Authors:
Felicitas Colombo
Dr. Enrique Chacon-Cruz
Professor Rino Rappuoli is a renowned Italian vaccinologist and microbiologist whose pioneering work has helped transform modern vaccine development. He is Scientific Director of the Fondazione Biotecnopolo di Siena, where he leads efforts to strengthen preparedness against future pandemics and antimicrobial resistance (AMR), among other initiatives.
A pioneer of reverse vaccinology, Prof. Rappuoli has played a major role in developing innovative approaches to vaccine discovery, including the use of genomics, monoclonal antibodies and, increasingly, artificial intelligence to identify and optimize vaccine targets. His work has contributed to the development of vaccines against major bacterial diseases and to advancing new strategies for addressing drug-resistant infections.
At the Fondazione Biotecnopolo, his work focuses on an end-to-end approach to pandemic preparedness, spanning discovery, preclinical research, clinical development and manufacturing. He has also championed the use of vaccines and human monoclonal antibodies as essential tools in the global response to AMR, alongside antibiotics, diagnostics and other emerging technologies.
Prof. Rappuoli is widely recognized for his contributions to vaccinology and for his leadership in translating scientific innovation into public-health solutions. His many contributions to vaccine science and immunology are nothing short of transformative.
AMR: the silent pandemic
Antimicrobial resistance (AMR) is often described as a “silent pandemic.” Unlike COVID-19, it does not arrive as a single global emergency that dominates headlines and transforms societies almost overnight. Yet, its cumulative impact is enormous. For Prof. Rappuoli, the scale of the challenge demands a fundamental change in thinking.
As AMR threatens to undermine some of the most important achievements of modern medicine, Prof. Rappuoli argues that the world needs to rethink how it approaches AMR and place vaccines, monoclonal antibodies, and other innovative tools as essential components at the center of the response.
He believes that the discovery of antibiotics in the 1930s and 1940s inadvertently led to vaccines receiving less attention as a tool against bacterial disease. As new classes of antibiotics became available, resistance could often be addressed by moving from one antibiotic to another. Over time, however, that approach became increasingly unsustainable.
“Trying to solve the problem of AMR with new antibiotics is a lost war,” he argues. “They cannot be used alone.”
The alternative, he says, is not to replace antibiotics, but to build a much broader supply that includes vaccines, human monoclonal antibodies, diagnostics, phages and emerging technologies.
Preparing for the next pandemic and AMR crisis
This philosophy is reflected in the mission of the Fondazione Biotecnopolo, an Italian government-funded foundation created in response to the lessons of COVID-19.
Italy was the first European country to experience the pandemic’s devastating impact, including significant mortality and economic disruption. The experience exposed gaps in preparedness and prompted the Italian government to invest in an institution capable of connecting research, development, clinical trials and manufacturing.
Prof. Rappuoli, who serves as Scientific Director, describes the foundation as an end-to-end institution, designed to move from discovery through Phase I and Phase II clinical trials and, potentially, toward emergency use of medical countermeasures.
That combination distinguishes the Fondazione Biotecnopolo from many other pandemic preparedness initiatives, according to Prof. Rappuoli. While much of the global preparedness agenda has focused primarily on emerging viruses, AMR represents a persistent and growing threat.
“We are building research capabilities that can address both acute pandemic threats and the slower-moving global crisis of drug-resistant infections,” he says.
Why bacterial vaccines are so difficult
The scientific challenge is formidable. Pathogens such as Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa continue to cause serious multidrug-resistant infections, particularly in healthcare settings. Developing vaccines against these organisms, however, is considerably more complex than developing vaccines against many viruses.
Prof. Rappuoli points to Klebsiella as an example. The bacterium has more than 100 capsular types, meaning that a conventional vaccine approach could require targeting numerous different polysaccharides.
“It’s much more complex than a virus,” he explains.
With COVID-19, researchers rapidly converged on a key viral protein as the target for vaccine development. Bacteria present hundreds of potential targets, and researchers must determine which are sufficiently conserved across strains, immunogenic and capable of generating protection.
This is where Prof. Rappuoli’s work on reverse vaccinology becomes particularly important.
From reverse vaccinology 1.0 to 3.0
Prof. Rappuoli’s team has progressively transformed the way vaccine targets can be identified. The approach begins not simply with the pathogen, but with people who have recovered from infection. Their blood contains antibodies generated during the immune response, including rare antibodies that may provide protection.
Researchers isolate memory B cells individually and screen thousands (sometimes as many as 70,000) to identify those producing antibodies capable of killing or neutralizing the bacteria.
“Once a protective antibody is identified, we can pursue two paths simultaneously,” he continues.
First, the antibody itself can potentially be developed as a monoclonal antibody for prevention or treatment. Second, identifying the antibody’s target reveals a potentially protective antigen that can serve as the basis for a vaccine.
This approach, originally described as reverse vaccinology 2.0, has now evolved into what Prof. Rappuoli calls reverse vaccinology 3.0, incorporating artificial intelligence (AI).
AI can accelerate the identification of targets and help researchers design improved antibodies and vaccine antigens. Rather than simply taking an antigen as it exists in nature, researchers can use computational approaches to optimize properties such as stability, immunogenicity, cross-reactivity and temperature tolerance.
“The objective is no longer simply to identify the antigen, but to redesign and optimize it,” he says.
Monoclonal antibodies developed in months
The acceleration is not limited to antigen discovery. Before COVID-19, developing a new human monoclonal antibody and bringing it into clinical testing could take two years or more.
During the pandemic, Prof. Rappuoli and his colleagues reduced that timeline to approximately eight months, demonstrating that the process could be dramatically accelerated under emergency conditions. He believes the timeline could eventually be reduced further.
“We are working on new ways of manufacturing antibodies that could take three months,” he says.
That raises an intriguing possibility: if a new bacterial or viral threat emerges, therapeutic monoclonal antibodies could potentially be developed and brought into clinical use within a matter of months.
Prof. Rappuoli is cautious about predicting development in days, but he sees two to three months as a realistic target for the future.
“We are not there. But that’s my target,” he asserts.
Vaccines as part of antimicrobial stewardship
Vaccines have proven highly effective in preventing infectious diseases at scale, while helping to reduce reliance on antibiotics and limiting the selective pressures that contribute to antimicrobial resistance.
For Prof. Rappuoli, vaccines should become an integral component of antimicrobial stewardship, not a secondary intervention against AMR. The idea is not entirely new. In 2021, the World Health Organization (WHO) published a dedicated framework calling for vaccines to be more fully integrated into strategies to prevent and control AMR, including through expanded use of existing vaccines and development of new vaccines specifically relevant to AMR. (WHO)
Yet, vaccines against antibiotic-resistant bacterial pathogens have not received the level of investment that their potential warrants. One reason is economic.
“There is not economic incentive for companies to invest in vaccines for bacteria resistant to antibiotics,” Prof. Rappuoli says. “The scientific challenge is significant, but so is the difficulty of establishing a sufficiently attractive market.”
That creates a task for governments and policymakers: if AMR is a major health and economic threat, society must create the incentives necessary to develop the tools capable of addressing it.
The missing number in vaccine health economics
Perhaps Prof. Rappuoli’s most striking policy proposal concerns how vaccines are evaluated.
Health technology assessments and cost-effectiveness analyses routinely consider outcomes such as deaths prevented, morbidity avoided and hospitalizations reduced. But, he argues, they often fail to capture another major benefit of vaccination: the reduction in antibiotic resistance.
“If you look at the cost-effectiveness of vaccines against bacteria, they usually miss a huge parameter,” he says. “The benefit vaccines can provide in addressing antibiotic resistance.”
This perspective is increasingly supported by global evidence. A 2024 World Health Organization analysis of 44 vaccines targeting 24 pathogens found that vaccination could play a substantial role in reducing antibiotic use, AMR-related disease and associated economic costs. The report underscores the need to incorporate these broader benefits when considering the value of vaccines. (WHO)
The WHO estimates that optimizing the use of vaccines against the pathogens assessed could reduce antibiotic use by 2.5 billion doses annually, while potentially saving approximately US$730 billion in hospital costs associated with AMR if vaccines against all evaluated pathogens were successfully rolled out. (WHO)
This omission can have important consequences. If the AMR benefit is not quantified, it is difficult for policymakers to incorporate it into decisions about vaccine implementation.
Prof. Rappuoli proposes an ambitious but straightforward change: the impact on antibiotic resistance should be explicitly recognized in vaccine labeling and subsequently incorporated into health-economic assessments.
His proposal echoes a growing body of health-economic research. Experts have argued that conventional vaccine economic evaluations should capture the broader health-system, epidemiological and ecological effects of vaccination on antimicrobial use and resistance, not simply the infections directly prevented by the vaccine. (OBS)
He uses pneumococcal vaccination as an example. A vaccine’s label could explicitly recognize its ability to prevent antibiotic-resistant pneumococcal disease, with the associated economic benefit incorporated into cost-effectiveness analyses.
For Prof. Rappuoli, this could trigger a broader policy cascade. Including AMR in the recognized benefits of vaccination could influence regulatory processes, advisory committee decisions, health-economic assessments, investment priorities and ultimately immunization policies.
“If it’s not in the label, it will never be part of any other consideration,” he says.
One Health: vaccinating animals
The argument extends beyond human health. Prof. Rappuoli emphasizes that vaccination of animals can also contribute to reducing antimicrobial use and resistance, making AMR a quintessential One Health challenge.
The One Health dimension is increasingly recognized in global AMR policy. WHO has emphasized the role of vaccination in reducing reliance on antimicrobials in animal husbandry, reinforcing the idea that human and animal vaccination should be considered together within broader AMR strategies. (WHO)
Prof. Rappuoli recalls the example of salmon farming in Norway, where large quantities of antibiotics were once used in production. When vaccination was introduced, concerns emerged that reducing antibiotic use would damage the industry’s economics. The opposite happened. Salmon production increased, while the use of antibiotics in the fjords was dramatically reduced. (Barnes et al 2022)
This principle, he argues, can be applied more broadly across animal health.
“Vaccination can simultaneously deliver a public health benefit, reduce antimicrobial use and generate an economic benefit,” Prof. Rappuoli affirms.
The promise and limits of AI
AI is rapidly transforming vaccine and antibody development. But Prof. Rappuoli offers an important warning against excessive confidence in computational predictions.
“Artificial intelligence, from my point of view, is not so intelligent, but it’s very powerful,” he says.
He describes AI as an extremely powerful calculator whose performance depends heavily on the quality of the data it receives.
For protein science, the situation is particularly promising because researchers have access to extensive databases of protein structures. This enables highly accurate predictions in many circumstances.
But proteins are dynamic. They can change shape and exist in multiple conformations. AI may recognize the beginning and end states without necessarily capturing every intermediate state.
He recommends using AI to accelerate scientific discovery, improve predictions and guide experimental work. However, its predictions must still be validated in the laboratory.
“Never trust it. Go back and check,” Prof. Rappuoli shares his unequivocal advice to scientists.
Three priorities for the next decade
Looking ahead, Prof. Rappuoli identifies a clear direction for the global response to AMR.
Recognize the limits of antibiotics alone. The world needs to acknowledge that the antibiotic-only approach cannot resolve AMR.
Invest in tools that already exist. Vaccines and human monoclonal antibodies have demonstrated their potential and should be developed more aggressively against resistant pathogens.
Continue searching for new solutions. Even vaccines and monoclonal antibodies will not be enough to address a problem of this magnitude. He points to phages, CRISPR-Cas technologies and other emerging approaches as part of a broader scientific arsenal.
“The challenge, however, is not only scientific. It is also cultural and economic,” he says. “What concerns me the most about the future of AMR and vaccines are two issues: complexity and investment.”
Science has the tools to make significant progress against some of the most important bacterial pathogens, he believes. But identifying the right targets is substantially more complicated than it was for COVID-19, and developing vaccines will require significant resources, time and sustained commitment.
The scientific community increasingly understands that AMR cannot be solved by continually developing new antibiotics. The technologies to broaden the response already exist, from vaccines and monoclonal antibodies to AI-enabled discovery, diagnostics and phage-based approaches.
What remains is to align science, policy and economics around the urgency of the problem. That may ultimately be the central task.
“The fight against AMR may be a long one. But if vaccines become a central part of the strategy, it may also become a fight with a much broader, and powerful, arsenal,” he concludes.
