Vaccine 32 (2014) 131–132
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Editorial
Foreword
Clinical trials of first generation pneumococcal conjugate vaccines (PCV), initiated in the mid- 1990s, demonstrated the potential impact of PCVs on invasive disease and mucosal infections caused by Streptococcus pneumonia in young children. The pneumococcus, an important of cause of morbidity and mortality worldwide, but especially in developing countries, had hitherto not been preventable in young children due to the poor immunogenicity of licensed pure polysaccharide vaccines in early life. Disease impact evaluations following introduction of PCVs into national immunization programs (NIPs) in various countries around the world has confirmed and extended these exciting initial observations with documented reductions in the rates of invasive pneumococcal disease, pneumonia and otitis media. Furthermore, the impact of PCVs on vaccine serotype pneumococcal nasopharyngeal carriage in the target age group (i.e. reduction in carriage prevalence through prevention of acquisition) has reduced transmission to unvaccinated community members and consequently reduced their pneumococcal disease rates; this has been observed in numerous countries with PCV in the NIP and high PCV coverage. Additional PCV products with different carrier proteins and/or a greater number of serotypes compared to the first licensed 7valent conjugate vaccine (PCV7) were already under development in the early 2000s, but the clinical evaluation programs were facing challenging circumstances. At that time a major roadblock was the complexity and cost of clinical trials to estimate the efficacy and expected effectiveness of PCVs in the target populations making the licensure and implementation of these new vaccines slow and doubtful. The conventional efficacy trial for PCV is based on a demonstrated impact on invasive pneumococcal disease (IPD) in a serotype-specific manner, which requires a large sample size (i.e. often over ten thousand vaccinees), and a detailed clinical and laboratory follow up, all of which are difficult to implement in developing country settings, the very places where evidence of efficacy was most needed. An immunologic surrogate for the required IPD endpoint was therefore derived from a joint analysis of the four existing PCV efficacy trials around the world. This serological antibody value (geometric mean concentration of 0.35 mcg/mL of type specific antibody), understood not as an individual level surrogate but instead as a measure in a group of vaccinated children that would be “predictive of protection”, was accepted by numerous licensing bodies, but was not derived on a serotype specific basis. In 2003 the Bill & Melinda Gates Foundation, with various partners, issued the Grand Challenges in Global Health (GCGH) initiative. Led by the late Helena Mäkelä and by Hanna Nohynek, the PneumoCarr Consortium was formed and funded by the GCGH initiative
0264-410X/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2013.05.066
to address the roadblocks to the licensure of novel pneumococcal vaccines. The PneumoCarr Consortium, made up of researchers from around the world with expertise in the field of pneumococcal colonization following PCV, proposed as a solution to this roadblock the use of pneumococcal colonization impact as an alternative biological licensure endpoint instead of IPD. The advantage gained would be enormous in terms of both sample size required and ease of endpoint detection. This approach has furthermore the beauty of measuring the impact on the pathogen (as opposed to immunogenicity), focusing on the first and necessary step of pneumococcal infection (i.e. colonization with pneumococcus) and measuring the total community public health impact of pneumococcal vaccine (i.e. incorporating the transmission of the bacteria measured as colonization or acquisition of carriage in the unvaccinated community members). Our goal thus was to establish whether measuring prevention of pneumococcal colonization could serve as a central component of pneumococcal vaccine licensure approaches and clinical vaccine effectiveness measures. During the project work (2006–2012) the research on and implementation of pneumococcal vaccines made huge advances, and accordingly the PneumoCarr project updated it’s aims and goals, but the original idea of using colonization as an endpoint in pneumococcal vaccine evaluation remained unchanged. It was highlighted that colonization could be used to evaluate both the direct and especially indirect vaccine effects with the latter emphasized because of the quantitative public health benefit of reductions in vaccine serotype pneumococcal disease throughout the population and because of unintended increases in non-vaccine serotype disease (i.e. replacement disease). The focus on pneumococcal colonization suggests a completely new way of thinking about immunity to pneumococcal diseases, bringing transmission of the pathogen and asymptomatic colonization, the reservoir for such transmission, to the foreground as the essential target for protection. This is what the PneumoCarr project addresses. It seeks a more comprehensive and more quantitative understanding of the colonization process than available until now, and provides a general model of colonization. The difficulties with use of pneumococcal disease as the primary endpoint of evaluations (large sample size, need of careful clinical follow up of rare events, time and cost associated with studies of disease endpoints, as well as the ethical dilemma to carry out large, placebo controlled phase III clinical trials when an efficacious vaccine already exists) are well known and formed a formidable roadblock to both development of
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Editorial / Vaccine 32 (2014) 131–132
new PCVs and continues to pose a roadblock to impact evaluations in the routine use setting. The use of prevention of colonization as a biologically functional endpoint makes clinical field assessments (phase III or IV) smaller, less costly, faster and technically feasible in a wide variety of locations. Therefore it can be used to assess not only new vaccine formulations but also address vaccine dosage and schedules relevant to the local vaccination programs. We also argue that it is a critical method for documenting PCV impact at the individual and community level following introduction into the routine immunization programs of countries; although it is not a disease endpoint in itself, where IPD surveillance is limited or not possible, colonization impact reveals the biologic impact of the vaccine on the organism and by bridging to other data where both IPD and colonization have been assessed, will allow for inferences about disease impact. Therefore, the specific PneumoCarr project goals were to (1) develop the use of vaccine efficacy against pneumococcal nasopharyngeal colonization (VE-colonization) as part of the regulatory licensure process, and (2) determine recommendations for how to optimally use NP colonization evaluations to inform the impact of PCV vaccines for public health purposes. The project objectives to meet these goals were to (1) develop the scientific basis and analytic tools for pneumococcal colonization studies as a supportive strategy for licensure, and (2) develop and support the technical community understanding and acceptance of pneumococcal colonization as an approach to licensure of novel pneumococcal vaccines. These two objectives address the key obstacles to use of VE-colonization as a strategy for the development, licensure and implementation of new pneumococcal vaccine products. An international consultation “Workshop to explore the role of carriage studies in the evaluation and licensing of new pneumococcal vaccines”, co-sponsored by WHO and PneumoCarr, was convened at WHO in Geneva, Switzerland, in March 2012 to provide vaccine manufacturers and regulators the opportunity to understand and comment on the “Case for Carriage, C4C” document, a PneumoCarr white paper that presents the justification for the inclusion of VE-col in pneumococcal vaccine licensure pathway. The meeting objectives were four-fold: (a) to share the C4C and supporting scientific work with external audiences; (b) to receive feedback on the C4C and what aspects contained therein are accepted and what aspects remain in question; (c) to reach a consensus on the role for NP carriage studies in licensure pathways; and (d) to generate a list of new work that must be undertaken to
further incorporate NP carriage evidence in the licensure pathway, if that is seen as a goal. These topics are addressed in this Special Section on Pneumococcal Carriage. The first part contains a report of the Geneva meeting with the Case for Carriage document as an appendix. The supporting data are gathered into separate papers included in this Special Section. We hope that the Case for Carriage document and the articles provide useful data for scientists, vaccine manufacturers, regulators and public health policy makers. We also hope that this work has relevance and is useful for the development, testing and licensure of new vaccines – not only against pneumococci, but also against other bacteria that colonize mucosal membranes before causing a disease, like meningococci or group B streptococci. Finally, we believe that this work will provide some of the key evidence base for wider acceptance of pneumococcal carriage as an essential endpoint to document the impact of pneumococcal vaccines in routine use settings, especially in the wide number of countries where assessing the impact on IPD or pneumonia is not possible. Pneumococcal colonization studies provide a clear way forward, and a biologically rich and meaningful outcome that has already and will continue to provide us the evidence needed to achieve pneumococcal disease reductions and control. H. Käyhty ∗,1 Department of Vaccination and Immune Protection, National Institute for Health and Welfare, Helsinki, Finland K.L. O’Brien 1 Center for American Indian Health & International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States D. Goldblatt 1 University College London, Institute of Child Health, London, United Kingdom ∗ Corresponding
author. E-mail address: Helena.Kayhty@thl.fi (H. Käyhty) 1
On behalf of Pneumococcal Carriage Consortium (PneumoCarr).
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Editorial
Foreword
Clinical trials of first generation pneumococcal conjugate vaccines (PCV), initiated in the mid- 1990s, demonstrated the potential impact of PCVs on invasive disease and mucosal infections caused by Streptococcus pneumonia in young children. The pneumococcus, an important of cause of morbidity and mortality worldwide, but especially in developing countries, had hitherto not been preventable in young children due to the poor immunogenicity of licensed pure polysaccharide vaccines in early life. Disease impact evaluations following introduction of PCVs into national immunization programs (NIPs) in various countries around the world has confirmed and extended these exciting initial observations with documented reductions in the rates of invasive pneumococcal disease, pneumonia and otitis media. Furthermore, the impact of PCVs on vaccine serotype pneumococcal nasopharyngeal carriage in the target age group (i.e. reduction in carriage prevalence through prevention of acquisition) has reduced transmission to unvaccinated community members and consequently reduced their pneumococcal disease rates; this has been observed in numerous countries with PCV in the NIP and high PCV coverage. Additional PCV products with different carrier proteins and/or a greater number of serotypes compared to the first licensed 7valent conjugate vaccine (PCV7) were already under development in the early 2000s, but the clinical evaluation programs were facing challenging circumstances. At that time a major roadblock was the complexity and cost of clinical trials to estimate the efficacy and expected effectiveness of PCVs in the target populations making the licensure and implementation of these new vaccines slow and doubtful. The conventional efficacy trial for PCV is based on a demonstrated impact on invasive pneumococcal disease (IPD) in a serotype-specific manner, which requires a large sample size (i.e. often over ten thousand vaccinees), and a detailed clinical and laboratory follow up, all of which are difficult to implement in developing country settings, the very places where evidence of efficacy was most needed. An immunologic surrogate for the required IPD endpoint was therefore derived from a joint analysis of the four existing PCV efficacy trials around the world. This serological antibody value (geometric mean concentration of 0.35 mcg/mL of type specific antibody), understood not as an individual level surrogate but instead as a measure in a group of vaccinated children that would be “predictive of protection”, was accepted by numerous licensing bodies, but was not derived on a serotype specific basis. In 2003 the Bill & Melinda Gates Foundation, with various partners, issued the Grand Challenges in Global Health (GCGH) initiative. Led by the late Helena Mäkelä and by Hanna Nohynek, the PneumoCarr Consortium was formed and funded by the GCGH initiative
0264-410X/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2013.05.066
to address the roadblocks to the licensure of novel pneumococcal vaccines. The PneumoCarr Consortium, made up of researchers from around the world with expertise in the field of pneumococcal colonization following PCV, proposed as a solution to this roadblock the use of pneumococcal colonization impact as an alternative biological licensure endpoint instead of IPD. The advantage gained would be enormous in terms of both sample size required and ease of endpoint detection. This approach has furthermore the beauty of measuring the impact on the pathogen (as opposed to immunogenicity), focusing on the first and necessary step of pneumococcal infection (i.e. colonization with pneumococcus) and measuring the total community public health impact of pneumococcal vaccine (i.e. incorporating the transmission of the bacteria measured as colonization or acquisition of carriage in the unvaccinated community members). Our goal thus was to establish whether measuring prevention of pneumococcal colonization could serve as a central component of pneumococcal vaccine licensure approaches and clinical vaccine effectiveness measures. During the project work (2006–2012) the research on and implementation of pneumococcal vaccines made huge advances, and accordingly the PneumoCarr project updated it’s aims and goals, but the original idea of using colonization as an endpoint in pneumococcal vaccine evaluation remained unchanged. It was highlighted that colonization could be used to evaluate both the direct and especially indirect vaccine effects with the latter emphasized because of the quantitative public health benefit of reductions in vaccine serotype pneumococcal disease throughout the population and because of unintended increases in non-vaccine serotype disease (i.e. replacement disease). The focus on pneumococcal colonization suggests a completely new way of thinking about immunity to pneumococcal diseases, bringing transmission of the pathogen and asymptomatic colonization, the reservoir for such transmission, to the foreground as the essential target for protection. This is what the PneumoCarr project addresses. It seeks a more comprehensive and more quantitative understanding of the colonization process than available until now, and provides a general model of colonization. The difficulties with use of pneumococcal disease as the primary endpoint of evaluations (large sample size, need of careful clinical follow up of rare events, time and cost associated with studies of disease endpoints, as well as the ethical dilemma to carry out large, placebo controlled phase III clinical trials when an efficacious vaccine already exists) are well known and formed a formidable roadblock to both development of
132
Editorial / Vaccine 32 (2014) 131–132
new PCVs and continues to pose a roadblock to impact evaluations in the routine use setting. The use of prevention of colonization as a biologically functional endpoint makes clinical field assessments (phase III or IV) smaller, less costly, faster and technically feasible in a wide variety of locations. Therefore it can be used to assess not only new vaccine formulations but also address vaccine dosage and schedules relevant to the local vaccination programs. We also argue that it is a critical method for documenting PCV impact at the individual and community level following introduction into the routine immunization programs of countries; although it is not a disease endpoint in itself, where IPD surveillance is limited or not possible, colonization impact reveals the biologic impact of the vaccine on the organism and by bridging to other data where both IPD and colonization have been assessed, will allow for inferences about disease impact. Therefore, the specific PneumoCarr project goals were to (1) develop the use of vaccine efficacy against pneumococcal nasopharyngeal colonization (VE-colonization) as part of the regulatory licensure process, and (2) determine recommendations for how to optimally use NP colonization evaluations to inform the impact of PCV vaccines for public health purposes. The project objectives to meet these goals were to (1) develop the scientific basis and analytic tools for pneumococcal colonization studies as a supportive strategy for licensure, and (2) develop and support the technical community understanding and acceptance of pneumococcal colonization as an approach to licensure of novel pneumococcal vaccines. These two objectives address the key obstacles to use of VE-colonization as a strategy for the development, licensure and implementation of new pneumococcal vaccine products. An international consultation “Workshop to explore the role of carriage studies in the evaluation and licensing of new pneumococcal vaccines”, co-sponsored by WHO and PneumoCarr, was convened at WHO in Geneva, Switzerland, in March 2012 to provide vaccine manufacturers and regulators the opportunity to understand and comment on the “Case for Carriage, C4C” document, a PneumoCarr white paper that presents the justification for the inclusion of VE-col in pneumococcal vaccine licensure pathway. The meeting objectives were four-fold: (a) to share the C4C and supporting scientific work with external audiences; (b) to receive feedback on the C4C and what aspects contained therein are accepted and what aspects remain in question; (c) to reach a consensus on the role for NP carriage studies in licensure pathways; and (d) to generate a list of new work that must be undertaken to
further incorporate NP carriage evidence in the licensure pathway, if that is seen as a goal. These topics are addressed in this Special Section on Pneumococcal Carriage. The first part contains a report of the Geneva meeting with the Case for Carriage document as an appendix. The supporting data are gathered into separate papers included in this Special Section. We hope that the Case for Carriage document and the articles provide useful data for scientists, vaccine manufacturers, regulators and public health policy makers. We also hope that this work has relevance and is useful for the development, testing and licensure of new vaccines – not only against pneumococci, but also against other bacteria that colonize mucosal membranes before causing a disease, like meningococci or group B streptococci. Finally, we believe that this work will provide some of the key evidence base for wider acceptance of pneumococcal carriage as an essential endpoint to document the impact of pneumococcal vaccines in routine use settings, especially in the wide number of countries where assessing the impact on IPD or pneumonia is not possible. Pneumococcal colonization studies provide a clear way forward, and a biologically rich and meaningful outcome that has already and will continue to provide us the evidence needed to achieve pneumococcal disease reductions and control. H. Käyhty ∗,1 Department of Vaccination and Immune Protection, National Institute for Health and Welfare, Helsinki, Finland K.L. O’Brien 1 Center for American Indian Health & International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States D. Goldblatt 1 University College London, Institute of Child Health, London, United Kingdom ∗ Corresponding
author. E-mail address: Helena.Kayhty@thl.fi (H. Käyhty) 1
On behalf of Pneumococcal Carriage Consortium (PneumoCarr).
