Investigating the Interaction between Negative Strand RNA Viruses and Their Hosts for Enhanced Vaccine Development and Production

The current pandemic has highlighted the ever-increasing risk of human to human spread of zoonotic pathogens. A number of medically-relevant zoonotic pathogens are negative-strand RNA viruses (NSVs). NSVs are derived from different virus families. Examples like Ebola are known for causing severe symptoms and high mortality rates. Some, like influenza, are known for their ease of person-to-person transmission and lack of pre-existing immunity, enabling rapid spread across many countries around the globe. Containment of outbreaks of NSVs can be difficult owing to their unpredictability and the absence of effective control measures, such as vaccines and antiviral therapeutics. In addition, there remains a lack of essential knowledge of the host–pathogen response that are induced by NSVs, particularly of the immune responses that provide protection. Vaccines are the most effective method for preventing infectious diseases. In fact, in the event of a pandemic, appropriate vaccine design and speed of vaccine supply is the most critical factor in protecting the population, as vaccination is the only sustainable defense. Vaccines need to be safe, efficient, and cost-effective, which is influenced by our understanding of the host–pathogen interface. Additionally, some of the major challenges of vaccines are the establishment of a long-lasting immunity offering cross protection to emerging strains. Although many NSVs are controlled through immunisations, for some, vaccine design has failed or efficacy has proven unreliable. The key behind designing a successful vaccine is understanding the host–pathogen interaction and the host immune response towards NSVs. In this paper, we review the recent research in vaccine design against NSVs and explore the immune responses induced by these viruses. The generation of a robust and integrated approach to development capability and vaccine manufacture can collaboratively support the management of outbreaking NSV disease health risks.

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Genome sequence, transcriptome, and annotation of rodent malaria parasite Plasmodium yoelii nigeriensis N67

BMC Genomics ◽

10.1186/s12864-021-07555-9 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Cui Zhang ◽

Cihan Oguz ◽

Sue Huse ◽

Lu Xia ◽

Jian Wu ◽

...

Keyword(s):

Dna Sequences ◽

Malaria Parasite ◽

Vaccine Development ◽

De Novo ◽

Gene Families ◽

Plasmodium Yoelii ◽

Control Measures ◽

Effective Control ◽

Malaria Parasites ◽

Rodent Malaria

Abstract Background Rodent malaria parasites are important models for studying host-malaria parasite interactions such as host immune response, mechanisms of parasite evasion of host killing, and vaccine development. One of the rodent malaria parasites is Plasmodium yoelii, and multiple P. yoelii strains or subspecies that cause different disease phenotypes have been widely employed in various studies. The genomes and transcriptomes of several P. yoelii strains have been analyzed and annotated, including the lethal strains of P. y. yoelii YM (or 17XL) and non-lethal strains of P. y. yoelii 17XNL/17X. Genomic DNA sequences and cDNA reads from another subspecies P. y. nigeriensis N67 have been reported for studies of genetic polymorphisms and parasite response to drugs, but its genome has not been assembled and annotated. Results We performed genome sequencing of the N67 parasite using the PacBio long-read sequencing technology, de novo assembled its genome and transcriptome, and predicted 5383 genes with high overall annotation quality. Comparison of the annotated genome of the N67 parasite with those of YM and 17X parasites revealed a set of genes with N67-specific orthology, expansion of gene families, particularly the homologs of the Plasmodium chabaudi erythrocyte membrane antigen, large numbers of SNPs and indels, and proteins predicted to interact with host immune responses based on their functional domains. Conclusions The genomes of N67 and 17X parasites are highly diverse, having approximately one polymorphic site per 50 base pairs of DNA. The annotated N67 genome and transcriptome provide searchable databases for fast retrieval of genes and proteins, which will greatly facilitate our efforts in studying the parasite biology and gene function and in developing effective control measures against malaria.

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Recent Advances in Nanovaccines Using Biomimetic Immunomodulatory Materials

Pharmaceutics ◽

10.3390/pharmaceutics11100534 ◽

2019 ◽

Vol 11 (10) ◽

pp. 534 ◽

Cited By ~ 12

Author(s):

Vijayan ◽

Mohapatra ◽

Uthaman ◽

Park

Keyword(s):

Immune Responses ◽

Targeted Delivery ◽

Vaccine Development ◽

Polymeric Nanoparticles ◽

Vital Role ◽

Effective Control ◽

Therapeutic Vaccines ◽

Hiv Therapy ◽

Recent Advances ◽

Wide Range

The development of vaccines plays a vital role in the effective control of several fatal diseases. However, effective prophylactic and therapeutic vaccines have yet to be developed for completely curing deadly diseases, such as cancer, malaria, HIV, and serious microbial infections. Thus, suitable vaccine candidates need to be designed to elicit appropriate immune responses. Nanotechnology has been found to play a unique role in the design of vaccines, providing them with enhanced specificity and potency. Nano-scaled materials, such as virus-like particles, liposomes, polymeric nanoparticles (NPs), and protein NPs, have received considerable attention over the past decade as potential carriers for the delivery of vaccine antigens and adjuvants, due to their beneficial advantages, like improved antigen stability, targeted delivery, and long-time release, for which antigens/adjuvants are either encapsulated within, or decorated on, the NP surface. Flexibility in the design of nanomedicine allows for the programming of immune responses, thereby addressing the many challenges encountered in vaccine development. Biomimetic NPs have emerged as innovative natural mimicking biosystems that can be used for a wide range of biomedical applications. In this review, we discuss the recent advances in biomimetic nanovaccines, and their use in anti-bacterial therapy, anti-HIV therapy, anti-malarial therapy, anti-melittin therapy, and anti-tumor immunity.

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Scaling laws describe memories of host–pathogen riposte in the HIV population

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1415386112 ◽

2015 ◽

Vol 112 (7) ◽

pp. 1965-1970 ◽

Cited By ~ 19

Author(s):

John P. Barton ◽

Mehran Kardar ◽

Arup K. Chakraborty

Keyword(s):

Neural Networks ◽

Immune Responses ◽

Scaling Laws ◽

Mechanistic Model ◽

Solvable Model ◽

Effective Control ◽

Immune Selection ◽

Exactly Solvable ◽

Host Pathogen ◽

Human Immune

The enormous genetic diversity and mutability of HIV has prevented effective control of this virus by natural immune responses or vaccination. Evolution of the circulating HIV population has thus occurred in response to diverse, ultimately ineffective, immune selection pressures that randomly change from host to host. We show that the interplay between the diversity of human immune responses and the ways that HIV mutates to evade them results in distinct sets of sequences defined by similar collectively coupled mutations. Scaling laws that relate these sets of sequences resemble those observed in linguistics and other branches of inquiry, and dynamics reminiscent of neural networks are observed. Like neural networks that store memories of past stimulation, the circulating HIV population stores memories of host–pathogen combat won by the virus. We describe an exactly solvable model that captures the main qualitative features of the sets of sequences and a simple mechanistic model for the origin of the observed scaling laws. Our results define collective mutational pathways used by HIV to evade human immune responses, which could guide vaccine design.

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Lessons from Bacillus Calmette-Guérin: Harnessing Trained Immunity for Vaccine Development

Cells ◽

10.3390/cells9092109 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2109

Author(s):

Samuel T. Pasco ◽

Juan Anguita

Keyword(s):

Mycobacterium Tuberculosis ◽

Immune Responses ◽

Vaccine Development ◽

Vaccine Design ◽

Innate Immune ◽

Bacillus Calmette Guerin ◽

Adaptive Immune Responses ◽

Trained Immunity ◽

Adaptive Immune ◽

Potential Methods

Vaccine design traditionally focuses on inducing adaptive immune responses against a sole target pathogen. Considering that many microbes evade innate immune mechanisms to initiate infection, and in light of the discovery of epigenetically mediated innate immune training, the paradigm of vaccine design has the potential to change. The Bacillus Calmette-Guérin (BCG) vaccine induces some level of protection against Mycobacterium tuberculosis (Mtb) while stimulating trained immunity that correlates with lower mortality and increased protection against unrelated pathogens. This review will explore BCG-induced trained immunity, including the required pathways to establish this phenotype. Additionally, potential methods to improve or expand BCG trained immunity effects through alternative vaccine delivery and formulation methods will be discussed. Finally, advances in new anti-Mtb vaccines, other antimicrobial uses for BCG, and “innate memory-based vaccines” will be examined.

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Special Issue “Recent Advances in Morbillivirus Vaccine Development and Oncolytic Virotherapy”

Viruses ◽

10.3390/v12030341 ◽

2020 ◽

Vol 12 (3) ◽

pp. 341

Author(s):

Liang-Tzung Lin

Keyword(s):

Vaccine Development ◽

Rna Viruses ◽

Oncolytic Virotherapy ◽

Special Issue ◽

Negative Strand ◽

Recent Advances

Members of the Morbillivirus genus are enveloped, negative-strand RNA viruses that include a number of highly contagious pathogens important to humans and animals [...]

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The Strand-biased Transcription of SARS-CoV-2 and Unbalanced Inhibition by Remdesivir

10.1101/2020.10.15.325050 ◽

2020 ◽

Author(s):

Yan Zhao ◽

Jing Sun ◽

Yunfei Li ◽

Zhengxuan Li ◽

Yu Xie ◽

...

Keyword(s):

Immune Responses ◽

Rna Polymerase ◽

Vaccine Development ◽

Rna Virus ◽

Innate Immune ◽

Innate Immune Responses ◽

Negative Strand ◽

Sense Strand ◽

Viral Vaccine ◽

Polymerase Inhibitor

AbstractSARS-CoV-2, a positive single-stranded RNA virus, caused the COVID-19 pandemic. During the viral replication and transcription, the RNA dependent RNA polymerase (RdRp) “jumps” along the genome template, resulting in discontinuous negative-stranded transcripts. In other coronaviruses, the negative strand RNA was found functionally relevant to the activation of host innate immune responses. Although the sense-mRNA architectures of SARS-CoV-2 were reported, its negative strand was unexplored. Here, we deeply sequenced both strands of RNA and found SARS-CoV-2 transcription is strongly biased to form the sense strand. During negative strand synthesis, apart from canonical sub-genomic ORFs, numerous non-canonical fusion transcripts are formed, driven by 3-15 nt sequence homology scattered along the genome but more prone to be inhibited by SARS-CoV-2 RNA polymerase inhibitor Remdesivir. The drug also represses more of the negative than the positive strand synthesis as supported by a mathematic simulation model and experimental quantifications. Overall, this study opens new sights into SARS-CoV-2 biogenesis and may facilitate the anti-viral vaccine development and drug design.One Sentence SummaryStrand-biased transcription of SARS-CoV-2.

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Self-Amplifying RNA Viruses as RNA Vaccines

International Journal of Molecular Sciences ◽

10.3390/ijms21145130 ◽

2020 ◽

Vol 21 (14) ◽

pp. 5130 ◽

Cited By ~ 4

Author(s):

Kenneth Lundstrom

Keyword(s):

Immune Responses ◽

Viral Vectors ◽

Ebola Virus ◽

Tumor Antigens ◽

Vaccine Development ◽

Rna Viruses ◽

Emerging Diseases ◽

Host Cells ◽

Phase Iii ◽

Rna Replicon

Single-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses and rhabdoviruses are characterized by their capacity of highly efficient self-amplification of RNA in host cells, which make them attractive vehicles for vaccine development. Particularly, alphaviruses and flaviviruses can be administered as recombinant particles, layered DNA/RNA plasmid vectors carrying the RNA replicon and even RNA replicon molecules. Self-amplifying RNA viral vectors have been used for high level expression of viral and tumor antigens, which in immunization studies have elicited strong cellular and humoral immune responses in animal models. Vaccination has provided protection against challenges with lethal doses of viral pathogens and tumor cells. Moreover, clinical trials have demonstrated safe application of RNA viral vectors and even promising results in rhabdovirus-based phase III trials on an Ebola virus vaccine. Preclinical and clinical applications of self-amplifying RNA viral vectors have proven efficient for vaccine development and due to the presence of RNA replicons, amplification of RNA in host cells will generate superior immune responses with significantly reduced amounts of RNA delivered. The need for novel and efficient vaccines has become even more evident due to the global COVID-19 pandemic, which has further highlighted the urgency in challenging emerging diseases.

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Development of ELISA based on Bacillus anthracis capsule biosynthesis protein CapA for naturally acquired antibodies against anthrax

PLoS ONE ◽

10.1371/journal.pone.0258317 ◽

2021 ◽

Vol 16 (10) ◽

pp. e0258317

Author(s):

Tuvshinzaya Zorigt ◽

Yoshikazu Furuta ◽

Manyando Simbotwe ◽

Akihiro Ochi ◽

Mai Tsujinouchi ◽

...

Keyword(s):

Bacillus Anthracis ◽

Vaccine Development ◽

Protective Antigen ◽

Protein Solubility ◽

Control Measures ◽

Effective Control ◽

Enzyme Linked Immunosorbent Assay ◽

Veterinary Vaccine ◽

C Terminus ◽

Vaccination History

Anthrax is a zoonotic disease caused by the gram-positive spore-forming bacterium Bacillus anthracis. Detecting naturally acquired antibodies against anthrax sublethal exposure in animals is essential for anthrax surveillance and effective control measures. Serological assays based on protective antigen (PA) of B. anthracis are mainly used for anthrax surveillance and vaccine evaluation. Although the assay is reliable, it is challenging to distinguish the naturally acquired antibodies from vaccine-induced immunity in animals because PA is cross-reactive to both antibodies. Although additional data on the vaccination history of animals could bypass this problem, such data are not readily accessible in many cases. In this study, we established a new enzyme-linked immunosorbent assay (ELISA) specific to antibodies against capsule biosynthesis protein CapA antigen of B. anthracis, which is non-cross-reactive to vaccine-induced antibodies in horses. Using in silico analyses, we screened coding sequences encoded on pXO2 plasmid, which is absent in the veterinary vaccine strain Sterne 34F2 but present in virulent strains of B. anthracis. Among the 8 selected antigen candidates, capsule biosynthesis protein CapA (GBAA_RS28240) and peptide ABC transporter substrate-binding protein (GBAA_RS28340) were detected by antibodies in infected horse sera. Of these, CapA has not yet been identified as immunoreactive in other studies to the best of our knowledge. Considering the protein solubility and specificity of B. anthracis, we prepared the C-terminus region of CapA, named CapA322, and developed CapA322-ELISA based on a horse model. Comparative analysis of the CapA322-ELISA and PAD1-ELISA (ELISA uses domain one of the PA) showed that CapA322-ELISA could detect anti-CapA antibodies in sera from infected horses but was non-reactive to sera from vaccinated horses. The CapA322-ELISA could contribute to the anthrax surveillance in endemic areas, and two immunoreactive proteins identified in this study could be additives to the improvement of current or future vaccine development.

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Prevalence and Evolution of Noroviruses between 1966 and 2019, Implications for Vaccine Design

Pathogens ◽

10.3390/pathogens10081012 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1012

Author(s):

Hong-Lu Zhou ◽

Li-Na Chen ◽

Song-Mei Wang ◽

Ming Tan ◽

Chao Qiu ◽

...

Keyword(s):

Vaccine Strain ◽

Primary Structure ◽

Acute Gastroenteritis ◽

Vaccine Development ◽

Rna Viruses ◽

Vaccine Design ◽

Population Based ◽

Hebei Province ◽

The Other ◽

Evolutionary Pattern

Noroviruses (NoVs), a group of single-stranded RNA viruses causing epidemic acute gastroenteritis in humans, are highly diverse, consisting of multiple genogroups with >30 genotypes. Their continual evolutions make NoV vaccine design and development difficult. Here, we report a study of NoV sequences obtained from a population-based diarrhea surveillance in Zhengding County of Hebei Province spanning from 2001 to 2019 and those available in the GenBank database from 1966 to 2019. NoV genotypes and/or variants that may evade immunity were screened and identified based on primary and conformational structures for vaccine design. We selected 366, 301, 139, 74 and 495 complete VP1-coding nucleotide sequences representing the predominant genotypes of GII.4, GII.2, GII.3, GII.6 and GII.17, respectively. A total of 16 distinct GII.4 variants were identified, showing a typical linear evolutionary pattern of variant replacement, while only 1–4 variants of the other genotypes were found to co-circulate over the 40–50-year period without typical variant replacement. The vaccine strain GII.4c is close to variant Sydney_2012 (0.053) in their primary structure, but they are distinct at epitopes A and E in conformations. Our data suggested GII.4 variant Sydney_2012, GII.2 variant A, a GII.3 strain, GII.6 variants B and C and GII.17 variant D are primary candidate strains for NoV vaccine development.

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Genome Sequence, Transcriptome, and Annotation of Rodent Malaria Parasite Plasmodium Yoelii Nigeriensis N67

10.21203/rs.3.rs-162427/v1 ◽

2021 ◽

Author(s):

Cui Zhang ◽

Cihan Oguz ◽

Sue Huse ◽

Lu Xia ◽

Jian Wu ◽

...

Keyword(s):

Dna Sequences ◽

Malaria Parasite ◽

Vaccine Development ◽

De Novo ◽

Gene Families ◽

Plasmodium Yoelii ◽

Control Measures ◽

Effective Control ◽

Malaria Parasites ◽

Rodent Malaria

Abstract Background: Rodent malaria parasites are important models for studying host-malaria parasite interactions such as host immune response, mechanisms of parasite evasion of host killing, and vaccine development. One of the rodent malaria parasites is Plasmodium yoelii, and multiple P. yoelii strains or subspecies that cause different disease phenotypes have been widely employed in various studies. The genomes and transcriptomes of several P. yoelii strains have been analyzed and annotated, including the lethal strains of Plasmodium y. yoelii YM (or 17XL) and non-lethal strains of Plasmodium y. yoelii 17XNL/17X. Genomic DNA sequences and cDNA reads from another subspecies P. y. nigeriensis N67 have been reported for studies of genetic polymorphisms and parasite response to drugs, but its genome has not been assembled and annotated. Results: We performed genome sequencing of the N67 parasite using the PacBio long-read sequencing technology, de novo assembled its genome and transcriptome, and predicted 5,383 genes with high overall annotation quality. Comparison of the annotated genome of the N67 parasite with those of YM and 17X parasites revealed a set of genes with N67-specific orthology, expansion of gene families, particularly the homologs of the Plasmodium chabaudi erythrocyte membrane antigen, large numbers of SNPs and indels, and proteins predicted to interact with host immune responses based on their functional domains. Conclusions: The genomes of N67 and 17X parasites are highly diverse, having approximately one polymorphic site per 50 base pairs of DNA. The annotated N67 genome and transcriptome provide searchable databases for fast retrieval of genes and proteins, which will greatly facilitate our efforts in studying the parasite biology and gene function and in developing effective control measures against malaria.

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