Potential approaches to combat COVID-19: a mini-review.

The outbreak of a novel coronavirus namely SARS-CoV-2, which first emerged from Wuhan, China, has wreaked havoc not only in China but the whole world that now has been engulfed in its wrath. In a short lapse of time, this virus was successful in spreading at a blistering pace throughout the globe, hence raising the flag of pandemic status. The mounting number of deaths with each elapsing day has summoned researchers from all around the world to play their part in driving this SARS-CoV-2 pandemic to an end. As of now, multiple research teams are immersed in either scrutinizing various antiviral drugs for their efficacy or developing different types of vaccines that will be capable of providing long-term immunity against this deadly virus. The mini-review sheds light on the possible approaches that can be undertaken to curb the COVID-19 spread. Possible strategies comprise viral vector-based, nucleic acid-based, protein-based, inactivated and weakened virus vaccines; COVID-19 vaccine being developed by deploying Hyleukin-7 technology; plant-based chimeric protein and subunit vaccines; humanized nano-bodies and human antibodies; intravenous immunoglobulin (IVIG) infusion therapy; inhibitors for ACE-2, Angiotensin 1 receptor (AT1R), complement system, viral proteins, host cell protease and endocytosis; shield immunity; IL-6R, NKG2A and hACE2-SARS-CoV-2-RBD interaction blocking monoclonal antibodies; SARS-CoV RdRp-based drugs, traditional Chinese medicine, repositioned and anti-viral drugs. These vaccines and drugs are currently being screened in the clinical trials as several of them have manifested positive results, hence increasing the probability of becoming one of the potential treatments for this disease.

Nanomedicine as a promising approach for diagnosis, treatment and prophylaxis against COVID-19.

The COVID-19 pandemic caused by the newly emerged severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) puts the world in an unprecedented crisis, leaving behind huge human losses and deep socioeconomic damages. Due to the lack of specific treatment against SARS-CoV-2, effective vaccines and antiviral agents are urgently needed to properly restrain the COVID-19 pandemic. Repositioned drugs such as remdesivir have revealed a promising clinical efficacy against COVID-19. Interestingly, nanomedicine as a promising therapeutic approach could effectively help win the battle between coronaviruses (CoVs) and host cells. This review discusses the potential therapeutic approaches, in addition to the contribution of nanomedicine against CoVs in the fields of vaccination, diagnosis and therapy.

Potential Repurposed Therapeutics and New Vaccines against COVID-19 and Their Clinical Status.

SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), was first reported in Wuhan, China, in December 2019. Since then, the virus has stretched its grip to almost all the countries in the world, affecting millions of people and causing enormous casualties. The World Health Organization (WHO) declared COVID-19 a pandemic on March 11, 2019. As of June 12, 2020, almost 7.30 million people have already been infected globally, with 413,000 reported casualties. In the United States alone, 2.06 million people have been infected and 115,000 have succumbed to this pandemic. A multipronged approach has been launched toward combating this pandemic, with the main focus on exhaustive screening, developing efficacious therapies, and vaccines for long-term immunity. Several pharmaceutical companies in collaboration with various academic institutions and governmental organizations have started investigating new therapeutics and repurposing approved drugs so as to find fast and affordable treatments against this disease. The present communication is aimed at highlighting the efforts that are currently underway to treat or prevent SARS-CoV-2 infection, with details on the science, clinical status, and timeline for selected investigational drugs and vaccines. This article is going to be of immense help to the scientific community and researchers as it brings forth all the necessary clinical information of the most-talked-about therapeutics against SARS-CoV-2. All the details pertaining to the clinical status of each therapeutic candidate have been updated as of June 12, 2020.

Regulatory aspects of quality and safety for live recombinant viral vaccines against infectious diseases in Japan.

Recombinant viral vaccines expressing antigens of pathogenic microbes (e.g., HIV, Ebola virus, and malaria) have been designed to overcome the insufficient immune responses induced by the conventional vaccines. Our knowledge of and clinical experience with the new recombinant viral vaccines are insufficient, and a clear regulatory pathway is needed for the further development and evaluation of recombinant viral vaccines. In 2018, the research group supported by the Ministry of Health, Labour and Welfare, Japan (MHLW) published a concept paper to address the development of recombinant viral vaccines against infectious diseases. Herein we summarize the concept paper-which explains the Japanese regulatory concerns about recombinant viral vaccines-and provide a focus of discussion about the development of recombinant viral vaccines.

Novel approaches to preclinical research and TB vaccine development.

The 4th Global Forum on TB Vaccines, convened in Shanghai, China, from 21 - 24 April 2015, brought together a wide and diverse community involved in tuberculosis vaccine research and development to discuss the current status of, and future directions for this critical effort. This paper summarizes the sessions on Low-Dose NHP Challenge Models, Novel Approaches to Animal Models for TB Vaccine R&D, Novel Antigen Delivery Strategies, and Next Generation TB Vaccines and Vaccine Concepts. Summaries of all sessions from the 4th Global Forum are compiled in a special supplement of Tuberculosis. [August 2016, Vol 99, Supp S1, S1-S30].

Iron oxide nanoparticles as a clinically acceptable delivery platform for a recombinant blood-stage human malaria vaccine.

This study explored the novel use of iron oxide (IO) nanoparticles (<20 nm) as a vaccine delivery platform without additional adjuvants. A recombinant malaria vaccine antigen, the merozoite surface protein 1 (rMSP1), was conjugated to IO nanoparticles (rMSP1-IO). Immunizations in outbred mice with rMSP1-IO achieved 100% responsiveness with antibody titers comparable to those obtained with rMSP1 formulated with a clinically acceptable adjuvant, Montanide ISA51 (2.7×10 vs. 1.6×10; respectively). Only rMSP1-1O could induce significant levels (80%) of parasite inhibitory antibodies. The rMSP1-IO was highly stable at 4°C and was amenable to lyophilization, maintaining its antigenicity, immunogenicity, and ability to induce inhibitory antibodies. Further testing in nonhuman primates, Aotus monkeys, also elicited 100% immune responsiveness and high levels of parasite inhibitory antibodies (55-100% inhibition). No apparent local or systemic toxicity was associated with IO immunizations. Murine macrophages and dendritic cells efficiently (>90%) internalized IO nanoparticles, but only the latter were significantly activated, with elevated expression/secretion of CD86, cytokines (IL-6, TNF-α, IL1-b, IFN-γ, and IL-12), and chemokines (CXCL1, CXCL2, CCL2, CCL3, CCL4, and CXCL10). Thus, the IO nanoparticles is a novel, safe, and effective vaccine platform, with built-in adjuvancy, that is highly stable and field deployable for cost-effective vaccine delivery.

Models for evaluation of relative immunogenic potential of protein particles in biopharmaceutical protein formulations.

An immune response to a therapeutic protein that compromises the biopharmaceutical activity or cross-reacts with an endogenous protein is a serious clinical event. The role of protein aggregates and particles in biopharmaceutical formulations in mediating this immune response has gained considerable attention over the recent past. Model systems that could consistently and reliably predict the relative immunogenicity of biopharmaceutical protein formulations would be extremely valuable. Several approaches have been developed in an attempt to provide this insight, including in silico algorithms, in vitro tests utilizing human leukocytes and in vivo animal models. This commentary provides an update of these various approaches as well as the author's perspectives on the pros and cons of these different methods.

Commonly used prophylactic vaccines as an alternative for synthetically produced TLR ligands to mature monocyte-derived dendritic cells.

Currently dendritic cell (DC)-based vaccines are explored in clinical trials, predominantly in cancer patients. Murine studies showed that only maturation with Toll-like receptor (TLR) ligands generates mature DCs that produce interleukin-12 and promote optimal T-cell help. Unfortunately, the limited availability of clinical-grade TLR ligands significantly hampers the translation of these findings into DC-based vaccines. Therefore, we explored 15 commonly used preventive vaccines as a possible source of TLR ligands. We have identified a cocktail of the vaccines BCG-SSI, Influvac, and Typhim that contains TLR ligands and is capable of optimally maturing DCs. These DCs (vaccine DCs) showed high expression of CD80, CD86, and CD83 and secreted interleukin-12. Although vaccine DCs exhibited an impaired migratory capacity, this could be restored by addition of prostaglandin E(2) (PGE(2); vaccine PGE(2) DCs). Vaccine PGE(2) DCs are potent inducers of T-cell proliferation and induce Th1 polarization. In addition, vaccine PGE(2) DCs are potent inducers of tumor antigen-specific CD8(+) effector T cells. Finally, vaccine PGE(2)-induced DC maturation is compatible with different antigen-loading strategies, including RNA electroporation. These data thus identify a new clinical application for a mixture of commonly used preventive vaccines in the generation of Th1-inducing clinical-grade mature DCs.

Method for the synthesis of multi-epitopic Streptococcus pyogenes lipopeptide vaccines using native chemical ligation.

The aim of this study was to investigate methods for the synthesis of highly pure, well-characterized analogues of the lipid core peptide (LCP) system. Difficulties synthesizing and purifying conventional LCP systems have led to the requirement for a technique to produce highly pure, LCP-based vaccines for potential use in human clinical trials. The current study describes methods for the attachment of lipophilic adjuvants onto multi-epitopic peptide vaccines. Described is the synthesis, using native chemical ligation, of a highly pure, tri-epitopic, group A streptococcal (GAS) lipopeptide vaccine candidate. Intranasal immunization of the described tri-epitopic GAS lipopeptide with the mucosal adjuvant cholera toxin B subunit induced high serum IgG antibody titers specific for each of the incorporated peptide epitopes.

Eficacia comparativa de las vías intradérmica e intramuscular en la inmunización activa contra la hepatitis B: resultados a largo plazo / Comparative efficacy of intradermally and intramuscular routes for active immunization against hepatitis B: long-term results

Se presentan los resultados a largo plazo de un estudio prospectivo, comparativo y randomizado con 119 voluntarios jóvenes sero-negativos, con riesgo aumentado de infección por el VHB, que evaluó la inmunogenicidad comparativa de una vacuna recombinante contra la hepatitis B, administrada por vía intramuscular (IM) o intradérmica (ID). La vacuna fue administrada en tres dosis consecutivas, en un esquema de inmunización de corta duración de 0,1 y 2 meses. Una dosis de refuerzo fue administrada al cabo de 1 año, por la misma vía utilizada en la inmunización original. La distribución por edad y sexo en ambos grupos fue similar. Los resultados obtenidos al cabo de las tres dosis mostraron tasas de seroconversión y seroprotección similares para ambos grupos (96 por ciento y 96 por ciento para la vía IM Vs. 98 por ciento y 93 por ciento para la vía ID, respectivamente). El promedio geométrico del título de anti-HBsAg en el suero de los individuos inmunizados por vía IM (155 UI/L) fue significativamente superior al obtenido en aquellos inmunizados por vía ID (71 UI/L). Por otro lado, la tasa de buenos respondedores (niveles de anti-HBsAg >100 UI/L ) fue igualmente más elevada en los vacunados por vía IM (67 por ciento Vs. 39 por ciento). El porcentaje de buenos respondedores en las mujeres fue consistentemente superior al de los varones para ambos grupos (75 por ciento Vs. 55 por ciento vía IM y 54 por ciento Vs. 13 por ciento vía ID, respectivamente). En 82 individuos estudiados 1 años más tarde, el promedio geométrico de los niveles de anti-HBsAg fue significativamente superior en los que recibieron la vía IM (278 UI/L) en comparación con los vacunados por vía ID (82,3 UI/L) y la tasa de seroprotección fue también superior (100 por ciento Vs. 84,8 por ciento respectivamente). De la misma manera, la respuesta de anti-HBsAg sérica a la dosis de refuerzo, fue mejor en los vacunados por vía IM (promedio geométrico 5.090 UI/L) con respecto a los que recibieron la vía ID.

HIV-1 recombinant gp160 vaccine induced antibodies in serum and saliva. The NIAID AIDS Vaccine Clinical Trials Network.

As part of a phase I safety and immunogenicity trial of a vaccinia-expressed HIV-1 recombinant gp160 (rgp160) candidate vaccine, we measured serum and saliva antibody responses in low risk, uninfected volunteers. Six healthy adult volunteers received 50 micrograms doses of rgp160 vaccine adjuvanted in alum and deoxycholate at months 0, 1, 6, and 12. A 200 micrograms rgp160 immunization was given to four volunteers at 18 months. The vaccine induced anti-envelope glycoprotein IgG and IgA serum antibodies in all six volunteers. Saliva antibodies to envelope glycoprotein appeared in some volunteers at certain timepoints. Three volunteers appeared to transiently develop vaccine-induced secretory IgA antibody to envelope glycoprotein in whole saliva.

Semisynthetic anti-LHRH vaccine causing atrophy of the prostate.

A modified luteinizing hormone releasing hormone (LHRH) analog (D-lys)6 was synthesized and linked to epsilon-amino caproic acid at the 6th position. The free amino group thus generated was used for conjugation to diphtheria toxoid. Immunogenicity and bioefficacy studies of this conjugate vaccine were carried out in rodents. All immunized animals produced antibodies reactive with native LHRH. A gradual decline in testosterone levels accompanied the rise in anti-LHRH titers. On necropsy, after 10 weeks, a significant reduction in the relative weights of testes and accessory sex organs was noticed. Of particular significance was the marked atrophy of the prostate, indicating a possible therapeutic application of this vaccine in the treatment of androgen-dependent carcinoma of the prostate.