The world of Pneumococcus

Doctor Ron Dagan is a Distinguished Professor of Pediatrics and Infectious Diseases at Ben-Gurion University of the Negev in Beer-Sheva, Israel. He is also a founding member of the World Society for Pediatric Infectious Diseases (WSPID) and a Fellow of the Infectious Diseases Society of America (IDSA).

He has gained international recognition for his pioneering research, which has primarily focused on vaccine-preventable diseases. His work has made significant contributions to several key areas, including: the development and impact of pneumococcal vaccines; understanding the epidemiology of hepatitis A and the introduction of hepatitis A vaccines; the epidemiology of respiratory infections in children; clinical aspects of vaccination against antibiotic-resistant pneumococci; the pathology of otitis media, including the role of resistant organisms and the prediction of bacteriological responses to various antibiotics; and the epidemiology and prevention of enteric and invasive infections in young children.

Prof. Dagan founded the Pediatric Infectious Disease Unit at Soroka University Medical Center in Beer-Sheva, Israel, and served as its director from 1987 until June 2014. Additionally, he served as an advisor for Infectious Diseases at the Israeli Ministry of Health and was President of the European Society for Pediatric Infectious Diseases (ESPID).

He received his MD degree in 1974 from Hadassah Medical School, Hebrew University, Jerusalem. In 1982, he pursued a three-year fellowship in pediatric infectious diseases at the University of Rochester, New York, where he was appointed Adjunct Associate Professor of Pediatrics. 

An active member of numerous national and international advisory committees, Prof. Dagan has contributed significantly to global health initiatives, such as the World Health Organization (WHO) on the Pneumococcal Nasopharyngeal Carriage Working Group and the Pneumonia Radiology Working Group. 

As he continues to build his legacy, Professor Dagan’s research has already played a pivotal role in advancing global understanding of critical health issues, especially in the realm of pediatric infectious diseases.

Pneumococcal conjugate vaccine

Conjugate vaccines are not a new concept, but their widespread use took time to develop. The first conjugate vaccine, the Haemophilus influenzae type b (Hib) vaccine, was relatively straightforward as it involved conjugating to a single antigen. However, the development of a pneumococcal conjugate vaccine presented a much more complex challenge, given that there are over 100 pneumococcal serotypes (STs). The initial challenge was to determine which serotypes were responsible for the most disease.

“And it came out, according to the limited studies that were done at that time, that maybe the seven serotypes that were included in PCV7 are the ones that caused most of disease in children,” recalls Prof. Dagan. The next hurdle was combining these seven serotypes into a single vaccine.

“In fact, it’s a combined vaccine with seven vaccines. It’s a very complex production. And, some other complex questions about what happens when you put all this together, when you conjugate them to the same carrier, which carrier to find that is safe enough, but immunogenic enough,” he adds.

The journey from a mono-vaccine to a bi-vaccine, then to a tetra-vaccine, took several years. However, in 2000, the first commercial pneumococcal conjugate vaccine (PCV) was introduced in the United States. Since then, the landscape of pneumococcal disease has evolved significantly.

“I remember when we were part of the people who were discussing PCV in the early 90s. It’s about 35 years ago, not like prehistory. And we all were talking about IPD (invasive pneumococcal disease). Because IPD is the easiest disease to look at because, by definition, it’s a Pneumococcus isolated from a sterile fluid. And you can do [test] the serotype, and you can do [test] susceptibility,” Prof. Dagan explains.

While IPD provided clear data on serotypes and disease burden, Prof. Dagan notes that it also had its limitations stating that “it was an easy definition, but a difficult issue to follow” because IPD was only detectable through blood cultures, CSF and other sterile site cultures, and not every case of pneumococcal disease is blood culture positive. Still, it allowed to gather valuable data on disease specificity, including serotype and disease rates, which helped estimate the burden of disease, in the range of a few dozens to hundreds per 100,000.

“This was our first concept. But we knew the Pneumococcus was much more important than that. We knew Pneumococcus causes a lot of pneumonias. We knew Pneumococcus causes a lot of acute otitis media (AOM). And we knew it causes sinusitis and other diseases. But we didn’t know how to measure [the contribution of Pneumococcus, especially that of vaccine serotypes, to] them,” he explains.

The roadmap to PCV7

Defining the pneumococcal burden was a big challenge. When Prof. Dagan and his team started the PCV7, new insights were gained.

“First, we understood the big effect [impact] of the pneumococcal conjugate [on] nasopharyngeal (NP) carriage. And, therefore, we understood the big effect on, on one hand, herd protection, and on the other hand, [serotype] replacement. Because we started to understand that Pneumococcus is part of the flora,” he details.

Prof. Dagan and his team then started to measure the effect of the vaccine on mucosal diseases, such as acute otitis media (AOM) and pneumonia, both difficult to the define, and with often unclear extent of the contribution of Pneumococcus. The researcher studying the impact of PCVs introduced the concept of vaccine probe, which means you introduce the vaccine, you observe the impact on the burden, and then you go back and you understand how much Pneumococcus, especially of vaccine serotypes, was responsible for that burden.

“When we understood [the true burden of] pneumococcal disease, we [appreciated] that the [estimated] PCV7 potential benefits [before implementation] was basically nothing compared to the real benefits that it brought in. This [PCV7 implementation] brought a huge reduction in IPD first, of course, especially in the developed countries where the 7 serotypes are more important. But it also did not take everything away because there are other serotypes,” asserts Prof. Dagan. 

Thus, the introduction of PCV7 had a huge effect. It brought relief in recurrent and complicated AOM, it was shown to reduced pneumonia, especially bacteremic pneumonia. Because the effect on carriage started to be very clear in countries that introduced PCV7 into the national immunization program (NIP), it also had an effect on other populations, like the non-vaccinated population (neonates, very young children, immunocompromised persons, and adults).

From PCV7 to PCV13 

One key realization for Prof. Dagan was that there had been insufficient real-world epidemiological data before the decision was made to introduce PCV7 as the optimal pneumococcal vaccine. While PCV7 studies had established its potential efficacy, effectiveness, and impact after introduction, the need for further data was clear.

“So, we understood that some STs, like serotype 1, serotype 5, were very, very important in pediatrics, especially the more important the more you go into developing worlds. And they were very invasive, and we just missed them at all in the PCV7,” he said.

During the use of PCV7, it became evident that some serotypes were still causing significant disease burden. As the impact of PCV7 began to wane due to increasing disease with some non-PCV7 invasive isolates, in certain populations, the need for a broader-spectrum pneumococcal vaccine became clear. This led to the introduction of PCV13 around 2010, which included six additional serotypes beyond those covered by PCV7. PCV13 showed a substantial improvement in preventing pneumococcal disease, including pneumonia and addressing the evolving challenges of pneumococcal disease.

Beyond PVC13

The question of the vaccine’s spectrum is crucial, and it’s important to remember that there are over 100 pneumococcal serotypes (STs) present in the nasopharynx (NP). After over 25 years of research, Prof. Dagan agrees that the current consensus is that pneumococci are an essential part of the normal flora in children and may not be completely eliminated.

On the one hand, we know that certain serotypes still cause significant disease. Though somewhat philosophical, according to Prof. Dagan, the question that remains is extremely important: How far can we go in targeting specific serotypes before we disrupt the child’s microbiome to the point where it causes harm?

We already know that even PCV7, and definitely PCV13, have changed the microbiome of the child, because each serotype that comes instead of the other serotype has different interactions. Because we are also a part of our microbiome, Prof. Dagan concerns on how much can we change before we start to change the child? And is it going to be a perpetual cycle? 

It is well-established that both PCV7 and PCV13 have already altered the child’s microbiome. Each serotype that replaces another can have different ecological interactions, and these changes might have broader implications. “We are, in essence, part of our microbiome,” Prof. Dagan points out, raising concerns about how much we can change it without negatively affecting the child’s health. 

“We’re going to give [eliminate] one more serotype, so others are going to come, and we will never be able to take care of them. And we know that each serotype has different invasiveness, and each serotype has different characteristics, but we cannot always predict,” he expands.

Despite these concerns, science has pushed forward, leading to the development of vaccines beyond PCV13. Currently, two new vaccines—PCV15 and PCV20—have received approval.

“And this contains very, very important STs that cause a lot of disease. If you go globally, the [additional] PCV20 serotypes [that are not included in PCV13] usually constitute currently anything between 30% to 60% of the leftover [IPD] disease in children,” Prof. Dagan explains. 

Several manufacturers are now working on vaccines beyond PCV20, each with slightly different serotype combinations. In the future, we will have a broader range of vaccine options, but this may raise challenges in terms of choosing the most appropriate vaccine.

An additional consideration is how vaccination affects the broader population. In vaccinated children, changes to the microbiome may alter the dynamics of serotype transmission within the community. On one hand, adults are exposed to fewer vaccine-targeted serotypes, resulting in a decrease in these diseases. However, certain serotypes that are not problematic in children can be particularly harmful to the elderly.

As a result, many countries are beginning to see a resurgence of IPD and pneumonia in older populations, that are not caused by vaccine serotypes, returning to pre-vaccination levels. One emerging strategy is to use a complementary vaccine approach: administering a conjugate vaccine with specific serotypes to children to protect both them and many adults through indirect protection, while also offering a different vaccine to adults, to complement for serotypes more problematic in adults.

Carrier-induced immunosuppression

Carrier-induced epitopic suppression (CIES) is a phenomenon in which pre-existing immunity to a vaccine carrier protein can reduce the antibody response to the antigens conjugated to that carrier. This well-known phenomenon was first described in humans by Prof. Dagan’s team during studies in the 1980s and early 1990s, involving tetravalent pneumococcal vaccines conjugated to tetanus or diphtheria toxoids.

As research progressed, other issues related to adjuvants came to light. The use of acellular pertussis vaccine which replaced the whole cell pertussis vaccines, for instance, reduced some of the adjuvanticity of the whole-cell vaccines when administered simultaneously or in combination with other vaccines, exacerbating the problem. Some companies developing combined Tetanus and Diphtheria conjugate vaccines, such as the 11-valent conjugate vaccine, ultimately halted production when they realized that the carrier-induced immunosuppression would pose significant challenges.

Prof. Dagan emphasized that this eminent phenomenon was not seen when they used only 7 CRM-conjugate serotypes in PCV7, underlying that PCV13, which added six serotypes to the PCV7 carrier, already faced similar issues.

“I don’t know how many remember or know, but PCV13 was licensed despite the fact that 2 serotypes did not meet the non-inferiority. It was 9V and 6B. It happens to be that the non-inferiority is something very, very complicated and artificial to be able to license new vaccines based on just immunogenicity rather than efficacy,” he recalls.

However, interestingly, those two serotypes that failed to meet non-inferiority were actually among the best-performing conjugates. In contrast, serotypes that met the non-inferiority benchmarks, like type 3, turned out to be less effective.

This shows that immunogenicity, an indirect measure of the impact on memory B cells and crucial for long-term protection, alone may not be the best indicator of vaccine effectiveness, since we do not really know the thresholds for protection by individual serotypes.

Serotype-specific memory B cells are key for long-term immunity. If the immune response is reduced too much at any point, adequate memory might not develop, which could result in a failure to protect against mucosal diseases or later infections. But where exactly is the tipping point? Nobody knows.

This uncertainty raises concerns about the limits of carrier technology. As the push for vaccines with more serotypes continues, Prof. Dagan warns that including more than 20 serotypes with the current technology may lead to diminishing returns. The conjugation process itself will need improvement to handle this complexity.

“There are several ways to do it. New carrier adjuvant is easy to say. It’s difficult to do because we took the old known carriers and adjuvants first in order to be safe and effective with children. And now we cannot just take new ones” explains Prof. Dagan, claiming that new carriers, new conjugation methods and new adjuvants are still interesting.

“But so far, I do not see with the new vaccine that are studied up to 30 serotypes with the results that were published in adults or in phase 1 or 2, I don’t see that we are getting to a new order of magnitude of immunogenicity,” he cautiously continues. “I think it’s a big concern. [However], I’m not concerned about PCV20. If you give enough boosters in your community, [allowing indirect protection for infants, even with somewhat lower immunogenicity after the primary series]”

As vaccine development continues, there is a growing need to balance the inclusion of additional serotypes with their immunogenicity. 

“So, we are yet very primitive in our way. I think that the conjugate vaccine is only one phase before we will know something else in the future. But, at the moment, I don’t see in the next five years anything that comes better than that,” he concludes.

Protein-based pneumococcal candidate vs. pneumococcal polysaccharide conjugate 

The pneumococcal polysaccharide conjugate vaccine is widely recognized for its safety. In contrast, protein-based pneumococcal vaccines may not offer the same level of safety, at least according to some of the data currently available. A large-scale study comparing the protein-based vaccine to the standard PCV10 in The Gambia and PCV13 in the United States, showed that while the protein-based vaccine had a safety profile similar to placebo, it did not demonstrate any significant effect on otitis or carriage.

The study also highlighted that most of the carriage in these children involved non-vaccine types, which suggests that a universal vaccine might have potential. The studies showed a nice safety profile. So, you could look at these children, and the addition of protein was very close to placebo. This, in turn, offers some insights into the vaccine’s efficacy. “So, the competition is twofold.”

Prof. Dagan elaborates on the two main challenges for protein-based vaccines. “One is how we can show efficacy against IPD where you cannot give placebo anymore. So, you only must aim non-vaccine serotype IPD in children vaccinated with PCV20. It will be very difficult,” he points out. “And the second is to evaluate immune response for protein vaccines in regard to predictability of the protection. We have sort of correlates of protection with polysaccharides. We don’t have correlates of protection with the protein.”

For example, while H. influenzae protein D, when combined pneumococcal polysaccharides  PHiD-CV (PCV10), elicited a strong immune response and demonstrated excellent safety, it did not provide any meaningful protection against H. influenzae. Far from something close to Prof. Dagan’s goals, he is not very enthusiastic about this direction.

Cost effectiveness

Prof. Dagan, a member of the Israeli National Committee for Infectious Diseases and Vaccines, is somewhat skeptical about how data is often manipulated to make cost-effectiveness decisions. He uses the example of PCV20 to illustrate his point.

“The new serotypes of PCV20 were licensed based on immunogenicity and [serological] non-inferiority. We don’t even know if they are effective. We think they should be effective. But effectiveness or efficacy was not tested,” he explains. “So, I’m laughing all the way home every time that I see people presenting cost effectiveness of PCV20. What does it mean? How do you evaluate the cost-effectiveness of the seven [additional PCV20] serotypes that have no efficacy studies done ever on them?”

Prof. Dagan further explains that, in making vaccine purchase decisions, the primary focus is often on the potential impact rather than cost-effectiveness. He emphasizes that they are confident that if a prevention method demonstrates a significant impact, the difference in effectiveness between vaccine A and vaccine B will ultimately make it cost effective.

Prof. Dagan stresses the importance of considering the burden of disease rather than just cost-effectiveness when evaluating vaccines. He believes that cost-effectiveness calculations should be taken “with a grain of salt,” emphasizing that a vaccine’s true value lies in its ability to work. 

“You show me one vaccine that is not cost effective, if it works,” he concludes eloquently.