A Novel Murine Cytomegalovirus Vaccine Vector Protects against <i>Mycobacterium tuberculosis</i>

Beverley, Peter C. L.; Ruzsics, Zsolt; Hey, Ariann; Hutchings, Claire; Simone, Boos; Bolinger, Beatrice; Marchi, Emanuele; O’Hara, Geraldine; Klenerman, Paul; Koszinowski, Ulrich H.; Tchilian, Elma

doi:10.4049/jimmunol.1302523

Cited by 42 publications

(38 citation statements)

References 62 publications

(110 reference statements)

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“…13 This approach has also been shown to protect against other infectious diseases, including Ebola and tuberculosis, in various animal models. 12, 14, 15, 16, 17, 18 Similar vectors have been evaluated for therapeutic utility against cancer leading to delayed growth or rejection of tumors and even for the purpose of immunocontraception in mice. 19, 20, 21 …”

Section: Introductionmentioning

confidence: 99%

Intranasal administration of RSV antigen-expressing MCMV elicits robust tissue-resident effector and effector memory CD8+ T cells in the lung

et al. 2017

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Cytomegalovirus vectors are promising delivery vehicles for vaccine strategies that aim to elicit effector CD8+ T cells. To determine how the route of immunization affects CD8+ T cell responses in the lungs of mice vaccinated with a murine cytomegalovirus vector expressing the respiratory syncytial virus matrix (M) protein, we infected CB6F1 mice via the intranasal or intraperitoneal route and evaluated the M-specific CD8+ T cell response at early and late time points. We found that intranasal vaccination generated robust and durable tissue-resident effector and effector memory CD8+ T cell populations that were undetectable after intraperitoneal vaccination. The generation of these antigen-experienced cells by intranasal vaccination resulted in earlier T cell responses, interferon gamma secretion, and viral clearance after respiratory syncytial virus challenge. Collectively, these findings validate a novel approach to vaccination that emphasizes the route of delivery as a key determinant of immune priming at the site of vulnerability.

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Section: Introductionmentioning

confidence: 99%

Intranasal administration of RSV antigen-expressing MCMV elicits robust tissue-resident effector and effector memory CD8+ T cells in the lung

et al. 2017

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“…The antigen-specific CD8 + T cells during latent infection bear predominantly a CD8T EM phenotype and localize in secondary lymphoid or non-lymphoid organs [14]. They may provide immune protection against diverse viral targets [13, 15–18], but also against bacterial [19] or tumor antigens [20, 21].…”

Section: Introductionmentioning

confidence: 99%

Mucosal CD8+ T cell responses induced by an MCMV based vaccine vector confer protection against influenza challenge

Zheng

Oduro

Boehme

et al. 2018

Preprint

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20Cytomegalovirus (CMV) is a ubiquitous β-herpesvirus that establishes life-long latent infection 21 in a high percentage of the population worldwide. CMV induces the strongest and most durable 22 CD8 + T cell response known in human clinical medicine. Due to its unique properties, the virus 23 represents a promising candidate vaccine vector for the induction of persistent cellular 24 immunity. To take advantage of this, we constructed a recombinant murine CMV (MCMV) 48 but only if we administered it through the nose, to activate killer T cells that will persist in the 49 lungs close to the airways. Therefore, our data show that the subset of lung-resident killer T 50 cells is sufficient to protect against influenza. 3 51 Introduction 52 Respiratory infections caused by influenza viruses usually are associated with mild-to-53 moderate disease symptoms but are linked with high morbidity and mortality in susceptible 54 populations like the elderly, young children, patients with co-morbidities and 55 immunocompromised patients. Influenza virus causes seasonal epidemics, with typically 3 to 56 5 million cases of severe illness worldwide, according to WHO reports [1], and influenza type 57 A viruses (IAV) cause the more severe disease form. Vaccines against influenza are based on 58 the induction of adaptive immunity that targets the projected yearly epidemics. While most 59 vaccines are based on inactivated IAV formulations inducing anti-IAV IgG responses, live 60 attenuated influenza vaccines (LAIV) are also used as formulations for i.n. administration. This 61 is based on the assumption that the induction of local immunity may provide superior immune 62 protection [2, 3]. However, it remains unclear whether this protection depends on local IgA 63 responses, on cytotoxic T cell responses, or on their combined antiviral activity. Of note, 64 functional T cell responses were shown to substantially contribute to antiviral IAV immunity [4-65 6]. In particular, cytotoxic influenza-specific CD8 + T lymphocytes (CTLs) promote viral 66 clearance indirectly by secretion of pro-inflammatory cytokines such as IFNγ [7] and directly 67 by perforin/Fas-mediated killing of infected epithelial cells in the bronchoalveolar space [8]. 68 However, it remained unclear if T cell responses alone may control IAV, or if Ig responses were 69 the crucial contributor to LAIV-mediated immune protection. We considered that this question 70 could be addressed by developing a vaccine formulation that optimizes T cell responses 71 against IAV, while excluding the humoral ones. 72 CMV infection induces sustained functional T cell responses that are stronger in the long-term 73 than the immune response to any other infectious pathogen [9]. Experiments in the mouse 74 model have shown that defined CMV epitope-specific CD8 + T cells accumulate in tissues and 75 blood and are maintained at stable high levels during mouse CMV (MCMV) latency [10]. This 76 phenomenon was termed ''Memory Inflation'' [11]. While some MCMV derived peptides, as the 77 ones de...

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“…2A, C57BL/6 mice were inoculated twice with MCMV-HBs, and then challenged with an HBV-expressing plasmid through HDI (see the Methods section for experimental details). Since the MCMV infection itself can negatively influence other infections (34) including HBV (35), the parental MCMV (‘MCMV’) devoid of the HBsAg expression cassette was included as negative control. While mice infected with empty MCMV exhibited continuous HBV viremia, the clearance of serum HBsAg, HBeAg, and HBV DNA was significantly accelerated in mice that received the MCMV-HBs vaccine (Fig.…”

Section: Resultsmentioning

confidence: 99%

Prophylactic and therapeutic HBV vaccination by an HBs-expressing cytomegalovirus vector lacking an interferon antagonist

Huang

Liu²,

Rückborn

et al. 2020

Preprint

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Cytomegalovirus (CMV)-based vaccines show promising effects against chronic infections in non-human primates. Therefore, we examined the potential of HBV vaccines based on mouse CMV (MCMV) vectors expressing the small HBsAg. Immunological consequences of vaccine virus attenuation were addressed by either replacing the dispensable gene m157 (‘MCMV-HBs’) or the gene M27 (‘ΔM27-HBs’), the latter encodes a potent interferon antagonist targeting the transcription factor STAT2. M27 was chosen, since human cytomegalovirus (HCMV) encodes an analogous gene product, which also induced proteasomal STAT2 degradation by exploiting Cullin RING ubiquitin ligases. Vaccinated mice were challenged with HBV through hydrodynamic injection. MCMV-HBs and ΔM27-HBs vaccination achieved accelerated HBV clearance in serum and liver as well as robust HBV-specific CD8+ T cell responses. When we explored the therapeutic potential of MCMV-based vaccines, especially the combination of ΔM27-HBs prime and DNA boost vaccination resulted in increased intrahepatic HBs-specific CD8+ T cell responses and HBV clearance in persistently infected mice. Our results demonstrated that vaccines based on a replication competent MCMV attenuated through the deletion of an interferon antagonist targeting STAT2 elicit robust anti-HBV immune responses and mediate HBV clearance in mice in prophylactic and therapeutic immunization regimes.

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A Novel Murine Cytomegalovirus Vaccine Vector Protects against Mycobacterium tuberculosis

Cited by 42 publications

References 62 publications

Intranasal administration of RSV antigen-expressing MCMV elicits robust tissue-resident effector and effector memory CD8+ T cells in the lung

Intranasal administration of RSV antigen-expressing MCMV elicits robust tissue-resident effector and effector memory CD8+ T cells in the lung

Mucosal CD8+ T cell responses induced by an MCMV based vaccine vector confer protection against influenza challenge

Prophylactic and therapeutic HBV vaccination by an HBs-expressing cytomegalovirus vector lacking an interferon antagonist

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