A Replicating Adenovirus Capsid Display Recombinant Elicits Antibodies against Plasmodium falciparum Sporozoites in Aotus nancymaae Monkeys

Karen, Kasey A.; Deal, Cailin; Adams, Robert J.; Nielsen, Carolyn M.; Ward, Cameron; Espinosa, Diego A.; Xie, Jane; Zavala, Fidel; Ketner, Gary

doi:10.1128/iai.02626-14

Cited by 11 publications

(9 citation statements)

References 38 publications

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“…Recently, a hexon modified adenovirus expressing a P . falciparum CSP epitope tested in monkeys reported differences in the strength of the humoral response which were attributed to the genetic diversity of the Aotus population [ 73 ]. We have been able to circumvent genetic restriction towards Plasmodium antigens both in mice [ 36 ] and humans [ 64 , 65 ] using our promiscuous T cell epitopes as critical component of the vaccine construct, this could also explain the less variability in the mice receiving the Ad5PyT53+P+P regimen.…”

Section: Discussionmentioning

confidence: 99%

A Plasmodium Promiscuous T Cell Epitope Delivered within the Ad5 Hexon Protein Enhances the Protective Efficacy of a Protein Based Malaria Vaccine

et al. 2016

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A malaria vaccine is a public health priority. In order to produce an effective vaccine, a multistage approach targeting both the blood and the liver stage infection is desirable. The vaccine candidates also need to induce balanced immune responses including antibodies, CD4+ and CD8+ T cells. Protein-based subunit vaccines like RTS,S are able to induce strong antibody response but poor cellular reactivity. Adenoviral vectors have been effective inducing protective CD8+ T cell responses in several models including malaria; nonetheless this vaccine platform exhibits a limited induction of humoral immune responses. Two approaches have been used to improve the humoral immunogenicity of recombinant adenovirus vectors, the use of heterologous prime-boost regimens with recombinant proteins or the genetic modification of the hypervariable regions (HVR) of the capsid protein hexon to express B cell epitopes of interest. In this study, we describe the development of capsid modified Ad5 vectors that express a promiscuous Plasmodium yoelii T helper epitope denominated PyT53 within the hexon HVR2 region. Several regimens were tested in mice to determine the relevance of the hexon modification in enhancing protective immune responses induced by the previously described protein-based multi-stage experimental vaccine PyCMP. A heterologous prime-boost immunization regime that combines a hexon modified vector with transgenic expression of PyCMP followed by protein immunizations resulted in the induction of robust antibody and cellular immune responses in comparison to a similar regimen that includes a vector with unmodified hexon. These differences in immunogenicity translated into a better protective efficacy against both the hepatic and red blood cell stages of P. yoelii. To our knowledge, this is the first time that a hexon modification is used to deliver a promiscuous T cell epitope. Our data support the use of such modification to enhance the immunogenicity and protective efficacy of adenoviral based malaria vaccines.

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Section: Discussionmentioning

confidence: 99%

A Plasmodium Promiscuous T Cell Epitope Delivered within the Ad5 Hexon Protein Enhances the Protective Efficacy of a Protein Based Malaria Vaccine

et al. 2016

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“…Lysates were screened by immunoblotting for reactivity with the L2 antibody RG-1 to confirm that they contained the L2 peptide. Recombinant adenovirus 1Ins was prepared by recombination in transfected 293 cells between the shuttle plasmid and virion DNA derived from a viable Ad5 recombinant bearing a Plasmodium falciparum circumsporozoite epitope (CSP) in hexon [ 55 ]. The recipient DNA was digested with NdeI , which cleaves the recombinant at a single site in hexon, reducing plaque formation by the parental virus.…”

Section: Methodsmentioning

confidence: 99%

Capsid display of a conserved human papillomavirus L2 peptide in the adenovirus 5 hexon protein: a candidate prophylactic hpv vaccine approach

Alkutkar

Karanam

et al. 2015

Virol J

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BackgroundInfection by any one of 15 high risk human papillomavirus (hrHPV) types causes most invasive cervical cancers. Their oncogenic genome is encapsidated by L1 (major) and L2 (minor) coat proteins. Current HPV prophylactic vaccines are composed of L1 virus-like particles (VLP) that elicit type restricted immunity. An N-terminal region of L2 protein identified by neutralizing monoclonal antibodies comprises a protective epitope conserved among HPV types, but it is weakly immunogenic compared to L1 VLP. The major antigenic capsid protein of adenovirus type 5 (Ad5) is hexon which contains 9 hypervariable regions (HVRs) that form the immunodominant neutralizing epitopes. Insertion of weakly antigenic foreign B cell epitopes into these HVRs has shown promise in eliciting robust neutralizing antibody responses. Thus here we sought to generate a broadly protective prophylactic HPV vaccine candidate by inserting a conserved protective L2 epitope into the Ad5 hexon protein for VLP-like display.MethodsFour recombinant adenoviruses were generated without significant compromise of viral replication by introduction of HPV16 amino acids L2 12–41 into Ad5 hexon, either by insertion into, or substitution of, either hexon HVR1 or HVR5.ResultsVaccination of mice three times with each of these L2-recombinant adenoviruses induced similarly robust adenovirus-specific serum antibody but weak titers against L2. These L2-specific responses were enhanced by vaccination in the presence of alum and monophoryl lipid A adjuvant. Sera obtained after the third immunization exhibited low neutralizing antibody titers against HPV16 and HPV73. L2-recombinant adenovirus vaccination without adjuvant provided partial protection of mice against HPV16 challenge to either the vagina or skin. In contrast, vaccination with each L2-recombinant adenovirus formulated in adjuvant provided robust protection against vaginal challenge with HPV16, but not against HPV56.ConclusionWe conclude that introduction of HPV16 L2 12–41 epitope into Ad5 hexon HVR1 or HVR5 is a feasible method of generating a protective HPV vaccine, but further optimization is required to strengthen the L2-specific response and broaden protection to the more diverse hrHPV.

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“…Successful epitope-display and antigen-specific immune responses in mice have been demonstrated for HAdV5 expressing the target epitope on HVR1 [ 56 , 57 , 58 , 59 , 62 , 63 ] ( Aotus nancymaae [ 58 ]), HVR5 [ 63 , 69 , 70 ] and HVR2 [ 70 ]. In particular, antigen-display via HVR1 is highly versatile.…”

Section: Hexon Antigen Displaymentioning

confidence: 99%

Progress in Adenoviral Capsid-Display Vaccines

Vujadinovic

Vellinga

2018

Biomedicines

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Adenoviral vectored vaccines against infectious diseases are currently in clinical trials due to their capacity to induce potent antigen-specific B- and T-cell immune responses. Heterologous prime-boost vaccination with adenoviral vector and, for example, adjuvanted protein-based vaccines can further enhance antigen-specific immune responses. Although leading to potent immune responses, these heterologous prime-boost regimens may be complex and impact manufacturing costs limiting efficient implementation. Typically, adenoviral vectors are engineered to genetically encode a transgene in the E1 region and utilize the host cell machinery to express the encoded antigen and thereby induce immune responses. Similarly, adenoviral vectors can be engineered to display foreign immunogenic peptides on the capsid-surface by insertion of antigens in capsid proteins hexon, fiber and protein IX. The ability to use adenoviral vectors as antigen-display particles, with or without using the genetic vaccine function, greatly increases the versatility of the adenoviral vector for vaccine development. This review describes the application of adenoviral capsid antigen-display vaccine vectors by focusing on their distinct advantages and possible limitations in vaccine development.

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A Replicating Adenovirus Capsid Display Recombinant Elicits Antibodies against Plasmodium falciparum Sporozoites in Aotus nancymaae Monkeys

Cited by 11 publications

References 38 publications

A Plasmodium Promiscuous T Cell Epitope Delivered within the Ad5 Hexon Protein Enhances the Protective Efficacy of a Protein Based Malaria Vaccine

A Plasmodium Promiscuous T Cell Epitope Delivered within the Ad5 Hexon Protein Enhances the Protective Efficacy of a Protein Based Malaria Vaccine

Capsid display of a conserved human papillomavirus L2 peptide in the adenovirus 5 hexon protein: a candidate prophylactic hpv vaccine approach

Progress in Adenoviral Capsid-Display Vaccines

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