- Email: [email protected]
Combination vaccine strategies to prevent enteric infections
Vaccine xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Combination vaccine strategies to prevent enteric infections Richard Walker a,⇑, Peter Dull b a b
Bill & Melinda Gates Foundation, Seattle, WA, United States PATH, Washington, DC, United States
a r t i c l e
i n f o
Article history: Available online xxxx Keywords: Combined vaccines Shigella ETEC Enterotoxigenic Escherichia coli Regulatory strategy
a b s t r a c t New vaccine candidates entering the current routine immunization schedule can best be accommodated as combination vaccines. A combined Shigella and enterotoxigenic E. coli (ETEC) vaccine could greatly benefit children in disease-endemic areas. New candidates are getting closer to being able to meet these needs, but they raise numerous strategic questions related to presentation, formulation, and regulatory approach. The ‘‘Combination Vaccine Strategies to Prevent Enteric Infections” workshop at the 2016 Vaccines Against Shigella and ETEC (VASE) Conference examined some of the considerations for developing such vaccines against enteric pathogens. Ó 2017 Published by Elsevier Ltd.
1. Introduction The agenda for the 2016 VASE Conference included nine breakout workshop sessions, of which conference attendees had the opportunity to attend two. One of the workshops aimed to present and discuss key concepts, issues, and challenges to consider in the development of combination vaccines to prevent enteric infections, with a particular focus on disease caused by Shigella and ETEC. Workshop attendees engaged in discussions with Peter Dull, Myron Levine (University of Maryland, Baltimore), Doran Fink (United States Food and Drug Administration), and Richard Walker concerning a variety of perspectives on combination vaccines. The presentations and discussions addressed the landscape of new vaccine introductions, the challenge of fitting additional vaccines into an increasingly crowded Expanded Programme on Immunization (EPI) schedule, and the rationale for a developing a combined Shigella-ETEC vaccine. The regulatory challenges related to the presentation and formulation of a combined vaccine, as well as pathways to address them, were considered by the workshop participants. 2. Why combined Shigella-ETEC vaccines are needed Achieving vaccine coverage goals according to the Global Vaccine Action Plan is a considerable challenge in global health. The trajectory toward achieving the coverage goals of current vaccines by 2020 remains elusive, and the addition of new vaccines to the ⇑ Corresponding author at: PATH, 455 Massachusetts Ave. NW, Washington, DC 20001-2621, United States. E-mail address: [email protected] (R. Walker).
EPI schedule in many countries provides further challenges to the system. Over the next five years, we anticipate that all countries eligible for support from Gavi, the Vaccine Alliance will be delivering rotavirus and pneumococcal vaccines as part of their infant EPI schedule. With new vaccines come new delivery challenges, including cold chain management, number of doses, physical space to store vaccines, increased costs, and the risk of Gavi-graduating countries accumulating a ‘‘mortgage” of new vaccines to pay for in the future. In short, new vaccines are being added to a system that is already challenged to manage the existing portfolio. Shigella and ETEC account for more than 15 percent of the approximately 500,000 annual deaths due to diarrheal diseases in children under five years of age [1]. The importance of these two pathogens has been upheld by the results of the Global Enteric Multicenter Study (GEMS), which reported the etiology of population-based burden of pediatric diarrheal diseases in subSaharan Africa and South Asia [2]. In analyses of stool samples from children less than five years of age with moderate-to-severe diarrhea, it was shown that Shigella and ETEC were among the top four enteric pathogens. While recent data show dropping mortality for enteric pathogens, many children infected with these pathogens suffer from diarrheal disease-associated intestinal enteropathy and malnutrition, and their consequent toll on physical and cognitive development [3–6]. Beyond mortality, infections with Shigella and ETEC are responsible for up to 13 million lost disabilityadjusted life years (DALYs) annually across the globe [7]. Shigella and ETEC have common target populations (infants, toddlers, preschool children, and travelers), and ample evidence shows that infection with both pathogens provides protection against re-infection [1,2]. While no vaccines are currently available
http://dx.doi.org/10.1016/j.vaccine.2017.06.076 0264-410X/Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Walker R, Dull P. Combination vaccine strategies to prevent enteric infections. Vaccine (2017), http://dx.doi.org/10.1016/ j.vaccine.2017.06.076
2
R. Walker, P. Dull / Vaccine xxx (2017) xxx–xxx
for either of these two important enteric pathogens, a combined Shigella-ETEC vaccine given on an EPI schedule would have numerous advantages. These include reduction of manufacturing costs, simplified and economized logistics of delivery, and a reduced number of injections or oral doses. The oral route is appealing because it is an effective way to achieve mucosal immunity and it avoids additional injections. In high-income countries, delivering multiple antigens simultaneously via an oral route has demonstrated high efficacy. However, challenges have been encountered when translating these successes to the developing world. Environmental enteropathy, among other hypothesized causes, has limited the impact of vaccines delivered by the oral route in low-resource settings. As a combination, a Shigella-ETEC vaccine represents both a more acceptable intervention profile for providers and an advantage for manufacturers in accessing a broader market of payers to include the EPI market plus the private and travelers’ markets. Although ETEC may not contribute greatly to mortality in lowincome countries, there is evidence of long-term morbidity effects due to ETEC infection in these areas, which points to the public health need for a vaccine. ETEC also remains a major cause of travelers’ diarrhea, which adds a level of attraction to a vaccine for higher-income markets. It is generally accepted that Shigella is not a compelling candidate as a standalone travelers’ vaccine but could improve the cost-effectiveness and uptake of a travelers’ vaccine when combined with ETEC. Conversely, Shigella is now perceived as one of the main vaccine-preventable disease threats in developing-country settings, and a vaccine targeting this pathogen could be improved by the inclusion of ETEC. Additionally, vaccine prophylaxis could have a significant global health impact on improving antimicrobial stewardship and avoiding the threat of antimicrobial resistance for these important pathogens. It is incumbent upon vaccine developers to think about how to deliver these new vaccines in this context. The injection burden, delivery challenges, and costs of new vaccines will make it increasingly challenging to support new standalone vaccines for endemic diseases. It seems likely that a combined Shigella-ETEC vaccine, whether given orally or parenterally, would be a much more acceptable product for uptake in developing countries than a standalone product. However, if the components for a combined vaccine have not reached the stage of development for combination, there could be a risk to product development with public health consequences if licensure of a standalone vaccine is delayed.
3. Current landscape for combined Shigella-ETEC candidates under development Numerous cellular and subunit candidates for Shigella and ETEC vaccines are becoming available, although some are much closer and more amenable to advanced testing as combinations than others. Some killed whole-cell candidates, as well as subunit antigens, may be combined by admixing the Shigella and ETEC components into a common formulation. For cellular vaccines, it is also possible to use them as vectors that express antigens of other pathogens. For example, the Center for Vaccine Development at the University of Maryland, Baltimore has developed a multivalent live attenuated (guanine auxotroph with sen and set mutations) Shigella vaccine with S. sonnei and S. flexneri 2a, 3a, and 6; the vaccine expresses multiple colonization factors and toxoids of heatstable toxin (ST) and heat-labile toxin (LT). So far in animal models these organisms are immunogenic, but clinical trials in human vol-
unteers will be needed to determine the performance of this candidate (E. Barry, personal communication).
4. Regulatory challenges to developing combined vaccines As per the 1997 US Food and Drug Administration (FDA) guidance document [8], combined vaccines can be two or more live organisms, inactivated organisms, or purified antigens, combined either by the manufacturer or mixed immediately before administration, that are intended to prevent multiple diseases or to prevent one disease caused by different strains or serotypes of the same organism. Most combined vaccines would not also be considered combination products, which are defined in federal regulations and typically comprise a combination of a drug and biologic, drug and device, or biologic and device (which would apply to vaccine/device combinations). Several considerations related to stability and potency, efficacy, and potential interference pose challenges and questions to presentation, formulation, and eventual licensure and regulation of combined vaccines. Stability and potency: Historically, there have been a number of standalone vaccines that have surprised developers and regulators in how they behaved when evaluated in combination. Thus, an important manufacturing consideration is how the combination of individual vaccine components affects their stability and potency. There may be more value in keeping the ‘‘final” product as separate components (so that each can be monitored independently), rather than the ‘‘final” product being a formulated combination. The approach to answering this question depends on whether components are formulated together or formulated and packaged separately and then combined prior to administration. To support licensure of a combined vaccine, testing will be needed to determine the potency of each active component within the combined vaccine. When adding a new active component to a previously licensed vaccine, non-inferiority immunogenicity studies should be done to demonstrate that potency of the previously licensed active component(s) is not diminished by addition of the new active component. Confidence in this approach assumes that a correlate of protection has been identified for the original vaccine. For all vaccines (including combined vaccines and vaccine/ device combination products), demonstration of manufacturing consistency is done through product characterization and lot-tolot consistency studies, which are typically clinical studies and must show statistically equivalent immune responses for all active ingredients between lots. For vaccine/device combinations, it is necessary to evaluate characterization and performance of the device, perform human factor studies to assess consistency of preparation and administration and assess potential for human error, and consider the issues of leachables and extractables. Vaccine efficacy: Under traditional approval based on clinical data, evidence of vaccine efficacy could include clinical data from one or more field efficacy trials (gold standard), a challenge trial, or an immunogenicity study using a scientifically wellestablished marker that predicts protection against disease (e.g., as serum bactericidal antibody was used to assess effectiveness for meningococcal vaccines). An immunogenicity study showing non-inferiority to an approved vaccine for which efficacy against disease caused by the same serotypes or groups has been previously demonstrated could also be used to infer vaccine efficacy to support licensure under the traditional approval pathway. However, there needs to be a scientific basis to believe that the mechanism of protection (i.e., elicited immune response) for the new vaccine is the same as that of the previously approved vaccine.
Please cite this article in press as: Walker R, Dull P. Combination vaccine strategies to prevent enteric infections. Vaccine (2017), http://dx.doi.org/10.1016/ j.vaccine.2017.06.076
R. Walker, P. Dull / Vaccine xxx (2017) xxx–xxx
Per the 1997 FDA guidance document, clinical efficacy studies to support licensure should aim to demonstrate the efficacy of each active component of a combined vaccine. However, the FDA’s Center for Biologics Evaluation and Research may consider alternative proposals for demonstrating the efficacy of multiple serotype/ strain combined vaccines if it would be difficult to determine efficacy of the vaccine against each strain. A single pivotal field efficacy trial is ideal but may not be feasible for combined enteric vaccines due to epidemiological factors and/or differences in developmental timelines for vaccine components. Options to address this issue may include conducting: Multiple pivotal field efficacy trials; One large trial with multiple sites; or Challenge trials. Immunogenicity-based licensure of a combined vaccine following efficacy-based licensure of individual components is also possible. For example, one strategy would be to license separate Shigella and ETEC vaccines based on field efficacy and/or challenge trials. Using immunogenicity measures that are clinically relevant to protection against disease, but are not necessarily established markers that predict protection on their own, an immunogenicity non-inferiority study may be performed comparing the combined vaccine to the individual component vaccines. A variation of this approach could be to first conduct field efficacy and/or challenge trials of a vaccine against one pathogen (e.g., ETEC) and then combine that vaccine with a second vaccine targeting an additional strain or pathogen (e.g., Shigella). In the case of a combined Shigella-ETEC vaccine, the licensure-enabling study could evaluate primary efficacy against Shigella and immunologic non-inferiority for the responses to the ETEC component(s). This could be done by comparing the combined vaccine against the standalone ETEC vaccine for which efficacy was previously demonstrated. Typically, one would expect the immuno-bridge to go back to a licensed vaccine, but with proper engagement and discussion with regulators, alternative approaches to speed licensure for a relevant combined vaccine may be appropriate on a case-by-case basis. The combined vaccine efficacy study could still evaluate efficacy endpoints for the ETEC component but may not be powered to do so formally. While FDA has licensed combined vaccines for multiple serotypes of the same pathogen and vaccines for multiple pathogens that are combinations of previously licensed products, there is no precedent yet for ‘‘de novo” FDA licensure of a combined vaccine for multiple pathogens for which no vaccine has previously been licensed in the United States. While the latter scenario could be done in theory, it would involve considerably more product development risk. Other regulatory considerations: In order to advance a combined vaccine toward licensure, it is necessary to assess the potential for interference between vaccine components, including adjuvants and excipients. For the likely scenario in which two vaccine components are at different stages of development, a licensure strategy could be followed in which one unlicensed component is added to an already licensed component, rather than waiting and trying to synchronize the development timeline of both components. It is uncertain if this would be acceptable from a regulatory perspective as combinations most often are formed from two separately licensed components. As with any new vaccine included in the EPI schedule, it will also be important to determine the potential for interference between new enteric vaccines and other vaccines administered concomitantly. A discussion with the regulators would determine whether such studies would be required pre- or post-licensure. Post-licensure product modifications may require additional clini-
3
cal studies to support label changes or licensure of a new product. Examples of such modifications include: Addition of new active ingredients, including combining two already licensed vaccines into a single product. Substantial formulation changes. Changes to the delivery device. 5. Conclusion While combination strategies for new vaccines against Shigella and ETEC face many challenges, new vaccine candidates and delivery techniques are under development and getting closer to being available. There is a strong rationale for the development of a combined vaccine based on reduced cost of goods along with simpler and more affordable cost of delivery. However, this approach may not be cost-effective in all settings, and it carries greater risk and uncertainty than the development and approval of each as standalone vaccines that could be subsequently used together as needed, depending on the specific setting needs. Given recent achievements and continued efforts in this area of research, these challenges may soon be overcome and the promise of a combined Shigella-ETEC vaccine may be realized. Conflict of interest statement The authors are employees of the respective indicated organizations and have no conflict of interest to declare. Funding This work was supported by the Bill & Melinda Gates Foundation, Seattle, WA (Grant No. OPP1112376). Acknowledgement The authors are grateful to Doran Fink and Myron Levine for their presentations, from which much of the content of this report was derived. We also acknowledge the extra review of the text by Dr. Fink and editorial review by Laura Kallen and Allison Clifford of PATH. References [1] Global Burden of Disease Study 2015. Global Burden of Disease Study 2015 (GBD 2015) results. Seattle (United States): Institute for Health Metrics and Evaluation (IHME); 2016. [2] Kotloff KI, Nataro JP, Blackwelder WC, Nasrin D, Farag TH, Panchalingam S, et al. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective case-control study. Lancet 2013;382:209–22. [3] Niehaus MD, Moore SR, Patrick PD, Derr II, Lorntz B, Limma AA, et al. Early childhood diarrhea is associated with diminished cognitive function 4–7 years late in children in a northeast Brazilian shantytown. Am J Trop Med Hyg 2002;66:590–3. [4] Guerrant RI, Kosek M, Moore S, Lorntz B, Brantley R, Lima AA. Magnitude and impact of diarrheal diseases. Arch Med Res 2002;33:351–5. [5] Guerrant RI, Kosek M, Lima AA, Lorntz B, Guyatt HI. Updating the DALYs for diarrhoeal disease. Trends Parasitol 2002;18:191–3. [6] Guerrant RI, Oria RB, Moore SR, Oria MO, Lima AA. Malnutritiion as an enteric infectious disease with long-term effects on child development. Nutr Rev 2008;66:487–505. [7] Global Burden of Disease Study 2015. Global Burden of Disease Study 2015 (GBD 2015) results. Seattle (United States): Institute for Health Metrics and Evaluation (IHME); 2016. [8] US Food and Drug Administration Center for Biologics Evaluation and Research. Guidance for industry for the evaluation of combination vaccines for preventable diseases: production, testing and clinical studies; 1997.
Please cite this article in press as: Walker R, Dull P. Combination vaccine strategies to prevent enteric infections. Vaccine (2017), http://dx.doi.org/10.1016/ j.vaccine.2017.06.076
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Combination vaccine strategies to prevent enteric infections Richard Walker a,⇑, Peter Dull b a b
Bill & Melinda Gates Foundation, Seattle, WA, United States PATH, Washington, DC, United States
a r t i c l e
i n f o
Article history: Available online xxxx Keywords: Combined vaccines Shigella ETEC Enterotoxigenic Escherichia coli Regulatory strategy
a b s t r a c t New vaccine candidates entering the current routine immunization schedule can best be accommodated as combination vaccines. A combined Shigella and enterotoxigenic E. coli (ETEC) vaccine could greatly benefit children in disease-endemic areas. New candidates are getting closer to being able to meet these needs, but they raise numerous strategic questions related to presentation, formulation, and regulatory approach. The ‘‘Combination Vaccine Strategies to Prevent Enteric Infections” workshop at the 2016 Vaccines Against Shigella and ETEC (VASE) Conference examined some of the considerations for developing such vaccines against enteric pathogens. Ó 2017 Published by Elsevier Ltd.
1. Introduction The agenda for the 2016 VASE Conference included nine breakout workshop sessions, of which conference attendees had the opportunity to attend two. One of the workshops aimed to present and discuss key concepts, issues, and challenges to consider in the development of combination vaccines to prevent enteric infections, with a particular focus on disease caused by Shigella and ETEC. Workshop attendees engaged in discussions with Peter Dull, Myron Levine (University of Maryland, Baltimore), Doran Fink (United States Food and Drug Administration), and Richard Walker concerning a variety of perspectives on combination vaccines. The presentations and discussions addressed the landscape of new vaccine introductions, the challenge of fitting additional vaccines into an increasingly crowded Expanded Programme on Immunization (EPI) schedule, and the rationale for a developing a combined Shigella-ETEC vaccine. The regulatory challenges related to the presentation and formulation of a combined vaccine, as well as pathways to address them, were considered by the workshop participants. 2. Why combined Shigella-ETEC vaccines are needed Achieving vaccine coverage goals according to the Global Vaccine Action Plan is a considerable challenge in global health. The trajectory toward achieving the coverage goals of current vaccines by 2020 remains elusive, and the addition of new vaccines to the ⇑ Corresponding author at: PATH, 455 Massachusetts Ave. NW, Washington, DC 20001-2621, United States. E-mail address: [email protected] (R. Walker).
EPI schedule in many countries provides further challenges to the system. Over the next five years, we anticipate that all countries eligible for support from Gavi, the Vaccine Alliance will be delivering rotavirus and pneumococcal vaccines as part of their infant EPI schedule. With new vaccines come new delivery challenges, including cold chain management, number of doses, physical space to store vaccines, increased costs, and the risk of Gavi-graduating countries accumulating a ‘‘mortgage” of new vaccines to pay for in the future. In short, new vaccines are being added to a system that is already challenged to manage the existing portfolio. Shigella and ETEC account for more than 15 percent of the approximately 500,000 annual deaths due to diarrheal diseases in children under five years of age [1]. The importance of these two pathogens has been upheld by the results of the Global Enteric Multicenter Study (GEMS), which reported the etiology of population-based burden of pediatric diarrheal diseases in subSaharan Africa and South Asia [2]. In analyses of stool samples from children less than five years of age with moderate-to-severe diarrhea, it was shown that Shigella and ETEC were among the top four enteric pathogens. While recent data show dropping mortality for enteric pathogens, many children infected with these pathogens suffer from diarrheal disease-associated intestinal enteropathy and malnutrition, and their consequent toll on physical and cognitive development [3–6]. Beyond mortality, infections with Shigella and ETEC are responsible for up to 13 million lost disabilityadjusted life years (DALYs) annually across the globe [7]. Shigella and ETEC have common target populations (infants, toddlers, preschool children, and travelers), and ample evidence shows that infection with both pathogens provides protection against re-infection [1,2]. While no vaccines are currently available
http://dx.doi.org/10.1016/j.vaccine.2017.06.076 0264-410X/Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Walker R, Dull P. Combination vaccine strategies to prevent enteric infections. Vaccine (2017), http://dx.doi.org/10.1016/ j.vaccine.2017.06.076
2
R. Walker, P. Dull / Vaccine xxx (2017) xxx–xxx
for either of these two important enteric pathogens, a combined Shigella-ETEC vaccine given on an EPI schedule would have numerous advantages. These include reduction of manufacturing costs, simplified and economized logistics of delivery, and a reduced number of injections or oral doses. The oral route is appealing because it is an effective way to achieve mucosal immunity and it avoids additional injections. In high-income countries, delivering multiple antigens simultaneously via an oral route has demonstrated high efficacy. However, challenges have been encountered when translating these successes to the developing world. Environmental enteropathy, among other hypothesized causes, has limited the impact of vaccines delivered by the oral route in low-resource settings. As a combination, a Shigella-ETEC vaccine represents both a more acceptable intervention profile for providers and an advantage for manufacturers in accessing a broader market of payers to include the EPI market plus the private and travelers’ markets. Although ETEC may not contribute greatly to mortality in lowincome countries, there is evidence of long-term morbidity effects due to ETEC infection in these areas, which points to the public health need for a vaccine. ETEC also remains a major cause of travelers’ diarrhea, which adds a level of attraction to a vaccine for higher-income markets. It is generally accepted that Shigella is not a compelling candidate as a standalone travelers’ vaccine but could improve the cost-effectiveness and uptake of a travelers’ vaccine when combined with ETEC. Conversely, Shigella is now perceived as one of the main vaccine-preventable disease threats in developing-country settings, and a vaccine targeting this pathogen could be improved by the inclusion of ETEC. Additionally, vaccine prophylaxis could have a significant global health impact on improving antimicrobial stewardship and avoiding the threat of antimicrobial resistance for these important pathogens. It is incumbent upon vaccine developers to think about how to deliver these new vaccines in this context. The injection burden, delivery challenges, and costs of new vaccines will make it increasingly challenging to support new standalone vaccines for endemic diseases. It seems likely that a combined Shigella-ETEC vaccine, whether given orally or parenterally, would be a much more acceptable product for uptake in developing countries than a standalone product. However, if the components for a combined vaccine have not reached the stage of development for combination, there could be a risk to product development with public health consequences if licensure of a standalone vaccine is delayed.
3. Current landscape for combined Shigella-ETEC candidates under development Numerous cellular and subunit candidates for Shigella and ETEC vaccines are becoming available, although some are much closer and more amenable to advanced testing as combinations than others. Some killed whole-cell candidates, as well as subunit antigens, may be combined by admixing the Shigella and ETEC components into a common formulation. For cellular vaccines, it is also possible to use them as vectors that express antigens of other pathogens. For example, the Center for Vaccine Development at the University of Maryland, Baltimore has developed a multivalent live attenuated (guanine auxotroph with sen and set mutations) Shigella vaccine with S. sonnei and S. flexneri 2a, 3a, and 6; the vaccine expresses multiple colonization factors and toxoids of heatstable toxin (ST) and heat-labile toxin (LT). So far in animal models these organisms are immunogenic, but clinical trials in human vol-
unteers will be needed to determine the performance of this candidate (E. Barry, personal communication).
4. Regulatory challenges to developing combined vaccines As per the 1997 US Food and Drug Administration (FDA) guidance document [8], combined vaccines can be two or more live organisms, inactivated organisms, or purified antigens, combined either by the manufacturer or mixed immediately before administration, that are intended to prevent multiple diseases or to prevent one disease caused by different strains or serotypes of the same organism. Most combined vaccines would not also be considered combination products, which are defined in federal regulations and typically comprise a combination of a drug and biologic, drug and device, or biologic and device (which would apply to vaccine/device combinations). Several considerations related to stability and potency, efficacy, and potential interference pose challenges and questions to presentation, formulation, and eventual licensure and regulation of combined vaccines. Stability and potency: Historically, there have been a number of standalone vaccines that have surprised developers and regulators in how they behaved when evaluated in combination. Thus, an important manufacturing consideration is how the combination of individual vaccine components affects their stability and potency. There may be more value in keeping the ‘‘final” product as separate components (so that each can be monitored independently), rather than the ‘‘final” product being a formulated combination. The approach to answering this question depends on whether components are formulated together or formulated and packaged separately and then combined prior to administration. To support licensure of a combined vaccine, testing will be needed to determine the potency of each active component within the combined vaccine. When adding a new active component to a previously licensed vaccine, non-inferiority immunogenicity studies should be done to demonstrate that potency of the previously licensed active component(s) is not diminished by addition of the new active component. Confidence in this approach assumes that a correlate of protection has been identified for the original vaccine. For all vaccines (including combined vaccines and vaccine/ device combination products), demonstration of manufacturing consistency is done through product characterization and lot-tolot consistency studies, which are typically clinical studies and must show statistically equivalent immune responses for all active ingredients between lots. For vaccine/device combinations, it is necessary to evaluate characterization and performance of the device, perform human factor studies to assess consistency of preparation and administration and assess potential for human error, and consider the issues of leachables and extractables. Vaccine efficacy: Under traditional approval based on clinical data, evidence of vaccine efficacy could include clinical data from one or more field efficacy trials (gold standard), a challenge trial, or an immunogenicity study using a scientifically wellestablished marker that predicts protection against disease (e.g., as serum bactericidal antibody was used to assess effectiveness for meningococcal vaccines). An immunogenicity study showing non-inferiority to an approved vaccine for which efficacy against disease caused by the same serotypes or groups has been previously demonstrated could also be used to infer vaccine efficacy to support licensure under the traditional approval pathway. However, there needs to be a scientific basis to believe that the mechanism of protection (i.e., elicited immune response) for the new vaccine is the same as that of the previously approved vaccine.
Please cite this article in press as: Walker R, Dull P. Combination vaccine strategies to prevent enteric infections. Vaccine (2017), http://dx.doi.org/10.1016/ j.vaccine.2017.06.076
R. Walker, P. Dull / Vaccine xxx (2017) xxx–xxx
Per the 1997 FDA guidance document, clinical efficacy studies to support licensure should aim to demonstrate the efficacy of each active component of a combined vaccine. However, the FDA’s Center for Biologics Evaluation and Research may consider alternative proposals for demonstrating the efficacy of multiple serotype/ strain combined vaccines if it would be difficult to determine efficacy of the vaccine against each strain. A single pivotal field efficacy trial is ideal but may not be feasible for combined enteric vaccines due to epidemiological factors and/or differences in developmental timelines for vaccine components. Options to address this issue may include conducting: Multiple pivotal field efficacy trials; One large trial with multiple sites; or Challenge trials. Immunogenicity-based licensure of a combined vaccine following efficacy-based licensure of individual components is also possible. For example, one strategy would be to license separate Shigella and ETEC vaccines based on field efficacy and/or challenge trials. Using immunogenicity measures that are clinically relevant to protection against disease, but are not necessarily established markers that predict protection on their own, an immunogenicity non-inferiority study may be performed comparing the combined vaccine to the individual component vaccines. A variation of this approach could be to first conduct field efficacy and/or challenge trials of a vaccine against one pathogen (e.g., ETEC) and then combine that vaccine with a second vaccine targeting an additional strain or pathogen (e.g., Shigella). In the case of a combined Shigella-ETEC vaccine, the licensure-enabling study could evaluate primary efficacy against Shigella and immunologic non-inferiority for the responses to the ETEC component(s). This could be done by comparing the combined vaccine against the standalone ETEC vaccine for which efficacy was previously demonstrated. Typically, one would expect the immuno-bridge to go back to a licensed vaccine, but with proper engagement and discussion with regulators, alternative approaches to speed licensure for a relevant combined vaccine may be appropriate on a case-by-case basis. The combined vaccine efficacy study could still evaluate efficacy endpoints for the ETEC component but may not be powered to do so formally. While FDA has licensed combined vaccines for multiple serotypes of the same pathogen and vaccines for multiple pathogens that are combinations of previously licensed products, there is no precedent yet for ‘‘de novo” FDA licensure of a combined vaccine for multiple pathogens for which no vaccine has previously been licensed in the United States. While the latter scenario could be done in theory, it would involve considerably more product development risk. Other regulatory considerations: In order to advance a combined vaccine toward licensure, it is necessary to assess the potential for interference between vaccine components, including adjuvants and excipients. For the likely scenario in which two vaccine components are at different stages of development, a licensure strategy could be followed in which one unlicensed component is added to an already licensed component, rather than waiting and trying to synchronize the development timeline of both components. It is uncertain if this would be acceptable from a regulatory perspective as combinations most often are formed from two separately licensed components. As with any new vaccine included in the EPI schedule, it will also be important to determine the potential for interference between new enteric vaccines and other vaccines administered concomitantly. A discussion with the regulators would determine whether such studies would be required pre- or post-licensure. Post-licensure product modifications may require additional clini-
3
cal studies to support label changes or licensure of a new product. Examples of such modifications include: Addition of new active ingredients, including combining two already licensed vaccines into a single product. Substantial formulation changes. Changes to the delivery device. 5. Conclusion While combination strategies for new vaccines against Shigella and ETEC face many challenges, new vaccine candidates and delivery techniques are under development and getting closer to being available. There is a strong rationale for the development of a combined vaccine based on reduced cost of goods along with simpler and more affordable cost of delivery. However, this approach may not be cost-effective in all settings, and it carries greater risk and uncertainty than the development and approval of each as standalone vaccines that could be subsequently used together as needed, depending on the specific setting needs. Given recent achievements and continued efforts in this area of research, these challenges may soon be overcome and the promise of a combined Shigella-ETEC vaccine may be realized. Conflict of interest statement The authors are employees of the respective indicated organizations and have no conflict of interest to declare. Funding This work was supported by the Bill & Melinda Gates Foundation, Seattle, WA (Grant No. OPP1112376). Acknowledgement The authors are grateful to Doran Fink and Myron Levine for their presentations, from which much of the content of this report was derived. We also acknowledge the extra review of the text by Dr. Fink and editorial review by Laura Kallen and Allison Clifford of PATH. References [1] Global Burden of Disease Study 2015. Global Burden of Disease Study 2015 (GBD 2015) results. Seattle (United States): Institute for Health Metrics and Evaluation (IHME); 2016. [2] Kotloff KI, Nataro JP, Blackwelder WC, Nasrin D, Farag TH, Panchalingam S, et al. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective case-control study. Lancet 2013;382:209–22. [3] Niehaus MD, Moore SR, Patrick PD, Derr II, Lorntz B, Limma AA, et al. Early childhood diarrhea is associated with diminished cognitive function 4–7 years late in children in a northeast Brazilian shantytown. Am J Trop Med Hyg 2002;66:590–3. [4] Guerrant RI, Kosek M, Moore S, Lorntz B, Brantley R, Lima AA. Magnitude and impact of diarrheal diseases. Arch Med Res 2002;33:351–5. [5] Guerrant RI, Kosek M, Lima AA, Lorntz B, Guyatt HI. Updating the DALYs for diarrhoeal disease. Trends Parasitol 2002;18:191–3. [6] Guerrant RI, Oria RB, Moore SR, Oria MO, Lima AA. Malnutritiion as an enteric infectious disease with long-term effects on child development. Nutr Rev 2008;66:487–505. [7] Global Burden of Disease Study 2015. Global Burden of Disease Study 2015 (GBD 2015) results. Seattle (United States): Institute for Health Metrics and Evaluation (IHME); 2016. [8] US Food and Drug Administration Center for Biologics Evaluation and Research. Guidance for industry for the evaluation of combination vaccines for preventable diseases: production, testing and clinical studies; 1997.
Please cite this article in press as: Walker R, Dull P. Combination vaccine strategies to prevent enteric infections. Vaccine (2017), http://dx.doi.org/10.1016/ j.vaccine.2017.06.076