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* The Wistar Institute, and
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A number of different vaccine modalities have undergone preclinical and, in part, clinical testing. The two vectors that elicited the most potent CD8+ T cell responses and provided the highest degree of protection in nonhuman primate models were E1-deleted adenovirus (Ad) 3 recombinants based on the human serotype 5 (AdHu5) and modified vaccinia Ankara (MVA) constructs used alone or in combination with DNA vaccine priming (4, 5, 6, 7, 8, 9). AdHu5 vaccines to gag of HIV-1 clade B have been tested in nonhuman primates in comparison to adjuvanted DNA and MVA vaccines expressing the same transgene product. The E1-deleted Adhu5 vaccine showed the highest efficacy and was the only vaccine in this study that upon challenge with the simian-HIV chimera, SHIV 89.6P, prevented CD4 loss and controlled both the acute viremia and the set-point viral load in all animals (4). Other studies have shown protection against disease progression in SHIV infection models in nonhuman primates with MVA or DNA vaccines given alone or as part of a prime-boost combination (5, 6, 7, 8).
However, a major limitation of adenoviral and, to a lesser extent, poxviral vectors is that neutralizing Abs to the vaccine carrier elicited by previous natural infections or vaccinations impact their efficacy. Nearly all adults have Abs to the common serotypes of human Ad and 35–45% of those in the US have high titers of virus neutralizing Abs to AdHu5 virus (10). This percentage is higher in some less developed countries (H. C. J. Ertl, unpublished observation). Humans vaccinated against smallpox have pre-existing immunity for MVA, and as widespread smallpox vaccination is again being considered, the prevalence of immunity to vaccinia virus could increase substantially.
To circumvent interference by pre-existing immunity to common human serotypes of Ad, we developed replication-defective vectors based on Ad viruses isolated from chimpanzees. One such vector of the chimpanzee serotype 68, termed AdC68, was shown previously to induce potent transgene product-specific CD8+ T and B cell responses that were not severely dampened in the presence of neutralizing Abs to human serotypes of adenovirus (11, 12). Assuming that the AdC68 vector that induces a potent immune response after a single immunization is unlikely to be suitable for repeated use as a vaccine carrier either to boost an immune response (13) or to immunize against a different pathogen, we developed an additional E1-deleted Ad vector of chimpanzee origin, termed AdC6, which represents a distinct serotype and is thus not cross-neutralized by Abs to AdC68 (J. M. Wilson, manuscript in preparation). In this study, we show, similar to the previously described AdC68 vector, that an E1-deleted AdC6 vector induces a potent transgene product-specific CD8+ T cell response that can be increased substantially by using a heterologous E1-deleted Ad recombinant expressing the same transgene product for booster immunization. This type of heterologous prime boost regimen is by far more effective than priming with a DNA vaccine followed by booster immunization with an Ad recombinant or by using the same Ad vaccine carrier repeatedly.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female 6- to 8-wk-old BALB/c mice were purchased from The Jackson Laboratory (Bar Harbor, ME) and kept at the Animal Facility of The Wistar Institute (Philadelphia, PA).
Cell lines
E1-transfected 293 cells and HeLa cells were propagated in DMEM supplemented with glutamine, sodium pyruvate, nonessential amino acids, HEPES buffer, antibiotic, and 10% FBS.
Generation, propagation, and titration of viral recombinants
The AdC6 virus was sequenced, the E1 domain was deleted, and the remaining genome was vectored as a molecular clone basically as described previously for human Ad vectors (14). The cDNA encoding a truncated codon-optimized form of gag of HIV-1 clade B or the rabies virus glycoprotein of the Evelyn Rokitniki Abelseth (ERA) strain was cloned into the pShuttle vector and from there into the AdC6 molecular clone. For viral rescue, the vector was transfected into 293 cells, which provide the E1 of AdHu5 virus. Virus was expanded on 293 cells, purified by CsCl gradient centrifugation, and the number of viral particles (vp) was determined by spectrophotometry. The stock viruses had titers of 
5 x 1012 vp/ml. All purified viruses were dosed according to the number of particles as is the accepted method by the Food and Drug Administration. PFU were determined in addition and typically ranged from 1 PFU per 100-1000 vp. The vaccinia virus recombinant expressing gag of HIV-1 clade B was obtained from the AIDS Reference and Reagents Center (Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD). This recombinant was propagated and titrated on HeLa cells.
DNA vaccine
The vector expressing a codon-optimized truncated form of HIV-1 clade B (pCMV37M1–10D) was most generously provided by Dr. G. Pavlakis (National Cancer Institute, Frederick, MD). This vector has been described in detail earlier (15). The vector was propagated in Escherichia coli strain DH5
in Luria-Bertani broth supplemented with kanamycin and was purified with the Qiagen MaxiKit (Valencia, CA). The vector was quantitated by spectrophotometry at 260 nm.
Expression of the transgene product
Gag protein was identified in supernatants of infected 293 cells by Western blotting. 293 cells (1 x 106) were infected for 48 h with AdHu5gag37 or AdC6gag37 virus (5 x 104 vp/cell). Additional 293 cells were infected with a control construct expressing the glycoprotein of rabies virus (AdHu5rab.gp). Proteins in the culture supernatant were separated on a 12% denaturing polyacrylamide gel and transferred by electroblotting to a polyvinylidene difluoride membrane (Millipore, Bedford, MA). The blot was stained with the mAb 183-H12-5C to HIV-1 p24 (Division of AIDS, AIDS Reference and Reagents Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, contributors: Dr. B. Chesebro and K. Wehrly).
Peptides
The AMQMLKETI peptide (16) that carries the immunodominant MHC class I epitope of gag for mice of the H-2d haplotype, and the control peptide 31D delineated from the nucleoprotein of rabies virus (17) were described previously.
Immunization of mice
Groups of four to five BALB/c mice were immunized at 6–8 wk of age with recombinant viruses or DNA vectors diluted in 50 µl of saline given i.m. Mice were boosted 2–4 mo later with recombinant viral vectors given i.m.
Intracellular cytokine staining
Intracellular cytokine staining was performed on splenocytes (1 x 106/sample) as described previously (11). A FITC-labeled Ab to mouse CD8 and a PE-labeled Ab to mouse IFN-
were obtained from BD PharMingen (San Diego, CA). Assays were repeated two to four times. The figures show the result of a representative experiment. The figure legends show the combined data for two to three representative experiments, i.e., number of experiments (n), mean percent of IFN-+CD8+ cells over all CD8+ T cells and (range of data). For these data, the percent of CD8+ cells that stained positive for IFN- in absence of the gag peptide was subtracted from the percent of CD8+ T cells that produced IFN- in presence of this peptide.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The AdC6gag37 recombinant virus carrying the gag gene of HIV-1 clade B was generated as a viral molecular clone in 293 cells transfected with E1 of AdHu5 virus basically as described before (17). A codon-modified sequence of gag (15) was used to avoid rev dependency (18). After selection of a stable AdC6gag37 vector, expression of the truncated, partially secreted p37 gag protein (p17 and p24, Ref.19) was confirmed in infected 293 cells by Western blot, as shown in Fig. 1.
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We initially determined the basic parameters of the gag-specific CD8+ T cell response in mice immunized i.m. with the AdC6gag37 vector. The response measured by intracellular IFN- staining of CD8+ T cells stimulated for 5 h with a peptide carrying the immunodominant epitope of gag peaked 10 days after immunization as previously reported for the CD8+ T cell response induced by an AdC68 vector (Fig. 2). Maximal CD8+ T cell frequencies were induced by a moderate dose of 5 x 109 vp of the AdC6gag37 vector. A further increase of the dose did not augment the response (Fig. 3). In most experiments, frequencies of gag-specific CD8+ T cells induced by the 5 x 109 vp of the AdC6 vector ranged from 10 to 15% of all splenic CD8+ T cells.
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1:100–1:200 (not shown), which is comparable to titers commonly seen in sera of adult humans. Two weeks later, mice were vaccinated either with the AdHu5gag37 or the AdC6gag37 constructs. Mice preimmune to AdHu5 virus failed to develop a gag-specific CD8+ T cell response after vaccination with the AdHu5gag37 vaccine as reported previously (11), while mice immunized with AdC6gag37 developed a potent CD8+ T cell response that was below that elicited in mice that had not been pre-exposed to the AdHu5 virus. Again, as demonstrated previously for the AdC68gag37 construct (11), the AdC6gag37 vaccine was thus not as strongly affected by pre-existing immunity to AdHu5 virus as the homologous AdHu5gag37 vector (Fig. 4).
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Priming with a DNA vaccine can augment the efficacy of vaccines based on recombinant viral vectors (13, 20). Priming of mice with a DNA vaccine expressing gag did not have a major impact on the CD8+ T cell response elicited by the AdC6gag37 vaccine. The effect of boosting of AdC6gag37-primed BALB/c mice with a heterologous Ad vector was far more impressive; boosting with the AdC68gag37 vector resulted in frequencies of gag-specific CD8+ T cell frequencies of close to 40% of all splenic CD8+ T cells while boosting with the AdHu5gag37 vector increased these frequencies to 55%. As expected, homologous prime boosting only resulted in a small increase of the CD8+ T cell response to gag (Fig. 6A). The results demonstrate that heterologous prime boost regimens based on distinct serotypes of Ad vectors surpass those based on DNA vaccine prime-Ad vector boost regimens as well as those based on the sequential use of homologous Ad vectors. In a follow-up experiment, we compared boosting of AdC6gag37-primed mice with either heterologous Ad vectors or an unrelated viral vector based on a vaccinia virus recombinant. As shown in Fig. 6B, boosting of AdC6gag37-primed mice with the vaccinia virus recombinant resulted in frequencies that were slightly higher compared with those obtained by boosting with a heterologous simian Ad vector. Nevertheless, boosting with the AdHu5gag37 vector resulted in the highest frequencies of gag-specific CD8+ T cells (Fig. 6B) indicating that boosting with an unrelated viral vector did not offer an advantage over a prime boost regimen based on heterologous adenoviral vaccine carriers.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Subsequent vaccine efforts were directed at inducing cell-mediated immune responses (6, 23, 24, 25). Optimized DNA vaccines expressing the gag of HIV-1 provided initial protection to nonhuman primates challenged with SHIV-89.6P virus (26). Nevertheless as the vaccine-induced CD8+ T cell response failed to provide complete clearance of the virus, most of the animals eventually succumbed to an overwhelming infection with escape mutants that evaded the vaccine-induced immune response (27) indicating that a HIV-1 vaccine had to induce CD8+ T cells to multiple epitopes to control the outgrowth of mutant virus.
Other vaccine modalities such as viral vector used either alone or in combination with DNA vaccines for priming have yielded encouraging results in preclinical nonhuman primate challenge studies and are currently undergoing clinical trials (4, 5, 28). Experimental animals vaccinated with AdHu5 recombinants were protected against CD4 loss and could control acute and set-point viral loads upon challenge with SHIV-89.6P virus (4). AdHu5 virus is a common human pathogen and a significant percentage of the adult human population carries neutralizing Abs to the surface proteins of this virus. When nonhuman primates were preimmunized with AdHu5 virus to mimic the situation in human patients, the dose of the AdHu5 vaccine to HIV-1 had to be increased 1000-fold to overcome the interference of neutralization of the vaccine carrier (4). Obviously such an increase in dose not only augments the cost of the vaccine but also increases the risk of serious side effects such as those encountered during gene therapy trials.
To circumvent interference by pre-existing neutralizing Abs, we developed E1-deleted adenoviral vectors from chimpanzees. These viruses do not circulate in the human population nor are they neutralized by Abs to common human serotypes of Ad virus (10). One of these vectors, termed AdC68, has been described previously to induce potent CD8+ T cell responses to gag of HIV-1 even in the presence of neutralizing Abs to AdHu5 virus (11, 12). The AdC68 vector, like any viral recombinant, induces not only a transgene product-specific immune response but also neutralizing Abs directed mainly against the adenoviral hexon. These neutralizing Abs are expected to reduce the efficacy of the vaccine carrier if used for sequential booster immunization. DNA vaccine priming has been used successfully in animal models and may in part blunt the Ab response to components of a viral vector vaccine carrier (21, 29). Nevertheless, DNA vaccines have performed poorly in clinical trials so far (30, 31) and it is thus uncertain whether DNA vaccine priming followed by a booster immunization with a viral recombinant will be as efficacious in humans as has been in preclinical experimental animal studies.
Therefore, we developed an additional E1-deleted Ad recombinant of chimpanzee origin to increase our repertoire of vaccine carriers that can be given sequentially. The AdC6 and AdC68 viruses belong to distinct serotypes and are not cross-neutralized by Abs to either vector. With regard to growth characteristics, both viruses are transcomplemented by the E1 of AdHu5 virus and can thus be propagated on available packaging cell lines. Viral stocks were characterized regarding vp as well as PFU as a measure of infectivity. Nevertheless, accurately linking these two parameters is not possible for Ad preparations derived from different serotypes, as the standard infectivity assay fails to appreciate the unique interactions of distinct serotype with the packaging cells, which in turn influences plaque formation.
In this study, which was designed as a proof of principle study for comparing induction of transgene product-specific CD8+ T cell frequencies with different prime boost regimens, we used a truncated form of gag which contains an immunodominant CD8+ T cell epitope for mice of the H-2d haplotype. For eventual clinical use, vectors containing more comprehensive sequences of HIV-1 need to be used to prevent the outgrowth of viral escape mutants.
Immunologically, the AdC6gag37 vector closely resembled the previously described AdC68gag37 vector with regard to kinetics of induction of CD8+ T cells, optimal dose, and lack of strong interference in animals pre-exposed to AdHu5 virus. The AdC6 vector resulted in slightly superior transgene product-specific CD8+ T cell frequencies, which may in part reflect differences in the adjuvant effects of the two vaccine carriers, a subtle difference in the amount of transgene product expression or differences in dosing due to the above-described difficulty to accurately compare the infectivity of Ad vectors of distinct serotypes.
We developed the AdC6 vector specifically as a tool to allow for sequential immunization with heterologous Ad vectors. Priming of mice with a DNA vaccine expressing gag37 was relatively inefficient in increasing frequencies of gag-specific CD8+ T cells upon booster immunization with the AdC6gag37 vector. Similarly, a repeated administration of the AdC6gag37 vector affected only a modest increase in frequencies of gag-specific CD8+ T cells, which presumably reflects in part that neutralizing Abs to the vaccine carrier prevented infection and hence expression of the transgene product. Booster immunization of AdC6gag37 vector-primed animals with a heterologous Ad vector, in contrast, resulted in an impressive increase of the frequencies of gag-specific CD8+ T cells with the AdHu5gag37 vector outperforming the AdC68gag37 construct. We do not know yet why the AdHu5gag37 vector is more efficacious than the AdC68gag37 vector in boosting an AdC6gag37-induced immune response especially as the AdC68 vector consistently induces higher frequencies of transgene product-specific CD8+ T cells than the AdHu5 vector in naive animals given a single immunization. The AdHu5 vector results in higher transgene product expression in most cell types compared with the simian vectors (H. C. J. Ertl, unpublished observation). As shown previously, AdC68 vectors (14) as well as AdC6 vectors (H. C. J. Ertl, unpublished observation) induce potent Th1 responses while AdHu5 vectors stimulate more balanced Th1/Th2 type responses. We assume that in naive animals, the predominance of the Th1-type response favors activation of CD8+ T cells upon vaccination with the simian Ad vectors while the Th2 components induced by the AdHu5 vectors allows for a more potent B cell response as shown previously (14). Priming with a simian Ad vector is expected to set-up the immune response toward the Th1 pathway, which should persevere upon booster immunization with either a different simian Ad vector or with the AdHu5 vector. The AdHu5 vector may, as shown in vitro, express higher levels of transgene product and thus favor superior activation of memory CD8+ T cells. We favor an alternative explanation. CD8+ T cells to adenoviral Ags show extensive cross-reactivity between simian and human Ads (H. C. J. Ertl, unpublished data). In mice primed with either a human or a simian Ad vector these CD8+ T cells are expected to lead to the demise of Ad vector-transduced APCs, which, as we showed previously (11), have a negative impact on the CD8+ T cell response to the simian vectors in AdHu5 virus pre-exposed mice (11). The delayed kinetics of CD8+ T cell induction shown by the simian as compared with the human Ad vectors, which may be a consequence of the comparatively low levels of transgene product expression, could allow for a higher impact of the CD8+ T cell-mediated killing of APCs expressing gag concomitantly with the adenoviral Ags of the vaccine carrier. To test whether an alternative viral recombinant vaccine that does not share cross-reactive Ags with adenoviral carriers would perform superiorly in a prime boost regimen, AdC6gag37-primed mice were boosted either with the AdHu5gag37 or AdC68gag37 vector or a vaccinia virus recombinant expressing gag. The vaccinia virus recombinant elicited an impressive increase of the frequency of splenic gag-specific CD8+ T cells, but, nevertheless, failed to outperform the AdHu5gag37 vector and only provided a marginal advantage over boosting with the AdC68gag37 vector. These data indicate that boosting with vaccinia virus that is not affected by any cross-reactive immune effector mechanisms elicited to the vaccine carrier used for priming fails to provide an advantage over a heterologous Ad vector prime-boost regimen. Therefore, sequential heterologous Ad prime-boost regimens may provide the best tool for inducing potent CD8+ T cell responses against the desired Ags.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Hildegund C. J. Ertl, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104. E-mail address: ertl{at}wistar.upenn.edu
3 Abbreviations used in this paper: Ad, adenovirus; MVA, modified vaccinia Ankara; SHIV, simian-HIV; vp, viral particle.
Received for publication May 13, 2003. Accepted for publication October 7, 2003.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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