A conversation with the father of reverse vaccinology, Prof. Rino Rappuoli
Authors:
Javier Casellas, M.D., Ph.D.
Enrique Chacon-Cruz, M.D., MSc
Felicitas Colombo, MPA
Prof. Rino Rappuoli is known globally for his work on vaccines discovery and immunology. He co-founded the field of cellular microbiology, a discipline combining cell biology and microbiology, and pioneered the genomic approach to vaccine development known as reverse vaccinology, an improvement of vaccinology that employs bioinformatics and reverse pharmacology practices.
As part of his many posts, Prof. Rappuoli led some of big pharma’s most influential research & development units. He also served as visiting scientist at Rockefeller University and Harvard Medical School and, in 2017, he received the European Inventor Lifetime Achievement Award for his ground-breaking new generation of vaccines, which eradicated infectious diseases such as diphtheria, bacterial meningitis and whooping cough in the developed world.
Prof. Rappuoli’s contributions to vaccine science and immunology are nothing short of transformative. His pioneering work in reverse vaccinology fundamentally reshaped how vaccines are developed, moving from traditional empirical methods to a more precise, genomics-driven approach.
Reverse Vaccinology
Prof. Rappuoli’s contributions to vaccine technology have indeed been monumental, with his work significantly impacting public health. The huge success of many vaccines based on reverse vaccinology, on Prof. Rappuoli’s invention, lends to unsurmountable appreciation of his legacy to public health and the inevitable question about its future.
Reverse Vaccinology emerged from Prof. Rappuoli’s insight into the potential of genomics for vaccine development. When he and his team embarked on this journey in the mid-1990s, it was driven by the challenge of developing a vaccine against meningococcus B, a pathogen that was proving resistant to conventional methods. The sequencing of the Haemophilus influenzae type b genome by Craig Venter was a pivotal moment that inspired this approach.
“And that was clearly a new, fascinating, revolutionary technology. I mean, we had never seen a complete genome of anything before. And the idea came that, if we could know the genome, we could make a vaccine,” reminisces Prof. Rappuoli, smiling at the thought of what now seems like a Stone Age of genomics.
By decoding the genome, Prof. Rappuoli and his colleagues could identify potential vaccine targets, dramatically shifting the vaccine development paradigm. After the years, genomes became routine.
Today’s genomic capabilities are a testament to the revolutionary impact of reverse vaccinology. Currently, the database of COVID and SARS-CoV-2 genomes is around 16 million. This vast database and the rapid sequencing technology underscore how far the field has come. The scale is different, but the pioneering principle is the same.
This progress has not only enhanced vaccine development but also deepened our understanding of pathogens and immune responses. As genomic data becomes more comprehensive, future directions could lead to more personalized vaccines tailored to individual genetic profiles or specific pathogen strains.
Beyond reverse vaccinology, Prof. Rappuoli highlights the significance of structural vaccinology, which has accelerated and refined vaccine development by allowing detailed analysis of protein tridimensional conformation.
Structural Vaccinology
Structural vaccinology builds on the principles of reverse vaccinology by adding a crucial layer: structural biology. While reverse vaccinology identifies potential antigens from a pathogen’s genome, structural vaccinology takes this a step further by using detailed information about the protein structures to design and optimize these antigens.
“But now, structural vaccinology is also pervasive in the design of every single antigen. Because not only you can solve a problem pre-fusion, post-fusion, but, you know, for people that have been doing vaccines, the stability of the antigens, the proteolytic cleavages, all these kinds of things are nightmares. I mean, you can spend years trying to fix these things with classical technologies,” said Prof. Rappuoli, an Honorary Professor of Vaccinology at Imperial College in London.
It certainly represents a major leap forward from reverse vaccinology, integrating structural biology with genome-based techniques to refine and optimize vaccine antigens. Prof. Rino Rappuoli’s insights into this field reveal its profound impact on vaccine development and its role in addressing complex challenges.
Conjugate vaccines
A conjugate vaccine is a type of subunit vaccine which combines a weak antigen with a strong antigen as a carrier so that the immune system has a stronger response to the weak antigen. Conjugate vaccines, for Hemophilus, meningococcus and pneumococcus, are among the safest, most effective and most important vaccines ever made.
“It’s true that, in the case of pneumococcus, we started with seven variants, and then we got to 13, now we are at 20. There are people working on 25, and others are 25, I think, 24, 25, are already in clinical trials, while the people are already thinking about 32, 34. And, as you said, there is one thing that is happening, which is where you go from seven to 13 to 20 and 24. I mean, you lose a little bit of the peak titers of the immunogenicity,” exemplified Prof. Rappuoli, Senior Professor of Molecular Biology at the University of Siena.
The problem with a protein-based vaccine for pneumococcus is that it would be impossible to license. The reason is that the conjugate technology works so well that a protein-based vaccine should show that it is at least as good, if not better, than the conjugate.
For antibiotic-resistant bacteria, Klebsiella and Shigella, among other examples, protein-based vaccines are still a possibility.
mRNA
Before the pandemic, mRNA vaccines were only a myth. Licensed globally since then, they became extremely popular not only for COVID, but also for respiratory syncytial virus (RSV) and many other infectious agents.
“I strongly believe in mRNA vaccines. The way they were licensed for COVID was because they were fast, and they were kind of mature enough, because they’ve been in a few phase I, phase II clinical trials. But, actually, they were not ready for commercial use. Without the pandemic, probably the mRNA vaccines were not going to become licensable for another seven or eight years, because they were not, still are not stable, temperature stable,” conveys Prof. Rappuoli, who thinks they are extremely powerful but still too reactogenic, especially when adding multiple valences.
Clearly, one incredible advantage of RNA is speed. According to Prof. Rappuoli, if you have a well-designed study, you can go to phase I clinical trial in 30 days. As a comparison, before the pandemic, it took 18 months with proteins before going to phase I. Hence, during the pandemic, the protein-based vaccine was lost in terms of speed and it’s now challenged as an option. Will mRNA vaccines replace other platforms?
RNA seems to be better than the other vaccines in combination with more antigens. With protein-based vaccines, making the new combination is like making another vaccine. Due to the many uncertainties and incompatibilities that it elicits, it requires massive clinical trials.
In contrast, not only are RNA more reactogenic but it looks like the immunogenicity provided doesn’t seem to last as long as the protein-based vaccines, especially the ones with adjuvants.
Prof. Rappuoli believes we will still use all the technologies available for different uses and RNA will become yet another platform, but it will not replace the others because they have shown to be safe, versatile, and provide remarkable immunity. Instead, they will complement and expand the repertoire of tools available for vaccination.
Is AMR driving vaccine technology?
According to the World Health Organization, antimicrobial resistance (AMR) is one of the top global public health and development threats. It is estimated that bacterial AMR was directly responsible for 1.27 million global deaths in 2019 and contributed to 4.95 million deaths. In addition to death and disability, AMR has significant economic costs. The World Bank estimates that AMR could result in US$ 1 trillion additional healthcare costs by 2050, and US$ 1 trillion to US$ 3.4 trillion gross domestic product (GDP) losses per year by 2030.
Prof. Rappuoli asserts that, for bacteria, we should be able to use any vaccine platform. The question is, why are we not developing vaccines for AMR?
The first vaccines developed for a bacterial infection were for typhoid fever, now used in Asia and Africa for a bacterium that, otherwise, would be extremely resistant to antibiotics. E. coli is emerging as another big concern, and the antibiotics available are not effective for many of the hypervirulent and pan-resistant cases. Prof. Rappuoli believes vaccines should be developed for bacteria-resistant antibiotics as an alternative tool for prevention and use antibiotics for cure. He recommends investing in other technologies, such as phase therapy or CRISPR-Cas.
“The advantage of vaccines is that usually there is no resistance to vaccines. There are some vaccines which have been around (diphtheria, tetanus, BCG) for a century and still there is no resistance. You can argue, well, but in the case of capsule polysaccharides you have a new capsule emerging. Or in the case of COVID, you have new variants. If you call that resistant, that’s okay. But it’s not comparison to antibiotics, where once you have a new antibiotic, five years later, it’s obsolete because bacteria become resistant everywhere,” claims Prof. Rappuoli, a pivotal pioneer in polysaccharide-protein conjugate vaccines.
Some viral vaccines against influenza have indeed proven to decrease the number of antibiotic prescriptions. It would be interesting to know whether this is also the case for the recently licensed vaccines against RSV, now treated with antibiotics. Prof. Rappuoli is convinced it should.
HIV vaccine
Interestingly, RSV vaccines came about trying to solve the HIV scientific dilemma. Even though many efforts are underway, there is currently no vaccine available to prevent HIV infection. Targeting germline precursors of broadly neutralizing antibodies is acknowledged as an important strategy for HIV vaccines. Yet, simulated research was an impossible task with HIV because of the variability of its rapid mutations in every person every day.
However, there are new insights coming from a germline targeting vaccines. There is expectation on the upcoming research describing the advances and advantages of germline targeting, which can be done with protein-based and RNA targets, adding speed to this innovation.
“I think we made pretty good progress the first two steps. But the final one is the most challenging one, and we are not there yet. So, the question is, when is it going to come? Not overnight. It’s not something that’s coming immediately,” explained Prof. Rappuoli.
He is not certain whether this approach will work for HIV but believes germline targeting will be yet another reliable platform available for all vaccines, not only HIV.
Impact and future of avian flu: Influenza A or H5N1
H5 bird flu is widespread in wild birds globally, causing outbreaks in poultry and cows with several recent reports in human cases in the United States. While the current public health risk is low, CDC is monitoring the situation amongst people with animal exposures. Prof. Rappuoli has been working with the H5 antigen since 1999 and confirms that H5N1 is on every infectious disease specialist’s list of priorities.
Since it had been around for so long, some scientists were skeptic H5N1 was ever going to jump into humans. Today, we are seeing an unprecedented wave of evolution of the virus and, although still rare, starting to spread into mammals.
His concerns are indeed serious and reflect a deep understanding of the virus’ potential impact. H5N1 is being a subject of intense study due to its capability to cause a severe pandemic.
Lessons learned from the pandemic
For Prof. Rappuoli, this pandemic has been a somewhat fascinating scientific experience. He claims science did things that had never been done before, like the speed of RNA vaccines licensing.
Prof. Rappuoli has been working on calculating the economic value of vaccines during the pandemic. His estimations rendered that the return of investment on the 12.5 billion (U.S. dollars) spent was of approximately 660%. He claims that the reduction in global economic losses due to the pandemic was a direct result of the rapid availability of vaccines.
“And the reason is that, basically the 12.5 billion were recovered by anticipating the vaccines by 12 hours. Because in 2021, basically 2020, 2021, there was a moment where the global economy was losing 900 billion [U.S. dollars] per month,” Prof. Rappuoli calculates.
Some lessons learned and future concerns are the lack of synergies between governments unable to work together. Something WHO is trying to mend through the pandemic prevention, preparedness and response accord.
After all the reviews and edits, Prof. Rappuoli, who supports diversifying vaccine production to low- and- middle income countries, is skeptic about the effectiveness of this agreement.
Divide and Conquer
As Chief Scientific Officer of the Fondazione Biotecnopolo di Siena, set up by the Italian government with the aim to have an entity that would help better prepare for future emerging diseases and infections, Prof. Rappuoli’s strategy is to get all the big players around the table, integrate the knowledge available, and share the work ahead. Under this proposition, he gathered international experts under the premise that together we can better prepare the world for emerging diseases.
“Basically, if we have 30 groups and each of them takes a family of viruses, maybe in five years, we have a solution for 30. If all 30 groups are going to go after the same virus, in five years, we’re going to have one solution,” explained Prof. Rappuoli, who earned his doctoral and bachelor’s degrees in biological sciences at the University of Siena.
The big question remains, who is going to coordinate and lead the way to integrate global efforts of preparedness? Even though WHO is very influential and sets the priorities worldwide, Prof. Rappuoli believes it should be a deliberate decision to participate on this integrated global preparedness initiative, which includes CEPI and the NIH, among other influential stakeholders.
“And the answer is that nobody can lead. It has to be a voluntary collaboration between different groups,” he continued, emphasizing that each government’s commitment and ultimate responsibility is to their taxpayers.
Prof. Rappuoli’s career is a testament to how visionary thinking and cutting-edge science can converge to solve some of the most pressing health challenges of our time. His legacy in vaccine development will likely influence future generations of scientists and public health professionals.
Bio Prof. Rino Rappuoli
https://www.epo.org/en/news-events/european-inventor-award/meet-the-finalists/rino-rappuoli
Source: https://vaccinesbeat.org/new-vaccine-platforms/