Charting a course for better pneumococcal vaccines
Vaccine Insights 2024; 3(1), 7–12
How did you first get involved in vaccine development?
RM: Starting my career in pediatrics at Boston Children’s Hospital in the early 1990s, I was very impressed by the impact of the Haemophilus influenzae type B (Hib) conjugate vaccine.
Conjugate vaccines were a new development at the time. By conjugating proteins to polysaccharides found in the bacterial surface we can essentially trick the body into responding to the polysaccharide as if it were a protein, and therefore elicit a more robust immune response. Importantly, it allows babies under the age of 2 years to make antibodies to bacterial polysaccharides, which they could not otherwise do.
During my internship, I cared for many children with meningitis and other forms of invasive disease caused by Hib, but a year later, the disease was virtually eliminated in the US after the conjugate vaccine was introduced. A few years later, I was a pediatric infectious diseases fellow working in a laboratory when I was lucky enough to meet one of the scientists behind the Hib vaccine: Dr Porter Anderson.
He told me he was working on one last research effort before his planned retirement: the development of an affordable vaccine against pneumococcus (Streptococcus pneumoniae), the pathogen most often associated with bacterial pneumonia. I was inspired by this mission, and eventually turned it into a full-blown research project, with Porter as my mentor. Porter has still not retired and the collaboration we started in the mid-1990s persists to this day!
Inspired by Porter, I realized that I wanted to dedicate myself to vaccine development; specifically, vaccines for countries that cannot afford the very expensive vaccines that are currently on the market. That has been one of the guiding principles of my research for the last 20-plus years at Boston Children’s Hospital.
What impact did you see in your practice—and in the wider population—after the introduction of pneumococcal conjugate vaccine 7?
RM: When pneumococcal conjugate vaccine 7/Prevnar® (which Porter also worked on) was introduced in 2000, some doctors hoped that we would see the eradication of pneumococcus as a cause of pneumonia, bacteremia, meningitis, ear infections, and so on. While there was certainly a very remarkable decline, it was not anywhere near as dramatic as the Hib vaccine experience.
Many bacteria cover their surface with polysaccharides, which define their serotype. Whereas Haemophilus influenzae consists of only a few serotypes that cause disease in humans (of which type b was predominant), pneumococcus has more than 90 serotypes. The polysaccharide included in the vaccine confers protection against only some strains of that serotype; as we vaccinate against some serotypes, others emerge to take their place. It’s like a game of whack-a-mole! My friend and colleague Marc Lipsitch predicted this serotype replacement effect as early as 1997 Lipsitch M. Vaccination against colonizing bacteria with multiple serotypes. Proc. Natl. Acad. Sci. USA 1997; 94(12), 6571–6576. and that is exactly what happened with pneumococcal vaccines Weinberger DM, Malley R, Lipsitch M. Serotype replacement in disease after pneumococcal vaccination. Lancet 2011; 378(9807), 1962–1973..
How have PCVs evolved?
RM: While serotype replacement did not eliminate the benefit of the conjugate vaccine strategy, it mitigated it significantly. In fact, we saw the rise of several serotypes not included in the original vaccine; serotype 19A was particularly problematic, as it was highly virulent and antibiotic-resistant, causing severe cases of meningitis and sepsis in children.
Inspired by Marc’s work, Porter and I realized that a strategy based on polysaccharide capsule immunity would require adding more and more serotypes, such that the cost of the vaccine, instead of reducing over time, would remain high or even rise. Sadly, that is what we have observed with the advent of PCV13, and now PCV15 and PCV20.
It is important to say that these vaccines are phenomenal; they have a very impressive effect on most of the serotypes included. But they are hard to produce and very expensive. Quality control issues make it difficult for other vaccine companies, especially those in lower- and middle-income countries, to manufacture. And due to serotype replacement, they have not eradicated pneumococcal disease altogether.
Interestingly, if you examine the immune response to the 13 serotypes also covered by PCV13, they are lower in PCV20 . We don’t yet know why this happens, nor the clinical consequences (if any) for children or adults. It is possible that simply adding more serotypes means the body is unable to produce as strong a response to each. A phenomenon in conjugate vaccines called carrier-induced epitopic suppression has been described, a situation in which using the same carrier over and over in different vaccines may exhaust the T cells’ ability to respond Dagan R, Eskola J, Leclerc C, Leroy O. Reduced response to multiple vaccines sharing common protein epitopes that are administered simultaneously to infants. Infect. Immun. 1998; 66(5), 2093–2098..
How did you set about trying to overcome these limitations?
RM: Initially, I was working on a whole-cell pneumococcal vaccine. Essentially, we stripped the bacteria of its polysaccharide capsule, made some mutations to enhance immunogenicity, and used the whole cell (minus the capsule) as a vaccine. This is a much cheaper approach than a conjugate vaccine and could be produced for pennies per dose. My group and I worked on the whole-cell vaccine for many years, in collaboration with Instituto Butantan in Brazil and with support from the Bill & Melinda Gates Foundation (BMGF) and PATH Keech CA, Morrison R, Anderson P et al. A Phase 1 randomized, placebo-controlled, observer-blinded trial to evaluate the safety and immunogenicity of inactivated Streptococcus pneumoniae whole-cell vaccine in adults. Pediatr. Infect. Dis. J. 2020; 39(4), 345–351., and it ultimately reached Phase 2 trials in toddlers in Kenya.
However, while the vaccine itself is cheap to produce, the clinical development plan proved complicated. Since the antigens being targeted are entirely different from the current conjugate vaccines, it is not possible to use existing correlates of protection. While PCV13 and PCV20 could be compared directly with their predecessors, one approach to obtain licensure of a new whole-cell vaccine could potentially require large-scale efficacy clinical trials enrolling thousands of patients. Efforts in this area are being pursued nevertheless, evaluating different clinical endpoints that may require fewer subjects.
Meanwhile, my close colleagues at Children’s, Fan Zhang and Yingjie Lu, and I developed a new technology: the multiple antigen presenting system (MAPS).
How does MAPS differ from the chemistry used in conjugate vaccines?
RM: In traditional conjugation technology, you chemically couple polysaccharides to a protein. Multiple proteins are entangled with multiple strands of polysaccharide in what we often refer to as a ‘spaghetti and meatball’ configuration.
It is a very good technology, but it is inefficient and requires a huge amount of expertise to ensure that the chemistry is right. In addition, in existing vaccines, the protein is not an immunogen in its own right and confers no protection.
With MAPS, a biotin molecule is bound to a polysaccharide, and a rhizavidin molecule is fused to a protein (which can be derived from the targeted organism). Biotin and rhizavidin have an extremely high affinity for each other, similar to the affinity between biotin and egg avidin, so when the molecules are combined, the polysaccharide and protein become tightly affinity-linked. These affinity links create a more consistent and ordered structure than traditional conjugation and leave both polysaccharide and protein molecules chemically intact.
The manufacturing process for MAPS is less complex and more efficient than traditional conjugation, and therefore cheaper and more suitable for technology transfer to lower- and middle-income countries. Plus, in animal and human studies, we have observed that the immunogenicity of MAPS-based vaccines seems to be superior to conjugate vaccines. Even though this is not a covalent bond, the immune system sees molecules linked by MAPS as if they were conjugated together.
What is the status of the MAPS pneumococcal vaccine, now being developed by GSK?
RM: With funding from the BMGF and others, we spun out Affinivax in 2014, to develop vaccines based on the MAPS technology. Affinivax was acquired by GSK in 2022, and I remain a consultant to the MAPS program.
I’m interested in every aspect of vaccine development, but I recognize that a small company like Affinivax successfully bringing vaccines to the market on a global scale would be very unusual, so putting the technology in the hands of a highly experienced pharmaceutical company like GSK is the best way to optimize the chances of success.
At Affinivax, we started by targeting 24 polysaccharides and two pneumococcal proteins Chichili GR, Smulders R, Santos V, et al. Phase 1/2 study of a novel 24-valent pneumococcal vaccine in healthy adults aged 18 to 64 years and in older adults aged 65 to 85 years. Vaccine 2022; 40(31), 4190–4198., then expanded to more than 30 polysaccharides and four proteins. The first version successfully completed Phase 2 in adults, will soon enter a Phase 3 clinical trial in older adults, and is now in Phase 2 trial in infants. We are hoping that the combination of so many polysaccharides, plus multiple proteins, might be the best way to control this organism and avoid the whack-a-mole problem that has plagued previous vaccines.
Is there hope for a fully serotype-independent pneumococcal vaccine in the future?
RM: This is an area where theory and practice are still quite far apart, but progress is being made. Our efforts on a whole-cell vaccine are ongoing and an Australian company, GPN Vaccines, is also developing a whole-cell vaccine. Many have tried and failed to date, but a vaccine targeting pneumococcal proteins is a very attractive idea—it would be inexpensive, and you could even imagine a mucosal administration through the nose or skin.
Scientifically, there are lots of exciting approaches that I’m still interested in working on, but practically, you have to compete with the remarkable efficacy of polysaccharide-based vaccines. Therefore, the approach we took with the MAPS pneumococcal vaccine—including proteins primarily as a means of enhancing the immune response to the polysaccharide—offers massive advantages. Time will tell if this vaccine also results in universal protection through protein-mediated immunity, to protect against serotypes that evade or are not covered by conjugate vaccines, and/or whether a protein-only-based approach can be successful in eradicating pneumococcal disease. That is the holy grail.
What does the future hold for pneumococcal vaccines?
RM: All in all, these are very exciting times for pneumococcal vaccine research. There is a lot of energy in this space because it is an important and global public health issue. Sanofi is making a 21-valent vaccine, Vaxcyte is evaluating a 24-valent and a 31-valent vaccine, and GSK is working on a 24-valent as well as a 30-plus-valent vaccine.
It’s very exciting to me, not just as a vaccine researcher, but as a clinician who wants to see a vaccine that can tackle the remaining pneumococcal disease in the US and across the world. The COVID-19 pandemic reminded us, if there ever was any need, that we live in a global community. I think people are increasingly recognizing that the massive inequity in vaccine deployment across the world is both morally unacceptable and a huge risk from a pandemic-preparedness standpoint. The idea that we’re making vaccines that are not just for the wealthy but for all, regardless of the geographical accident of their birth, is something that has motivated me throughout my career and is still fueling my research today.
1. Lipsitch M. Vaccination against colonizing bacteria with multiple serotypes. Proc. Natl. Acad. Sci. USA 1997; 94(12), 6571–6576. Crossref
2. Weinberger DM, Malley R, Lipsitch M. Serotype replacement in disease after pneumococcal vaccination. Lancet 2011; 378(9807), 1962–1973. Crossref
3. Watson W. PCV20 Phase 2/3 study results among children. Presented at: Advisory Committee on Immunization Practices (ACIP) Meeting. Feb 22–24, 2023. Crossref
4. Dagan R, Eskola J, Leclerc C, Leroy O. Reduced response to multiple vaccines sharing common protein epitopes that are administered simultaneously to infants. Infect. Immun. 1998; 66(5), 2093–2098. Crossref
5. Keech CA, Morrison R, Anderson P et al. A Phase 1 randomized, placebo-controlled, observer-blinded trial to evaluate the safety and immunogenicity of inactivated Streptococcus pneumoniae whole-cell vaccine in adults. Pediatr. Infect. Dis. J. 2020; 39(4), 345–351. Crossref
6. Chichili GR, Smulders R, Santos V, et al. Phase 1/2 study of a novel 24-valent pneumococcal vaccine in healthy adults aged 18 to 64 years and in older adults aged 65 to 85 years. Vaccine 2022; 40(31), 4190–4198. Crossref
Rick Malley received his early education at L’École Active Bilingue in Paris, France, then a BA from Yale University, MD from Tufts University, and pediatrics, pediatric infectious diseases and emergency medicine training at Boston Children’s Hospital (BCH). A chance meeting with Dr Porter Anderson led to his interest in the development of a universal pneumococcal vaccine and vaccinology in general. Under Anderson’s mentorship, he shifted his research to the development of novel vaccines. His current clinical activities include attending on the inpatient Infectious Diseases consult service, and directing the Travel and Geographic Medicine clinic at BCH.
Malley runs a research laboratory with funding from the National Institutes of Health, PATH, and the Bill & Melinda Gates Foundation (BMGF). In collaboration with PATH and the BMGF, Malley led an international effort for the development of a pneumococcal vaccine for developing countries. In 2014, Malley and collaborators started Affinivax, a biotechnology company seed-funded by BMGF, and based on a novel technology called MAPS (multiple antigen presenting system) to develop vaccines for both developed and developing countries. From December 2021 to August 2022, he served as Chief Scientific Officer at Affinivax (part-time, split with BCH activities); with Affinivax’s acquisition by GSK in August 2022, he became Chief MAPS scientist and the clinical representative of the pneumococcal vaccine program at GSK-Affinivax, a role he held until March 31, 2023, after which he returned full time to Boston Children’s Hospital.
Rick Malley PhD
Senior Physician in Pediatrics,
Boston Children’s Hospital,
Professor of Pediatrics,
Harvard Medical School
Authorship & Conflict of Interest
Contributions: All named authors take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosure and potential conflicts of interest: Malley R has potential future royalties on MAPS vaccines (via being an employer at Boston Children’s Hospital). Malley R was a Member of the Board of Directors for Affinivax from 2014 to 2023.
Malley R has several patents issues/planned/pending on MAPS technology. Malley R has stock options in Corner Therapeutics and Amplitude.
Funding declaration: Malley R received consulting fee payments from GSK and Merck Vaccines. Malley R has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck Vaccines. Malley R received travel grants for travel to ISPPD12 (Toronto), Merck Vaccines (Les Pensieres), ACPID meeting, and Asian Pneumococcal Symposium (South Korea).
Article & Copyright Information
Copyright: Published by Vaccine Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.
Attribution: Copyright © 2024 Malley R. Published by Vaccine Insights under Creative Commons License Deed CC BY NC ND 4.0.
Article source: Invited; interview held on Nov 19, 2023.
Revised manuscript received: Jan 24, 2024; Publication date: Jan 26, 2024.