Cytomegalovirus-Based Vaccine Expressing a Modified Tumor Antigen Induces Potent Tumor-Specific CD8+ T-cell Response and Protects Mice from Melanoma

Qiu, Zhijuan; Huang, Hanchun; Grenier, Jeremy; Perez, Oriana A.; Smilowitz, Henry M.; Adler, Barbara; Khanna, Kamal M.

doi:10.1158/2326-6066.cir-14-0044

Cited by 55 publications

(65 citation statements)

References 49 publications

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“…CMV-based vectors have shown promising results in diverse infectious and cancer models, but the success of these vaccines is considered T cell mediated (5,55,56). Recently, it has been shown that CMV vectors encoding additional antigens also can induce protective anti-melanoma or anti-tetanus toxin antibodies (8,9).…”

Section: Discussionmentioning

confidence: 99%

Viral Persistence Induces Antibody Inflation without Altering Antibody Avidity

Welten

Redeker

Toes

et al. 2016

J Virol

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Antibodies are implicated in long-term immunity against numerous pathogens, and because of this property, antibody induction is the basis for many vaccines. Little is known about the influence of viral persistence on the evolving antibody response. Here, we examined the characteristics of antibody responses to persistent infection by employing the prototypic betaherpesvirus family member cytomegalovirus (CMV) in experimental mouse models. During the course of infection, mouse CMV (MCMV)-specific IgM and IgG responses are elicited; however, IgG levels gradually inflate in the persistent phase of infection while IgM levels are stably maintained. Whereas CD27-CD70 interactions are dispensable, the CD28/B7 costimulatory pathway is critical for the class switching of MCMV-specific IgM-to-IgG B cell responses, which corresponds to the CD28/B7-dependent formation of CD4 ؉ T follicular helper cells (T FH ) and germinal center (GC) B cells. Furthermore, the initial viral inoculum dose dictates the height of the antibody levels during IgG antibody inflation and relates to the induction of long-lived plasma cells and memory B cells. Antibody avidity nonetheless is not altered after the establishment of viral persistence and occurs independently of the inoculum doses. However, repetitive challenge with intact viral particles, accompanied by increased GC reactivity, promotes the development of high-avidity IgG responses with neutralizing capacity. These insights can be used for the rational design of CMV-based vaccines aimed at inducing antibody responses. IMPORTANCE Antibodies provide long-term protection to different pathogens. However, how antibody responses develop during persistent virus infection is not entirely clear.Here, we characterize factors that influence the virus-specific antibody response to persistent CMV. This study describes that during persistent infection, CMV-specific IgM antibody levels are stably maintained while IgG2b and IgG2c levels gradually inflate over time. In contrast, the IgG avidity remains similar after the establishment of viral persistence. The induction of T follicular helper cells and GC B cells requires CD4 ؉ T cell help and CD28/B7 costimulation signals and is essential for the development of CMV-specific IgG antibody responses. Furthermore, neutralizing CMV-specific antibodies appear to develop late after infection, yet the neutralizing capacity can be improved upon repetitive viral challenge that is associated with increased GC reactivity. The results described here could inform the use of CMV-based vaccines and may help to understand how our immune system copes with this persistent virus.T he maintenance of long-lived humoral responses after infection and vaccination is attributed to both long-lived plasma cells that continuously produce antibodies and to memory B cells that are able to form antibody-secreting cells after reexposure (1, 2). Antibodies can protect against numerous pathogens by direct neutralization and/or by supporting effector functions of immune cells (1, ...

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Section: Discussionmentioning

confidence: 99%

Viral Persistence Induces Antibody Inflation without Altering Antibody Avidity

Welten

Redeker

Toes

et al. 2016

J Virol

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“…CD4 inflation has been much less studied. In a seminal work, a CD4 T cell response specific for the MCMV m09 [133][134][135][136][137][138][139][140][141][142][143][144][145][146][147] peptide was found to be inflationary (although the size of the response was less impressive than those observed in CD8 inflation), indicating that CD4 T cell responses are diverse and may be an interesting target for immunization [117]. This will be expanded on the section dedicated to CD4 T response.…”

Section: Cellular Response-t Cellsmentioning

confidence: 99%

“…On the other hand, MCMV vectors carrying modified epitopes with increased antigenicity were shown to induce immune responses that are sufficient to provide protection in therapeutic settings. For instance, the MCMV expressing the B16 melanoma antigen gp100 (MCMV-gp100KGP) induced a strong, long-lasting gp100-specific CD8 T-cell response with a durable, polyfunctional phenotype with inflationary kinetics [147]. The modified gp100 (gp100KGP) expressed by MCMV induces stronger cytotoxic T lymphocyte responses [148] than an MCMV vector with the original gp100 epitope.…”

Section: Cellular Response-t Cellsmentioning

confidence: 99%

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

2019

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Cytomegalovirus (CMV) species have been gaining attention as experimental vaccine vectors inducing cellular immune responses of unparalleled strength and protection. This review outline the strengths and the restrictions of CMV-based vectors, in light of the known aspects of CMV infection, pathogenicity and immunity. We discuss aspects to be considered when optimizing CMV based vaccines, including the innate immune response, the adaptive humoral immunity and the T-cell responses. We also discuss the antigenic epitopes presented by unconventional major histocompatibility complex (MHC) molecules in some CMV delivery systems and considerations about routes for delivery for the induction of systemic or mucosal immune responses. With the first clinical trials initiating, CMV-based vaccine vectors are entering a mature phase of development. This impetus needs to be maintained by scientific advances that feed the progress of this technological platform.Vaccines 2019, 7, 152 2 of 28 CMV-based vaccines, the large pool of functional antigen-specific T cells in the periphery and the possibility to modify CMV genomes due to improvements in viral genetics [11] draw a strong interest to CMV as a vaccine vector [12,13] (Table 1). The inflationary response appears linked to immune protection [14,15] and has been proposed as a target for immunization induction [16]. Vaccines 2019, 7, 152 3 of 28 Full-length HPV16 E6 and E7 Antigen fused to the C-terminus of ie2 Transient limitation of tumour cell growth MCMV IE2E7 [14] MHC-I restricted HPV16 E7 49-57 epitope Epitope fused to the C-terminus of ie2 No tumour cell growth upon challenge MCMV-M79-FKBP-E7 [36] MCMV Smith Strain with FKBP-mediated destabilization of the essential M79 gene Vaccines 2019, 7, 152 5 of 28Besides the exceptional induction of adaptive immune response in humans [2,37], CMV possesses assets that conveniently address weaknesses common to other vector candidates. The cloning of CMV genomes as bacterial artificial chromosomes in Escherichia coli [38] has allowed genetic engineering approaches to effectively express multiple exogenous immunogens or modify large genome portions [39,40]. Furthermore, CMV is known to superinfect hosts with a history of prior exposure to the virus [41] due to its immune evasive properties that protect the virus from recognition by primed T-cells [42] and CMV vectors induce protective immunity in experimentally vaccinated animals with documented prior exposure to 36]. Therefore, CMV vector candidates would avoid immune interference as described for AdV. CMV is a pathogenic organism in immunodeficient populations [43] or in congenitally infected children. Therefore, it is imperative for any HCMV vaccine vector to be attenuated. The generation of replication deficient CMVs that maintain their immunogenicity [36,44] and the modification of genome portions that contain evasions genes [45], as well as the insertion of activating ligands to increase immune control of CMV [46][47][48] are strategies that will be described in this review. Inter...

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“…Most recently, a study by Qiu and colleagues described a cytomegalovirus vector expressing modified tumor antigens. The vaccine candidate elicited tumor-specific T-cell responses, protecting mice from melanoma (73). Another promising study used a live attenuated poliovirus type 1 to vaccinate against glioblastoma multiforme (74).…”

Section: Prospects Advantages and Challenges Of Multivalent And Mulmentioning

confidence: 99%

Multivalent and Multipathogen Viral Vector Vaccines

Lauer

Borrow

Blanchard

2017

Clin Vaccine Immunol

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The presentation and delivery of antigens are crucial for inducing immunity and, desirably, lifelong protection. Recombinant viral vectors-proven safe and successful in veterinary vaccine applications-are ideal shuttles to deliver foreign proteins to induce an immune response with protective antibody levels by mimicking natural infection. Some examples of viral vectors are adenoviruses, measles virus, or poxviruses. The required attributes to qualify as a vaccine vector are as follows: stable insertion of coding sequences into the genome, induction of a protective immune response, a proven safety record, and the potential for large-scale production. The need to develop new vaccines for infectious diseases, increase vaccine accessibility, reduce health costs, and simplify overloaded immunization schedules has driven the idea to combine antigens from the same or various pathogens. To protect effectively, some vaccines require multiple antigens of one pathogen or different pathogen serotypes/serogroups in combination (multivalent or polyvalent vaccines). Future multivalent vaccine candidates are likely to be required for complex diseases like malaria and HIV. Other novel strategies propose an antigen combination of different pathogens to protect against several diseases at once (multidisease or multipathogen vaccines).

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Cytomegalovirus-Based Vaccine Expressing a Modified Tumor Antigen Induces Potent Tumor-Specific CD8+ T-cell Response and Protects Mice from Melanoma

Cited by 55 publications

References 49 publications

Viral Persistence Induces Antibody Inflation without Altering Antibody Avidity

Viral Persistence Induces Antibody Inflation without Altering Antibody Avidity

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

Multivalent and Multipathogen Viral Vector Vaccines

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