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Current Opinion in HIV & AIDS:
doi: 10.1097/COH.0b013e328363d389
CHANGING ENVIRONMENT IN HIV VACCINE: Edited by Nelson L. Michael and Glenda Gray

Development of replication-competent viral vectors for HIV vaccine delivery

Parks, Christopher L.a; Picker, Louis J.b,c; King, C. Richtera

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Author Information

aThe International AIDS Vaccine Initiative, AIDS Vaccine Design and Development Laboratory, Brooklyn, New York

bVaccine and Gene Therapy Institute

cThe Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA

Correspondence to Christopher Parks, PhD, International AIDS Vaccine Initiative, Brooklyn, New York 11220 USA. E-mail: cparks@iavi.org

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Abstract

Purpose of review: To briefly describe some of the replication-competent vectors being investigated for development of candidate HIV vaccines focusing primarily on technologies that have advanced to testing in macaques or have entered clinical trials.

Recent findings: Replication-competent viral vectors have advanced to the stage at which decisions can be made regarding the future development of HIV vaccines. The viruses being used as replication-competent vector platforms vary considerably, and their unique attributes make it possible to test multiple vaccine design concepts and also mimic various aspects of an HIV infection. Replication-competent viral vectors encoding simian immunodeficiency virus or HIV proteins can be used to safely immunize macaques, and in some cases, there is evidence of significant vaccine efficacy in challenge protection studies. Several live HIV vaccine vectors are in clinical trials to evaluate immunogenicity, safety, the effect of mucosal delivery, and potential effects of preexisting immunity.

Summary: A variety of DNA and RNA viruses are being used to develop replication-competent viral vectors for HIV vaccine delivery. Multiple viral vector platforms have proven to be well tolerated and immunogenic with evidence of efficacy in macaques. Some of the more advanced HIV vaccine prototypes based on vesicular stomatitis virus, vaccinia virus, measles virus, and Sendai virus are in clinical trials.

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INTRODUCTION

Although HIV was linked to AIDS more than 25 years ago [1,2], development of an effective vaccine remains a major challenge [3]. Importantly, findings from the RV144 clinical trial showed that the incidence of HIV transmission could be reduced with an HIV vaccine regimen based on a nonreplicating canarypox vector encoding Gag, Pro, and Env immunogens, and an Envelope subunit protein [4], but the results also pointed to the need to increase the frequency of vaccine-induced immunity and durability of immune protection [5].

The fact that live-attenuated viral vaccines (LAVVs) have been remarkably effective in both human and animal healthcare [6,7] suggests that delivery of an HIV vaccine with a live vector might be one approach to improving efficacy. Licensed LAVVs induce durable, multicomponent immunity that prevents illness and controls the spread of highly infectious pathogens [8▪], making a compelling case for investigating some form of live HIV vaccine. Furthermore, the success of licensed LAVVs are mirrored by results in the rhesus macaque model in which live-attenuated viruses like SIVmac239Δnef are the most effective experimental vaccine for preventing AIDS [9]. Unfortunately, applying the LAVV strategy to HIV is impractical at this time, because there are safety risks associated with lentivirus genome recombination, genetic reversion to a more virulent phenotype, and host chromosome modification caused by provirus integration [10–14]. Thus, replication-competent viral vectors presently are a more practical alternative for delivering HIV immunogens in the context of a viral infection.

To elicit protective immunity, replication-competent vectors probably will need to incorporate features of LAVVs as well as live-attenuated SIVmac239. Perhaps the most important feature will be sufficient replicative capacity to produce a mild infection, which will stimulate pathogen recognition and cell death pathways, provide prolonged antigen exposure, and engage the adaptive arm of the immune system [15–17]. A vaccine vector also may need to induce potent immunity that strengthens defenses at the mucosal barrier and in submucosal tissues, which are at the front lines of HIV transmission by sexual contact [18]. Some replication-competent viral vectors are well suited to achieve this as they naturally infect mucosal surfaces and initiate replication in submucosal tissues. Viral vectors that preferentially replicate in lymphoid tissues have similar potential advantages [19▪▪].

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Although there are many probable benefits to developing HIV vaccines based on replicating viruses, advancing replication-competent vectors to clinical trial is challenging and dependent on the strategic selection of a virus genetic background, the ability to readily engineer stable recombinant viruses, and the availability of relevant animal models. Common hurdles include attaining adequate immunogen expression, engineering genetically stable vectors, reaching reasonable yields of vaccine from qualified cell substrates, development of downstream processes needed to make a vaccine with acceptable purity, stability, and potency and, perhaps the most challenging, achieving the correct balance of replicative capacity and attenuation that ensures both immunogenicity and safety [20,21]. In-vivo models also are vital to demonstrate vaccine immunogenicity and to assess safety risks [21] and, importantly, they must be tractable to allow iterative study while developing and improving the vaccine concept. Taken together, it is clear that sustained commitment will be necessary to fully test and advance replication-competent vectors for use as HIV vaccines.

Below we provide a relatively brief description of replication-competent vectors in development, focusing primarily on those being tested in macaques or in clinical trails, and we refer readers to other informative reviews [21–30] on the topic. Table 1[31▪,32–34,35▪,36–73] also includes references to some additional vector technologies not described in the text.

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DNA VIRUS VECTORS

Adenovirus, vaccinia virus, and herpes viruses including cytomegalovirus each have distinct advantages for the construction of an HIV vaccine.

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Adenovirus

Replication-competent adenovirus technology has both advantages and disadvantages when compared with the widely used nonreplicating vectors [74,75]. Foreign insert capacity in the replication-competent vector is more limited because essential genes in the E1 region must be retained. Deletion in the E3 region generates capacity for inserts, and also attenuates replication in vivo. An important advantage of replication-competent adenovirus vectors is their natural ability to infect mucosal surfaces and subsequently replicate [25]. Moreover, there is clinical experience with LAVVs based on adenovirus type 4 (Ad4) and Ad7, which are delivered orally to immunize US Military personnel for prevention of respiratory and enteric illness [76].

Several different replicating adenovirus technologies are emerging. Recent clinical experience with an Ad4 vector that encodes influenza virus polypeptides [31▪] should facilitate advancement of a mucosally delivered HIV vaccine candidate. Moreover, an Ad4-HIV Env vaccine was shown to be immunogenic in rabbits [77], and it is anticipated that a vaccine composed of Ad4-Gag and Ad4-Env will enter a phase 1 clinical trial in 2013 (M. Gurwith, personal communication). Replicating Ad5 [32,33] and Ad26 [34] also are being advanced as mucosal delivery vectors. Replication-competent Ad5-SIV vectors expressing Gag, Env, and Rev were immunogenic in macaques after administration by several different mucosal routes [33] and, when used in combination with an SIV Env gp120 boost, some control over SIVmac251 infection was observed. For Ad26, clinical development will be necessary to further evaluate immunogenicity as replication of this adenovirus serotype is restricted in simian cells. Finally, because nonreplicating chimp adenoviruses have shown promise in human trials [78,79], new simian viruses are being identified [35▪] and developed as replication-competent vectors (D. Barouch, personal communication).

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Cytomegalovirus

Cytomegaloviruses (CMV) are members of the herpesvirus family= and, as such, persist indefinitely in their host following primary infection [80]. CMV persistence and resulting continuous, low-level immune stimulation maintains an expanded pool of effector-differentiated T cells, which control infection and prevents CMV disease [81]. Thus, vectors based on rhesus CMV (RhCMV) were ideally suited to test the hypothesis that persistent antigen exposure could confer immune control over SIV infection.

A multivalent RhCMV-SIV vaccine covering nearly the complete SIVmac239 proteome was studied extensively in the SIVmac239 challenge-protection model [36,37]. As designed, the RhCMV-SIV vectors established persistent infections and maintained expanded pools of T cells responsive to a sizable breadth of SIV epitopes. Additionally, it should be emphasized that preexisting CMV infection and immunity did not compromise vector immunogenicity as all animals were RhCMV-seropositive before vaccination. The SIV-specific immunity induced in two independent studies protected 50% of the macaques from progressive SIVmac239 infection. Protected animals were infected, but viral control was early, stringent, and durable with SIVmac239 genome copies in the blood reduced to undetectable levels, regardless of whether challenge was conducted rectally [36] or vaginally (L.J.P., in preparation).

The notable efficacy of RhCMV-SIV vector warrants clinical development of a prototype CMV-based HIV vaccine. This approach will be challenging, as a new vector based on human CMV (HCMV) must be developed due to tight host-restriction. Although HCMV and RhCMV are biologically highly homologous and the majority of viral proteins is related, their very large complex genomes express unique polypeptides and microRNAs [82–84], and thus developing an exact HCMV analog of the RhCMV vector is not straightforward. Furthermore, HCMV infection during pregnancy is linked to birth defects [85], and the virus also causes serious complications in some immunosuppressed patients undergoing organ transplants [81], thus use of an attenuated HCMV strain for clinical development is essential to minimize risk. Using RhCMV as a model, and focusing on genes that are conserved between HCMV and the rhesus virus, gene knockouts have been identified that highly attenuate RhCMV replication in vivo, but still allow the virus to establish a persistent infection with full immunogenicity (L.J.P, unpublished).

In considering clinical development, it also is important to note that HCMV infection is relatively widespread by an early age [81]. As mentioned above, studies with RhCMV indicate that superinfection is possible, thus preexisting immunity will not be a significant hurdle for use of an hCMV-HIV vaccine.

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Rhadinovirus

Rhesus rhadinovirus (RRV), another member of the herpes virus family, also has been used to develop a vector that can establish a persistent infection. Like CMV, RRV encoding SIV immunogens could infect seropositive animals. Notably, in vaccinated macaques, peak and chronic virus loads were reduced more than 10-fold following a stringent intravenous SIVmac239 challenge [39].

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Poxviruses

Poxviruses that abortively infect human cells have been studied extensively as vaccine vectors particularly host-restricted modified vaccinia virus Ankara (MVA) and the modified Copenhagen strain (NYVAC) and avipoxviruses (fowlpox and canarypox) [86]. Interest remains high in the development of the nonreplicating vectors because they can be used safely in humans, are immunogenic and, notably, a canarypox vector was used in the RV-144 clinical trial [4].

The replication-competent poxvirus vector in the most advanced clinical trials is based on the Tiantan vaccinia virus strain, which is derived from the smallpox vaccine once used in China [87]. In a Phase 1 study, the Tiantan vaccinia virus-HIV (TV-HIV) vaccine delivered by scarification caused skin reactions typical of smallpox vaccination and induced HIV-specific T-cell responses in vaccinia virus-naive study participants [28,41]. TV-HIV is presently advancing to a Phase II study (National Center for AIDS/STD Control and Prevention, China CDC; ClinicalTrials. gov NCT01705223), in which it will be used as a boost for a DNA prime administered by electroporation. Notably, significant protection from mucosal SIVmac239 challenge was observed recently in Chinese rhesus macaques vaccinated with a regimen including Tiantan vaccinia virus–SIV (TV-SIV) prime administered mucosally and intramuscular Ad5-SIV boost [88▪].

Additional Tiantan vaccinia virus vectors also are being investigated [44], which have alterations in virus-encoded immune modulatory functions.

New replication-competent vaccinia virus vectors have been generated by systematically adding genes back to the host-restricted NYVAC strain [89] restoring varying degrees of replicative capacity in human cells [42,43]. Replication-competent derivatives of NYVAC vectors (NYVAC-KC) have been tested safely in macaques and were found to be more potent inducers of cellular and humoral immunity when compared with vectors based on nonreplicating NYVAC (G. Pantaleo, personal communication); consequently, a NYVAC-KC vector is being considered for advancement to a Phase I trial.

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RNA VIRUS VECTORS

RNA viruses are attractive vector platforms as a number of LAVVs are already used to vaccinate people and animals. Recent progress has been made in developing RNA virus vectors for mucosal delivery, targeting vaccine delivery to specific tissues, and producing virus particles that incorporate envelope.

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Negative-strand RNA viruses

Technology needed to engineer vectors from this class of viruses emerged more slowly than for most others, because naked genomic RNA cannot initiate an infectious cycle following transfection [90,91]. Development of a virus rescue system made it possible to investigate multiple different negative-strand viruses as HIV vaccine vectors.

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Vesicular stomatitis virus

Vesicular stomatitis (VSV) was one of the earliest RNA viruses investigated as a live HIV vaccine vector [30]. Administration by several different routes, including intranasal, was well tolerated and the resulting immunity controlled simian-human immunodeficiency virus (SHIV) 89.6P infection following challenge [61]. In this study, it was notable that 2nd and 3rd vaccine administrations were performed with vectors in which the VSV glycoprotein was exchanged for glycoproteins of a different serotype to minimize effects of antivector immunity [60,61].

Following the positive preclinical results, Profectus Biosciences, Inc., (New York, USA). and the National Institute of Allergy and Infectious Diseases developed a modified highly attenuated prototype VSV-HIV gag vaccine [62,63]. Recent Phase I trial results indicated that the vector induced T cells specific for Gag after intramuscular injection without causing serious adverse reactions [92]. In a follow-up study (clintrials. gov NCT01578889), the VSV-HIV gag vector will be used as a boost following DNA prime administered by electroporation. An expanded repertoire of HIV genes is being considered for use in the next generation of vaccines and a candidate expressing the env gene from the clade C transmitted/founder strain 1086.C [93] has completed manufacture (J. Eldridge, personal communication).

Evidence of efficacy has been observed in multiple macaque studies conducted with other VSV-based SIV and HIV vaccines [71,94–97]. Serious adverse reactions have not been reported even though these vectors were not engineered specifically to attenuate replication as was done for the vaccine tested in humans. Findings from these studies also showed that replication-competent VSV-based vaccines are potent additions to heterologous prime-boost regimens and that they are immunogenic when administered mucosally.

VSV also has been used to develop chimeric vaccines in which VSV glycoprotein is replaced by a functional heterologous cell surface receptor binding glycoprotein such as Env [65]. Promising results have been produced during preclinical evaluation of chimeric vaccines for Ebola virus and Marburg [98,99], and chimeric VSV vectors [64] with SIV or HIV Env functioning as the attachment protein are being tested in macaques currently (C.L.P. and C.R.K.). These chimeras are of particular interest as their design imparts multiple features similar to an infectious HIV particle: CD4/coreceptor-dependent infection; expression of functional trimeric Env; and incorporation of Env spikes into progeny VSV particles. The ability to incorporate functional Env into the vector particles makes this a potentially important immunogen display technology, and we are actively studying the characteristics of the incorporated Envelope trimer in our laboratory (C.L.P. and C.R.K.).

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Rabies virus

Live vectors based on rabies virus [56,57], a rhabdovirus related to VSV, have been developed using a glycoprotein serotype exchange strategy similar to those described above [60,61]. In macaques, vaccination with rabies virus vectors evoked T and B-cell responses [56,57] and reduced SIVmac251 viremia [57] or provided protection from acute illness caused by simian-human immunodeficiency virus strain 89.6P (SHIV89.6P) [56].

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Sendai virus

Replication-competent Sendai virus (SeV) vectors are being developed to determine whether intranasal vaccination enhances mucosal immunity, as this virus naturally infects the respiratory tract of rodents [100]. Encouragingly, priming macaques with DNA-SIV followed by an intranasal SeV-SIV vector boost resulted in strong suppression of SIVmac239 replication following IV challenge [58,59].

A clinical trial has commenced with a prototype SeV-HIV gag vector (International AIDS Vaccine Initiative and DNAVEC, Japan; ClinicalTrials. gov Identifier: NCT01705990). The trial is designed to evaluate immunogenicity following intranasal vaccination, assess SeV and Ad35 in a heterologous prime-boost regimen, and monitor the potential effects of preexisting cross-reacting human parainfluenza virus type 1 antibodies [101]. Interestingly, preclinical studies indicate that the intranasal vaccination route may reduce the negative effects of preexisting cross-reactive immunity on SeV vector administration [102].

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Measles virus and canine distemper virus

Measles virus (MeV) and canine distemper virus (CDV) are related morbilliviruses, which are controlled by widespread use of LAVVs. They are important vaccine platforms because they are naturally lymphotropic [103,104] making them applicable to producing vectors that target lymphoid tissues mimicking a prominent feature of attenuated SIVmac239 [19▪▪]. It also is worth noting that cells infected with morbilliviruses may persist for some time following cessation of symptoms [105], which may help to evoke lasting immune responses.

When administered parentally, like the live measles–mumps–rubella vaccine, MeV-HIV vectors are immunogenic in macaques, and as expected, cause no serious adverse reactions [49,50]. These favorable results spurred advancement of MeV-HIV vaccine vector candidates into a Phase 1 clinical trial, which has been concluded (Institut Pasteur, ClinicalTrials. gov NCT01320176).

Preexisting immunity generated by widespread measles vaccination is a perceived limitation to use of MeV vectors. The modest serum antibody titers induced by measles vaccination are significantly lower than produced following a natural infection [106,107] nevertheless they may reduce the potency of a MeV vector. Strategies to minimize potential effects of preexisting antibodies might include vaccine administration mucosally [102,108,109], using higher doses, or introducing vector modifications such as replacing MeV glycoproteins with those from CDV [110] or a more distantly related virus [111] such as HIV [51].

CDV also is being developed as a vector to take advantage of morbillivirus lymphoid tissue targeting while lessening potential effects of preexisting anti-MeV antibodies [47]. CDV neutralizing antibodies are reported to be quite low in humans [110], and a serum survey is in progress to analyze this further (C.L.P. and C.R.K.). In considering a potential path to clinical development for a CDV vector, it is relevant to note that no human diseases are associated with CDV infection [112] and attenuated canine vaccines can be used as the genetic background for vector development. Testing of a CDV-SIV vaccine developed from a veterinary vaccine is underway in macaques, and preliminary results indicate that intranasal vaccination caused no observable adverse reactions and immune responses were induced against SIV Gag and Env (C.L.P. and C.R.K.).

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Positive-strand RNA viruses

Poliovirus was one of the earliest positive-strand RNA viruses to be investigated as an autonomously replicating HIV vaccine vector [38,68]. Limited insert capacity and genetic stability associated with this class of viral vectors has focused most vaccine development effort on single-cycle replicons [26,113]. Some recent progress made in developing novel replicating vectors is provided below.

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Yellow fever virus

Live attenuated Yellow fever virus strain 17D (YF 17D) has been widely used to control disease in endemic areas [114], thus it is an attractive background for replication-competent vector development. Chimeric Yellow fever virus vectors in which the natural attachment proteins are replaced with those from Dengue virus, West Nile virus, or Japanese encephalitis virus [21] are immunogenic and in some cases approved for use as vaccines [115,116].

Introducing foreign glycoprotein genes into Yellow fever virus chimeras has been very successful because these proteins are essential for vector replication. It has been much more challenging to find a way to introduce and maintain a foreign coding sequence for which there is no selective advantage. Recently, progress has been made stabilizing foreign sequence inserts encoding SIV immunogens, and the resulting YFV-SIV vectors have been tested in macaques [72,73]. The results show that these YFV-SIV vectors primed T-cell responses that were boosted effectively with a heterologous Ad5-SIV vaccine.

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Venezuelan equine encephalitis virus

Venezuelan equine encephalitis virus (VEEV) is an alphavirus that also has been used to construct chimeric viruses. To more closely mimic an HIV or SIV particle, novel replication-competent VEEV-SHIV or VEEV-SIV chimeras were generated in which Env was introduced in place of the VEEV glycoproteins and a modified SIV Gag replaced much of the natural capsid and nucleocapsid functions. Consequently, VEEV-SHIV or VEEV-SIV chimeric particles contain functional Env on their surface and viral genomic RNA is packaged inside mature Gag particles [117]. Preliminary studies indicate that the replication-competent VEEV-SIV chimera can be administered to macaques with no obvious clinical reactions, and importantly, anti-Env antibodies capable of neutralizing tier-1 SIV pseudoviruses were induced (R. Johnston, K. Young, V. Traina-Dorge, J. Whitley, C. LaBranche, D. Montefiori, and C. Jurgens, personal communication).

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Semliki Forrest virus

Finally, a unique vector has been developed based on a Semliki Forrest virus (SFV) RNA replicon [70] that propagates in membrane vesicles. Replication-competent SFV replicons encoding SIV Gag or Env have been used as a boost for macaques primed with replication-competent VSV-SIV. Vaccinated animals effectively suppressed chronic infection by SIVsmE660 [71].

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CONCLUSION

A varied menu of replication-competent viral vectors is now available and data are accumulating to demonstrate safety as well as immunogenicity, and in some cases, efficacy in challenge-protection studies. The availability of these prototype vaccines makes it possible to evaluate new vaccination regimes and determine the benefits of using replication-competent vectors with distinctive properties. As more comprehensive in-vivo studies are conducted, greater insight into how these vectors modulate the immune response will guide vector design improvements. We anticipate that some replication-competent vectors will emerge as strong candidates for clinical development because they enhance immunity at the mucosal barrier, induce a greater magnitude and/or breadth of durable T-cell responses, or elicit protective antibodies against Env.

The replication-competent vectors are effective priming or boosting agents and we can expect continued exploration of such regimes preclinically and clinically. Replication-competent vectors also provide one possible option for testing a modified RV-144 regimen in which ALVAC-HIV component might be substituted with a live vector, perhaps one that is capable of expressing an immunogen that closely resembles a native Env spike.

Having replication-competent vectors available provides important new options for HIV vaccine development. Although immune correlates of protection remain unclear for any HIV vaccine, new information flowing from continued analysis of the RV-144 trial or the more recent DNA prime/Ad5 boost HVTN 505 phase IIb study (clinicaltrials. gov NCT00865566) should provide further insight into immune response patterns that must be evoked. During final preparation of this review, the HVTN 505 phase IIb trial (clinicaltrials.gov NCT00865566) was halted for futility [118]. Analysis of the immune responses induced by vaccination as well as the incidence of HIV infection in vaccine and placebo groups is ongoing, but it was notable that a nonstatistically significant trend toward more HIV infections in the vaccine group was observed reminiscent of the HVTN 502 (Step Study) trial. However, it seems clear from the results of HVTN 505, as well as the other AIDS vaccine efficacy trials conducted to date [3], that vaccine design will need to achieve a significant improvement in the magnitude and quality of immune responses. Live vectors might provide an effective mechanism to achieve the desired response. Designing vaccines that overcome the HIV genetic diversity also is necessary and replication-competent vectors may be part of the solution if they can significantly increase the magnitude or breadth of responses against T-cell immunogens composed of conserved elements or mosaic polypeptides [119–121]. An HIV vaccine also will need to induce antibodies with specificity for the trimeric Env spike, but expressing immunogens that mimic the structure of a functional trimer has been a long-term technical hurdle [122] and, accordingly, we as well as others are investigating replication-competent vectors designed to express authentic Env spikes on virus particles. In conclusion, we can anticipate an exciting period over the next few years as replication-competent vectors advance through both preclinical and clinical testing with the goal of developing a well tolerated and effective HIV vaccine.

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Acknowledgements

The authors gratefully acknowledge support from the Bill and Melinda Gates Foundation, Collaboration for AIDS Vaccine Discovery (CAVD), USAID, NIAID, and IAVI Donors. Award Number R01AI084840 from the National Institute Of Allergy And Infectious Diseases supported some of unpublished research attributed to C.L.P.; the content is solely the responsibility of the author and does not necessarily represent the official views of the National Institute Of Allergy And Infectious Diseases or the National Institutes of Health. We also thank colleagues Giuseppe Pantelo (Swiss Vaccine Research Institute), Dan Barouch (Harvard Medical School), Robert Johnston (Global Vaccines, Inc) John Eldridge (Profectus Biosciences, Inc), and Marc Gurwith (PaxVax Corporation) for providing updates on unpublished data and Xinsheng Zhang for helpful comments. Megan Finnegan and Lisa Gieber provided excellent assistance with literature review and article preparation.

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Conflicts of interest

Funding disclosure: Collaboration for AIDS Vaccine Discovery, The Bill and Melinda Gates Foundation; International AIDS Vaccine Initiative and its donors; USAID; National Institute of Allergy and Infectious Diseases.

C.L.P. and C.R.K. are named as inventors on patent applications submitted by The International AIDS Vaccine Initiative related to canine distemper virus and vesicular stomatitis virus vector technology. These authors have no conflict of interest. L.J.P. and Oregon Health and Science University (OHSU) have a significant financial interest in TomegaVax, Inc., a company with a commercial interest in CMV vector technology. The potential individual and institutional conflicts of interest have been reviewed and managed by OHSU.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 513).

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Keywords:

HIV vaccine; replication-competent viral vectors; SIV challenge model

© 2013 Lippincott Williams & Wilkins, Inc.

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