Enteric Disease: The Achilles Heel of Oral Vaccines

Oral vaccines – administered via the mouth – possess advantageous features for use in low-income countries as means to reduce the burden of infectious diseases. They negate the need for syringes that run the risk of contamination and can be administered by less-experienced healthcare professionals compared to syringe-based vaccines, increasing accessibility.

However, oral vaccines are less immunogenic when administered in low-income countries compared to high-income countries. Several factors can contribute to this reduced efficacy. Intestinal diseases, such as environmental enteric dysfunction (EED), which are prevalent in countries with poor sanitation, are one example. However, the precise biological mechanisms by which these diseases reduce oral vaccine efficacy are poorly understood. A new research study by UPMC Children’s Hospital of Pittsburgh and University of Pittsburgh School of Medicine scientists utilized a mouse model of EED to further investigate this phenomenon and to search for possible solutions.

Dr. Timothy Hand, assistant professor in the departments of pediatrics and immunology at the University of Pittsburgh, is the lead author of the new study. Technology Networks interviewed Hand to learn more about the study findings, the role of the microbiome in vaccine efficacy and how we can look to reduce oral vaccine failure.

Molly Campbell (MC): Can you discuss what an oral vaccine is and how it activates the immune system? How does this differ to other administrative routes, such as an intramuscularly injected vaccine, for example?

Timothy Hand (TH): Oral vaccines differ from more traditional vaccines in two main ways. First, they are delivered orally and require no syringe. More importantly, oral vaccines provide superior protection at "mucosal barrier" sites (e.g., the intestine, lungs, nose etc.). Since most infections traffic through these sites, protection at these barriers can be very effective, preventing the bacteria/virus from gaining a foothold in the body.

MC: Why are oral vaccines advantageous for regions of the world where sanitation is poor?

TH: Sanitation prevents gastrointestinal infection. As mentioned above, oral vaccines are better at preventing intestinal infections, so they are beneficial in places where these infections are common.

MC: In your new study, you explored how the gut disorder, environmental enteric dysfunction (EED), impacts oral vaccine success using a mouse model of the disease. Can you discuss the rationale behind your study?

TH: Places of the world where EED is common also show very poor efficacy of oral vaccines. It was long believed that some of the symptoms of EED (less intestinal surface area and immune cell infiltration of the intestine) might contribute to this failure, but it has never been clearly shown. Studying EED in humans is difficult; obtaining small intestine biopsies is challenging and even more so from people in low-to-middle Income Countries (LMICs) with EED.  A mouse model is very helpful in allowing us to advance biology in this subject. Our mouse model replicates human EED in multiple respect, the mice show stunting, shifts in the microbiome, intestinal damage and leakiness and fail to respond efficiently to oral vaccination. 

MC: You found that the microbiome was implicated in oral vaccine failure in EED. Can you expand on this, and how we might look to target the microbiome to prevent such failure?

TH: We would hypothesize that, to "fix" EED, we need to reset the microbiome. We would argue that judicious use of antibiotics followed by restoration of a healthy diet would allow just such a reset. These patients might then be able to be vaccinated to prevent the cycle of infection, malnutrition, inflammation and microbiome dysbiosis that underlies this disease.

MC: The study was conducted in mice. How might the results translate to humans?

TH: We think that our model reflects the human condition pretty well and, as we have demonstrated, provides the ability to test mechanistically what is going on with regards to the immune response and microbiome that drives disease. We would love to see whether some of the phenomena we have seen causing EED in the mouse model are shared by humans suffering with EED. Such findings would allow us to move forward with targeted therapies to restore intestinal health and mucosal immunity in patients with EED.

MC: What are your next research steps in this space?

TH: We hope to collaborate with researchers studying oral vaccines in humans to see if our results are relevant to what is going on in humans with EED. We think that our model still has a great deal to teach us about how the intestine, immune system and microbiome act together to respond to malnutrition.

MC: What else can be done to combat oral vaccine failure?

TH: LMICs need better toilets. We need the whole world to be able to safely handle their waste.

Timothy Hand was speaking to Molly Campbell, Science Writer for Technology Networks.