Preparing for a Pandemic: What Awaits After COVID-19?
Earlier this year, the World Health Organisation (WHO) declared COVID-19 to no longer constitute a public health emergency of international concern. Whilst this appears to officially mark the end of that pandemic, scientific communities generally agree that there will inevitably be another one. It is less clear, though, what the causal agent of the next pandemic will be.
In this insight, we will consider various candidate causal agents, with a focus on some of the RNA viruses of current concern, before exploring the technologies that may enable us to prepare for, and respond to, the next pandemic.
Viruses of ‘pandemic potential’
A pandemic is broadly defined as the spread of a disease around the globe. This is in contrast to an epidemic, where a disease is confined to a specific geographical area. All of the pandemics documented since 1918 have been linked to an RNA virus, and the ‘pandemic potential’ of many RNA viruses are of ongoing concern.
In the last 20 years, three deadly human-infecting coronaviruses have emerged, namely severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2.
So-called because of the solar corona-like appearance of the surface spike proteins, coronaviruses were once not considered threats to humans. The 10% case fatality rate of SARS-CoV-1, therefore, came as a surprise in the early 2000s. About a decade later, MERS-CoV emerged, exhibiting an astonishing case fatality rate of over 30%. Despite knowledge of these two deadly coronaviruses, the ‘pandemic potential’ of coronaviruses was not truly recognised until around another decade later with the emergence of SARS-CoV-2, the causal agent of COVID-19.
Compared to many other RNA viruses, coronaviruses mutate relatively slowly. However, certain mutations, when they do occur, can give rise to new variants that exhibit increased infectivity and/or immune escape. Many of these mutations localise to the spike protein, which is a structural component that enables viral entry into host cells. As the spike protein is also the primary target of many COVID-19 vaccines, spike mutations can lead to the emergence of new SARS-CoV-2 variants that are not only more infectious but also capable of evading existing vaccine-induced immunity.
Even known variants that are near-extinct in humans can persist in animal reservoirs and be reintroduced into human populations at a later date. In North America, SARS-CoV-2 variants that were last documented in humans in 2020 have been found in white-tailed deer well into 2022. The risk of reintroduction into humans could become especially high once the immunity of older people wanes and previously unexposed younger people form a larger proportion of the population.
Beyond SARS-CoV-2 variants, closely related, potentially more lethal, coronavirus species continue to circulate in animal reservoirs and could jump from non-human hosts to humans at any point.
In the influenza virus family, only influenza A viruses are known to cause pandemics. Influenza A viruses can be classified into subtypes and then clades. Subtype classification is based on the combination of two viral proteins: hemagglutinin (H, selected from H1 through to H18) and neuraminidase (N, selected from N1 through to N11). Subtype H1N1, for example, was responsible for the 1918 flu pandemic and the 2009 swine flu pandemic. Strains related to that which caused the swine flu pandemic still circulate in humans, contributing to seasonal flu epidemics.
Aside from human-adapted influenza A viruses, there has been considerable media attention on bird-adapted highly pathogenic avian influenza (HPAI) A viruses, in particular, HPAI A(H5N1). One clade of HPAI A(H5N1) that was first detected in wild birds along the Adriatic flyway in 2020 has now spread across multiple continents.
Coinciding with the global spread of HPAI A(H5N1) of this clade in birds, there have been an increasing number of reported cases in mammals. In late 2022, an outbreak occurred in farmed minks in Spain, causing haemorrhagic pneumonia and red hepatisation of the lungs. Earlier this year, nearly 3,500 infected sea lions were also found dead or dying along Peruvian coasts over five weeks. Clinical signs observed in dying sea lions include convulsions and paralysis. These outbreaks in minks and sea lions may represent the first HPAI A(H5N1) outbreaks to be driven by mammal-to-mammal transmission.
The increasing number of infections in mammals is concerning because the infections could provide opportunities for adaptation in mammalian hosts. As humans are more closely related to other mammals than to birds, these mammalian hosts are more likely than birds to transmit the virus to humans.
Certain practices continue to drive the emergence of new avian influenza viruses of ‘pandemic potential’, one such practice being intensive mink farming. Notably, minks are closely related to ferrets, which are the gold-standard experimental model for studying the airborne transmissibility of influenza viruses in humans. Moreover, although minks are mostly solitary in the wild, the crowded conditions in intensive farming provide unusual opportunities for minks to act as influenza virus mixing vessels. Indeed, influenza viruses possess multiple RNA segments. When a cell is co-infected with different influenza viruses, RNA segments derived from those viruses can be shuffled to generate progeny viruses with a novel combination of RNA segments. Should a mink be co-infected with a bird-adapted influenza virus capable of replicating efficiently in mammals and a human-adapted seasonal influenza virus, a viral progeny with genetic traits conferring efficient replication in, and selectivity for, human cells could arise. If the viral progeny is also capable of sustained human-to-human transmission, the result could be catastrophic, given that there is likely little to no existing immunity in general human populations.
Genetic markers of mammalian adaptation remain rare in HPAI A(H5N1) isolates, and there is yet to be any evidence of sustained human-to-human transmission of HPAI A(H5N1). Even so, in the last two decades, nearly 900 sporadic cases of HPAI A(H5N1) infection in humans have been reported, with a staggering case fatality rate of over 50%. Thus, there should be no room for complacency.
Spread predominantly through the bite of infected mosquitoes, Zika virus has long been assumed to cause no more than symptoms similar to those associated with mild forms of dengue fever. However, following outbreaks in the Americas and an epidemic beginning in 2015, an association was found between infection in pregnancy and infant microencephaly. In rare cases, infection in adults can lead to Guillain-Barré syndrome, which involves rapid-onset muscle weakness caused by the immune system damaging the peripheral nervous system.
The global distribution of the most cited carrier, the yellow fever mosquito, is presently more extensive than ever recorded, partially due to global trade and travel. A mosquito population capable of carrying Zika virus has even been found in Washington DC and may have survived at least four consecutive winters in the region according to genetic studies. Although Zika virus is largely confined to tropical areas, rising global temperatures and increased precipitation threaten to further expand the distribution of its main carrier. To date, no clinically approved vaccines against Zika virus are available.
Technologies for pandemic preparation
In previous pandemics, innovation in biomedicine and genomics has enabled not only the detection and characterisation of the causal agent but also the development of new vaccines and therapies. Innovation will similarly be essential for containing any future pandemics, whatever the causal agent may be.
For some, the term “vaccines” is almost synonymous with “pandemic preparedness”.
Vaccine platforms may be genetic (in the form of mRNA or DNA) or non-genetic (in the form of inactivated viruses, protein subunits or viral vectors). Non-genetic platforms are well established and in use against influenza virus strains that cause seasonal flu. Beyond these non-genetic platforms, the COVID-19 pandemic saw the clinical approval of mRNA vaccines for use in humans for the first time. As discussed in a previous insight, mRNA vaccines have many advantages over traditional vaccines; they can be simpler to produce and more easily modified for use against new viral strains or variants. Building upon years of prior RNA research, it only took Moderna around two months to go from obtaining the genomic sequence of SARS-CoV-2 to beginning phase I clinical trials of its mRNA-1273 vaccine. Moderna’s mRNA-1893 vaccine is now in phase II clinical trials and could be the first clinically approved vaccine against Zika virus.
DNA vaccines are also relatively simple to produce and modify, and may be similarly useful in a pandemic where the causal agent is constantly changing. It appears that DNA vaccines currently do not induce sufficient cellular and humoral immune responses in humans. Ongoing research in DNA codon optimisation, adjuvants, and electroporation will be necessary to overcome this hurdle.
Many developed countries have stockpiles of H5N1 vaccines. However, as viruses can change over time, it is impractical to stockpile millions of doses of vaccines against every known viral strain or variant. It is arguably better to develop vaccines that provide broad protection and update them when necessary.
This is where antigenic cartography comes in. Using data from virus samples, antigenic cartography can quantify and visualise antigenic differences between viruses. Specifically, in the process of updating seasonal flu vaccines, data is obtained by exposing ferrets to different influenza virus strains to raise an immune response. If the antibodies raised in response to a first strain (e.g. a strain targeted by a seasonal flu vaccine) can effectively neutralise a second strain (e.g. a new strain predicted to spread and cause illness in an upcoming flu season), then the first and second strains are considered antigenically similar and any flu vaccines protective against the first strain would be expected to be protective against the second. In contrast, if the antibodies cannot effectively neutralise the second strain, then flu vaccines protective against the first strain will need to be updated to provide protection against the second in the upcoming flu season.
Accordingly, antigenic data is useful for identifying whether a vaccine provides broad protection and when it needs updating. By further visualising the data using antigenic cartography, unassuming mutations that cause large antigenic differences can be revealed and long-term trends can be identified to improve our understanding of antigenic evolution.
The WHO has used antigenic cartography in the flu vaccine strain selection process for the last two decades. Antigenic cartography also played a part in the response to the COVID-19 pandemic and is often considered a core tool for pandemic preparedness.
The distribution of certain viral vectors, such as the yellow fever mosquito, is expanding. However, proof-of-concept studies have shown that populations of viral vectors can be controlled by introducing gene drives into the genome of these viral vectors using CRISPR-Cas9 technology.
Gene drives are genetic elements that reduce individual fitness but nonetheless are inherited at higher-than-expected frequencies. In one application, gene drives can be introduced to bias sex ratios, hence causing population decline and reducing vector-borne disease transmission. For instance, homing gene drives, which ‘home’ into a target genomic site, have been used to disrupt female fertility genes in germline cells of mosquitoes to achieve male bias and cause a population crash.
In theory, gene drives could spread indefinitely through a species. Societal consensus should, therefore, be reached through public engagement prior to the deployment of any gene drives into the wild. Ultimately, the potential ecological consequences of gene drives spreading beyond target populations and impacting wider ecosystems should be balanced against the potential benefits for public health.
Preparation to be in a better position
Pandemics are increasingly likely to happen in view of more frequent human-animal interactions and climate change. Beyond coronaviruses, influenza viruses and Zika virus, there is a plethora of other pathogens that could cause a major disease outbreak. The last few years have been testament to the importance of scientific ingenuity and innovation in mounting an effective response to a pandemic. However, the technologies that helped combat COVID-19 did not materialise overnight but were the culmination of years of research and preparation. Equally, it is the ongoing research and innovation of today that will put the world in a better position to respond to what is around the corner.
J A Kemp has expertise in a number of areas relevant to infectious diseases, including in Animal Health and Productivity, Antibodies and Biologics, Genomics, Immunology and Immunotherapy, Pharmaceuticals, and Vaccines and Virology.