- Email: [email protected]
Enteric vaccines for pediatric use
Vaccine 23 (2005) 5432–5439
Enteric vaccines for pediatric use Workshop summary Richard I. Walker a,∗ , Lillian L. Van De Verg b , Robert H. Hall b , Clare K. Schmitt b , Katherine Woo c , Victoria Hale c a
b
Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike (HFM-425), Rockville, MD 20851-1448, USA Enteric and Hepatic Diseases Branch, DMID, NIAID, NIH, 6600 Rockledge Drive, Bethesda, MD 20892-7630, USA c Institute for OneWorld Health, 580 California Street, Suite 900, San Francisco, CA 94104, USA Received 9 January 2005; accepted 18 January 2005 Available online 2 April 2005
Abstract Diarrheal diseases remain a major cause of death in children under 5 in less developed countries (LDCs). Vaccine development and implementation offers the best near-term approach to alleviating this problem. For this reason, a workshop to examine the possibilities for making enteric vaccines available to meet the specific needs of children in LDCs was convened in Virginia on April 24–26, 2004. Discussants considered research and development needs, regulatory and business issues, and previous experiences with enteric vaccine development and implementation. No insurmountable roadblocks to progress in this area were noted, and the possibility currently exists that properly supported efforts will enable the realization of enteric vaccines for pediatric use. © 2005 Elsevier Ltd. All rights reserved. Keywords: Pediatric vaccines; Enteric pathogens; Vaccine development and implementation
Every day over 5500 children in less developed countries (LDCs) die as a consequence of diarrhea. Diarrheal diseases are second only to respiratory infections as killers of children under the age of five. In some countries, death due to diarrhea exceeds those attributable to HIV and malaria. And these numbers are dwarfed by the societal costs from diarrhea-associated morbidity, including malnutrition and both physical and mental deficits that result from untreated illness during early childhood. Vaccines specifically designed for pediatric use, along with hygienic and therapeutic interventions, can play a major role in reducing these unacceptable numbers. The challenges and possibilities for development of enteric vaccines, and providing them to children in LDCs were addressed by participants in a workshop, “Enteric Vaccines for Pediatric Use”, held at the Airlie Center, War∗
Corresponding author. Tel.: +1 301 4961014; fax: +1 301 4022776. E-mail address: [email protected] (R.I. Walker).
0264-410X/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2005.01.161
renton, VA, 24–26 April, 2004 (see www.oneworldhealth. org/diseases/diarrhea.php). The workshop brought together over 40 individuals representing expertise in the scientific, regulatory, and business issues involved in the development of enteric vaccines. The aim of the meeting was to identify the opportunities and obstacles to the adoption of enteric vaccines into the health programs of the countries where they are most needed. The following is a summation of those discussions.
1. The role for pediatric enteric vaccines in the least developed countries The special needs of LDC pediatric populations are often overlooked in the prevailing commercial development climate. The burden of diarrheal disease and its consequences are much greater among infants and children in LDCs than in any other target population. It was noted that the rela-
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tive importance of many enteric pathogens is obscured by the fact that there are few sites with adequate surveillance, that reporting of cases is sporadic, and the reported incidence can represent a gross underestimate of the true disease burden. While epidemics are more likely to be detected than endemic disease, endemic disease is the larger public health problem. Despite the shortage of accurate, current epidemiological data, it is clear that diarrheal diseases cause at least 2 million deaths annually in LDCs. Severe dehydrating diarrhea can be rapidly fatal, and swift intervention is necessary. Despite the remarkable accomplishments of Oral Rehydration Therapy (ORT), the “treatment of choice” for nearly 40 years, the global burden of diarrheal disease remains alarming. It was recognized that no single intervention would be sufficient to significantly lower the mortality rate due to secretory diarrhea. A successful strategy would require a combination of approaches. Among the major approaches to preventing diarrheal disease in LDC, vaccination offers the most feasible remedy for the short and medium term. While safe water and access to treatment are for the most part inaccessible to the most impoverished people, mass vaccination campaigns generally seek to protect these groups. Organized vaccination efforts can put protections in place prior to the time when severe environmental problems or major epidemics put extreme demands on limited health care resources. Vaccination that results in selflimiting infection or reduced mortality without necessarily eliminating disease remains important in relieving pressure during outbreak situations. Since the early 1990s the WHO has focused on a priority list of five enteric vaccines: Rotavirus, enterotoxigenic Escherichia coli (ETEC), Shigella, cholera, and typhoid fever. The target groups for all these pathogens include children, whereas S. dysenteriae 1, cholera and typhoid vaccines are also needed for adults. The incidence of particular serotypes remains unknown for most critical populations in the key endemic areas. Currently, licensed enteric vaccine formulations could have a significant impact if they were used in the situations where they are most needed. Although improved vaccines obviously would be beneficial it is not appropriate to delay the use of the existing products. In any event, improved vaccination approaches are predicated upon improved epidemiological studies in the most severely afflicted regions. Improved, field-ready diagnostic tools are also needed to complement vaccine development efforts. Meeting participants identified a number of important issues specific to the use of vaccines for the pediatric populations of LDCs. 1. Considerations must be given at the onset to the goal of integrating into Expanded Program of Immunization (EPI) schedules in order to leverage infrastructure already in place. 2. Strategies to elicit robust immunological responses in infants should be considered, and the impact of maternal im-
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munity on conferring passive protective immunity needs to be better defined. 3. Individuals in LDCs are presumably naturally exposed to the antigens of enteric pathogens multiple times during childhood. Thus, an enteric vaccine given to children in a LDC might be boosted by natural exposure. 4. The intestinal physiology of infants living in areas with endemic enteric disease will probably be significantly different from the intestinal physiology of na¨ıve individuals living in developed countries. One example presented showed striking histological differences between the intestinal epithelium from an infant living in an industrialized country compared to an infant living with a burden of enteric disease in an LDC. In addition, the intestinal flora of the infant from an LDC possessed a higher number of Gram-negative organisms than the flora from an infant living in an industrialized country. Differences such as these may account in part for the diminished immunogenicity observed with some oral vaccine candidates in LDC populations. This phenomenon of diminished immunogenicity has been observed for the oral polio vaccine, rotavirus, CVD 103HgR and BS/WCV cholera vaccines, and SC602 Shigella flexneri 2a. Ways must be found to formulate products with predictable immunogenicity for such populations. 5. It remains to be determined if vaccines shown to be safe for adults can be used at safe immunogenic doses in infants in LDCs. Observations with an inactivated ETEC vaccine showed that children under 6 months of age vomited an adult dose of this vaccine that was well tolerated by older children. Dilution of the vaccine 1:4 eliminated this problem without compromising immunogenicity. Vaccines for use by children in LDCs should be designed to be inexpensive, stable at room temperature (or heat-stable in tropical climates), and simple to administer to infants. Administration may take various forms. Individual vaccine formulations may be administered separately or coincidently (co-administered). Combination vaccines comprising a collection of individual components may be administered as a single formulation. Multivalent vaccines representing a single entity with several distinctive immunogens may be provided to confer protection against more than one pathogen. Practical considerations favor a vaccine formulation that would protect against multiple agents and be readily administered by non-medical personnel using a needle-free delivery method. Enteric vaccines for use in LDCs must meet the public health goals of the country, and appropriate personnel from these countries must be brought into the planning process at an early stage. The Diseases of the Most Impoverished (DOMI) Program, funded by the Bill and Melinda Gates Foundation and coordinated by the International Vaccine Institute (IVI; see www.ivi.org) has for the last 5 years addressed many critical issues associated with vaccine introduction in LDCs. As a first step, a survey of health policy-
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makers was performed in the seven DOMI partner countries, namely Bangladesh, China, India, Indonesia, Pakistan, Thailand and Vietnam. The goal of the policy-maker survey was to develop an investment case for introducing enteric vaccines into countries with the greatest need. The policy survey results indicated that vaccines were recognized as potentially important tools for the control of typhoid, shigellosis, and cholera provided the vaccine was <$1 per dose, and showed at least moderate efficacy. Policymakers described four major needs: 1. Burden of disease data. A determined effort is needed in LDC to collect epidemiological data on the burden, distribution, and etiology of enteric disease in the most susceptible pediatric populations. The data must be robust and provide the microbiological detail that allows the antigenic profile of pathogens to be characterized. Simple diagnostics should be developed to support such studies. 2. Cost-effectiveness estimates. Cost-effectiveness studies involve estimating real economic costs for impoverished individuals who seek treatment. An example for typhoid fever in an urban Delhi slum showed costs comprising both private out-of-pocket expenses and non-private costs total $102 for blood-culture positive infections and $129 for clinical typhoid fever. The economic impact of introducing cholera and typhoid vaccines into public health programs can also be estimated using tools such as Quality Adjusted Life Years (QALYs) or Disability Adjusted Life Years (DALYs), nutritional consequences, developmental delays, or economic loss. Policymakers expressed a need for more information on community perceptions about the importance of these diseases, the need for vaccinating, vaccine demand, and willingness to pay. The DOMI program has assessed public perceptions in the targeted populations as well as middle-class communities that might subsidize lower-cost vaccines for the poor. 3. Vaccine demonstration projects. Demonstration projects such as a well-publicized trial in Beira, Mozambique provided valuable experience working with partners in realistic settings, in this case by responding to the East African cholera epidemic. In this study, vaccination with two doses of the killed, rBS-WS Dukurol cholera vaccine product (SBL, Ltd. Stockholm, Sweden) was administered to 40,878 individuals from December 2003 to January 2004. This project provided the first large-scale test of an enteric vaccine in a population with a high prevalence of HIV infection. 4. Increased supply of preferably locally- or regionallyproduced vaccines. An area that clearly was lacking in the 1990s was an adequate and cost-competitive supply of vaccines. Developing an industrial and clinical trial capacity in countries with endemic disease was therefore a cornerstone of the DOMI program. A partnering approach was adopted to transfer key processes to several countries. Capacity-building allows studies to be conducted through Ministries of Health with substantial involvement of local
producers, thereby significantly changing the dynamics of the interactions with host countries. The integral role played by countries partnering in the DOMI Program is the synthesis and communication of research to policymakers at the international, regional, and national levels. The innovation of the DOMI program is specifically aimed at addressing many years of frustration and disappointment encountered in efforts to introduce vaccines into the poorest nations. Experience with cholera, typhoid and shigellosis is validating the key DOMI approach of partnering with all major stakeholders. These studies greatly facilitate accomplishing the broader goals of vaccine introductions.
2. Status of vaccines under development against major enteric pathogens In spite of the technological complexity and challenges in translating research and development to the field, dedicated researchers, many of whom participated in this workshop, have produced a number of enteric vaccine candidates that may be applicable to pediatric populations. Many enteric vaccines are reviewed by Svennerholm and Steele (Best Practice and Research Clinical Gastroenterology, 2004; 18: 421–445). Future research will surely add new candidates to the list. Of the major enteric pathogens on the WHO list, workshop participants identified Shigella spp. and ETEC as the two initial targets of an effort to develop pediatric vaccines. It was recognized that work towards a rotavirus vaccine is well underway with support from the pharmaceutical industry. Although new vaccines are still under development for S. typhi and V. cholerae, licensed vaccines against these pathogens do exist. It is hoped that additional demonstration projects (e.g. mass campaigns in schools) and other efforts will encourage more uptake in LDCs. It is likely that better surveillance data will identify additional pathogens that are important to the control of enteric diseases in LDCs. It is a daunting challenge to develop vaccines against Shigella spp. and ETEC, each with multiple serotypes, species, and colonization factor antigens. There are 15 relevant serotypes of S. flexneri alone. It remains to be determined if immunity to serotypes 2a, 3a and 6 of S. flexneri can protect humans against all serotypes. If the pattern of protection seen in animals extends to humans, then a penta (5)-valent Shigella vaccine containing these three serotypes of S. flexneri, plus S. dysenteriae and S. sonnei could be effective. For a multivalent ETEC vaccine to be effective, toxin antigens as well as CFA1 and CS1–6 in some combination may be required. It may be desirable to co-administer multiple enteric vaccines. However, when multiple parenteral vaccines have been administered in combination, adverse immunological interference has occurred, including additive reactogenicity and diminished response to one or more vaccine antigens. Regulatory hurdles for combination products are considerable, complicating the path to achieving inexpensive formulations.
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So far, the results have been highly positive when two oral vaccines have been co-administered (e.g., live oral polio and live oral rotavirus vaccines, or CVD 103-HgR live oral cholera vaccine co-administered with the live oral typhoid vaccine Ty21a). Similarly, a favorable outcome occurred when multiple serotypes of attenuated viruses (e.g., polio; rotavirus [tetravalent Wyeth Rotashield and Merck pentavalent rotavirus vaccine]), and attenuated bacteria (e.g., live attenuated V. cholerae O1 El Tor Ogawa CVD 111 and classical Inaba CVD 103-HgR), or inactivated V. cholerae O1 and O139 were co-delivered. The practicality of combining or co-administering enteric vaccines is an open question. There will clearly be formulation, commercial, and liability issues. If the epidemiological studies indicate significant geographical variation in pathogen incidence, co-administration could be preferable to combination vaccines.
3. Regulatory considerations affecting the development of enteric vaccines There remains a lack of clarity of the exact role that regulatory agencies in industrialized countries, such as the FDA, may play in the development of pediatric enteric vaccines for primary or exclusive use in developing countries. One scenario could be that a LDC national regulatory authority would request help from an outside regulatory agency. The many forms that this assistance could take need further consideration. It was recognized that many countries outside the US and Europe have well-organized regulatory authorities that may provide valuable resources. Vaccine products for use in LDCs could be developed clinically under the status of an investigational new drug application (IND). The FDA, for example, could provide a full and continuous review even if all manufacturing occurred outside the US. This approach could benefit the development of multivalent formulations, and could enhance product acceptance by the LDC population as well as facilitate subsequent development and licensure for use in the domestic traveler’s diarrhea market. Strong internal regulatory expertise is essential in any coordinated vaccine development effort, as is an early and ongoing dialogue with the relevant regulatory community. Although it is expected that new regulatory challenges will be encountered as work progresses, meeting participants did not believe that any major new regulatory roadblocks to development currently exist. Product requirements for enteric vaccine candidates vary depending on the nature of the product, but are expected to resemble the requirements for other vaccines. An enteric vaccine developer must ensure that appropriate tests are available to characterize the components making up the final product. Vaccines must be produced in a controlled safe manner. Product safety issues vary with the product and route of administration. For example, there is considerable experience with
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oral administration of live attenuated bacteria, but intranasal administration of live attenuated organisms raises new concerns separate from issues associated with administration to the intestinal tract. A vaccine for infants or children in LDC would likely proceed through different clinical trial paradigms from those for a traveler’s diarrhea vaccine. Although details will be affected by the nature of the products involved and scientific findings as development progresses, some general points can be made. It is likely that a Phase I trial for the vaccine or for each component of the vaccine would be conducted separately in healthy adults in an industrialized country to gain baseline safety and immunogenicity data for the product components (i.e. species or serotypes). As the components become available, a follow-up Phase I trial in a similar population could provide data with the components pooled into a combination vaccine candidate. Some dose optimization may be necessary during this second Phase I step. Depending on the outcome of these results, Phase I trials with the vaccine would be conducted first in healthy adults in a LDC, followed by older children, younger children and finally infants. If infants were the target group, then further dose optimization and immunogenicity studies would be conducted in this population, leading subsequently through Phase III studies. Upon successful completion of Phase III trials, one vaccine might be combined with another without further Phase III testing as long as immunological non-inferiority of components in the combined vaccine could be demonstrated. It is expected that at least for some vaccine components, Phase IV data would need to be collected. As Phase I testing begins in a LDC, challenge trials may need to be undertaken in an industrialized country to help support the scientific basis of the vaccine. In contrast to end points for traveler’s vaccines, the end point for the pediatric vaccine in a LDC could be reduction of severe disease to minimize mortality, and not elimination of all disease. For infants, in particular, it would be important to reduce the severity of the first episode, as natural immunity could be acquired to limit the impact of subsequent exposure.
4. Business considerations for product development A hurdle for many public health product development initiatives is the assignment of Intellectual Property (IP) rights. Therefore, IP issues need to be considered early in the process. Currently, private sector programs of the small to medium-sized biotechnology companies generally target the traveler’s market, which is considered economically viable. Consequently, there are promising in-license candidates available for pediatric use in LDCs. A “dual market” approach, which has been successfully applied to drug development, may be a possible model for enteric vaccines. In this approach, only the rights to the developing world are acquired for each product. The private sector partners would retain the traveler’s market for the same product. Licensing should allow the transfer of manufacturing to facilities in the
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developing world, because as was learned from the DOMI experience, it would likely encourage LDC involvement, and allow an affordable and steady supply at the local level. There was concern about the availability of quality pilotlot manufacturers as well as manufacturing capacity when an eventual licensed product comes on-line. The availability of pilot and product manufacturing facilities internationally needs further investigation. It is possible that relatively minimal investment in existing facilities, particularly in LDCs, could alleviate deficits in production capabilities. Various views were presented regarding whether vaccines should be manufactured exclusively in the developing countries. A study by the Global Alliance for Vaccines and Immunization (GAVI) was cited that indicated that costs in the US might not be much higher than in India. However, it is noted that local manufacturing has several advantages, including a likelihood of increased local acceptance and therefore usage of vaccines, and increased likelihood of sustained production due to willingness of local manufacturers to co-invest (along with public funds) to improve their factories. In the end, the positive experience of the DOMI program with partnering and a desire to improve local public health infrastructure were cited as important factors for consideration. A priori, product liabilities for pediatric vaccines would appear to add substantially to the price of the final products. Ironically, meeting participants, many with manufacturing experience, did not see these to be insurmountable. While trial sponsors would assume liability during the clinical trial stage, the responsibility for the eventual product lies with the manufacturer, who could include the cost of liability insurance in the final price calculation. For risk management, the panel discussed models used in childhood vaccine compensation programs, where a tax on the vaccines creates a fund, with a cap on potential awards, to cover potential law suits. It was advised that further strategies are needed in light of the alien tort claims act, where lawsuits could be filed in the US. Liability risk would be reduced with an increased stringency on product quality and product selection criteria. There are also implications on regulatory strategy: though the process of having the vaccine approved by a regulatory agency such as the FDA or EMEA would entail higher costs up-front, it may be cost-effective in the long run, since liability costs are likely to be lowered for the eventual marketed product. Therefore, one way to manage liability risk would be to have the product approved at the highest standards, and for the vaccine developer to bear part of the future liability costs through increased spending on the regulatory steps.
5. Vaccination implementation strategy: epidemiology and uptake Disease surveillance and disease burden data are critical for identifying high risk areas where vaccines could be targeted, as well as for use in advocacy in LDCs. It is of prime
importance to obtain more and better quality disease surveillance data in the affected populations. Three types of disease burden data are needed: (1) distributional, based on bacterial phenotype, to assist in identifying vaccine formulation; (2) absolute disease burden; and (3) data for advocacy, which can be some combination of the above data. The development of schema for differential diagnosis for use in endemic areas is an essential prerequisite to epidemiological studies that will underpin vaccination efforts. Common protocols are key to allow data to be compared across multiple regions. Well-designed epidemiological surveillance studies in multiple sites and settings for each target country are necessary, as are any correlation with HIV and malaria burden, where relevant. These studies must be ongoing in order to accurately assess changing needs as a consequence of public health efforts, changes in demographics, social stability, or environmental stressors. Another challenge to successful vaccination of children against diarrheal disease in LDCs is public perception of the health problem. Health resources in many countries are already stretched to their limits by current efforts to protect the population. Meeting participants saw that advocacy and marketing through close cooperation with local health authorities would be essential to the success of any enteric vaccine that might be developed. Ongoing monitoring of disease burden and vaccination coverage before and after implementation will also be important to evaluating the success of these efforts. It was acknowledged that a separate subgroup was needed to address these data needs in more detail. Vaccination coverage has remained stagnant in many countries, particularly in the African regions. There is a critical need for partnerships that include representation of the prospective vaccinee populations along the lines of previous major vaccine efforts. The commercial landscape remains unappealing to the for-profit sector. It is conceivable that if a strong investment case can be prepared, certain enteric vaccines may become eligible for support by the GAVI, thereby providing an initial trial period to eligible countries. As currently configured, after 5 years, developing countries would have to pay for the enteric vaccine if they wished to continue the vaccination program.
6. Scientific challenges to further development of enteric vaccines While a few enteric vaccine candidates are ready to move into clinical trials, there is still much to be learned regarding the pathogens themselves, the nature of protective immunity against them, and the means to induce safe and effective immune responses in the target population. The panel identified several general needs. The establishment of correlates of immunity against various pathogens is paramount for successful clinical trials. Challenges remain in making genetically stable organisms with sufficient atten-
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uation but effective immunogenicity. For potentially safer inactivated whole cell vaccines, further research is needed to obtain maximum immunogenicity at mucosal sites. Little is currently known regarding optimal means of mucosal immunization. Multiple routes and regimens are being studied with a variety of delivery systems. Adjuvants for mucosal immune responses offer promise but still require significant research. The need to clarify the importance of known antigens and possibly discover new ones applies to all the enteric pathogens. Cross-reactive protective antigens for groups of enteric pathogens, i.e. Shigella spp., or multiple ETEC strains, could help restrict the number of components necessary for a vaccine regimen. In addition, vaccine formulation and preservation techniques to eliminate cold chain requirements and the availability of needle-free delivery should receive a high priority for vaccines to be used in LDCs. Better animal models for human-restricted pathogens represent another over-arching need. One approach is the development of mice with “humanized” intestinal or immunological properties. Yet another general need is for improved access to clinical samples, and accelerated exchanges between research and clinical scientists. The mechanisms of bacterial-induced reactive arthritis need further investigation for the construction of safe vaccines. For vaccine candidates that are already available, trials are needed to verify safety and immunogenicity in newborns as well as in immunocompromised and co-infected populations. Specific research gaps include: Enterotoxigenic E. coli There are many serotypes of ETEC bearing distinctive colonization factors that cause diseases in LDCs. Further epidemiological studies of ETEC are needed since an effective vaccine would have to include components that induce protection among multiple serotype-specific strains. For example, the colonization factor antigens (CFA), coli surface antigens (CS), heat labile (LT) and heat-stable (ST) enterotoxins of ETEC could be pursued as vaccine antigens, but there is still not consensus on the relative importance of these components. If these factors are essential in a vaccine, it may be necessary to develop formulations that ensure their survival in the digestive tract. The protective effect of a vaccine inducing high antibody titers to LT should be evaluated. Some studies have shown that the B subunit of cholera toxin, which cross-reacts with the B subunit of LT, can protect against disease caused by LT-producing ETEC strains. Most ETEC strains also produce ST, which is not naturally immunogenic due to its small size. Shigella species As with ETEC, the challenge in vaccines against Shigella lies in the antigenic heterogeneity among the many serotypes, and improved epidemiologic studies are also needed for this pathogen. Animal studies indicate that a pentavalent vaccine may be possible, but this approach hinges on the expectation that a vaccine combination of S.
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flexneri 2a, 3a and 6 serotypes will cross protect against all clinically-relevant serotypes of S. flexneri. It is an open question whether Shigella antigens other than lipopolysaccharide (LPS) might be protective. In the case of S. dysenteriae Type 1, which produces a deadly toxin, an LPS-based vaccine may not be efficacious. Shigella vaccine research would benefit from efforts to better define the pro-inflammatory response, and also to engineer live attenuated strains incapable of survival outside the host. Salmonella enterica serovar Typhi An effective live, attenuated typhoid vaccine should mimic the capacity of the wild type strain to colonize and invade host cells. This goal will benefit from studies to determine the molecular genetic control of pathogenesis. Although a licensed S. Typhi vaccine exists, this vaccine has not been evaluated in newborns or immunocompromised populations. An animal model of human disease is a critical need for this pathogen. Work is also needed to determine how the carrier state is established and how it can best be eliminated, as well as the means by which S. Typhi induces a Th1 to Th2 switch. Vibrio cholerae Although the mechanism of protection against V. cholerae is not known, the serum level of vibriocidal antibodies (against LPS) has been shown to be a good correlate of immunity. Other possible vaccine targets include protein antigens such as attachment factors, colonization factors, flagella and outer membrane proteins. There is evidence that the serogroups and biotypes of cholera share some common epitopes in the major structural subunit of the fimbrial adherence factor TcpA. An effective vaccine based on cross protective cholera antigens would obviate the need for vaccine mixtures. There are also knowledge gaps in the areas of TLR polymorphisms, the antibody repertoire of the humoral immune response, the role IgA polymorphisms play in determining susceptibility to cholera, and the role of endogenous flora on vaccine efficacy. In that regard, the benefit of clearing infants of parasitic worms prior to vaccination should be determined. Campylobacter jejuni The disease burden of Campylobacter should be determined to establish the requirements for a vaccine for this pathogen in infants in LDCs. The problem of GuillainBarre Syndrome as a sequela of C. jejuni infection, and the association of reactive arthritis with this enteric pathogen was noted as a concern in Campylobacter vaccine construction as well as in challenge trials. The mechanisms for these complications are unknown. Likewise, association of these events with living versus non-living vaccines has not been established. Antigenic heterogeneity is also a problem in Campylobacter vaccine development. The degree of cross-reactivity for a successful vaccine and the existence of protective cross-reactive antigens are both unknowns. Specific studies to characterize the native structure of sur-
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face antigens and the mechanism of their glycosylation are needed. Rotavirus Live, attenuated viruses are the basis of existing rotavirus vaccine candidates. The genetic stability and transmission profiles of these vaccines in normal and immunocompromised children should be determined. It is not known whether all rotaviruses can cause intussusception, as was observed in one recently licensed vaccine. Studies of cellular entry and pathogenesis and the contribution of extraintestinal replication of rotaviruses to induction of immunity require further study. The use of reverse genetics methodologies to produce alternative vaccine candidates should be explored. Non-replicating vaccines have been safely used to protect animals against rotavirus, but studies have not yet been done in humans. For example, the protective capability of the rotavirus enterotoxin NSP4 has not been tested in humans. Finally, correlates of immunity would add greatly to advancing vaccine development against rotavirus. Live bacterial vectors Genetically-modified enteric pathogens have the potential to be effective vaccine vectors for other enteric pathogens, and they offer several possible advantages over other systems. There are promising candidates that are safe, efficacious, orally-administered, and stable under lyophilization, which obviates the need for the cold chain or the risks and expense of needles. The effectiveness of these delivery systems may be improved if means to downregulate dominant vector antigens and increase target antigen expression can be developed. Other desired vector characteristics might include stimulation of innate immunity, enhancement of either Th-1 or Th-2 dependent immunity, and induction of long-term T-cell memory. Safety assessments with these vectors should be conducted from the earliest stages in the LDC target population. Mucosal immunization Although much has been learned about immune responses to vaccination, questions remain about appropriate mucosal immunization strategies. For example, can a combination of sequential systemic prime/mucosal boosts be used to enhance immunity? Other areas of pertinent research include determining appropriate dose intervals, number of doses, and optimal routes for mucosal immunization in humans; such findings must then be applied to the specific needs of infants in LDCs. Maternal immunization could boost anti-enteric pathogen antibodies in mothers with resultant passive protection through transplacental and lactogenic transfer. Studies are needed to evaluate the effectiveness of this strategy for immunizing infants in LDCs. Following exposure, infants with passive antibody may develop mild disease, thereby priming the immune system to develop strong active immunity. Studies are needed to establish the safety and immunogenicity of existing vac-
cine candidates in infants. These efforts may benefit from development of models to mimic the intestinal tract of infants in LDCs, determination of correlates of immunity, and the simplification and standardization of assays such as the ELISPOT. Adjuvants Mucosal adjuvants are generally critical for nonreplicating vaccines. Such adjuvants may also serve to link innate and acquired immunity. Enterotoxins such as the ADP-ribosylating CT and LT are powerful mucosal adjuvants, but work is still needed to determine whether it is possible to fully separate enterotoxicity from adjuvanticity. For CT and LT, it is recognized that some level of ADPribosylating activity is required for effective adjuvanticity. Adjuvant effects may be achieved by use of biological response modifiers such as the TLR agonists, CPG-DNA, MPL and flagellin. However, since such agents often activate NFB, there is a need to balance the effects of using these as part of a vaccine regimen for young children. For most adjuvants, there are research gaps in the areas of general mechanism of adjuvanticity and specific effects when in combination with a particular vaccine antigen(s). Targeting of dendritic cells and cells relevant to mucosal immunity is another area where further research is needed. Details of current research projects and funding opportunities in enteric diseases supported by the National Institute for Allergy and Infectious Diseases are available at www.niaid.nih.gov.
7. A plan forward The difficulties that have been encountered by vaccinologists in recent years have led to a frustrating under-utilization of an historically powerful public health tool. Careful analysis of the barriers to the development and introduction of enteric vaccines provides some hope that many of the hurdles can be addressed. The workshop participants found no insurmountable obstacles to further the use of currently licensed vaccines as well as developing new and improved products to protect infants and children in LDCs from diarrheal diseases. In addition, opportunities already exist for answering important vaccine development questions and for developing some candidates into useful products. All vaccine introduction efforts to date have been through international alliances due to the range of required expertise. It may be helpful to move beyond ad hoc collaborations to improve the crossover of expertise from one area of vaccinology to other areas. These opportunities may best be realized through international alliances that integrate vaccine research, development, and implementation. There are many candidate vaccines at various levels of development that would benefit from a focused product development effort to funnel vaccines towards the pediatric population in LDCs. But development of enteric vaccines and their adoption into the public health programs of
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the key countries is not likely to happen, particularly for the pediatric population, unless sufficiently supported and coordinated efforts are made. Investigators who have to date made heroic efforts to carry the torch could be greatly assisted by a partner with a corporate-like product development program, with clear milestones and data-driven decision making and accountability. Such a structure was viewed as a possible approach to ensure that product development could proceed in a cost-effective and timely manner with less individual risk. Elements of existing disease-specific vaccine programs such as those that exist now for malaria and tuberculosis could be relevant to the structuring of an enteric vaccine effort. Activities under this approach could support development of promising candidates that often are stalled due to the lack of expertise in translating research to the targeted populations. These efforts could include vaccine development, trials, and licensing, and go further to support epidemiology, infrastructure development, clinical testing, production, and other resources. In summary, workshop participants were optimistic that a variety of enteric vaccine candidates do exist which could play an important role in preventing morbidity and mortal-
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ity among infants and children in the LDCs. A great range of expertise must be applied to move enteric vaccine candidates forward efficiently, including major participation by the recipient countries themselves. While challenges facing the development and implementation of these life-saving products are significant, it is recognized that many opportunities now exist to move enteric vaccines from concept to use. Adequately supported alliances to realize this opportunity are needed now to help bring an end to the suffering and deaths of millions of children annually from infectious diarrhea.
Acknowledgements The organizers wish to thank all of the workshop participants for providing their time and expertise. This workshop was supported by a grant to the Institute for OneWorld Health from the Bill and Melinda Gates Foundation, funding from the National Vaccine Program Office and the National Institute for Allergy and Infectious Diseases and other support from the Food and Drug Administration.
Enteric vaccines for pediatric use Workshop summary Richard I. Walker a,∗ , Lillian L. Van De Verg b , Robert H. Hall b , Clare K. Schmitt b , Katherine Woo c , Victoria Hale c a
b
Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike (HFM-425), Rockville, MD 20851-1448, USA Enteric and Hepatic Diseases Branch, DMID, NIAID, NIH, 6600 Rockledge Drive, Bethesda, MD 20892-7630, USA c Institute for OneWorld Health, 580 California Street, Suite 900, San Francisco, CA 94104, USA Received 9 January 2005; accepted 18 January 2005 Available online 2 April 2005
Abstract Diarrheal diseases remain a major cause of death in children under 5 in less developed countries (LDCs). Vaccine development and implementation offers the best near-term approach to alleviating this problem. For this reason, a workshop to examine the possibilities for making enteric vaccines available to meet the specific needs of children in LDCs was convened in Virginia on April 24–26, 2004. Discussants considered research and development needs, regulatory and business issues, and previous experiences with enteric vaccine development and implementation. No insurmountable roadblocks to progress in this area were noted, and the possibility currently exists that properly supported efforts will enable the realization of enteric vaccines for pediatric use. © 2005 Elsevier Ltd. All rights reserved. Keywords: Pediatric vaccines; Enteric pathogens; Vaccine development and implementation
Every day over 5500 children in less developed countries (LDCs) die as a consequence of diarrhea. Diarrheal diseases are second only to respiratory infections as killers of children under the age of five. In some countries, death due to diarrhea exceeds those attributable to HIV and malaria. And these numbers are dwarfed by the societal costs from diarrhea-associated morbidity, including malnutrition and both physical and mental deficits that result from untreated illness during early childhood. Vaccines specifically designed for pediatric use, along with hygienic and therapeutic interventions, can play a major role in reducing these unacceptable numbers. The challenges and possibilities for development of enteric vaccines, and providing them to children in LDCs were addressed by participants in a workshop, “Enteric Vaccines for Pediatric Use”, held at the Airlie Center, War∗
Corresponding author. Tel.: +1 301 4961014; fax: +1 301 4022776. E-mail address: [email protected] (R.I. Walker).
0264-410X/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2005.01.161
renton, VA, 24–26 April, 2004 (see www.oneworldhealth. org/diseases/diarrhea.php). The workshop brought together over 40 individuals representing expertise in the scientific, regulatory, and business issues involved in the development of enteric vaccines. The aim of the meeting was to identify the opportunities and obstacles to the adoption of enteric vaccines into the health programs of the countries where they are most needed. The following is a summation of those discussions.
1. The role for pediatric enteric vaccines in the least developed countries The special needs of LDC pediatric populations are often overlooked in the prevailing commercial development climate. The burden of diarrheal disease and its consequences are much greater among infants and children in LDCs than in any other target population. It was noted that the rela-
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tive importance of many enteric pathogens is obscured by the fact that there are few sites with adequate surveillance, that reporting of cases is sporadic, and the reported incidence can represent a gross underestimate of the true disease burden. While epidemics are more likely to be detected than endemic disease, endemic disease is the larger public health problem. Despite the shortage of accurate, current epidemiological data, it is clear that diarrheal diseases cause at least 2 million deaths annually in LDCs. Severe dehydrating diarrhea can be rapidly fatal, and swift intervention is necessary. Despite the remarkable accomplishments of Oral Rehydration Therapy (ORT), the “treatment of choice” for nearly 40 years, the global burden of diarrheal disease remains alarming. It was recognized that no single intervention would be sufficient to significantly lower the mortality rate due to secretory diarrhea. A successful strategy would require a combination of approaches. Among the major approaches to preventing diarrheal disease in LDC, vaccination offers the most feasible remedy for the short and medium term. While safe water and access to treatment are for the most part inaccessible to the most impoverished people, mass vaccination campaigns generally seek to protect these groups. Organized vaccination efforts can put protections in place prior to the time when severe environmental problems or major epidemics put extreme demands on limited health care resources. Vaccination that results in selflimiting infection or reduced mortality without necessarily eliminating disease remains important in relieving pressure during outbreak situations. Since the early 1990s the WHO has focused on a priority list of five enteric vaccines: Rotavirus, enterotoxigenic Escherichia coli (ETEC), Shigella, cholera, and typhoid fever. The target groups for all these pathogens include children, whereas S. dysenteriae 1, cholera and typhoid vaccines are also needed for adults. The incidence of particular serotypes remains unknown for most critical populations in the key endemic areas. Currently, licensed enteric vaccine formulations could have a significant impact if they were used in the situations where they are most needed. Although improved vaccines obviously would be beneficial it is not appropriate to delay the use of the existing products. In any event, improved vaccination approaches are predicated upon improved epidemiological studies in the most severely afflicted regions. Improved, field-ready diagnostic tools are also needed to complement vaccine development efforts. Meeting participants identified a number of important issues specific to the use of vaccines for the pediatric populations of LDCs. 1. Considerations must be given at the onset to the goal of integrating into Expanded Program of Immunization (EPI) schedules in order to leverage infrastructure already in place. 2. Strategies to elicit robust immunological responses in infants should be considered, and the impact of maternal im-
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munity on conferring passive protective immunity needs to be better defined. 3. Individuals in LDCs are presumably naturally exposed to the antigens of enteric pathogens multiple times during childhood. Thus, an enteric vaccine given to children in a LDC might be boosted by natural exposure. 4. The intestinal physiology of infants living in areas with endemic enteric disease will probably be significantly different from the intestinal physiology of na¨ıve individuals living in developed countries. One example presented showed striking histological differences between the intestinal epithelium from an infant living in an industrialized country compared to an infant living with a burden of enteric disease in an LDC. In addition, the intestinal flora of the infant from an LDC possessed a higher number of Gram-negative organisms than the flora from an infant living in an industrialized country. Differences such as these may account in part for the diminished immunogenicity observed with some oral vaccine candidates in LDC populations. This phenomenon of diminished immunogenicity has been observed for the oral polio vaccine, rotavirus, CVD 103HgR and BS/WCV cholera vaccines, and SC602 Shigella flexneri 2a. Ways must be found to formulate products with predictable immunogenicity for such populations. 5. It remains to be determined if vaccines shown to be safe for adults can be used at safe immunogenic doses in infants in LDCs. Observations with an inactivated ETEC vaccine showed that children under 6 months of age vomited an adult dose of this vaccine that was well tolerated by older children. Dilution of the vaccine 1:4 eliminated this problem without compromising immunogenicity. Vaccines for use by children in LDCs should be designed to be inexpensive, stable at room temperature (or heat-stable in tropical climates), and simple to administer to infants. Administration may take various forms. Individual vaccine formulations may be administered separately or coincidently (co-administered). Combination vaccines comprising a collection of individual components may be administered as a single formulation. Multivalent vaccines representing a single entity with several distinctive immunogens may be provided to confer protection against more than one pathogen. Practical considerations favor a vaccine formulation that would protect against multiple agents and be readily administered by non-medical personnel using a needle-free delivery method. Enteric vaccines for use in LDCs must meet the public health goals of the country, and appropriate personnel from these countries must be brought into the planning process at an early stage. The Diseases of the Most Impoverished (DOMI) Program, funded by the Bill and Melinda Gates Foundation and coordinated by the International Vaccine Institute (IVI; see www.ivi.org) has for the last 5 years addressed many critical issues associated with vaccine introduction in LDCs. As a first step, a survey of health policy-
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makers was performed in the seven DOMI partner countries, namely Bangladesh, China, India, Indonesia, Pakistan, Thailand and Vietnam. The goal of the policy-maker survey was to develop an investment case for introducing enteric vaccines into countries with the greatest need. The policy survey results indicated that vaccines were recognized as potentially important tools for the control of typhoid, shigellosis, and cholera provided the vaccine was <$1 per dose, and showed at least moderate efficacy. Policymakers described four major needs: 1. Burden of disease data. A determined effort is needed in LDC to collect epidemiological data on the burden, distribution, and etiology of enteric disease in the most susceptible pediatric populations. The data must be robust and provide the microbiological detail that allows the antigenic profile of pathogens to be characterized. Simple diagnostics should be developed to support such studies. 2. Cost-effectiveness estimates. Cost-effectiveness studies involve estimating real economic costs for impoverished individuals who seek treatment. An example for typhoid fever in an urban Delhi slum showed costs comprising both private out-of-pocket expenses and non-private costs total $102 for blood-culture positive infections and $129 for clinical typhoid fever. The economic impact of introducing cholera and typhoid vaccines into public health programs can also be estimated using tools such as Quality Adjusted Life Years (QALYs) or Disability Adjusted Life Years (DALYs), nutritional consequences, developmental delays, or economic loss. Policymakers expressed a need for more information on community perceptions about the importance of these diseases, the need for vaccinating, vaccine demand, and willingness to pay. The DOMI program has assessed public perceptions in the targeted populations as well as middle-class communities that might subsidize lower-cost vaccines for the poor. 3. Vaccine demonstration projects. Demonstration projects such as a well-publicized trial in Beira, Mozambique provided valuable experience working with partners in realistic settings, in this case by responding to the East African cholera epidemic. In this study, vaccination with two doses of the killed, rBS-WS Dukurol cholera vaccine product (SBL, Ltd. Stockholm, Sweden) was administered to 40,878 individuals from December 2003 to January 2004. This project provided the first large-scale test of an enteric vaccine in a population with a high prevalence of HIV infection. 4. Increased supply of preferably locally- or regionallyproduced vaccines. An area that clearly was lacking in the 1990s was an adequate and cost-competitive supply of vaccines. Developing an industrial and clinical trial capacity in countries with endemic disease was therefore a cornerstone of the DOMI program. A partnering approach was adopted to transfer key processes to several countries. Capacity-building allows studies to be conducted through Ministries of Health with substantial involvement of local
producers, thereby significantly changing the dynamics of the interactions with host countries. The integral role played by countries partnering in the DOMI Program is the synthesis and communication of research to policymakers at the international, regional, and national levels. The innovation of the DOMI program is specifically aimed at addressing many years of frustration and disappointment encountered in efforts to introduce vaccines into the poorest nations. Experience with cholera, typhoid and shigellosis is validating the key DOMI approach of partnering with all major stakeholders. These studies greatly facilitate accomplishing the broader goals of vaccine introductions.
2. Status of vaccines under development against major enteric pathogens In spite of the technological complexity and challenges in translating research and development to the field, dedicated researchers, many of whom participated in this workshop, have produced a number of enteric vaccine candidates that may be applicable to pediatric populations. Many enteric vaccines are reviewed by Svennerholm and Steele (Best Practice and Research Clinical Gastroenterology, 2004; 18: 421–445). Future research will surely add new candidates to the list. Of the major enteric pathogens on the WHO list, workshop participants identified Shigella spp. and ETEC as the two initial targets of an effort to develop pediatric vaccines. It was recognized that work towards a rotavirus vaccine is well underway with support from the pharmaceutical industry. Although new vaccines are still under development for S. typhi and V. cholerae, licensed vaccines against these pathogens do exist. It is hoped that additional demonstration projects (e.g. mass campaigns in schools) and other efforts will encourage more uptake in LDCs. It is likely that better surveillance data will identify additional pathogens that are important to the control of enteric diseases in LDCs. It is a daunting challenge to develop vaccines against Shigella spp. and ETEC, each with multiple serotypes, species, and colonization factor antigens. There are 15 relevant serotypes of S. flexneri alone. It remains to be determined if immunity to serotypes 2a, 3a and 6 of S. flexneri can protect humans against all serotypes. If the pattern of protection seen in animals extends to humans, then a penta (5)-valent Shigella vaccine containing these three serotypes of S. flexneri, plus S. dysenteriae and S. sonnei could be effective. For a multivalent ETEC vaccine to be effective, toxin antigens as well as CFA1 and CS1–6 in some combination may be required. It may be desirable to co-administer multiple enteric vaccines. However, when multiple parenteral vaccines have been administered in combination, adverse immunological interference has occurred, including additive reactogenicity and diminished response to one or more vaccine antigens. Regulatory hurdles for combination products are considerable, complicating the path to achieving inexpensive formulations.
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So far, the results have been highly positive when two oral vaccines have been co-administered (e.g., live oral polio and live oral rotavirus vaccines, or CVD 103-HgR live oral cholera vaccine co-administered with the live oral typhoid vaccine Ty21a). Similarly, a favorable outcome occurred when multiple serotypes of attenuated viruses (e.g., polio; rotavirus [tetravalent Wyeth Rotashield and Merck pentavalent rotavirus vaccine]), and attenuated bacteria (e.g., live attenuated V. cholerae O1 El Tor Ogawa CVD 111 and classical Inaba CVD 103-HgR), or inactivated V. cholerae O1 and O139 were co-delivered. The practicality of combining or co-administering enteric vaccines is an open question. There will clearly be formulation, commercial, and liability issues. If the epidemiological studies indicate significant geographical variation in pathogen incidence, co-administration could be preferable to combination vaccines.
3. Regulatory considerations affecting the development of enteric vaccines There remains a lack of clarity of the exact role that regulatory agencies in industrialized countries, such as the FDA, may play in the development of pediatric enteric vaccines for primary or exclusive use in developing countries. One scenario could be that a LDC national regulatory authority would request help from an outside regulatory agency. The many forms that this assistance could take need further consideration. It was recognized that many countries outside the US and Europe have well-organized regulatory authorities that may provide valuable resources. Vaccine products for use in LDCs could be developed clinically under the status of an investigational new drug application (IND). The FDA, for example, could provide a full and continuous review even if all manufacturing occurred outside the US. This approach could benefit the development of multivalent formulations, and could enhance product acceptance by the LDC population as well as facilitate subsequent development and licensure for use in the domestic traveler’s diarrhea market. Strong internal regulatory expertise is essential in any coordinated vaccine development effort, as is an early and ongoing dialogue with the relevant regulatory community. Although it is expected that new regulatory challenges will be encountered as work progresses, meeting participants did not believe that any major new regulatory roadblocks to development currently exist. Product requirements for enteric vaccine candidates vary depending on the nature of the product, but are expected to resemble the requirements for other vaccines. An enteric vaccine developer must ensure that appropriate tests are available to characterize the components making up the final product. Vaccines must be produced in a controlled safe manner. Product safety issues vary with the product and route of administration. For example, there is considerable experience with
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oral administration of live attenuated bacteria, but intranasal administration of live attenuated organisms raises new concerns separate from issues associated with administration to the intestinal tract. A vaccine for infants or children in LDC would likely proceed through different clinical trial paradigms from those for a traveler’s diarrhea vaccine. Although details will be affected by the nature of the products involved and scientific findings as development progresses, some general points can be made. It is likely that a Phase I trial for the vaccine or for each component of the vaccine would be conducted separately in healthy adults in an industrialized country to gain baseline safety and immunogenicity data for the product components (i.e. species or serotypes). As the components become available, a follow-up Phase I trial in a similar population could provide data with the components pooled into a combination vaccine candidate. Some dose optimization may be necessary during this second Phase I step. Depending on the outcome of these results, Phase I trials with the vaccine would be conducted first in healthy adults in a LDC, followed by older children, younger children and finally infants. If infants were the target group, then further dose optimization and immunogenicity studies would be conducted in this population, leading subsequently through Phase III studies. Upon successful completion of Phase III trials, one vaccine might be combined with another without further Phase III testing as long as immunological non-inferiority of components in the combined vaccine could be demonstrated. It is expected that at least for some vaccine components, Phase IV data would need to be collected. As Phase I testing begins in a LDC, challenge trials may need to be undertaken in an industrialized country to help support the scientific basis of the vaccine. In contrast to end points for traveler’s vaccines, the end point for the pediatric vaccine in a LDC could be reduction of severe disease to minimize mortality, and not elimination of all disease. For infants, in particular, it would be important to reduce the severity of the first episode, as natural immunity could be acquired to limit the impact of subsequent exposure.
4. Business considerations for product development A hurdle for many public health product development initiatives is the assignment of Intellectual Property (IP) rights. Therefore, IP issues need to be considered early in the process. Currently, private sector programs of the small to medium-sized biotechnology companies generally target the traveler’s market, which is considered economically viable. Consequently, there are promising in-license candidates available for pediatric use in LDCs. A “dual market” approach, which has been successfully applied to drug development, may be a possible model for enteric vaccines. In this approach, only the rights to the developing world are acquired for each product. The private sector partners would retain the traveler’s market for the same product. Licensing should allow the transfer of manufacturing to facilities in the
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developing world, because as was learned from the DOMI experience, it would likely encourage LDC involvement, and allow an affordable and steady supply at the local level. There was concern about the availability of quality pilotlot manufacturers as well as manufacturing capacity when an eventual licensed product comes on-line. The availability of pilot and product manufacturing facilities internationally needs further investigation. It is possible that relatively minimal investment in existing facilities, particularly in LDCs, could alleviate deficits in production capabilities. Various views were presented regarding whether vaccines should be manufactured exclusively in the developing countries. A study by the Global Alliance for Vaccines and Immunization (GAVI) was cited that indicated that costs in the US might not be much higher than in India. However, it is noted that local manufacturing has several advantages, including a likelihood of increased local acceptance and therefore usage of vaccines, and increased likelihood of sustained production due to willingness of local manufacturers to co-invest (along with public funds) to improve their factories. In the end, the positive experience of the DOMI program with partnering and a desire to improve local public health infrastructure were cited as important factors for consideration. A priori, product liabilities for pediatric vaccines would appear to add substantially to the price of the final products. Ironically, meeting participants, many with manufacturing experience, did not see these to be insurmountable. While trial sponsors would assume liability during the clinical trial stage, the responsibility for the eventual product lies with the manufacturer, who could include the cost of liability insurance in the final price calculation. For risk management, the panel discussed models used in childhood vaccine compensation programs, where a tax on the vaccines creates a fund, with a cap on potential awards, to cover potential law suits. It was advised that further strategies are needed in light of the alien tort claims act, where lawsuits could be filed in the US. Liability risk would be reduced with an increased stringency on product quality and product selection criteria. There are also implications on regulatory strategy: though the process of having the vaccine approved by a regulatory agency such as the FDA or EMEA would entail higher costs up-front, it may be cost-effective in the long run, since liability costs are likely to be lowered for the eventual marketed product. Therefore, one way to manage liability risk would be to have the product approved at the highest standards, and for the vaccine developer to bear part of the future liability costs through increased spending on the regulatory steps.
5. Vaccination implementation strategy: epidemiology and uptake Disease surveillance and disease burden data are critical for identifying high risk areas where vaccines could be targeted, as well as for use in advocacy in LDCs. It is of prime
importance to obtain more and better quality disease surveillance data in the affected populations. Three types of disease burden data are needed: (1) distributional, based on bacterial phenotype, to assist in identifying vaccine formulation; (2) absolute disease burden; and (3) data for advocacy, which can be some combination of the above data. The development of schema for differential diagnosis for use in endemic areas is an essential prerequisite to epidemiological studies that will underpin vaccination efforts. Common protocols are key to allow data to be compared across multiple regions. Well-designed epidemiological surveillance studies in multiple sites and settings for each target country are necessary, as are any correlation with HIV and malaria burden, where relevant. These studies must be ongoing in order to accurately assess changing needs as a consequence of public health efforts, changes in demographics, social stability, or environmental stressors. Another challenge to successful vaccination of children against diarrheal disease in LDCs is public perception of the health problem. Health resources in many countries are already stretched to their limits by current efforts to protect the population. Meeting participants saw that advocacy and marketing through close cooperation with local health authorities would be essential to the success of any enteric vaccine that might be developed. Ongoing monitoring of disease burden and vaccination coverage before and after implementation will also be important to evaluating the success of these efforts. It was acknowledged that a separate subgroup was needed to address these data needs in more detail. Vaccination coverage has remained stagnant in many countries, particularly in the African regions. There is a critical need for partnerships that include representation of the prospective vaccinee populations along the lines of previous major vaccine efforts. The commercial landscape remains unappealing to the for-profit sector. It is conceivable that if a strong investment case can be prepared, certain enteric vaccines may become eligible for support by the GAVI, thereby providing an initial trial period to eligible countries. As currently configured, after 5 years, developing countries would have to pay for the enteric vaccine if they wished to continue the vaccination program.
6. Scientific challenges to further development of enteric vaccines While a few enteric vaccine candidates are ready to move into clinical trials, there is still much to be learned regarding the pathogens themselves, the nature of protective immunity against them, and the means to induce safe and effective immune responses in the target population. The panel identified several general needs. The establishment of correlates of immunity against various pathogens is paramount for successful clinical trials. Challenges remain in making genetically stable organisms with sufficient atten-
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uation but effective immunogenicity. For potentially safer inactivated whole cell vaccines, further research is needed to obtain maximum immunogenicity at mucosal sites. Little is currently known regarding optimal means of mucosal immunization. Multiple routes and regimens are being studied with a variety of delivery systems. Adjuvants for mucosal immune responses offer promise but still require significant research. The need to clarify the importance of known antigens and possibly discover new ones applies to all the enteric pathogens. Cross-reactive protective antigens for groups of enteric pathogens, i.e. Shigella spp., or multiple ETEC strains, could help restrict the number of components necessary for a vaccine regimen. In addition, vaccine formulation and preservation techniques to eliminate cold chain requirements and the availability of needle-free delivery should receive a high priority for vaccines to be used in LDCs. Better animal models for human-restricted pathogens represent another over-arching need. One approach is the development of mice with “humanized” intestinal or immunological properties. Yet another general need is for improved access to clinical samples, and accelerated exchanges between research and clinical scientists. The mechanisms of bacterial-induced reactive arthritis need further investigation for the construction of safe vaccines. For vaccine candidates that are already available, trials are needed to verify safety and immunogenicity in newborns as well as in immunocompromised and co-infected populations. Specific research gaps include: Enterotoxigenic E. coli There are many serotypes of ETEC bearing distinctive colonization factors that cause diseases in LDCs. Further epidemiological studies of ETEC are needed since an effective vaccine would have to include components that induce protection among multiple serotype-specific strains. For example, the colonization factor antigens (CFA), coli surface antigens (CS), heat labile (LT) and heat-stable (ST) enterotoxins of ETEC could be pursued as vaccine antigens, but there is still not consensus on the relative importance of these components. If these factors are essential in a vaccine, it may be necessary to develop formulations that ensure their survival in the digestive tract. The protective effect of a vaccine inducing high antibody titers to LT should be evaluated. Some studies have shown that the B subunit of cholera toxin, which cross-reacts with the B subunit of LT, can protect against disease caused by LT-producing ETEC strains. Most ETEC strains also produce ST, which is not naturally immunogenic due to its small size. Shigella species As with ETEC, the challenge in vaccines against Shigella lies in the antigenic heterogeneity among the many serotypes, and improved epidemiologic studies are also needed for this pathogen. Animal studies indicate that a pentavalent vaccine may be possible, but this approach hinges on the expectation that a vaccine combination of S.
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flexneri 2a, 3a and 6 serotypes will cross protect against all clinically-relevant serotypes of S. flexneri. It is an open question whether Shigella antigens other than lipopolysaccharide (LPS) might be protective. In the case of S. dysenteriae Type 1, which produces a deadly toxin, an LPS-based vaccine may not be efficacious. Shigella vaccine research would benefit from efforts to better define the pro-inflammatory response, and also to engineer live attenuated strains incapable of survival outside the host. Salmonella enterica serovar Typhi An effective live, attenuated typhoid vaccine should mimic the capacity of the wild type strain to colonize and invade host cells. This goal will benefit from studies to determine the molecular genetic control of pathogenesis. Although a licensed S. Typhi vaccine exists, this vaccine has not been evaluated in newborns or immunocompromised populations. An animal model of human disease is a critical need for this pathogen. Work is also needed to determine how the carrier state is established and how it can best be eliminated, as well as the means by which S. Typhi induces a Th1 to Th2 switch. Vibrio cholerae Although the mechanism of protection against V. cholerae is not known, the serum level of vibriocidal antibodies (against LPS) has been shown to be a good correlate of immunity. Other possible vaccine targets include protein antigens such as attachment factors, colonization factors, flagella and outer membrane proteins. There is evidence that the serogroups and biotypes of cholera share some common epitopes in the major structural subunit of the fimbrial adherence factor TcpA. An effective vaccine based on cross protective cholera antigens would obviate the need for vaccine mixtures. There are also knowledge gaps in the areas of TLR polymorphisms, the antibody repertoire of the humoral immune response, the role IgA polymorphisms play in determining susceptibility to cholera, and the role of endogenous flora on vaccine efficacy. In that regard, the benefit of clearing infants of parasitic worms prior to vaccination should be determined. Campylobacter jejuni The disease burden of Campylobacter should be determined to establish the requirements for a vaccine for this pathogen in infants in LDCs. The problem of GuillainBarre Syndrome as a sequela of C. jejuni infection, and the association of reactive arthritis with this enteric pathogen was noted as a concern in Campylobacter vaccine construction as well as in challenge trials. The mechanisms for these complications are unknown. Likewise, association of these events with living versus non-living vaccines has not been established. Antigenic heterogeneity is also a problem in Campylobacter vaccine development. The degree of cross-reactivity for a successful vaccine and the existence of protective cross-reactive antigens are both unknowns. Specific studies to characterize the native structure of sur-
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face antigens and the mechanism of their glycosylation are needed. Rotavirus Live, attenuated viruses are the basis of existing rotavirus vaccine candidates. The genetic stability and transmission profiles of these vaccines in normal and immunocompromised children should be determined. It is not known whether all rotaviruses can cause intussusception, as was observed in one recently licensed vaccine. Studies of cellular entry and pathogenesis and the contribution of extraintestinal replication of rotaviruses to induction of immunity require further study. The use of reverse genetics methodologies to produce alternative vaccine candidates should be explored. Non-replicating vaccines have been safely used to protect animals against rotavirus, but studies have not yet been done in humans. For example, the protective capability of the rotavirus enterotoxin NSP4 has not been tested in humans. Finally, correlates of immunity would add greatly to advancing vaccine development against rotavirus. Live bacterial vectors Genetically-modified enteric pathogens have the potential to be effective vaccine vectors for other enteric pathogens, and they offer several possible advantages over other systems. There are promising candidates that are safe, efficacious, orally-administered, and stable under lyophilization, which obviates the need for the cold chain or the risks and expense of needles. The effectiveness of these delivery systems may be improved if means to downregulate dominant vector antigens and increase target antigen expression can be developed. Other desired vector characteristics might include stimulation of innate immunity, enhancement of either Th-1 or Th-2 dependent immunity, and induction of long-term T-cell memory. Safety assessments with these vectors should be conducted from the earliest stages in the LDC target population. Mucosal immunization Although much has been learned about immune responses to vaccination, questions remain about appropriate mucosal immunization strategies. For example, can a combination of sequential systemic prime/mucosal boosts be used to enhance immunity? Other areas of pertinent research include determining appropriate dose intervals, number of doses, and optimal routes for mucosal immunization in humans; such findings must then be applied to the specific needs of infants in LDCs. Maternal immunization could boost anti-enteric pathogen antibodies in mothers with resultant passive protection through transplacental and lactogenic transfer. Studies are needed to evaluate the effectiveness of this strategy for immunizing infants in LDCs. Following exposure, infants with passive antibody may develop mild disease, thereby priming the immune system to develop strong active immunity. Studies are needed to establish the safety and immunogenicity of existing vac-
cine candidates in infants. These efforts may benefit from development of models to mimic the intestinal tract of infants in LDCs, determination of correlates of immunity, and the simplification and standardization of assays such as the ELISPOT. Adjuvants Mucosal adjuvants are generally critical for nonreplicating vaccines. Such adjuvants may also serve to link innate and acquired immunity. Enterotoxins such as the ADP-ribosylating CT and LT are powerful mucosal adjuvants, but work is still needed to determine whether it is possible to fully separate enterotoxicity from adjuvanticity. For CT and LT, it is recognized that some level of ADPribosylating activity is required for effective adjuvanticity. Adjuvant effects may be achieved by use of biological response modifiers such as the TLR agonists, CPG-DNA, MPL and flagellin. However, since such agents often activate NFB, there is a need to balance the effects of using these as part of a vaccine regimen for young children. For most adjuvants, there are research gaps in the areas of general mechanism of adjuvanticity and specific effects when in combination with a particular vaccine antigen(s). Targeting of dendritic cells and cells relevant to mucosal immunity is another area where further research is needed. Details of current research projects and funding opportunities in enteric diseases supported by the National Institute for Allergy and Infectious Diseases are available at www.niaid.nih.gov.
7. A plan forward The difficulties that have been encountered by vaccinologists in recent years have led to a frustrating under-utilization of an historically powerful public health tool. Careful analysis of the barriers to the development and introduction of enteric vaccines provides some hope that many of the hurdles can be addressed. The workshop participants found no insurmountable obstacles to further the use of currently licensed vaccines as well as developing new and improved products to protect infants and children in LDCs from diarrheal diseases. In addition, opportunities already exist for answering important vaccine development questions and for developing some candidates into useful products. All vaccine introduction efforts to date have been through international alliances due to the range of required expertise. It may be helpful to move beyond ad hoc collaborations to improve the crossover of expertise from one area of vaccinology to other areas. These opportunities may best be realized through international alliances that integrate vaccine research, development, and implementation. There are many candidate vaccines at various levels of development that would benefit from a focused product development effort to funnel vaccines towards the pediatric population in LDCs. But development of enteric vaccines and their adoption into the public health programs of
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the key countries is not likely to happen, particularly for the pediatric population, unless sufficiently supported and coordinated efforts are made. Investigators who have to date made heroic efforts to carry the torch could be greatly assisted by a partner with a corporate-like product development program, with clear milestones and data-driven decision making and accountability. Such a structure was viewed as a possible approach to ensure that product development could proceed in a cost-effective and timely manner with less individual risk. Elements of existing disease-specific vaccine programs such as those that exist now for malaria and tuberculosis could be relevant to the structuring of an enteric vaccine effort. Activities under this approach could support development of promising candidates that often are stalled due to the lack of expertise in translating research to the targeted populations. These efforts could include vaccine development, trials, and licensing, and go further to support epidemiology, infrastructure development, clinical testing, production, and other resources. In summary, workshop participants were optimistic that a variety of enteric vaccine candidates do exist which could play an important role in preventing morbidity and mortal-
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ity among infants and children in the LDCs. A great range of expertise must be applied to move enteric vaccine candidates forward efficiently, including major participation by the recipient countries themselves. While challenges facing the development and implementation of these life-saving products are significant, it is recognized that many opportunities now exist to move enteric vaccines from concept to use. Adequately supported alliances to realize this opportunity are needed now to help bring an end to the suffering and deaths of millions of children annually from infectious diarrhea.
Acknowledgements The organizers wish to thank all of the workshop participants for providing their time and expertise. This workshop was supported by a grant to the Institute for OneWorld Health from the Bill and Melinda Gates Foundation, funding from the National Vaccine Program Office and the National Institute for Allergy and Infectious Diseases and other support from the Food and Drug Administration.