Citation: Aguilar, J.C.; Aguiar, J.A.; Akbar, S.M.F. Action Mechanisms and Scientific Rationale of Using Nasal Vaccine (HeberNasvac) for the Treatment of Chronic Hepatitis B. Vaccines 2022, 10, 2087. https:// doi.org/10.3390/vaccines10122087 Academic Editor: Yee-Joo Tan Received: 12 November 2022 Accepted: 5 December 2022 Published: 7 December 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. 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 (https:// creativecommons.org/licenses/by/ 4.0/). Review Action Mechanisms and Scientific Rationale of Using Nasal Vaccine (HeberNasvac) for the Treatment of Chronic Hepatitis B Julio Cesar Aguilar 1, *, Jorge Agustin Aguiar 1 and Sheikh Mohammad Fazle Akbar 2 1 Hepatitis B Therapeutic Vaccine Project, Center for Genetic Engineering and Biotechnology, La Habana 10600, Cuba 2 Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama 791-0295, Japan * Correspondence: julio.aguilar@cigb.edu.cu; Tel.: +53-53573176 Abstract: Nasvac (HeberNasvac ® ) is a novel therapeutic vaccine for chronic hepatitis B (CHB). This product is a formulation of the core (HBcAg) and surface (HBsAg) antigens of the hepatitis B virus (HBV), administered by nasal and subcutaneous routes, in a distinctive schedule of immunizations. In the present review article, we discuss the action mechanisms of HeberNasvac, considering the immunological properties of the product and their antigens. Specifically, we discuss the capacity of HBcAg to activate different pathways of innate immunity and the signal transduction after a multi-TLR agonist effect, and we review the results of recent clinical trials and in vitro studies. Aimed at understanding the clinical results of Nasvac and other therapeutic vaccines under development, we discuss the rationale of administering a therapeutic vaccine through the nasal route and also the current alternatives to combine therapeutic vaccines and antivirals (NUCs). We also disclose potential applications of this product in novel fields of immunotherapy. Keywords: HeberNasvac; chronic hepatitis B; therapeutic vaccine; innate immunity; acute respiratory infections 1. Introduction Hepatitis B virus (HBV) is a non-cytopathic, hepatotropic virus, able to induce a per- sistent infection, which might lead to acute and chronic diseases. The HBV genome consists of a small DNA genome, which is a partially double-stranded and relaxed circular DNA (rcDNA) molecule. The HBV attacks the liver and can cause both acute and chronic disease. The WHO estimates that 296 million people were living with chronic hepatitis B (CHB) infection in 2019, with 1.5 million new infections each year. In 2019, hepatitis B resulted in an estimated 820,000 deaths, mostly from cirrhosis and hepatocellular carcinoma [1], 30.4 million people (10.5% of all people estimated to be living with hepatitis B) were aware of their infection, and 6.6 million (22%) were on treatment [1]. Two types of products have been approved for CHB treatment: Peginterferon (PEG-IFN), with antiviral and immune modulatory properties and nucleoside/nucleotide analogs (NUCs), direct inhibitors of the reverse transcriptase enzyme interfering in viral replication. These drugs have poor efficacy in terms of sustained post-treatment viral suppression and generate important secondary effects during and after therapy. Although these products have been studied in combination, at present, the coadministration is not recommended [2]. The treatment of CHB requires the commitment of patients and a solid healthcare system. Apart from product expenses and limitations, additional costs are required to study HBV DNA levels during 3 to 6 months, as well as biochemical, serological, and histological characterizations of patients are needed for treatment decision. Periodical evaluation on therapy further complicates the follow-up of patients, especially in the case of PEG-IFN due to multiple adverse reactions [2]. Consequently, inexpensive, non-reactogenic, finite, and liver-protecting therapies are desirable qualities for novel and competitive products. Vaccines 2022, 10, 2087. https://doi.org/10.3390/vaccines10122087 https://www.mdpi.com/journal/vaccines