How structural biology is informing vaccine design


Reece Armstrong speaks to Melanie Adams-Cioaba, Senior Director and General Manager of pharma (cryo-EM), Thermo Fisher Scientific about advances in vaccine design.

RA: How can rational design approaches help advance vaccine development?    

MA: Regarding vaccine development specifically, and the role my team plays in the development of cryogenic electron microscopy (cryo-EM) technology, we see the study and dissemination of virus structures, and the proteins that comprise them, as vital to vaccine design. Using structural biology as central to vaccine design and development, and to drug discovery more generally, is what we mean by “rational design.” Rational design approaches allow us to see and understand the virus structure in exquisite detail. We can also elucidate the structures of individual proteins from the virus/vaccine and study how the body’s immune system will likely respond to vaccination. This informed awareness of biological structure and function allows for enhanced information sharing with the general public, which we hope then translates to increased trust and reliability among those considering vaccination. 

Key to this is the ability to rapidly determine protein structures alone and in combination with antibodies or small molecules. For vaccine design, modern cryo-EM workflows allow researchers to quickly determine high resolution structures of relevant viral proteins, assess structure-function impact, and map binding for previously known broadly neutralising antibodies that are critical to vaccine design. New epitope mapping workflows, such as electron microscopy-based polyclonal epitope mapping (EMPEM), also allows researchers to directly define epitope specificity for serum-derived antibodies following vaccination of infection.

RA: How reliable are vaccines now for respiratory viruses such as flu?  

MA: Respiratory viruses represent a diverse group of pathogens. Regarding flu, annual vaccinations typically have a significant impact on reducing the burden of infection. For example, a 2023 study in the Journal of Infectious Disease estimated that the risk of flu-related emergency department and urgent care visits reduced by almost half, and hospitalisations reduced by more than a third among US adults during the 2022-2023 season because of vaccination.

For flu, however, we lack a universal vaccine that can provide long term protection. Instead, updated vaccinations are often required each year, especially for highly sensitive populations. Structural biology is playing an important role in the hunt for a universal vaccine. Researchers are using cryo-EM to understand the structure of the hemagglutinins (HAs), which are proteins on the surface of the influenzae virus. Combining these structures/images of the HAs with information on regions that change rapidly as viruses evolve, as well as imaging of how our immune system’s antibodies bind to these viral proteins, is allowing researchers to design next generation vaccines that are less susceptible to seasonal changes in the virus. 

RA: What advances have been made to improve the reliability of vaccines?  

MA: Foundationally, new vaccines and monoclonal antibody treatments benefit from protein structure determination efforts to visualise the viral antigen at high resolution, alone and in complex with a variety of antibodies. Today, advancements in cryo-EM hardware combined with workflow automation are allowing high resolution protein structures to be elucidated with ease. This allows researchers to quickly view, for example, how many different antibodies are binding to a vaccine or virus. 

In parallel, novel vaccine formats (mRNA vaccines, complex subunit vaccines, etc.) are allowing researchers to make vaccines in a robust, well-controlled, well-characterised manner using synthetic components. 

RA: What are some of the major misconceptions / worries people have when considering taking something like flu or Covid vaccine?  

MA: There are a range of misconceptions regarding vaccination programs surrounding safety, efficacy, and general issues of trust and transparency. Post-pandemic, we have a collective opportunity to understand these hesitancies and better educate the public on the modern, rational, data-based research and development that goes into vaccine design.

RA: How much effort is put into vaccine research for high-risk populations? 

MA: While I can’t comment on this specifically, I would refer to the latest efforts on the RSV vaccine, which specifically targets high risk populations, as an example. 

Advancements in RSV vaccines made headlines in 2023 when the FDA cleared two RSV vaccines targeting adults aged 60 or older, one of which was also approved for maternal use to protect infants up to eight months. The agency also approved a monoclonal antibody to protect newborns and infants during their first RSV season and for children up to 24 months.

RA: Following that, what are the technologies being used that enable these approaches (cryo-EM etc)? 

MA: Rapid genomics sequencing of global pathogens to identify new strains and changes in key proteins are important for vaccine design. For example, there are global monitoring efforts for new Covid strains. With that information, researchers can map sequence changes to the spike protein to assess whether there are obvious concerns with vaccine coverage or antibody therapies. They can also look at impact of sequence changes to proteins like Mpro to assess utility or future design iterations for anti-viral small molecule.

Critical technologies supporting RNA design and production, delivery vehicle design, and formulation (e.g. LNPs) have also been vital in ensuring the production of safe, effective vaccines at scale, in highly scalable formats. 

RA: How much learning has there been for vaccine design since the pandemic? 

MA: Rational vaccine design, or structural vaccinology, is poised to become a routine approach and is touted to lead to the development of vaccines for diseases that are hard to target.  

The pandemic brought together earlier efforts in structural vaccinology and synthetic biology (mRNA design and packing) to bring vaccines to market in record time. Together, the rapid innovation brought forth during the pandemic creates a foundation for vaccine design that can prevent or cure diverse diseases, even beyond infectious diseases, including metabolic diseases, neurodegenerative diseases and cancer.  

RA: And in terms of vaccine development for infectious diseases or respiratory viruses, do you think we’re globally better prepared to deal with a pandemic again?  

MA: There have been significant advancements in key technologies and workflows over the past 10+ years, accelerated by the Covid pandemic, that certainly put us in a much better position to respond rapidly to future viral threats. Structural vaccinology will remain at the heart of antigen design which, when combined with novel delivery vehicle formulation and rapid manufacturing responses, will continue to reduce time to clinic for vaccines to combat novel pathogens. 

RA: Do you think clear explanation of the development process and its safeguards can help prevent vaccine hesitancy? 

MA: Absolutely. This is also an area where structural biology can have an important and positive impact as it is possible to provide visual explanations of complex ideas to explain how the virus “works,” what we understand about the impact of changes to the virus, how our bodies respond to viral infection and how this information is used to develop highly effective, safe vaccines.

RA: Following that, how do you direct people to the right information? Is it the job of government, healthcare, industry, or a collaborative effort?   

MA: I believe that all stakeholders have a role to play when it comes to ensuring that everyone has access to clear, easy-to-understand information about the disease, vaccine design and validation, safety and efficacy, and rationale for target populations. At the leading edge of technological developments, drug and vaccine development workflows powered by high throughput and high resolution cryo-EM structure determination that not only deliver on the rapid design of new vaccines, but also provide pictures and videos of the underlying science that are accessible to diverse, non-specialist audiences.

DDW Volume 25 – Issue 2, Spring 2024


Melanie Adams-CioabaDr Adams-Cioaba is the Senior Director and General Manager of Pharma/Biotech for Electron Microscopy at Thermo Fisher Scientific. An experienced biochemist and structural biologist, Adams-Cioaba has a passion for the development and commercialisation of novel solutions for life sciences research.


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