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 4) [
71]. 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 [
72]. 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 [
72]. The most important advantage of buccal and sublingual administration is that the vaccine can produce both systemic and mucosal immunity [
73]. 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 [
74,
75]. 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 [
76]. 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 [
77]. 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.