key: cord-0735267-sq6zsqqi
authors: Zaheer, Tean; Pal, Kaushik; Zaheer, Iqra
title: Topical Review On Nano-vaccinology: Biochemical Promises and Key Challenges
date: 2020-09-28
journal: Process Biochem
DOI: 10.1016/j.procbio.2020.09.028
sha: 5cd94bad76b775b31e721c957ff656919ec1ab5d
doc_id: 735267
cord_uid: sq6zsqqi

Nanomaterials have wide-ranging biomedical applications in prevention, treatment and control of diseases. Nanoparticle based vaccines have proven prodigious prophylaxis of various infectious and non-infectious diseases of human and animal concern. Nano-vaccines outnumber the conventional vaccines by virtue of plasticity in physio-chemical properties and ease of administration. The efficacy of nano-based vaccines may be attributed to the improved antigen stability, minimum immuno-toxicity, sustained release, enhanced immunogenicity and the flexibility of physical features of nanoparticles. Based on these, the nano-based vaccines have potential to evoke both cellular and humoral immune responses. Targeted and highly specific immunological pathways required for solid and long lasting immunity may be achieved with specially engineered nano-vaccines. This review presents an insight into the prevention of infectious diseases (of bacterial, viral and parasitic origin) and non-infectious diseases (cancer, auto-immune diseases) using nano-vaccinology. Additionally, key challenges to the effective utilization of nano-vaccines from bench to clinical settings have been highlighted as research domains for future.

'Chemistry' behind the nanoparticles and their multi-dimensional exclusive applications is quite fascinating. Nanoparticles (<100nm size) have been successfully applied in many fields of biomedical science including therapeutics e.g. (drug screening and targeted delivery), diagnostics, vaccine production, surgical intervention, gene delivery, theragnostic, biomarker assisted mapping, toxicity of pathogenic organisms, etc. [1] [2] [3] [4] . The nano-carriers/adjuvants e.g. liposomes, proteasomes, emulsions, synthetic polymeric nanoparticles, nano-beads, ISCOMs, biological polymeric nanoparticles (exosome, bacteriophage) and inorganic nanomaterials have been utilized to prevent infectious and non-infectious diseases [5, 6] . The inertia of surface modification and ability to effectively co-deliver the adjuvants makes nanoparticles potential candidate for commercial vaccines. Also, the nano adjuvants in vaccines protect the target antigen from degradation and enhance uptake by immune mediators of biological systems. This approach is malleable, having the ability to present the antigen in a repetitive manner leading to stable immunogenic properties.

Nano vaccines have been widely experimented as prophylaxis of important diseases such as: bacterial (E. coli, Helicobacter sp.), viral (HIV, HPV, influenza), cancers (primary and metastatic), parasitic (malaria, toxoplasmosis, coccidiosis) and auto-immune disorders [7] [8] [9] . Wide variety of nanoparticles as vaccine scaffolds, enzyme, cargo have opened a new avenue towards precision medicine. These vaccines could be replicated in disease models of multi-drug resistant pathogens, which historically have J o u r n a l P r e -p r o o f presented as a great clinical challenge. Deploying biological nano-polymers like proteins, peptides, DNA, RNA and others have improvised the immunotherapy up to 100 folds, compared to previous clinical options [10] .

The efficacy of nano-assembled vaccines may be attributed to the improved antigen stability, minimum immuno-toxicity, sustained release, enhanced immunogenicity and the flexibility of physical features (e.g. Size, morphology, surface characteristics) [11] . Nano-vaccines have a huge potential of relatively easy engineering. Moreover, tailor-made personalized immune therapy is possible by harnessing the potential of nano-vaccines reveals a conceptual idea.The challenge areas of nano-vaccines are biodistribution which needs to be well-investigated and consigned.The quantitation of host immune interactions on exposure to nano-based vaccine demand in clinical trials for efficient commercialization.

This paper reflects into account the novel premise, utilizations and future perspectives of nano-vaccines in human and animal diseases.Brief insights and way forward for commercialization of nano-vaccines in clilnical settings have been summarized in the article.

Contemporary vaccine strategies employ either killed or live attenuated antigens. Live attenuated vaccines may induce clinical disease arising from same or mutated genotypes [12] . Therefore, the level of desired immune response may not be achived. The nanoparticles having efficient surface properties, making them more suitable candidates for stimulating the immune system and eliciting better immunological response. The hydrophobicity of nano-sized materials enhances the expression and release of inflammatory mediators and cytokines. Superior adjuvancity, owing to the exceptional surface properties of nanomaterials make them stand-out the conventional vaccine adjuvants [13] . Some of nano-based adjuvants have been officially licensed for use in making commercial antiviral vaccines J o u r n a l P r e -p r o o f 5 [14] . Moreover, increment towards dendritic-cell mediated autophagy and presentation of antigens to the immune cells lead to a solid cellular and humoral immunity against target pathogen.

First and second generation vaccines differ from nano-vaccines on the basis of lowfunctionalized plasmid DNA, highly labile to degrading enzymes, lacking the smart size and hydrophobic nature. All of these properties contribute to halt efficient transfection of antigens within target cells [15] . Moreover, the difficulty in administration and development of slower immunological response based on time-taking chemical interactions at cellular levels were major issues with DNA vaccines. Chitosan nanoparticles have the intrinsic ability to adhere with mucosal layers of host; this cationic feature makes them efficient cargo for antigen delivery [16] . Similarly, by virtue of ionic crosslinkages, the use of biopolymers could improvise endocytosis by host cells. This internalization stimulates a sustained pattern of exposure to antigen presenting cells, resulting in a stable immunological response. This response is characterized by the interaction and front-line response by many immunomodulators of the host. The liposomal vaccine carriers, due to hydrophobic interactions, can facilitate fusion within cellular membranes [17] . Also, the cationic nature further enhances cytosolic release, which is highly desirable in DNA based vaccines.

Most importantly, nanoparticle-based vaccines have been shown to stimulate longer immunological memory in the host [18] . This property, combined with the ability to elicit antigen-specific (IgA) mucosal immunity is the mainstay of popularity earned by nano-vaccines. Brief pathway opted by nanovaccines to bring cell mediated and humoral immunity in host are being illustrated in Fig.1 . The nucleic peptides might become very unstable within the host cells and may fail to produce desired immunological response due to proteolytic degradation inside the cells [13] . Nano-adjuvants provide a biologically compatible carrier platforms, that not only enhance antigen protection and sustained release but also enhance immune stimulation in the host for a stable and solid immunity.

Use of natural biomolecules such as albumin, chitosan, mannose, peptides, enzymes, chemical immunomodulators (Interleukins, cytokines) or immunoglobulins as nano-carriers for vaccines have shown long span, more stable and ubiquitous peripheral tissue response to in cancer immune therapy [10] . Nano vaccines have brought a revolution in the science of small by evading cellular pathways and efficient absorption up to blood vessels [15] . Admirable performance explored in pre-clinical and clinical trials, liposomal and VLPs based nano-vaccines, there are more than 10 commercial vaccines in human practice or clinical trials. Classical examples to VLP-based commercial vaccines include the porcine-circo virus vaccine, human cervical cancer and anti-hepatitis B nano-vaccines and multi-epitope anti-malarial and anti-hepatitis B vaccines [19, 20] . The desired level of epitope density and costimulation is a very unique and high precision characteristic of nano-based vaccines. Additionally, revamping the ability of nanomaterials to selectively enhance one of desirable, antigen specific immune responses in order to achieve optimal immunity holds huge potential in future engineered vaccines. As a case study, it is imperative to commend the most effective yet rapidly developed COVID-19 vaccine which is based on gold nanomaterials [21-23]. The plasmonic stabilization and functionalization has made the vaccine perform fairly well in pre-clinical as well as clinical trials and safety evaluations.

The world is dealing with ever rising population of super bug pathogens, the multi-drug resistant bacteria, rapidly mutating viruses, anthelmintic resistant parasites and secondary cancers. Most recently, COVID-19 pandemic has moved the major stakeholders to come up with very practical and promising candidates for prevention and therapeutic management of the virus [24]. The first-ever, highly progressive anti-Covid-19 vaccine is also based on nanomaterials [21] . Overview of most recent developments in nano-vaccinology during the current decade has been given in Table. 1. 

Nano-vaccinology has also been trialed to control many human and animal diseases of bacterial origin, Major types of nano-adjuvants/ nano-carriers/ nano-scaffolds employed for vaccinology have been illustrated in Fig.3. 

Viral diseases have historically caused and still posing a great threat to the integrity of entire ecosystems. Limitation of availability, high cost of production and promise in emerging viral strains are major challenges to anti-viral drug production. However, vaccines have shown to almost counter these areas of concern. Heterosubtypic immune protection in influenza strains (H1N1, H5N1) is a muchneeded approach for rapidly mutating viruses [31, 32] . A highly significant pathogen of humans, including HBV, HPV, HIV, DENV-E have been prevented using precisely engineered nano vaccines, that have shown to offer up to 95-100% effective immune protection [33] . Anti-AIDS nano-vaccines may be utlilized at clilnical settings to prevent the disease and associated complications at endemic regions of the world. The viral moieties in HIV are better functionalized and presented in a sustained manner. The nano-adjuvants to AIDS vaccines have shown a stable, least toxigenic and a long-lived immunological response, based on specific immunologlobulin activation.

Poliovirus is one of the most significant endemic pathogens of many developing countries. To this end, Marsian and co-workers have proposed a plant-mediated nano-vaccine, by utilizing virus like particles 

Drug resistance and slower development of modern anti-parasitic drugs are the major concern to widespread neglected tropical diseases. Parasitic diseases of prime concern like-wise: leishmaniasis, malaria, toxoplasmosis, anaplasmosis, schistosomiasis, and coccidiosis have been treated and prevented using several forms of nanoparticles [33, 37] . To date, there is no commercially available nano-vaccine against any parasite. The benefit of nanoparticles-assembled vaccines has shown highly desirable, Th1mediated immunological protection against leishmaniasis. Recently, epitope-based nano-vaccine, using Self-Assembling Protein Nanoparticle approach (SAPN) has been successfully developed against toxoplasma sp. Similarly, malaria (Anaplasma sp.) nano-vaccines have undergone huge development and several promising vaccine antigens have offered protective immunity in laboratory attempts [38, 39] . Similarly, this approach could be applied to parasitic vectors (mosquito, tick, flies) of human, animal and zoonotic diseases. There is a need to further channelize and utilize the potential of nanovaccine induced mucosal immunity for development of anti-parasitic vaccines. 

Engineering the surfaces of nanoparticles by chemical means may alter their potential biocompatibilities [43] . The chemical transformations therefore, indicate the necessity of developing the assays/ tests indicative of owning target set of characteristics, before functionalization with candidate antigens/proteins. Similarly, the uniformity of nanomaterials and the reproducibility of experiments yielding nano-vaccines needs to be enhanced. This applies as a significant quality standard for biogenic nanomaterials, where scaling-up uniformly is a concern.

VLPs have shown promising performance, regarding their easy engineering, exceptionally malleable size and surface properties and potential immunogenic properties. However, there is a concern of associated ability to rapidly mutate the proteins of viral origin, being utilized for their synthesis [44] .

Similar concerns may arise in the application of other nano-carriers or adjuvants used in the vaccine core antigen potentiation. Closely relevant animal models may be devised to carry out the pre-clinical J o u r n a l P r e -p r o o f evaluation of such nano-vaccines [45] . Biologically mediated nanomaterials have been proven as effective carriers of chemotherapeutic and chemoprophylactic agents.

Proven non-pathogenic viral vectors for protective immune coverage and sustained immunological memory may be further investigated for probability of efficient commercialization [46, 47] . The exact biochemical interactions and the active constitutents of nano-vaccines making them a good choice need further exploration within biological models. Thorough studies upto molecular pathways are warranted to understand the dynamics of actual mechanism behind protective immunological response due to nano-vaccines. Moreover, to harness the collaborative potential of computational modelling and simulation, its highly indicated to analyze and declare most promising nano-adjuvants or peptides, based on their in-silico biological structures and functions analyses. It is imperative to look up and further rationalize the potential aspects of nanomaterials, for instance the facile synthesis, requirement of lower doses yet alleviation of repetitive booster injections, easy routes of administration, etc. of nano-vaccines over conventional vaccines [48, 49] .

There is need to materialize the concept of nano-immunology against auto-immune diseases of idiopathic origin. For this purpose, the investigation and communication of biochemical and molecular pathways making nano-vaccines promising is imperative. The ease of administration and efficient immunogenesis has made nano-vaccines applicable at aquatic eco-systems. Biological distribution of nanoparticles and uptake by excretory systems within the host need further explanation and safety evaluation. Also, the commercialization of biological adjuvant-based nano-vaccines needs greater reproducibility and scaling-up of production.

Nano-vaccinology is the science of smaller particles, possessing huge potential. The laboratory as well as the clinical scale premise of nano-vaccines can push the boundaries towards an eco-friendly, more 

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