An attenuated Lassa vaccine in SIV-infected rhesus macaques does not persist or cause arenavirus disease but does elicit Lassa virus-specific immunity

Zapata, Juan Carlos; Poonia, Bhawna; Bryant, Joseph; Davis, Harry; Ateh, Eugene; George, Lanea; Crasta, Oswald; Zhang, Yan; Slezak, Tom; Jaing, Crystal; Pauza, C. David; Goicochea, Marco; Moshkoff, Dmitry; Lukashevich, Igor S.; Salvato, María S.

doi:10.1186/1743-422x-10-52

Cited by 47 publications

(52 citation statements)

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“…Although it was easier to isolate ML29 virus from SIV-infected macaques, the viremia and levels of ML29 remained transient and low (15). Given the attenuated nature of ML29, those animals did not show increased signs of pathology or shortened life spans due to the SIV infection; however, they did show both humoral and cell-mediated immune responses to LASV GP and NP similar to those of non-SIV-infected animals (15).…”

Section: Discussionmentioning

confidence: 98%

Genetic Variation In Vitro and In Vivo of an Attenuated Lassa Vaccine Candidate

Zapata

Goicochea

Nadai

et al. 2014

J Virol

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The attenuated Lassa vaccine candidate ML29 is a laboratory-produced reassortant between Lassa and Mopeia viruses, two Old World arenaviruses that differ by 40% in nucleic acid sequence. In our previous studies, ML29 elicited sterilizing immunity against Lassa virus challenge in guinea pigs and marmosets and virus-specific cell-mediated immunity in both simian immunodeficiency virus (SIV)-infected and uninfected rhesus macaques. Here, we show that ML29 is stable after 12 passages in vitro without losing its plaque morphology or its attenuated phenotype in suckling mice. Additionally, we used deep sequencing to characterize the viral population comprising the original stock of ML29, the stock of ML29 after 12 passages in Vero cells, and the ML29 isolates obtained from vaccinated animals. Twenty-seven isolates bore approximately 77 mutations that exceeded 20% of the single-nucleotide polymorphism (SNP) changes at any single locus. Of these 77 mutations, 5 appeared to be host specific, for example, appearing in mice but not in primates. None of these mutations were reversions of ML29 to the sequences of the parental Lassa and Mopeia viruses. The host-specific mutations indicate viral adaptations to virus-host interactions, and such interactions make reasonable targets for antiviral approaches. Variants capable of chronic infection did not emerge from any of the primate infections, even in immune-deficient animals, indicating that the ML29 reassortant is reasonably stable in vivo. In conclusion, the preclinical studies of ML29 as a Lassa virus vaccine candidate have been advanced, showing high levels of protection in nonhuman primates and acceptable stability both in vitro and in vivo.

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Section: Discussionmentioning

confidence: 98%

Genetic Variation In Vitro and In Vivo of an Attenuated Lassa Vaccine Candidate

Zapata

Goicochea

Nadai

et al. 2014

J Virol

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“…Accordingly, significant efforts aimed at developing safe and effective vaccines against HFAs have been made (15,39). The Mopeia virus/LASV reassortant ML29 is a promising LASV LAV candidate (40). However, although the genetic differences that distinguish ML29 from the pathogenic LASV are known, the mechanisms of ML29 attenuation remain unknown, which raises concerns about the phenotypic stability of ML29 in response to additional mutations.…”

Section: Discussionmentioning

confidence: 99%

The High Degree of Sequence Plasticity of the Arenavirus Noncoding Intergenic Region (IGR) Enables the Use of a Nonviral Universal Synthetic IGR To Attenuate Arenaviruses

Iwasaki

Cubitt

Sullivan

et al. 2016

J Virol

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Hemorrhagic fever arenaviruses (HFAs) pose important public health problems in regions where they are endemic. Concerns about human-pathogenic arenaviruses are exacerbated because of the lack of FDA-licensed arenavirus vaccines and because current antiarenaviral therapy is limited to an off-label use of ribavirin that is only partially effective. We have recently shown that the noncoding intergenic region (IGR) present in each arenavirus genome segment, the S and L segments (S-IGR and L-IGR, respectively), plays important roles in the control of virus protein expression and that this knowledge could be harnessed for the development of live-attenuated vaccine strains to combat HFAs. In this study, we further investigated the sequence plasticity of the arenavirus IGR. We demonstrate that recombinants of the prototypic arenavirus lymphocytic choriomeningitis virus (rLCMVs), whose S-IGRs were replaced by the S-IGR of Lassa virus (LASV) or an entirely nonviral S-IGR-like sequence (Ssyn), are viable, indicating that the function of S-IGR tolerates a high degree of sequence plasticity. In addition, rLCMVs whose L-IGRs were replaced by Ssyn or S-IGRs of the very distantly related reptarenavirus Golden Gate virus (GGV) were viable and severely attenuated in vivo but able to elicit protective immunity against a lethal challenge with wild-type LCMV. Our findings indicate that replacement of L-IGR by a nonviral Ssyn could serve as a universal molecular determinant of arenavirus attenuation. IMPORTANCEHemorrhagic fever arenaviruses (HFAs) cause high rates of morbidity and mortality and pose important public health problems in regions where they are endemic. Implementation of live-attenuated vaccines (LAVs) will represent a major step to combat HFAs. Here we document that the arenavirus noncoding intergenic region (IGR) has a high degree of plasticity compatible with virus viability. This observation led us to generate recombinant LCMVs containing nonviral synthetic IGRs. These rLCMVs were severely attenuated in vivo but able to elicit protective immunity against a lethal challenge with wild-type LCMV. These nonviral synthetic IGRs can be used as universal molecular determinants of arenavirus attenuation for the rapid development of safe and effective, as well as stable, LAVs to combat HFA. H emorrhagic fever arenaviruses (HFAs) pose important public health problems in regions where they are endemic (1-3). Thus, Lassa virus (LASV) infects several hundred thousand individuals yearly in West Africa, resulting in a high number of Lassa fever (LF) cases, which are associated with high rates of morbidity and significant mortality (4). Notably, increased travel has led to the importation of LF cases into metropolitan areas around the globe where the virus is not endemic (5, 6). Moreover, the regions where LASV is endemic are expanding (4), and the association of the recently identified arenavirus Lujo virus with a recent outbreak of hemorrhagic fever in South Africa (7, 8) has raised concerns about the emergence of novel HF...

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“…These studies have shown that use of NP, GPC or the 2 G proteins or a combination of NP/GPC is protective in a variety of animal models. 10,14,15,[42][43][44][45][46][47][48][49][50][51][52][53][54][55][56] Studies of convalescent sera from patients with Lassa Fever or human HLA transgenic mice identified a number of epitope targets within the NP, GP1, GP2 and GS proteins. 11,12,16,19,[57][58][59][60][61][62][63] Recent work in a guinea pig model utilizing the GP1 and GP2 proteins in a DNA vaccine resulted in adequate protection from challenge virus.…”

Section: Discussionmentioning

confidence: 99%

VaxCelerate II: Rapid development of a self-assembling vaccine for Lassa fever

Leblanc

Moise

Luza

et al. 2014

Human Vaccines & Immunotherapeutics

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Development of effective vaccines against emerging infectious diseases (EID) can take as much or more than a decade to progress from pathogen isolation/identification to clinical approval. As a result, conventional approaches fail to produce field-ready vaccines before the EID has spread extensively. Lassa is a prototypical emerging infectious disease endemic to West Africa for which no successful vaccine is available. We established the VaxCelerate Consortium to address the need for more rapid vaccine development by creating a platform capable of generating and pre-clinically testing a new vaccine against specific pathogen targets in less than 120 d. A self-assembling vaccine is at the core of the approach. It consists of a fusion protein composed of the immunostimulatory Mycobacterium tuberculosis heat shock protein 70 (MtbHSP70) and the biotin binding protein, avidin. Mixing the resulting protein (MAV) with biotinylated pathogen-specific immunogenic peptides yields a self-assembled vaccine (SAV). To meet the time constraint imposed on this project, we used a distributed R&D model involving experts in the fields of protein engineering and production, bioinformatics, peptide synthesis/design and GMP/GLP manufacturing and testing standards. SAV immunogenicity was first tested using H1N1 influenza specific peptides and the entire VaxCelerate process was then tested in a mock live-fire exercise targeting Lassa fever virus. We demonstrated that the Lassa fever vaccine induced significantly increased class II peptide specific interferon-g CD4C T cell responses in HLA-DR3 transgenic mice compared to peptide or MAV alone controls. We thereby demonstrated that our SAV in combination with a distributed development model may facilitate accelerated regulatory review by using an identical design for each vaccine and by applying safety and efficacy assessment tools that are more relevant to human vaccine responses than current animal models.

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An attenuated Lassa vaccine in SIV-infected rhesus macaques does not persist or cause arenavirus disease but does elicit Lassa virus-specific immunity

Cited by 47 publications

References 50 publications

Genetic Variation In Vitro and In Vivo of an Attenuated Lassa Vaccine Candidate

Genetic Variation In Vitro and In Vivo of an Attenuated Lassa Vaccine Candidate

The High Degree of Sequence Plasticity of the Arenavirus Noncoding Intergenic Region (IGR) Enables the Use of a Nonviral Universal Synthetic IGR To Attenuate Arenaviruses

VaxCelerate II: Rapid development of a self-assembling vaccine for Lassa fever

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