaths than expected. Similar results were obtained from other groups (
in: Jamison DT Gelband H Horton S Jha P Laxminarayan R Mock CN Nugent R Disease control priorities: improving health and reducing poverty. The International Bank for Reconstruction and Development /The World Bank,
Washington (DC)2017 Nov 27
). There is a broad recognition among stakeholders that health systems need to change post-COVID-19 to provide a better basis to manage future pandemics. Active debate is taking place regarding initiatives such as improving prevention and early care; strengthening health, public health and social services; integrating elements of global health security with universal health coverage; developing resilience in health care systems; applying equity as a basis for all health care systems; moving from reactive, short-term approaches to planning for longer-term outcomes; maximizing digital health care and information systems; rebuilding trust in governments and healthcare systems; enhancing high-value and eliminating low-value services; (
); at present, it is unknown whether this will impact upon effectiveness of COVID-19 vaccines. Obesity has become a serious health care concern, even in low- and middle-income countries, and is associated with increased risk for diseases such as cancer, diabetes and cardiovascular disease, as well as with a weaker immune system. Numerous studies have shown that obese patients with COVID-19 have a higher risk of severe disease outcomes and death, and the highest death rates have been seen in countries with the highest proportion of overweight individuals (
The genome of the SARS-CoV-2 virus was fully sequenced within a few weeks of identification of the first patients with unidentified pneumonia in China (
). The Global Initiative on Sharing All Influenza Data (GISAID) was launched in 2008 with the aim of sharing influenza genomic data, and the initiative played an important role in the response to the 2009 influenza A/H1N1 pandemic and now to the COVID-19 pandemic (
). As of March 2021, nearly one million SARS-CoV-2 genomic sequences have been made available via the GISAID platform. Genomic epidemiology combines genomics data with epidemiological investigations and is able to answer key questions about virus outbreaks more quickly than traditional epidemiological case tracking (
). For example, data from two cohort studies of influenza conducted by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) have been used to estimate the case fatality rate during the 2009 A/H1N1 influenza pandemic (
). The COVID-19 pandemic has illustrated how rapidly research can be shared, with extensive use of online journal publications and pre-print uploads.
The Coalition for Epidemic Preparedness Innovations (CEPI) was founded in 2017 as a public–private partnership to develop vaccines for future epidemics and enable equitable access to vaccines during outbreaks (
). During the COVID-19 pandemic, CEPI has formed the COVAX collaboration with the WHO and Gavi, the Vaccine Alliance; it aims to produce 2 billion SARS-CoV-2 vaccine doses for distribution in 2021 and is providing funding for the development of 11 vaccine candidates (
The International Health Regulations (IHR) 2005 are an international legal agreement between 196 countries, including all WHO Member States, whose implementation is coordinated by the WHO (
). The WHO also coordinates the Global Influenza Programme (GIP) with the aim of providing strategic guidance, technical support and coordination of activities to prepare health systems for seasonal, zoonotic and pandemic influenza threats (
). Activities include surveillance and monitoring via the Global Influenza Surveillance and Response System (GISRS) and platforms such as FluNet and FluID125. It also includes the Pandemic Influenza Preparedness Framework which came into effect in 2011 and whose goals are to improve sharing of influenza viruses with human pandemic potential and to increase access of developing countries to vaccines and other pandemic-related supplies (
World Health Organization. Pandemic influenza preparedness (PIP) framework. 2020d. Available at: https://www.who.int/influenza/pip/en/ (accessed October 2020).
). Under this framework, an advance supply contract with manufacturers, research institutes and other bodies ensures that the WHO receives supplies of vaccines and other products needed to respond to a pandemic.
A 2011 review of the IHR and the response to the 2009 A/H1N1 pandemic made three summary conclusions: (1) The IHR improved preparedness for public health emergencies, but capacities called for in the IHR were not fully operational nor on a path towards timely implementation; (2) The WHO performed well in many ways, confronted systemic difficulties and demonstrated some shortcomings; (3) The world is ill-prepared for a severe influenza pandemic or similar event (
World Health Organization. Strengthening response to pandemics and other public-health emergencies: report of the review committee on the functioning of the international health regulations (2005) and on Pandemic Influenza (H1N1) 2009. 2011. https://www.who.int/ihr/publications/RC_report/en/ (accessed October 2020).
). The review made a total of 15 recommendations, including to accelerate implementation of core capacities, reinforce evidence-based decisions on international travel and trade, develop and apply measures to assess severity, create a more extensive public health reserve workforce, reach agreement on sharing of viruses and access to vaccines and pursue a comprehensive influenza research programme (
World Health Organization. Strengthening response to pandemics and other public-health emergencies: report of the review committee on the functioning of the international health regulations (2005) and on Pandemic Influenza (H1N1) 2009. 2011. https://www.who.int/ihr/publications/RC_report/en/ (accessed October 2020).
Misinformation about COVID-19 has spread widely, particularly on, but not limited to, social media. Common misinformation has included erroneous health advice, such as self-injection with bleach and use of hydroxychloroquine, as well as conspiracy theories such as bioengineering of the SARS-CoV-2 virus and the role of 5G networks in spreading the virus (
Patterns of media use, strength of belief in COVID-19 conspiracy theories, and the prevention of COVID-19 From March to July 2020 in the United States: survey study.
). At the same time, the number of scientific papers has proliferated. Unfortunately, the quality of some of the papers is uncertain and the rate of retractions is higher than other related research topics (
The 2009 A/H1N1 pandemic, in which a vaccine did not become available until after the peak of the pandemic had passed, illustrates the problems associated with traditionally delivered influenza vaccines in the pandemic setting (
World Health Organization. Report of the WHO pandemic influenza A(H1N1) vaccine deployment initiative. 2012. Available at: https://apps.who.int/iris/handle/10665/44795 (accessed March 2021).
). A major problem is the difficulty in predicting which virus will cause the next pandemic and the use of vaccines based on influenza virus cultures in eggs. This method of manufacture cannot be upscaled quickly, in contrast to the adenovirus and RNA-based vaccines that have been developed against SARS-CoV-2. Because it was widely believed that the next pandemic would be caused by an influenza virus, significant effort has been invested in development of 'ready to go' pre-pandemic influenza vaccines (
National Academies of Sciences, Engineering, Medicine Exploring lessons learned from a century of outbreaks: readiness for 2030: proceedings of a workshop.
National Academies Press (US),
Washington (DC)2019
). As of October 2020, the WHO had identified 41 vaccine candidates against influenza A/H5 viruses, 22 candidates against influenza A/H7 viruses and eight candidates against influenza A/H9N2 virus (
National Academies of Sciences, Engineering, Medicine Exploring lessons learned from a century of outbreaks: readiness for 2030: proceedings of a workshop.
National Academies Press (US),
Washington (DC)2019
). Therefore, the focus in more recent years has changed towards development of vaccine platforms; the theory behind this approach is that any platform can be used to present any immunogen from any pathogen (
). In addition, for influenza vaccines, substantial work has been done towards development of a universal vaccine capable of eliciting a broad immune response against antigenically diverse influenza viruses (
Several vaccine platforms are available or under development (Figure 2). Whole virus vaccines include inactivated virus vaccines and live attenuated virus vaccines. Inactivated vaccines are widely used in licensed vaccines such as influenza, polio and hepatitis A (
Several live attenuated vaccines are also available, including oral polio vaccine, influenza vaccine, measles, mumps and rubella vaccine (MMR), and varicella (chickenpox) vaccine (
). Replicating or non-replicating viral vector vaccines use a viral backbone that is genetically engineered to express antigens from the target virus (
). Replicating viral vector vaccines use a weakened viral backbone such as measles; although they can still replicate within cells, they are unable to cause disease (
). High seroprevalence of neutralising antibodies against the vector was largely blamed for the failure of a human adenovirus-based HIV vaccine and the finding that study participants with high titres of anti-adenovirus antibodies were more susceptible to HIV infection than those without such antibodies (
). Licensed viral vector vaccines are available against Ebola, dengue fever and Japanese encephalitis, and the technology for large-scale production already exists (
). Virus-like particles (VLPs) comprise empty virus shells that contain no genetic material. Both subunit and VLP technologies are well established, but the vaccines can be poorly immunogenic and might require repeated administration or use of an adjuvant (
Nucleic acid vaccines (mRNA or DNA) use only genetic material from the target pathogen, inserted into human cells which then produce copies of the virus protein encoded by the genetic material, leading to acquired immunity (
). RNA vaccines use an RNA-containing vector, such as lipid nanoparticles, while DNA vaccines use a genetically engineered plasmid to deliver the genetic sequence to the cells. The vaccines are non-infectious, with advantages over other platforms in terms of safety, and are also easy to produce and scale up (
Development of vaccines against human coronaviruses
Immunological considerations
Studies have shown that SARS-CoV-1, SARS-CoV-2 and MERS-CoV efficiently suppress activation of the innate immune system, which might explain the long pre-symptomatic period observed with SARS-CoV-2 infection (
Identification of a receptor-binding domain in the S protein of the novel human coronavirus Middle East respiratory syndrome coronavirus as an essential target for vaccine development.
). Antibodies that bind to the S1 receptor binding domain of SARS-CoV-1 block its interaction with ACE2, while antibodies binding with other regions of S1 inhibit conformational changes of the S protein (
Generation and characterization of human monoclonal neutralizing antibodies with distinct binding and sequence features against SARS coronavirus using XenoMouse.
Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study.
), suggesting that this protein could also be a useful target for vaccine development. Currently, no immune correlate of protection has been identified for any of the coronaviruses.
T-cell mediated immunity is also an important element in COVID-19 vaccine design. A study of patients recovering from COVID-19 showed that SARS-CoV-2-specific CD4+ and CD8+ T-cells were detected in 100% and 70% of patients, respectively (
). Other studies have shown that T-cell activation is delayed in SARS-CoV-2 infection (as well as SARS-CoV-1 and MERS-CoV infection), particularly for CD8+ T-cells (
). Further evidence suggests that patients with less severe COVID-19 illness have higher levels of CD8+ memory T-cells compared with more severe cases (
Peng Y, Mentzer AJ, Liu G, et al. Broad and strong memory CD4 (+) and CD8 (+) T cells induced by SARS-CoV-2 in UK convalescent COVID-19 patients. 2020. bioRxiv 2020 8;2020.06.05.134551. doi: 10.1101/2020.06.05.134551.
Two types of vaccine-enhanced disease are currently recognised: antibody-dependent enhancement (ADE) and vaccine-associated enhanced respiratory disease (VAERD) (
). ADE is mediated by the Fc antibody portion, whereby a virus-antibody complex binds more efficiently to cells bearing an Fc receptor, facilitating virus entry to the cell (
Immunization with modified vaccinia virus Ankara-based recombinant vaccine against severe acute respiratory syndrome is associated with enhanced hepatitis in ferrets.
). In the RSV trial, it was observed that a high ratio of binding antibody to neutralising antibody could result in immune complex deposition and complement activation (
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