Recombinant rabies virus expressing dog GM-CSF is an efficacious oral rabies vaccine for dogs

Zhou, Ming; Wang, Lei; Zhou, Songqin; Wang, Zhao; Ruan, Juncheng; Tang, Lijun; Jia, Ziming; Cui, Min; Zhao, Ling; Fu, Zhen F.

doi:10.18632/oncotarget.5904

Cited by 33 publications

(24 citation statements)

References 54 publications

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“…Following this rationale, the rRABV expressing GM-CSF (LBNSE-GM-CSF) developed in our previous studies demonstrated the capacity to upregulate DC and B-cell activation both in vitro and in vivo, resulting in enhanced humoral immune responses and protection against rabies in both murine and canine models (10,13,14). Compared with LBNSE-GM-CSF, the rRABV expressing CXCL13 (LBNSE-CXCL13) developed in this study does not promote the activation of DCs in RABV-immunized mice.…”

Section: Discussionmentioning

confidence: 99%

A Novel Rabies Vaccine Expressing CXCL13 Enhances Humoral Immunity by Recruiting both T Follicular Helper and Germinal Center B Cells

Zhao

Zhou

et al. 2017

J Virol

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Rabies remains a public health threat in most parts of the world, and approximately 99% of the cases are transmitted by dogs. There is an urgent need to develop an efficacious and affordable vaccine to control canine-transmitted rabies in developing countries. Our previous studies demonstrate that overexpression of chemokines/cytokines such as CCL-3 (MIP-1␣) and granulocyte-macrophage colonystimulating factor (GM-CSF) can enhance the immunogenicity of rabies vaccines. In the present study, the chemokine CXCL13 was inserted into the genome of the recombinant rabies virus (rRABV) strain LBNSE, and the effect of the chemokine CXCL13 on the immunogenicity of RABV was investigated. It was found that LBNSE-CXCL13 recruited follicular helper T (Tfh) and germinal center (GC) B cells, promoted the formation of GCs, and increased the population of plasma cells in immunized mice. Further studies showed that mice immunized with LBNSE-CXCL13 produced more rabies virus-neutralizing antibodies (VNAs) and developed better protection than those immunized with the parent virus LBNSE or the GM-CSF-expressing RABV (LBNSE-GM-CSF). Collectively, these findings provide a better understanding of the role of CXCL13 expression in the immunogenicity of the RABV, which may help in designing more-efficacious rabies vaccines.IMPORTANCE Rabies is endemic in most parts of the world, and more effort is needed to develop affordable and effective vaccines to control or eliminate this disease. The chemokine CXCL13 recruits both Tfh and B cells, which is essential for the homing of Tfh cells and the development of B cell follicles. In this study, the effect of the overexpression of CXCL13 on the immunogenicity of the RABV was evaluated in a mouse model. We found that CXCL13 expression promoted humoral immunity by recruiting Tfh and GC B cells, facilitating the formation of GCs, and increasing the number of plasma cells. As expected, the overexpression of CXCL13 resulted in enhanced virus-neutralizing antibody (VNA) production and protection against a virulent RABV challenge. These findings provide a better understanding of the role of CXCL13 in RABV-induced immune responses, which will help in designing more efficacious rabies vaccines.KEYWORDS CXCL13, rabies virus, T follicular helper cells, germinal center B cells, humoral immunity R abies, a fatal and ancient neurological disease that occurs in both humans and warm-blooded animals (1, 2), still causes more than 59,000 human deaths every year and poses a potential threat to more than 3.3 billion people (3, 4). Its pathogen,

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Section: Discussionmentioning

confidence: 99%

A Novel Rabies Vaccine Expressing CXCL13 Enhances Humoral Immunity by Recruiting both T Follicular Helper and Germinal Center B Cells

Zhao

Zhou

et al. 2017

J Virol

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“…The ability of MPLA to modulate immune responses has been well studied before [20,32]. Activation of dendritic cells (DC) was reported to contribute to humoral immune responses induced by live rabies vaccine [19,31,33]. In order to evaluate the ability of MPLA to activate DCs in vitro, bone marrow-derived dendritic cells (BMDC) from wild type (WT) mice and TLR4 knock-out (TLR4 −/− ) mice were cultured for 6 days, and then harvested with the above-mentioned method.…”

Section: Mpla Facilitates the Maturation Of Bmdc Via A Tlr4-dependentmentioning

confidence: 99%

Monophosphoryl-Lipid A (MPLA) is an Efficacious Adjuvant for Inactivated Rabies Vaccines

Chen

Zhang

et al. 2019

Viruses

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Rabies, as one of the most threatening zoonoses in the world, causes a fatal central nervous system (CNS) disease. So far, vaccination with rabies vaccines has been the most effective measure to prevent and control this disease. At present, inactivated rabies vaccines are widely used in humans and domestic animals. However, humoral immune responses induced by inactivated rabies vaccines are relatively low and multiple shots are required to achieve protective immunity. Supplementation with an adjuvant is a practical way to improve the immunogenicity of inactivated rabies vaccines. In this study, we found that monophosphoryl-lipid A (MPLA), a well-known TLR4 agonist, could significantly promote the maturation of bone marrow-derived dendritic cells (BMDC) through a TLR4-dependent pathway in vitro and the maturation of conventional DCs (cDCs) in vivo. We also found that MPLA, serving as an adjuvant for inactivated rabies vaccines, could significantly facilitate the generation of T follicular helper (Tfh) cells, germinal center (GC) B cells, and plasma cells (PCs), consequently enhancing the production of RABV-specific total-IgG, IgG2a, IgG2b, and the virus-neutralizing antibodies (VNAs). Furthermore, MPLA could increase the survival ratio of mice challenged with virulent RABV. In conclusion, our results demonstrate that MPLA serving as an adjuvant enhances the intensity of humoral immune responses by activating the cDC–Tfh–GC B axis. Our findings will contribute to the improvement of the efficiency of traditional rabies vaccines.

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“…However, in China, as well as lacking an oral vaccine for the control of rabies in stray dogs and wild animals, no veterinary rabies vaccine has so far been developed or imported for domestic animals except owned dogs [6,7]. Although rabies prophylactic vaccination has been recommended for cattle by the World Organization for Animal Health (OIE), and successfully performed in rabies endemic countries [8], it is uncertain that emergency immunization using local canine rabies vaccine products has been able to block the spread of infection in ruminants.…”

Section: Introductionmentioning

confidence: 99%

Rabies Outbreaks and Vaccination in Domestic Camels and Cattle in Northwest China

Liu

Zhang

et al. 2016

PLoS Negl Trop Dis

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In contrast to many countries where rabies has been well controlled in humans and livestock, even in wildlife, rabies is still endemic in almost regions of China. In Northwest China, rabies transmitted by stray dogs and wild foxes has caused heavy economic losses to local herdsmen, as well as causing numbers of human cases. In this study, as part of an investigation of ways to prevent rabies epidemics in livestock, we report an analysis of domestic cattle and camel rabies cases in Ningxia Hui (NHAR) and Inner Mongolia Autonomous Region (IMAR) and the immune efficacy of canine inactivated rabies vaccines in these animals. We found that rabies viruses from these animals are closely related to dog-hosted China I and fox-associated China III lineages, respectively, indicating that the infections originated from two different sources (dogs and wild foxes). As well as the previously reported Arctic and Arctic-related China IV lineage in IMAR, at least three separate phylogenetic groups of rabies virus consistently exist and spread throughout Northwest China. Since there is no licensed oral vaccine for wild foxes and no inactivated vaccine for large livestock, local canine inactivated vaccine products were used for emergency immunization of beef and milk cattle and bactrian (two-humped) camels in local farms. Compared with a single injection with one (low-efficacy) or three doses (high-cost), a single injection of a double dose of canine vaccine provided low-price and convenience for local veterinarians while inducing levels of virus neutralizing antibodies indicative of protection against rabies for at least 1 year in the cattle and camels. However, licensed vaccines for wildlife and large domestic animals are still needed in China.

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Recombinant rabies virus expressing dog GM-CSF is an efficacious oral rabies vaccine for dogs

Cited by 33 publications

References 54 publications

A Novel Rabies Vaccine Expressing CXCL13 Enhances Humoral Immunity by Recruiting both T Follicular Helper and Germinal Center B Cells

A Novel Rabies Vaccine Expressing CXCL13 Enhances Humoral Immunity by Recruiting both T Follicular Helper and Germinal Center B Cells

Monophosphoryl-Lipid A (MPLA) is an Efficacious Adjuvant for Inactivated Rabies Vaccines

Rabies Outbreaks and Vaccination in Domestic Camels and Cattle in Northwest China

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