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      Live Bacterial Vectors—A Promising DNA Vaccine Delivery System

      review-article
      Medical Sciences
      MDPI
      lactic acid bacteria, antigen expression, oral delivery, carrier

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          Abstract

          Vaccination is one of the most successful immunology applications that has considerably improved human health. The DNA vaccine is a new vaccine being developed since the early 1990s. Although the DNA vaccine is promising, no human DNA vaccine has been approved to date. The main problem facing DNA vaccine efficacy is the lack of a DNA vaccine delivery system. Several studies explored this limitation. One of the best DNA vaccine delivery systems uses a live bacterial vector as the carrier. The live bacterial vector induces a robust immune response due to its natural characteristics that are recognized by the immune system. Moreover, the route of administration used by the live bacterial vector is through the mucosal route that beneficially induces both mucosal and systemic immune responses. The mucosal route is not invasive, making the vaccine easy to administer, increasing the patient’s acceptance. Lactic acid bacterium is one of the most promising bacteria used as a live bacterial vector. However, some other attenuated pathogenic bacteria, such as Salmonella spp. and Shigella spp., have been used as DNA vaccine carriers. Numerous studies showed that live bacterial vectors are a promising candidate to deliver DNA vaccines.

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          Most cited references80

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          Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial.

          Despite preventive vaccines for oncogenic human papillomaviruses (HPVs), cervical intraepithelial neoplasia (CIN) is common, and current treatments are ablative and can lead to long-term reproductive morbidity. We assessed whether VGX-3100, synthetic plasmids targeting HPV-16 and HPV-18 E6 and E7 proteins, delivered by electroporation, would cause histopathological regression in women with CIN2/3.
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            A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease.

            The use of living, genetically modified bacteria is an effective approach for topical delivery of immunomodulatory proteins. This strategy circumvents systemic side effects and allows long-term treatment of chronic diseases. However, treatment of patients with a living, genetically modified bacterium raises questions about the safety for human subjects per se and the biologic containment of the transgene. We treated Crohn's disease patients with genetically modified Lactococcus lactis (LL-Thy12) in which the thymidylate synthase gene was replaced with a synthetic sequence encoding mature human interleukin-10. Ten patients were included in a placebo-uncontrolled trial. Patients were assessed daily for the presence of potential adverse effects by direct questioning and assessment of disease activity. We evaluated the presence and kinetics of LL-Thy12 release in the stool of patients by conventional culturing and quantitative polymerase chain reaction of LL-Thy12 gene sequences. Treatment with LL-Thy12 was safe because only minor adverse events were present, and a decrease in disease activity was observed. Moreover, fecally recovered LL-Thy12 bacteria were dependent on thymidine for growth and interleukin-10 production, indicating that the containment strategy was effective. Here we show that the use of genetically modified bacteria for mucosal delivery of proteins is a feasible strategy in human beings. This novel strategy avoids systemic side effects and is biologically contained; therefore it is suitable as maintenance treatment for chronic intestinal disease.
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              Nanoparticle conjugation of CpG enhances adjuvancy for cellular immunity and memory recall at low dose.

              In subunit vaccines, strong CD8(+) T-cell responses are desired, yet they are elusive at reasonable adjuvant doses. We show that targeting adjuvant to the lymph node (LN) via ultrasmall polymeric nanoparticles (NPs), which rapidly drain to the LN after intradermal injection, greatly enhances adjuvant efficacy at low doses. Coupling CpG-B or CpG-C oligonucleotides to NPs led to better dual-targeting of adjuvant and antigen (codelivered on separate NPs) in cross-presenting dendritic cells compared with free adjuvant. This led to enhanced dendritic cell maturation and T helper 1 (Th1)-cytokine secretion, in turn driving stronger effector CD8(+) T-cell activation with enhanced cytolytic profiles and, importantly, more powerful memory recall. With only 4 μg CpG, NP-CpG-B could substantially protect mice from syngeneic tumor challenge, even after 4 mo of vaccination, compared with free CpG-B. Together, these results show that nanocarriers can enhance vaccine efficacy at a low adjuvant dose for inducing potent and long-lived cellular immunity.
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                Author and article information

                Journal
                Med Sci (Basel)
                Med Sci (Basel)
                medsci
                Medical Sciences
                MDPI
                2076-3271
                23 March 2018
                June 2018
                : 6
                : 2
                : 27
                Affiliations
                Department of Pharmacy, Medical Faculty, Universitas Brawijaya, East Java 65145, Malang, Indonesia; v_yurina@ 123456ub.ac.id ; Tel.: +62-341-569-117
                Article
                medsci-06-00027
                10.3390/medsci6020027
                6024733
                29570602
                e024a64e-dc97-4191-a62c-f8c96945a94a
                © 2018 by the author.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 24 January 2018
                : 19 March 2018
                Categories
                Review

                lactic acid bacteria,antigen expression,oral delivery,carrier

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