Elsevier

Vaccine

Volume 28, Issue 18, 19 April 2010, Pages 3257-3264
Vaccine

Co-administration of viral vector-based vaccines suppresses antigen-specific effector CD8 T cells

https://doi.org/10.1016/j.vaccine.2010.01.065Get rights and content

Abstract

In this study, we explored immune responses after intramuscular co-administration of the HIV-1 gp160 Env gene-expressing adenovirus (Ad) vector and modified vaccinia virus Ankara (MVA) vector in a mouse model. Surprisingly, the simultaneous vaccination of the two vaccines, either as a mixture or separately, suppressed responses, when compared with the administration of each vaccine separately. Ad vaccine or MVA vaccine, co-administered with a mock MVA or mock Ad vector, also resulted in suppressing HIV-specific effector T-cell responses, and a part of antigen-specific memory T-cell responses. In an in vitro experiment, the two vectors infected individual cells and MVA suppressed the transgene expression produced by the adenovirus vector. This viral interference may involve soluble factor(s), secreted by virus-infected cells. Our study may help in designing a vaccination regimen and in investigating viral interference.

Introduction

Viral interference refers to a phenomenon, whereby infection by one replication-competent virus results in the inhibition of replication of another replication-competent virus. Viral interference has been reported as early as 1954 [1]. A defective interfering virus containing replication origin plays a key role in viral interference. However, viral interference between replication-deficient viruses is still unknown. In this study, we explored antigen-specific immune response induced by co-immunization of the adenovirus (Ad) vector and modified vaccinia virus Ankara (MVA) vector in vivo and transgene expression by two viral vectors in vitro.

In the last decade, several novel vaccine platforms have been studied for their utility in the development of prophylactic vaccines against infection by viral pathogens (e.g., HIV, hepatitis, and influenza viruses). Some of the most important studies have involved vector-based vaccines that utilize Ad and vaccinia vectors. The human Ad is classified into six subgroups, ranging from A to F [2]. Most Ad serotypes belong to subgroups A, C, D, E, and F and use the coxsackievirus and adenovirus receptor (CAR) as a cellular receptor [3]. Ad serum type 5 (Ad5, subgroup C) has well-defined biological properties and has been widely used as a vector in gene therapy and vaccine development. Results from human and non-human primate studies suggest that deficient Ad vectors induce antigen-specific cell-mediated immune responses in vivo[4], [5], [6]. The Ad5 vector is of particular interest since its safety has been proven in clinical trials; it is of high quality; and it can be produced easily [4], [5], [6], [7], [8]. Unfortunately, a recent large-scale phase IIb clinical trial showed that subjects vaccinated 3 times with the Ad5 vector expressing HIV Gag, Pol, and Nef were not protected against HIV infection. Vaccination did not reduce the HIV viral load or improve the CD4 T cell count after HIV infection occurred in the trial participants [9]. Furthermore, a two-fold increase in HIV acquisition was observed among vaccinated recipients, along with increased Ad5-neutralizing antibody titers, when compared with the increase in placebo recipients. This probably occurred because vaccination provides a more conducive environment for HIV replication via the activation of dendritic cells by the Ad5–antibody complex [10].

Another viral vector used in this study was the MVA virus. MVA is derived from live vaccinia virus by more than 500 passages in chicken embryo fibroblast cells. It loses 15% of the genome compared to its parent vaccinia virus, leading to severe restriction in replication and virulence processes [11], [12]. In humans, MVA is a replication-deficient virus. MVA has been safely administered to approximately 120,000 individuals as smallpox vaccine [13], and it has been clinically tested as a vaccine vector against other diseases such as HIV and cancer [14].

Since no single viral vector has been able to protect against HIV infection in clinical trials, the prime-boost regimen using different vaccines has been explored in animal models and has been found to elicit much higher immune response than a single vaccine [6], [15], [16], [17], [18]. However, the effect of the two viral vectors when administered simultaneously is unclear because both the Ad virus and MVA virus are double-stranded, and their viral protein and genome DNA are capable of inducing innate immune responses [19], [20], [21], [22], [23], [24], resulting in type I interferon (IFN) secretion following activation of adaptive immunity. On the other hand, type I interferon has innate antiviral activity against a variety of viruses.

In this study, we co-administered Ad and MVA vectors encoding the HIV-1 gp160 Env gene or reporter genes to mice. We found that immune responses to either vector were suppressed when vectors were co-administered in vivo. The inhibition of adenovirus vector expression by MVA was also confirmed through in vitro experiments. Furthermore, the suppression factor(s) included an undefined soluble protein, besides cytokines such as type I IFN.

Section snippets

Viruses

Two viral vectors were used in this study: One vector was an E1/3-deleted adenovirus vector expressing the secreted alkaline phosphatase SEAP gene (Ad-SEAP), HIVIIIB gp160 Env (Ad-HIV) [4], the green fluorescent protein (Ad-GFP) or mCherry fluorescent protein (Ad-Cherry). Another vector was modified vaccinia virus Ankara expressing HIVBH2 gp160 Env and a report gene LacZ (MVA-HIV, a kind gift from Dr. Bernard Moss, National Institutes of Health, Rockville, MD) or the green fluorescent protein

Effector T cells after co-administration of vaccines

Previously, our group and other researchers have reported that the prime-boost regimen with diverse antigen-expressing viral vectors enhances antigen-specific immune responses to an extent greater than that achieved by an individual vector. In this study, we explored immune responses after vaccination with a mixture of two viral vectors or simultaneous vaccination on different sites. Twelve days after immunization, a single injection of Ad-HIV and MVA-HIV induced 10.3% and 3.7% of HIV-specific

Discussion

In this study, we co-administered Ad-HIV and MVA-HIV, either as a mixture or separately, to mice, and we noticed a suppression of HIV-specific effector CD8 T cell immune responses, by both the tetramer assay and ICS. However, the co-administration increased the proportion of HIV-specific memory CD8 T cells. In vitro experiments indicated that the two replication-deficient viral vectors suppressed the transgene expressions via soluble factor(s) secreted by virus-infected cells. These results

Acknowledgments

We thank NIH Tetramer Core Facility (Atlanta, GA) for tetramers. This work was partially supported by a Grant-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan.

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    S.Y. and M.S. contributed equally to this work.

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