COVID-19. Flu. AIDS. Pathogens like these have had a profound impact on our lives, whether it’s prolonging quarantine or causing annual pandemics that kill thousands of people every year. In response, we’ve developed vaccines against them. Still, how do modern vaccines work? And what’s next in the pipeline?
A history of vaccines
Vaccines have been around since at least the 18th century. One of the earliest instances of vaccination came from Edward Jenner, who observed that infection with smallpox could be prevented or lessened by exposure to cowpox. Later, using a weakened version of the infectious agent was found to give protection, as shown for rabies in the 1800s. This same technique has been used for the flu vaccine and is still used today. It was eventually found that vaccines cause our bodies to produce molecules called antibodies that bind target molecules on the infection, called antigens, which help prevent infection or control its spread. Later, scientists found that inactivating the agent could also yield an effective vaccine. Currently, we can also produce antigen structures artificially in a lab.
Despite all of these approaches to vaccines, we still face a major problem. The various variants of the COVID-19 virus, from Delta to Omicron, show that pathogens can evolve rapidly in response to vaccines. At the molecular level, the antigens that antibodies bind can change to evade our immune systems, effectively changing their form and making them look new to our bodies.
So what can we do? We can design vaccines from the ground up, taking into account what parts of the antibody targets don’t change over time. This has also been done for flu in an approach called COBRA, where the sequences of proteins from different variants are aligned together into a single, artificial protein sequence. This artificial protein theoretically contains invariable regions of its component strains that can elicit broadly effective antibodies. Therefore, when this artificial protein is used as a vaccine, it can protect against several variants, which would be great for highly mutable pathogens like flu, COVID-19, and HIV. To design these proteins, we need structural information about antigens, and which parts give the broadest and most effective protection.
How scientists look at the molecular targets of antibodies
Scientists can mix antibodies and antigens together and look at how they interact in a technique called X-ray crystallography. Here, proteins are mixed with chemicals that cause them to form crystals in a controlled manner. X-rays are then shot at these protein crystals, revealing a diffraction pattern that can be used to determine their molecular structure. The downside of this technique, however, is that it requires extensive screening of different chemical conditions that coax proteins into forming crystals.
More recently, a new technique to determine protein structures has emerged, called cryogenic electron microscopy, or cryo-EM. Here, proteins are purified in a solution, then cooled rapidly to roughly -200 degrees Celsius in fractions of seconds on a thin surface. This creates a thin layer of ice containing several molecules of proteins in a layer just a few protein molecules thick, which is imaged by an electron microscope. We can use the images to reconstruct a three-dimensional image of the protein. This approach has several advantages over X-ray crystallography. Cryo-EM keeps the protein in a state closer to what it might be in the body, takes less time to find ideal parameters, and uses less protein to get good-quality images.
The next generation of structure-based vaccines
In the field of structural biology, technological advances have driven the next generation of vaccines. Scientists have designed vaccines using invariable regions of pathogens that allow for a better immune response to pathogens like influenza and SARS-CoV-2, the virus responsible for COVID-19. This has been driven by structural analysis of which antibodies bind to which part of the protein, and how broadly they can be effective against diverse viruses. Relatively recently, groups have designed molecular scaffolds that present antigens in a way that elicits broad protection. In one example, self-assembling nanoparticles that present flu or COVID-19 antigens from various strains in an array broadened protection against a wide number of strains, whether for flu or COVID-19.
Vaccines have an extensive history, coming a long way from inactivating infectious agents to taking molecules from these agents, and now, to designing new molecules entirely that drive an effective immune response. As scientists’ methods continue to improve, we can get a better picture of how to keep one step ahead of the next pandemic, one structure at a time.
