Microparticles for intranasal immunization

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Abstract

Of the several routes available for mucosal immunization, the nasal route is particularly attractive because of ease of administration and the induction of potent immune responses, particularly in the respiratory and genitourinary tracts. However, adjuvants and delivery systems are required to enhance immune responses following nasal immunization. This review focuses on the use of microparticles as adjuvants and delivery systems for protein and DNA vaccines for nasal immunization. In particular we discuss our own work on poly(lactide co-glycolide) (PLG) microparticles with entrapped protein or adsorbed DNA as a vaccine delivery system. The possible mechanisms involved in the enhancement of immune responses through the use of DNA adsorbed onto PLG microparticles are also discussed.

Section snippets

Mucosal delivery of vaccines

The origin of mucosal vaccination is several thousands years old and originates from the time when Chinese medicine men allowed children to inhale powders made from dried crusts of pox scars [1]. Even so, vaccination through the mucosal routes remains a challenging concept and has not yet been successfully commercialized for a wide range of products. Almost all of the currently available vaccines are injected systemically, with a few exceptions, e.g., live attenuated polio and Salmonella

The advantages of IN immunization

There are several mucosal routes available for local immunization including oral, nasal, pulmonary, vaginal and rectal. Of these, the nasal route is attractive for several reasons. The nose, like the mouth is a practical site for easy self-administration of vaccines, using commercially available delivery devices. Delivery of vaccines to the lower lung is much more difficult, requiring sophisticated technologies, and causes significant concerns in relation to potential toxicity. Although the

Poly(lactide co-glycolide) (PLG) microparticles for vaccine delivery

In recent years, the principal polymers used for the preparation of microencapsulated vaccines have been the aliphatic polyesters, the poly(lactide co-glycolides) (PLGs). PLGs are the primary candidates for the development of microencapsulated vaccines because they are biodegradable and biocompatible, and have been used in humans for many years as suture material and as controlled release drug delivery systems [69]. PLG polymers have also been extensively evaluated for the development of

Immunity following IN immunization with protein antigens

It is clear that the term ‘IN’ immunization has often been used loosely and inaccurately. For example, the term IN immunization has often been used to describe IN administration of vaccines to anesthetized mice. However, it is clear that anesthetizing mice prior to IN administration results in the delivery of the bulk of the vaccine into the lung. This results in relatively easy access of the vaccine to the systemic lymphoid tissue and the induction of potent systemic immunity. This cannot

Alternative microencapsulation approaches for IN immunization

Strong evidence for dissemination of antigen-specific antibody-secreting cells from NALT to the cervical lymph nodes and spleen following IN immunizations has been provided by Heritage et al. [26]. These local and systemic humoral responses were generated by entrapment of human serum albumin (HSA) in polymer-grafted microparticles [3-(triethoxysilyl)propyl-terminated polydimethylsiloxane (TS-PDMS)] with a size range of 1–100 μm. McDermott et al. reported that polymer-grafted starch

IN immunization with mutants of heat labile enterotoxin (LT) from Escherichia coli

As discussed in detail elsewhere in the current issue of Advanced Drug Delivery Reviews (Mucosal adjuvants for nasal vaccination by Rino Rappuoli) genetically detoxified mutants of heat labile enterotoxin (LT) have been shown to be potent adjuvants for inducing mucosal and systemic immune responses. LT is toxic in its native state and induces accumulation of intestinal fluid and diarrhea in human [51]. In order to retain the adjuvanticity of these molecules but reduce their toxicity, several

Induction of cytotoxic T lymphocyte (CTL) responses through IN immunization

Although most studies on the induction of immune responses through IN immunization have involved induction of humoral immunity, IN immunization can also result in induction of strong cell mediated immunity. Mora et al. [37] reported that IN immunization of anesthetized mice with a lipidated HIV-1 gp120 peptide entrapped in PLG particles induced gp120-specific CTL and antibody responses. Moreover, IN immunization with HIV-1 gp120 entrapped in microparticles induced systemic CTL responses and

IN immunization with DNA adsorbed onto PLG microparticles

Although traditional vaccines have comprised proteins, live attenuated viruses, or killed bacteria, much attention has recently been focused on DNA vaccines. Immunization with DNA has several advantages over immunization with proteins, including the induction of potent CTL responses in human and non-human primates [15], [16]. The ruggedness and simplicity of DNA offers the potential for improved vaccine stability and reduced costs for vaccine production. Moreover, compared to attenuated viruses

Local presence of antigen following IN immunization with proteins or DNA

Antigens administered to the nasal cavity are believed to be taken up by M cells overlying the follicle associated epithelium of the nasal associated lymphoid tissue NALT [23], [65]. It is well established that M cells are highly efficient in the uptake of particulate antigens and microparticles and delivery to underlying antigen-presenting cells in the local lymphoid structure [39], [65]. Following IT delivery, it is likely that microparticles are engulfed by macrophages or dendritic cells and

Concluding remarks

IN immunization with protein or DNA encapsulated in or adsorbed onto PLG microparticles offers an attractive approach for enhancement of local and systemic cell mediated and humoral immune responses. The IN route of immunization has several advantages over other routes of mucosal immunization, including the potential for the induction of enhanced immunity in the genitourinary, respiratory and gastrointestinal tracts. Polymeric delivery systems can be designed to enhance the efficacy of

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