Recent development of oral vaccines (Review).

Oral immunization can elicit an effective immune response and immune tolerance to specific antigens. When compared with the traditional injection route, delivering antigens via the gastrointestinal mucosa offers superior immune effects and compliance, as well as simplicity and convenience, making it a more optimal route for immunization. At present, various oral vaccine delivery systems exist. Certain modified bacteria, such as Salmonella, Escherichia coli and particularly Lactobacillus, are considered promising carriers for oral vaccines. These carriers can significantly enhance immunization efficiency by actively replicating in the intestinal tract following oral administration. The present review provided a discussion of the main mechanisms of oral immunity and the research progress made in the field of oral vaccines. Additionally, it introduced the advantages and disadvantages of the currently more commonly administered injectable COVID-19 vaccines, alongside the latest advancements in this area. Furthermore, recent developments in oral vaccines are summarized, and their potential benefits and side effects are discussed.

Oral Vaccines: A Better Future of Immunization.

Oral vaccines are gaining more attention due to their ease of administration, lower invasiveness, generally greater safety, and lower cost than injectable vaccines. This review introduces certified oral vaccines for adenovirus, recombinant protein-based, and transgenic plant-based oral vaccines, and their mechanisms for inducing an immune response. Procedures for regulatory approval and clinical trials of injectable and oral vaccines are also covered. Challenges such as instability and reduced efficacy in low-income countries associated with oral vaccines are discussed, as well as recent developments, such as Bacillus-subtilis-based and nanoparticle-based delivery systems that have the potential to improve the effectiveness of oral vaccines.

Retraction: Sung et al. Expression of SARS-CoV-2 Spike Protein Receptor Binding Domain on Recombinant B. subtilis on Spore Surface: A Potential COVID-19 Oral Vaccine Candidate. Vaccines 2022, 10, 2.

The journal retracts the article "Expression of SARS-CoV-2 Spike Protein Receptor Binding Domain on Recombinant B. subtilis on Spore Surface: A Potential COVID-19 Oral Vaccine Candidate"[...].

Safety and Immunogenicity of Inactivated Bacillus subtilis Spores as a Heterologous Antibody Booster for COVID-19 Vaccines.

The coronavirus diseases 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have threatened the world for more than 2 years. Multiple vaccine candidates have been developed and approved for emergency use by specific markets, but multiple doses are required to maintain the antibody level. Preliminary safety and immunogenicity data about an oral dose vaccine candidate using recombinant Bacillus subtilis in healthy adults were reported previously from an investigator-initiated trial in Hong Kong. Additional data are required in order to demonstrate the safety and efficacy of the candidate as a heterologous booster in vaccinated recipients. In an ongoing, placebo-controlled, observer-blinded, fixed dose, investigator-initiated trial conducted in the Macau, we randomly assigned healthy adults, 21 to 62 years of age to receive either placebo or a Bacillus subtilis oral dose vaccine candidate, which expressed the spike protein receptor binding domain of SARS-CoV-2 on the spore surface. The primary outcome was safety (e.g., local and systemic reactions and adverse events); immunogenicity was a secondary outcome. For both the active vaccine and placebo, participants received three courses in three consecutive days. A total of 16 participants underwent randomization: 9 participants received vaccine and 7 received placebo. No observable local or systemic side-effect was reported. In both younger and older adults receiving placebo, the neutralizing antibody levels were gradually declining, whereas the participants receiving the antibody booster showed an increase in neutralizing antibody level.

Expression of SARS-CoV-2 Spike Protein Receptor Binding Domain on Recombinant B. subtilis on Spore Surface: A Potential COVID-19 Oral Vaccine Candidate.

Various types of vaccines, such as mRNA, adenovirus, and inactivated virus by injection, have been developed to prevent SARS-CoV-2 infection. Although some of them have already been approved under the COVID-19 pandemic, various drawbacks, including severe side effects and the requirement for sub-zero temperature storage, may hinder their applications. Bacillus subtilis (B. subtilis) is generally recognized as a safe and endotoxin-free Gram-positive bacterium that has been extensively employed as a host for the expression of recombinant proteins. Its dormant spores are extraordinarily resistant to the harsh environment in the gastrointestinal tract. This feature makes it an ideal carrier for oral administration in resisting this acidic environment and for release in the intestine. In this study, an engineered B. subtilis spore expressing the SARS-CoV-2 spike protein receptor binding domain (sRBD) on the spore surface was developed. In a pilot test, no adverse health event was observed in either mice or healthy human volunteers after three oral courses of B. subtilis spores. Significant increases in neutralizing antibody against sRBD, in both mice and human volunteers, after oral administration were also found. These findings may enable the further clinical developments of B. subtilis spores as an oral vaccine candidate against COVID-19 in the future.

The First Approved Gene Therapy Product for Cancer Ad-p53 (Gendicine): 12 Years in the Clinic.

Gendicine (recombinant human p53 adenovirus), developed by Shenzhen SiBiono GeneTech Co. Ltd., was approved in 2003 by the China Food and Drug Administration (CFDA) as a first-in-class gene therapy product to treat head and neck cancer, and entered the commercial market in 2004. Gendicine is a biological therapy that is delivered via minimally invasive intratumoral injection, as well as by intracavity or intravascular infusion. The wild-type (wt) p53 protein expressed by Gendicine-transduced cells is a tumor suppressor that is activated by cellular stress, and mediates cell-cycle arrest and DNA repair, or induces apoptosis, senescence, and/or autophagy, depending upon cellular stress conditions. Based on 12 years of commercial use in >30,000 patients, and >30 published clinical studies, Gendicine has exhibited an exemplary safety record, and when combined with chemotherapy and radiotherapy has demonstrated significantly higher response rates than for standard therapies alone. In addition to head and neck cancer, Gendicine has been successfully applied to treat various other cancer types and different stages of disease. Thirteen published studies that include long-term survival data showed that Gendicine combination regimens yield progression-free survival times that are significantly longer than standard therapies alone. Although the p53 gene is mutated in >50% of all human cancers, p53 mutation status did not significantly influence efficacy outcomes and long-term survival rate for Ad-p53-treated patients. To date, Shenzhen SiBiono GeneTech has manufactured 41 batches of Gendicine in compliance with CFDA QC/QA requirements, and 169,571 vials (1.0 × 1012 vector particles per vial) have been used to treat patients. No serious adverse events have been reported, except for vector-associated transient fever, which occurred in 50-60% of patients and persisted for only a few hours. The manufacturing accomplishments and clinical experience with Gendicine, as well as the understanding of its cellular mechanisms of action and implications, could provide valuable insights for the international gene therapy community and add valuable data to promote further developments and advancements in the gene therapy field.

Evaluation of oral immunization with recombinant avian influenza virus HA1 displayed on the Lactococcus lactis surface and combined with the mucosal adjuvant cholera toxin subunit B.

The development of safe and efficient avian influenza vaccines for human and animal uses is essential for preventing virulent outbreaks and pandemics worldwide. In this study, we constructed a recombinant (pgsA-HA1 gene fusion) Lactococcus lactis strain that expresses and displays the avian influenza virus HA1 antigens on its surface. The vectors were administered by oral delivery with or without the addition of cholera toxin subunit B (CTB). The resulting immune responses were analyzed, and the mice were eventually challenged with lethal doses of H5N1 viruses. Significant titers of hemagglutinin (HA)-specific serum IgG and fecal IgA were detected in the group that also received CTB. Cellular immunities were also shown in both cell proliferation and gamma interferon (IFN-γ) enzyme-linked immunospot (ELISpot) assays. Most importantly, the mice that received the L. lactis pgsA-HA1 strain combined with CTB were completely protected from lethal challenge of the H5N1 virus. These findings support the further development of L. lactis-based avian influenza virus vaccines for human and animal uses.

Immunoprotection against influenza H5N1 virus by oral administration of enteric-coated recombinant Lactococcus lactis mini-capsules.

Edible vaccines that can be made widely available and easily administered could bring great benefit to the worldwide battle against pandemic viral infections. They can be used not only for the vaccination of humans and domesticated animals, but also for wild herds and live stock which are otherwise difficult to vaccinate. In this study, we report the development of an edible mini-capsule form of live, non-persisting, recombinant Lactococcus lactis (L. lactis) vaccine against the highly virulent influenza H5N1 strain. Recombinant L. lactis-based H5N1 HA antigen expression constructs were made and shown to be able to induce higher levels of HA-specific serum IgG and fecal IgA antibody production after oral administration. The vectors were then formulated into a mini-capsule dosage form and fed to mouse. Four doses of oral administration rendered complete protection of the mouse against lethal challenges of H5N1 virus.

Non-mitogenic human acidic fibroblast growth factor reduces retinal degeneration induced by sodium iodate.

PURPOSE: To investigate the protective effects of non-mitogenic human acidic fibroblast growth factor on retinal degeneration induced by NaIO(3) in rats. METHODS: Retinal degeneration was induced in adult male Wistar rats via caudal-vein injection of 1% NaIO(3) at 50 mg/kg. One h after NaIO(3) treatment, the right eyes received intravitreal injection of 2.5 microg nm-haFGF in 10 microL saline and the left eyes received saline alone as vehicle-treated eyes. Retinal function in rats was evaluated by electroretinogram (ERG) before injection and 1, 7, and 21 days postinjection. Additional rat eyes were enucleated 7 and 21 days postinjection, fixed, and processed for histological examination. RESULTS: A model of retinal degeneration in rat was established successfully using NaIO(3) injection. Significant decreases in both ERG a- and b-wave amplitudes were detected in NaIO(3)-injected rats when compared with the normal animals (P < 0.05) on day 7 postinjection. Importantly, at the seventh day after intravitreal nm-haFGF treatment on NaIO(3)-injected rats, the nm-haFGF-treated eyes showed a significant improvement in the ERG amplitudes of both a- and b-waves when compared with vehicle-treated eyes (P < 0.05). In addition, the disruptions of photoreceptor outer segments and the retinal pigment epithelium monolayer were much less frequently observed in the nm-haFGF-treated eyes than the vehicle-treated eyes, and the outer nuclear layer thickness in the nm-haFGF-treated eyes was similar to that of the normal eyes. CONCLUSIONS: Intravitreal delivery of nm-haFGF appears to have neuroprotective effect on retinal degeneration induced by NaIO(3).