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 Table of Contents  
Year : 2021  |  Volume : 9  |  Issue : 2  |  Page : 108-113

“Race for SARS-CoV2 vaccine:” The propitious oral route

1 Department of Oral Medicine and Radiology, Babu Banarasi Das College of Dental Sciences, Babu Banarasi Das University, Lucknow, Uttar Pradesh, India
2 Department of Oral Medicine and Radiology, People's College of Dental Sciences and Research Center, People's University, Bhopal, Madhya Pradesh, India
3 Department of Oral Medicine and Radiology, KIMS Dental College and Hospital, East Godavari, Andhra Pradesh, India

Date of Submission23-Jun-2021
Date of Acceptance11-Aug-2021
Date of Web Publication17-Dec-2021

Correspondence Address:
Dr. Areeba Shahid
Department of Oral Medicine and Radiology, Flat no. C-1, Tuba Palace,15, Madan Mohan Malviya Marg, Lucknow
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jhnps.jhnps_30_21

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In today's pandemic era, the public is eyeing eminent scientists to develop a successful vaccine against the highly contagious SARS-CoV2 infection, commonly known as COVID-19. It will be a relief to the overwhelmed medical fraternity. The oral cavity can be a great medium to deliver needle-free vaccination, which is psychologically beneficial to the general public. It is the most exigent vaccination method and still lacks protocols to investigate the efficacy of these systems. However, oral vaccination seems promising, offers several benefits at the societal level, is economically beneficial and hints at the possibility of rendering both cellular and antibody-mediated immunity. Here, this review article gives an overall view of oral vaccination, its challenges, and possibilities, with a focus on vaccine development against SARS-CoV2, administered via the oral route.

Keywords: COVID-19, oral immunization, oral route, oral vaccine, SARS-CoV2

How to cite this article:
Shahid A, Misra N, Channaiah SG, Narayanappa SM. “Race for SARS-CoV2 vaccine:” The propitious oral route. J Head Neck Physicians Surg 2021;9:108-13

How to cite this URL:
Shahid A, Misra N, Channaiah SG, Narayanappa SM. “Race for SARS-CoV2 vaccine:” The propitious oral route. J Head Neck Physicians Surg [serial online] 2021 [cited 2023 Jun 4];9:108-13. Available from: https://www.jhnps.org/text.asp?2021/9/2/108/332716

  Introduction Top

Vaccines are the tugboats of preventive health. -William Foege

Latin term, Variolae vaccinae (cowpox) gives birth to the word “vaccine.”[1] Vaccination can be used as a prophylactic intervention or as a remedial measure. Immunization is a convenient strategy that safeguards the prevaccinated individuals and additionally aids in the genesis of herd immunity in a particular clique.[2] Unfortunately, most modes of vaccination are injection based. Hypodermal injections form the major bulk of authorized vaccines. Less commonly in liquid form orally or by intranasal routes.

An upsurge of an acute febrile respiratory illness was first noted in Wuhan, China. It was initiated on December 19, 2019. It was the result of an unprecedented coronavirus strain, originally named COVID-19 and later renamed SARS-CoV2.[3] Following it, the entire world is suffering from a pandemic crisis and is anticipating a successful and efficacious vaccine, against the highly contagious virus. Various vaccine models have been developed over these few months and have reached different levels of vaccine testing phase trials, even clinical but still a long way to be made accessible to the general public. Previously, “in 2002 and 2012, respectively, seven coronaviruses possessing the capability of causing infection in humans resulted in two major outbreaks caused by SARS-CoV and MERS CoV.”[4] Since then, there has been researched and analysis on the development of vaccines related to coronaviruses.

Delivery through the oral route is most prudent for uncomplicated vaccination. It is satisfying and well accepted by the patient, as a routine, over 60% of commercialized medications are taken orally.[5] However, it is believed that there are obstacles in the gastrointestinal tract. This includes fragile antigens getting jarred in the enteric environment and also need of ample doses to stimulate immunity, substituting tolerance. Due to this reason, only a small segment of the available commercial vaccines are oral preparations. Since it is still in the experimental stage, therefore the vaccine designers need to have a distinctive outlook and careful consideration.[6] It is crucial to dispel various myths associated with these challenges, which oppose the existence of oral vaccines.

Oral immunization holds the potential of rendering humoral and cellular immunity at the systemic level and on mucosal surfaces. It can also improve vaccine blueprints by exalting the approachability and exploration.[7],[8] Oral vaccine offers several advantages such as self-ease of administration and being cost-effective. Besides, the needle stick injuries leading to bloodborne conditions like HIV/AIDS and Hepatitis would be eliminated as oral administration is needle-free. The most prime mucosal vaccine formulated against a highly contagious human enterovirus was the oral polio vaccine (OPV).[9] This has resulted in the complete elimination of the poliovirus almost worldwide.

This review article subsequently discusses the advantages of oral vaccination, the challenges associated with it, and debunking such myths, as well as its future potential. Oral immunization needs continuous exploration and needs to be worked upon, owing to its great advantages. If experimental studies and clinical trials are continued with scientific zeal, then definitely we can hope for a future concerning SARS-CoV2 also.

  Oral Immunization and Efficacy Top

Human vaccine manufacturing takes a reasonable amount of time because they require extensive testing for safety and a boost for bulk produce.[10] Prophylactic vaccination is a potent way to safeguard against infectious diseases.

Oral immunization is ideally the most suitable route of all the traditional routes as it offers abundant facilities. The gain of “mucosal immunity” via oral vaccination can behave as a protective barrier opposing the infective pathogens causing contagion. Through oral vaccine delivery, targeting the mucosal barrier is possible because it “facilitates both IgA and IgG secretion in the body” (responsible for mucosal and cellular immunity, respectively), contradictory to intravenous, intramuscular or subcutaneous, which are unable to halt the pathogens in the mucosal barrier.[11]

Live and nonliving attenuated carriers delivered via the oral route are known to induce good responses at mucosal and systemic levels. For this, appropriate immunostimulants are used, and advancement in technologies helps target antigens to the gut-associated immune cells.[12],[13] Cytotoxic T lymphocytes and prolonged immunoglobulin A mucosal memories are more actively delivered through oral immunization than systemically. Oral vaccine booster doses can help upregulate the body's natural resistance resulting in substantial long-lasting mucosal and systemic immunity. Patients do not object to repetitive administration as the vaccine is in the form of a caplet or individual solid form. It is completely inoffensive as patients can self-administer such vaccines as compared to an injection-based which requires technicality and precision.[14]

  Challenges Top

The largest immune structure in the body is the “intestine,” harboring the majority of the body's immune cells.[15] The oral delivery route is the most demanding medium of vaccination and various elements hinder the ingestion and processing of particulate antigens by the gastroenteric epithelium. The gastrointestinal tract has a unique anatomical presentation, well adapted to produce defense and clearance mechanisms, establishing a balance between immunity and oral resistance in the abdominal space. The following literature speaks about the obstacles in the enteric environment.

First, if a vaccine is proteinaceous, it is exposed to many hurdles in the enteric environment. Low gastric pH, metabolic enzymes, and biliary salts are the main culprits causing deactivation and disruption of the vaccine constituents. Therefore, vaccines need to be protected to facilitate epithelial absorption.

Second, the vaccine constituents must skip uptake in the “small intestine,” and furnished inequitably to the “large intestine.”

Third, after pulling through this, the vaccine needs to transverse the epithelium and enter the “gut-associated lymphoid tissue,” wherein the mucosal immunity is stimulated.

However, according to New,[14] his literature gives irrefutable proof of demystifying the above-mentioned myths. Oral vaccine can transport antigens through the intestinal epithelium via distinctive routes, as follows:[14]

  1. Microcapillaries into the local and peripheral vascular system
  2. Lamina propria and gastroenteric lymphatics into the mesenteric lymph nodes
  3. Direct uptake in Peyer's patches by M cells.

The first myth being the enteric barrier. This can be prevented if the vaccine is in solid capsule form, with a pH-sensitive polymeric veneering, are insoluble and impermeable and protect antigens at acidic pH in the gastric mucosa (“vulnerable at pH values above 5–5·5”), after having transported unchanged into the small intestine, wherein they dissolve at alkaline pH.[16] The absorbed antigen liquifies in the gut lumen; therefore, practically, vaccine in rigid form is the most stable.

The second myth is the mucus covering the intestinum.[14] It is believed to be a barrier. However, Peyer's patches comprise “very few goblet cells, so mucin secretion is almost negligible.” Therefore, easy diffusion across a thick mucus layer is impossible. A good example is the poliomyelitis vaccine, which passes unaltered to the site, following the same mechanism and allows efficient transport.

  Advantages Top

In the majority, syringe vaccines require proper storage rooms with cold temperatures to maintain their proper shelf life. Hypodermic injections cannot be self-administered and require precision techniques. Moreover, they are painful on a pinch and can induce needle phobia, especially in young individuals. Developing countries also deal with the problem of discarding the hospital waste improperly and even allow the reuse of used syringes contaminated with infected blood, which is a major safety concern.[17]

Oral vaccination eliminates all of the above problems. It provides socioeconomic benefits, especially in evolving countries. It offers the following advantages:[6],[14],[15],[16],[17],[18]

  • Syringeless
  • Cost-effective
  • Occupy little space
  • Easy transportation
  • Self-administration is possible
  • Can be done at home itself
  • Feasible booster administrations
  • Convenient mode of remote immunization
  • Can be performed by healthcare workers regardless of any professional training
  • Greater stability
  • Eliminates the possibility of contamination
  • Eliminates rigorous containment measures
  • Hasslefree waste disposal
  • Large-scale “antigen purification” is inessential in the formulation of oral vaccines since the gut mucosa is richly flourished with gut-friendly bacteria, thereby simplifying the overall issue of logistics.

  Oral Vaccine Delivery Forms Top

  • Tabs, capsules, or caplets (solid dose)
  • Liquid jet
  • Drops
  • Buccal patch or film
  • Sublingual route vaccine.

  Licensed Oral Vaccines in Clinical Use Top

Sabin procured a preventible cure for the debilitating polio infection, in the form of the foremost mucosal, i.e., OPV, which was introduced into the market in 1961. Administered in three spaced doses induces mucosal and antibody-mediated immunity.[9],[19] Oral vaccine for adenovirus has been developed, responsible for acute respiratory disease. Oral administration allows the infection to occur and is retained in the lower abdominal section while sparing the immune upper respiratory component.[6]

The oral vaccines available currently on the market have been listed in [Table 1].[14] Ignoring the fact that there are numerous challenges regarding oral immunization, the presence of existing ones has made oral immunization a sizable goal for future infections and diseases.
Table 1: Oral vaccines in clinical use. (This table is not intended to be a comprehensive list.)

Click here to view

  Oral Vaccination Against Respiratory Infections Top

Developing countries witness epidemics of many infectious diseases, which occur annually and are responsible for wiping a great part of a healthy population.[17]

Various in vitro and experimental studies on animal models have been conducted against various infections with promising results of oral immunization. Oral administration of the adenovirus vaccine has shown protection in mice from infectious viruses.[17] Literature reveals a study done on potential nasal, oral and sublingual vaccines against bacterial respiratory pathogens like Streptococcus pneumoniae, Haemophilus influenzae, Mycobacterium tuberculosis, etc.[20]

Several clinical trials have been conducted which exhibit immunogenic properties and negligible side effects regarding oral vaccines. Liebowitz et al.[21] conducted a “clinical trial to establish the safety and immunogenicity of an influenza H1N1 vaccine when delivered orally by tablets.” It was well tolerated by the study participants and elicited humoral responses in them. Peters et al.[22] also conducted a human trial for “orally delivered avian influenza vaccine in the form of capsules.” The study demonstrated that an orally delivered vaccine can induce immune responses to antigenic factors safely. Teo et al.[23] in their meta-analysis review talk about the assessment of the effectiveness of the “oral H. influenzae vaccine in patients suffering from recurrent episodes of chronic bronchial infection.”

The 2009 H1N1 influenza virus pandemic persuaded the vaccine scientists to switch their production pipelines quickly from seasonal to pandemic vaccines by changing the basic intricate design.[24] Currently, we are facing a new challenge because there are no existing vaccines for human use or preexisting immunity against coronavirus.

  Oral Vaccination Against Coronaviruses Top

The coronavirus structural proteins have shown to be highly immunogenic and can produce neutralizing humoral responses against infections caused by the corresponding analogs when introduced into animals.

Yuen et al.[25] carried out a successful experimental study on “oral mucosal DNA-based vaccine for SARS-CoV infections in mice models.”

  Current Status on Vaccine Development Against SARS-COV2 Top

Speaking of the current position for the SARS-CoV2 vaccine, many renowned pharmaceutical companies all over the world, have battled to come up with an effective and secure vaccine to be made available for general public use as soon as possible. After gaining global approval for vaccine development, COVID-19 has become the 28th preventable human viral infection. Understanding the time frame, it is not easy to generate a vaccine. This is usually followed by two critical steps that are typically needed before introducing a vaccine into clinical trials:

First, the vaccine is tested in suitable animal models to ensure a safety profile. However, this virus does not grow in mice and transgenic animals, which are standard animals for experimental laboratory tests. Few potential animal models include other mammals, for which pathogenicity studies are ongoing. Second, vaccines need to undergo toxicological assessment in animals, e.g., in rabbits. The time duration for which is typical is 3–6 months. For some vaccine platforms, where lies an emergency, part of the safety testing might be skipped and are considered if already sufficient data is available.[10]

We know from previous studies done on different coronavirus strains that the “S protein present on the surface of the virus is an ideal target for a vaccine.”[4] This glycoprotein facilitates the entry of the virus into the healthy host cell. Being the most crucial immunogenic agent makes it a prospective corrival for a vaccine.[4] Studies conducted by Lan et al.[26] and Wrapp et al.,[27] justify the above very clearly. We are still in infancy to understand the efficacious outcome of developed COVID-19 vaccines in their entirety. [Table 2]. summarises the currently developed vaccines against SARS-COV2.[28],[29]
Table 2: Currently existing global COVID-19 vaccines (non-oral route)

Click here to view

In consonance with the latest reports, a “US-based biotech firm Avalon Globo Care in collaboration with an Austrian university, which specializes in the study of life sciences” has aimed to develop a vaccine against COVID-19, purposefully for intranasal or oral administration. They noted that the vaccine candidate shares similar structural properties with the viral protein and is said to facilitate ease of manufacturing and delivery. The concept of this vaccine is expected to both decrease the severity of the infection observed in serious COVID-19 patients and also build immunity against the virus.

Chumakov et al.,[30] a small international team of researchers, are deliberating over the fact that OPV is tested to see if it might help against SARS-CoV2.

It would probably take weeks to vaccinate a large proportion of the population. Having said that, the population is currently naive to this type of coronavirus; therefore, it is highly likely that multiple vaccine doses will be required. Booster dose regimens are typically used in such unprecedented cases, and the time interval between two doses is usually kept 3 and 4 weeks apart. Acquired protective immunity is likely to be achieved within 1–2 weeks after the second vaccination. This adds a few more weeks to the existing timeline. Even if a continuous effort is applieswd, it is unlikely to have a fully efficacious vaccine ready 6 months post the initiation of clinical trials. Therefore, realistically speaking, it is nearly impossible to achieve a completely potent SARS-CoV2 vaccine for yet another 2–3 years, keeping in mind the above aspects and the actual time duration of 5–15 years required in vaccine fabrication.[10],[28] This provides a long-time frame for oral immunization against SARS-CoV2 to be worked upon.

  Future Challenges and Potential Top

Oral vaccines against Rotavirus, V. cholerae and E. Coli have been found to be less effective in developing countries, ascribed to the differences in nutritional status, natural/maternal antibodies, poor sanitation and gut microflora alterations.[18] A number of vitamins (A, B complex, folate, C, D and E) and trace elements (zinc, copper, selenium, iron) have been demonstrated to play key roles in supporting the human immune system and reducing risk of infections.[31] Gut dysbiosis associated with malnutrition, vitamin A or zinc deficiency, and malabsorption of nutrients has been described as a feature in COVID-19. This may all result in diminished mucosal immunity in response to oral vaccination. However, it is important to note that there are no published nutrition based studies in the context of SARS-CoV2.

However, with recent revolutionization newer generation oral vaccines are expected to comply with high safety, stability, and immunogenicity standards and must generate protective and therapeutic immune responses. The simplified production, storage, and administration method for oral vaccination might preferentially favor it over conventional needle methods during pandemic situations.[32] An effective SARS-CoV-2 vaccine will need to overcome these issues and ensure protection in a scenario of recurrent seasonal epidemics caused by an endemic virus. This promises light at the end of the tunnel.

  Conclusion Top

In the last few decades, syringeless mucosal vaccines have been introduced to enhance the well-being of healthcare workers and the population in general, following apprehensions regarding rampant epidemics and insurgency. Already there are successful oral vaccines available in the market. We need noninvasive immunization methods for every infection possible to be at the forefront. Vaccine delivery via the oral cavity seems to be a promising nonintrusive immunization method that helps invigorate immunity at the mucosal surfaces. The world will continue to witness a surge in the occurrence of mutating novel viruses. Understandably, scientists are still studying this novel coronavirus; however, the multidimensional aspect of science always gives a ray of hope. Therefore, we can anticipate a prospective positive role of oral immunization in fighting against SARS-CoV2 infection and other respiratory pathogens too. Regarding SARS-CoV2, there might be a delay in vaccines available for human use in mass, especially after this first wave of this pandemic. However, hopes are still high, they might turn out to be useful in a postpandemic scenario or if upcoming waves are anticipated by the scientists, as SARS-CoV2 continues to have a seasonal course.

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Conflicts of interest

There are no conflicts of interest.


This material has never been published and is not currently under evaluation in any other peer-reviewed publication.

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  [Table 1], [Table 2]


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