By Professor Sir Dave Stuart FRS, Director of Life Sciences at Diamond Light Source and MRC Professor of Structural Biology at the University of Oxford.
Vaccines have saved 154 million lives in the last 50 years – that is up to as many as 5 million deaths prevented annually.
These inventions have facilitated a major decline in, now preventable, diseases like measles, polio or diphtheria and have also been critical in controlling disease outbreaks and reducing the growing threat of antimicrobial resistance.
Progress in the field has been remarkable, and one of the biggest game-changers in making vaccine development faster is more effective imaging.
Structural research tools have allowed scientists to understand how a vaccine achieves its desired mechanism of action – a crucial step for validating new candidates before they ever reach a syringe.
Despite this, continued investment into this research and efforts to close immunisation gaps are still needed to ensure that everyone, everywhere, can benefit from the protection that vaccines provide.
Vaccines simulate the infection generated by a pathogen, a disease-causing organism, to teach the immune system to recognise it without exposing the body to the full risks of disease.
Traditional vaccines contain either weakened, inactivated or small pieces of the pathogen, while some newer vaccines contain the genetic blueprint (DNA or RNA) of the pathogen and work by providing the genetic instructions for our cells to manufacture these pieces – usually proteins that sit on the pathogen’s surface.
When the immune system encounters one of these proteins, called antigens, it responds by producing antibodies, proteins that specifically bind to that antigen, to then neutralise it or flag it for destruction by other immune cells.
Crucially, this process also creates memory cells, which provide long-term immunity and enables the body to create a rapid, stronger defence if it encounters the pathogen in the future. Advances in structural imaging techniques have evolved to allow scientists to capture exactly whether antigens are acting as they should.
The power of light
The UK’s national synchrotron facility, Diamond Light Source, is powering some important advances in vaccine research. The machine accelerates electrons to near-light speeds generating light 10 billion times brighter than the Sun.
These bright beams of light are then directed off into individual laboratories known as beamlines. In each beamline, scientists use the light to study a vast range of samples at a molecular level, from new medicines and treatments for disease to innovative engineering and cutting-edge technology.
At the Diamond’s electron Bio-Imaging Centre (eBIC), scientists use state-of-the-art experimental equipment and expertise in the field of cryo-electron microscopy, for both single particle analysis and tomography.
Recent advances in cryogenic electron tomography (Cryo-ET) have enabled researchers to observe viruses and the cellular processes they trigger in the most native cell environments with near-atomic resolution.
Cryo-ET involves flash-freezing biological samples and imaging a series of tilted high-resolution, two-dimensional projection images using electron microscopy to reconstruct detailed three-dimensional volumes. This approach provides not only individual molecular structures, like proteins but at the cellular level it reveals interactions inside cells with unprecedented detail.
Diamond also houses a macromolecular crystallography (MX) science group, this technique allows the high-throughput screening of biological molecules in a crystal form. Diamond’s MX beamlines are among the most productive in the world – in fact, in 2024 they generated almost as many protein structure depositions to the Protein Data Bank as the American synchrotrons combined. Through automation, samples are queued, imaged, and analysed within days, which has improved the journey from discovery to design.
Another research area is soft X-ray tomography (cryoSXT) which uses the B24 beamline and enables cryo-imaging of cells and cell populations in 3D to a resolution of 25nm.
This can be complemented by super-resolution fluorescence structured illumination microscopy (cryoSIM) resulting in a cellular equivalent to a full-body CT scan. These beamlines have facilitated structural insights that have furthered our understanding of biological processes occurring during immunisation.
Uncovering vaccine insights
During the early stages of the COVID-19 pandemic, for example, cryo-ET studies conducted using Diamond’s facilities enabled researchers to rapidly verify the structure of the SARS-CoV-2 spike protein, a crucial antigen used in nearly all COVID-19 vaccine designs.
One of the critical insights gained through this high-resolution imaging was the importance of presenting the spike protein in its pre-fusion conformation – which facilitates the production of antibodies that are significantly more potent at neutralising the virus. The light source’s imaging capabilities contributed to the selection of vaccine candidates, such as Oxford-AstraZeneca’s, that could generate stronger, broader, and more durable protection.
But the beamlines’ capabilities extend far beyond COVID-19. They have played a vital role in uncovering how viruses like HIV-1 infiltrate host cells and continue to be utilised with other human and non-human pathogens like polio or foot-and-mouth disease virus (FMDV). Diseases like polio and foot-and-mouth persist, partly due to the limitations of vaccines made from live or inactivated viruses. Working with global partners, Diamond’s researchers have developed safer, structure-guided alternatives – such as a non-replicating polio virus produced in insect cells, or adaptable FMDV vaccines that don’t require live viruses. These advances promise faster, more secure responses to outbreaks in both human and animal health.
Global immunisation through data and collaboration
As our response to infectious diseases becomes more sophisticated, the convergence of imaging, artificial intelligence, and structural biology is redefining how we build vaccines. Scientists are already utilising machine learning and artificial intelligence to select regions of interest and capture the right images or to visualise the three-dimensional confirmation of the images’ proteins.
Diamond’s beamlines stand at the frontier of this effort through collaborations with synchrotrons across the world helping to further enable the kind of precise, real-time structural analysis that will be essential for rapidly responding to future outbreaks.
For example, as a key player in Instruct‑ERIC, a pan-European research infrastructure, Diamond facilitates collaboration between national centres and synchrotrons across the continent – including facilities in Hamburg, Grenoble, and Switzerland. These partnerships have led to major advances, from standardising sample mounting to enabling remote access and data sharing. International coordination makes it possible to move faster, scale up innovation, and reduce duplication – critical in global health emergencies.
Looking ahead, researchers are beginning to explore how imaging systems will be capable of visualising protein interactions in vivo, inside live whole cells or tissues, and scaling up current electron microscopy capabilities.
Current vaccines are the products of half a century of international science, sustained collaboration and innovation. As we look for the next generation of vaccines, structural insights provided by facilities like Diamond Light Source will continue to illuminate the path ahead.
