Biodegradable poly(lactic-co-glycolic acid) microparticles for injectable delivery of vaccine antigens

Abstract

Injectable biodegradable polymeric particles (usually microspheres) represent an exciting approach to control the release of vaccine antigens to reduce the number of doses in the immunization schedule and optimize the desired immune response via selective targeting of antigen to antigen presenting cells. After the first couple of decades of their study, much progress has been made towards the clinical use of antigen-loaded microspheres. Poly(lactide-co-glycolic acids) (PLGAs) have been studied most commonly for this purpose because of their proven safety record and established use in marketed products for controlled delivery of several peptide drugs. PLGA microspheres have many desirable features relative to standard aluminum-based adjuvants, including the microspheres' ability to induce cell-mediated immunity, a necessary requirement for emergent vaccines against HIV and cancer. This review examines several impediments to PLGA microparticle development, such as PLGA-encapsulated antigen instability and deficiency of animal models in predicting human response, and describes new trends in overcoming these important issues. PLGA microparticles have displayed unprecedented versatility and safety to accomplish release of one or multiple antigens of varying physical–chemical characteristics and immunologic requirements, and have now met numerous critical benchmarks in development of long-lasting immunity after a single injected dose.

Introduction

In spite of great successes with vaccines against infectious diseases (e.g., small pox, polio, tetanus, diphtheria, and several others [1]), because of a logistical difficulty to attain immunization coverage with existing vaccines in certain parts of the world, especially in developing countries, these diseases are still leading killers. The World Health Organization estimates that over 14 million people die each year from infectious disease, about a quarter of all deaths worldwide [2]. Inadequate coverage for the six vaccines against diphtheria, pertussis (whooping cough), polio, measles, tetanus and tuberculosis still causes two million unnecessary deaths each year [3].

Several factors have been largely responsible for the inability of vaccines to protect against infectious diseases. One of the most significant factors includes the unavailability of vaccines against intracellular pathogens, or infected or altered cells, such as malaria and HIV, which rely on cell-mediated immunity [4], [5], [6]. Second, progress in the field of adjuvants for use with human vaccines has been inadequate, and the range of adjuvant activities represented by existing adjuvants, mainly aluminum compounds, is limited, often prohibiting optimization of the magnitude and direction of the immune response (i.e., the role of the adjuvant [7]). Aluminum compounds (often termed alum after potassium aluminum sulfate [8]), which are the only adjuvants used with human vaccines in the United States, are well known for their inability to induce cell-mediated immunity [9]. The EU has accepted vaccines containing a few additional adjuvants, such as calcium compounds and MF59 [7], but their potential for cell-mediated immunity is also limited [5]. Third, high dropout rates for receiving booster vaccine doses have left significant fractions of people in developing countries not fully immunized, often due to poor or limited access to medical care, and lack of education regarding the importance of booster vaccination [10]. Finally, incompletely immunized women (mostly in developing countries) cannot pass immunity to neonates, leaving newborns susceptible to infections, e.g., umbilical cord infections [11].

Whereas aluminum compounds have been used with a large number of antigens, these adjuvants are not suitable for all antigens and are insufficient in many respects, including variable or poor adsorption of some antigens, the difficulty to lyophilize, the general requirement for booster doses, the inability to elicit cytotoxic T-cell (CTL) responses, the inability to elicit muscosal IgA antibody responses and the rare occurrence of hypersensitivity reactions in some subjects [8], [9], [12], [13]. Because of these limitations of aluminum compounds, additional adjuvants are needed to overcome the aforementioned difficulties with existing vaccine preparations, and to lend support to the newer, and often less immunogenic, antigens under development. To this end, biodegradable polymer microparticles, most commonly microspheres, with microencapsulated peptide or protein antigens have been studied for more than 20 years after early reports of the possibility to control the release of protein antigens over extended time periods for the purpose to eliminate booster doses [14], [15], [16]. Primarily because of their safety, including everyday use in healthy people (including children) as resorbable sutures, and their use in several commercial controlled-release drug products, copolymers of lactic and glycolic acid (PLGA) have become the most widely studied polymer to help meet this goal. Moreover, PLGA microspheres have several additional advantages, such as the ability to elicit CTL responses, and the potential for mucosal immunization and DNA delivery (see reviews by O'Hagan et al. [6] and Gupta and Siber [12]; reviewed also by Alpar et al. and by Foster and Hirst in this issue).

Therefore, the primary objective of this review is to examine PLGA microparticles as a parenterally administered controlled-release antigen carrier or adjuvant with a focus on identifying primary developmental barriers and recent progress to overcome them. In light of the ambitious aim of future vaccines, e.g., to provide maximum efficacy with minimum number of doses, delivered safely and easily [7], these novel adjuvants have the potential to compliment or replace aluminum-based adjuvants, for existing and future protein/subunit vaccine antigens. Mucosal vaccines as well as the mechanisms of processing of polymer microparticles by cells of the immune system will be examined in detail elsewhere in this issue (see Alpar et al. and Johansen et al., respectively)