Secretory IgA as a vaccine carrier for delivery of HIV antigen to M cells

Abstract

HIV transmission and spread in the host are based on the survival of the virus or infected cells present in mucosal secretions, and the virus' ability to cross the epithelial barrier and access immune target cells, which leads to systemic infection. Therefore, HIV-specific immunity at mucosal sites is critical for control of infection. Although mucosal delivery would ensure the best onset of protective immunity, most candidate vaccines are administered through the parenteral route. Remarkably, secretory IgA (SIgA) interacts specifically with mucosal microfold (M) cells present in gut-associated lymphoid tissues. Here we evaluate the feasibility of delivering chemically bound p24HIV antigen via SIgA into the intestinal mucosae in mice. After oral administration, p24-SIgA complexes are quickly delivered into the tissue and selectively captured by CX3CR1 + dendritic cells. Oral immunization with p24gag linked to SIgA (p24-SIgA) adjuvanted with E. coli heat labile enterotoxin (HLT) elicits both humoral and cellular immune responses against p24 at the systemic and mucosal levels and induces efficient protection against rectal challenge with a recombinant vaccinia virus encoding gag. This is the first study which underscores the remarkable potential of SIgA to serve as a vaccine carrier for an HIV antigen in mucosal administration targeting the gastrointestinal environment.Keywords: HIV vaccine strategy r Microfold cells r Oral vaccination r SIgA reverse transcytosis Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionOral delivery of vaccines is an attractive mode of immunization because of its high acceptability and convenience of use. Moreover, the GALT plays a central role in the induction of immunity and homeostasis to infectious agents. In Peyer's Patches (PPs), DCs are separated from the intestinal lumen by the follicle-associated epithelium (FAE), allowing the transfer of pathogens to under- Results and discussionSpecific uptake and transport of p24-SIgA across murine FAEWe sought to assess whether association of p24 with SIgA can improve the delivery of antigen across the FAE of PPs. Administration into intestinal ligated loops revealed the presence of p24-SIgA in the SED region of PPs (Fig. 1A), whereas no localization of p24 administered alone could be detected above background in PPs (Fig. 1B). Moreover, p24-SIgA complexes, besides to be taken up by Dectin-1 + M cells [3], were found in close association with DC-SIGN + ( Fig. 1C) and CX3CR1 + (Fig. 1D) DCs present in the SED region, as illustrated by the appearance of yellow dots. In contrast, green DCs in the SED region and red p24 located in the lumen were only detected when the antigen was delivered alone (Fig. 1E). This finding prompted us to investigate whether oral immunization with p24-SIgA complexes can induce subsequent p24-specific intestinal and systemic immune responses. p24-Specific Ab responses after oral administration of p24-SIgA complexesPostoral immunization, p24-sp...

Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems

“…Human SIgA were shown to bind to the DC-specific ICAM-3 grabbing nonintegrin (DC-SIGN) and be internalized suggesting that binding to this receptor is a mechanism used by SIgA to prime adaptive immune responses in mucosal tissues (89). This concept was further confirmed by murine studies, which showed that when used as vaccine antigen delivery system, SIgA interacts specifically with M cells present in the GALT or NALT and delivers antigen to mucosal DC for optimal induction of antigen-specific mucosal and systemic immunity (90, 91). …”

IgA: Structure, Function, and Developability

“…Based on the interaction of SIgA with mucosal microfold (M) cells, another study explored the transport of an HIV antigen for immunisation via this mechanism. SIgA bound to the HIV antigen was delivered orally and transported across the epithelial barrier to be captured by dendritic cells, starting mucosal and systemic immune responses that ultimately showed to be protective against infection by a recombinant virus expressing the HIV antigen [203]. Therefore, infection can be impaired by several IgA associated mechanisms, either by immune exclusion, intracellular inactivation, or recognition and activation of the immune system.…”

The era of the immunoglobulin A Fc receptor FcαRI; its function and potential as target in disease

“…A trial in Southern Africa demonstrated that HIV‐uninfected women had HIV‐1‐specific IgA antibodies in their vaginal secretions . Interestingly, a recent in vivo study in mice showed the potential of SIgA to serve as a vaccine carrier for a HIV antigen via mucosal administration to target the gastrointestinal environment . In these mice, chemically bound HIV antigen to SIgA was delivered into the intestinal mucosal via oral administration, where SIgA interacted with mucosal microfold cells present in gut‐associated lymphoid tissues.…”

“…In these mice, chemically bound HIV antigen to SIgA was delivered into the intestinal mucosal via oral administration, where SIgA interacted with mucosal microfold cells present in gut‐associated lymphoid tissues. These complexes were subsequently selectively captured by dendritic cells and this elicited both humoral and cellular immune responses at systemic and mucosal levels .…”