Prevention of Infection by a Granulocyte-Macrophage Colony-Stimulating Factor Co-Expressing DNA/Modified Vaccinia Ankara Simian Immunodeficiency Virus Vaccine

Lai, Lilin; Kwa, Suefen; Kozlowski, Pamela A.; Montefiori, David C.; Ferrari, Guido; Johnson, Welkin E.; Hirsch, Vanessa M.; Villinger, François; Chennareddi, Lakshmi; Earl, Patricia L.; Moss, Bernard; Amara, Rama Rao; Robinson, Harriet L.

doi:10.1093/infdis/jir199

Cited by 95 publications

(137 citation statements)

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“…Protection against viral acquisition has recently been demonstrated using a variety of vaccine regimens, including replicating vectors, and different challenge viruses. Lai et al (11), using a combination of DNA prime and modified vaccinia Ankara boost, reported significant protection against infection with the heterologous SIVsmE660 in macaques receiving GM-CSF as vaccine adjuvant. Protection correlated with the avidity of Ab against Env of the challenge virus.…”

Section: Discussionmentioning

confidence: 99%

“…The RV144 clinical trial showed modest protection against infection, and this protection apparently correlated with anti-Env bAb, especially IgG antibodies against the V1V2 region (22, 23), but no evidence of vaccine-induced virus control was found in the individuals who became infected. Clearly, a vaccine regimen able to prevent acquisition (11,19,20,24) and reduce viral replication after infection has become possible (11,19,24) using the macaque model. In agreement with those findings, we report that our SIVmac239-based vaccine elicited systemic and mucosal anti-Env humoral immune responses able to significantly delay acquisition of the heterologous SIVsmE660, and SIV-specific cellular responses that efficiently contribute to postacquisition control of viral replication.…”

Section: Discussionmentioning

confidence: 99%

“…The control group received empty vector or rmIL-12 DNA, respectively (n = 4 each). The animals were challenged intrarectally at weekly intervals using a well-characterized SIVsmE660 stock (11).…”

Section: Methodsmentioning

confidence: 99%

“…Inclusion of inactivated viral particles in the vaccine further increased the Ab levels, especially against Env (see below). After a rest period of 26 wk, the macaques were challenged intrarectally at weekly intervals with a titrated dose of a well-characterized heterologous SIVsmE660 (11). Within this swarm, the SIVsmE660 Env variants differ by ∼17% from the SIVmac239 Env sequence, mimicking the interclade Env diversity of HIV-1.…”

mentioning

confidence: 99%

“…Within this swarm, the SIVsmE660 Env variants differ by ∼17% from the SIVmac239 Env sequence, mimicking the interclade Env diversity of HIV-1. The control group was expanded by 15 previously reported animals (11,12), which were challenged with the same SIVsmE660 viral stock using an identical infection protocol (Table S2). After 11 challenges all control animals became infected, whereas after 14 challenges two of the eight animals from group 2 (DNA+protein coimmunization) still remained uninfected (Fig.…”

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DNA and virus particle vaccination protects against acquisition and confers control of viremia upon heterologous simian immunodeficiency virus challenge

Patel¹,

Jalah

Kulkarni

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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116

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We have previously shown that macaques vaccinated with DNA vectors expressing SIVmac239 antigens developed potent immune responses able to reduce viremia upon high-dose SIVmac251 challenge. To further improve vaccine-induced immunity and protection, we combined the SIVmac239 DNA vaccine with protein immunization using inactivated SIVmac239 viral particles as protein source. Twenty-six weeks after the last vaccination, the animals were challenged intrarectally at weekly intervals with a titrated dose of the heterologous SIVsmE660. Two of DNA-protein coimmunized macaques did not become infected after 14 challenges, but all controls were infected by 11 challenges. Vaccinated macaques showed modest protection from SIVsmE660 acquisition compared with naïve controls (P = 0.050; stratified for TRIM5α genotype). Vaccinees had significantly lower peak (1.6 log, P = 0.0048) and chronic phase viremia (P = 0.044), with 73% of the vaccinees suppressing viral replication to levels below assay detection during the 40-wk follow-up. Vaccine-induced immune responses associated significantly with virus control: binding antibody titers and the presence of rectal IgG to SIVsmE660 Env correlated with delayed SIVsmE660 acquisition; SIV-specific cytotoxic T cells, prechallenge CD4 + effector memory, and postchallenge CD8 + transitional memory cells correlated with control of viremia. Thus, SIVmac239 DNA and proteinbased vaccine protocols were able to achieve high, persistent, broad, and effective cellular and humoral immune responses able to delay heterologous SIVsmE660 infection and to provide long-term control of viremia. These studies support a role of DNA and protein-based vaccines for development of an efficacious HIV/AIDS vaccine.T he use of a combination vaccine consisting of the recombinant Canarypox ALVAC-HIV (vCP1521; containing Gag, PR, and Env) together with gp120 Env protein (AIDSVAX B/E) resulted in modest, but statistically significant protection from infection in the RV144 vaccine trial conducted in Thailand (1). The limited efficacy and the fact that the vaccine-induced responses waned over time suggest that improved vaccine designs are needed to achieve long-lasting cross-clade-specific immune responses able to prevent infection. Rhesus macaque simian immunodeficiency virus (SIV) challenge models provide an excellent system to test different vaccine modalities and to compare efficacy using different challenge viruses and infection routes.DNA as priming immunization together with boosting by recombinant viral vectors is a vaccine platform widely used in the HIV/SIV field. DNA as the only vaccine component has been considered poorly immunogenic in humans, although recent results showed that in vivo DNA electroporation (EP) results in more efficient vaccine delivery, a higher frequency of responders, and higher, longer-lasting immunity than needle/syringe delivery (2). Similarly, the inclusion of DNA encoding the cytokine IL-12 as molecular adjuvant has been shown to be advantageous (3). These recent data suggest that DN...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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DNA and virus particle vaccination protects against acquisition and confers control of viremia upon heterologous simian immunodeficiency virus challenge

Patel¹,

Jalah

Kulkarni

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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116

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Nonhuman Primate Models for HIV/AIDS Vaccine Development

et al. 2013

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The development of HIV vaccines has been hampered by the lack of an animal model that can accurately predict vaccine efficacy. Chimpanzees can be infected with HIV-1 but are not practical for research. However, several species of macaques are susceptible to the Simian Immunodeficiency Viruses (SIV) that causes a disease in macaques that closely mimics HIV in humans. Thus, macaque-SIV models of HIV infection have become a critical foundation for AIDS vaccine development. Here, we examine the multiple variables and considerations that must be taken into account to use this NHP model effectively. These include the species and subspecies of macaques, virus strain, dose and route of administration and macaque genetics including Major Histocompatibility Complex molecules that affect immune responses and other virus restriction factors. We illustrate how these NHP models can be used to carry out studies of immune responses in mucosal and other tissues than could not easily be performed on human volunteers. Futhermore macaques are an ideal model system to optimize adjuvants, test vaccine platforms, and identify correlates of protection that can advance the HIV vaccine field. We also illustrate techniques used to identify different macaque lymphocyte populations and review some poxvirus vaccine candidates that are in various stages of clinical trials. Understanding how to effectively use this valuable model will greatly increase the likelihood of finding a successful vaccine for HIV.

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‘Omics Investigations of HIV and SIV Pathogenesis and Innate Immunity

Palermo

Fuller

2012

Current Topics in Microbiology and Immunology

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In the 30 years since the advent of the AIDS epidemic, the biomedical community has put forward a battery of molecular therapies that are based on the accumulated knowledge of a limited number of viral targets. Despite these accomplishments, the community still confronts unanswered foundational questions about HIV infection. What are the cellular or biomolecular processes behind HIV pathogenesis? Can we elucidate the characteristics that distinguish those individuals who are naturally resistant to either infection or disease progression? The discovery of simian immunodeficiency viruses (SIVs) and the ensuing development of in vivo, nonhuman primate (NHP) infection models was a tremendous advance, especially in abetting the exploration of vaccine strategies. And while there have been numerous NHP infection models and vaccine trials performed, fundamental questions remain regarding host-virus interactions and immune correlates of protection. These issues are, perhaps, most starkly illustrated with the appreciation that many species of African nonhuman primates are naturally infected with strains of SIV that do not cause any appreciable disease while replicating to viral loads that match or exceed those seen with pathogenic SIV infections in Asian species of nonhuman primates. The last decade has seen the establishment of high-throughput molecular profiling tools, such as microarrays for transcriptomics, SNP arrays for genome features, and LC-MS techniques for proteins or metabolites. These provide the capacity to interrogate a biological model at a comprehensive, systems level, in contrast to historical approaches that characterized a few genes or proteins in an experiment. These methods have already had revolutionary impacts in understanding human diseases originating within the host genome such as genetic disorders and cancer, and the methods are finding increasing application in the context of infectious disease. We will provide a review of the use of such 'omics investigations as applied to understanding of HIV pathogenesis and innate immunity, drawing from our own research as well as the literature examples that utilized in vitro cell-based models or studies in nonhuman primates. We will also discuss the potential for systems biology to help guide strategies for HIV vaccines that offer significant protection by either preventing acquisition or strongly suppressing viral replication levels post-infection.

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Prevention of Infection by a Granulocyte-Macrophage Colony-Stimulating Factor Co-Expressing DNA/Modified Vaccinia Ankara Simian Immunodeficiency Virus Vaccine

Cited by 95 publications

References 46 publications

DNA and virus particle vaccination protects against acquisition and confers control of viremia upon heterologous simian immunodeficiency virus challenge

DNA and virus particle vaccination protects against acquisition and confers control of viremia upon heterologous simian immunodeficiency virus challenge

Nonhuman Primate Models for HIV/AIDS Vaccine Development

‘Omics Investigations of HIV and SIV Pathogenesis and Innate Immunity

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