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First International Pneumonia Vaccines Workshop on Prevention of Childhood Pneumonia by Vaccination: Lessons from the Past and Implications for the Future, 15 December 2007, Seoul, Korea
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Meeting report First International Pneumonia Vaccines Workshop on Prevention of Childhood Pneumonia by Vaccination: Lessons from the Past and Implications for the Future, 15 December 2007, Seoul, Korea
a b s t r a c t The primary objective of the 1st Pneumonia Vaccines Workshop was to review current and emergent data and assess how key lessons learned in preventing pneumonia can provide insights for future efforts. This conference provided substantial insight into many facets of pneumonia prevention as well as addressing the overarching question: What are the characteristics of pneumococcal vaccines that are associated with protection against pneumonia?
1. Conference background On 15 December 2007 an international workshop was convened in Seoul, Korea to evaluate the progress made to date in preventing pneumonia, especially in children under 5 years of age. Pneumonia kills more children than any other illness—more than AIDS, malaria, and measles combined. More than two million children under 5 years of age die from pneumonia each year, accounting for almost one in five under-5 deaths worldwide. Substantial effort, some with great success, has gone into developing a preventative approach. The serotype composition of the first pneumococcal conjugate vaccine to be licensed (PCV7; PrevnarTM ) was based on common serotypes found to cause invasive pneumococcal disease. Pneumococcal vaccine development currently is focused on 10- and 13-valent vaccines that are expected to increase protection against invasive pneumococcal disease in most regions of the world. Issues voiced at the workshop included identifying: • Which are the most relevant serotypes to incorporate into a vaccine? • In what concentration(s) should the various serotypes be incorporated? • Should strategies include multi-species vaccines, if so, which and how? • How will restrictions on vaccine injection volume affect vaccine immunogenicity? • What conjugate formulation(s) should be used? Another question raised was whether vaccines with fewer serotypes, but targeted against locally common (and pathologically relevant) serotypes in developing countries, could be produced as an economically viable alternative for developing countries, along with relevant boosters? The primary objective of the 1st Pneumonia Vaccines Workshop was to review current and emergent data and assess how key lessons learned in preventing pneumonia can provide insights for future efforts. This conference provided substantial insight into 0264-410X/$ – see front matter doi:10.1016/j.vaccine.2008.04.014
many facets of pneumonia prevention as well as addressing the overarching question.
What are the characteristics of pneumococcal vaccines that are associated with protection against pneumonia? Faculty presentations and in-depth group discussions addressed the following areas of importance: • The global burden of pneumonia. • The impact of Hib conjugate vaccines on childhood pneumonia. • The impact of pneumococcal conjugate vaccines on childhood pneumonia. • The pathologic/immunologic mechanism(s) of protection against pneumonia. • Pneumococcal serotypes and other pathogens in pneumonia and how best to include them in vaccines. The outcome from this effort was to (1) provide a scientific foundation addressing the overarching question; (2) obtain the collective thoughts on key concepts related to the prevention of pneumonia; (3) assess the value emergent vaccines may bring to the prevention of pneumonia. It was expected that the efforts of the 1st Pneumonia Vaccines Workshop would extend upon published statements from a recent WHO-sponsored report evaluating how best to construct pneumococcal conjugate vaccines for poorresource countries. The relevant WHO statements included: 1. There is recognition of the substantial value of the currently available 7-valent (PCV7) in addressing the burden of pneumococcal disease, including in developing countries. 2. The 10-valent and 13-valent pneumococcal conjugate vaccines under development are likely to cover most serotypes causing serious disease worldwide. 3. There is a role for multivalent vaccines with serotype composition different from that in the currently licensed PCV7. Different formulations for different country groupings are acceptable in principle.
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4. The focus of new formulations should be the impact of the new product for disease prevention in infants and young children through routine immunization. 5. The basis of evaluation should be the potential of such formulations to reduce disease and their cost effectiveness. The exact composition of such vaccines should be left to individual manufacturers, based on the populations that they target and in discussion with country decision-makers. 6. The use of opsonophagocytic assays (OPA) for clinical evaluation of conjugate vaccines needs to be explored and included in the revised guidelines. 7. The use of nasopharyngeal carriage as an efficacy end point is an important proposition as the frequency of acquisition events allows rapid evaluation of vaccine efficacy against this end point. Currently regulatory agencies do not consider this as a sole effectiveness end point for regulatory purposes. This should be explored further and may provide an alternative method for evaluating the potential impact of non-conjugate vaccines. This Meeting Report serves as an adjunct to the manuscripts published in this Vaccine Journal Supplement. It captures the key questions and discussions that occurred at the 1st Pneumonia Vaccines Workshop. 2. Key questions and discussion emerging from faculty presentations on the value of pneumococcal conjugate vaccines 1. When comparing vaccine efficacy over different populations and regions/countries, how can differences in population health and health infrastructure be normalized so data can be more easily compared? Case definitions: Discussion began addressing case definitions. Dr. Levine remarked that when comparing vaccine efficacy in different settings, great care must be taken in the initial evaluations; it is critical to make sure that comparable (and highly specific) case definitions are used. It was made clear that in some instances, studies that have used non-specific case definitions have failed to demonstrate significant vaccine efficacy, and in turn, result in more questions than answers provided about disease burden. Further, to compare study outcomes equitably and correctly, specific case definitions are needed to properly measure the burden of disease. Specific case definitions will also aid as much as possible in making more clear the complex messages that often emerge from these studies. The faculty agreed it is important for clinical trials to have specific end points (based on case definitions) to ensure that useful, consistent measurements are obtained. Dr. Nohynek suggested case definitions need to include age. From her and other presentations at the workshop, age appears to play a critical (though variable) role when assessing vaccine efficacy, especially in the second year of life or after. The unanswered question remains why, once a person has good protection and antibody concentrations at 9 months, does protection wane after 12 or 24 months? One suggestion to explain this observation was that efficient vaccine immunization results in herd protection, so that the overall burden of disease in the community decreases, resulting in an apparent reduced vaccine efficacy. Vaccine efficacy in essence is biased to zero since there is so little infectious pressure. A discussion concerning the use of less specific case definitions ensued. Dr. Nohnyek offered her experience with several IMCI programs that use case definitions for acute respiratory infection (ARI) and lower respiratory infection. She indicated that from a treatment perspective, these non-specific case defi-
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nitions are functioning well as the children get referred and are taking antibiotics. However, the argument was made that IMCI is used for clinical care and treatment and that does not necessarily mean that it is the ideal end point to measure the effectiveness of a vaccine program. In effect, using non-specific ways to measure vaccine impact, though attractive in its simplicity, might actually create major problems as the data become difficult to explain if they do not demonstrate vaccine impact. Dr. Levine summarized the discussion and offered the viewpoint that the faculty, as a group, need to be prepared that there might not be a simple solution and that proposing simple solutions and endorsing simple solutions might turn out in the long run to be a mistake. Epidemiologic differences: Dr. Levine restated a phrase used during the faculty presentations: “one size may not fit all.” Background epidemiologic differences across sites may influence the apparent efficacy of a vaccine, as example the data comparing vaccine efficacy in Asia versus Africa. In many cases it may be more appropriate to think about this in terms of antibiotic use or access to care in various settings and less to whether it is an Asian setting or an African one. As Dr. Gessner aptly stated, what separates Asia and Africa is geography, but what makes them consistent is that they are both areas represented by pretty high mortality and limited access to care. So, the stark lessons to be gained from the pneumonia studies are that background epidemiologic differences may influence what we see and/or think about measuring vaccine efficacy, and in some ways should bias what to expect. Dr. Madhi offered a calculation during his presentation that was in many ways unique. The calculation showed the proportion of pneumonia prevented using varying case-definitions compared to the preventable pneumonia captured by the X-ray consolidation definition [of pneumonia] alone. In his example, compared to the pneumonia outcome based on radiographic or clinical criteria, in The Gambia, 88% of all the pneumonia that was prevented had X-ray consolidation; by comparison in South Africa, 59% of all of the pneumonia prevented had X-ray consolidation. This clearly re-makes the point that there are tangible differences relating to background epidemiology. In this context it is important to discuss the clinical definition of pneumonia, especially WHO tachypnea showing variability in efficacy across sites and regions. That variability may also reflect differences in etiology of the pneumonia syndrome across various populations, again highlighting the importance of looking closely at background epidemiologic differences. In closing comments on this question, the reality is that a one size fits all approach may not be useful with regard to assessing vaccine efficacy. However, regardless of “definition,” these vaccines impact on morbidity and mortality associated with pneumonia, which may be important to different degrees in different places. 2. What is/are the best end points for diagnosis, hence comparisons of vaccine efficacy? Do we really know the etiologic agent in pneumonia “prevented” by vaccine? How valuable is the WHO case definition in comparing vaccine efficacy and is it equally valid across all settings. If not, then what? Dr. Levine indicated that the group had briefly discussed aspects related to the variability of the WHO case definition. One issue that transcends any of the end points used to measure vaccine efficacy is if, in fact, reductions in disease that are observed are fully due to pneumococcal vaccine. Are they overestimated? Underestimated? If so, in what ways and how can that be determined? Much of that answer has as a common denominator: knowing the primary etiologic agent.
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As example, discussion followed on lessons learned from evaluating the impact of pneumococcal conjugate vaccine in The Gambia and in the Philippines. In the end, it is difficult to always identify the actual etiologic agent in pneumonia. Dr. Levine summarized that the current discussion really relates to what the trials might be telling us about either the (1) etiology of what is called WHO pneumonia in different settings; or (2) the specificity of that diagnosis in different areas, and less so about the biological activity of the vaccine. Assessing vaccine efficacy becomes very complicated when comparing population and regional/country differences; in fact, what we may be learning is not “true” vaccine efficacy but a proxy for the specificity of the diagnosis and potential disease etiology in different clinical syndromes occurring in different etymological settings. Following on that point, Dr. Whitney surmized that although there is no great answer at present, when evaluating pneumonia, and as discussed by Professor Spier, viruses come in and out of the study population. Those infections over the years of study at one location can dynamically skew results. To normalize this impact, with regard to observational studies, large and multi-site studies compared to studying isolated populations is the approach that may provide a cleaner result. Dr. Levine next summarized the value of the WHO case definition for pneumonia. First, it is clear from published data and data presented at this workshop that the value and the efficacy of pneumococcal vaccines to prevent pneumonia is measurable in clinical trials. While not referred to directly, most would accept that X-ray interpretations of pneumonia can be standardized. Such interpretations are far from perfect, but the WHO process successfully improved the standardized interpretation of chest X-rays perhaps beyond even what many people thought possible at the outset. In the high mortality area of The Gambia, as recently published and in data from that trial presented by Dr. Mahdi, WHO X-ray consolidation did predict likely pneumococcal pneumonia. From that study it was impressive that many of the confirmed pneumococcal pneumonias were accounted for using the Xray consolidation. Further, mortality rate was also captured and highest in the X-ray consolidation group compared to the other infiltrates and no infiltrates. But it was also clear upon overall review that there is real variability in the value of the WHO case definition across sites/locations; and that the proportion of preventable pneumonia that is captured by X-ray consolidation is not consistent. Another area touched upon is use of an adjunct along with X-ray evaluation to identify pneumococcal pneumonia. Data provided by Dr. Madhi did appear to show that sensitivity for identifying preventable pneumococcal pneumonias was improved with the use of C-reactive protein (CRP) in combination with abnormal X-ray without overly sacrificing specificity. 3. What role if any is there for CRP in identifying pneumococcal disease? Is it useful for only disease caused by certain pneumococcal serotypes? Is it useful in addition to procalcitonin and hypoxemia as a marker (or are they better without CRP)? Should CRP be included in prospective trials to assess its value under controlled conditions? Comments were sought on experience in diagnosing based on use of X-rays, or X-rays with consolidation, and/or use of X-rays of other infiltrates plus CRP. While higher CRP levels seem to correlate with [more] severe pneumonia, it is not an absolute correlation. For example, in South Africa, there was a very high associative level of CRP for patients with alveolar consolidation. But overall, it probably is not [yet] meaningful to define a certain level of CRP as sufficient
to define severe pneumonia. Notwithstanding, Dr. Levine challenged the faculty by reiterating Dr. Madhi’s data, focusing on an observed consistency in using the “other infiltrate” category plus CRP greater than 40 to help make the diagnosis. On further group discussion, the major issue in ascribing such value to CRP is not having sufficient data to unequivocally support its use as an adjunct to X-rays in diagnosing acute pneumonia. CRP, for example, might be suggesting a pneumococcal infection, rather than a “pneumonia,” thus when consolidation is not present high CRP may imply the presence of S. pneumoniae, although not necessarily in the lung. The faculty voiced another substantial confounder to using CRP as a diagnostic adjunct for pneumococcal pneumonia: it almost impossible to ascertain whether CRP discriminates sufficiently between acute bacterial and viral infections; and the concentration of CRP can be affected by antibiotic treatment. A case in point is the difference between South Africa and The Gambia with regard to radiographically confirmed pneumonia: a median CRP of 33 compared to approximately 140, respectively, with the fundamental difference likely to be greater/more widespread use of antibiotics in South Africa compared with The Gambia. Dr. Dagan raised the point that perhaps high CRP levels in blood not only related to viral [co-]infection but might also be more specific for infection with a particular pneumococcal serotype(s) than the pneumococcus in general. He provided background data of clinical cases in which pneumococcal serotype 1 or 5 was carried in the nasopharynx during alveolar pneumonia, with extremely high CRP levels compared to alveolar pneumonias populated with other pneumococcal serotypes, higher by an order of magnitude. He continued that while viral coinfection, or infection with adenovirus, results in very high CRP levels, is his clinical experience the [nasopharyngeal] presence of serotype 1 rarely occurs in the absence of high CRP. So a critical question is if CRP actually provides increased sensitivity to disease based on specific pneumococcal serotypes as opposed to generalized pneumonia? If so, this would be valuable in one sense, but less valuable overall. Further discussion on this point focused on the increased likelihood of having disease when colonized with pneumococcal serotypes 1 and 5, suggesting that nasopharyngeal isolates of these serotypes in pneumonia may be in fact more predictive of pneumococcal disease than colonization with other vaccine-type serotypes. Dr. Whitney expanded discussion beyond CRP, indicating that in evaluating the benefit of CRP, she also assessed procalcitonin and hypoxemia as indicators for disease severity. She indicated that in a trial in which she is involved, CRP was found to be not that useful; conversely, procalcitonin did predict the severity of infection. Moreover, the combination of hypoxemia and a procalcitonin above three appeared quite specific and very useful when measuring vaccine impact. However, data from The Gambia demonstrated procalcitonin not to be useful, again highlighting that acute phase reactants suffer from being very non-specific and very much associated with tissue injury. The conclusion from this discussion was though interesting and in cases very useful, acute phase reactants may not be the ultimate answer to identifying specific pneumococcal etiology. Nonetheless, CRP and other acute phase reactants were considered worthy of additional analysis. 4. With respect to Hib vaccines, what is the relationship(s) between decreased carriage and disease? Can observations with Hib vaccines be extrapolated to PCV? Dr. Gessner was questioned on his statement that the impact of Hib vaccines on carriage was less than on invasive disease. He
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expanded that except for the really isolated populations, such as the Alaskan natives, reductions in invasive disease were up in the 90% range but for reductions in carriage, were more in the range of 60–70%. Across the board, on average, the impact of Hib vaccines on carriage was less than on disease. However, there are examples like The Gambia that provide a counterpoint, where the initial reductions in carriage were not impressive but over the years there was essentially no Hib carriage. Thus, perhaps the important component is time. But it is clear that there is no need to eliminate carriage to see indirect effects and have a huge impact on disease. The conclusion of the discussion was that there may be more similarity than difference between the two and although not completely correlated, reduced carriage is related to reduced disease but carriage reduction appears to lag behind reductions in invasive disease. On a related note there was discussion concerning the virulence of Hib. The comparative point was that if you match the usually low carriage rates for Hib (around 5%) compared with carriage of pneumococci (around 100%), the ratio of severe disease incidence to carriage prevalence is higher for Hib than for pneumococci of all serotypes as a group. However, specific pneumococcal serotypes may have higher virulence than Hib, such as serotype 1 which is infrequently carried and yet is a common serotype in invasive pneumococcal disease. In the end however, even if carriage is to be considered a proxy for vaccine efficacy, the more important outcome of vaccination is the creation of immunity, the reduction of disease, and perhaps the extended protection to non-immunized individuals through indirect immunity. Dr. Gessner finished the discussion with reiteration of key points relevant to carriage and Hib vaccine impact: Relevant points relating to carriage • Hib conjugate vaccine has had a major impact on Hib carriage, accounting for large indirect reductions in disease. • Pre-vaccine introduction Hib carriage prevalence does not correlate particularly well with invasive disease incidence. • No data exist on the correlation between vaccine impact on Hib carriage and reduction in non-bacteremic pneumonia, with the latter the major target of pneumococcal conjugate vaccines. This is particularly problematic for pneumococcal vaccines, since the serotype distribution of non-bacteremic pneumonia is poorly documented (although data from vaccine probe studies can allow inference as to the relative contribution of vaccine serotypes). • Substantial differences between Hib and pneumococcal molecular genetics, microbiology, and epidemiology make it difficult to extrapolate from the results of Hib vaccine impact on carriage to potential pneumococcal conjugate vaccine impact on carriage, either globally or in specific locations. Relevant points relating to Hib vaccine impact • During the pre-vaccine era, Hib caused high burdens of disease throughout the world, but it is likely that most cases and deaths occurred in Asia since most of the pediatric population resides in Asia. • Hib conjugate vaccine impact was relatively easy to measure as vaccine targeted meningitis (with etiology easy to identify), only one serotype existed to any substantial degree making serotype replacement less of an issue, and vaccine led to a strong effect on carriage leading to disease reduction even in areas with relatively poor vaccination coverage. • It may be more difficult to measure vaccine impact for pneumococcal vaccine because many serotypes cause disease, few developing countries have serotyping capacity, serotype
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replacement likely occurs, and the primary target outcome is non-bacteremic pneumonia for which etiologic determination is difficult. • While few resources were needed to document Hib conjugate vaccine impact, it is likely that substantial investments will need to be made to document pneumococcal conjugate vaccine impact; nevertheless, given the potential for serotype replacement and resultant limited impact of vaccine over time, such investments in surveillance are mandatory. 5. How do we reconcile early success with PPV with contemporary failures? Are those PPV failures related to different antigen concentrations, hence resulting in different antibody concentrations; and/or to antibody functionality? Dr. Dagan addressed the striking differences between the earliest results using PPV with what is commonly observed today. The early and very successful studies used 50–60 g per polysaccharide but newer vaccines use approximately 25 g for each polysaccharide. He noted further that the first studies were done on healthy adults, at a double antigen dose, with fewer serotypes but epidemic serotypes. He concluded that it is quite clear that the PPV vaccine that is being used today, the 23-valent, is not the same vaccine that Ian Riley used or that was used in South African gold miners. A discussion ensued on frustration that original PPV vaccine is not being used or tested in Africa, based on the two original studies that showed how well they worked in very poor settings, settings with substantial transmission and burden of disease, and probably a good amount of serotype 1 involvement. Not all agreed. Others thought it more appealing to consider studying the 23-valent or a 14-valent PPV in a different population, especially one more like the population of miners, and that perhaps the better recommendation is to probe around and identify more about what the differences are between vaccines/populations. Dr. Whitney agreed, stating that the PPV vaccine used today is just a different story and that one cannot extrapolate outcomes from the earlier studies. The final issue discussed the apparently decreased efficacy of PPV in older individuals. The suggestion was that this observation may be related to immunology, more specifically, the quality of the antibody produced at different ages. The point was made that certain data demonstrated significant negative change over time in the production of antibodies as measured in the opsonophagocytic assay, with very ineffective antibodies in those older than 55 or 65. This observation is supported by data that young adults make high quality antibody when vaccinated with PPV while older individuals make a good amounts of not very functional antibody. 6. Can it be inferred that a vaccine (pneumococcal serotype) that protects effectively at a mucosal surface (e.g. against OM) will, with high likelihood, protect against disease at a distant mucosal surface (lungs; pneumococcal pneumonia)? What supports or refutes this inference? Are biofilms important and is there a role in prevention for antibodies to Haemophilus protein D? Can it be inferred that a vaccine that prevents a mucosal infection such as otitis media will prevent a different mucosal infection at a different site? Can data from the POET study on prevention of acute otitis media be extrapolated to imply prevention of pneumococcal pneumonia caused by identical serotypes? Dr. Dagan remarked that most important it is not the same mucosa, it is not the same environment or milieu, and the pathogenic mechanism of disease is not the same. Overall, while the relevant antibodies may get to the relevant locations, because
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there are so many other unknowns (including the relevance of the different pneumococcal serotypes in otitis or invasive disease), assuming equivalent activity of vaccine serotype-related antibodies at a similar [mucosal] surface is not currently justified. He continued that we need to be very careful in approaching this question. One commonality between protection against otitis media and pneumonia appears to be measures of antibody concentration, although that alone does not serve as a suitable proxy. Biofilms are another consideration not well discussed with regard to their role in disease. For otitis media, when chronic, there is a biofilm milieu. Haemophilus is an important component in that biofilm community, as are pneumococcal serotypes. And for Haemophilus, antibody to protein D prevents some critical functions and many researchers believe that antibodies to Haemophilus protein D can prevent Haemophilus from being successful in the biofilm. It was concluded that while it is helpful to look to otitis media for guidance on the value of any particular pneumococcal vaccine, there are limitations to how much otitis media can tell us about pneumonia. Clearly, extrapolating that protection observed against otitis media will necessarily relate to prevention against pneumonia is not appropriate. 7. Is there evidence to support a role for NTHi in pneumonia? There was discussion on the role of NTHi in pneumonia. It was agreed that there is clearly some controversy. Overall, Haemophilus influenza type B is important in pneumonia, but from the data presented, the available evidence does not suggest a major role for NTHi in bacteremic pneumonias but does not exclude the possibility that it is involved in other lower respiratory tract infections. This would fit with the biology of the organism, since it is likely the capsule plays an important role in survival in the bloodstream. 3. Main session discussion Overarching question: What are the characteristics of pneumococcal vaccines that are associated with protection against pneumonia? Dr. Levine expressed his view that it would be valuable to begin with an open discussion centering on what are the characteristics of pneumococcal vaccines that the assembled group thinks are associated with protection against pneumonia? Dr. Whitney suggested there were two valuable end points, ELISA titers and rates of carriage, especially carriage, as its reduction means pneumococci are not in the body and will not cause pneumonia. She continued that carriage is certainly not an exact/direct measure as there are some differences between serotypes, such as 1 and 5, but for the serotypes that are frequently carried it would be a reasonable proxy. It would be unexpected for any vaccine that had a characteristic of reducing carriage of pneumonia-related serotypes to not prevent pneumonia. Dr. Dagan stated that good insight can be gained by looking at results with the currently available PCV7 vaccine. First, it is clear that whatever has been learned with PCV7 will not relate to predictions of an impact on pneumonia for serotypes 1, 5, and 7F as there currently are not sufficient data accrued to make the correlation. Nonetheless, should any emergent pneumococcal vaccine containing the 7 serotypes contained within PCV7 protect at least as well as PCV7, that is of the same order of magnitude or better, a good outcome should be expected with that emergent vaccine. The second argument for an emergent vaccine to be effective is the capacity to show efficacy against otitis media. And while it is
clear from data presented at the workshop that there is no direct evidence that the 10-valent pneumococcal vaccine currently under development has an impact on otitis media, what is clear from the POET study is that its precursor, its prototype, worked effectively against AOM. While we have to take on faith that the changes from the prototype to the current 10-valent vaccine are not ones that will reduce its efficacy, Dr. Dagan indicated he would be satisfied and expect that in view of the critical evidence presented at the workshop that any vaccine with these characteristics will provide protection against pneumonia at least as good if not better than the current 7-valent vaccine (PCV7). Lastly, he agreed with Dr. Whitney that should the 10-valent pneumococcal conjugate vaccine also effect/reduce carriage, he would be surprised if it did not also prevent pneumonia. Dr. Levine probed deeper, focusing on the question of immunogenicity and the role of circulating antibody in relation to protection at mucosal surfaces. He noted that discussions had addressed and ascribed a certain relevance to carriage reductions and reductions in the incidence of otitis media, implying that these would be supportive evidence of the potential for a vaccine to be effective against pneumonia. However, statements that any new vaccine should have similar immunogenicity to the 7valent vaccine remained unclear and required clarification. Exactly what gauge of immunogenicity equivalence is sufficient: a similar percent seroconversion or perhaps geometric mean concentration (GMC). . . or is this unknown? There was some preference in the group for GMCs because that threshold was appropriate for evaluating carriage. Dr. Dagan agreed that GMC is important but suggested that what is potentially more important to functionality, to effectiveness, is the geometric mean titer (GMT) of the opsonophagocytic antibodies (which he noted often move together but not always). OPA GMTs that are high are important, as is a boosterability. Dr. Dagan clarified further by stating that it is important to evaluate OPA antibodies both after primary immunization and again after booster as a means to provide evidence for similarity/equivalence/differences between vaccines. If all end points had favorable comparisons, that finding would be a good proxy for equivalent/superior efficacy. Dr. Whitney questioned the absolute need for data from a 6-month booster. Dr. Levine questioned if booster data was a musthave or would be nice-to-have to make comparisons between the current 7-valent vaccine and any emergent vaccine. Consensus was that these data would be would be nice-to-have but not essential to making a value statement. Dr. Madhi commented that while OPA certainly is predictive in terms of protection against invasive pneumococcal disease, the association between OPA and pneumonia is far less clear because there simply are no implicit data. He also stressed the importance of being able to impact colonization as a means to show comparative efficacy between vaccines and to be able to predict protection when using a particular vaccine, yet there is not any [definitive] correlation between OPA and colonization. What data exist are the correlation between antibody concentration and its effect on colonization. Thus, he questioned if it is really sufficient to concentrate so heavily on OPA as a proxy for predicted efficacy, and if antibody concentration should not be the major end point when assessing a predictive impact on pneumonia? Dr. Dagan agreed there is correlation between antibody concentration and what is measured in ELISA. Further, while OPA end points are not likely related to invasive disease, what they do measure is how much of the antibody is functional. So, what is being stressed is not antibody titer but antibody functionality. Dr. Dagan believed that it is not a feasible position that functional antibodies will be functional in one site and [be] functionally different in some other site.
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Table 1 Characteristics supporting the value proposition for an emerging vaccine as beneficial in the prevention of pneumonia Desired characteristics 1. Similar or superior immunogenicity to existing vaccines that have proven efficacy and that include(s) IgG responses 2. Similar or superior GMC to existing vaccines that have proven efficacy, preferably a high GMC 3. Similar or superior OPA titers 4. Prevention of otitis media and/or colonization as important supporting information 5. “Evidence of boosterability” 6. Safe
Table 2 Caveats to consider when assessing the value proposition for an emerging vaccine as beneficial in the prevention of pneumonia Important caveats and conditions 1. Real-world impact/value of serotypes 1, 5, and 7F cannot be determined at this time; however, we should anticipate a characteristic for success being a formulation of serotypes that match leading invasive pneumococcal serotypes 2. The exact relationship between OPA and pneumonia or OPA and mucosal protection is not fully clear at this time 3. Immunization schedules other than 3 + 1 or 3 + 0 in infancy should be considered risky at the moment 4. But, the value of a booster is not fully clear at this time
Dr. Levine re-stated that what the assemblage was trying to do was identify what the characteristics of a vaccine needed to be for the faculty to feel comfortable that, if achieved, the vaccine would possess those attributes typically associated with pneumococcal conjugate vaccines that are effective against pneumonia. Summarizing, they have included (1) similar or superior immunogenicity to the existing vaccines that have proven efficacy, including IgG functional responses; (2) that GMC similarity or superiority is important and that ideally the GMC should both be similar and high; (3) that OPA GMT is at least as important as antibody titers, if possibly not more important as it measures antibody function; (4) that prevention of otitis media and/or colonization is also important supporting information; and (5) measurable boosterability (Table 1). Dr. Levine mentioned two caveats: (1) it is difficult to forecast prevention of pneumonia due to serotypes 1, 5, and 7F based on experience with the 7-valent or even 9-valent because we have not had enough experience or seen enough of the characteristics that might be associated with successful protection against 1, 5 and 7F; and, as Dr. Mahdi indicated, (2) OPA is important, but the relationship between OPA and pneumonia or OPA and mucosal protection is less clear. Dr. Dagan stated that there is another caveat that must be stressed very strongly: immunization schedules. There is currently no proof that a shortened schedule with PCV7 or any other PCVs is equivalent in terms of protection against pneumococcus when compared with the “classical” 3 + 1 schedule.
Dr. Levine added the third (3) caveat that the characteristics of the vaccines that have confirmed, proven efficacy against pneumonia and in which the faculty have confidence utilize a three-dose regimen, in infancy. Dr. Dagan stressed a 3 + 1 [immunization/booster schedule] regimen. . . a schedule of 3 + 1 or 3 + 0 in some countries. Dr. Levine agreed that the third (3) caveat implies that we as faculty are not comfortable yet extrapolating to regimens of fewer than three doses in infancy. However, the role of a booster in providing long-term protection against pneumonia is not clear yet but may well be important (Table 2). The suggestion was made to finish the conference with a brief discussion of vaccine formulations. What should they include? Dr Levine noted that this is a critical issue and that collectively there has always been the conversation about not knowing which serotypes cause non-bacteremic pneumonia. However, in reality, and in data presented by Dr. Hausdorff at the workshop, the coverage of vaccines against the leading invasive serotypes has been pretty effective, with reductions in pneumonia an important characteristic of those vaccines. In closing, all agreed that characteristics of a successful pneumococcal conjugate vaccine will be a formulation of pneumococcal serotypes that at the least matches leading invasive pneumococcal serotypes and contain, where possible, immunologically relevant and novel protein conjugates. And, certainly, any vaccine must also be safe (Table 1).
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Meeting report First International Pneumonia Vaccines Workshop on Prevention of Childhood Pneumonia by Vaccination: Lessons from the Past and Implications for the Future, 15 December 2007, Seoul, Korea
a b s t r a c t The primary objective of the 1st Pneumonia Vaccines Workshop was to review current and emergent data and assess how key lessons learned in preventing pneumonia can provide insights for future efforts. This conference provided substantial insight into many facets of pneumonia prevention as well as addressing the overarching question: What are the characteristics of pneumococcal vaccines that are associated with protection against pneumonia?
1. Conference background On 15 December 2007 an international workshop was convened in Seoul, Korea to evaluate the progress made to date in preventing pneumonia, especially in children under 5 years of age. Pneumonia kills more children than any other illness—more than AIDS, malaria, and measles combined. More than two million children under 5 years of age die from pneumonia each year, accounting for almost one in five under-5 deaths worldwide. Substantial effort, some with great success, has gone into developing a preventative approach. The serotype composition of the first pneumococcal conjugate vaccine to be licensed (PCV7; PrevnarTM ) was based on common serotypes found to cause invasive pneumococcal disease. Pneumococcal vaccine development currently is focused on 10- and 13-valent vaccines that are expected to increase protection against invasive pneumococcal disease in most regions of the world. Issues voiced at the workshop included identifying: • Which are the most relevant serotypes to incorporate into a vaccine? • In what concentration(s) should the various serotypes be incorporated? • Should strategies include multi-species vaccines, if so, which and how? • How will restrictions on vaccine injection volume affect vaccine immunogenicity? • What conjugate formulation(s) should be used? Another question raised was whether vaccines with fewer serotypes, but targeted against locally common (and pathologically relevant) serotypes in developing countries, could be produced as an economically viable alternative for developing countries, along with relevant boosters? The primary objective of the 1st Pneumonia Vaccines Workshop was to review current and emergent data and assess how key lessons learned in preventing pneumonia can provide insights for future efforts. This conference provided substantial insight into 0264-410X/$ – see front matter doi:10.1016/j.vaccine.2008.04.014
many facets of pneumonia prevention as well as addressing the overarching question.
What are the characteristics of pneumococcal vaccines that are associated with protection against pneumonia? Faculty presentations and in-depth group discussions addressed the following areas of importance: • The global burden of pneumonia. • The impact of Hib conjugate vaccines on childhood pneumonia. • The impact of pneumococcal conjugate vaccines on childhood pneumonia. • The pathologic/immunologic mechanism(s) of protection against pneumonia. • Pneumococcal serotypes and other pathogens in pneumonia and how best to include them in vaccines. The outcome from this effort was to (1) provide a scientific foundation addressing the overarching question; (2) obtain the collective thoughts on key concepts related to the prevention of pneumonia; (3) assess the value emergent vaccines may bring to the prevention of pneumonia. It was expected that the efforts of the 1st Pneumonia Vaccines Workshop would extend upon published statements from a recent WHO-sponsored report evaluating how best to construct pneumococcal conjugate vaccines for poorresource countries. The relevant WHO statements included: 1. There is recognition of the substantial value of the currently available 7-valent (PCV7) in addressing the burden of pneumococcal disease, including in developing countries. 2. The 10-valent and 13-valent pneumococcal conjugate vaccines under development are likely to cover most serotypes causing serious disease worldwide. 3. There is a role for multivalent vaccines with serotype composition different from that in the currently licensed PCV7. Different formulations for different country groupings are acceptable in principle.
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4. The focus of new formulations should be the impact of the new product for disease prevention in infants and young children through routine immunization. 5. The basis of evaluation should be the potential of such formulations to reduce disease and their cost effectiveness. The exact composition of such vaccines should be left to individual manufacturers, based on the populations that they target and in discussion with country decision-makers. 6. The use of opsonophagocytic assays (OPA) for clinical evaluation of conjugate vaccines needs to be explored and included in the revised guidelines. 7. The use of nasopharyngeal carriage as an efficacy end point is an important proposition as the frequency of acquisition events allows rapid evaluation of vaccine efficacy against this end point. Currently regulatory agencies do not consider this as a sole effectiveness end point for regulatory purposes. This should be explored further and may provide an alternative method for evaluating the potential impact of non-conjugate vaccines. This Meeting Report serves as an adjunct to the manuscripts published in this Vaccine Journal Supplement. It captures the key questions and discussions that occurred at the 1st Pneumonia Vaccines Workshop. 2. Key questions and discussion emerging from faculty presentations on the value of pneumococcal conjugate vaccines 1. When comparing vaccine efficacy over different populations and regions/countries, how can differences in population health and health infrastructure be normalized so data can be more easily compared? Case definitions: Discussion began addressing case definitions. Dr. Levine remarked that when comparing vaccine efficacy in different settings, great care must be taken in the initial evaluations; it is critical to make sure that comparable (and highly specific) case definitions are used. It was made clear that in some instances, studies that have used non-specific case definitions have failed to demonstrate significant vaccine efficacy, and in turn, result in more questions than answers provided about disease burden. Further, to compare study outcomes equitably and correctly, specific case definitions are needed to properly measure the burden of disease. Specific case definitions will also aid as much as possible in making more clear the complex messages that often emerge from these studies. The faculty agreed it is important for clinical trials to have specific end points (based on case definitions) to ensure that useful, consistent measurements are obtained. Dr. Nohynek suggested case definitions need to include age. From her and other presentations at the workshop, age appears to play a critical (though variable) role when assessing vaccine efficacy, especially in the second year of life or after. The unanswered question remains why, once a person has good protection and antibody concentrations at 9 months, does protection wane after 12 or 24 months? One suggestion to explain this observation was that efficient vaccine immunization results in herd protection, so that the overall burden of disease in the community decreases, resulting in an apparent reduced vaccine efficacy. Vaccine efficacy in essence is biased to zero since there is so little infectious pressure. A discussion concerning the use of less specific case definitions ensued. Dr. Nohnyek offered her experience with several IMCI programs that use case definitions for acute respiratory infection (ARI) and lower respiratory infection. She indicated that from a treatment perspective, these non-specific case defi-
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nitions are functioning well as the children get referred and are taking antibiotics. However, the argument was made that IMCI is used for clinical care and treatment and that does not necessarily mean that it is the ideal end point to measure the effectiveness of a vaccine program. In effect, using non-specific ways to measure vaccine impact, though attractive in its simplicity, might actually create major problems as the data become difficult to explain if they do not demonstrate vaccine impact. Dr. Levine summarized the discussion and offered the viewpoint that the faculty, as a group, need to be prepared that there might not be a simple solution and that proposing simple solutions and endorsing simple solutions might turn out in the long run to be a mistake. Epidemiologic differences: Dr. Levine restated a phrase used during the faculty presentations: “one size may not fit all.” Background epidemiologic differences across sites may influence the apparent efficacy of a vaccine, as example the data comparing vaccine efficacy in Asia versus Africa. In many cases it may be more appropriate to think about this in terms of antibiotic use or access to care in various settings and less to whether it is an Asian setting or an African one. As Dr. Gessner aptly stated, what separates Asia and Africa is geography, but what makes them consistent is that they are both areas represented by pretty high mortality and limited access to care. So, the stark lessons to be gained from the pneumonia studies are that background epidemiologic differences may influence what we see and/or think about measuring vaccine efficacy, and in some ways should bias what to expect. Dr. Madhi offered a calculation during his presentation that was in many ways unique. The calculation showed the proportion of pneumonia prevented using varying case-definitions compared to the preventable pneumonia captured by the X-ray consolidation definition [of pneumonia] alone. In his example, compared to the pneumonia outcome based on radiographic or clinical criteria, in The Gambia, 88% of all the pneumonia that was prevented had X-ray consolidation; by comparison in South Africa, 59% of all of the pneumonia prevented had X-ray consolidation. This clearly re-makes the point that there are tangible differences relating to background epidemiology. In this context it is important to discuss the clinical definition of pneumonia, especially WHO tachypnea showing variability in efficacy across sites and regions. That variability may also reflect differences in etiology of the pneumonia syndrome across various populations, again highlighting the importance of looking closely at background epidemiologic differences. In closing comments on this question, the reality is that a one size fits all approach may not be useful with regard to assessing vaccine efficacy. However, regardless of “definition,” these vaccines impact on morbidity and mortality associated with pneumonia, which may be important to different degrees in different places. 2. What is/are the best end points for diagnosis, hence comparisons of vaccine efficacy? Do we really know the etiologic agent in pneumonia “prevented” by vaccine? How valuable is the WHO case definition in comparing vaccine efficacy and is it equally valid across all settings. If not, then what? Dr. Levine indicated that the group had briefly discussed aspects related to the variability of the WHO case definition. One issue that transcends any of the end points used to measure vaccine efficacy is if, in fact, reductions in disease that are observed are fully due to pneumococcal vaccine. Are they overestimated? Underestimated? If so, in what ways and how can that be determined? Much of that answer has as a common denominator: knowing the primary etiologic agent.
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As example, discussion followed on lessons learned from evaluating the impact of pneumococcal conjugate vaccine in The Gambia and in the Philippines. In the end, it is difficult to always identify the actual etiologic agent in pneumonia. Dr. Levine summarized that the current discussion really relates to what the trials might be telling us about either the (1) etiology of what is called WHO pneumonia in different settings; or (2) the specificity of that diagnosis in different areas, and less so about the biological activity of the vaccine. Assessing vaccine efficacy becomes very complicated when comparing population and regional/country differences; in fact, what we may be learning is not “true” vaccine efficacy but a proxy for the specificity of the diagnosis and potential disease etiology in different clinical syndromes occurring in different etymological settings. Following on that point, Dr. Whitney surmized that although there is no great answer at present, when evaluating pneumonia, and as discussed by Professor Spier, viruses come in and out of the study population. Those infections over the years of study at one location can dynamically skew results. To normalize this impact, with regard to observational studies, large and multi-site studies compared to studying isolated populations is the approach that may provide a cleaner result. Dr. Levine next summarized the value of the WHO case definition for pneumonia. First, it is clear from published data and data presented at this workshop that the value and the efficacy of pneumococcal vaccines to prevent pneumonia is measurable in clinical trials. While not referred to directly, most would accept that X-ray interpretations of pneumonia can be standardized. Such interpretations are far from perfect, but the WHO process successfully improved the standardized interpretation of chest X-rays perhaps beyond even what many people thought possible at the outset. In the high mortality area of The Gambia, as recently published and in data from that trial presented by Dr. Mahdi, WHO X-ray consolidation did predict likely pneumococcal pneumonia. From that study it was impressive that many of the confirmed pneumococcal pneumonias were accounted for using the Xray consolidation. Further, mortality rate was also captured and highest in the X-ray consolidation group compared to the other infiltrates and no infiltrates. But it was also clear upon overall review that there is real variability in the value of the WHO case definition across sites/locations; and that the proportion of preventable pneumonia that is captured by X-ray consolidation is not consistent. Another area touched upon is use of an adjunct along with X-ray evaluation to identify pneumococcal pneumonia. Data provided by Dr. Madhi did appear to show that sensitivity for identifying preventable pneumococcal pneumonias was improved with the use of C-reactive protein (CRP) in combination with abnormal X-ray without overly sacrificing specificity. 3. What role if any is there for CRP in identifying pneumococcal disease? Is it useful for only disease caused by certain pneumococcal serotypes? Is it useful in addition to procalcitonin and hypoxemia as a marker (or are they better without CRP)? Should CRP be included in prospective trials to assess its value under controlled conditions? Comments were sought on experience in diagnosing based on use of X-rays, or X-rays with consolidation, and/or use of X-rays of other infiltrates plus CRP. While higher CRP levels seem to correlate with [more] severe pneumonia, it is not an absolute correlation. For example, in South Africa, there was a very high associative level of CRP for patients with alveolar consolidation. But overall, it probably is not [yet] meaningful to define a certain level of CRP as sufficient
to define severe pneumonia. Notwithstanding, Dr. Levine challenged the faculty by reiterating Dr. Madhi’s data, focusing on an observed consistency in using the “other infiltrate” category plus CRP greater than 40 to help make the diagnosis. On further group discussion, the major issue in ascribing such value to CRP is not having sufficient data to unequivocally support its use as an adjunct to X-rays in diagnosing acute pneumonia. CRP, for example, might be suggesting a pneumococcal infection, rather than a “pneumonia,” thus when consolidation is not present high CRP may imply the presence of S. pneumoniae, although not necessarily in the lung. The faculty voiced another substantial confounder to using CRP as a diagnostic adjunct for pneumococcal pneumonia: it almost impossible to ascertain whether CRP discriminates sufficiently between acute bacterial and viral infections; and the concentration of CRP can be affected by antibiotic treatment. A case in point is the difference between South Africa and The Gambia with regard to radiographically confirmed pneumonia: a median CRP of 33 compared to approximately 140, respectively, with the fundamental difference likely to be greater/more widespread use of antibiotics in South Africa compared with The Gambia. Dr. Dagan raised the point that perhaps high CRP levels in blood not only related to viral [co-]infection but might also be more specific for infection with a particular pneumococcal serotype(s) than the pneumococcus in general. He provided background data of clinical cases in which pneumococcal serotype 1 or 5 was carried in the nasopharynx during alveolar pneumonia, with extremely high CRP levels compared to alveolar pneumonias populated with other pneumococcal serotypes, higher by an order of magnitude. He continued that while viral coinfection, or infection with adenovirus, results in very high CRP levels, is his clinical experience the [nasopharyngeal] presence of serotype 1 rarely occurs in the absence of high CRP. So a critical question is if CRP actually provides increased sensitivity to disease based on specific pneumococcal serotypes as opposed to generalized pneumonia? If so, this would be valuable in one sense, but less valuable overall. Further discussion on this point focused on the increased likelihood of having disease when colonized with pneumococcal serotypes 1 and 5, suggesting that nasopharyngeal isolates of these serotypes in pneumonia may be in fact more predictive of pneumococcal disease than colonization with other vaccine-type serotypes. Dr. Whitney expanded discussion beyond CRP, indicating that in evaluating the benefit of CRP, she also assessed procalcitonin and hypoxemia as indicators for disease severity. She indicated that in a trial in which she is involved, CRP was found to be not that useful; conversely, procalcitonin did predict the severity of infection. Moreover, the combination of hypoxemia and a procalcitonin above three appeared quite specific and very useful when measuring vaccine impact. However, data from The Gambia demonstrated procalcitonin not to be useful, again highlighting that acute phase reactants suffer from being very non-specific and very much associated with tissue injury. The conclusion from this discussion was though interesting and in cases very useful, acute phase reactants may not be the ultimate answer to identifying specific pneumococcal etiology. Nonetheless, CRP and other acute phase reactants were considered worthy of additional analysis. 4. With respect to Hib vaccines, what is the relationship(s) between decreased carriage and disease? Can observations with Hib vaccines be extrapolated to PCV? Dr. Gessner was questioned on his statement that the impact of Hib vaccines on carriage was less than on invasive disease. He
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expanded that except for the really isolated populations, such as the Alaskan natives, reductions in invasive disease were up in the 90% range but for reductions in carriage, were more in the range of 60–70%. Across the board, on average, the impact of Hib vaccines on carriage was less than on disease. However, there are examples like The Gambia that provide a counterpoint, where the initial reductions in carriage were not impressive but over the years there was essentially no Hib carriage. Thus, perhaps the important component is time. But it is clear that there is no need to eliminate carriage to see indirect effects and have a huge impact on disease. The conclusion of the discussion was that there may be more similarity than difference between the two and although not completely correlated, reduced carriage is related to reduced disease but carriage reduction appears to lag behind reductions in invasive disease. On a related note there was discussion concerning the virulence of Hib. The comparative point was that if you match the usually low carriage rates for Hib (around 5%) compared with carriage of pneumococci (around 100%), the ratio of severe disease incidence to carriage prevalence is higher for Hib than for pneumococci of all serotypes as a group. However, specific pneumococcal serotypes may have higher virulence than Hib, such as serotype 1 which is infrequently carried and yet is a common serotype in invasive pneumococcal disease. In the end however, even if carriage is to be considered a proxy for vaccine efficacy, the more important outcome of vaccination is the creation of immunity, the reduction of disease, and perhaps the extended protection to non-immunized individuals through indirect immunity. Dr. Gessner finished the discussion with reiteration of key points relevant to carriage and Hib vaccine impact: Relevant points relating to carriage • Hib conjugate vaccine has had a major impact on Hib carriage, accounting for large indirect reductions in disease. • Pre-vaccine introduction Hib carriage prevalence does not correlate particularly well with invasive disease incidence. • No data exist on the correlation between vaccine impact on Hib carriage and reduction in non-bacteremic pneumonia, with the latter the major target of pneumococcal conjugate vaccines. This is particularly problematic for pneumococcal vaccines, since the serotype distribution of non-bacteremic pneumonia is poorly documented (although data from vaccine probe studies can allow inference as to the relative contribution of vaccine serotypes). • Substantial differences between Hib and pneumococcal molecular genetics, microbiology, and epidemiology make it difficult to extrapolate from the results of Hib vaccine impact on carriage to potential pneumococcal conjugate vaccine impact on carriage, either globally or in specific locations. Relevant points relating to Hib vaccine impact • During the pre-vaccine era, Hib caused high burdens of disease throughout the world, but it is likely that most cases and deaths occurred in Asia since most of the pediatric population resides in Asia. • Hib conjugate vaccine impact was relatively easy to measure as vaccine targeted meningitis (with etiology easy to identify), only one serotype existed to any substantial degree making serotype replacement less of an issue, and vaccine led to a strong effect on carriage leading to disease reduction even in areas with relatively poor vaccination coverage. • It may be more difficult to measure vaccine impact for pneumococcal vaccine because many serotypes cause disease, few developing countries have serotyping capacity, serotype
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replacement likely occurs, and the primary target outcome is non-bacteremic pneumonia for which etiologic determination is difficult. • While few resources were needed to document Hib conjugate vaccine impact, it is likely that substantial investments will need to be made to document pneumococcal conjugate vaccine impact; nevertheless, given the potential for serotype replacement and resultant limited impact of vaccine over time, such investments in surveillance are mandatory. 5. How do we reconcile early success with PPV with contemporary failures? Are those PPV failures related to different antigen concentrations, hence resulting in different antibody concentrations; and/or to antibody functionality? Dr. Dagan addressed the striking differences between the earliest results using PPV with what is commonly observed today. The early and very successful studies used 50–60 g per polysaccharide but newer vaccines use approximately 25 g for each polysaccharide. He noted further that the first studies were done on healthy adults, at a double antigen dose, with fewer serotypes but epidemic serotypes. He concluded that it is quite clear that the PPV vaccine that is being used today, the 23-valent, is not the same vaccine that Ian Riley used or that was used in South African gold miners. A discussion ensued on frustration that original PPV vaccine is not being used or tested in Africa, based on the two original studies that showed how well they worked in very poor settings, settings with substantial transmission and burden of disease, and probably a good amount of serotype 1 involvement. Not all agreed. Others thought it more appealing to consider studying the 23-valent or a 14-valent PPV in a different population, especially one more like the population of miners, and that perhaps the better recommendation is to probe around and identify more about what the differences are between vaccines/populations. Dr. Whitney agreed, stating that the PPV vaccine used today is just a different story and that one cannot extrapolate outcomes from the earlier studies. The final issue discussed the apparently decreased efficacy of PPV in older individuals. The suggestion was that this observation may be related to immunology, more specifically, the quality of the antibody produced at different ages. The point was made that certain data demonstrated significant negative change over time in the production of antibodies as measured in the opsonophagocytic assay, with very ineffective antibodies in those older than 55 or 65. This observation is supported by data that young adults make high quality antibody when vaccinated with PPV while older individuals make a good amounts of not very functional antibody. 6. Can it be inferred that a vaccine (pneumococcal serotype) that protects effectively at a mucosal surface (e.g. against OM) will, with high likelihood, protect against disease at a distant mucosal surface (lungs; pneumococcal pneumonia)? What supports or refutes this inference? Are biofilms important and is there a role in prevention for antibodies to Haemophilus protein D? Can it be inferred that a vaccine that prevents a mucosal infection such as otitis media will prevent a different mucosal infection at a different site? Can data from the POET study on prevention of acute otitis media be extrapolated to imply prevention of pneumococcal pneumonia caused by identical serotypes? Dr. Dagan remarked that most important it is not the same mucosa, it is not the same environment or milieu, and the pathogenic mechanism of disease is not the same. Overall, while the relevant antibodies may get to the relevant locations, because
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there are so many other unknowns (including the relevance of the different pneumococcal serotypes in otitis or invasive disease), assuming equivalent activity of vaccine serotype-related antibodies at a similar [mucosal] surface is not currently justified. He continued that we need to be very careful in approaching this question. One commonality between protection against otitis media and pneumonia appears to be measures of antibody concentration, although that alone does not serve as a suitable proxy. Biofilms are another consideration not well discussed with regard to their role in disease. For otitis media, when chronic, there is a biofilm milieu. Haemophilus is an important component in that biofilm community, as are pneumococcal serotypes. And for Haemophilus, antibody to protein D prevents some critical functions and many researchers believe that antibodies to Haemophilus protein D can prevent Haemophilus from being successful in the biofilm. It was concluded that while it is helpful to look to otitis media for guidance on the value of any particular pneumococcal vaccine, there are limitations to how much otitis media can tell us about pneumonia. Clearly, extrapolating that protection observed against otitis media will necessarily relate to prevention against pneumonia is not appropriate. 7. Is there evidence to support a role for NTHi in pneumonia? There was discussion on the role of NTHi in pneumonia. It was agreed that there is clearly some controversy. Overall, Haemophilus influenza type B is important in pneumonia, but from the data presented, the available evidence does not suggest a major role for NTHi in bacteremic pneumonias but does not exclude the possibility that it is involved in other lower respiratory tract infections. This would fit with the biology of the organism, since it is likely the capsule plays an important role in survival in the bloodstream. 3. Main session discussion Overarching question: What are the characteristics of pneumococcal vaccines that are associated with protection against pneumonia? Dr. Levine expressed his view that it would be valuable to begin with an open discussion centering on what are the characteristics of pneumococcal vaccines that the assembled group thinks are associated with protection against pneumonia? Dr. Whitney suggested there were two valuable end points, ELISA titers and rates of carriage, especially carriage, as its reduction means pneumococci are not in the body and will not cause pneumonia. She continued that carriage is certainly not an exact/direct measure as there are some differences between serotypes, such as 1 and 5, but for the serotypes that are frequently carried it would be a reasonable proxy. It would be unexpected for any vaccine that had a characteristic of reducing carriage of pneumonia-related serotypes to not prevent pneumonia. Dr. Dagan stated that good insight can be gained by looking at results with the currently available PCV7 vaccine. First, it is clear that whatever has been learned with PCV7 will not relate to predictions of an impact on pneumonia for serotypes 1, 5, and 7F as there currently are not sufficient data accrued to make the correlation. Nonetheless, should any emergent pneumococcal vaccine containing the 7 serotypes contained within PCV7 protect at least as well as PCV7, that is of the same order of magnitude or better, a good outcome should be expected with that emergent vaccine. The second argument for an emergent vaccine to be effective is the capacity to show efficacy against otitis media. And while it is
clear from data presented at the workshop that there is no direct evidence that the 10-valent pneumococcal vaccine currently under development has an impact on otitis media, what is clear from the POET study is that its precursor, its prototype, worked effectively against AOM. While we have to take on faith that the changes from the prototype to the current 10-valent vaccine are not ones that will reduce its efficacy, Dr. Dagan indicated he would be satisfied and expect that in view of the critical evidence presented at the workshop that any vaccine with these characteristics will provide protection against pneumonia at least as good if not better than the current 7-valent vaccine (PCV7). Lastly, he agreed with Dr. Whitney that should the 10-valent pneumococcal conjugate vaccine also effect/reduce carriage, he would be surprised if it did not also prevent pneumonia. Dr. Levine probed deeper, focusing on the question of immunogenicity and the role of circulating antibody in relation to protection at mucosal surfaces. He noted that discussions had addressed and ascribed a certain relevance to carriage reductions and reductions in the incidence of otitis media, implying that these would be supportive evidence of the potential for a vaccine to be effective against pneumonia. However, statements that any new vaccine should have similar immunogenicity to the 7valent vaccine remained unclear and required clarification. Exactly what gauge of immunogenicity equivalence is sufficient: a similar percent seroconversion or perhaps geometric mean concentration (GMC). . . or is this unknown? There was some preference in the group for GMCs because that threshold was appropriate for evaluating carriage. Dr. Dagan agreed that GMC is important but suggested that what is potentially more important to functionality, to effectiveness, is the geometric mean titer (GMT) of the opsonophagocytic antibodies (which he noted often move together but not always). OPA GMTs that are high are important, as is a boosterability. Dr. Dagan clarified further by stating that it is important to evaluate OPA antibodies both after primary immunization and again after booster as a means to provide evidence for similarity/equivalence/differences between vaccines. If all end points had favorable comparisons, that finding would be a good proxy for equivalent/superior efficacy. Dr. Whitney questioned the absolute need for data from a 6-month booster. Dr. Levine questioned if booster data was a musthave or would be nice-to-have to make comparisons between the current 7-valent vaccine and any emergent vaccine. Consensus was that these data would be would be nice-to-have but not essential to making a value statement. Dr. Madhi commented that while OPA certainly is predictive in terms of protection against invasive pneumococcal disease, the association between OPA and pneumonia is far less clear because there simply are no implicit data. He also stressed the importance of being able to impact colonization as a means to show comparative efficacy between vaccines and to be able to predict protection when using a particular vaccine, yet there is not any [definitive] correlation between OPA and colonization. What data exist are the correlation between antibody concentration and its effect on colonization. Thus, he questioned if it is really sufficient to concentrate so heavily on OPA as a proxy for predicted efficacy, and if antibody concentration should not be the major end point when assessing a predictive impact on pneumonia? Dr. Dagan agreed there is correlation between antibody concentration and what is measured in ELISA. Further, while OPA end points are not likely related to invasive disease, what they do measure is how much of the antibody is functional. So, what is being stressed is not antibody titer but antibody functionality. Dr. Dagan believed that it is not a feasible position that functional antibodies will be functional in one site and [be] functionally different in some other site.
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Table 1 Characteristics supporting the value proposition for an emerging vaccine as beneficial in the prevention of pneumonia Desired characteristics 1. Similar or superior immunogenicity to existing vaccines that have proven efficacy and that include(s) IgG responses 2. Similar or superior GMC to existing vaccines that have proven efficacy, preferably a high GMC 3. Similar or superior OPA titers 4. Prevention of otitis media and/or colonization as important supporting information 5. “Evidence of boosterability” 6. Safe
Table 2 Caveats to consider when assessing the value proposition for an emerging vaccine as beneficial in the prevention of pneumonia Important caveats and conditions 1. Real-world impact/value of serotypes 1, 5, and 7F cannot be determined at this time; however, we should anticipate a characteristic for success being a formulation of serotypes that match leading invasive pneumococcal serotypes 2. The exact relationship between OPA and pneumonia or OPA and mucosal protection is not fully clear at this time 3. Immunization schedules other than 3 + 1 or 3 + 0 in infancy should be considered risky at the moment 4. But, the value of a booster is not fully clear at this time
Dr. Levine re-stated that what the assemblage was trying to do was identify what the characteristics of a vaccine needed to be for the faculty to feel comfortable that, if achieved, the vaccine would possess those attributes typically associated with pneumococcal conjugate vaccines that are effective against pneumonia. Summarizing, they have included (1) similar or superior immunogenicity to the existing vaccines that have proven efficacy, including IgG functional responses; (2) that GMC similarity or superiority is important and that ideally the GMC should both be similar and high; (3) that OPA GMT is at least as important as antibody titers, if possibly not more important as it measures antibody function; (4) that prevention of otitis media and/or colonization is also important supporting information; and (5) measurable boosterability (Table 1). Dr. Levine mentioned two caveats: (1) it is difficult to forecast prevention of pneumonia due to serotypes 1, 5, and 7F based on experience with the 7-valent or even 9-valent because we have not had enough experience or seen enough of the characteristics that might be associated with successful protection against 1, 5 and 7F; and, as Dr. Mahdi indicated, (2) OPA is important, but the relationship between OPA and pneumonia or OPA and mucosal protection is less clear. Dr. Dagan stated that there is another caveat that must be stressed very strongly: immunization schedules. There is currently no proof that a shortened schedule with PCV7 or any other PCVs is equivalent in terms of protection against pneumococcus when compared with the “classical” 3 + 1 schedule.
Dr. Levine added the third (3) caveat that the characteristics of the vaccines that have confirmed, proven efficacy against pneumonia and in which the faculty have confidence utilize a three-dose regimen, in infancy. Dr. Dagan stressed a 3 + 1 [immunization/booster schedule] regimen. . . a schedule of 3 + 1 or 3 + 0 in some countries. Dr. Levine agreed that the third (3) caveat implies that we as faculty are not comfortable yet extrapolating to regimens of fewer than three doses in infancy. However, the role of a booster in providing long-term protection against pneumonia is not clear yet but may well be important (Table 2). The suggestion was made to finish the conference with a brief discussion of vaccine formulations. What should they include? Dr Levine noted that this is a critical issue and that collectively there has always been the conversation about not knowing which serotypes cause non-bacteremic pneumonia. However, in reality, and in data presented by Dr. Hausdorff at the workshop, the coverage of vaccines against the leading invasive serotypes has been pretty effective, with reductions in pneumonia an important characteristic of those vaccines. In closing, all agreed that characteristics of a successful pneumococcal conjugate vaccine will be a formulation of pneumococcal serotypes that at the least matches leading invasive pneumococcal serotypes and contain, where possible, immunologically relevant and novel protein conjugates. And, certainly, any vaccine must also be safe (Table 1).