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1.
Vaccine ; 40(9): 1208-1212, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1757896

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in catastrophic damage worldwide. Accordingly, the development of powerful, safe, easily accessible vaccines with long-term effectiveness is understood as an urgently needed countermeasure against this ongoing pandemic. Guided by this strong promise of using AAVs, we here designed, optimized, and developed an AAV-based vaccines (including AAV-RBD(max), AAV-RBD(wt), AAV-2xRBD, and AAV-3xRBD) that elicit strong immune responses against the RBD domain of the SARS-CoV-2 S protein. These immunogenic responses have proven long-lived, with near peak levels for at least six months in mice. Notably, the sera immunized with AAV-3xRBD vaccine contains powerful neutralizing antibodies against the SARS-CoV-2 pseudovirus. Further evidence proven that potent specific antibodies could also be elicited in canines after vaccination with AAV-3xRBD vaccine.


Subject(s)
COVID-19 , Viral Vaccines , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , Dogs , Humans , Mice , Mice, Inbred BALB C , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Viral Vaccines/genetics
2.
Proc Natl Acad Sci U S A ; 119(14): e2119093119, 2022 04 05.
Article in English | MEDLINE | ID: covidwho-1751830

ABSTRACT

SignificanceUsing SARS-CoV-2 as a relevant case study for infectious disease, we investigate the structure-function relationships that dictate antiviral spherical nucleic acid (SNA) vaccine efficacy. We show that the SNA architecture can be rapidly employed to target COVID-19 through incorporation of the receptor-binding domain, and that the resulting vaccine potently activates human cells in vitro and mice in vivo. Furthermore, when challenged with a lethal viral infection, only mice treated with the SNA vaccine survived. Taken together, this work underscores the importance of rational vaccine design for infectious disease to yield vaccines that elicit more potent immune responses to effectively fight disease.


Subject(s)
Communicable Disease Control , Nucleic Acids/immunology , Vaccines, DNA/immunology , Animals , Biotechnology , COVID-19/prevention & control , Communicable Disease Control/methods , Communicable Diseases/etiology , Communicable Diseases/immunology , Humans , Nucleic Acids/chemistry , SARS-CoV-2/immunology , Vaccines, DNA/genetics , Viral Vaccines/genetics , Viral Vaccines/immunology
3.
Viruses ; 14(2)2022 02 12.
Article in English | MEDLINE | ID: covidwho-1687051

ABSTRACT

The persistent expansion of the coronavirus disease 2019 (COVID-19) global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires the rapid development of safe and effective countermeasures to reduce transmission, morbidity, and mortality. Several highly efficacious vaccines are actively being deployed around the globe to expedite mass vaccination and control of COVID-19. Notably, viral vectored vaccines (VVVs) are among the first to be approved for global distribution and use. In this review, we examine the humoral, cellular, and innate immune responses elicited by viral vectors, and the immune correlates of protection against COVID-19 in preclinical and clinical studies. We also discuss the durability and breadth of immune response induced by VVVs and boosters. Finally, we present challenges associated with VVVs and offer solutions for overcoming certain limitations of current vaccine regimens. Collectively, this review provides the rationale for expanding the portfolio of VVVs against SARS-CoV-2.


Subject(s)
COVID-19/prevention & control , Genetic Vectors/immunology , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Viral Vaccines/genetics , Viral Vaccines/immunology , Animals , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Clinical Trials as Topic , Disease Models, Animal , Immunity, Cellular , Immunity, Humoral , Immunity, Innate , Immunization, Secondary , Spike Glycoprotein, Coronavirus/genetics , Vaccination , Viral Vaccines/classification
4.
Front Immunol ; 12: 824728, 2021.
Article in English | MEDLINE | ID: covidwho-1686477

ABSTRACT

We generated an optimized COVID-19 vaccine candidate based on the modified vaccinia virus Ankara (MVA) vector expressing a full-length prefusion-stabilized SARS-CoV-2 spike (S) protein, termed MVA-CoV2-S(3P). The S(3P) protein was expressed at higher levels (2-fold) than the non-stabilized S in cells infected with the corresponding recombinant MVA viruses. One single dose of MVA-CoV2-S(3P) induced higher IgG and neutralizing antibody titers against parental SARS-CoV-2 and variants of concern than MVA-CoV2-S in wild-type C57BL/6 and in transgenic K18-hACE2 mice. In immunized C57BL/6 mice, two doses of MVA-CoV2-S or MVA-CoV2-S(3P) induced similar levels of SARS-CoV-2-specific B- and T-cell immune responses. Remarkably, a single administration of MVA-CoV2-S(3P) protected all K18-hACE2 mice from morbidity and mortality caused by SARS-CoV-2 infection, reducing SARS-CoV-2 viral loads, histopathological lesions, and levels of pro-inflammatory cytokines in the lungs. These results demonstrated that expression of a novel full-length prefusion-stabilized SARS-CoV-2 S protein by the MVA poxvirus vector enhanced immunogenicity and efficacy against SARS-CoV-2 in animal models, further supporting MVA-CoV2-S(3P) as an optimized vaccine candidate for clinical trials.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccines, DNA/immunology , Viral Vaccines/immunology , Aged , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/mortality , COVID-19 Vaccines/genetics , Cell Line, Tumor , Chick Embryo , Chlorocebus aethiops , Cytokines/analysis , Female , HeLa Cells , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Plasmids/genetics , Spike Glycoprotein, Coronavirus/genetics , Vaccines, DNA/genetics , Vaccinia virus/immunology , Vero Cells , Viral Vaccines/genetics
6.
J Microbiol ; 60(3): 238-246, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1652456

ABSTRACT

Middle East Respiratory Syndrome coronavirus (MERS-CoV), a contagious zoonotic virus, causes severe respiratory infection with a case fatality rate of approximately 35% in humans. Intermittent sporadic cases in communities and healthcare facility outbreaks have continued to occur since its first identification in 2012. The World Health Organization has declared MERS-CoV a priority pathogen for worldwide research and vaccine development due to its epidemic potential and the insufficient countermeasures available. The Coalition for Epidemic Preparedness Innovations is supporting vaccine development against emerging diseases, including MERS-CoV, based on platform technologies using DNA, mRNA, viral vector, and protein subunit vaccines. In this paper, we review the usefulness and structure of a spike glycoprotein as a MERS-CoV vaccine candidate molecule, and provide an update on the status of MERS-CoV vaccine development. Vaccine candidates based on both DNA and viral vectors coding MERS-CoV spike gene have completed early phase clinical trials. A harmonized approach is required to assess the immunogenicity of various candidate vaccine platforms. Platform technologies accelerated COVID-19 vaccine development and can also be applied to developing vaccines against other emerging viral diseases.


Subject(s)
COVID-19 , Middle East Respiratory Syndrome Coronavirus , Viral Vaccines , Antibodies, Viral , COVID-19 Vaccines , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Viral Vaccines/genetics
7.
Methods Mol Biol ; 2410: 229-263, 2022.
Article in English | MEDLINE | ID: covidwho-1575944

ABSTRACT

Vaccines are one of mankind's greatest medical advances, and their use has drastically reduced and in some cases eliminated (e.g., smallpox) disease and death caused by infectious agents. Traditional vaccine modalities including live-attenuated pathogen vaccines, wholly inactivated pathogen vaccines, and protein-based pathogen subunit vaccines have successfully been used to create efficacious vaccines against measles, mumps, rubella, polio, and yellow fever. These traditional vaccine modalities, however, take many months to years to develop and have thus proven less effective for use in creating vaccines to emerging or reemerging infectious diseases (EIDs) including influenza, Human immunodeficiency virus (HIV), dengue virus (DENV), chikungunya virus (CHIKV), West Nile virus (WNV), Middle East respiratory syndrome (MERS), and the severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV and SARS-CoV-2). As factors such as climate change and increased globalization continue to increase the pace of EID development, newer vaccine modalities are required to develop vaccines that can prevent or attenuate EID outbreaks throughout the world. One such modality, DNA vaccines, has been studied for over 30 years and has numerous qualities that make them ideal for meeting the challenge of EIDs including; (1) DNA vaccine candidates can be designed within hours of publishing of a pathogens genetic sequence; (2) they can be manufactured cheaply and rapidly in large quantities; (3) they are thermostable and have reduced requirement for a cold-chain during distribution, and (4) they have a remarkable safety record in the clinic. Optimizations made in plasmid design as well as in DNA vaccine delivery have greatly improved the immunogenicity of these vaccines. Here we describe the process of making a DNA vaccine to an EID pathogen and describe methods used for assessing the immunogenicity and protective efficacy of DNA vaccines in small animal models.


Subject(s)
Communicable Diseases, Emerging , Vaccines, DNA , Viral Vaccines , Animals , COVID-19 , Communicable Diseases, Emerging/prevention & control , Humans , Immunity , SARS Virus , SARS-CoV-2 , Vaccines, Attenuated/immunology , Vaccines, DNA/immunology , Vaccines, Inactivated/immunology , Vaccines, Synthetic/immunology , Viral Vaccines/genetics , Viral Vaccines/immunology
8.
Methods Mol Biol ; 2410: 111-129, 2022.
Article in English | MEDLINE | ID: covidwho-1575756

ABSTRACT

Infectious diseases are a leading cause of death worldwide, and vaccines are the cheapest and efficient approach to preventing diseases. Use of conventional vaccination strategies such as live, attenuated, and subunit has limitations as it does not fully provide protection against many infectious diseases. Hence, there was a need for the development of a new vaccination strategy. Use of nucleic acids-DNA and RNA-has emerged as promising alternative to conventional vaccine approaches. Knowledge of mRNA biology, chemistry, and delivery systems in recent years have enabled mRNA to become a promising vaccine candidate. One of the advantages of a mRNA vaccine is that clinical batches can be generated after the availability of a sequence encoding the immunogen. The process is cell-free and scalable. mRNA is a noninfectious, nonintegrating molecule and there is no potential risk of infection or mutagenesis. mRNA is degraded by normal cellular processes, and its in vivo half-life can be regulated by different modifications and delivery methods. The efficacy can be increased by modifications of the nucleosides that can make mRNA more stable and highly translatable. Efficient in vivo delivery can be achieved by formulating mRNA into carrier molecules, allowing rapid uptake and expression in the cytoplasm. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The spike (S) glycoprotein mediates host cell attachment and is required for viral entry; it is the primary vaccine target for many candidate SARS-CoV-2 vaccines. Development of a lipid nanoparticle encapsulated mRNA vaccine that encodes the SARS-CoV-2 S glycoprotein stabilized in its prefusion conformation conferred 95% protection against Covid-19.


Subject(s)
Viral Vaccines , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Liposomes , Nanoparticles , Spike Glycoprotein, Coronavirus , Viral Vaccines/genetics
9.
Biotechnol Lett ; 44(1): 45-57, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1536319

ABSTRACT

After its emergence in late 2019 SARS-CoV-2 was declared a pandemic by the World Health Organization on 11 March 2020 and has claimed more than 2.8 million lives. There has been a massive global effort to develop vaccines against SARS-CoV-2 and the rapid and low cost production of large quantities of vaccine is urgently needed to ensure adequate supply to both developed and developing countries. Virus-like particles (VLPs) are composed of viral antigens that self-assemble into structures that mimic the structure of native viruses but lack the viral genome. Thus they are not only a safer alternative to attenuated or inactivated vaccines but are also able to induce potent cellular and humoral immune responses and can be manufactured recombinantly in expression systems that do not require viral replication. VLPs have successfully been produced in bacteria, yeast, insect and mammalian cell cultures, each production platform with its own advantages and limitations. Plants offer a number of advantages in one production platform, including proper eukaryotic protein modification and assembly, increased safety, low cost, high scalability as well as rapid production speed, a critical factor needed to control outbreaks of potential pandemics. Plant-based VLP-based viral vaccines currently in clinical trials include, amongst others, Hepatitis B virus, Influenza virus and SARS-CoV-2 vaccines. Here we discuss the importance of plants as a next generation expression system for the fast, scalable and low cost production of VLP-based vaccines.


Subject(s)
COVID-19 Vaccines/biosynthesis , Plants, Genetically Modified/metabolism , SARS-CoV-2/immunology , Vaccines, Virus-Like Particle/biosynthesis , Antigens, Viral/genetics , Antigens, Viral/metabolism , COVID-19 Vaccines/economics , COVID-19 Vaccines/genetics , Gene Expression , Plants, Genetically Modified/genetics , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Vaccines, Virus-Like Particle/economics , Vaccines, Virus-Like Particle/genetics , Viral Vaccines/biosynthesis , Viral Vaccines/genetics
10.
Proc Natl Acad Sci U S A ; 118(43)2021 10 26.
Article in English | MEDLINE | ID: covidwho-1481965

ABSTRACT

Self-amplifying RNA replicons are promising platforms for vaccine generation. Their defects in one or more essential functions for viral replication, particle assembly, or dissemination make them highly safe as vaccines. We previously showed that the deletion of the envelope (E) gene from the Middle East respiratory syndrome coronavirus (MERS-CoV) produces a replication-competent propagation-defective RNA replicon (MERS-CoV-ΔE). Evaluation of this replicon in mice expressing human dipeptidyl peptidase 4, the virus receptor, showed that the single deletion of the E gene generated an attenuated mutant. The combined deletion of the E gene with accessory open reading frames (ORFs) 3, 4a, 4b, and 5 resulted in a highly attenuated propagation-defective RNA replicon (MERS-CoV-Δ[3,4a,4b,5,E]). This RNA replicon induced sterilizing immunity in mice after challenge with a lethal dose of a virulent MERS-CoV, as no histopathological damage or infectious virus was detected in the lungs of challenged mice. The four mutants lacking the E gene were genetically stable, did not recombine with the E gene provided in trans during their passage in cell culture, and showed a propagation-defective phenotype in vivo. In addition, immunization with MERS-CoV-Δ[3,4a,4b,5,E] induced significant levels of neutralizing antibodies, indicating that MERS-CoV RNA replicons are highly safe and promising vaccine candidates.


Subject(s)
Coronavirus Infections/prevention & control , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/immunology , RNA, Viral/administration & dosage , Replicon , Viral Vaccines/administration & dosage , Animals , Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , Coronavirus Infections/genetics , Coronavirus Infections/immunology , Coronavirus Infections/virology , Defective Viruses/genetics , Defective Viruses/immunology , Female , Gene Deletion , Genes, env , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Middle East Respiratory Syndrome Coronavirus/pathogenicity , RNA, Viral/genetics , RNA, Viral/immunology , Vaccines, DNA , Vaccines, Virus-Like Particle/administration & dosage , Vaccines, Virus-Like Particle/genetics , Vaccines, Virus-Like Particle/immunology , Viral Vaccines/genetics , Viral Vaccines/immunology , Virulence/genetics , Virulence/immunology
11.
Arch Virol ; 166(10): 2803-2815, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1415036

ABSTRACT

Porcine reproductive and respiratory syndrome virus (PRRSV) is the most important pathogen in the Korean swine industry. Despite efforts including improved biosecurity and vaccination protocols, the virus continues to circulate and evolve. Based on phylogenetic analysis of open reading frame 5 (ORF5), Korean PRRSVs are known to form not only globally circulating lineages but also country-specific lineages (Lin Kor A, B, and C). To understand the recent epidemiological status of PRRSV in Korea, a total of 1349 ORF5 sequences of Korean PRRSV isolates from 2014 to 2019 were analyzed. Phylogenetic analysis was conducted using the maximum-likelihood method, and temporal changes in the relative prevalence of lineages were investigated. The analysis showed that PRRSV1 and PRRSV2 were both highly prevalent throughout the years examined. Among the PRRSV1 isolates, subgroup A (90.1%) and vaccine-like subgroup C (9.0%) composed most of the population. For PRRSV2 isolates, vaccine-like lineage 5 (36.3%) was dominant, followed by Lin Kor B (25.9%), Kor C (16.6%), lineage 1 (11.6%), and Kor A (9.1%). The PRRSV2 lineage 1 population increased from 2014 (1.8%) to 2019 (29.6%) in Korea due to the continual spread of sublineage 1.8 (NADC30-like) and introduction of sublineage 1.6 into the country. Additional genetic analysis, including analysis of non synonymous and synonymous mutations, revealed evidence of diversification and positive selection in immunologically important regions of the genome, suggesting that current vaccination is failing and promoting immune-mediated selection. Overall, these findings provide insights into the epidemiological and evolutionary dynamics of cocirculating viral lineages, and constant surveillance of PRRSV occurrence is needed.


Subject(s)
Porcine Reproductive and Respiratory Syndrome/virology , Porcine respiratory and reproductive syndrome virus/genetics , Viral Envelope Proteins/genetics , Amino Acid Sequence , Animals , Genetic Variation , Genotype , Phylogeny , Porcine Reproductive and Respiratory Syndrome/epidemiology , Porcine respiratory and reproductive syndrome virus/classification , Porcine respiratory and reproductive syndrome virus/isolation & purification , Prevalence , Republic of Korea/epidemiology , Swine , Viral Vaccines/genetics
12.
Viruses ; 13(5)2021 04 28.
Article in English | MEDLINE | ID: covidwho-1302471

ABSTRACT

In recent years, the CRISPR/Cas9-based gene-editing techniques have been well developed and applied widely in several aspects of research in the biological sciences, in many species, including humans, animals, plants, and even in viruses. Modification of the viral genome is crucial for revealing gene function, virus pathogenesis, gene therapy, genetic engineering, and vaccine development. Herein, we have provided a brief review of the different technologies for the modification of the viral genomes. Particularly, we have focused on the recently developed CRISPR/Cas9-based gene-editing system, detailing its origin, functional principles, and touching on its latest achievements in virology research and applications in vaccine development, especially in large DNA viruses of humans and animals. Future prospects of CRISPR/Cas9-based gene-editing technology in virology research, including the potential shortcomings, are also discussed.


Subject(s)
Biomedical Research , CRISPR-Cas Systems , Gene Editing , Vaccinology/methods , Viral Vaccines/genetics , Viruses/genetics , Animals , Biomedical Research/methods , Genetic Therapy/methods , Humans , Viral Vaccines/immunology , Viruses/immunology
13.
Methods Mol Biol ; 2099: 53-68, 2020.
Article in English | MEDLINE | ID: covidwho-1292546

ABSTRACT

Over the past two decades, several coronavirus (CoV) infectious clones have been engineered, allowing for the manipulation of their large viral genomes (~30 kb) using unique reverse genetic systems. These reverse genetic systems include targeted recombination, in vitro ligation, vaccinia virus vectors, and bacterial artificial chromosomes (BACs). Quickly after the identification of Middle East respiratory syndrome-CoV (MERS-CoV), both in vitro ligation and BAC-based reverse genetic technologies were engineered for MERS-CoV to study its basic biological properties, develop live-attenuated vaccines, and test antiviral drugs. Here, I will describe how lambda red recombination can be used with the MERS-CoV BAC to quickly and efficiently introduce virtually any type of genetic modification (point mutations, insertions, deletions) into the MERS-CoV genome and recover recombinant virus.


Subject(s)
Bacteriophage lambda/genetics , Chromosomes, Artificial, Bacterial/genetics , Coronavirus Infections/virology , Genome, Viral/genetics , Middle East Respiratory Syndrome Coronavirus/genetics , Viral Vaccines/genetics , Coronavirus Infections/prevention & control , Deoxyribonuclease I/genetics , Deoxyribonuclease I/metabolism , Genetic Engineering , Homologous Recombination , Humans , Middle East Respiratory Syndrome Coronavirus/immunology , Mutation , Vaccines, Attenuated/genetics , Vaccinia virus/genetics
14.
Vet Microbiol ; 254: 109014, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1107294

ABSTRACT

TW-like infectious bronchitis virus (IBV) with high pathogenicity is becoming the predominant IBV type circulating in China. To develop vaccines against TW-like IBV strains and investigate the critical genes associated with their virulence, GD strain was attenuated by 140 serial passages in specific-pathogen-free embryonated eggs and the safety and efficacy of the attenuated GD strain (aGD) were examined. The genome sequences of GD and aGD were also compared and the effects of mutations in the S gene were observed. The results revealed that aGD strain showed no obvious pathogenicity with superior protective efficacy against TW-like and QX-like virulent IBV strains. The genomes of strains aGD and GD shared high similarity (99.87 %) and most of the mutations occurred in S gene. Recombinant IBV strain rGDaGD-S, in which the S gene was replaced with the corresponding regions from aGD, showed decreased pathogenicity compared with its parental strain. In conclusion, attenuated TW-like IBV strain aGD is a potential vaccine candidate and the S gene is responsible for its attenuation. Our research has laid the foundation for future exploration of the attenuating molecular mechanism of IBV.


Subject(s)
Chickens/virology , Infectious bronchitis virus/genetics , Infectious bronchitis virus/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Viral Vaccines/genetics , Virulence Factors/genetics , Animals , Chick Embryo , Coronavirus Infections/prevention & control , Infectious bronchitis virus/immunology , Poultry Diseases/prevention & control , Poultry Diseases/virology , Reverse Genetics/methods , Serial Passage , Specific Pathogen-Free Organisms , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Attenuated/immunology , Viral Vaccines/immunology
15.
J Immunother Cancer ; 9(6)2021 06.
Article in English | MEDLINE | ID: covidwho-1266401

ABSTRACT

SARS-CoV-2 infection and the resulting COVID-19 have afflicted millions of people in an ongoing worldwide pandemic. Safe and effective vaccination is needed urgently to protect not only the general population but also vulnerable subjects such as patients with cancer. Currently approved mRNA-based SARS-CoV-2 vaccines seem suitable for patients with cancer based on their mode of action, efficacy, and favorable safety profile reported in the general population. Here, we provide an overview of mRNA-based vaccines including their safety and efficacy. Extrapolating from insights gained from a different preventable viral infection, we review existing data on immunity against influenza A and B vaccines in patients with cancer. Finally, we discuss COVID-19 vaccination in light of the challenges specific to patients with cancer, such as factors that may hinder protective SARS-CoV-2 immune responses in the context of compromised immunity and the use of immune-suppressive or immune-modulating drugs.


Subject(s)
COVID-19 Vaccines , Neoplasms/therapy , RNA, Messenger , SARS-CoV-2/immunology , Viral Vaccines , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines/genetics , COVID-19 Vaccines/therapeutic use , Drug Stability , Humans , Influenza, Human/epidemiology , Influenza, Human/immunology , Influenza, Human/prevention & control , Neoplasms/epidemiology , Neoplasms/immunology , Pandemics , RNA Stability/physiology , RNA, Messenger/administration & dosage , RNA, Messenger/adverse effects , RNA, Messenger/chemistry , RNA, Messenger/genetics , SARS-CoV-2/genetics , Vaccination/methods , Viral Vaccines/adverse effects , Viral Vaccines/chemistry , Viral Vaccines/genetics
16.
Med Sci Monit ; 27: e932915, 2021 May 04.
Article in English | MEDLINE | ID: covidwho-1215733

ABSTRACT

There have been rapid developments in safe and effective mRNA vaccines for zoonotic infections in the past year. Years of research have made these advances possible, leading to in vitro-transcribed (IVT) mRNA expressing therapeutic proteins. There are several advantages of mRNA vaccines that include their low-cost manufacturing process, large-scale and rapid production, and the ability to modify the vaccines in response to emerging infections and viral variants. The COVID-19 pandemic and successful vaccination programs for SARS-CoV-2 have highlighted the advantages of mRNA vaccines. Also, mRNA vaccines are in development for several other potential pandemic zoonotic infections, including Ebola virus, rabies virus, Zika virus, HIV-1, and influenza. There may also be hope for the control of pandemic avian influenza by the combination of improved and rapid viral genotyping and the rapid development and mass production of mRNA vaccines. This Editorial aims to present a brief overview of how mRNA vaccines may help control and future epidemic, pandemic, and endemic zoonotic virus infections.


Subject(s)
RNA, Messenger , RNA, Viral , Viral Vaccines/immunology , Virus Diseases/epidemiology , Virus Diseases/prevention & control , Zoonoses/epidemiology , Zoonoses/prevention & control , Animals , Humans , RNA, Messenger/genetics , RNA, Messenger/immunology , RNA, Viral/genetics , RNA, Viral/immunology , Viral Vaccines/genetics , Virus Diseases/virology
17.
J Immunol ; 206(11): 2566-2582, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1207829

ABSTRACT

Over the last two decades, there have been three deadly human outbreaks of coronaviruses (CoVs) caused by SARS-CoV, MERS-CoV, and SARS-CoV-2, which has caused the current COVID-19 global pandemic. All three deadly CoVs originated from bats and transmitted to humans via various intermediate animal reservoirs. It remains highly possible that other global COVID pandemics will emerge in the coming years caused by yet another spillover of a bat-derived SARS-like coronavirus (SL-CoV) into humans. Determining the Ag and the human B cells, CD4+ and CD8+ T cell epitope landscapes that are conserved among human and animal coronaviruses should inform in the development of future pan-coronavirus vaccines. In the current study, using several immunoinformatics and sequence alignment approaches, we identified several human B cell and CD4+ and CD8+ T cell epitopes that are highly conserved in 1) greater than 81,000 SARS-CoV-2 genome sequences identified in 190 countries on six continents; 2) six circulating CoVs that caused previous human outbreaks of the common cold; 3) nine SL-CoVs isolated from bats; 4) nine SL-CoV isolated from pangolins; 5) three SL-CoVs isolated from civet cats; and 6) four MERS strains isolated from camels. Furthermore, the identified epitopes: 1) recalled B cells and CD4+ and CD8+ T cells from both COVID-19 patients and healthy individuals who were never exposed to SARS-CoV-2, and 2) induced strong B cell and T cell responses in humanized HLA-DR1/HLA-A*02:01 double-transgenic mice. The findings pave the way to develop a preemptive multiepitope pan-coronavirus vaccine to protect against past, current, and future outbreaks.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Epitopes, T-Lymphocyte , Genome, Viral/immunology , Middle East Respiratory Syndrome Coronavirus , SARS Virus , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Animals , Epitopes, T-Lymphocyte/genetics , Epitopes, T-Lymphocyte/immunology , Female , Genome-Wide Association Study , Humans , Male , Middle Aged , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/immunology , SARS Virus/genetics , SARS Virus/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Viral Vaccines/genetics , Viral Vaccines/immunology
18.
JCI Insight ; 6(10)2021 05 24.
Article in English | MEDLINE | ID: covidwho-1197299

ABSTRACT

Emerging coronaviruses from zoonotic reservoirs, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have been associated with human-to-human transmission and significant morbidity and mortality. Here, we study both intradermal and intramuscular 2-dose delivery regimens of an advanced synthetic DNA vaccine candidate encoding a full-length MERS-CoV spike (S) protein, which induced potent binding and neutralizing antibodies as well as cellular immune responses in rhesus macaques. In a MERS-CoV challenge, all immunized rhesus macaques exhibited reduced clinical symptoms, lowered viral lung load, and decreased severity of pathological signs of disease compared with controls. Intradermal vaccination was dose sparing and more effective in this model at protecting animals from disease. The data support the further study of this vaccine for preventing MERS-CoV infection and transmission, including investigation of such vaccines and simplified delivery routes against emerging coronaviruses.


Subject(s)
Coronavirus Infections/veterinary , Macaca mulatta/immunology , Middle East Respiratory Syndrome Coronavirus/immunology , Vaccines, DNA/therapeutic use , Viral Vaccines/therapeutic use , Animals , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Immunogenicity, Vaccine , Injections, Intradermal , Middle East Respiratory Syndrome Coronavirus/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vaccines, DNA/administration & dosage , Vaccines, DNA/genetics , Viral Vaccines/administration & dosage , Viral Vaccines/genetics
19.
Cell Host Microbe ; 29(3): 327-333, 2021 03 10.
Article in English | MEDLINE | ID: covidwho-1126778

ABSTRACT

Most viral vaccines are based on inducing neutralizing antibodies (NAbs) against the virus envelope or spike glycoproteins. Many viral surface proteins exist as trimers that transition from a pre-fusion state when key NAb epitopes are exposed to a post-fusion form in which the potential for virus-cell fusion no longer exists. For optimal vaccine performance, these viral proteins are often engineered to enhance stability and presentation of these NAb epitopes. The method involves the structure-guided introduction of proline residues at key positions that maintain the trimer in the pre-fusion configuration. We review how this technique emerged during HIV-1 Env vaccine development and its subsequent wider application to other viral vaccines including SARS-CoV-2.


Subject(s)
Proline/chemistry , Proline/immunology , Viral Vaccines/chemistry , Viral Vaccines/immunology , Antibodies, Neutralizing/immunology , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Humans , Models, Molecular , Proline/genetics , Protein Engineering , Viral Vaccines/genetics
20.
EMBO J ; 40(5): e106228, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1086195

ABSTRACT

Nucleoprotein (N) is an immunodominant antigen in many enveloped virus infections. While the diagnostic value of anti-N antibodies is clear, their role in immunity is not. This is because while they are non-neutralising, they somehow clear infection by coronavirus, influenza and LCMV in vivo. Here, we show that anti-N immune protection is mediated by the cytosolic Fc receptor and E3 ubiquitin ligase TRIM21. Exploiting LCMV as a model system, we demonstrate that TRIM21 uses anti-N antibodies to target N for cytosolic degradation and generate cytotoxic T cells (CTLs) against N peptide. These CTLs rapidly eliminate N-peptide-displaying cells and drive efficient viral clearance. These results reveal a new mechanism of immune synergy between antibodies and T cells and highlights N as an important vaccine target.


Subject(s)
Antibodies, Viral/immunology , Immunity, Cellular , Lymphocytic choriomeningitis virus/immunology , Nucleocapsid Proteins/immunology , Ribonucleoproteins/immunology , T-Lymphocytes, Cytotoxic/immunology , Animals , Lymphocytic Choriomeningitis/genetics , Lymphocytic Choriomeningitis/immunology , Lymphocytic choriomeningitis virus/genetics , Mice , Mice, Knockout , Nucleocapsid Proteins/genetics , Ribonucleoproteins/genetics , Viral Vaccines/genetics , Viral Vaccines/immunology
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