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HIV Vaccines: New Frontiers in Vaccine Development

  1. Ann Duerr1,
  2. Judith N. Wasserheit1,2, and
  3. Lawrence Corey1,2
  1. 1Clinical Research Division, Fred Hutchinson Cancer Research Center, Washington
  2. 2Department of Medicine, University of Washington, Seattle, Washington
  1. Reprints or correspondence: Dr. Ann Duerr, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, LE-500, Seattle, WA 98109-1024 (aduerr{at}hvtn.org).
 
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Abstract

A human immunodeficiency virus (HIV) vaccine is the most promising and feasible strategy to prevent the events during acute infection that simultaneously set the course of the epidemic in the community and the course of the disease for the individual. Because safety concerns limit the use of live, attenuated HIV and inactivated HIV, a variety of alternate approaches is being investigated. Traditional antibody-mediated approaches using recombinant HIV envelope proteins have shown no efficacy in 2 phase III trials. Current HIV vaccine trials are focusing primarily on cytotoxic T lymphocyte–mediated products that use viral vectors, either alone or as boosts to DNA plasmids that contain viral genes. The most immunogenic of these products appear to be the recombinant adenovirus vector vaccines, 2 of which are now in advanced clinical development.

The human immunodeficiency virus (HIV) pandemic is now in its third decade. To date, ∼20 million people have died of AIDS, and ∼14,000 are newly infected with HIV every day. Prevention strategies—including behavioral interventions, antibiotic treatment for sexually transmitted diseases other than HIV (such as syphilis), and prescreening of blood products—have failed to control the spread of HIV infection in many populations. Antiretroviral therapies remain woefully inadequate to meet the needs of all who require treatment for HIV infection. Even if one were able to use antiretroviral therapy to treat everyone with HIV infection, it could not be initiated quickly enough to prevent critical early events, such as enhanced transmission to sexual partners during the spike in the HIV viremia that is associated with acute infection [1] and the massive destruction of gut CD4+ T cells that occurs within the initial weeks of HIV infection [2].

An HIV vaccine is the most promising and feasible strategy to prevent these events that influence both HIV disease course and transmission. Yet, despite initial optimism and evaluation of >30 products in >85 trials, the search for an HIV vaccine has yet to reach its goal after >20 years. Although there are no established correlates of protection and no candidates capable of eliciting a sterilizing immunity, the field has seen a rapid expansion in recent years in the number and types of candidate vaccines. Although spontaneous clearing of HIV infection that is attributable to natural immunity has not been observed, testing in animal models suggest that vaccine-induced cellular immunity reduces the HIV viremia and prevents CD4+ T cell loss. Ongoing trials will test whether vaccine-induced immunity leads to amelioration of disease course. Although developing a safe, globally effective HIV vaccine is a daunting challenge, it is perhaps the world's highest public health priority.

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Key Biological Dimensions of the Challenge

Although correlates of protection and animal models would facilitate the search for an HIV vaccine, 3 fundamental, biological properties of the virus make HIV a cunning foe. First, like all retroviruses, HIV is rapidly reverse-transcribed and integrated into host DNA, thereby establishing a beachhead for lifelong infection. The resulting reservoir of latently infected CD4+ T cells means that, without induction of durable, sterilizing immunity, HIV vaccines are unlikely to prevent persistent infection. Second, HIV infection progressively disables the very host immune responses required for vaccine efficacy and for control of viral replication. Although direct destruction of infected CD4+ T helper cells is a primary mechanism for this immune dysfunction, uninfected immune system cells may also be depleted or functionally compromised as a result.

Continuously evolving antigenic variation in HIV poses the third formidable challenge to vaccine development. On the basis of full-length genome sequences, HIV is classified into 3 main groups: M (main), O (outlier), and N (non-M, non-O). The vast majority of HIV subtypes belong to the M group, which contains 22 circulating genetic forms. Nine of these forms are designated HIV subtypes or "clades" (subtypes A–D, F–H, J–K), which differ by ∼25%–35% in env sequences and ∼15% in gag sequences [3]. A growing number of new circulating recombinant forms are being identified. The tremendous global variation in HIV strains (figure 1), which dwarfs that of other vaccine-preventable pathogens such as influenza virus [4], raises concern about whether vaccine candidates can effectively protect against the wide diversity of globally circulating vaccines. Novel approaches to the formulation of multivarient vaccines are likely to be required.

Figure 1
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Figure 1

Global distribution of HIV-1 subtypes and recombinants. Reproduced with permission from the International AIDS Vaccine Initiative Report, published by the International AIDS Vaccine Initiative. (Source: F. E. McCutchan and international colleagues, Henry M. Jackson Foundation, personal communication).

Because cellular responses to natural infection or immunization are generally broader than humoral responses, cross-clade cytotoxic T lymphocytes (CTLs) are detected in individuals infected with a single HIV subtype [5]. Vaccination with products directed at subtype B viruses results in CTL responses that recognize multiple subtypes, although intraclade responses are generally strongest [5–13]. This cross-clade response is due not only to generation of CTLs that recognize conserved epitopes common to several clades, but also to the promiscuity of the T cell receptor, which can accommodate variability in the epitopes it recognizes. However, escape from CTL–mediated containment is well described.

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Approaches to Development of Preventive Hiv Vaccines

The traditional strategy: stimulating neutralizing antibodies. Ideally, all preventive HIV vaccines would abort HIV infection by providing sterilizing immunity, through stimulation of high titers of broadly neutralizing antibodies. Indeed, most licensed vaccines depend primarily on such responses [14]; in the 1990s, experiments in nonhuman primates indicated that passive transfer of neutralizing antibodies could protect against experimental challenge from primate lentiviruses [15–17]. Therefore, the initial strategy for HIV vaccine development used recombinant HIV envelope proteins (gp160 or gp120) in an attempt to elicit neutralizing antibodies. A large variety of these proteins were administered in various adjuvants. Although the products proved to be very safe [18–20], the antibody responses they elicited were generally low in titer, narrow in breadth, and limited in their ability to neutralize primary isolates (i.e., viruses isolated from recently infected individuals) [21]. Two recent phase III trials of rgp120 products evaluated a clade B candidate in the United States, Canada, and Europe and a clade B/E mixture in Thailand. Neither vaccine prevented infection or ameliorated postinfection course [22–25].

Several features of HIV envelope contribute to its ability to evade effective surveillance by the humoral immune system. The HIV envelope is a trimer of heterodimers. Each heterodimer consists of a surface subunit (gp120) and a transmembrane subunit (gp41) that are noncovalently bound to each other. Maintenance of this native trimeric structure appears necessary to elicit the production of neutralizing antibodies. Conversely, the native structure of the HIV envelope shields it from many potentially neutralizing epitopes, such as the coreceptor binding site, which is made accessible only after CD4+ T cell binding [26]. Similarly, mutational substitution studies of glycosylation sites demonstrated that changes at these sites affected neutralization of distant epitopes [27].

Several human monoclonal antibodies that have broadly neutralizing activities have been described, and their study may provide insights into vaccine design. These antibodies include F105 and b12, which are specific to the CD4+ T cell binding site on gp120; 2G12, which recognizes a complex epitope on gp120; and 2F5 and 4E10, which recognize linear epitopes on gp41 (figure 2) [28]. Combinations of these monoclonal antibodies reveal strong cross-clade neutralization against clades A, B, C, and D in vitro, as well as strong antiviral protection in neonatal macaques [29, 30]. The use of these epitopes in vaccine development is the object of intense study. For example, the b12 monoclonal antibody has an unusual, extended, antigen-binding finger that accesses a normally recessed epitope on gp120, thereby blocking CD4+ T cell binding [26]. Moreover, antibodies that target gp41 domains involved in virus fusion with the target cell, as 2F5 and 4E10 do, may be limited by steric hindrance and by the rapidity of the fusion process [26, 31]. Understanding how to develop immunogens that can mimic the effects of these monoclonal antibodies and that can elicit the production of effective neutralizing antibodies to a wide variety of circulating strains of HIV remains a challenge.

Figure 2
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Figure 2

Schematic revealing the location of neutralizing antibody epitopes on gp120 and gp 41 (shown in the native form and the transient, prehairpin form). Reproduced with permission from [28].

The current strategy: stimulating cellular immunity. Faced with the lack of efficacy of products designed to elicit the production of neutralizing antibodies, HIV vaccine development has shifted its primary focus to cellular immunity. Most ongoing trials are testing vaccine candidates that are meant to induce HIV-specific CTL production. These immune effector cells recognize HIV epitopes that are displayed on cell surfaces in conjunction with human leukocyte antigen but do not recognize free viruses. They limit the spread of HIV infection by destroying infected cells via apoptosis or by secreting chemokines and cytokines that interfere with subsequent rounds of infection.

Work in nonhuman primates indicates that vaccines that elicit the production of HIV-specific CTLs probably act by limiting HIV replication, thereby reducing the HIV load in infected individuals, rather than by preventing HIV acquisition. In some animals, viral replication appears to be completely suppressed with the use of these vaccines, whereas limited residual viral replication continues in other animals [32–34]. In humans, the set-point viral load predicts the subsequent disease course [35], whereas transmission to sexual partners correlates with the plasma viral load and may be completely prevented when the viral load decreases to <1500 copies/mL [36]. Thus, HIV-specific CTLs may mitigate the individual- and population-level effects of HIV infection, even if they do not prevent acquisition of infection itself.

Considerations in vaccine design. Since 1798, when Edward Jenner established the vaccine era with his treatise on ariolae vaccinae [37], 5 basic approaches to viral vaccine design have been used (table 1). Two of the most effective approaches have harnessed live, attenuated organisms and inactivated organisms. Unfortunately, neither has proven optimal for HIV vaccine development. Live, attenuated virus vaccines initially appeared to be successful in preventing experimental challenge in nonhuman primates [38, 39]; however, attenuated HIV mutants appear to be pathogenic in humans: late-onset immunosuppression occurred in 3 of 6 individuals who were exposed through blood transfusion to HIV carrying deletions in both nef and the long terminal repeat [38, 39]. The delayed pathogenicity of such a double-deletion virus has cast doubt on the safety of using live, attenuated approaches.

Table 1
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Table 1

Potential advantages and disadvantages of major HIV vaccine design strategies.

A variety of killed vaccines has been tested, with little efficacy in nonhuman primate models [38, 39]. Interest in pursuing this approach has been limited by a lack of inducible T cell immunity and by safety concerns about potential residual infectivity in the product due to incomplete inactivation (such as that which occurred during the Cutter incident with the Salk polio vaccine [40]).

Other approaches to vaccine development have employed viral proteins, peptides, or subunits, DNA plasmids carrying viral genes, and other viruses or bacteria as "Trojan horse" vectors to deliver viral genes. As discussed above, HIV envelope proteins have not proven efficacious in 2 phase III vaccine trials [22–24] (table 2). Therefore, the primary emphasis of current HIV vaccine trials has shifted to viral vectors, either alone or in combination with DNA plasmid vaccines (table 2).

Table 2
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Table 2

HIV vaccine candidates in ongoing clinical trials.

DNA plasmids that deliver viral genes that code for HIV epitopes do not integrate into the host cells of vaccinated individuals. They remain episomal and act as expression vectors, producing peptides that can induce cellular immunity. In contrast to viral or bacterial vectors, protein production in response to DNA vaccines can focus the immune response more narrowly on HIV insert sequences. Although immunization with DNA plasmids that contain HIV inserts has elicited substantial cellular responses in mice and nonhuman primates, these products have been poorly immunogenic in humans. One strategy to increase immune response has incorporated genetic adjuvants—specifically, the coadministration of DNA plasmids coding for cytokines (most notably IL-12 and IL-15).

The second approach to increase immune response uses DNA as a prime, followed by a protein or a viral vector boost. Experiments in nonhuman primates have had promising results. For example, animals primed with DNA and then boosted with poxvirus vaccines (modified vaccinia Ankara or fowlpox) displayed strong CD8+ T cell responses [41, 42] and controlled viremia after parenteral or mucosal challenge [43, 44]. Currently, the most promising DNA candidate appears to be a multiclade construct developed by the National Institutes of Health's Vaccine Research Center (VRC) that expresses clades A, B, and C of the env gene and clade B of the gag, pol, and nef genes [45]. Early data suggest that this vaccine elicits antibody production and CD4+ T cell responses in the majority of vaccinees, and CD8+ T cell responses in up to 35% of vaccinees [46].

Although several viral vectors are being explored in the design of HIV vaccines, poxviruses and adenoviruses have received the most attention. The most extensive trial experience has been with poxvirus vectors; more than a dozen are currently in clinical trials. Early trials evaluated vaccinia-vectored products; the 2 most commonly studied of these products elicited cellular immune responses to simian immunodeficiency virus antigens in nonhuman primate models and HIV antigens in human test subjects [47, 48]. However, concerns about preexisting immunity to poxvirus vectors and about potential dissemination of vaccinia in areas with a high prevalence of immunodeficient individuals has resulted in the construction of more attenuated poxvirus vectors [49].

Among the poxviruses, the canarypox vector and 2 attenuated vaccinia strains, modified vaccinia Ankara and the New York strain, have been most studied. Modified vaccinia Ankara was initially used in Turkey in smallpox vaccine production.

In the 1950s, this strain was brought to Germany, and it was further attenuated by repeated passage through chick embryo fibroblasts—a process that resulted in an accumulation of multiple mutations and the deletion of ∼15% of the genome [50]. A very favorable safety profile was seen in the 120,000 vaccinees who received this product in Turkey and Germany as part of the smallpox campaign. Modified vaccinia Ankara has subsequently been used in experimental HIV, malaria, and cancer vaccines [50]. The New York strain of vaccinia was developed through a deletion of 18 open reading frames and is blocked at an early stage of replication [51]. These attenuated viruses retain little or no ability to replicate in human cells, but they can elicit humoral and cellular responses to vaccine inserts and viral sequences.

Unfortunately, although most recombinant HIV vaccines using poxvirus vectors are effective in nonhuman primate models [41, 44, 52, 53], they have much more limited immunogenicity in humans. For example, initial trials of modified vaccinia Ankara vectors in humans were disappointing—only 10%–25% of participants in trials of a DNA/modified vaccinia Ankara regimen were shown to have anti-HIV cellular responses by ELISPOT [54]. Other prototype vaccines using different inserts and promoters have recently entered clinical trials. Data indicating whether these constructs display increased immunogenicity are forthcoming.

Canarypox vectors have also been studied extensively in humans. Five different canarypox constructs containing HIV-1 clade B and E genes have been tested in >1500 subjects. These vectors have been very well tolerated by test subjects, with reactogenicity levels comparable to those of currently licensed vaccines [19]. However, like most poxvirus vectors, canarypox vaccines have not induced durable CTL responses. In chromium release assays in which postvaccination PBMCs are stimulated with HIV-1, ∼40%–50% of vaccinees demonstrate T cell responses [20, 55, 56]. However, in more quantitative ex vivo assays, the level of immunogenicity is much lower (<20% of vaccinees) [57]. A phase III trial in Thailand of a canarypox vector (vCP 1521) containing the HIV-1 clade B env, gag, and protease genes, in combination with gp120 (clade B and E) completed enrollment in January 2006; follow-up is ongoing.

Recombinant adenovirus type 5 (Ad5) vectors are the most immunogenic viral vectors in HIV vaccine development today. These viral vectors are rendered replication-defective by mutations and by deletion of an adenovirus gene; HIV genes are inserted in place of the deleted adenovirus gene under the control of exogenous promoters and regulatory elements that drive high-level gene expression. The replication-incompetent adenoviruses retain the ability to infect cells and to deliver their genomes to these cells' nuclei. Two different products, both using replication-incompetent Ad5 backbones, are currently in advanced clinical development. The first, produced by Merck, is an admixture of 3 adenoviruses, each containing codon-optimized subtype B gag, pol, or nef genes. These 3 HIV genes are highly conserved (80% to >90%) across subtypes. The Merck adenovirus vectors that contain the gag gene alone or that are a trivalent preparation containing the gag, pol, and nef genes, produce robust CD8+ CTL responses in macaques (500–1000 IFN-γ–producing cells/106 PBMCs after vaccination with 1011 viral particles) [58, 59].

The second Ad5 candidate, developed by the National Institutes of Health's VRC, is an admixture of 4 adenoviruses, 1 of which contains a subtype B gag-pol gene fusion. The other 3 adenoviruses contain subtype A, B, or C envelope genes. This VRC construct has also elicited strong humoral and cellular responses in macaques; the magnitude and breadth of the response was improved by prior priming of the product with the DNA plasmids discussed above [45, 60].

Both approaches (the Merck trigenic adenovirus vaccine and the VRC DNA prime/adenovirus boost vaccine) provided protection in animal models. Vaccinated macaques were intravenously challenged with SHIV 89.6P, a pathogenic simian immunodeficiency virus/HIV chimeric virus. Although there was no protection from infection, HIV replication was suppressed; test animals experienced a mild course of infection, which did not progress to AIDS during the follow-up period (280 days in the Merck study and 168 days in the VRC study) [34, 45, 61].

Although there is debate about how accurately these experiments will predict results in humans, these results are promising; several phase I trials have been conducted with these Ad5 products [62, 63]. The Merck Ad5 HIV vaccines have been safe and well tolerated in >2000 study participants to date [62]. T cell responses have been elicited in ∼70% of trial participants, with slightly lower response rates among participants with prior adenovirus immunity [62]. Interestingly, compared with Merck's monogene product, their multigene Ad5 vaccine appears to increase the frequency and breadth of responses and to reduce the response disparity between participants with and without preexisting Ad5 immunity (table 3) [62]. The VRC vaccine regimen, consisting of 3 doses of DNA boosted with Ad5, also elicits humoral and cellular responses in the majority of trial participants [63]. Of note, the VRC Ad5 candidate seems to stimulate more frequent CTL responses to env antigens than to structural gene products.

Table 3
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Table 3

Comparison of ELISPOT responses, elicited by MRK gag only and by multigene adenovirus type 5 vaccines.

A blunted immune response to Ad5 HIV vaccines because of prior immunity to the vector [58–60, 64] presents a potential problem for use of this approach in some of the regions that are hardest hit by the HIV pandemic, where the high-titer Ad5 seroprevalence increases rapidly with age to 50%–80% [65]. A number of strategies to overcome this problem are currently being investigated, including use of adenovirus vectors of uncommon serotypes, production of chimeric adenoviruses, priming with DNA, or prime-boost combinations of Ad5 with other adenovirus or poxvirus vectors [58–60]. This limitation notwithstanding, the Merck Ad5 product is in efficacy trials, and the VRC prime-boost regimen is expected to follow suit in 2007. A 3000-person test-of-concept trial (STEP study) is being conducted by Merck and the HIV Vaccine Trials Network in the United States, South America, and the Caribbean, to evaluate efficacy in reducing either HIV acquisition or viral load set point [66]. The VRC, HIV Vaccine Trials Network, US Military HIV Research Program, and International AIDS Vaccine Initiative are jointly testing the VRC's DNA-adenovirus prime-boost regimen in a phase II trial in the Americas and in eastern and southern Africa, to qualify it for efficacy testing.

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Conclusions

Last year, HIV vaccine development entered the era of CTL-mediated vaccine efficacy trials with the initiation of the HIV Vaccine Trials Network/Merck STEP study. Together with other ongoing and upcoming trials, this landmark study will determine whether the current viral vector vaccines are capable of eliciting the quantity and quality of T cell responses that might alter the course of individual and global HIV-1 infection.

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Acknowledgments

We thank Francine McCutchen, Robin Isaacs, and the International AIDS Vaccine Initiative for generously sharing data for manuscript figures and tables; and Cecilia Morgan, Margaret Wecker, Richard Newman, Erik Schwab, Benjamin Sheppard, and Aleta Howard for their outstanding assistance in preparation of this manuscript.

Financial support. National Institutes of Health/National Institute of Allergy and Infectious Diseases UO1 AI-46747 (HIV Vaccine Trials Network).

Potential conflicts of interest. All authors: no conflicts.

  • Received February 3, 2006.
  • Accepted April 22, 2006.
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  1. Clin Infect Dis. (2006) 43 (4): 500-511. doi: 10.1086/505979
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