Vaccine Candidates - Immunology of HIV Infections

VACCINE CANDIDATES

There have been many attempts to construct a vaccine that is both protective and has a low cost of production; yet, there is still not a promising candidate. Part of the problem is that to be effective the vaccine has to be given early or before exposure to the virus. Ideally a vaccine could prevent the disease entirely or at least shut down the viremie phase (see panel B of Figure 8.4). For the sake of convenience, we have listed the vaccine approaches separately with their promises and caveats.

Live Attenuated Vaccines

The observation that NEF strains could offer protection against challenge with pathogenic SIV infections in rhesus macaques served as the model for the use of this type of attenuated vaccine. However, this mutant’s drawback is that it produces a lifelong persistent viral infection in the host. The positive side is that although the attenuated vaccine does not prevent infection with a wild-type SIV infection, it does prevent that infection from going on to produce the disease AIDS. Thus, this approach does not appear feasible now. However, what is being explored is the nature of the protective immune response in these monkeys after infection with the attenuated virus.

Several reports raise the question whether these attenuated vaccines will give the broad protection so eagerly sought. As Anne Piantadosi and colleagues (2007) have pointed out, HIV-1 superinfection (reinfec-tion) does not always protect against other strains. In their studies, they screened a cohort of high-risk Kenyan women by com-paring partial gag and envelope sequences over a five-year period, beginning with the primary infection. Of thirty-seven women screened, seven were found to have superinfections, including cases in which both viruses were from the same HIV-1 subtype A. In five cases, the superinfect-ing strain was detected in only one of the two genomes examined, suggesting that recombination frequently occurs following HIV-1 superinfection. They conclude that superinfection commonly occurs after the immune response against the initial infec-tion has had time to develop and mature. Supporting this claim was an earlier report by Altfeld et al. in Nature in which this superinfection occurred despite broad CD8+ T-cell responses (twenty-five distinct epitopes) to many HIV viral proteins. They conclude that superinfection can occur in the setting of a strong and broadly directed virus-specific CD8+ T-cell response.

Yet, other reports by Chakraborty and colleagues indicate that superinfection may not be so high. They studied fourteen HIV seroconcordant couples (i.e., partners were

independently infected with different HIV-1 strains) with high risk of re-exposure to the virus. Phylogenetic analyses based on pol and env global sequences obtained from more than a 100 longitudinal plasma samples over one to four years failed to detect HIV-1 superinfection in this cohort of patients. They conclude that chronic HIV infection seems to confer protection against superinfection with a second HIV-1 strain. Obviously, more work needs to be done to determine what factors are responsible for superinfection in some individuals and protection in others, both at high risk of reinfection.

Inactivated Viral Vaccines

Although the initial results with inacti-vated vaccine were negative with high doses of formalin treatment (loss of anti-genicity of the viral envelope proteins), it was quickly discovered that by using low doses of formalin, the antigenicity of the envelope proteins was preserved. This preparation was capable of inducing viral neutralizing antibodies in both mice and nonhuman primates. This area is presently being actively pursued, but the problem will be overcoming the rapidly changing antigens of the wild-type virus.

A second approach has been to inacti-vate the domains of two nucleocapsid pro-tein zinc fingers. This has been achieved by treating these complexes with mild oxidation or alkylation procedures, which completely inactivates both HIV-1 and SIV but keeps the envelope glycoprotein spikes intact and functional. Studies in the SIV macaque model revealed that monkeys vaccinated with the inactivated virus were not protected against infection with the wild-type virus, but the levels of SIV vire-mia were low and there was no depletion of CD4+ T cells.

Subunit Vaccines

Most of the research efforts in HIV vaccines have gone into the subunit vaccines involv-ing the gp120 envelope proteins, which also includes the gp41 domain. Both of these proteins do elicit neutralizing antibodies to the homologous vaccine strain but not to heterologous primary isolates in the animal model. Despite these caveats, two large-scale phase III clinical trials of this type of vaccine have been carried out involving 7,500 high-risk individuals. Neither of these trials showed a significant reduction in HIV infection in the vaccinated individuals, even with continuous booster shots dur-ing the three-year trial. A number of other trials involving trimeric gp140, a DNA vac-cine encoding a V2-deleted gp140 and other combinations, are in various phases, but the results are not known at present.

Cellular Vaccines

A strong and specific T-cell immune response in the absence of broadly neu-tralizing antibodies may blunt the ini-tial viremia, even if the infection is not completely prevented. Thus, more recent vaccine efforts have been directed toward stimulating the cellular immune response. Particular attention has been paid to those vaccines that induce an HIV-specific CD8+ CTL response whose role in the con-trol of virus load and evolution of disease has been well documented in the macaque model. Although the T-cell vaccines do not prevent the HIV infection, they do help vaccinees who get infected to control viral replication and reduce viral loads, thus resulting in less risk of transmission of the disease to seronegative partners.

Vaccines have been based on this strat-egy with particular emphasis on the use of naked DNA vaccines and live recombinant vectors, for example, naked DNA vaccines expressing the HIV-1 gag gene and either IL-12 or Il-15, which was developed by Wyeth and is presently in several phase I trials in the United States, Brazil, and Thailand. DNA vaccines have been found to be most useful as priming vaccines in prime-boost strategies, using live recombi-nant vaccines for booster immunization.

While the original recombinant HIV vaccines used vaccinia virus and were well tolerated, safety considerations in immu-nodeficient hosts has led investigators to substitute the canarypox virus for the vac-cinia virus. However, the immunogenicity of the pox-virus-based vaccines in humans has been relatively modest with less than 35 percent of the vaccinees scoring positive for T-cell responses. In contrast, replication-defective adenovirus type 5 (ad5) appears to be one of the most promising live virus vectors for HIV vaccines. Merck has used this complex and showed that 50 percent of the volunteers had significantly long-lasting CD8+ T-cell responses to HIV-1 peptides. A trivalent recombinant ad5-gag/ pol/nef complex has been engineered and retested in human volunteers. A phase II trial of this candidate is being investigated in 1,200 men and 400 women at high risk of exposure to HIV infection who will be followed for three years. The results of this trial will appear in 2008.