1. has been incorporated recently which plays a significant

1.        Nanotechnologies in vaccine delivery

Although the progress of conventional vaccine remains at high rate, there are certain unmet concerns such as weak immunogenicity, intrinsic stability, toxicity, and multiple administrations which limit its clinical approach. To overcome the aforementioned bottlenecks, nanotechnology has been incorporated recently which plays a significant flat form for the delivery of the vaccine.

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It enables to encapsulate the vaccine antigen without the loss of their biological activity during formulation and also protects the vaccine from degradation in the acidic environment. The logistical advantage of this technology includes encapsulation of multiple antigens and targeting ligands within the same particle and the release kinetics can be controlled in order to minimize the systemic effects.

The nanotechnologists have provided insights into the importance of selecting the wide variety of biodegradable and biocompatible polymers from natural and synthetic source. The strategy of using the biodegradable nanoparticles for effective delivery of vaccines shows great promises as the submicron size of nanoparticles can be easily internalized by the antigen presenting cells such as macrophages and dendrite cells. This enables the processing of antigens and activation of the immune system. More importantly targeting the dendrites with an antigen in biodegradable polymeric particles plays a substantial role in activating the T- cell-mediated immune system by processing the antigens through Major histocompatibility complex I and II pathways (MHC I and MHC II) further, presenting the fragmented antigen peptides to CD4+ and CD8+ cells for humoral and cell-mediated response. Amongst some of the nanoparticle systems used for the delivery of vaccines are…..

It is known that inherent immunogenicity of the particulate structures can be enhanced by engineering the delivery systems through chemical compositions (immunostimulating ligands, multiple antigens) or physicochemical properties. However, this evidence at molecular/cellular levels is poorly understood. Indeed, the mechanism how to engineer the particle properties remains unclear and further studies are required.

Nanoparticle properties that affect vaccine immunity:

Nanoparticles are expounded as particles that have at least one dimension smaller than 100 nm. Studies have shown that without the aid of migratory (Antigen-presenting cell) APC’s, nanoparticles (size of 20-30 nm) could traffic the lymph nodes in less than 2 h, by using the convective flow from the interstitium. Particle size has significant role due to its influence on localization, lymph node trafficking, cross-protection and adaptive immune responses. However, the nanoparticles of larger size will retain at the site of injection as they need the migratory APC’s for their transport. Also, the particles with a smaller size (70-100 nm) have shown to increase the efficiency of cross presentation. In contrast, few studies suggested that particles of all ranges, small (40 nm), intermediate (200 nm), and large (1000 nm) can access the lymph nodes directly via afferent lymphatics similar to bacteria and viruses infection. The influence of the injection site and the local hydrodynamic forces on particle size for the initiation of the immune response to the particulate vaccines needs to be further investigated.

Particle charge and shape finds a dominant role in the cellular uptake of the particulate vaccine; some studies demonstrate the enhanced internalization of the spherical particles over the nanoparticles of other forms. The attachment of the nanoparticles to the cell membrane favors the internalization by the macrophages; in contrary, the longer particles attached more efficiently to the cell membrane, but the internalization was inhibited by their size.

Positively charged nanoparticles usually own a higher inflammatory potential than negatively charged or neutral nanoparticles. Particle charge has an influence on their internalization by the cells; this property of the particles has been exploited for the localization at the mucosal surfaces, which is essential to enhance the mucosal immune responses against the pathogens.

Hydrophobicity of the particle is another danger signal that the innate immune system recognizes and enhances the immune response. The particle with lower hydrophobicity was effectively internalized by (Dendritic cells) DC’s and induced increased secretion of cytokines. No surface markers were expressed and the vice versa was seen in the case of the more hydrophobic particles.

The particle base nanoparticulate vaccines offer several advantages over the traditional formulations; by increasing the density of the vaccine antigens, controlling the rate of the intracellular cargo release and provide the ability to co-administer the adjuvants and immunomodulatory agents.

High density array of vaccine antigens, can be delivered to the APC’s by encapsulating the antigens into the nanoparticles. This is very important because the subunit vaccines, when introduced in free and soluble form, do not effectively induce the antibody response as the B cells have evolved to recognize the dense and the highly repetitive epitope arrangements on the surface of the pathogens. The ability of the nanoparticles to control the density and the confirmation of the antigen can significantly modulate the immune response, which is the major advantage of the particulate systems. In some cases, the nanoparticulate systems can directly substitute the protein carriers; carrier proteins are essentially conjugated to the small moieties like haptens, to elicit the immune response.

Adjuvants and the immunomodulatory agents can be simultaneously delivered with the vaccine antigens, in order to maximize the delivery to the same immune cells and to enhance the vaccine efficacy. The immunomodulatory agents and the ligands can be incorporated into the nanoparticles either by encapsulation, covalent conjugation or physical adsorption. Several studies have shown that co-administration of the immunomodulatory agents like DC-targeting antibodies and the ligands can enhance the immune response produced against the vaccine antigens.

Controlling the rates of intracellular cargo release can be achieved by the use of the nanoparticulate vaccines; the release of the encapsulate antigen occurs on intracellular degradation, which will enhance the cross presentation of antigens among the APC’s via MHC I.  To generate the CD8+ T cell response, the antigens in the particulate form should be cross presented by the APC’s. Several strategies like pH, redox and enzymatic response have been engineered and employed to release the antigens intracellularly by stimuli responsive mechanisms. Some studies showed the faster release of the antigens within the phagosomes enhanced the cross presentation, which also showed the antigens released after 25 min were degraded by the lysosomal enzymes and did not contribute to the cross presentation; which suggests there is a limited time window for the productive antigen release. In conclusion the studies show that the particles that are degraded faster intra cellularly contributes to the better MHC I and MHC II mediated cross presentation.

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1.1.               Contributions of nanotechnology in nasal vaccines

An Ideal mucosal formulation should protect vaccine from enzymatic degradation and their elimination by mucosal barriers, should be capable of targeting mucosal inductive sites or M cells on the membrane, should stimulate innate immunity and evoke the adaptive immunity appropriately.

In 2015, Weilin Qiao et al. suggested that the conjugation of ?- glucan is an effective strategy to improve the CPS specific immunogenicity of the conjugate vaccine. In this instance they identified that conjugation of ?-glucan enhanced the CPS-specific and TT-specific immunogenicity of the conjugate vaccine (CPS-TT) but the CPS-specific and TT-specific immunogenicity of CPS-TT was suppressed by co-administration of ?-glucan. (1).

1n 2015, Xu Jh et al. explained the streptococcus pneumonia infection is mainly via mucosal route. Therefore intranasal vaccination is an effective immunization strategy using appropriate mucosal delivery system. In this work chitosan has been used to form chitosan-mpsaA nanoparticles to produce the immune response against the pneumococcal serotypes 3 and 14. The results were strongly encouraging showing the survival rate was 100 % in the groups administered with chitosan- mPsaA, compared to 60% in groups administered with free mPsaA. This supports the hypothesis that the mucosal vaccines are successful when they are in particulate or multimeric form, when they can adhere to the mucosal surfaces like M cells; they should be able to stimulate innate responses effectively and should be capable of evoking adaptive immune responses that are appropriate to the target pathogens(2).

In 2007, Hanniffy et al, have investigated the use of L. lactis with intracellular PSPA as particulate vaccines, for the intranasal immunization against pneumonia(3).

The use of fusion proteins, aims in targeting the multiple virulence factors to block the infection. The study performed by Liu et al, shows combining two proteins that are important for bacterial pathogenicity, to form a vaccine could be an effective strategy. The study showed that the PSPS-PsaA fusion protein were efficient in inducing protective immune response against fatal pneumococcal challenge, in BALB/c mice, regardless of the challenge route.(4)

The use of desired adjuvant is essential to have the effective administration. The studies performed by Jakobsen et al in 1999, showed the induction of mucosal IgA when the glycoconjugate vaccines were administered intranasally, in the presence of rhinovax adjuvant. No response was observed when administered without adjuvant (5)

Interestingly, Jakobsen H et al. demonstrates the intranasal administration of non toxic E. coli LT mutant could be used to modulate and to enhance the PPS specific antibody response. The E. coli LT as an adjuvant for the pneumococcal glycoconjugate produced higher IgG2a, IgG3 and IgA  antibodies against both the carrier protein and capsular polysaccharides, when compared to the groups administered with the glycoconjugate alone via SC(6).

Other strategies like using the zwitterionic polysaccharides, conjugated to the carrier proteins act as a potential vaccine candidate, by inducing high T-cell and antibody response against both carrier proteins and the capsular polysaccharides. The zwitterionic PS were produced by introducing the positive charge to the anionic polysaccharide, that helps in producing the vaccine with antigenicity and adjuvant property. The study suggests the chemical modification of the polysaccharide structure enhances the polysaccharide specific IgG response(7).

The studies performed by laurance et al in 1999, shows the neonatal mice were protected against the GBS II and VII, when the adult mice were vaccinated with the glycoconjugate vaccine. The pups were challenged against the bacteria, 24 h after they were born. The survival rate was 97.5 % in case of the pups born to the mice immunized with the glycoconjugates; whereas, the survival rate in the pups born to the mice immunized with CPS was only 3 %(8).

Some interesting insights about the dosing were obtained from the studies performed by the Shen et al in 2001. The results obtained shows the better CPS and the IgA response was seen in case of the mice, where both the priming and the booster dose is glycoconjugate vaccine(9).

The use of the disease specific carrier protein is strongly suggested for the glycoconjugates, which is supported by a very interesting observation. The preimmunization of the mice with the carrier CTB reduced the serum and mucosal IgA. This might be due to the pre-existing anticarrier CTB immunity, that can have inhibitory effect on the mucosal immune response elicited by the conjugate vaccines given intranasally(9).

 

How nanotechnologies can affect the efficacy of glycoconjugates

1.2.               Glycoconjugate uptake by APC’s in particulate form, over free form

 

1.                 Qiao W, Ji S, Zhao Y, Hu T. Conjugation of ?-glucan markedly increase the immunogencity of meningococcal group Y polysaccharide conjugate vaccine. Vaccine (2015) 33:2066–2072. doi:10.1016/j.vaccine.2015.02.045

2.                 Xu JH, Dai WJ, Chen B, Fan XY. Mucosal Immunization with PsaA Protein, Using Chitosan as a Delivery System, Increases Protection Against Acute Otitis Media and Invasive Infection by Streptococcus pneumoniae. Scand J Immunol (2015) 81:177–185. doi:10.1111/sji.12267

3.                 Hanniffy SB, Carter AT, Hitchin E, Wells JM. Mucosal Delivery of a Pneumococcal Vaccine Using Lactococcus lactis Affords Protection against Respiratory Infection. J Infect Dis (2007) 195:185–193. doi:10.1086/509807

4.                 Lu J, Sun T, Wang D, Dong Y, Xu M, Hou H, Kong FT, Liang C, Gu T, Chen P, et al. Protective Immune Responses Elicited by Fusion Protein Containing PsaA and PspA Fragments. Immunol Invest (2015) 44:482–496. doi:10.3109/08820139.2015.1037956

5.                 Jakobsen  Saeland,E.,Gizurarson,S., Schulz,D. And Jonsdottir,I. H, Jakobsen H, Saeland E, Gizurarson S, Schulz D, Jónsdóttir I. Intranasal Immunization with Pneumococcal Polysaccharide Conjugate Vaccines Protects Mice against Invasive Pneumococcal Infections . Infect Immun (1999) 67:4128–4133. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=96716=pmcentrez=abstract

6.                 Jakobsen H, Adarna BC, Schulz D, Rappuoli R, Jonsdottir I. Characterization of the antibody response to pneumococcal glycoconjugates and the effect of heat-labile enterotoxin on IGg subclasses after intranasal immunization. J Infect Dis (2001) 183:1494–1500. doi:JID001499 pii
10.1086/320202

7.                 Gallorini S, Berti F, Mancuso G, Cozzi R, Tortoli M, Volpini G, Telford JL, Beninati C, Maione D, Wack A. Toll-like receptor 2 dependent immunogenicity of glycoconjugate vaccines containing chemically derived zwitterionic polysaccharides. Proc Natl Acad Sci U S A (2009) 106:17481–17486. doi:10.1073/pnas.0903313106

8.                 Paoletti LC, Pinel J, Johnson KD, Reinap B, Ross RA, Kasper DL. Synthesis and preclinical evaluation of glycoconjugate vaccines against group B Streptococcus types VI and VIII. J Infect Dis (1999) 180:892–895. doi:10.1086/314955

9.                 Shen X, Lagergård T, Yang Y, Lindblad M, Fredriksson M, Wallerström G, Holmgren J. Effect of pre-existing immunity for systemic and mucosal immune responses to intranasal immunization with group B Streptococcus type III capsular polysaccharide-cholera toxin B subunit conjugate. Vaccine (2001) 19:3360–3368. doi:10.1016/S0264-410X(00)00532-6