A review of HIV infection and transmission can be found in Chapter 2. As the AIDS epidemic persists and spreads unabated in much of the world, the search for an effective HIV vaccine is becoming critical. In 1997, President Clinton chal- lenged scientists to develop an effective HIV vaccine by the year 2007. Since clinical trials ﬁrst began in 1987, at least 34 different HIV candidate vaccines have begun phase I trials, and a handful of these have progressed to phase II or III trials (212). 74 additional HIV vaccine candidates are reported to be in research and development or preclinical testing in animals, and this number has likely increased (212).
Recombinant subunit HIV vaccines are genetically engi- neered from HIV surface envelope proteins, such as gp120 or gp160. Because they do not contain live virus or DNA, there is no risk of causing infection. A therapeutic trial was carried out with gp160 subunit immunization every 3 months for 3 years in HIV-positive persons in addition to antiretroviral therapy (244). Results demonstrated a modest effect on CD4 counts, but no clinical beneﬁt. These results were consistent with similar earlier studies (245,246). A recombinant gp120 candi- date vaccine (AIDSVAX) was evaluated in phase III trials for the prevention of HIV. This three-year placebo-controlled trial enlisted 5000 high-risk seronegative persons. A similar vac- cine was studied in Thailand in 2500 HIV-negative drug users. Earlier research suggested that this subunit vaccine stimulates antibody production, but may not induce cellular immunity. HIV research has shown that the induction of cyto- toxic T lymphocytes may be an important correlate for protec- tive efﬁcacy of HIV vaccines (247). Unfortunately, this candidate vaccine was not able to prevent infection in serone- gative individuals.
Recombinant live-virus vector vaccines use virus carriers which are genetically engineered to express particular HIV genes. The ﬁrst candidate to be tested was a vaccinia vector with the insertion of HIV gp160 gene. The vaccine alone induced little antibody (212). However, when used as a primer followed by boosting with the recombinant gp160 vaccine, results showed strong induction of cellular immunity and antibody responses (248). Phase I trials are underway for a recombinant vaccinia HIV primer followed by boosting with a recombinant gp120 vaccine (212).
Because of concerns over shedding of the vaccinia virus and possible disseminated disease in immunosuppressed per- sons, more attention has been focused on canarypox and ade- novirus vectors which can infect humans but cannot replicate. Replication in humans continues long enough to produce the necessary HIV proteins before abortion of the cycle (249). Early results have shown that recombinant canarypox vector vaccines can induce humoral and cellular immune responses, including cytotoxic lymphocytes (250). The greatest interest for these vaccine candidates lies in the prime and boost approach. The canarypox vaccine primer induces a strong cel- lular immunity, followed by a recombinant subunit vaccine which boosts the antibody response (249). The combination of both vaccines induces a stronger immune response than either one alone (247,251). Recent results from a phase II trial (252) showed that 93% of subjects who received the combina- tion of vaccines developed neutralizing antibodies. Also, almost one-third of the recipients developed a cytotoxic lym- phocyte response. Additional studies have investigated canary- pox vectors expressing gp160 or gp120/gag/pol HIV-1 antigens given along with recombinant gp160 or gp120 subunit vac- cines (253). When comparing data from different trials of several candidate canarypox vector HIV vaccines, more than half of the recipients developed durable, HIV-speciﬁc cytotoxic T-lymphocyte responses (254). Researchers suggest that a broader recombinant vector vaccine would likely increase the percentage of responders (254).
A trial in Uganda studying the effect of a canarypox vec- tor vaccine alone commenced in February 1999 (255). The vac- cine, called ALVAC vCP205, contains three HIV genes in a weakened version of canarypox virus. The particular genes come from clade B viruses, which are the predominant subtype of HIV found in the United States and Europe. However, the majority of HIV infections that occur in Uganda are due to clades A and D. This study will ﬁrst evaluate the cross-reactivity among these viral subunits and compare the immune responses in recipients. DNA (or nucleic acid) vaccines are another promising prospect for HIV immunization. With this approach, puriﬁed DNA that encodes for particular immunogenic anti- gens is injected. This antigen is presented to the host immune system in its native form and is processed similar to that for a natural viral infection (250). Therapeutic immunization with a plasmid/gp160 and gag+ pol DNA vaccine in HIV- positive chimpanzees revealed a signiﬁcant decrease in viral load and a boost in the immune response (256). Studies in seronegative primates demonstrated the induction of neu- tralizing antibodies and cytotoxic T-lymphocyte responses, but the vaccine did not protect against infection (212). A phase I clinical trial of two DNA vaccine candidates is currently in progress (212).
Several other approaches to HIV vaccine development are under investigation. Live-attenuated virus vaccines are known to generate a broad and durable immune response, but these have not been tested in humans due to potential safety concerns with live HIV virus (212). Whole-inactivated vac- cines are generally thought to be safer than live-attenuated ones. However, inactivation of the virus often leads to a vac- cine that is less potent or immunogenic. Studies of whole- killed virus vaccines in chimpanzees thus far have not been able to demonstrate protection from HIV infection (212). In addition, there is concern that inadvertently incomplete inactivation could lead to HIV infection of vaccine recipients. Virus-like particles (VLP) are a safer option, since they consist of a noninfectious HIV look-alike that does not contain the HIV genome. One such candidate, known as p17/p24:TY, has reached the stage of clinical trials. Early results have shown that this vaccine leads to low levels of HIV binding antibodies and T-cell memory responses, but induces very little cytotoxic T-lymphocyte activity (212). Other VLP candidates are under development. Many important controversies exist in HIV vaccine development, such as the issue of whether neutraliz- ing antibodies as typically measured are relevant to clinical protection.