Current Opinion in HIV & AIDS:
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
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: firstname.lastname@example.org
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.
Although HIV was linked to AIDS more than 25 years ago [1,2], development of an effective vaccine remains a major challenge . 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 , but the results also pointed to the need to increase the frequency of vaccine-induced immunity and durability of immune protection .
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 . 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 . 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▪▪].
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  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.
DNA VIRUS VECTORS
Adenovirus, vaccinia virus, and herpes viruses including cytomegalovirus each have distinct advantages for the construction of an HIV vaccine.
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 . 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 .
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 , 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  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  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).
Cytomegaloviruses (CMV) are members of the herpesvirus family= and, as such, persist indefinitely in their host following primary infection . 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 . 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  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 , and the virus also causes serious complications in some immunosuppressed patients undergoing organ transplants , 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 . 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.
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 .
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) . 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 .
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 . 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 , 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  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.
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.
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.
Vesicular stomatitis virus
Vesicular stomatitis (VSV) was one of the earliest RNA viruses investigated as a live HIV vaccine vector . 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 . 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 . 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  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 . Promising results have been produced during preclinical evaluation of chimeric vaccines for Ebola virus and Marburg [98,99], and chimeric VSV vectors  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.).
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  or provided protection from acute illness caused by simian-human immunodeficiency virus strain 89.6P (SHIV89.6P) .
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 . 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 . Interestingly, preclinical studies indicate that the intranasal vaccination route may reduce the negative effects of preexisting cross-reactive immunity on SeV vector administration .
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 , 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  or a more distantly related virus  such as HIV .
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 . CDV neutralizing antibodies are reported to be quite low in humans , 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  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.).
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.
Yellow fever virus
Live attenuated Yellow fever virus strain 17D (YF 17D) has been widely used to control disease in endemic areas , 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  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.
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 . 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).
Semliki Forrest virus
Finally, a unique vector has been developed based on a Semliki Forrest virus (SFV) RNA replicon  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 .
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 . 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 , 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  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.
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.
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.
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).
1. Montagnier L. 25 years after HIV discovery: prospects for cure and vaccine. Virology 2010; 397:248–254.
2. Gallo RC. A reflection on HIV/AIDS research after 25 years. Retrovirology 2006; 3:72.
3. Girard MP, Koff WC. Plotkin SA, Orenstein WA, Offit PA. Human immunodeficiency virus vaccines. Vaccines. Philadelphia:Elsevier Saunders; 2012. 1097–1121.
4. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 2009; 361:2209–2220.
5. Girard MP, Plotkin SA. HIV vaccine development at the turn of the 21st century. Curr Opin HIV AIDS 2012; 7:4–9.
6. Meeusen EN, Walker J, Peters A, et al. Current status of veterinary vaccines. Clin Microbiol Rev 2007; 20:489–510.
7. Plotkin SL, Plotkin SA. Plotkin SA, Orenstein WA, Offit PA. A short history of vaccination. Vaccines 6 editionPhiladelphia:Elsevier Saunders; 2012. 1–13.
8▪. Plotkin SA. Complex correlates of protection after vaccination. Clin Infect Dis 2013.
Informative analysis and description of immune functions induced by vaccination and correlates of protection.
9. Koff WC, Johnson PR, Watkins DI, et al. HIV vaccine design: insights from live attenuated SIV vaccines. Nat Immunol 2006; 7:19–23.
10. Baba TW, Liska V, Khimani AH, et al. Live attenuated, multiply deleted simian immunodeficiency virus causes AIDS in infant and adult macaques. Nat Med 1999; 5:194–203.
11. Duerr A, Wasserheit JN, Corey L. HIV vaccines: new frontiers in vaccine development. Clin Infect Dis 2006; 43:500–511.
12. Learmont J, Cook L, Dunckley H, et al. Update on long-term symptomless HIV type 1 infection in recipients of blood products from a single donor. AIDS Res Hum Retroviruses 1995; 11:1.
13. Learmont J, Tindall B, Evans L, et al. Long-term symptomless HIV-1 infection in recipients of blood products from a single donor. Lancet 1992; 340:863–867.
14. Whitney JB, Ruprecht RM. Live attenuated HIV vaccines: pitfalls and prospects. Curr Opin Infect Dis 2004; 17:17–26.
15. Querec TD, Akondy RS, Lee EK, et al. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nat Immunol 2009; 10:116–125.
16. Gaucher D, Therrien R, Kettaf N, et al. Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses. J Exp Med 2008; 205:3119–3131.
17. Nakaya HI, Pulendran B. Systems vaccinology: its promise and challenge for HIV vaccine development. Curr Opin HIV AIDS 2012; 7:24–31.
18. Haase AT. Early events in sexual transmission of HIV and SIV and opportunities for interventions. Annu Rev Med 2011; 62:127–139.
19▪▪. Fukazawa Y, Park H, Cameron MJ, et al. Lymph node T cell responses predict the efficacy of live attenuated SIV vaccines. Nat Med 2012; 18:1673–1681.
Demonstration that attenuated SIV persists in the lymphoid tissues of vaccinated macaques. SIV specific T cells in the lymphoid tissues correlate with control of wild-type SIVmac239 infection postchallenge.
20. Ulmer JB, Valley U, Rappuoli R. Vaccine manufacturing: challenges and solutions. Nat Biotechnol 2006; 24:1377–1383.
21. Guy B, Guirakhoo F, Barban V, et al. Preclinical and clinical development of YFV 17D-based chimeric vaccines against dengue, West Nile and Japanese encephalitis viruses. Vaccine 2010; 28:632–649.
22. Draper SJ, Heeney JL. Viruses as vaccine vectors for infectious diseases and cancer. Nat Rev Microbiol 2010; 8:62–73.
23. Koff WC, Parks CL, Berkhout B, et al. Replicating viral vectors as HIV vaccines Summary Report from IAVI Sponsored Satellite Symposium, International AIDS Society Conference July 22 2007. Biologicals 2008; 36:277–286.
24. Robert-Guroff M. Replicating and nonreplicating viral vectors for vaccine development. Curr Opin Biotechnol 2007; 18:546–556.
25. Patterson LJ, Robert-Guroff M. Replicating adenovirus vector prime/protein boost strategies for HIV vaccine development. Expert Opin Biol Ther 2008; 8:1347–1363.
26. Liniger M, Zuniga A, Naim HY. Use of viral vectors for the development of vaccines. Expert Rev Vaccines 2007; 6:255–266.
27. Li S, Locke E, Bruder J, et al. Viral vectors for malaria vaccine development. Vaccine 2007; 25:2567–2574.
28. Excler JL, Parks CL, Ackland J, et al. Replicating viral vectors as HIV vaccines: summary report from the IAVI-sponsored satellite symposium at the AIDS vaccine 2009 conference. Biologicals 2010; 38:511–521.
29. Picker LJ, Hansen SG, Lifson JD. New paradigms for HIV/AIDS vaccine development. Annu Rev Med 2012; 63:95–111.
30. Clarke DK, Cooper D, Egan MA, et al. Recombinant vesicular stomatitis virus as an HIV-1 vaccine vector. Springer Semin Immunopathol 2006; 28:239–253.
31▪. Gurwith M, Lock M, Taylor EM, et al. Safety and immunogenicity of an oral, replicating adenovirus serotype 4 vector vaccine for H5N1 influenza: a randomised, double-blind, placebo-controlled, phase 1 study. Lancet Infect Dis 2013; 13:238–250.
Clinical trial results using a live oral Ad4 vaccine vector encoding influenza virus immunogens.
32. Patterson LJ, Kuate S, Daltabuit-Test M, et al. Replicating adenovirus-simian immunodeficiency virus (SIV) vectors efficiently prime SIV-specific systemic and mucosal immune responses by targeting myeloid dendritic cells and persisting in rectal macrophages, regardless of immunization route. Clin Vaccine Immunol 2012; 19:629–637.
33. Xiao P, Patterson LJ, Kuate S, et al. Replicating adenovirus-simian immunodeficiency virus (SIV) recombinant priming and envelope protein boosting elicits localized, mucosal IgA immunity in rhesus macaques correlated with delayed acquisition following a repeated low-dose rectal SIV(mac251) challenge. J Virol 2012; 86:4644–4657.
34. Abbink P, Maxfield LF, Barouch DH. Development of replication-competent adenovirus based vaccine vectors. Retrovirology 2012; 9 (suppl. 2):P310.
35▪. Handley SA, Thackray LB, Zhao G, et al. Pathogenic simian immunodeficiency virus infection is associated with expansion of the enteric virome. Cell 2012; 151:253–266.
Identification of new simian adenoviruses isolated from the rhesus monkey gut that can be used for development of replication-competent vectors.
36. Hansen SG, Ford JC, Lewis MS, et al. Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature 2011; 473:523–527.
37. Hansen SG, Vieville C, Whizin N, et al. Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nat Med 2009; 15:293–299.
38. Murphy CG, Lucas WT, Means RE, et al. Vaccine protection against simian immunodeficiency virus by recombinant strains of herpes simplex virus. J Virol 2000; 74:7745–7754.
39. Bilello JP, Manrique JM, Shin YC, et al. Vaccine protection against simian immunodeficiency virus in monkeys using recombinant gamma-2 herpesvirus. J Virol 2011; 85:12708–12720.
40. Willer DO, Ambagala AP, Pilon R, et al. Experimental infection of Cynomolgus Macaques (Macaca fascicularis) with human varicella-zoster virus. J Virol 2012; 86:3626–3634.
41. Shao Y, Li T, Wolf H, et al. The safety and immunogenicity of HIV-1 vaccines based on DNA and replication competent vaccinia virus vector in phase 1 clinical trial. In AIDS Vaccine 2009, vol. 6. pp. P404. Paris, France: Retrovirology; 2009:P404.
42. Kibler KV, Gomez CE, Perdiguero B, et al. Improved NYVAC-based vaccine vectors. PLoS One 2011; 6:e25674.
43. Quakkelaar ED, Redeker A, Haddad EK, et al. Improved innate and adaptive immunostimulation by genetically modified HIV-1 protein expressing NYVAC vectors. PLoS One 2011; 6:e16819.
44. Dai K, Liu Y, Liu M, et al. Pathogenicity and immunogenicity of recombinant Tiantan Vaccinia Virus with deleted C12L and A53R genes. Vaccine 2008; 26:5062–5071.
45. Zhu R, Huang W, Wang W, et al. Comparison on virulence and immunogenicity of two recombinant vaccinia vaccines, Tian Tan and Guang9 strains, expressing the HIV-1 envelope gene. PLoS One 2012; 7:e48343.
46. Zhang X, Sobue T, Isshiki M, et al. Elicitation of both anti HIV-1 Env humoral and cellular immunities by replicating vaccinia prime Sendai virus boost regimen and boosting by CD40Lm. PLoS One 2012; 7:e51633.
47. Zhang X, Richlak S, Nguyen HT, et al. Development of chimeric HIV Env immunogens for mucosal delivery with attenuated canine distemper virus (CDV) vaccine vectors. Retrovirology 2012; 9 (suppl. 2):298.
48. Reece JC, Alcantara S, Gooneratne S, et al. Trivalent live attenuated Influenza-SIV vaccines: efficacy and evolution of CTL escape in macaques. J Virol 2013; 87:4146–4160.
49. Stebbings R, Fevrier M, Li B, et al. Immunogenicity of a recombinant measles-HIV-1 clade B candidate vaccine. PLoS One 2012; 7:e50397.
50. Lorin C, Segal L, Mols J, et al. Toxicology, biodistribution and shedding profile of a recombinant measles vaccine vector expressing HIV-1 antigens, in cynomolgus macaques. Naunyn Schmiedebergs Arch Pharmacol 2012; 385:1211–1225.
51. Mourez T, Mesel-Lemoine M, Combredet C, et al. A chimeric measles virus with a lentiviral envelope replicates exclusively in CD4+/CCR5+ cells. Virology 2011; 419:117–125.
52. Xu R, Nasar F, Megati S, et al. Prime-boost vaccination with recombinant mumps virus and recombinant vesicular stomatitis virus vectors elicits an enhanced human immunodeficiency virus type 1 Gag-specific cellular immune response in rhesus macaques. J Virol 2009; 83:9813–9823.
53. Khattar SK, Samal S, Devico AL, et al. Newcastle disease virus expressing human immunodeficiency virus type 1 envelope glycoprotein induces strong mucosal and serum antibody responses in Guinea pigs. J Virol 2011; 85:10529–10541.
54. Maamary J, Array F, Gao Q, et al. Newcastle disease virus expressing a dendritic cell-targeted HIV gag protein induces a potent gag-specific immune response in mice. J Virol 2011; 85:2235–2246.
55. Carnero E, Li W, Borderia AV, et al. Optimization of human immunodeficiency virus gag expression by newcastle disease virus vectors for the induction of potent immune responses. J Virol 2009; 83:584–597.
56. McKenna PM, Koser ML, Carlson KR, et al. Highly attenuated rabies virus-based vaccine vectors expressing simian-human immunodeficiency virus89.6P Env and simian immunodeficiency virusmac239 Gag are safe in rhesus macaques and protect from an AIDS-like disease. J Infect Dis 2007; 195:980–988.
57. Faul EJ, Aye PP, Papaneri AB, et al. Rabies virus-based vaccines elicit neutralizing antibodies, poly-functional CD8+ T cell, and protect rhesus macaques from AIDS-like disease after SIV(mac251) challenge. Vaccine 2009; 28:299–308.
58. Matano T, Kobayashi M, Igarashi H, et al. Cytotoxic T lymphocyte-based control of simian immunodeficiency virus replication in a preclinical AIDS vaccine trial. J Exp Med 2004; 199:1709–1718.
59. Kawada M, Tsukamoto T, Yamamoto H, et al. Long-term control of simian immunodeficiency virus replication with central memory CD4+ T-cell preservation after nonsterile protection by a cytotoxic T-lymphocyte-based vaccine. J Virol 2007; 81:5202–5211.
60. Rose NF, Roberts A, Buonocore L, et al. Glycoprotein exchange vectors based on vesicular stomatitis virus allow effective boosting and generation of neutralizing antibodies to a primary isolate of human immunodeficiency virus type 1. J Virol 2000; 74:10903–10910.
61. Rose NF, Marx PA, Luckay A, et al. An effective AIDS vaccine based on live attenuated vesicular stomatitis virus recombinants. Cell 2001; 106:539–549.
62. Cooper D, Wright KJ, Calderon PC, et al. Attenuation of recombinant vesicular stomatitis virus-human immunodeficiency virus type 1 vaccine vectors by gene translocations and g gene truncation reduces neurovirulence and enhances immunogenicity in mice. J Virol 2008; 82:207–219.
63. Johnson JE, Coleman JW, Kalyan NK, et al. In vivo biodistribution of a highly attenuated recombinant vesicular stomatitis virus expressing HIV-1 Gag following intramuscular, intranasal, or intravenous inoculation. Vaccine 2009; 27:2930–2939.
64. Jurgens CK, Morrow G, Boggiano C, et al. Evaluation of a replication-competent VSV-SIV vaccine candidate. Retrovirology 2012; 9:329.
65. Johnson JE, Schnell MJ, Buonocore L, et al. Specific targeting to CD4+ cells of recombinant vesicular stomatitis viruses encoding human immunodeficiency virus envelope proteins. J Virol 1997; 71:5060–5068.
66. Gu R, Stagnar C, Zaichenko L, et al. Induction of mucosal HIV-specific B and T cell responses after oral immunization with live coxsackievirus B4 recombinants. Vaccine 2012; 30:3666–3674.
67. Crotty S, Andino R. Poliovirus vaccine strains as mucosal vaccine vectors and their potential use to develop an AIDS vaccine. Adv Drug Deliv Rev 2004; 56:835–852.
68. Crotty S, Miller CJ, Lohman BL, et al. Protection against simian immunodeficiency virus vaginal challenge by using Sabin poliovirus vectors. J Virol 2001; 75:7435–7452.
69. Virnik K, Ni Y, Berkower I. Live attenuated rubella viral vectors stably express HIV and SIV vaccine antigens while reaching high titers. Vaccine 2012; 30:5453–5458.
70. Rose NF, Publicover J, Chattopadhyay A, et al. Hybrid alphavirus-rhabdovirus propagating replicon particles are versatile and potent vaccine vectors. Proc Natl Acad Sci U S A 2008; 105:5839–5843.
71. Schell JB, Rose NF, Bahl K, et al. Significant protection against high-dose simian immunodeficiency virus challenge conferred by a new prime-boost vaccine regimen. J Virol 2011; 85:5764–5772.
72. Martins MA, Bonaldo MC, Rudersdorf RA, et al. Immunogenicity of seven new recombinant yellow fever viruses 17D expressing fragments of SIVmac239 Gag, Nef, and Vif in Indian rhesus macaques. PLoS One 2013; 8:e54434.
73. Bonaldo MC, Martins MA, Rudersdorf R, et al. Recombinant yellow fever vaccine virus 17D expressing simian immunodeficiency virus SIVmac239 gag induces SIV-specific CD8+ T-cell responses in rhesus macaques. J Virol 2010; 84:3699–3706.
74. Barouch DH, Nabel GJ. Adenovirus vector-based vaccines for human immunodeficiency virus type 1. Hum Gene Ther 2005; 16:149–156.
75. Tatsis N, Ertl HC. Adenoviruses as vaccine vectors. Mol Ther 2004; 10:616–629.
76. Hoke CH Jr, Snyder CE Jr. History of the restoration of adenovirus type 4 and type 7 vaccine, live oral (Adenovirus Vaccine) in the context of the Department of Defense acquisition system. Vaccine 2013; 31:1632.
77. Alexander J, Gurwith M, Mendy J, et al. Development of a HIV-1 vaccine using an orally-administered, replication-competent adenovirus serotype 4 vector expressing Env clade C glycoprotein. In AIDS Vaccine 2012, vol. 9. pp. P35. Boston, Massachusetts USA: Retrovirology 2012; 9(suppl. 2):P35.
78. O’Hara GA, Duncan CJ, Ewer KJ, et al. Clinical assessment of a recombinant simian adenovirus ChAd63: a potent new vaccine vector. J Infect Dis 2012; 205:772–781.
79. Borthwick NJ, Ahmed T, Rose A, et al. Immunogenicity of a universal HIV-1 vaccine vectored by DNA, MVA and CHADV-63 in a Phase I/IIA clinical trial. Retrovirology 2012; 9(suppl. 2):P118.
80. Mocarski ES, Shenk T, Pass RF. Knipe DM, Howley PM. Cytomegaloviruses. Fields Virology. Volume 2 5th editionPhiladelphia:Lippincott Williams and Wilkins; 2007. 2701–2772.
81. Britt W. Manifestations of human cytomegalovirus infection: proposed mechanisms of acute and chronic disease. Curr Top Microbiol Immunol 2008; 325:417–470.
82. Murphy E, Shenk T. Human cytomegalovirus genome. Curr Top Microbiol Immunol 2008; 325:1–19.
83. Malouli D, Nakayasu ES, Viswanathan K, et al. Reevaluation of the coding potential and proteomic analysis of the BAC-derived rhesus cytomegalovirus strain 68-1. J Virol 2012; 86:8959–8973.
84. Davison AJ, Dolan A, Akter P, et al. The human cytomegalovirus genome revisited: comparison with the chimpanzee cytomegalovirus genome. J Gen Virol 2003; 84:17–28.
85. Pereira L, Maidji E. Cytomegalovirus infection in the human placenta: maternal immunity and developmentally regulated receptors on trophoblasts converge. Curr Top Microbiol Immunol 2008; 325:383–395.
86. Pantaleo G, Esteban M, Jacobs B, et al. Poxvirus vector-based HIV vaccines. Curr Opin HIV AIDS 2010; 5:391–396.
87. Zhang Q, Tian M, Feng Y, et al. Genomic sequence and virulence of clonal isolates of vaccinia virus tiantan, the chinese smallpox vaccine strain. PLoS One 2013; 8:e60557.
88▪. Sun C, Chen Z, Tang X, et al. Mucosal prime with a replicating vaccinia-based vaccine elicits protective immunity against SIV challenge in rhesus monkeys. J Virol 2013; 87:5669–5677.
Vaccinia virus vectors used for mucosal vaccination induce protective responses.
89. Paoletti E, Tartaglia J, Taylor J. Safe and effective poxvirus vectors--NYVAC and ALVAC. Dev Biol Stand 1994; 82:65–69.
90. Conzelmann KK. Reverse genetics of mononegavirales. Curr Top Microbiol Immunol 2004; 283:1–41.
91. Neumann G, Whitt MA, Kawaoka Y. A decade after the generation of a negative-sense RNA virus from cloned cDNA - what have we learned? J Gen Virol 2002; 83:2635–2662.
92. Fuchs JD, Frank I, Kochar N, et al. First-in-human phase 1 clinical trial of a recombinant vesicular stomatitis virus (rVSV)-based preventative vaccine. Retrovirology 2012; 9(suppl. 2):P134.
93. Abrahams MR, Anderson JA, Giorgi EE, et al. Quantitating the multiplicity of infection with human immunodeficiency virus type 1 subtype C reveals a non-Poisson distribution of transmitted variants. J Virol 2009; 83:3556–3567.
94. Marthas ML, Van Rompay KK, Abbott Z, et al. Partial efficacy of a VSV-SIV/MVA-SIV vaccine regimen against oral SIV challenge in infant macaques. Vaccine 2011; 29:3124–3137.
95. Van Rompay KK, Abel K, Earl P, et al. Immunogenicity of viral vector, prime-boost SIV vaccine regimens in infant rhesus macaques: attenuated vesicular stomatitis virus (VSV) and modified vaccinia Ankara (MVA) recombinant SIV vaccines compared to live-attenuated SIV. Vaccine 2010; 28:1481–1492.
96. Schell J, Rose NF, Fazo N, et al. Long-term vaccine protection from AIDS and clearance of viral DNA following SHIV89.6P challenge. Vaccine 2009; 27:979–986.
97. Egan MA, Chong SY, Megati S, et al. Priming with plasmid DNAs expressing interleukin-12 and simian immunodeficiency virus gag enhances the immunogenicity and efficacy of an experimental AIDS vaccine based on recombinant vesicular stomatitis virus. AIDS Res Hum Retroviruses 2005; 21:629–643.
98. Geisbert TW, Feldmann H. Recombinant vesicular stomatitis virus-based vaccines against Ebola and Marburg virus infections. J Infect Dis 2011; 204 (Suppl 3):S1075–S1081.
99. Gunther S, Feldmann H, Geisbert TW, et al. Management of accidental exposure to Ebola virus in the biosafety level 4 laboratory, Hamburg, Germany. J Infect Dis 2011; 204 (Suppl 3):S785–790.
100. Faisca P, Desmecht D. Sendai virus, the mouse parainfluenza type 1: a longstanding pathogen that remains up-to-date. Res Vet Sci 2007; 82:115–125.
101. Hara H, Hara H, Hironaka T, et al. Prevalence of specific neutralizing antibodies against Sendai virus in populations from different geographic areas: implications for AIDS vaccine development using Sendai virus vectors. Hum Vaccin 2011; 7:639–645.
102. Moriya C, Horiba S, Kurihara K, et al. Intranasal Sendai viral vector vaccination is more immunogenic than intramuscular under preexisting antivector antibodies. Vaccine 2011; 29:8557–8563.
103. de Vries RD, Lemon K, Ludlow M, et al. In vivo tropism of attenuated and pathogenic measles virus expressing green fluorescent protein in macaques. J Virol 2010; 84:4714–4724.
104. von Messling V, Milosevic D, Cattaneo R. Tropism illuminated: lymphocyte-based pathways blazed by lethal morbillivirus through the host immune system. Proc Natl Acad Sci U S A 2004; 101:14216–14221.
105. Lin WH, Kouyos RD, Adams RJ, et al. Prolonged persistence of measles virus RNA is characteristic of primary infection dynamics. Proc Natl Acad Sci U S A 2012; 109:14989–14994.
106. Chen RT, Markowitz LE, Albrecht P, et al. Measles antibody: reevaluation of protective titers. J Infect Dis 1990; 162:1036–1042.
107. Dine MS, Hutchins SS, Thomas A, et al. Persistence of vaccine-induced antibody to measles 26–33 years after vaccination. J Infect Dis 2004; 189 (Suppl 1):S123–130.
108. Croyle MA, Patel A, Tran KN, et al. Nasal delivery of an adenovirus-based vaccine bypasses preexisting immunity to the vaccine carrier and improves the immune response in mice. PLoS One 2008; 3:e3548.
109. Knuchel MC, Marty RR, Morin TN, et al. Relevance of a preexisting measles immunity prior immunization with a recombinant measles virus vector. Hum Vaccin Immunother 2013. 9.
110. Miest TS, Yaiw KC, Frenzke M, et al. Envelope-chimeric entry-targeted measles virus escapes neutralization and achieves oncolysis. Mol Ther 2011; 19:1813–1820.
111. Hudacek AW, Navaratnarajah CK, Cattaneo R. Development of measles virus-based shielded oncolytic vectors: suitability of other paramyxovirus glycoproteins. Cancer Gene Ther 2013; 20:109–116.
112. Rima BK, Duprex WP. Morbilliviruses and human disease. J Pathol 2006; 208:199–214.
113. Rayner JO, Dryga SA, Kamrud KI. Alphavirus vectors and vaccination. Rev Med Virol 2002; 12:279–296.
114. Monath TP. Yellow fever vaccine. Expert Rev Vaccines 2005; 4:553–574.
115. Seino KK, Long MT, Gibbs EP, et al. Comparative efficacies of three commercially available vaccines against West Nile Virus (WNV) in a short-duration challenge trial involving an equine WNV encephalitis model. Clin Vaccine Immunol 2007; 14:1465–1471.
116. Halstead SB, Thomas SJ. New Japanese encephalitis vaccines: alternatives to production in mouse brain. Expert Rev Vaccines 2011; 10:355–364.
117. Jurgens CK, Young KR, Madden VJ, et al. A novel self-replicating chimeric lentivirus-like particle. J Virol 2012; 86:246–261.
118. Statement: NIH Discontinues Immunizations in HIV Vaccine Study. [http://http://www.niaid.nih.gov
/news/newsreleases/2013/Pages/HVTN505April2013.aspx]. Accessed 25 April 2012.
119. Santra S, Liao HX, Zhang R, et al. Mosaic vaccines elicit CD8+ T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys. Nat Med 2010; 16:324–328.
120. Letourneau S, Im EJ, Mashishi T, et al. Design and preclinical evaluation of a universal HIV-1 vaccine. PLoS One 2007; 2:e984.
121. Kulkarni V, Rosati M, Valentin A, et al. HIV-1 p24(gag) Derived Conserved Element DNA Vaccine Increases the Breadth of Immune Response in Mice. PLoS One 2013; 8:e60245.
122. van Gils MJ, Sanders RW. Broadly neutralizing antibodies against HIV-1: templates for a vaccine. Virology 2013; 435:46–56.
HIV vaccine; replication-competent viral vectors; SIV challenge model
© 2013 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read