Vaccines inducing immunity to Lassa virus glycoprotein and nucleoprotein protect macaques after a single shot

2019 ◽  
Vol 11 (512) ◽  
pp. eaaw3163 ◽  
Author(s):  
Mathieu Mateo ◽  
Stéphanie Reynard ◽  
Xavier Carnec ◽  
Alexandra Journeaux ◽  
Nicolas Baillet ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Measles Virus ◽  
Vaccine Candidate ◽  
Lassa Fever ◽  
Lassa Virus ◽  
Single Shot ◽  
Efficacy Analysis ◽  
Western Africa ◽  
Efficacious Vaccine

Lassa fever is a major threat in Western Africa. The large number of people living at risk for this disease calls for the development of a vaccine against Lassa virus (LASV). We generated live-attenuated LASV vaccines based on measles virus and Mopeia virus platforms and expressing different LASV antigens, with the aim to develop a vaccine able to protect after a single shot. We compared the efficacy of these vaccines against LASV in cynomolgus monkeys. The vaccines were well tolerated and protected the animals from LASV infection and disease after a single immunization but with varying efficacy. Analysis of the immune responses showed that complete protection was associated with robust secondary T cell and antibody responses against LASV. Transcriptomic and proteomic analyses showed an early activation of innate immunity and T cell priming after immunization with the most effective vaccines, with changes detectable as early as 2 days after immunization. The most efficacious vaccine candidate, a measles vector simultaneously expressing LASV glycoprotein and nucleoprotein, has been selected for further clinical evaluation.

scholarly journals A single-shot Lassa vaccine induces long-term immunity and protects cynomolgus monkeys against heterologous strains

2021 ◽  
Vol 13 (597) ◽  
pp. eabf6348
Author(s):  
Mathieu Mateo ◽  
Stéphanie Reynard ◽  
Alexandra Journeaux ◽  
Clara Germain ◽  
Jimmy Hortion ◽  
...  
Keyword(s):  
Immune Responses ◽  
Virus Vaccine ◽  
Measles Virus ◽  
Lassa Virus ◽  
Single Shot ◽  
Virus Infections ◽  
Cynomolgus Monkeys ◽  
Western Africa ◽  
High Diversity

A safe and protective Lassa virus vaccine is crucially needed in Western Africa to stem the recurrent outbreaks of Lassa virus infections in Nigeria and the emergence of Lassa virus in previously unaffected countries, such as Benin and Togo. Major challenges in developing a Lassa virus vaccine include the high diversity of circulating strains and their reemergence from 1 year to another. To address each of these challenges, we immunized cynomolgus monkeys with a measles virus vector expressing the Lassa virus glycoprotein and nucleoprotein of the prototypic Lassa virus strain Josiah (MeV-NP). To evaluate vaccine efficacy against heterologous strains of Lassa virus, we challenged the monkeys a month later with heterologous strains from lineage II or lineage VII, finding that the vaccine was protective against these strains. A second cohort of monkeys was challenged 1 year later with the homologous Josiah strain, finding that a single dose of MeV-NP was sufficient to protect all vaccinated monkeys. These studies demonstrate that MeV-NP can generate both long-lasting immune responses and responses that are able to protect against diverse strains of Lassa virus.

scholarly journals A Lassa Virus Live-Attenuated Vaccine Candidate Based on Rearrangement of the Intergenic Region

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Yingyun Cai ◽  
Masaharu Iwasaki ◽  
Daisuke Motooka ◽  
David X. Liu ◽  
Shuiqing Yu ◽  
...  
Keyword(s):  
Intergenic Region ◽  
Guinea Pigs ◽  
Cultured Cells ◽  
Vaccine Candidate ◽  
Lassa Fever ◽  
Lassa Virus ◽  
Wild Type ◽  
Live Attenuated Vaccine ◽  
Attenuated Vaccine ◽  
Western Africa

ABSTRACT Lassa virus (LASV) poses a significant public health problem within the regions of Lassa fever endemicity in Western Africa. LASV infects several hundred thousand individuals yearly, and a considerable number of Lassa fever cases are associated with high morbidity and lethality. No approved LASV vaccine is available, and current therapy is limited to an off-label usage of ribavirin that is only partially effective and associated with significant side effects. The impact of Lassa fever on human health, together with the limited existing countermeasures, highlights the importance of developing effective vaccines against LASV. Here, we present the development and characterization of a recombinant LASV (rLASV) vaccine candidate [rLASV(IGR/S-S)], which is based on the presence of the noncoding intergenic region (IGR) of the small (S) genome segment (S-IGR) in both large (L) and S LASV segments. In cultured cells, rLASV(IGR/S-S) was modestly less fit than wild-type rLASV (rLASV-WT). rLASV(IGR/S-S) was highly attenuated in guinea pigs, and a single subcutaneous low dose of the virus completely protected against otherwise lethal infection with LASV-WT. Moreover, rLASV(IGR/S-S) was genetically stable during serial passages in cultured cells. These findings indicate that rLASV(IGR/S-S) can be developed into a LASV live-attenuated vaccine (LAV) that has the same antigenic composition as LASV-WT and a well-defined mechanism of attenuation that overcomes concerns about increased virulence that could be caused by genetic changes in the LAV during multiple rounds of multiplication. IMPORTANCE Lassa virus (LASV), the causative agent of Lassa fever, infects several hundred thousand people in Western Africa, resulting in many lethal Lassa fever cases. No U.S. Food and Drug Administration-licensed countermeasures are available to prevent or treat LASV infection. We describe the generation of a novel LASV live-attenuated vaccine candidate rLASV(IGR/S-S), which is based on the replacement of the large genomic segment noncoding intergenic region (IGR) with that of the small genome segment. rLASV(IGR/S-S) is less fit in cell culture than wild-type virus and does not cause clinical signs in inoculated guinea pigs. Importantly, rLASV(IGR/S-S) protects immunized guinea pigs against an otherwise lethal exposure to LASV.

scholarly journals A Lassa Fever Live-Attenuated Vaccine Based on Codon Deoptimization of the Viral Glycoprotein Gene

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yingyun Cai ◽  
Chengjin Ye ◽  
Benson Cheng ◽  
Aitor Nogales ◽  
Masaharu Iwasaki ◽  
...  
Keyword(s):  
Guinea Pigs ◽  
Vaccine Candidate ◽  
Lassa Fever ◽  
Lassa Virus ◽  
Off Label Use ◽  
Wild Type ◽  
Glycoprotein Precursor ◽  
Live Attenuated Vaccine ◽  
Off Label ◽  
Western Africa

ABSTRACT Lassa virus (LASV) is endemic in Western Africa and is estimated to infect hundreds of thousands of individuals annually. A considerable number of these infections result in Lassa fever (LF), which is associated with significant morbidity and a case-fatality rate as high as 69% among hospitalized confirmed patients. U.S. Food and Drug Administration-approved LF vaccines are not available. Current antiviral treatment is limited to off-label use of a nucleoside analogue, ribavirin, that is only partially effective and associated with significant side effects. We generated and characterized a recombinant LASV expressing a codon-deoptimized (CD) glycoprotein precursor gene (GPC), rLASV-GPC/CD. Comparison of growth kinetics and peak titers showed that rLASV-GPC/CD is slightly attenuated in cell culture compared to wild-type (WT) recombinant LASV (rLASV-WT). However, rLASV-GPC/CD is highly attenuated in strain 13 and Hartley guinea pigs, as reflected by the absence of detectable clinical signs in animals inoculated with rLASV-GPC/CD. Importantly, a single subcutaneous dose of rLASV-GPC/CD provides complete protection against an otherwise lethal exposure to LASV. Our results demonstrate the feasibility of implementing a CD approach for developing a safe and effective LASV live-attenuated vaccine candidate. Moreover, rLASV-GPC/CD might provide investigators with a tool to safely study LASV outside maximum (biosafety level 4) containment, which could accelerate the elucidation of basic aspects of the molecular and cell biology of LASV and the development of novel LASV medical countermeasures. IMPORTANCE Lassa virus (LASV) infects several hundred thousand people in Western Africa, resulting in many lethal Lassa fever (LF) cases. Licensed LF vaccines are not available, and anti-LF therapy is limited to off-label use of the nucleoside analog ribavirin with uncertain efficacy. We describe the generation of a novel live-attenuated LASV vaccine candidate. This vaccine candidate is based on mutating wild-type (WT) LASV in a key region of the viral genome, the glycoprotein precursor (GPC) gene. These mutations do not change the encoded GPC but interfere with its production in host cells. This mutated LASV (rLASV-GPC/CD) behaves like WT LASV (rLASV-WT) in cell culture, but in contrast to rLASV-WT, does not cause disease in inoculated guinea pigs. Guinea pigs immunized with rLASV-GPC/CD were protected against an otherwise lethal exposure to WT LASV. Our results support the testing of this candidate vaccine in nonhuman primate models ofLF.

scholarly journals Attenuated Replication of Lassa Virus Vaccine Candidate ML29 in STAT-1-/- Mice

Pathogens ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 9 ◽  
Author(s):  
Dylan Johnson ◽  
Jenny Jokinen ◽  
Igor Lukashevich
Keyword(s):  
Vaccine Development ◽  
Vaccine Candidate ◽  
Small Animal ◽  
Vero Cells ◽  
Lassa Fever ◽  
Effective Vaccine ◽  
Cell Mediated Immunity ◽  
Lassa Virus ◽  
Cell Responses ◽  
Fold Reduction

Lassa virus (LASV), a highly prevalent mammalian arenavirus endemic in West Africa, can cause Lassa fever (LF), which is responsible for thousands of deaths annually. LASV is transmitted to humans from naturally infected rodents. At present, there is not an effective vaccine nor treatment. The genetic diversity of LASV is the greatest challenge for vaccine development. The reassortant ML29 carrying the L segment from the nonpathogenic Mopeia virus (MOPV) and the S segment from LASV is a vaccine candidate under current development. ML29 demonstrated complete protection in validated animal models against a Nigerian strain from clade II, which was responsible for the worst outbreak on record in 2018. This study demonstrated that ML29 was more attenuated than MOPV in STAT1-/- mice, a small animal model of human LF and its sequelae. ML29 infection of these mice resulted in more than a thousand-fold reduction in viremia and viral load in tissues and strong LASV-specific adaptive T cell responses compared to MOPV-infected mice. Persistent infection of Vero cells with ML29 resulted in generation of interfering particles (IPs), which strongly interfered with the replication of LASV, MOPV and LCMV, the prototype of the Arenaviridae. ML29 IPs induced potent cell-mediated immunity and were fully attenuated in STAT1-/- mice. Formulation of ML29 with IPs will improve the breadth of the host’s immune responses and further contribute to development of a pan-LASV vaccine with full coverage meeting the WHO requirements.

scholarly journals Identification of Common CD8+ T Cell Epitopes from Lassa Fever Survivors in Nigeria and Sierra Leone

2020 ◽  
Vol 94 (12) ◽  
Author(s):  
Saori Sakabe ◽  
Jessica N. Hartnett ◽  
Nhi Ngo ◽  
Augustine Goba ◽  
Mambu Momoh ◽  
...  
Keyword(s):  
T Cell ◽  
West Africa ◽  
Sierra Leone ◽  
T Cell Responses ◽  
Lassa Fever ◽  
Health Concern ◽  
Lassa Virus ◽  
T Cell Epitopes ◽  
Virus Surface ◽  
Cell Responses

ABSTRACT Early and robust T cell responses have been associated with survival from Lassa fever (LF), but the Lassa virus-specific memory responses have not been well characterized. Regions within the virus surface glycoprotein (GPC) and nucleoprotein (NP) are the main targets of the Lassa virus-specific T cell responses, but, to date, only a few T cell epitopes within these proteins have been identified. We identified GPC and NP regions containing T cell epitopes and HLA haplotypes from LF survivors and used predictive HLA-binding algorithms to identify putative epitopes, which were then experimentally tested using autologous survivor samples. We identified 12 CD8-positive (CD8+) T cell epitopes, including epitopes common to both Nigerian and Sierra Leonean survivors. These data should be useful for the identification of dominant Lassa virus-specific T cell responses in Lassa fever survivors and vaccinated individuals as well as for designing vaccines that elicit cell-mediated immunity. IMPORTANCE The high morbidity and mortality associated with clinical cases of Lassa fever, together with the lack of licensed vaccines and limited and partially effective interventions, make Lassa virus (LASV) an important health concern in its regions of endemicity in West Africa. Previous infection with LASV protects from disease after subsequent exposure, providing a framework for designing vaccines to elicit similar protective immunity. Multiple major lineages of LASV circulate in West Africa, and therefore, ideal vaccine candidates should elicit immunity to all lineages. We therefore sought to identify common T cell epitopes between Lassa fever survivors from Sierra Leone and Nigeria, where distinct lineages circulate. We identified three such epitopes derived from highly conserved regions within LASV proteins. In this process, we also identified nine other T cell epitopes. These data should help in the design of an effective pan-LASV vaccine.

scholarly journals Immunoinformatic Approach for the identification of T Cell and B Cell Epitopes in the Surface Glycoprotein and Designing a Potent Multiepitope Vaccine Construct Against SARS-CoV-2 including the new UK variant

2021 ◽  
Author(s):  
Kaveri Krishnasamy ◽  
Gracy Fathima Selvaraj ◽  
Kiruba Ramesh ◽  
Padmaoriya Padmanabhan ◽  
Vidya Gopalan ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
B Cell ◽  
T Lymphocyte ◽  
Vaccine Candidate ◽  
Surface Glycoprotein ◽  
T Cell Epitopes ◽  
B Cell Epitopes ◽  
New Variant

The emergence of a novel coronavirus in China in late 2019 has turned into a SARS-CoV-2 pandemic affecting several millions of people worldwide in a short span of time with high fatality. The crisis is further aggravated by the emergence and evolution of new variant SARS-CoV-2 strains in UK during December, 2020 followed by their transmission to other countries. A major concern is that prophylaxis and therapeutics are not available yet to control and prevent the virus which is spreading at an alarming rate, though several vaccine trials are in the final stage. As vaccines are developed through various strategies, their immunogenic potential may drastically vary and thus pose several challenges in offering both arms of immunity such as humoral and cell-mediated immune responses against the virus. In this study, we adopted an immunoinformatics-aided identification of B cell and T cell epitopes in the Spike protein, which is a surface glycoprotein of SARS-CoV-2, for developing a new Multiepitope vaccine construct (MEVC). MEVC has 575 amino acids and comprises adjuvants and various cytotoxic T-lymphocyte (CTL), helper T-lymphocyte (HTL), and B-cell epitopes that possess the highest affinity for the respective HLA alleles, assembled and joined by linkers. The computational data suggest that the MEVC is non-toxic, non-allergenic and thermostable with the capability to elicit both humoral and cell-mediated immune responses. The population coverage of various countries affected by COVID-19 with respect to the selected B and T cell epitopes in MEVC was also investigated. Subsequently, the biological activity of MEVC was assessed by bioinformatic tools using the interaction between the vaccine candidate and the innate immune system receptors TLR3 and TLR4. The epitopes of the construct were analyzed with that of the strains belonging to various clades including the new variant UK strain having multiple unique mutations in S protein. Due to the advantageous features, the MEVC can be tested in vitro for more practical validation and the study offers immense scope for developing a potential vaccine candidate against SARS-CoV-2 in view of the public health emergency associated with COVID-19 disease caused by SARS-CoV-2.

scholarly journals Protection From Lethal Lassa Disease Can Be Achieved Both Before and After Virus Exposure by Administration of Single-Cycle Replicating Lassa Virus Replicon Particles

2019 ◽  
Vol 220 (8) ◽  
pp. 1281-1289 ◽  
Author(s):  
Markus H Kainulainen ◽  
Jessica R Spengler ◽  
Stephen R Welch ◽  
JoAnn D Coleman-McCray ◽  
Jessica R Harmon ◽  
...  
Keyword(s):  
Vaccine Candidate ◽  
Lassa Fever ◽  
Stable Cell Line ◽  
Lassa Virus ◽  
Single Cycle ◽  
Before And After ◽  
Chronic Morbidity ◽  
Virus Exposure ◽  
High Yields ◽  
Guinea Pig Model

AbstractLassa fever is a frequently severe human disease that is endemic to several countries in West Africa. To date, no licensed vaccines are available to prevent Lassa virus (LASV) infection, even though Lassa fever is thought to be an important disease contributing to mortality and both acute and chronic morbidity. We have previously described a vaccine candidate composed of single-cycle LASV replicon particles (VRPs) and a stable cell line for their production. Here, we refine the genetic composition of the VRPs and demonstrate the ability to reproducibly purify them with high yields. Studies in the guinea pig model confirm efficacy of the vaccine candidate, demonstrate that single-cycle replication is necessary for complete protection by the VRP vaccine, and show that postexposure vaccination can confer protection from lethal outcome.

scholarly journals Induction of Multifunctional Broadly Reactive T Cell Responses by a Plasmodium vivax Circumsporozoite Protein Recombinant Chimera

2015 ◽  
Vol 83 (9) ◽  
pp. 3749-3761 ◽  
Author(s):  
Monica Cabrera-Mora ◽  
Jairo Andres Fonseca ◽  
Balwan Singh ◽  
Joseli Oliveira-Ferreira ◽  
Josué da Costa Lima-Junior ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Plasmodium Vivax ◽  
Vaccine Candidate ◽  
Chimeric Protein ◽  
Plasmodium Yoelii ◽  
Circumsporozoite Protein ◽  
Soluble Form ◽  
Content Type

Plasmodium vivaxis the most widespread species ofPlasmodium, causing up to 50% of the malaria cases occurring outside sub-Saharan Africa. An effective vaccine is essential for successful control and potential eradication. A well-characterized vaccine candidate is the circumsporozoite protein (CSP). Preclinical and clinical trials have shown that both antibodies and cellular immune responses have been correlated with protection induced by immunization with CSP. On the basis of our reported approach of developing chimericPlasmodium yoeliiproteins to enhance protective efficacy, we designed PvRMC-CSP, a recombinant chimeric protein based on theP. vivaxCSP (PvCSP). In this engineered protein, regions of the PvCSP predicted to contain human T cell epitopes were genetically fused to an immunodominant B cell epitope derived from the N-terminal region I and to repeat sequences representing the two types of PvCSP repeats. The chimeric protein was expressed in soluble form with high yield. As the immune response to PvCSP has been reported to be genetically restricted in the murine model, we tested the immunogenicity of PvRMC-CSP in groups of six inbred strains of mice. PvRMC-CSP was able to induce robust antibody responses in all the mouse strains tested. Synthetic peptides representing the allelic forms of theP. vivaxCSP were also recognized to a similar extent regardless of the mouse strain. Furthermore, the immunization regimen induced high frequencies of multifunctional CD4+and CD8+PvRMC-CSP-specific T cells. The depth and breadth of the immune responses elicited suggest that immunization with PvRMC-CSP can circumvent the genetic restriction of the immune response toP. vivaxCSP. Interestingly, PvRMC-CSP was also recognized by naturally acquired antibodies from individuals living in areas where malaria is endemic. These features make PvRMC-CSP a promising vaccine candidate for further development.

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