Comparative Cell‐Mediated Immunogenicity of DNA/DNA, DNA/Adenovirus Type 5 (Ad5), or Ad5/Ad5 HIV‐1 Clade B<i>gag</i>Vaccine Prime‐Boost Regimens

Asmuth, David M.; Brown, Elizabeth Levine; DiNubile, Mark J.; Sun, Xiao; Rı́o, Carlos del; Harro, Clayton; Keefer, Michael C.; Kublin, James G.; Dubey, Sheri; Kierstead, Lisa; Casimiro, Danilo R.; Shiver, John W.; Robertson, Michael; Quirk, Erin; Mehrotra, Devan V.

doi:10.1086/648591

Cited by 48 publications

(51 citation statements)

References 38 publications

(54 reference statements)

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“…rAd5 genetic vaccines for EBOV provide potent protective immunity in macaques and have been proven safe and immunogenic in human clinical trials (2,12,16,21). Studies of macaques and humans have shown that preexisting vector-directed immunity can limit the potency of viral vector-based vaccines (5,29).…”

Section: Resultsmentioning

confidence: 99%

“…Adenovirus-based vaccines have several advantages as human vaccines-they can be produced to high titers under good manufacturing practice (GMP) conditions and have proven to be safe and immunogenic in humans (2,6,12,16,18). While most of the initial vaccine work was conducted using rAd serotype 5 (rAd5) due to its significant potency in eliciting broad antibody and CD8 ϩ T-cell responses, preexisting immunity to rAd5 in humans may limit efficacy (5)(6)(7)29).…”

mentioning

confidence: 99%

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Recombinant Adenovirus Serotype 26 (Ad26) and Ad35 Vaccine Vectors Bypass Immunity to Ad5 and Protect Nonhuman Primates against Ebolavirus Challenge

Geisbert

Bailey

Hensley

et al. 2011

J Virol

186

165

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Replication-defective adenovirus (rAd) vectors are powerful inducers of cellular immune responses and have therefore come to serve as useful vectors for gene-based vaccines, particularly for lentiviruses and filoviruses, as well as other nonviral pathogens (14,34,39,40,43,44,46). Adenovirus-based vaccines have several advantages as human vaccines-they can be produced to high titers under good manufacturing practice (GMP) conditions and have proven to be safe and immunogenic in humans (2,6,12,16,18). While most of the initial vaccine work was conducted using rAd serotype 5 (rAd5) due to its significant potency in eliciting broad antibody and CD8 ϩ T-cell responses, preexisting immunity to rAd5 in humans may limit efficacy (5-7, 29). This property might restrict the use of rAd5 vectors in clinical applications for many vaccines that are currently in development, including those for Ebolavirus (EBOV) and Marburg virus (MARV).To circumvent the issue of preexisting immunity to rAd5, several alternative vectors are currently under investigation. These include adenoviral vectors derived from rare human serotypes and vectors derived from other animals, such as chimpanzees (1,39,49). Research on the use of animal-derived adenoviral vectors is relatively nascent, while human adenoviruses possess the advantages of having well-characterized biology and tropism on human cells, as well as documented manufacturability (48). Immunogenicity of these vectors and their potential as vaccines has been demonstrated with animal models, primarily as prime-boost combinations with heterologous vectors (1, 41).Adenovirus seroprevalence frequencies are cohort dependent (28), but among the large group of 51 human adenoviruses tested, Ad35 and Ad11 were the most rarely neutralized by sera from six geographic locations (49). rAd35 vector vaccines have been shown to be immunogenic in mice, nonhuman primates (NHPs), and humans and are able to circumvent Ad5 immunity (4,30,31,36,47). rAd35 vectors grow to high titers in cell lines suitable for production of clinical-grade vaccines (13) and have been formulated for injection as well as stable inhalable powder (15). These vectors show efficient transduction of human dendritic cells (8,26) and thus have the capability to mediate high-level antigen delivery and presentation.Prime-boost regimens based on vectors derived from closely related adenovirus serotypes, such as Ad11 and Ad35, both from subgroup B, are less immunogenic than combinations of more genetically and immunologically distinct adenoviral vec-* Corresponding author. Mailing address:

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Recombinant Adenovirus Serotype 26 (Ad26) and Ad35 Vaccine Vectors Bypass Immunity to Ad5 and Protect Nonhuman Primates against Ebolavirus Challenge

Geisbert

Bailey

Hensley

et al. 2011

J Virol

186

165

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“…In addition there was a trend toward greater magnitude of ICS and greater breadth across proteins in group A than B. This hidden priming effect, where the immune response quality is enhanced by the DNA prime, has been seen in trials where adenoviral or poxvirus vectors are used as a boost (18,23,24,26,45,48). The immune response quality and quantity appear to be enhanced by the "hidden" DNA prime and manifests itself by increased polyfunctionality of the T cells and increased numbers of terminally differentiated T cells with a cytotoxic effector potential (19,52).…”

Section: Figmentioning

confidence: 91%

“…The DNA backbone, dose, number of administrations, insert, and method of delivery are all variables associated with effectiveness of the DNA (8,46,47). Some studies have shown that DNA alone is immunogenic in humans, albeit with low-magnitude responses as measured by ELISPOT and/or ICS (26,48,49). Use of Biojector does not seem to enhance immune responses to DNA in either humans or nonhuman primates, though few studies have directly compared standard intramuscular administration of DNA to Biojector in humans (49)(50)(51).…”

Section: Figmentioning

confidence: 99%

Safety and Immunogenicity of DNA Prime and Modified Vaccinia Ankara Virus-HIV Subtype C Vaccine Boost in Healthy Adults

Hayes¹,

Gilmour²,

Lieven³

et al. 2013

Clin. Vaccine Immunol.

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f A randomized, double-blind, placebo-controlled phase I trial was conducted in 32 HIV-uninfected healthy volunteers to assess the safety and immunogenicity of 3 doses of DNA vaccine (Advax) plus 1 dose of recombinant modified vaccinia virus Ankara (MVA) (TBC-M4) or 3 doses of TBC-M4 alone (groups A and B, respectively). Both vaccine regimens were found to be safe and well tolerated. Gamma interferon (IFN-␥) enzyme-linked immunosorbent spot (ELISPOT) assay responses were detected in 1/10 (10%) individuals in group A after three Advax primes and in 9/9 individuals (100%) after the MVA boost. In group B, IFN-␥ ELISPOT responses were detected in 6/12 (50%) and 7/11 (64%) individuals after the second and third MVA vaccinations, respectively. Responses to all vaccine components, but predominantly to Env, were seen. The breadth and magnitude of the T cell response and viral inhibition were greater in group A than in group B, indicating that the quality of the T-cell response was enhanced by the DNA prime. Intracellular cytokine staining indicated that the T-cell responses were polyfunctional but were skewed toward Env with a CD4 ؉ phenotype. At 2 weeks after the last vaccination, HIV-specific antibody responses were detected in all (100%) group B and 1/11 (9.1%) group A vaccinees. Vaccinia virus-specific responses were detected in all (100%) group B and 2/11 (18.2%) group A vaccinees. In conclusion, HIV-specific T-cell responses were seen in the majority of volunteers in groups A and B but with a trend toward greater quality of the T-cell response in group A. Antibody responses were better in group B than in group A.

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“…This candidate was advanced to a Phase IIb efficacy evaluation that was stopped at a scheduled interim analysis when it was apparent that there was no effect on postinfection viral RNA level (Buchbinder et al 2008), despite demonstration of apparent immunogenicity in Phase I clinical trials and evidence of viral load control in the SHIV/NHP model (Shiver et al 2002;Casimiro et al 2003;Wilson et al 2006;Priddy et al 2008;Harro et al 2009;Asmuth et al 2010). Although mechanisms underlying failure of this vaccine remain elusive, one explanation is that this homologous vector vaccine, which elicits frequent IFN-g ELISpot responses (77% of vaccinees overall) when given in three doses, generates a limited breadth of antigen-specific responses (McElrath et al 2008).…”

Section: Adenoviral Vector Vaccine Trialsmentioning

confidence: 99%

Human Immunodeficiency Virus Vaccine Trials

O’Connell

Kim

Corey

et al. 2012

Cold Spring Harbor Perspectives in Medicine

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Comparative Cell‐Mediated Immunogenicity of DNA/DNA, DNA/Adenovirus Type 5 (Ad5), or Ad5/Ad5 HIV‐1 Clade BgagVaccine Prime‐Boost Regimens

Abstract: The DNA vaccine alone or as a priming regimen for the Ad5 vaccine did not increase unfractionated ELISpot responses compared with the Ad5 vaccine alone. Qualitative T cell responses to different vaccine regimens deserve further study.

Cited by 48 publications

References 38 publications

Recombinant Adenovirus Serotype 26 (Ad26) and Ad35 Vaccine Vectors Bypass Immunity to Ad5 and Protect Nonhuman Primates against Ebolavirus Challenge

Recombinant Adenovirus Serotype 26 (Ad26) and Ad35 Vaccine Vectors Bypass Immunity to Ad5 and Protect Nonhuman Primates against Ebolavirus Challenge

Safety and Immunogenicity of DNA Prime and Modified Vaccinia Ankara Virus-HIV Subtype C Vaccine Boost in Healthy Adults

Human Immunodeficiency Virus Vaccine Trials

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