Vaccine Development Global Program

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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, and we aim to identify 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 vaccines.

Killed whole-cell vaccines

Whole-cell vaccines offer a superior safety profile, a relatively simple and cost-effective manufacturing process, and stability at room temperature. However, these vaccines may elicit poor immune responses from people in endemic countries. We’re looking for ways to maximize the protection these vaccines could offer in low-resource settings.

PATH is partnering with the University of Gothenburg in Sweden to evaluate a tetravalent inactivated whole-cell ETEC vaccine candidate. After positive results from Phase 1 and 2 proof-of-concept studies, we are now supporting a Phase 1 study of the vaccine with and without an adjuvant (an ingredient added to vaccines to help strengthen the immune response) to determine if its immunogenicity can be enhanced.

We are also collaborating with the Walter Reed Army Institute of Research (WRAIR) in Silver Spring, Maryland, to conduct early clinical research on an inactivated Shigella whole-cell vaccine candidate. Following a Phase 1 trial that is currently underway, we will conduct a challenge trial to verify the effectiveness of this vaccine approach.

Subunit vaccines

PATH is 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 potentially greater safety profiles, but they frequently lack the immunogenicity needed to be protective in animal models or human trials.

We’re currently partnering with two groups to conduct preclinical research on subunit vaccine concepts against ETEC. The International Enteric Vaccine Consortium (EntVac), a group of universities anchored by the University of Maryland School of Medicine, has a candidate that targets the heat-stable enterotoxin (ST) that is expressed by approximately 66 percent of the ETEC strains associated with diarrheal disease in travelers and in children living in endemic areas. An ST toxoid vaccine offers the prospect of broad protection against ETEC, but requires additional research and evaluation, which EntVac is pursuing.

In addition, we’re helping support the US Naval Medical Research Center in Silver Spring, Maryland, to research a subunit vaccine concept that targets the conserved fimbrial tip adhesin proteins of ETEC. Upon completion of an ongoing Phase 1 trial where the protein is being administered intradermally along with a mucosal adjuvant, we anticipate that the vaccine will be evaluated in a challenge trial.

We’re also supporting work at Oklahoma State University to evaluate a Shigella subunit vaccine approach comprising conserved proteins as a novel means of inducing broad immune coverage.

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 reactogencity in clinical trials performed in the United States and other developed-world sites. They also have shown 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.

PATH supported TD Vaccines (formerly ACE BioSciences), a Danish biotechnology company, to conduct Phase 1 and 2 clinical trials of its ACE527 vaccine candidate against ETEC. ACE527 is a live, whole-cell vaccine comprised of three attenuated ETEC strains. Results from these studies were promising and we are now conducting a Phase 1 study of ACE527 with and without an adjuvant to see if its immunogenicity can be improved. We also collaborated with TD Vaccines and PATH’s Technology Solutions Global Program on research to develop temperature-stable, oral ETEC vaccine formulations.

We’re also partnering with WRAIR and icddr,b (a Bangladesh-based international public health research institution) to support the clinical development of a Shigella sonnei vaccine candidate. We plan to evaluate WRAIR’s oral, live attenuated WRSS1 candidate for safety and immunogenicity in a descending-age study in Bangladesh, expected to launch in 2013.

ETEC vaccine development portfolio snapshot

Snapshot of the ETEC vaccine candidates and associated partners receiving support through PATH's enteric vaccine initiative.

Shigella vaccine development portfolio snapshot

Snapshot of the Shigella vaccine candidates and associated partners receiving support through PATH's enteric vaccine initiative.

Research to support vaccine development

We’re working with several partners on supporting research that may also benefit the broader enteric-vaccine community. PATH in-licensed the double mutant heat-labile toxin (dmLT) vaccine component/adjuvant, LTR192G/L211A, from Tulane University in New Orleans, Louisiana. This highly promising new vaccine/adjuvant is an ETEC antigen that may offer protection against both diarrhea and intestinal infection. We worked with the US National Institutes of Health’s Division of Microbiology and Infectious Diseases on an ascending-dose Phase 1 study of the dmLT given orally, which had positive results with no safety concerns identified. We’re now testing the dmLT in conjunction with two oral enteric vaccine candidates, and hope to test the dmLT alone using alternative delivery routes in the future.

New vaccines must be practical for use with infants and children in low-resource countries, so we’re optimizing vaccine stabilization and investigating new formulations that may make the vaccines more immunogenic and easier to administer in these populations. For instance, we’re conducting research on novel vaccine formulation options, such as a fast-dissolving tablet technology platform and intradermal- and sublingual-delivery options.

In addition, we partnered with Johns Hopkins University in Baltimore, Maryland, to refine an ETEC challenge model for assessing the protective efficacy of candidate vaccines. Results from studies we conducted in 2009 found that the standard human challenge model has been utilizing a higher dose than is necessary to determine effectiveness. Using a challenge dose that is too high may result in premature elimination of promising vaccines that could work in low-resource populations. We extended this work in 2011 to test an even lower ETEC challenge dose, but our research determined that a lower dose wouldn’t be suitable for challenge studies because the attack rate would be too low and the sample size requirements wouldn’t be practical.

Finally, in collaboration with BIO Ventures for Global Health in Washington, DC, we conducted an assessment of the opportunities and potential markets that exist for low-cost and effective ETEC vaccines in order to better inform potential manufacturers and understand supply and demand drivers for the development of these vaccines. We are currently adapting this model to conduct a similar assessment of the Shigella vaccine market, with a report expected in 2013.

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