A successful vaccine to prevent HIV infection will likely require both the elicitation of antibody and cell-mediated responses. Virus specific CD8+ cytotoxic T lymphocytes (CTL) are critically important to the control of viral replication and disease progression for HIV-1. Viral vector-based HIV vaccines have been traditionally considered in the light of eliciting cell-mediated responses, but recent work suggests that certain vectors may elicit significant antibody responses as well. The nonreplicating viral vectors are attractive because of their inherent immunogenicity and safety profile. Some of the viral-vectored vaccine approaches have reached advanced testing – with two vaccine strategies reaching clinical efficacy trials – canarypox virus (ALVAC) and adenovirus serotype 5 (Ad5). The best-studied nonreplicating viral vector approaches for HIV vaccines include the poxviruses, adenoviruses, adeno-associated virus, rhabdoviruses, and alphaviruses (Table 1) [1–15,16▪▪,17▪▪,18▪,19,20]. Considerations in evaluating novel nonreplicating vectors include: preexisting vector specific immunity, replication incompetence, nature of illness associated with the wild type virus, tissue tropism, quality of the immune response elicited, manufacturability, and of course all available human clinical trial data.
The poxvirus vectors are double-stranded DNA virus vectors, which have been extensively studied in preclinical and clinical studies over the past 2 decades with recent promising results. The large genomes of these vectors allow for larger inserts while maintaining high levels of gene expression allowing for induction of HIV-specific immune responses. The four poxvirus vectors which have been most extensively studied as HIV vaccine vectors and have undergone clinical trials include: ALVAC, two vaccinia vectors – modified vaccinia Ankara (MVA) and highly attenuated vaccinia virus (NYVAC), and fowlpox.
ALVAC is derived from a canarypox virus, which had been passaged repeatedly in chick embryo fibroblasts. Canarypox is host range restricted and does not replicate in mammalian cells; this property fundamentally decreases the potential pathogenicity of this vector in humans. In the domain of veterinary medicine, multiple ALVAC-vector-based vaccines are currently licensed for clinical use for cats and horses, including vaccines for rabies, influenza, and West Nile virus. In humans, some concerns have been raised that canarypox (and fowlpox) vectors may be less immunogenic than other human virus vectors, but a theoretical advantage to these particular vectors is the absence of preexisting vector immunity in humans. ALVAC has been shown to be generally well tolerated in early clinical trials, advancing to phase II and III clinical trials in adults and also to early clinical trials in infants. HPTN 027 was a phase 1 trial of 60 HIV-exposed infants in Uganda who were randomized to receive ALVAC-HIV vCP1521 or placebo. The vaccine was safe with tolerable reactogenicity . In a US study, infants born to HIV-infected mothers were randomized to receive ALVAC vCP1452 with and without boost from r-gp120 subunit proteins or placebo. Both vaccine strategies were well tolerated and the prime–boost regimen induced lymphoproliferative responses and neutralizing activity to HIV-1 in ∼ 50% of the infants .
In adults, ALVAC-based vaccines were modestly effective at inducing HIV antibodies, but the cellular immune responses in early trials were considered sub-optimal by standard assays in use at the time. In HIV Vaccine Trials Network (HVTN 203), ALVAC vCP1452 boosted with recombinant gp120 (MN-GNE8 rgp120) yielded interferon γ (IFN-γ) enzyme-linked immunosorbent spot (ELISPOT) reactions in 16% of the vaccinated participants . This prime–boost regimen failed to produce predetermined significant CD8+ CTL responses in the phase II study, leading some in the field to argue to reconsider any further development of this vaccine approach against HIV. However, a prime–boost regimen with ALVAC and recombinant gp120 boost was advanced to a phase III efficacy trial (RV144) and did show a significant but modest protective effect, illustrating that our understanding of the laboratory markers of clinically relevant immunologic protection against HIV acquisition remain limited and highlighting the critical importance of human field trials.
The RV-144 trial was a phase III study of a prime–boost regimen of two initial injections of ALVAC-HIV (vCP 1521) followed by two more injections of ALVAC-HIV, which were given concurrent with booster injections of protein-based AIDSVAX B/E (recombinant gp120 subunit vaccine) . The study enrolled over 16 000 participants in Thailand at ‘community risk’ for HIV acquisition. Within this group, the studied prime–boost regimen yielded a 31.2% reduction in HIV-1 acquisition, as per the modified intention to treat analysis at 3.5 years after vaccination. The vaccine induced Env-specific and Gag-specific IFN-γ ELISPOT responses and Env-specific intracellular cytokine staining, and lymphoproliferative responses and binding antibodies to Env in most vaccine recipients . In those participants who acquired HIV despite vaccination, the vaccine did not appear to alter the course of HIV infection [25▪▪]. There have been multiple subsequent analyses of the available data and there are ongoing investigations of the potential correlates of immune protection and viral sieve analysis from RV144 with findings to date suggesting an IgG response against the V2 loop may be protective [26▪,27]. As the protective response seen with the vaccine strategy in RV144 appeared to wane after 6 months postvaccination, strategies to boost this response are being investigated. One such investigation is an ongoing study of additional late boost regimens of AIDSVAX B/E, ALVAC-HIV or the combination in HIV-uninfected participants from RV 144, which is scheduled to be completed in October 2013 . The Pox-Protein Public-Private Partnership, otherwise known as P5, was established in 2010 to build on the results of RV144. Through this effort, further studies are planned in Thailand and southern Africa to improve the regimen used in RV144 and test new vaccine candidates.
In contrast to canarypox, vaccinia vectors are highly immunogenic in humans, but preexisting population immunity because of prior smallpox vaccination may be problematic in some demographics. The NYVAC vector is derived from the Copenhagen strain of attenuated vaccinia (VACV) and is rendered attenuated by deletions in 18 genes encoding proteins involved in host range and virulence. In a phase I study (EV01) of NYVAC-C (vP2010) alone the vaccine was well tolerated and elicited ELISPOT responses in half of the vaccine recipients, generating interest in further studies with NYVAC in prime–boost regimens . Early clinical trials of DNA prime with NYVAC boost, including EV02, have shown that this strategy is generally well tolerated and elicits greater immune response than NYVAC alone, with predominantly CD4+ T-cell responses [3,29]. There are additional ongoing and planned studies of NYVAC in prime–boost combinations with DNA and protein-based immunogens (AIDSVAX B/E) [4,5]. Chronically, HIV-infected patients have received a NYVAC-based vaccine with expression of gag, pol, nef, and env from HIV clade B in Theravac-01, and this increased HIV-specific T-cell responses in all vaccine recipients and expanded preexisting T-cell responses .
MVA was prepared by serial passaging in chick embryo fibroblasts resulting in loss of more than 10% of its genome, which renders it unable to replicate in nearly all mammalian cells. Approximately 120 000 persons were vaccinated with MVA, primarily in west Germany and Turkey, as a part of smallpox eradication efforts and no significant safety concerns were identified in this context . MVA has also been used as a vector for therapeutic cancer vaccine, advancing to phase III clinical trials in prostate cancer patients, and has been given to hematopoietic stem cell transplant recipients, with no significant safety concerns in either population [32,33]. Interestingly, the route of administration of MVA has been shown to have a significant effect on immunogenicity, with similar responses to an intramuscular injection as to a 10-fold lower dose of intradermally administered MVA . Preclinical studies of MVA-based HIV vaccines have shown greater antigen expression, particularly in human dendritic cells, and increased T-cell stimulation as compared with ALVAC . Many early clinical studies with MVA-based HIV vaccines have been completed, often with promising results, but no MVA-based vaccines have yet advanced to efficacy trials. A phase I study of MVA with fowlpox (HVTN 055) demonstrated that this heterologous prime–boost regimen generated increased CD8+ T-cell responses than MVA alone . Further, work has shown that repeated doses of an MVA vaccine (up to five doses) does not increase the immune response to MVA beyond two doses and that elicitation of vaccine-induced vector (MVA) immunity does not appear to abrogate insert (anti-HIV) responses [36▪].
Prime–boost regimens with DNA prime and MVA boost have also been shown to elicit greater T-cell responses than administration of MVA alone. HVTN 065 was a phase 1 study of prime–boost series with Geovax HIV-1 DNA vaccine (pGA2/JS7 DNA) and MVA62 (encoding gag, PR, RT, Env), both producing virus-like particles, compared with the MVA vaccine alone. In this study, one of the prime–boost strategies was most immunogenic, with persistent CD4+ and CD8+ T-cell responses, and the MVA62 generated greater T-cell responses than the canarypox vaccine used in RV144 . Building on these early data, a follow-up phase 2a clinical trial  of Geovax DNA prime with MVA/HIV62 boost has been completed and results from this study are anticipated soon. Another follow-up study of Geovax DNA prime coexpressing granulocyte macrophage colony-stimulating factor (GM-CSF) along with the HIV-1-derived insert and an MVA62 boost is currently underway . Multigenic MVA vaccine candidates have been studied in early clinical trials and future studies with multigenic MVA vaccines alone and in prime–boost strategies are planned .
Fowlpox vaccines have been widely studied in cancer therapeutics, most frequently for breast and prostate cancer. Fowlpox-based HIV vaccines have been studied in early clinical trials with evidence of safety and some immunogenicity. As discussed above, a prime–boost regimen of recombinant MVA with fowlpox with matched HIV-1 inserts yielded a modest CD8+ CTL response in HVTN 055 . However, no fowlpox-based HIV vaccines have advanced to clinical efficacy trials, and future HIV vaccine studies with this delivery system are uncertain.
Adenoviruses, which have a 3 decade history of development for gene therapy, are now widely studied as vectors for HIV vaccines, as well as other disease targets, including malaria, hepatitis C, and tumor therapies. There are many attractive features of adenoviruses as vaccine candidates including manufacturability, safety profile, and ability to elicit broad immune responses. These double-stranded DNA viruses can target mucosal sites, infect both dividing and nondividing cells, including dendritic cells, and elicit high levels of antigen expression as well as cytokine and chemokine responses, resulting in potent immune responses. This outcome is achieved without integration into the host genome. One challenge with adenovirus vectors, especially Ad5, is the prevalence of high-level antivector immunity in large segments of the population especially in sub-Saharan Africa. This theoretical concern is being formally examined in ongoing studies, and this obstacle may be minimized by use of rare serotypes and engineered chimeric vectors.
Adenovirus serotype 5
Ad5 has been particularly well studied, with preclinical and clinical evidence of immunogenicity and safety. The Step study (HVTN 502/Merck 023) was a multicenter phase IIb study of the Merck Ad5 HIV-1 clade B gag/pol/nef vaccine compared with placebo. The multiple enrollment sites for the 3000 participants included North America, South America, the Caribbean, and Australia, where clade B HIV-1 is the predominant clade, and the study population included mostly men who have sex with men (MSM) and heterosexual women at high risk for HIV acquisition. The study was halted in October of 2007 because of lack of efficacy. The vaccine did elicit IFN-γ ELISPOT responses and polyfunctional T cells, but there was no effect on HIV acquisition or viral load setpoint. Posthoc analysis showed more HIV infections in the subgroup of vaccine recipients consisting of uncircumcised men who were Ad5 seropositive prior to enrollment . This generated widespread concern that the vaccine may lead to a window of increased susceptibility to HIV infection shortly after vaccination, although the available data and analysis are limited on this point [37▪▪]. Additional studies of the Step population have shown that the vaccine did not affect the course of HIV infection among vaccine recipients who became HIV infected, despite the CD8+ T-cell responses elicited by the vaccine . A similar study (Phambili/HVTN 503) of the same Merck Ad5 vaccine in heterosexual men and women in South Africa also showed no effect on HIV acquisition or viral setpoint in those who became HIV-infected. Vaccinations in this study were also stopped early, after 801 of the planned 3000 participants had been enrolled, in light of the Step data, which had emerged during the early part of this trial. Few participants received the full vaccination series and the study was unblinded very early, thus it is difficult to make firm conclusions from these data .
Despite the lack of efficacy with the Merck Ad5 vaccine in the Step study, another Ad5-based vaccine regimen advanced to an efficacy trial. HVTN 505 was designed to assess the efficacy of the Vaccine Research Center (VRC) multiclade HIV-1 DNA plasmid (EnvA, EnvB, EnvC, gagB, polB, nefB) boosted with rAd5 (EnvA, EnvB, EnvC, gag/polB) at moderating the course of HIV infection among those who became infected despite vaccination. The study opened in 2009, enrolling circumcised MSM who were Ad5 seronegative at enrollment. During enrollment the scope of the study was expanded to detect efficacy in preventing HIV-1 acquisition during the 18 months following completion of the vaccination regimen. The study completed enrollment in March 2013 with 2504 participants . In April 2013 a prescheduled Data Safety Monitoring Board (DSMB) review indicated that the study had reached statistical futility thresholds – there was no possibility of demonstrating efficacy at HIV prevention or efficacy at achieving lower viral load setpoint for those who became infected after vaccination. So, vaccinations were halted early in this study because of futility. At the time of the DSMB analysis there were 71 incident HIV infections (41 in vaccine and 30 in placebo recipients) of which 48 HIV infections occurred after 28 weeks or 4 weeks after completing the vaccination regimen. Of these 48 incident HIV infections, 27 occurred among the vaccine recipients and 21 among the placebo recipients. The difference in number of HIV infections between the vaccine and placebo groups was not statistically significant . There were 14 HIV infections among participants who had only received DNA priming and had not reached the Ad5 boosting portion of the study, compared with nine infections among placebo recipients who had reached the same stage in the study. Follow-up of the study participants, now unblinded and without further vaccinations, is ongoing; hopefully additional data and analysis from this study will enhance our understanding of these early findings of futility with this Ad5-based vaccine regimen.
Other adenovirus serotypes
Despite the recent failure of the DNA-Ad5 combination in the HVTN 505 efficacy trial, other adenovirus serotypes remain promising vector candidates because of their lower seroprevalence and other advantageous biological differences. Both Ad26 and Ad35 are rare serotypes in the USA and southeast Asia, both generally have lower seroprevalence than Ad5 in Africa, and even when seropositive Ad26 neutralizing antibody titers are generally substantially lower than with Ad5 [38–41]. It has also become clear that different Ad serotypes are substantially biologically different . Ad26 utilizes different cellular receptors  and exhibits different in-vivo tropism , interaction with dendritic cells [45,46], innate immune profiles , adaptive immune phenotypes [48▪], and improved preclinical protective efficacy [49,50▪], as compared with Ad5. Emerging data also suggest that Ad26 triggers substantially less systemic and mucosal inflammation than Ad5.
In a phase 1 dose-escalation study an Ad26-based EnvA-insert HIV vaccine elicited Ad26 vector-specific and EnvA insert-specific responses that persisted for at least 1 year after vaccination, and the vaccine was generally well tolerated up to a dose of 1011[16▪▪]. Significant humoral and cellular responses were elicited, with a dose-dependent expansion of epitope diversity of the Env-specific binding antibody responses and antibody-dependent cell-mediated phagocytosis and virus inhibition [17▪▪]. Additional studies of Ad26-based HIV vaccines have shown the elicitation of anti-HIV mucosal responses and significant responses even in participants with prior Ad26 vector immunity . A prime–boost regimen with Ad26-ENVA and an Ad35-based vaccine (Ad35-ENV) is under investigation in another phase I multicenter study, which has completed enrolment but not yet reported results . Preclinical trials with Ad26-MVA prime–boost regimens have yielded promising results, such that phase I clinical trials of the Ad26/MVA regimen with mosaic antigen are planned to initiate enrolment in 2013.
Adenovirus 35 (Ad35) offers similar advantages to Ad26. Preclinical studies with heterologous and homologous vectors and gene inserts using rAd35 and rMVA constructs yielded robust cellular immune responses with the heterologous prime–boost regimens [52▪]. In a phase I dose escalation study of Ad35-GRIM (HIV-1 subtype A gag, RT, integrase, nef) and Ad35-ENVA both were generally well tolerated and immunogenic, with elicitation of IFN-γ ELISPOT responses in more than 90% of participants [18▪]. In addition to the ongoing Ad26-Ad35 prime–boost phase I study, another phase I study with intranasal Sendai virus-vectored HIV vaccine prime and Ad35-GRIN boost is planned .
Nonhuman adenovirus vectors are also under investigation for possible use in HIV vaccines. Chimpanzee adenovirus vectors have been shown to elicit T-cell immune responses in animal models, although these have not been used in humans yet [54▪,55,56]. Simian adenovirus vectors, such as ChAd63, are also in ongoing development [57▪,58]. The clinical utility of these nonhuman viral vectors remains to be seen.
Attenuated recombinant rabies virus has been used as a vector for HIV vaccines in animal studies, in which these have been shown to be generally well tolerated and immunogenic. The low prevalence of immunity to rhabdovirus in humans is an attractive feature of these viruses as vectors for HIV vaccines. In order to eliminate the risk of vector-associated disease in humans a recombinant rabies virus with a glycoprotein G mutation to remove the neurotropic quality was constructed. Nonhuman primate studies of this highly-attenuated vaccine demonstrated elicitation of immune responses including control of subsequent simian immunodeficiency virus (SIV) challenge, without notable toxicities . Rhabdovirus vector HIV vaccines have also been evaluated in a preclinical prime–boost study with VSV (vesicular stomatitis virus), again with evidence of humoral and cellular immune responses . There are two main VSV serotypes that occur in the USA, in particular in Indiana and New Jersey, both are typically livestock associated. Consequences of wild-type infection with VSV in humans include a febrile illness in some infected individuals . However, the potential exists for significant neurologic disease, especially with another VSV serotype, Chandipura, which occurs in India . Thus, significant effort has occurred to attenuate a recombinant VSV vector, which is being developed as a candidate HIV vaccine with multiple genetic manipulations to substantially decrease the risk of human neurovirulence . A phase I study (HVTN 090) of the VSV serotype Indiana HIV vaccine is ongoing .
Within the alphavirus family, Venezuelan equine encephalitis virus has been used in an attenuated replicon form as an HIV vaccine vector. The AVX101 alphavirus-based HIV vaccine was studied in two consecutive early clinical trials (HVTN 040 and 059), both of which were stopped early because of the vaccine stability and manufacturing issues. AVX101 was found to be well tolerated in both studies, but the cellular and humoral immune responses were limited [64▪].
The array of nonreplicating vectors for HIV vaccines is varied, but against this background of numerous vectors and prime–boost strategies there are points of light, such as RV144, which offer hints to a path forward toward an effective vaccine. In addition to the ongoing and planned studies discussed with candidate vaccine delivery systems, significant work is ongoing to improve the inserts to elicit a broad anti-HIV response given the global HIV diversity. One such strategy is the development of mosaic inserts to hopefully improve clinically-relevant immune response by HIV vaccines. The nonreplicating viral vectors, including Ad26, MVA, and NYVAC, will be the vectors of choice in the upcoming clinical trials of these novel mosaic insert strategies. Assessment of these candidate delivery systems in combination with other strategies such as DNA and protein are areas of active investigation. The spectrum of nonreplicating viral vectors forms a broad platform for ongoing research toward an effective HIV vaccine.
Conflicts of interest
There were no funding conflicts from any author with this article, no funding used directly in this article. The authors report the following funding sources for their research:
J.A J.: NIH/NIAID, Ragon Institute.
D.H.B.: NIH, Gates Foundation, Ragon Institute, Henry Jackson Foundation, Crucell, Pfizer.
L.R.B.: NIH/NIAID, Ragon Institute.
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 (pp. 513–514).
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This first-in-human evaluation of a novel Ad26 vector-based vaccine demonstrated dose-related reactogenicity and no significant toxicities, providing an alternative to Ad5 among the adenovirus vector candidates for HIV vaccines.
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Vector seropositivity does not affect immunogenicity for MVA-based vaccine
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Increased risk of HIV acquisition after AD5-based vaccine in Step study was documented within the first 18 months after vaccination, but waned after that time period.
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As compared with Ad5, the alternative serotype Ad vectors (Ad26, Ad35, and Ad48) exhibited longer-lasting functional memory T-cell responses, which may translate into immunologic advantages of these vectors for HIV vaccines.
49. Letvin NL, Rao SS, Montefiori DC, et al. Immune and genetic correlates of vaccine protection against mucosal infection by SIV in monkeys. Sci Transl Med 2011; 3:81ra36.
50▪. Barouch DH, Liu J, Maxifeild LF, et al. Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys. Nature 2012; 482:89–93.
Prime–boost vaccine regimens (Ad26/MVA or Ad26/Ad26) were effective in preventing acquisition of SIV in rhesus monkeys despite pathogenic heterologous neutralization-resistant SIV challenges. The inclusion of Env in the vaccine was critical to the protective effect.
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When compared with homologous prime–boost (MVA-MVA or Ad35GE-Ad35GE), a heterologous prime–boost approach (Ad35-GE prime, MVA boost) generated superior immune responses.
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Preclinical data on a nonhuman adenovirus vector which may be an option for use in HIV vaccine development in the future.
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64▪. Wecker M, Gilbert P, Russell N, et al. Phase I safety and immunogenicity evaluations of an alphavirus replicon HIV-1 subtype C gag vaccine in healthy HIV-1-uninfected adults. Clin Vaccine Immunol 2012; 19:1651–1660.
This was the first in-human study of alphavirus-based HIV vaccine; the vaccine was well tolerated, but only modest immunogenicity observed.