M-Cell Targeting of Whole Killed Bacteria Induces Protective Immunity against Gastrointestinal Pathogens

Abstract

As the majority of human pathogens infect via a mucosal surface, delivery of killed vaccines by mucosal routes could potentially improve protection against many such organisms. Our ability to develop effective killed mucosal vaccines is inhibited by a lack of adjuvants that are safe and effective in humans. The Ulex europaeus agglutinin I (UEA-I) lectin specifically binds M cells lining the murine gastrointestinal tract. We explored the potential for M-cell-targeted vaccination of whole, killed Helicobacter pylori, the main causative agent of peptic ulcer disease and gastric cancer, and Campylobacter jejuni, the most common cause of diarrhea. Oral delivery of UEA-I-agglutinated H. pylori or C. jejuni induced a significant increase in both serum and intestinal antibody levels. This elevated response (i) required the use of whole bacteria, as it did not occur with lysate; (ii) was not mediated by formation of particulate clumps, as agglutination with a lectin with a different glycan specificity had no effect; and (iii) was not due to lectin-mediated, nonspecific immunostimulatory activity, as UEA-I codelivery with nonagglutinated bacteria did not enhance the response. Vaccination with UEA-I-agglutinated, killed whole H. pylori induced a protective response against subsequent live challenge that was as effective as that induced by cholera toxin adjuvant. Moreover, vaccination against C. jejuni by this approach resulted in complete protection against challenge in almost all animals. We believe that this is the first demonstration that targeting of whole killed bacteria to mucosal M cells can induce protective immunity without the addition of an immunostimulatory adjuvant.

Importance of disrupted intestinal barrier in inflammatory bowel diseases

“…128,129 As M cells are specialized for antigen sampling while simultaneously possessing different surface receptors, they have become the target cells for a putative way of delivering oral vaccines. 130,131 However, due to the small number of M cells present in the human gastrointestinal tract (<10% of the human FAE 130 ), and the difficulty to perform in vivo studies, the use of an in vitro coculture model has greatly improved achievements in understanding M cell physiology and function.…”

Sampling of the Intestinal Microbiota by Epithelial M Cells

“…Cholera toxin is an effective mucosal adjuvant but also causes severe diarrhea, making it unsuitable for human use. Feeding killed bacteria coated with UEA-I (without additional adjuvant) was able to confer protective immunity in mice, although targeting to M cells was not shown [49]. Natural selection has certainly developed the most effective M cell delivery systems.…”

Avances en la búsqueda de la vacuna contra Helicobacter pylori

“…Por un lado, si bien en la mayoría de casos se observa algún grado de respuesta, esta ha fallado consistentemente en producir inmunidad esterilizante [12][13][14] y por el otro, en la mayoría de ellos, aun utilizando estrategias de inmunización totalmente diferentes, se consiguen resultados muy similares con disminuciones en los niveles de colonización de la bacteria de entre uno y dos logaritmos 66,67 . Los resultados fallidos de esos estudios probablemente reflejan características propias de la infección por H. pylori y de la respuesta del huésped, características que podrían ser entendidas e intervenidas en el futuro para lograr una vacuna de mayor éxito.…”

“…Varias estrategias de vacunación han sido ensayadas en modelos animales con éxito variable en términos de la disminución de la carga bacteriana o en la producción de anticuerpos, en evitar infecciones de novo y en la capacidad para producir erradicación esterilizante (vacuna terapéutica) [12][13][14] . Desafortunadamente la carga bacteriana residual, encontrada en casi todos los estudios, continúa causando las enfermedades asociadas a H. pylori 15 .…”