Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 + 3137 word(s) 3137 2021-10-14 13:17:13 |
2 The format is correct + 731 word(s) 3868 2021-10-20 03:55:48 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Uddin, M. COVID-19 Oral Particulate Vaccine. Encyclopedia. Available online: (accessed on 18 June 2024).
Uddin M. COVID-19 Oral Particulate Vaccine. Encyclopedia. Available at: Accessed June 18, 2024.
Uddin, Mohammad. "COVID-19 Oral Particulate Vaccine" Encyclopedia, (accessed June 18, 2024).
Uddin, M. (2021, October 19). COVID-19 Oral Particulate Vaccine. In Encyclopedia.
Uddin, Mohammad. "COVID-19 Oral Particulate Vaccine." Encyclopedia. Web. 19 October, 2021.
COVID-19 Oral Particulate Vaccine

Particulate vaccines can be administered as either oral solutions or in sublingual or buccal film dosage forms. Besides improved patient compliance, the major advantage of oral, sublingual, and buccal routes of administration is that they can elicit mucosal immunity. Mucosal immunity, along with systemic immunity, can be a strong defense against SARS-CoV-2 as the virus enters the system through inhalation or saliva.

COVID-19 vaccines SARS-CoV-2 pandemic oral particulate vaccine

1. Introduction

Particulate COVID vaccine is a vaccine that can be developed by using nano- or microparticles as platforms. Particles consist of an active principle (drug or biologically active material) that is dissolved, entrapped, or encapsulated [1]. Microparticles and nanoparticles can be utilized as drug carriers into which drugs or antigens may be incorporated in the form of solid solutions or solid dispersions. Nano- or microparticles have been shown to enhance the delivery of certain drugs across several natural and artificial membranes. Although the currently marketed mRNA vaccines are in particulate form, these are administered via the intramuscular route. This route of administration is at a disadvantage due to decreased patient compliance associated with injections. Therefore, particulate vaccines that can be administered by some other, painless route such as buccal or sublingual can be a better option for this vaccine. In this article, we will review some of the current COVID-19 vaccine platforms and discuss their limitations. We will further explore the feasibility of developing a COVID vaccine that can be administered orally, sublingually or via the buccal route by utilizing nano- or microparticles as a platform.

2. Limitations of Current COVID-19 Vaccines

2.1. Side Effects

According to the CDC, the most common side effects experienced after receiving the COVID-19 vaccine include pain at the injection site, redness, swelling, tiredness, headache, chills, fever, and nausea. Other effects include sensitive skin, menstrual cycle changes, and blood clotting [2][3]. Furthermore, because all of the vaccines are administered intramuscularly (IM), they are in a liquid form which needs to be preserved at low temperatures. This is a limitation in many countries with meager resources. Furthermore, the vaccine requires an expensive cold chain network for preservation, storage, and transportation, something that many resource-poor countries cannot afford. Therefore, a vaccine formulation that can be preserved, stored, and transported at room temperature would be most preferable and globally applicable. Furthermore, the IM route of administration involves needles, which many patients have a fear of. The anxiety associated with a needle stick and the aftermath of injection consequences result in hesitation among these patients. Thus, a needle-free delivery system can increase the mass vaccination rate.

2.2. Refusal of Vaccines

One major challenge for mass vaccination is the refusal to be vaccinated. The frequency of vaccine refusal, which is associated with many factors, is increasing worldwide. However, the refusal tendency among the population varies from country to country. A study was conducted by Meriggi, N.F. et al. to analyze COVID-19 vaccine acceptance across 15 survey samples covering 10 low- and middle-income countries (LMICs) in Asia, Africa and South America, Russia (an upper-middle-income country) and the United States, for a total of 44,260 individuals [4]. The results showed considerably higher willingness to take a COVID-19 vaccine in LMIC samples (mean 80.3%; median 78%; range 30.1 percentage points) compared with the United States (mean 64.6%) and Russia (mean 30.4%). It was found that the higher vaccine acceptance in LMICs is primarily due to individuals’ interests in personal protection against COVID-19, while concern about side effects is the most common reason for hesitancy [4].

2.3. Blood Clotting

The blood clotting effect after COVID vaccination has recently received attention from scientists and media. Blood clotting has mostly occurred as a result of the COVID vaccine produced by Johnson and Johnson. Several cases of blood clotting after vaccination have been reported [5]. As of 12 April 2021, more than 6.8 million doses of the Johnson & Johnson (Janssen) vaccine had been administered in the U.S. The CDC and FDA reviewed the data involving six reported U.S. cases of a rare and severe type of blood clot in individuals after receiving the J&J vaccine. In these cases, a type of blood clot called cerebral venous sinus thrombosis (CVST) was seen in combination with low levels of blood platelets (thrombocytopenia). Injections of Johnson & Johnson’s coronavirus vaccine were halted across the USA on 13 April 2021, after federal health agencies called for a pause in the vaccine’s use as they examined the rare blood-clotting disorder that emerged in six recipients. Besides the USA, Johnson & Johnson also delayed the rollout of its vaccine in Europe, where several countries were poised to start administering the vaccine at around the same time. Additionally, South Africa, which was devastated by a more contagious variant of the virus that had emerged there, suspended use of the vaccine. Australia also announced it would not purchase any Johnson & Johnson vaccine [6].

2.4. Needle Fear

A study was conducted to evaluate the prevalence of needle fear and summarize the characteristics of individuals who exhibit this fear [7]. Most children exhibited needle fear, while prevalence estimates for needle fear ranged from 20–50% in adolescents and 20–30% in young adults. In general, needle fear decreased with increasing age. Both needle fear and needle phobia were more prevalent in females than males. Avoidance of influenza vaccination because of needle fear occurred in 16% of adult patients, 27% of hospital employees, 18% of workers at long-term care facilities, and 8% of healthcare workers at hospitals. Needle fear was common when undergoing venipunctures and blood donations, and in those with chronic conditions requiring injection [7]. This fear of needles can result in avoidance of preventative measures and treatment of various diseases, including COVID-19. Currently, all the COVID vaccines are IM injectable. As such, needle fear has hindered mass vaccination thus far during the pandemic.

2.5. Route of Administration

Route of administration plays an important role in vaccination outcomes, as it can affect the extent and quality of immune response [8][9]. Almost all the current COVID vaccines are designed for intramuscular administration. Since COVID-19 primarily causes respiratory infection, developing mucosal immune protection is critical as it provides additional protection. Thus, mucosal vaccinations (e.g., intranasal, pulmonary, oral) might be superior to parenteral vaccinations.

3. Potential of Micro- or Nano Particulate COVID Vaccines

A particulate COVID vaccine can be produced by loading an antigen or drug of interest into nanoparticles or microparticles. These particles can be administered via the oral, sublingual, or buccal route. Particulate vaccines have been developed and studied before. The measles vaccine’s microparticles were made with biocompatible and biodegradable bovine serum albumin (BSA) polymer and processed by spray-dried production of microparticles. These vaccine microparticles were then incorporated into an orally dissolvable film. The vaccine particles were non-cytotoxic, induced a significant innate immune response, and increased the antigen presentation and co-stimulatory molecule expression of antigen-presenting cells. In vivo, the ODF vaccine formulation was tested in juvenile pigs. After 2 weeks, there was a significantly higher antibody titer plateauing through week 6. The results from this study suggest that the ODF measles vaccine formulation is a viable alternative dosage form for noninvasive immunization [10].
A particulate vaccine formulation has huge potential, as the particle can possibly be used as antigen carrier and an adjuvant. Particulate carriers can serve as effective antigen delivery systems that are able to enhance and/or facilitate the uptake of antigens by antigen-presenting cells (APCs) such as dendritic cells (DCs) or macrophages [11][12]. Furthermore, when delivered orally, particulate vaccine formulations have the ability to protect the integrity of antigens against acidic and enzymatic degradation in the stomach and GI tract until they are delivered to the immune cells [13][14].
Another advantage of using a particulate vaccine formulation is that it can eliminate the use of adjuvants which have minimal immunogenic effect. The immunologic effect of particulate vaccines is related to the size, stability, antigen-loading and antigen-release kinetic properties of the particle [15]. The immune response is also influenced by particle interaction with APCs and antigen presentation and processing by APCs [16].
Micro- or nanoparticles have some unique physiochemical properties that make them ideal candidates for vaccine delivery. They have a higher surface-to-volume ratio, small size, the ability to encapsulate various drugs, and tunable surface chemistry, all of which gives them many advantages over their bulky counterparts. These advantages include multivalent surface modification with targeting ligands, efficient navigation of the complex in an in vivo environment, enhanced intracellular trafficking, and the potential for addition of charged particles to increase target selectivity and sustained release of drug [17]. These advantages make nanoparticles ideal candidates for formulating vaccine delivery systems that can be applied for COVID vaccines.
The advantages of nanoparticle-based delivery of vaccines and drugs include improved biological stability of the antigen or drug and efficacy in targeting APCs for induction of innate and adaptive immunity due to Class I and Class II presentations [18]. Nanoparticles may also provide enhanced intracellular concentrations, controlled release of vaccine antigen or drug, and a reduced number of administrations due to enhanced immune response. Furthermore, nano-sized particles can themselves act as immune stimulating adjuvants. Gamvrellis et al. have shown that a nano-particulate antigen delivery system was able to induce a substantial immune response without inducing any inflammation [19].
A nanoparticle formulation of a vaccine is more immunogenic when compared to the solution form of the antigen. It has been found that poly (d, l-lactic-co-glycolic acid) nanoparticles (PLGA-NPs) can be used to formulate a vaccine delivery system which has potential in the development of future therapeutic cancer vaccines [20]. This nanoparticle can target dendritic cells (DCs) which can effectively initiate antitumor activity. The PLGA nanoparticle-containing antigens along with immune-stimulatory molecules (adjuvants) can target not only DCs but also provide immune activation and rescue impaired DCs from tumor-induced immunosuppression [1]. The authors further assessed the extent of maturation of DCs after treatment with the antigen, monophosphoryl lipid A (MPLA), and encapsulated PLGA nanoparticles. The generation of primary T-cell immune responses elicited by DCs was monitored. Results showed that the high amounts of pro-inflammatory and TH1 (T helper 1) polarizing cytokines and chemokines released by the nanoparticles are greater than that achieved by MPLA in solution [21].
Biodegradable and biocompatible polymers, copolymers and lipids can be used for COVID particulate vaccine preparation. It has been found previously that these polymers have been used to prepare nano/micro-particles as vaccine-delivery systems [19][22][23]. The material is selected based on several factors, including biocompatibility, degradation rate, hydrophilicity or lipophilicity, surface charge, and polarity. The SARS-2 virus infects mainly the area of the lungs, therefore nanoparticulate formulation has the advantage in fighting this virus due to their ability to reach deeper into the lung area.
Figure 1 shows how the spray drying method can be utilized for producing nano- or microparticles [24][25]. A biodegradable polymer-based particulate vaccine can act as an adjuvant itself. Therefore, there may be no need for using salt-based adjuvants, thus, eliminating the adverse effects caused by adjuvants. In addition, it is also possible to increase the efficiency of the particulate vaccine by adding appropriate ligands, charged particles or any other biocompatible chemicals to increase the specificity of the nano- or microparticles for targeted delivery [26].
Figure 1. Formulation of microparticles or nanoparticles using spray drying method.

4. Possible Particulate COVID Vaccine Delivery System for Oral, Sublingual and Buccal Administrations

4.1. Oral Administration

Oral administration is the most preferred route for drug delivery as it is the most patient compliant. Oral administration of vaccines is more acceptable to the patient as it is needle-free, easy to administer, requires less-trained personnel for administration, and is easy to apply to the mass population. One of the most common oral vaccines is the oral polio vaccine, which has been used to eradicate polio. The oral polio vaccine has been the mainstay of the global polio eradication initiative (GPEI) in most countries. The polio vaccine allows for the encounter of the polio virus by the immune system to be less threatening while still allowing the body to mount a humoral response for protection against any future exposure to the virus [27]. Upon administration, the vaccine elicits a local immune response in the intestinal mucous membranes, a location at which the poliovirus multiplies [27][28]. After administration, the live-attenuated oral poliovirus vaccine replicates in gut-associated tissues, eliciting mucosal and systemic immunity. The oral polio vaccine is both therapeutic and preventative, protects from disease, and limits poliovirus spread. As such, mass vaccination with the oral polio vaccine has been used as a strategy to end the circulation of all polioviruses [29].
Acknowledging this, developing an oral COVID vaccine with high efficiency and low cost will eliminate the limitations that the current vaccines have. The oral route will also eliminate the need for trained personnel to administer the vaccine, which will give the vaccine a more global character as it will be easily available and applicable in resource-poor countries. In addition, oral vaccines have the potential to stimulate mucosa-associated lymphoid tissue (MALT) located in the digestive tract and gut-associated lymphoid tissue (GALT). About half the lymphocytes of the immune system are in the MALT [30]. Structurally, MALT tissue ranges from loose, barely organized clusters of lymphoid cells in lamina propria of intestinal villi to well-organized structures such as tonsils, appendix and Peyer’s patches [31]. The tonsils are found in three locations: lingual at the base of the tongue, palatine at the sides of the back of the mouth, and pharyngeal, in the adenoids. Also, under the epithelial cell layer of lamina propria and tonsils, there are many B cells, plasma cells, activated TH cells, and macrophages [31]. MALT can be functionally divided into effector and inductive sites [30]. Inductive sites contain secondary lymphoid tissues in which IgA class switching and clonal expansion of B-cells occurs in response to antigen specific T-cell activation. After activation and IgA class switching, T- and B-cells migrate from inductive sites to effector sites. Effector sites are present in all mucosal tissues as disseminated lymphoid tissues diffusely distributed throughout the lamina or substantia propria [30]. In effector sites, secretory IgA, or S-IgA (two IgA molecules joined by a J-chain and bound to a secretory component, an epithelial cell membrane receptor) is secreted across the mucosal epithelium [32]. Therefore, oral administration, and even sublingual and buccal administration, takes advantage of this location and structure of MALT tissues. For the SARS-2 virus, an elevated mucosal immune response could serve as a first line of protection against infection. The oral delivery of vaccines as an alternative immunization route and the efficiency of mucosal immunization for different antigens has been studied [33]. In addition, the intranasal route of administration for vaccine delivery has been investigated. Results from studies of both oral and intranasal routes of administration show the potential of mucosal immunization with VLP-based HPV vaccines [33][34]. A COVID vaccine which is mRNA-based is in particulate form with lipids but is injected as a solution via the IM route. Therefore, the vaccine is already in particulate form, which can be converted into microparticles by adding other polymers, and these microparticles can be delivered via the oral route in solution or suspension form.
Also, when dosed intranasally, a vaccine is intrinsically prone to inducing Th17 immune responses [35], which may not be ideal for the clearance of SARS-CoV-2 viral particles from the lungs. Another limiting factor for a nasal or pulmonary COVID-19 vaccine is the need for a special and costly delivery device, which may also exert pressure on the vaccine formulation. For example, a loss of virus titer was observed when using a nebulizer to deliver a live virus formulation [36]. Therefore, it is not surprising that almost all COVID-19 vaccine candidates advanced to clinical trials are given by injection (see Table 1), although they may not induce specific mucosal immunity [37].
Table 1. List of some of the current marketed and investigational vaccine candidates for SARS-CoV-2.
Vaccine Candidates Classification of Vaccine Clinical Phase Lead Development Company/Collaboration
GRAd-COV2 Adenovirus-based vaccine Phase 1 ReiThera; Leukocare; Univercells; Lazzaro Spallanzani National Institute for Infection
ChAd-SARS-CoV-2-S Adenovirus-based vaccine Preclinical Washington University School of Medicine in St. Louis
LinealDNA DNA Vaccine Preclinical Takis Biotech
AG0301-COVID19 DNA vaccine Phase 1/2 AnGes, Inc.
GX-19 DNA vaccine Phase 1/2 Genexine
INO-4800 DNA vaccine
Phase 1/2 Inovio Pharmaceuticals; Center for Pharmaceutical Research, Kansas City. Mo.; University of Pennsylvania, Philadelphia
ZyCoV-D DNA vaccine
Phase 2 Zydus Cadila
AAVCOVID Gene-based vaccine Preclinical Massachusetts General Hospital; University of Pennsylvania
No name given gp96-based vaccine Preclinical Heat Biologics; University of Miami Miller School of Medicine
No name given Ii-Key peptide COVID-19 vaccine Preclinical Generex Biotechnology
No name given Inactivated vaccine Phase 1/2 Research Institute for Biological Safety Problems, Rep of Kazakhstan
No name given Inactivated vaccine Phase 3 Wuhan Institute of Biological Products; China National Pharmaceutical Group (Sinopharm); Henan Provincial Center for Disease Control and Prevention
Covaxin Inactivated vaccine Phase 2 Bharat Biotech; National Institute of Virology
No name given Inactivated vaccine Phase 1/2 Chinese Academy of Medical Sciences, Institute of Medical Biology; West China Second University Hospital, Yunnan Center for Disease Control and Prevention
No name given Inactivated vaccine Preclinical Shenzhen Kangtai Biological Products
BBIBP-CorV Inactivated vaccine Phase 3 Beijing Institute of Biological Products; China National Pharmaceutical Group (Sinopharm); Henan Provincial Center for Disease Control and Prevention
CoronaVac Inactivated vaccine (formalin with alum adjuvant) Phase 3 Sinovac; Sinovac Research and Development Co., Ltd.
AdCOVID Intranasal vaccine Preclinical Altimmune; University of Alabama at Birmingham
T-COVIDTM Intranasal vaccine Preclinical Altimmune
Bacillus Calmette-Guerin (BCG) vaccine Live-attenuated vaccine Phase 2/3 University of Melbourne and Murdoch Children’s Research Institute; Radboud University Medical Center; Faustman Lab at Massachusetts General Hospital
V591 Replicating viral vector Phase 1 University of Pittsburgh’s Center for Vaccine Research; Themis Biosciences; Institut Pasteur
bacTRL-Spike Monovalent oral vaccine (bifidobacteria) Preclinical Symvivo
COVAX-19 Protein subunit
Monovalent spike protein vaccine
Phase 1 Vaxine Pty Ltd.; Royal Adelaide Hospital
No name announced mRNA lipid nanoparticle Early research CanSino Biologics, Precision NanoSystems
mRNA-1273 LNP-encapsulated mRNA vaccine Phase 3 Moderna; Kaiser Permanente Washington Health Research Institute
BNT162 3 LNP-mRNAs-based vaccine Phase 3 Pfizer, BioNTech
CVnCoV mRNA-based vaccine Phase 1 CureVac
No name given mRNA-based vaccine Preclinical Chulalongkorn University’s Center of Excellence in Vaccine Research and Development
UB-612 Multitope peptide-based vaccine Phase 1 COVAXX; United Biomedical Inc. (UBI)
JNJ-78436735 Non-replicating viral vector Phase 3 Johnson & Johnson
Sputnik V
COVID-Vac; Гам-КОВИД-Вак20
Non-replicating viral vector
Adenovirus-based vaccine
Phase 3 Gamaleya Research Institute, Acellena Contract Drug Research and Development
EpiVacCorona Peptide vaccine Phase 1/2 Federal Budgetary Research Institution State Research Center of Virology and Biotechnology
No name given Plant-based adjuvant vaccine Phase 1 Medicago; GSK; Dynavax
No name given Protein subunit vaccine
S protein20
Phase 1/2 Sanofi; GlaxoSmithKline
No name given Protein subunit
RBD-based vaccine
Phase 1/2 Kentucky Bioprocessing, Inc.
AdimrSC-2f Protein subunit vaccine Phase 1 Adimmune
No name given Protein subunit vaccine Phase 1 CSL; The University of Queensland; Seqirus
SCB-2019 Protein subunit vaccine Phase 1 GlaxoSmithKline, Sanofi, Clover Biopharmaceuticals, Dynavax and Xiamen Innovax; Linear Clinical Research (Australia)
No name given Protein subunit vaccine Preclinical University of Saskatchewan Vaccine and Infectious Disease Organization-International Vaccine Centre
PittCoVacc Recombinant protein subunit vaccine Preclinical UPMC/University of Pittsburgh School of Medicine
Protein subunit
Adjuvanted recombinant protein
Phase 2 Anhui Zhifei Longcom Biopharmaceutical, Institute of Microbiology of the Chinese Academy of Sciences
No name given Recombinant vaccine Preclinical Sanofi, Translate Bio
Ad5-nCoV Recombinant vaccine (adenovirus type 5 vector) Phase 3 CanSino Biologics; Tongji Hospital
VXA-CoV2-1 Recombinant vaccine (adenovirus vector) Phase 1 Vaxart
V590 Recombinant vaccine (stomatitis virus) Phase 1 Merck; IAVI
DelNS1-2019-nCoV-RBD-OPT1 Replicating viral vector Phase 1 Xiamen University, Beijing Wantai Biological Pharmacy; Jiangsu Provincial Centre for Disease Control and Prevention
No name announced Replicating viral vector Preclinical Federal Budgetary Research Institution (FBRI); State research center of virology and biotechnology “VECTOR”
Non-Replicating viral vector vaccine Phase 3 The University of Oxford; AstraZeneca; IQVIA; Serum Institute of India
HDT-301 RNA vaccine Preclinical University of Washington; National Institutes of Health Rocky Mountain Laboratories; HDT Bio Corp.
LNP-CoVsaRNA Self-amplifying RNA vaccine Phase 1/2 Imperial College London
HaloVax Self-assembling vaccine Preclinical Voltron Therapeutics, Inc.; Hoth Therapeutics, Inc.; MGH Vaccine and Immunotherapy Center
LUNAR-COV19 [38] Self-replicating RNA vaccine Phase 1/2 Arcturus Therapeutics and Duke-NUS Medical School
CDX-005 [39][40] Weakened Phase 1 Codagenix, Serum Institute of India

4.2. Film-Based Particulate COVID Vaccine for Sublingual and Buccal Administration

Although placed in the oral cavity, the administration of drugs via sublingual and buccal routes are different from oral (per oral, PO) administration. Unlike oral routes, sublingual, or buccal routes are systemic, directly accessible to the blood. The nano- or microparticle of vaccine-loaded films can be prepared by solvent casting or using a 3D bioprinter (Figure 2) [41]. Instead of passing through the GI tracts such as the esophagus, stomach or intestine, the drug can directly enter the blood through the membrane. Medications taken by buccal or sublingual administration provide consistent drug concentration levels in the blood, dissolve quickly, have immediate onset of action, and can avoid the first pass effect. Since there is no first pass effect, the bioavailability is high. Therefore, compared to oral administration, less drug can be used to elicit the desired effect. Additionally, the patient does not need to swallow the drug in sublingual or buccal administration. Another advantage of buccal and sublingual administration is that they do not subject proteins and/or peptides to the degradation that is usually caused by gastrointestinal administration [42]. Also, oral films are easy to prepare, administer, and handle. Normally, any biodegradable and biocompatible polymers can be used to prepare the film, including any other material needed such as a permeation enhancer, plasticizer, etc., in a simple method [42]. The most important advantage of buccal and sublingual administration is that the vaccine can produce both systemic and mucosal immunity [43]. SARS-2 virus infects the host through the mucosa. Several signs after COVID infection, such as loss of taste, dry mouth, and mucosal lesions such as ulcerations, enanthema, and macules imply that the virus infects the mucosa. However, the mucosal infection has not been completely understood. To address this, Sinjari B et al. and Huang et al. have generated and analyzed two single-cell RNA sequencing datasets of the human minor salivary glands and gingiva. Their studies showed that the oral cavity is an important site for SARS-CoV-2 infection and implicates saliva as a potential route of SARS-CoV-2 transmission [44][45]. Therefore, an ideal COVID vaccine should induce protective immunity at mucosal sites to act as a first line of defense against infections. However, most of the vaccines currently in use are administered via injection (such as intramuscular route) and have very limited mucosal immunity. However, vaccines administered via mucosal routes have proven to be effective for the induction of both systemic and local immunity [46]. Additionally, mucosal immunization via sublingual and buccal administration makes vaccine delivery easier and safer than parenteral administration routes. These are very suitable for mass immunizations during pandemic situations and improve vaccine acceptability, especially among children [47]. Therefore, mucosal administration of vaccines via buccal or sublingual routes could be a great choice for mass protection. Among the two, buccal drug delivery was identified as a better option for administration. A quickly-soluble tablet or film dosage form can be used as drug carrier for buccal administration. The quickly-soluble oral film dosage form has several advantages over other dosage forms for vaccines or drugs. Lower bioavailability of solid oral drugs, the inconvenience of administering injections, and inaccurate dosing by liquid formulations have turned the focus of pharmaceutical companies to developing oral film forms of medications that eliminate several of these limitations. Oral films are easy to prepare, administer, and handle. Normally, any biodegradable and biocompatible polymer can be used to prepare the film, including any other material needed such as permeation enhancer, plasticizer, etc., by a simple method.
Figure 2. Formulation of oral dissolving films (ODF) with either microparticles or nanoparticles using 3D bioprinter.


  1. Kreuter, J. Nanoparticles and microparticles for drug and vaccine delivery. J. Anat. 1996, 189 Pt 3, 503–505.
  2. Blumenthal, K.G.; Freeman, E.E.; Saff, R.R.; Robinson, L.B.; Wolfson, A.R.; Foreman, R.K.; Hashimoto, D.; Banerji, A.; Li, L.; Anvari, S.; et al. Delayed Large Local Reactions to mRNA-1273 Vaccine against SARS-CoV-2. N. Engl. J. Med. 2021, 384, 1273–1277.
  3. Pfizer vs. Moderna Vaccines: Does One Have More Side Effects?—NBC Chicago. Available online: (accessed on 13 May 2021).
  4. Solís Arce, J.S.; Warren, S.S.; Meriggi, N.F.; Scacco, A.; McMurry, N.; Voors, M.; Syunyaev, G.; Malik, A.A.; Aboutajdine, S.; Adeojo, O.; et al. COVID-19 vaccine acceptance and hesitancy in low- and middle-income countries. Nat. Med. 2021, 27, 1385–1394.
  5. Joint CDC and FDA Statement on Johnson & Johnson COVID-19 Vaccine | CDC Online Newsroom | CDC. Available online: (accessed on 13 May 2021).
  6. Johnson & Johnson Delays Its COVID-19 Vaccine Rollout in EUROPE—The New York Times. Available online: (accessed on 8 July 2021).
  7. McLenon, J.; Rogers, M.A.M. The fear of needles: A systematic review and meta-analysis. J. Adv. Nurs. 2019, 75, 30–42.
  8. Belyakov, I.M.; Ahlers, J.D. What Role Does the Route of Immunization Play in the Generation of Protective Immunity against Mucosal Pathogens? J. Immunol. 2009, 183, 6883–6892.
  9. Mohanan, D.; Slütter, B.; Henriksen-Lacey, M.; Jiskoot, W.; Bouwstra, J.A.; Perrie, Y.; Kündig, T.M.; Gander, B.; Johansen, P. Administration routes affect the quality of immune responses: A cross-sectional evaluation of particulate antigen-delivery systems. J. Control. Release 2010, 147, 342–349.
  10. Gala, R.P.; Popescu, C.; Knipp, G.T.; McCain, R.R.; Ubale, R.V.; Addo, R.; Bhowmik, T.; Kulczar, C.D.; D’Souza, M.J. Physicochemical and Preclinical Evaluation of a Novel Buccal Measles Vaccine. AAPS PharmSciTech 2017, 18, 283–292.
  11. Anderson, E.J.; Rouphael, N.G.; Widge, A.T.; Jackson, L.A.; Roberts, P.C.; Makhene, M.; Chappell, J.D.; Denison, M.R.; Stevens, L.J.; Pruijssers, A.J.; et al. Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults. N. Engl. J. Med. 2020, 383, 2427–2438.
  12. Walter, E.; Dreher, D.; Kok, M.; Thiele, L.; Kiama, S.G.; Gehr, P.; Merkle, H.P. Hydrophilic poly(dl-lactide-co-glycolide) microspheres for the delivery of DNA to human-derived macrophages and dendritic cells. J. Control. Release 2001, 76, 149–168.
  13. Slütter, B.; Soema, P.C.; Ding, Z.; Verheul, R.; Hennink, W.; Jiskoot, W. Conjugation of ovalbumin to trimethyl chitosan improves immunogenicity of the antigen. J. Control. Release 2010, 143, 207–214.
  14. O’Hagan, D. Microparticles and polymers for the mucosal delivery of vaccines. Adv. Drug Deliv. Rev. 1998, 34, 305–320.
  15. Panyam, J.; Labhasetwar, V. Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv. Drug Deliv. Rev. 2003, 55, 329–347.
  16. Tobío, M.; Gref, R.; Sánchez, A.; Langer, R.; Alonso, M.J. Stealth PLA-PEG nanoparticles as protein carriers for nasal administration. Pharm. Res. 1998, 15, 270–275.
  17. Uddin, M.N.; Kouzi, S.A.; Hussain, M.D. Strategies for Developing Oral Vaccines for Human Papillomavirus (HPV) Induced Cancer Using Nanoparticle Mediated Delivery System. J. Pharm. Pharm. Sci. 2015, 18, 220.
  18. Parkin, J.; Cohen, B. An overview of the immune system. Lancet 2001, 357, 1777–1789.
  19. Gamvrellis, A.; Gloster, S.; Jefferies, M.; Mottram, P.L.; Smooker, P.; Plebanski, M.; Scheerlinck, J.-P.Y. Characterisation of local immune responses induced by a novel nano-particle based carrier-adjuvant in sheep. Vet. Immunol. Immunopathol. 2013, 155, 21–29.
  20. Thiele, L.; Merkle, H.P.; Walter, E. Phagocytosis and phagosomal fate of surface-modified microparticles in dendritic cells and macrophages. Pharm. Res. 2003, 20, 221–228.
  21. Elamanchili, P.; Diwan, M.; Cao, M.; Samuel, J. Characterization of poly (d,l-lactic-co-glycolic acid) based nanoparticulate system for enhanced delivery of antigens to dendritic cells. Vaccine 2004, 22, 2406–2412.
  22. Hamdy, S.; Haddadi, A.; Hung, R.W.; Lavasanifar, A. Targeting dendritic cells with nano-particulate PLGA cancer vaccine formulations. Adv. Drug. Deliv. Rev. 2011, 63, 943–955.
  23. Elamanchili, P.; Lutsiak, C.M.E.; Hamdy, S.; Diwan, M.; Samuel, J. “Pathogen-Mimicking” Nanoparticles for Vaccine Delivery to Dendritic Cells. J. Immunother. 2007, 30, 378–395.
  24. Nettey, H.; Haswani, D.; Oettinger, C.W.; D’Souza, M.J. Formulation and testing of vancomycin loaded albumin microspheres prepared by spray-drying. J. Microencapsul. 2006, 23, 632–642.
  25. Joshi, D.; Chbib, C.; Uddin, M.N.; D’Souza, M.J. Evaluation of Microparticulate (S)-4,5-Dihydroxy-2,3-pentanedione (DPD) as a Potential Vaccine Adjuvant. AAPS J. 2021, 23, 84.
  26. Combadière, B.; Mahé, B. Particle-based vaccines for transcutaneous vaccination. Comp. Immunol. Microbiol. Infect. Dis. 2008, 31, 293–315.
  27. O’Grady, M.; Bruner, P.J. Polio Vaccine. StatPearls. 2021. Available online: (accessed on 19 September 2021).
  28. Poliomyelitis. Available online: (accessed on 27 August 2021).
  29. Yeh, M.T.; Bujaki, E.; Dolan, P.T.; Smith, M.; Wahid, R.; Konz, J.; Weiner, A.J.; Bandyopadhyay, A.S.; Van Damme, P.; De Coster, I.; et al. Engineering the Live-Attenuated Polio Vaccine to Prevent Reversion to Virulence. Cell Host Microbe 2020, 27, 736–751.e8.
  30. Cesta, M.F. Normal Structure, Function, and Histology of Mucosa-Associated Lymphoid Tissue. Toxicol. Pathol. 2006, 34, 599–608.
  31. Goldsby, R.; Kindt, T.; Osborne, B.; Kuby, J. Immunology, 5th ed.; W. H. Freeman: New York, NY, USA, 2002; ISBN 0716749475.
  32. Pabst, R. The anatomical basis for the immune function of the gut. Anat. Embryol. 1987, 176, 135–144.
  33. Thönes, N.; Müller, M. Oral immunization with different assembly forms of the HPV 16 major capsid protein L1 induces neutralizing antibodies and cytotoxic T-lymphocytes. Virology 2007, 369, 375–388.
  34. Chang, S.; Warner, J.; Liang, L.; Fairman, J. A novel vaccine adjuvant for recombinant flu antigens. Biologicals 2009, 37, 141–147.
  35. Du, L.; Zhao, G.; Lin, Y.; Sui, H.; Chan, C.; Ma, S.; He, Y.; Jiang, S.; Wu, C.; Yuen, K.-Y.; et al. Intranasal Vaccination of Recombinant Adeno-Associated Virus Encoding Receptor-Binding Domain of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Spike Protein Induces Strong Mucosal Immune Responses and Provides Long-Term Protection against SARS-CoV infection. J. Immunol. 2008, 180, 948–956.
  36. Smith, J.H.; Papania, M.; Knaus, D.; Brooks, P.; Haas, D.L.; Mair, R.; Barry, J.; Tompkins, S.M.; Tripp, R.A. Nebulized live-attenuated influenza vaccine provides protection in ferrets at a reduced dose. Vaccine 2012, 30, 3026–3033.
  37. Wang, J.; Peng, Y.; Xu, H.; Cui, Z.; Williams, R.O. The COVID-19 Vaccine Race: Challenges and Opportunities in Vaccine Formulation. AAPS PharmSciTech 2020, 21, 1–12. Available online: (accessed on 17 September 2021).
  38. Uddin, M.; Henry, B.; Carter, K.D.; Roni, M.A.; Kouzi, S.A. A Novel Formulation Strategy to Deliver Combined DNA and VLP Based HPV Vaccine. J. Pharm. Pharm. Sci. 2019, 22, 536–547.
  39. Jeffers, S.A.; Tusell, S.M.; Gillim-Ross, L.; Hemmila, E.M.; Achenbach, J.E.; Babcock, G.J.; Thomas, W.D.; Thackray, L.B.; Young, M.D.; Mason, R.J.; et al. Cd209l (L-Sign) Is a Receptor for Severe Acute Respiratory Syndrome Coronavirus. Proc. Natl. Acad. Sci. USA 2004, 101, 15748–15753.
  40. Callaway, E. The Race for coronavirus vaccines. Nature 2020, 580, 576–577.
  41. Panraksa, P.; Udomsom, S.; Rachtanapun, P.; Chittasupho, C.; Ruksiriwanich, W.; Jantrawut, P. Hydroxypropyl Methylcellulose E15: A Hydrophilic Polymer for Fabrication of Orodispersible Film Using Syringe Extrusion 3D Printer. Polymers 2020, 12, 2666.
  42. Uddin, M.N.; Allon, A.; Roni, M.A.; Kouzi, S. Overview and Future Potential of Fast Dissolving Buccal Films as Drug Delivery System for Vaccines. J. Pharm. Pharm. Sci. 2019, 22, 388–406.
  43. Anselmo, A.C.; Gokarn, Y.; Mitragotri, S. Non-invasive delivery strategies for biologics. Nat. Rev. Drug Discov. 2019, 18, 19–40.
  44. Sinjari, B.; D’Ardes, D.; Santilli, M.; Rexhepi, I.; D’Addazio, G.; Di Carlo, P.; Chiacchiaretta, P.; Caputi, S.; Cipollone, F. SARS-CoV-2 and Oral Manifestation: An Observational, Human Study. J. Clin. Med. 2020, 9, 3218.
  45. Huang, N.; Pérez, P.; Kato, T.; Mikami, Y.; Okuda, K.; Gilmore, R.C.; Conde, C.D.; Gasmi, B.; Stein, S.; Beach, M.; et al. SARS-CoV-2 infection of the oral cavity and saliva. Nat. Med. 2021, 27, 892–903.
  46. Brandtzaeg, P. Function of mucosa-associated lymphoid tissue in antibody formation. Immunol. Investig. 2010, 39, 303–355.
  47. Amorij, J.-P.; Kersten, G.F.A.; Saluja, V.; Tonnis, W.F.; Hinrichs, W.L.J.; Slütter, B.; Bal, S.M.; Bouwstra, J.A.; Huckriede, A.; Jiskoot, W. Towards tailored vaccine delivery: Needs, challenges and perspectives. J. Control. Release 2012, 161, 363–376.
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to :
View Times: 504
Revisions: 2 times (View History)
Update Date: 20 Oct 2021
Video Production Service