Vaccination is the most important public health measure and tool for the prevention and control of human infectious diseases. Intramuscular or subcutaneous injection is the most common vaccination method. It can induce effective systemic immunity but provides weak mucosal immunity, resulting in poor protective effects against some pathogens that infect through mucous membranes.
An ideal oral viral vaccine not only enables painless, cold chain-free, and self-administered mass vaccination quickly but, most crucially, can simultaneously induce effective mucosal and systemic immunity to achieve optimal protective effects. The development and optimization of Oral Viral Vaccines have become a research hotspot in the field of vaccinology due to their unique advantages.
01 Marketed Oral Live Attenuated Viral Vaccines
Marketed oral viral vaccines include three types of live attenuated vaccines: oral poliovirus vaccine, oral adenovirus vaccine, and oral rotavirus vaccine. These oral viral vaccines all use live attenuated pathogens. Similar to wild-type viruses, live attenuated oral viral vaccines can be transported in the gastric and intestinal environments, prevent degradation, maintain sufficient antigenicity, and trigger effective immune responses and immune protection in the gastrointestinal mucosa.
1.1 Oral Poliovirus Vaccine
The oral poliovirus vaccine (OPV) was the first successfully developed oral viral vaccine. Since 1960, the oral viral vaccine live attenuated poliovirus vaccine has been used in humans. Serum antibodies induced by OPV can prevent the spread of poliovirus to the nervous system, thereby protecting individuals from paralytic poliomyelitis.
In addition, compared with the inactivated poliovirus vaccine (IPV) administered by injection,OPV as a representative Oral Viral Vaccines generates a high level of local SIgA immune response in the intestinal mucosa, which is the main site for poliovirus entry and replication. This local intestinal mucosal response can extremely effectively block the human-to-human transmission of wild poliovirus.
Studies have shown that OPV carries an extremely low risk of neurovirulence reversion (1/2,500,000). Although this Oral Viral Vaccines has proven its excellent efficacy in inducing humoral and mucosal immunity, its safety issues still need to be comprehensively considered based on the goals of disease prevention and control. Since the global successful eradication of the disease through extensive OPV vaccination programs, the risk of acquiring the disease from wild-type pathogens is lower than that from OPV administration. Therefore, OPV has been replaced by IPV in most industrialized countries.
1.2 Oral Adenovirus Vaccine
For decades, oral replicating adenovirus (Ad) vaccines have been used by the U.S. military as Oral Viral Vaccines to prevent adenovirus type 4 and type 7 respiratory diseases in new recruits. A 1971 study on trainees showed that oral Ad4 and Ad7 serotype vaccines are safe, have no side effects, and are more than 95% effective in preventing adenovirus respiratory diseases.
The licensed oral adenovirus vaccines as Oral Viral Vaccines are encapsulated in enteric-coated tablets, allowing them to overcome degradation caused by the acidic pH of the stomach, cause asymptomatic infections in the lower intestines, and induce immunity in the upper respiratory tract. Their protective effect is associated with the presence of specific serum-neutralizing antibodies.
1.3 Oral Rotavirus Vaccine
Rotavirus is the main pathogen causing severe diarrhea in human infants and young children. Currently, six types of oral live attenuated rotavirus vaccines have been approved for marketing worldwide as Oral Viral Vaccines, playing a significant role in reducing the global disease burden of diarrhea, especially rotavirus diarrhea. These include the pentavalent rotavirus vaccine (RotaTeq) and monovalent rotavirus vaccine (Rotarix), which are widely used globally Oral Viral Vaccines, and were the first to receive World Health Organization (WHO) prequalification in 2008 and 2009, respectively. One monovalent and one pentavalent vaccine approved for use in India also obtained WHO prequalification in 2018 as Oral Viral Vaccines.
In addition, the Lanzhou monovalent lamb rotavirus vaccine (LLR) approved in China and the monovalent human rotavirus vaccine (Rotavin-M1) approved in Vietnam are regional Oral Viral Vaccines only used in their respective countries.
Although the efficacy of these oral viral vaccines varies, their efficacy in low-income countries is significantly lower than that in high-income countries.
The reasons for this difference are not fully clear but are believed to be multifactorial, including the inhibitory effect of maternally derived antibodies (rotavirus-specific IgA) acquired through the placenta or breast milk, the impact of concurrently administered oral poliovirus vaccine, the interference of different human leukocyte antigen (HLA) types, and malnutrition, environmental factors, chronic and co-infections, all of which may inhibit or interfere with the body’s immune response to rotavirus (RV) vaccines.
Recent studies have shown that the composition and diversity of the intestinal microbiota, especially bacteria, may also affect the immunogenicity of oral RV and other oral viral vaccines.
02 Investigational Oral Viral Vaccines.
2.1 Oral Vector Vaccines
Oral vector vaccines are an important category of investigational Oral Viral Vaccines, which can be mainly divided into oral non-pathogenic bacterial vector vaccines and oral viral vector vaccines, with viral vectors being the main type for oral viral vector vaccines. Intestinally infecting viruses are good candidates as antigen carriers for oral vaccines. Adenoviruses, in particular, can resist the intestinal environment and infect intestinal cells.
The principle is to insert the target antigen gene into a viral vector through recombinant DNA technology. The recombinant viral vector is packaged in vitro to form a recombinant vector virus. The recombinant vector virus infects the human body through the oral route. While replicating, the recombinant vector virus can express a large amount of the target antigen gene, thereby activating and inducing a specific immune response against the target antigen.
However, potential safety issues of live viral vectors must be taken seriously and eliminated, such as the reversion to wild-type virus that can occur with oral vaccines using poliovirus as a vector. Currently, the main investigational oral viral vectors are adenoviral vectors, and certain progress has also been made in oral vaccines using rotavirus and poliovirus as vectors.
2.2 Oral Protein Vaccines
Attempts have been made to develop oral vaccines based on protein antigens against infectious diseases such as dengue fever, influenza, tetanus, diphtheria, hepatitis, and Middle East respiratory syndrome coronavirus (MERS-CoV). However, oral protein vaccines usually have low stability and poor efficacy in inducing antibody and cellular immune responses.
To overcome these limitations, current research mainly focuses on adding adjuvants to enhance immune responses through immunostimulants or immune delivery systems. For example, polymeric microparticles and nanoparticles have been widely used in the development of protein vaccines. The chemical structure of oral protein vaccines needs to be controlled to a certain extent, so it is necessary to better utilize natural polymers to design formulations and continue to evaluate them in clinical studies.
In terms of evaluating vaccine immunogenicity and protectiveness, research has been limited to the assessment of antibody responses in humoral immunity, but cellular immune responses are also important. Further analysis of immune indicators and mechanisms related to vaccine protectiveness in this field is needed. In addition, lipid vaccine carriers, including liposomes, virosomes, and immunostimulating complexes, as well as other carriers with adjuvant functions, are also under development. Their further use and optimization will surely contribute to the production of oral protein vaccines against mucosal diseases.
2.3 Oral Nucleic Acid Vaccines
Oral nucleic acid vaccines are oral vaccines that use nucleic acids (DNA or RNA) as the source of antigens against pathogens. RNA vaccines can be further divided into two types: modified mRNA and self-replicating RNA. Investigational oral nucleic acid vaccines mainly include oral DNA vaccines and oral mRNA vaccines.
DNA and mRNA vaccines have the potential for rapid and low-cost production, thus having special significance in responding to pandemics. However, they are highly sensitive to degradation, making it difficult to achieve effective oral administration. Studies have shown that the encoded proteins of oral DNA vaccines can be expressed in intestinal epithelial cells, the spleen, mesenteric lymph nodes, etc., and can significantly stimulate systemic cellular and humoral immune responses, such as cytotoxic T cell activity and specific IgG antibody production, as well as induce specific secretory IgA (SIgA) locally in the intestinal mucosa.
Currently, the oral DNA vaccine S2-Ag85 (for brucellosis) has been proven to protect humans, and oral DNA vaccines against viruses are also under development, including those for human immunodeficiency virus (HIV), influenza, hepatitis B virus (HBV), herpes simplex virus (HSV), and human papillomavirus (HPV).
If these vaccines are successful, they may usher in a new era of treating diseases with oral DNA vaccines. To date, all approved mRNA vaccines are administered by injection, while oral mRNA vaccines are still in the early stages of research, including studies on delivering mRNA vaccines via oral capsules.
Such capsules can deliver approximately 150μg of mRNA to the stomach of pigs, a dose exceeding that of currently used injectable mRNA COVID-19 vaccines. The research team found that gastric cells in pigs successfully produced the reporter protein, but it was not detected in other organs and tissues. The team stated that they will improve the nanoparticle composition or administer higher doses in subsequent studies to increase the absorption of delivered mRNA by other organs.
The team also suggested that delivering mRNA only to the stomach may be sufficient to induce a strong immune response. This oral administration method of mRNA indicates the potential for further development of oral mRNA vaccines.
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