Vaccines for enteric diseases: a meeting summary

Abstract

The 6th Vaccines for Enteric Diseases Symposium was held in Cannes, France, on 14–16 September 2011, drawing approximately 200 vaccine developers, academics and public health experts globally. Infectious diarrhea is a worldwide problem with high mortality and morbidity, particularly among children in the developing world. The WHO estimated approximately 8.8 million deaths in 2008 in young children aged 1–59 months, of which almost 2 million could be attributed to diarrheal illnesses – more than malaria, HIV/AIDS and TB combined. New breakthroughs in vaccine development, early clinical trials for the enterotoxigenic Escherichia coli, Shigella, noroviruses and conjugate typhoid vaccines, and updates on the implementation of rotavirus, cholera and typhoid vaccines were reported.

Keywords::

• diarrhea
• Escherichia coli
• rotavirus
• Shigella

The preventable burden of diarrheal diseases

Two large global projects support the recent WHO estimates of diarrheal mortality and morbidity [1]. Etiologically, recent data from the Global Enteric Multi-Center Study (GEMS), coordinated by Mike Levine (University of Maryland, MD, USA) confirm the targeted pathogens of the WHO priority list, including rotavirus, Shigella, enterotoxigenic Escherichia coli (ETEC) and Vibrio cholerae O1. However, preliminary results also indicate age- and country-specific variations, as well as other pathogens including Cryptosporidium and Campylobacter jejuni, which appear to be frequently associated with moderate-to-severe diarrhea globally.

Furthermore, diarrheal illness carries enormous costs in terms of morbidity, loss of productivity and utilization of medical resources in settings where such added burdens compound. An international effort, led by Michael Gottlieb (Foundation for the NIH, MD, USA) the interactions of malnutrition and enteric infections (MAL-ED): consequences for child health and development, explores the factors associated with a child’s risk of enteric infection, chronic diarrhea and malnutrition, with impaired gut function, vaccine response, and cognitive and physical development [101]. Novel research is exploring and identifying the potential impact of repeated episodes of diarrheal disease and stunting in early childhood, as well as associations of chronic health problems of obesity, diabetes and hypertension in later adulthood.

Clearly, the brunt of the morbidity and mortality is on the developing world as well as international travelers – acute infectious diarrhea is a frequent cause for outpatient visits and hospitalization throughout the developed world. Similar to the developing world, the impacts of these domestic and travel-associated infections extend beyond the acute illness and can be attributed to a number of chronic health consequences, including Guillain–Barré syndrome, reactive arthritis and hemolytic uremic syndrome, which can result in excess mortality and life-long disability. Emerging epidemiologic efforts have identified a number of other chronic health outcomes including functional disorders such as irritable bowel syndrome, constipation, dyspepsia and nonfunction disorders such as celiac disease and gastroesophageal reflux disease. Parallel to these epidemiological studies linking acute enteric infections with common chronic health sequelae are developments of new animal models demonstrating the pathoetiological mechanisms whereby neuromotility, microbiomic and epithelial dysfunction effects may be linked [2]. Understanding the full impact of the preventable burden of diarrheal diseases is crucial to understanding their relative importance to other vaccine targets.

Rotavirus & rotavirus vaccines

Despite the revised WHO estimates indicating a reduction in global diarrheal mortality [1], rotavirus-associated deaths remain close to 500,000 per year [3], emphasizing the need for the introduction of rotavirus vaccines globally. Rotavirus vaccines have been introduced into the routine immunization schedules of several countries showing early impact of the vaccines against diarrheal hospitalizations and death. Vesta Richardson (Ministry of Health, Mexico) reported a 45% reduction in diarrheal mortality in children under the age of 5 years after the nationwide introduction of rotavirus vaccines in Mexico in 2007 [4]. Nicola Page (National Institute of Communicable Diseases, South Africa) reported the early impact of rotavirus immunization in South Africa, which was the first African country to introduce the vaccine. Even with moderate coverage (<60%), a 50% reduction in the classic rotavirus winter peak was demonstrated with a delayed shift in this peak, similar to the effects observed in the USA after vaccine introduction.

Intussusception remains a current issue for rotavirus vaccines, and has been recorded to occur in some settings at low levels within the first week after the first dose of vaccine [5]. Manish Patel (US Centers for Disease Control, GA, USA) presented an analysis of the observed risks of intussusception after rotavirus immunization in Mexico and Brazil, highlighting the enormous benefits of the vaccination in preventing a significant number of rotavirus deaths and hospitalizations [6].

New rotavirus vaccine developments include other live, oral rotavirus vaccines and inactivated vaccine approaches. A stable, dissolvable thin film formulation for live vaccine delivery was described by Truong (Aridis Pharmaceuticals, CA, USA).

Norovirus vaccine development

Recent advances in vaccine development for noroviruses, which are a major cause of diarrheal illness in children and in foodborne outbreaks, have been reported. Two Phase I studies with different norovirus subunit vaccines administered via different routes demonstrated good tolerability and immunogenicity, showing demonstrable progress in this field [7].

Update on Escherichia coli & Shigella vaccines

No licensed vaccines are available for either ETEC or Shigella, although recent donor investments from the USA (Bill & Melinda Gates Foundation) and Europe (STOPENTERICS, GLOBVAC-EntVac) have reinvigorated the efforts on vaccine development. Prior studies suggest that live-attenuated or inactivated whole-cell vaccines may be viable options if safety and immunogenicity issues can be overcome. Encouraging protection data in this regard were reported from two recently completed Phase IIb immunization challenge studies evaluating a new multivalent live-attenuated ETEC vaccine (ACE527) by Clayton Harro (Johns Hopkins University, Baltimore, MD, USA) [8] and a live-attenuated Shigella sonnei vaccine (WRSS1) by Ladaporn Bodhidatta (AFRIMS, Thailand). The WRRS1 vaccine was 50% efficacious in Thai adults challenged with S. sonnei strain 53G, whereas the ACE527 vaccine significantly reduced both the incidence and severity of ETEC diarrhea following the challenge [9].

Inactivated whole-cell vaccines for ETEC and Shigella also showed impressive progress. An inactivated ETEC vaccine composed of four E. coli strains engineered to overexpress CFA/I, CS3, CS5 and CS6 and supplemented with a LTB–CTB hybrid toxoid (Jan Holmgren, Goteborg University, Göteborg, Sweden) induced strong intestinal and serum antibody responses to these antigens in a mouse model, which could be significantly improved by administration with the double mutant heat-labile toxin mucosal adjuvant. In a human Phase I trial, an inactivated, overexpressing CFA/I strain and the new hybrid toxoid induced stronger intestinal (fecal IgA) or intestinal-derived antibody responses to CFA/I and LTB than the first-generation ETEC-inactivated vaccine. The mucosal and systemic immunogenicity and protective efficacy of the trivalent Shigella vaccine (serotypes Shigella flexneri 2a and 3a, and S. sonnei) were demonstrated in both mice and guinea pig models (Robert W Kaminski, Walter Reed Army Institute [WRAI] of Research, MD, USA).

Exciting new antigen discovery utilizing the application of advanced genomic and proteomic technologies and new vaccine delivery routes are also being investigated. Secondary analysis of a Phase III LT-patch transcutaneous immunization study demonstrated significant protection against ETEC-LT strains (Larry Ellingsworth, Intercell, MD, USA). Also, a prototype conserved ETEC tip-adhesin (FTA)-based vaccine, delivered by transcutaneous immunization and intradermal routes was well tolerated and induced impressive levels of anti-tip adhesin ELISA and functional antibodies (Stephen Savarino, Naval Medical Research Center, MD, USA). Results from ongoing nonhuman primate studies demonstrated that intradermal immunization with FTA and mLT induced significant protection (84%) against challenge with a fully virulent ETEC strain.

Shigella vaccine development efforts based on conserved subunit antigens were highlighted. Genetically derived outer membrane particles from S. sonnei and S. flexneri 2a, termed ‘generalized modules for membrane antigens’, conferred cross-protection against heterologous serotypes and the mucosal route of immunization achieved the best results (Christiane, Gerke, Novartis Vaccines, Siena, Italy). The conserved IpaB and IpaD proteins of the Shigella type III secretion system were highly immunogenic when delivered mucosally (intranasally) with double mutant heat-labile toxin, and both induced high levels of cross-serotype protection in the mouse lethal pulmonary challenge model [10].

Conjugate vaccines against S. sonnei have been shown to be protective in field studies, but efficacy has been diminished in those younger than 3 years of age. Laurence Mulard (Institut Pasteur, Paris, France) described the substantial progress made toward the development of a multivalent Shigella vaccine candidate based on synthetic oligosaccharides mimicking the protective determinants carried by the O-Ag on selected Shigella serotypes [11]. Michael Wacker described GlycoVaxyn’s (Schlieren, Switzerland) highly novel technology for using genetically modified E. coli to synthesize bioconjugate vaccines in vivo. Their initial prototype conjugate against Shigella dysenteriae was safe and elicited strong IgG, IgA and IgM anti-LPS responses in volunteers [12].

Mucosal immunology

Reports presented in the mucosal immunology session highlighted new strategies to enhance mucosal responses to vaccines. Promising studies with LT-derived adjuvants support their use with a wide range of candidate vaccines, including the inactivated ETEC whole-cell vaccine described above. Better vaccine responses may also be obtained through the use of novel routes of delivery. For example, Saul Tzipori (Tufts University, MA, USA) reported that sublingual immunization may be an alternative strategy to induce better mucosal vaccine responses. In addition, new delivery vehicles, such as bacterial-like particles derived from the food-grade bacterium Lactococcus lactis, make it possible to orally deliver subunit antigens attached to particulate carriers (Kees Leenhouts, Mucosis BV, The Netherlands).

Cholera immunization strategies

A special session was devoted to examining the extent of the cholera burden globally, both in regions where it is considered endemic and in explosive epidemics as has been seen in Haiti. There is an urgent need to consider various immunization strategies to address these prolonged outbreaks, including the implementation of a global cholera vaccine stockpile. Recent 3-year efficacy data from a WHO prequalified cholera vaccine, Shancol®, has given the impetus to developing such a strategy.

Typhoid vaccines

The Coalition against Typhoid [13] arranged a special session to discuss the typhoid burden in Africa and Asia and effective vaccine studies conducted in Asia. Despite the high burden of enteric fever and the availability of inexpensive, licensed vaccines, which are demonstrated to be safe, effective and feasible to use in large mass immunization programs [14], the world waits for the promise of conjugate typhoid vaccines. One such conjugate vaccine showed good safety and immunogenicity, and is ready for further clinical evaluation [15].

Disclaimer

The opinions and assertions in this article should not be construed as official or representing the views of the Department of the Navy, the Department of Defense or the US Government. This is a US Government work. There are no restrictions on its use.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.