Vaccine Development Global Program

ETEC and Shigella vaccine development

PATH is collaborating with private- and public-sector partners to speed the development of safe, effective, and affordable vaccines against the top bacterial causes of diarrhea—enterotoxigenic Escherichia coli (ETEC) and Shigella—for children in low-resource countries. We’re pursuing a wide range of promising vaccine approaches and related research, with the goal of identifying at least one vaccine candidate for each pathogen to prioritize for late-stage development. We’re also assessing manufacturing partners, mostly in emerging countries, to take on the eventual manufacture and distribution of these new vaccines.

Live attenuated strains

Live attenuated vaccines made from weakened bacteria have shown promise with ETEC and Shigella, as they can more closely mimic natural infection and may induce more protective immune responses. However, some vaccines of this type have shown unacceptable levels of reactogenicity in clinical trials or reduced immunogenicity in low-resource countries, particularly in infants and young children. We’re investigating potential live attenuated ETEC and Shigella vaccines that could be safe, effective, and affordable.

  • ACE527 is an oral, whole-cell ETEC vaccine candidate comprised of three attenuated strains. We previously supported early clinical research on ACE527, including a Phase 1/2b challenge trial of the vaccine given in combination with a novel mucosal adjuvant (an ingredient added to vaccines to help strengthen the immune response) called double-mutant heat-labile toxin (dmLT). Results indicated that the ACE527/dmLT combination provided significant protection against diarrhea of any severity and was highly efficacious against severe ETEC diarrhea. We are currently engaging with emerging-country manufacturers to further the development of ACE527.
  • WRSS1 is an oral, single-strain Shigella vaccine component developed by the Walter Reed Army Institute of Research (WRAIR). We’re currently supporting a descending-age study of WRSS1 at icddr,b (an international public health research institution) in Bangladesh, with the long-term goal of developing a multivalent vaccine designed to prevent illness from the most common disease-causing Shigella strains.

Killed whole-cell vaccines

Whole-cell vaccines offer a superior safety profile, as well as a relatively simple and cost-effective manufacturing process, although it remains to be seen whether these vaccines will demonstrate sufficient immunogenicity and protective efficacy among infants and young children living in endemic countries. We’re looking for ways to maximize the protection that these vaccines could offer in low-resource settings.

  • We’re working with the University of Gothenburg and Scandinavian BioPharma in Sweden to evaluate a tetravalent, inactivated whole-cell ETEC vaccine candidate called ETVAX. After successful proof-of-concept studies to test the vaccine’s immunogenicity compared to an earlier version of the candidate, we assessed it in combination with the dmLT adjuvant. Results showed that ETVAX was safe, well tolerated, and more immunogenic than expected. We are now conducting additional studies to evaluate the ETVAX/dmLT combination among children in Bangladesh, particularly the extent to which the dmLT adjuvant may facilitate vaccine dose sparing.
  • In collaboration with WRAIR, we conducted a current Good Manufacturing Practice (cGMP) manufacture and preclinical assessment of a formalin-inactivated, trivalent whole-cell Shigella vaccine candidate. It was previously thought that live attenuated bacteria were the most promising approach to eliciting a strong immune response, but a prototype of this vaccine elicited a robust immune response during an initial clinical trial. We are currently planning additional clinical studies to evaluate the safety, immunogenicity, and protection of this new multi-strain vaccine given in combination with the dmLT adjuvant.

Subunit vaccines

We are working with several partners to evaluate promising ETEC and Shigella subunit antigens, which may confer broader protective coverage to vaccines. These types of vaccines offer excellent safety profiles, but it has been difficult to effectively achieve mucosal immunization with them because they do not survive oral delivery. To address this challenge, we’re also involved in innovative research on intradermal and sublingual delivery routes to improve intestinal mucosal response.

  • A vaccine that targets the conserved fimbrial tip adhesin proteins of ETEC is being developed by the US Naval Medical Research Center (NMRC), with PATH providing technical support. This candidate completed early clinical testing using the intradermal and transcutaneous routes. Intradermal immunization resulted in higher immunogenicity results, so NMRC is now testing the vaccine via this route in a Phase 2b immunization and challenge study.
  • Heat-stable enterotoxin (ST) is associated with the most common and serious ETEC infections. We’re partnering with the International Enteric Vaccine Consortium, a group of universities anchored by the University of Maryland School of Medicine, to conduct preclinical research on an ST toxoid vaccine to determine if ST can be rendered non-toxic while retaining its ability to induce toxin-neutralizing antibody responses.
  • The invasion plasmid antigens (Ipa proteins) of Shigella may be able to serve as broadly protective antigens against diverse serotypes and species. We worked with researchers at Oklahoma State University (now located at University of Kansas) to develop a Shigella vaccine based on IpaB and IpaD that, when combined genetically into a single fusion protein (DB Fusion), successfully protected mice against infection with several different Shigella serotypes. Activities are now underway to produce a cGMP lot of DB Fusion suitable for clinical testing as an intradermally delivered vaccine. This groundbreaking product could be the first serotype-independent vaccine against Shigella.
  • PATH and WRAIR are working in partnership to conduct a preclinical evaluation of different formulations of Invaplex, a vaccine candidate consisting of Shigella lipopolysaccharide (LPS) in complex with IpaB, IpaC, and IpaD proteins. Using detoxified forms of the LPS component, the candidate is being evaluated in combination with the original Ipa proteins, as well as with the Ipa DB Fusion described above.

ETEC vaccine development portfolio snapshot

EVI portfolio chart


Shigella vaccine development portfolio snapshot

EVI portfolio chart_shigella

Innovative research to support vaccine development

Adjuvants: Adjuvants—ingredients that may enhance the effectiveness of some vaccines—could be a potential game-changer for the field of enteric vaccines. PATH in-licensed from Tulane University the highly promising dmLT adjuvant, an ETEC antigen that may protect against both diarrhea and intestinal infection. LT is also one of the most effective mucosal adjuvants known. Due to its improved attenuation, dmLT could provide a breakthrough in mucosal adjuvants. In addition to testing the dmLT adjuvant in conjunction with several of our vaccine candidates, we’re working with the US National Institutes of Health’s Division of Microbiology and Infectious Diseases on early clinical studies of dmLT being administered orally, sublingually, and intradermally.

Formulation and delivery: In recognition that new vaccines must be practical for use with infants and children in low-resource countries, we’re studying innovative approaches to enteric vaccine formulation and delivery:

  • To address the challenge of ensuring the survival of multiple strains in attenuated vaccines, we have developed a holding buffer system that may allow live cells to be stored until all components are available to be mixed and lyophilized rather than completing this step for each strain individually.
  • We’re also conducting research on novel vaccine-formulation options, such as a fast-dissolving tablet technology platform. Because infants may not be able to tolerate the large volumes of buffer used with oral vaccines, we are developing a low-volume buffer that can still effectively neutralize stomach acids.
  • We’re supporting preclinical studies in several animal models to evaluate intradermal vaccination as a means to elicit intestinal immunity. This delivery route has been gaining interest due to its potential for dose sparing and recent technological advances that enhance its safety and simplicity.
  • Finally, work supported by PATH has shown that intradermal coadministration of an enterotoxin-based adjuvant such as dmLT with an antigen induces a robust immune response in the intestine. This novel paradigm for inducing intestinal immune responses may facilitate the development of new vaccines.

Systems biology approaches: We recently began exploring innovative, iterative approaches to vaccine development based on systems biology. One such approach involves applying novel immune analysis technologies such as protein microarrays to samples from our clinical trials in order to gain a better understanding of the immunological mechanisms involved in protection. These technologies can also provide insights into novel antigens that could better guide the composition of future vaccines and help us discern subtle responses induced by adjuvant and formulation changes in a vaccine. This information will ultimately make the vaccine development process more robust and efficient.

Microbiome research: Another new PATH effort is to develop a better understanding of the intestinal microbiome—or the collection of microorganisms that live in the human gut—with a particular focus on the pediatric intestinal microbiome. These microorganisms may play a role in determining children’s susceptibility and/or resistance to infection and vaccine uptake. Gaining insight into the pediatric intestinal microbiome will help better guide the development of vaccines geared toward children in ETEC- and Shigella-endemic countries.

Controlled human infection models: We are supporting the development of controlled human infection models for enteric diseases, including the refinement of ETEC human challenge models to improve the sensitivity of vaccine testing. PATH aims to continue refining human challenge models for Shigella as well as ETEC.

Vaccine combination and integration: PATH is tackling difficult questions around the feasibility of developing combined ETEC/Shigella vaccines as well as how new stand-alone ETEC and Shigella vaccines can be integrated into the existing childhood immunization regimen. We want to know how this integration could impact diarrhea-associated morbidity and mortality in younger age groups.

Consensus building: We support research and other efforts that aim to benefit the broader enteric vaccine community and maintain the pipeline of future vaccines. We have organized several expert scientific meetings to address cutting-edge problems, such as the potential autoimmune consequences of some vaccines or the cause of poor intestinal responses to oral enteric vaccines.

Market assessments: Finally, in 2011, we helped conduct an assessment of the market opportunity for ETEC vaccines to provide product developers and donors with a business case for investment. The resulting analysis demonstrated that ETEC vaccines may represent a moderate opportunity for industry investment, with an estimated annual revenue potential of more than US$600 million 10 years after global launch. We also identified a clear need for additional studies to assess the societal impact of diarrhea, such as disease burden, lost work time, and quality of life. We are now preparing a similar investment case for Shigella vaccines, with a heavier focus on these societal impacts, as well as an assessment of the feasibility of and markets for a combined ETEC/Shigella vaccine.

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