Combined parenteral and oral immunization results in an enhanced mucosal immunoglobulin A response to Shigella flexneri

Abstract

Achieving a vigorous secretory immunoglobulin A (IgA) response in intestinal secretions usually requires multiple doses of antigen given orally, while systemic immunity is more easily attained by parenteral immunization. This study examines the role of combined parenteral and oral immunizations to enhance the early mucosal immune response to an enteropathogen. We have used a chronically isolated intestinal-loop model in rabbits as a probe to monitor kinetically the initial (primary) local immune response to shigella lipopolysaccharide (LPS) following combinations of parenteral immunization intramuscularly (i.m.) and oral stimulation with shigellae. Predictably, effective stimulation of systemic immunity was elicited when heat-killed preparations of Shigella sp. strain X16 were given i.m., as shown by strong serum IgG and weak intestinal IgA activity to shigella LPS. A single oral dose of live Shigella sp. strain X16 given to unprimed rabbits elicited only a typical weak IgA response in intestinal secretions. However, when an i.m. dose of heat-killed shigellae was followed 1 day later by an oral dose of live Shigella sp. strain X16, a hyperstimulation of the early secretory IgA response was elicited, and the response reached levels found previously only after multiple oral administrations of live shigellae. This stimulation did not require the use of an adjuvant. At the same time, the animals receiving this combined oral and i.m. regimen had a lower IgG antishigella LPS activity in serum compared with their response after receiving parenteral antigen in adjuvant alone. These findings indicate that while a dichotomy exists between the systemic and mucosal immune responses, careful orchestration of the stimulatory events can promote a vigorous early local IgA response.

Oral immunization of mice with attenuated Salmonella typhimurium containing a recombinant plasmid which codes for production of a 31-kilodalton protein of Brucella abortus

“…It has been shown in rats that as much as 90% of the serum-derived IgA is transported into the bile and that this mechanism contributes to the low level of serum IgA detected in rats (11). To enhance mucosal immunity, Keren et al (15) have reported that a parenteral dose of antigen 1 day prior to oral inoculation enhanced intestinal IgA secretion. A parenteral dose of specific antigen may be necessary to optimize the secretion of intestinal IgA prior to oral stimulation with a live-vector vaccine.…”

The ABCs (Antibody, B Cells, and Carbohydrate Epitopes) of Cholera Immunity: Considerations for an Improved Vaccine

“…If so, we need to know if the sIgA response is required for protection; thus sIgA-deficient individuals should be included in the experimental groups. There is a developing literature that suggests that a combination of oral and parenteral immunization is an effective immunization strategy (120,237). This is consitent with the multiple cholera vaccine studies that suggested boosters enhance the efficacy of the current oral cholera vaccines.…”

Parenteral and mucosal prime-boost immunization strategies in mice with hepatitis B surface antigen and CpG DNA

“…One possible approach to improve immune responses has been the use of combined mucosalp arenteral immunizations. Simultaneous parenteral^mucosal immunization [6,7], mucosal prime^parenteral boost [8,9] or parenteral prime^mucosal boost [10] strategies can generate stronger immune responses than either route alone. Induction of an immune response in speci¢c lymph nodes, for example by direct injection in or near that particular lymph node, can modulate subsequent mucosal responses developing through the same lymph node [11,12], and it has been proposed that for a parenteral prime^mucosal boost strategy to be most e¡ective, the same lymph nodes must be targeted by both routes [13].…”