Preventative vaccines have eliminated smallpox and nearly eliminated polio, two of the worst global infectious diseases. By contrast vaccines for many other infectious diseases, such as malaria and HIV, which involve intracellular pathogens, are poorly developed or simply unavailable (Singh and O'Hagan, Pharm. Res., 19(6):715-28 (2002); O'Hagan and Valiante, Nat. Rev. Drug Discov., 2(9):727-35 (2003)). The lack of such vaccines results in two million unnecessary deaths each year in many parts of the world (WHO, State of the Art New Vaccines (2003)).
Several key variables are needed in the design of effective vaccines (Pashine, et al., Nat. Med., 11(4 Suppl):563-8 (2005), Bramwell and Perrie, Drug Discovery Today, 10(22):1527-34 (2005)). The first variable is the form of the antigen itself, which can be whole inactivated or attenuated organisms, purified proteins and peptides, or DNA encoded antigens. Human pathogens are continually emerging and changing (e.g. SARS, avian flu) meaning that new potential immunogens are constantly appearing. Thus, there is a clear need to design vaccine systems that can rapidly and efficiently test the efficacy of vaccines involving new antigens (Bramwell, et al., Adv. Drug Deliv Rev. 57(9):1247-65 (2005)). Large scale and safe production of stable vaccine products typically involves the purification of natural or recombinant forms of antigenic subunits. Once purified, however, individual antigens often become less immunogenic compared to whole pathogens or crude extracts, necessitating a means to amplify the immune response against the purified subunit antigen. Thus, a second necessary component of a vaccine involves providing an adjuvant or other means for potentiating or stimulating both the innate and adaptive arms of the immune system to the antigen subunit (Pashine, et al., Nat. Med., 11(4 Suppl):563-8 (2005), Bramwell and Perrie, Drug Discovery Today, 10(22):1527-34 (2005)).
Immune potentiators may include bacterial products, toxins or other molecules that augment specific immunity. Potentiators have various benefits, but also attendant risks such as triggering deleterious inflammatory responses. To affect optimal stimulation to a given antigen, a formulation is needed that delivers the correct amount of antigen in a repetitive or sustained fashion, to the appropriate immune cells and to the appropriate compartments within those cells. Thus, a designed delivery vehicle (adjuvant) should target the vaccine antigen and facilitate delivery of both antigen and immune potentiating molecules selectively to target cells of the immune system. This is highly reminiscent of the strategy taken by viruses that inactivate specific components of the immune system during infection. Traditional methods for increasing the effectiveness of vaccines have focused on co-administration of adjuvants or use of a delivery system.
While the adjuvant role is critical, there are obvious risks, costs and limitations associated with this traditional approach. For example, currently available adjuvants, represented predominately by colloidal alum (aluminum sulfate or aluminum hydroxide) or montanide polymers, have a limited capacity to adsorb many antigens and have greatly limited immunostimulatory properties (Gupta and Siber, Vaccine, 13(14):1263-76 (1995); Lindblad, Vaccine, 22(27-28):3658-68 (2004)). There are also risks associated with using live attenuated vaccines and allergic side effects associated with aluminum salts (Lindblad, Vaccine, 22(27-28):3658-68 (2004); Gupta, et al., Vaccine, 11(3):293-306 (1993)). Additionally, because of the historical emphasis on eliciting humoral immune responses, most adjuvants are optimized for effective induction of high antibody serum titers, but are ineffective at eliciting a strong cellular, T cell-mediated immune response or strong mucosal immune response. T cell responses are essential for inducing lasting viral immunity (or immune responses to cancer); mucosal immunity is essential for protective responses to cellular and viral pathogens that are transmitted through mucosal surfaces (e.g. human immunodeficiency virus, HIV; herpes simplex virus, HSV; enteric pathogens). These factors, coupled with the difficulties of manufacture, storage, and transport have together greatly limited the utility of current approaches in the clinic and in the field (O'Hagan and Valiante, Nat. Rev. Drug Discov., 2(9):727-35 (2003); Sigh and Srivastava, Curr. HIV Res., 1(3):309-20 (2003), Singh and O'Hagan, Nat. Biotechnol., 17(11):1075-81 (1999)).
Thus, in addition to economic factors, as outlined above, there are a number of significant scientific challenges that have limited the development of vaccines for deadly diseases. First, few if any approaches are available that efficiently prime cell-mediated immunity by direct intracellular delivery of an antigen. Second, ‘tunable’ adjuvants, that is, adjuvants that can be engineered to optimize the magnitude and direction of an immune response (Jiang, et al., Adv. Drug Deliv. Rev., 57(3):391-410 (2005); Sesardic and Dobbelaer, Vaccine, 22(19):2452-6 (2004)) have not been developed. Third, alternatives are not available for the general requirement for parenteral (i.e. subcutaneous or intramuscular injection) administration of vaccines, a situation that has made it difficult to deploy vaccines in underdeveloped countries where medical support systems, resources, and cold-storage are limited. Finally, there is no general approach to designing oral vaccines targeted to both systemic and mucosal immunity. This would be highly advantageous since oral vaccines are significantly less expensive to administer and transport. Thus, there is a critical need for safe and stable vaccine systems that would address all these factors (Friede and Aguado, Adv. Drug Deliv. Rev., 57(3):325-31 (2005); Storni, et al., Adv. Drug Deliv. Rev., 57(3):333-55 (2005); Gupta, et al., Adv. Drug Deliv. Rev., 32(3):225-246 (1998); Aguado and Lambert, Immunobiology, 184(2-3):113-25 (1992)).
It is therefore an object of the invention to provide stable vaccine formulations which can be orally administered.
It is another object of the invention to provide modular nanoparticulate vaccine compositions which provide for flexible addition and subtraction of elements.
It is still another object of the invention to provide means for modulating an immune response, either to increase or decrease the response, or bias the response to a humoral or cellular immune response.
It is a further object of the invention to provide methods for making and using such modular nanoparticulate vaccine compositions.