The endemic circulation of pathogenic viruses is a major concern worldwide. Among these, foot and mouth disease viruses (FMDV) cause widespread, periodic outbreaks with substantial economic, health and wellbeing impacts. As this virus readily moves between wild and agricultural animals in Africa and other regions of the world, it provides a compelling example of One Health, the shared health connections between animals, humans and the environment. With FMDV, the constant genetic change of the virus (evolutionary variability) provides a driving force for endemic circulation and a challenge to effective responses.
South Africa has been in the grip of an FMDV outbreak since 2020, when there was just one serotype in one province, to five serotypes across all the provinces, as well as in Lesotho and Eswatini in 2026. As of mid-2026, nearly 25 000 cases were reported, causing substantial lost revenue for the country.
Brian G. Fox, who presented the second public lecture of the semester, illustrated the basic biochemistry of the FMDV viral lifecycle, the efficiency and elegance of how the virus assembles its working parts from one long protein chain (viral polyprotein maturation), the stunning symmetry and stability of its protective outer shell (capsid), and the ability of the virus to hijack the host’s own cells to cause damage.
He explained how vaccines work and the possible logistical and technological approaches to improved diagnosis and prevention, including an overview of newly emerging, powerful messenger RNA approaches to produce vaccines. He also considered the societal context and regulatory landscape of moving from gene to vaccine and from lab to public use, with some nuggets of advice specific to the FMDV outbreak in South Africa.
Fox has a BA in Chemistry from Carleton College, Northfield, Minnesota, and a PhD in Biochemistry from the University of Minnesota. He is the Vilas Distinguished Achievement Professor at the University of Wisconsin–Madison, USA. His current research focuses on the structure and mechanism of enzymes that catalyse difficult reactions, and adapting enzymes and bacteria to produce ingredients used in pharmaceuticals, synthetic fibres, and biodegradable plastics from renewable materials. His work has been patented by the Wisconsin Alumni Research Foundation and made available to the public.
Fox co-led a multi-investigator team that founded the UW-Madison Center for Eukaryotic Structural Genomics. As part of the US National Institutes of Health Protein Structure Initiative, this work laid the foundation for computational determination of protein three-dimensional structures. He is also a leader in the enzymatic deconstruction of plant biomass and a research contributor to the US Department of Energy-funded Great Lakes Bioenergy Research Center. He has held several senior leadership roles including Associate Vice Chancellor for Research Policy and Integrity, chair of the Department of Biochemistry, and director of the NIH-funded Biotechnology Training Program at the University of Wisconsin-Madison. He has a long history of fostering cross-continental student exchanges for educational collaborations and translational research in South Africa.
Tiny and deadly
“Viruses are minuscule (ranging in size from 20 to 300 nanometres in diameter) but deadly, with huge implications for human and animal life,” he said. “A human is a billion times smaller than the sun; FMDV is another billion times smaller than a human. The first plants on Earth were 400 000 years ago, first dinosaurs 130 000, but cells can divide in four hours, proteins can arrange in seconds, drugs bind and release in milliseconds, and molecules vibrate at a billion times per second. These time and size scales are almost incomprehensible.”
“Viruses are a small set of genes that hijack the living part of a cell to copy themselves”, he added. “It is simple, elegant and deadly with the sole purpose of reproducing.”
“The central dogma of biology is that all life depends on the genome – DNA transcribes to mRNA, then to amino acids, polypeptides and proteins which create hair, nails, etc,” he continued. “FMDV has no DNA – it’s a positive-strand RNA virus with about 8500 nucleotides (humans have about 309 000 000). Because it has no DNA, it has jumped one layer of simplicity.”
“The viral capsid is amazing and fascinating. It’s able to self-assemble into a triangle shape and from there to a pentamer and then a dodecahedron. This is all spontaneous, driven by physical forces, with no life energy needed.”
Fox then turned to the body’s response, explaining that we have both an innate and adaptive immune system response, with the innate acting first and attaching, engulfing and digesting pathogens and displaying the pieces back out. In the adaptive response, the aim is for a vaccine to cause the naïve B cells, with help from T cells and CD4 proteins, to learn to also engulf and destroy the viral cells and for memory cells to remember how to do this for future encounters.
He also explained the different types of vaccines. In attenuated vaccines, an active, infective virus is prepared in large amounts; the virus is weakened, not dead; and it usually gives a strong, protective response. There are many successful examples, including the oral polio virus, MMR, yellow fever and varicella. Inactive vaccines use large amounts of inactive viral particles and can be active, then inactivated or intentionally inactive. Such vaccines usually give good neutralisation; however, they often have a weak memory response, so boosters are usually needed. Successful examples include injected polio vaccine, influenza, pertussis, hepatitis A, rabies, the Covaxin COVID-19 vaccine and FMDV.
Lastly, the overall steps for producing synthetic vaccines comprise in vitro transcription of DNA to mRNA; recombinant protein expression, which converts to protein antigens; and tissue culture to produce the antibodies to neutralise antigens. Various combinations of these are used to produce new vaccines on a more rapid development cycle than previously possible.
“Synthetic systems need to be robust and automatic,” said Fox. “They are based on long-standing technologies and reflect the need to move away from living systems to lower-risk options. Modified nucleosides are being used to increase stability and potency, allowing a new wave of technology that is proving effective.”
FMDV-specific challenges
But if there are successful FMDV vaccines – and, in fact, South Africa started rolling out a locally manufactured one this year – how come the outbreak is still progressing?
Fox pointed out that viral mutations are a problem – “FMDV mutates a lot – it makes errors when copying itself. On average, each FMDV particle has 10 mutations.” Such mutations can mean that a vaccine developed for one strain of the virus is not as effective against another.
Also, the outbreak in South Africa covers a large area – “at least 1.8 million square kms”, making it hard to roll out vaccination programmes, and the animal herd sizes are huge “with approximately 40 million agricultural animals and potentially another half a million wild animals”.
“Over time the virus is spreading, moving and changing its nature all in real time.”
Fox therefore offered some of his thoughts on the local needs and capacity.
At an institutional level, he noted the need to promote public-private partnerships; account for cultural/economic variations to build a collective will to succeed; develop clear lines of responsibility and a chain of command; and undertake regular review of best practice and performance.
At a logistical level, he highlighted the need to re-establish the perimeter and lost infrastructure; build a modern, data-driven early surveillance network; and align supply chains to ensure operations and timely response.
At a technical level he emphasised the importance of integrating surveillance with predictive modelling of the spread and the creation design of new vaccines; leveraging the growing local biotech base to create vaccines for Africa in Africa; and, involving the public and private sector to educate for capacity and understanding.
“There are many biotechnology opportunities,” he continued. “But all efforts must be guided by data from surveillance networks and predictive modelling. South Africa should use hybrid approaches to vaccine design (continuing with inactive capsid approaches; developing recombinant Trojan Horse capsids; and exploiting mRNA and in vitro approaches); and all phases of the viral life cycle need to be attacked (all protein interactions, protease functions, capsid and genome replication). There is a need to improve adjuvants to give thermal stability and memory, as well as to develop rapid, simple, stable and affordable diagnostic kits so that we know what’s here and what isn’t.”
“Different types of farming need to be accounted for, and we need to know the nature of the enemy by smart surveillance. South Africa needs a flexible, adaptive response not only customised to one problem. The country had the capacity to produce inactivated capsid vaccines – this needs to be restored first because this gives the ability to consider how to apply new technologies to fight others. The country needs to take more shots at the goal, make the early stages as quick and cheap as possible, lock down what you know how to do, and stabilise and keep it going.”
“We know from all the human and animal diseases we have tackled that worldwide vaccination depends on the will and desire of people to do something.”
Article: Michelle Galloway
Picture: Curt Ruiters, Quickclick Productions