Novel vaccine vectors for HIV-1

Dan H. Barouch; Louis J. Picker

doi:10.1038/nrmicro3360

Second-Generation Rabies Virus-Based Vaccine Vectors Expressing Human Immunodeficiency Virus Type 1 Gag Have Greatly Reduced Pathogenicity but Are Highly Immunogenic

Journal of Virology ◽

10.1128/jvi.77.1.237-244.2003 ◽

2003 ◽

Vol 77 (1) ◽

pp. 237-244 ◽

Cited By ~ 73

Author(s):

James P. McGettigan ◽

Roger J. Pomerantz ◽

Catherine A. Siler ◽

Philip M. McKenna ◽

Heather D. Foley ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Rabies Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Second Generation ◽

Great Promise ◽

Vaccine Vectors ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Rabies virus (RV) vaccine strain-based vectors show great promise as vaccines against other viral diseases such as human immunodeficiency virus type 1 (HIV-1) infection and hepatitis C, but a low residual pathogenicity remains a concern for their use. Here we describe several highly attenuated second-generation RV-based vaccine vehicles expressing HIV-1 Gag. For this approach, we modified the previously described RV vaccine vector SPBN by replacing the arginine at position 333 (R333) within the RV glycoprotein (G) with glutamic acid (E333), deleting 43 amino acids of the RV G cytoplasmic domain (CD), or combining the R333 exchange and the CD deletion. In addition, we constructed a new RV vector that expresses HIV-1 Gag from an RV transcription unit upstream of the RV phosphoprotein gene (BNSP-Gag) instead of upstream of the G gene. As expected and as demonstrated for SPBN-Gag, all vaccine vehicles were apathogenic after peripheral administration. However, the new, second-generation vaccine vectors containing modifications in the RV G were also apathogenic after intracranial infection with 105 infectious particles, and BNSP-Gag produced a 50%-reduced mortality in mice. Of note, the observed attenuation of pathogenicity did not result in either the attenuation of the humoral response against the RV G or the previously observed robust cellular response against HIV-1 Gag. These findings demonstrate that very safe and highly effective RV-based vaccines can be constructed and further emphasize their potential utility as efficacious antiviral vaccines.

Download Full-text

Host Restricted Poxviruses Produce Distinct Host Responses in an In Vivo Mouse Model with Implications for Future Use as HIV-1 Vaccine Vectors

AIDS Research and Human Retroviruses ◽

10.1089/aid.2014.5553.abstract ◽

2014 ◽

Vol 30 (S1) ◽

pp. A248-A248

Author(s):

Kristy Offerman ◽

Olivia Carulei ◽

Armin Deffur ◽

Nicola Douglass ◽

Anna-Lise Williamson

Keyword(s):

Mouse Model ◽

Host Responses ◽

Vaccine Vectors ◽

Hiv 1

Download Full-text

Recombinant Isfahan Virus and Vesicular Stomatitis Virus Vaccine Vectors Provide Durable, Multivalent, Single-Dose Protection against Lethal Alphavirus Challenge

Journal of Virology ◽

10.1128/jvi.01729-16 ◽

2017 ◽

Vol 91 (8) ◽

Cited By ~ 9

Author(s):

Farooq Nasar ◽

Demetrius Matassov ◽

Robert L. Seymour ◽

Theresa Latham ◽

Rodion V. Gorchakov ◽

...

Keyword(s):

Single Dose ◽

Vesicular Stomatitis Virus ◽

Clinical Studies ◽

Vaccine Vector ◽

Vaccine Vectors ◽

Content Type ◽

Multivalent Vaccine ◽

Equine Encephalitis Virus ◽

Vesicular Stomatitis ◽

Hiv 1

ABSTRACT The demonstrated clinical efficacy of a recombinant vesicular stomatitis virus (rVSV) vaccine vector has stimulated the investigation of additional serologically distinct Vesiculovirus vectors as therapeutic and/or prophylactic vaccine vectors to combat emerging viral diseases. Among these viral threats are the encephalitic alphaviruses Venezuelan equine encephalitis virus (VEEV) and Eastern equine encephalitis virus (EEEV), which have demonstrated potential for natural disease outbreaks, yet no licensed vaccines are available in the event of an epidemic. Here we report the rescue of recombinant Isfahan virus (rISFV) from genomic cDNA as a potential new vaccine vector platform. The rISFV genome was modified to attenuate virulence and express the VEEV and EEEV E2/E1 surface glycoproteins as vaccine antigens. A single dose of the rISFV vaccine vectors elicited neutralizing antibody responses and protected mice from lethal VEEV and EEEV challenges at 1 month postvaccination as well as lethal VEEV challenge at 8 months postvaccination. A mixture of rISFV vectors expressing the VEEV and EEEV E2/E1 glycoproteins also provided durable, single-dose protection from lethal VEEV and EEEV challenges, demonstrating the potential for a multivalent vaccine formulation. These findings were paralleled in studies with an attenuated form of rVSV expressing the VEEV E2/E1 glycoproteins. Both the rVSV and rISFV vectors were attenuated by using an approach that has demonstrated safety in human trials of an rVSV/HIV-1 vaccine. Vaccines based on either of these vaccine vector platforms may present a safe and effective approach to prevent alphavirus-induced disease in humans. IMPORTANCE This work introduces rISFV as a novel vaccine vector platform that is serologically distinct and phylogenetically distant from VSV. The rISFV vector has been attenuated by an approach used for an rVSV vector that has demonstrated safety in clinical studies. The vaccine potential of the rISFV vector was investigated in a well-established alphavirus disease model. The findings indicate the feasibility of producing a safe, efficacious, multivalent vaccine against the encephalitic alphaviruses VEEV and EEEV, both of which can cause fatal disease. This work also demonstrates the efficacy of an attenuated rVSV vector that has already demonstrated safety and immunogenicity in multiple HIV-1 phase I clinical studies. The absence of serological cross-reactivity between rVSV and rISFV and their phylogenetic divergence within the Vesiculovirus genus indicate potential for two stand-alone vaccine vector platforms that could be used to target multiple bacterial and/or viral agents in successive immunization campaigns or as heterologous prime-boost agents.

Download Full-text

Enhanced humoral HIV-1-specifc immune responses generated from recombinant rhabdoviral-based vaccine vectors co-expressing HIV-1 proteins and IL-2

Virology ◽

10.1016/j.virol.2005.09.004 ◽

2006 ◽

Vol 344 (2) ◽

pp. 363-377 ◽

Cited By ~ 20

Author(s):

James P. McGettigan ◽

Martin L. Koser ◽

Philip M. McKenna ◽

Mary Ellen Smith ◽

Julie M. Marvin ◽

...

Keyword(s):

Immune Responses ◽

Vaccine Vectors ◽

Hiv 1

Download Full-text

Molecular Characterization of Heterologous HIV-1gp120 Gene Expression Disruption inMycobacterium bovisBCG Host Strain: A Critical Issue for Engineering Mycobacterial Based-Vaccine Vectors

Journal of Biomedicine and Biotechnology ◽

10.1155/2010/357370 ◽

2010 ◽

Vol 2010 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Joan Joseph ◽

Raquel Fernández-Lloris ◽

Elías Pezzat ◽

Narcís Saubi ◽

Pere-Joan Cardona ◽

...

Keyword(s):

Gene Expression ◽

Critical Issue ◽

Host Strain ◽

Expression Vectors ◽

Vaccine Vectors ◽

E Coli ◽

Hiv 1 ◽

Complete Deletion ◽

Genetic Rearrangements

Mycobacterium bovisBacillus Calmette-Guérin (BCG) as a live vector of recombinant bacterial vaccine is a promising system to be used. In this study, we evaluate the disrupted expression of heterologous HIV-1gp120 gene in BCG Pasteur host strain using replicative vectors pMV261 and pJH222. pJH222 carries a lysine complementing gene in BCG lysine auxotrophs. The HIV-1 gp120 gene expression was regulated by BCG hsp60 promoter (in plasmid pMV261) andMycobacteriaspp.α-antigen promoter (in plasmid pJH222). Among 14 rBCG:HIV-1gp120 (pMV261) colonies screened, 12 showed a partial deletion and two showed a complete deletion. However, deletion was not observed in all 10 rBCG:HIV-1gp120 (pJH222) colonies screened. In this study, we demonstrated thatE. coli/Mycobacterial expression vectors bearing a weak promoter and lysine complementing gene in a recombinant lysine auxotroph of BCG could prevent genetic rearrangements and disruption of HIV 1gp120 gene expression, a key issue for engineering Mycobacterial based vaccine vectors.

Download Full-text

Erratum: Novel vaccine vectors for HIV-1

Nature Reviews Microbiology ◽

10.1038/nrmicro.2017.134 ◽

2017 ◽

Vol 15 (11) ◽

pp. 696-696 ◽

Cited By ~ 2

Author(s):

Dan H. Barouch ◽

Louis J. Picker

Keyword(s):

Vaccine Vectors ◽

Hiv 1

Download Full-text

Construction and Evaluation of Novel Rhesus Monkey Adenovirus Vaccine Vectors

Journal of Virology ◽

10.1128/jvi.02950-14 ◽

2014 ◽

Vol 89 (3) ◽

pp. 1512-1522 ◽

Cited By ~ 28

Author(s):

Peter Abbink ◽

Lori F. Maxfield ◽

David Ng'ang'a ◽

Erica N. Borducchi ◽

M. Justin Iampietro ◽

...

Keyword(s):

Rhesus Monkey ◽

Sub Saharan Africa ◽

Candidate Vaccine ◽

Human Populations ◽

Potential Candidate ◽

Vaccine Vectors ◽

Humoral And Cellular Immunity ◽

Adenovirus Vectors ◽

Adenovirus Vaccine ◽

Hiv 1

ABSTRACTAdenovirus vectors are widely used as vaccine candidates for a variety of pathogens, including HIV-1. To date, human and chimpanzee adenoviruses have been explored in detail as vaccine vectors. The phylogeny of human and chimpanzee adenoviruses is overlapping, and preexisting humoral and cellular immunity to both are exhibited in human populations worldwide. More distantly related adenoviruses may therefore offer advantages as vaccine vectors. Here we describe the primary isolation and vectorization of three novel adenoviruses from rhesus monkeys. The seroprevalence of these novel rhesus monkey adenovirus vectors was extremely low in sub-Saharan Africa human populations, and these vectors proved to have immunogenicity comparable to that of human and chimpanzee adenovirus vaccine vectors in mice. These rhesus monkey adenoviruses phylogenetically clustered with the poorly described adenovirus species G and robustly stimulated innate immune responses. These novel adenoviruses represent a new class of candidate vaccine vectors.IMPORTANCEAlthough there have been substantial efforts in the development of vaccine vectors from human and chimpanzee adenoviruses, far less is known about rhesus monkey adenoviruses. In this report, we describe the isolation and vectorization of three novel rhesus monkey adenoviruses. These vectors exhibit virologic and immunologic characteristics that make them attractive as potential candidate vaccine vectors for both HIV-1 and other pathogens.

Download Full-text

Attenuation of Replication-Competent Adenovirus Serotype 26 Vaccines by Vectorization

Clinical and Vaccine Immunology ◽

10.1128/cvi.00510-15 ◽

2015 ◽

Vol 22 (11) ◽

pp. 1166-1175 ◽

Cited By ~ 5

Author(s):

Lori F. Maxfield ◽

Peter Abbink ◽

Kathryn E. Stephenson ◽

Erica N. Borducchi ◽

David Ng'ang'a ◽

...

Keyword(s):

Phase 1 ◽

Replicative Capacity ◽

Wild Type ◽

Vaccine Vectors ◽

Gene Insertion ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Transgene Insertion

ABSTRACTReplication-competent adenovirus (rcAd)-based vaccine vectors may theoretically provide immunological advantages over replication-incompetent Ad vectors, but they also raise additional potential clinical and regulatory issues. We produced replication-competent Ad serotype 26 (rcAd26) vectors by adding the E1 region back into a replication-incompetent Ad26 vector backbone with the E3 or E3/E4 regions deleted. We assessed the effect of vectorization on the replicative capacity of the rcAd26 vaccines. Attenuation occurred in a stepwise fashion, with E3 deletion, E4 deletion, and human immunodeficiency virus type 1 (HIV-1) envelope (Env) gene insertion all contributing to reduced replicative capacity compared to that with the wild-type Ad26 vector. The rcAd26 vector with E3 and E4 deleted and containing the Env transgene exhibited 2.7- to 4.4-log-lower replicative capacity than that of the wild-type Ad26in vitro. This rcAd26 vector is currently being evaluated in a phase 1 clinical trial. Attenuation as a result of vectorization and transgene insertion has implications for the clinical development of replication-competent vaccine vectors.

Download Full-text

Characterization of a Single-Cycle Rabies Virus-Based Vaccine Vector

Journal of Virology ◽

10.1128/jvi.01870-09 ◽

2010 ◽

Vol 84 (6) ◽

pp. 2820-2831 ◽

Cited By ~ 34

Author(s):

Emily A. Gomme ◽

Elizabeth J. Faul ◽

Phyllis Flomenberg ◽

James P. McGettigan ◽

Matthias J. Schnell

Keyword(s):

T Cell ◽

Rabies Virus ◽

T Cell Responses ◽

Vaccine Vector ◽

Host Cells ◽

Cytotoxic T Cell ◽

Single Cycle ◽

Vaccine Vectors ◽

Cell Responses ◽

Hiv 1

ABSTRACT Recombinant rabies virus (RV)-based vectors have demonstrated their efficacy in generating long-term, antigen-specific immune responses in murine and monkey models. However, replication-competent viral vectors pose significant safety concerns due to vector pathogenicity. RV pathogenicity is largely attributed to its glycoprotein (RV-G), which facilitates the attachment and entry of RV into host cells. We have developed a live, single-cycle RV by deletion of the G gene from an RV vaccine vector expressing HIV-1 Gag (SPBN-ΔG-Gag). Passage of SPBN-ΔG-Gag on cells stably expressing RV-G allowed efficient propagation of the G-deleted RV. The in vivo immunogenicity data comparing single-cycle RV to a replication-competent control (BNSP-Gag) showed lower RV-specific antibodies; however, the overall isotype profiles (IgG2a/IgG1) were similar for the two vaccine vectors. Despite this difference, mice immunized with SPBN-ΔG-Gag and BNSP-Gag mounted similar levels of Gag-specific CD8+ T-cell responses as measured by major histocompatibility complex class I Gag-tetramer staining, gamma interferon-enzyme-linked immunospot assay, and cytotoxic T-cell assay. Moreover, these cellular responses were maintained equally at immunization titers as low as 103 focus-forming units for both RV vaccine vectors. CD8+ T-cell responses were significantly enhanced by a boost with a single-cycle RV complemented with a heterologous vesicular stomatitis virus glycoprotein. These findings demonstrate that single-cycle RV is an effective alternative to replication-competent RV vectors for future development of vaccines for HIV-1 and other infectious diseases.

Download Full-text