Human Immunodeficiency Virus Vaccine

5 Jun

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.

Random Posts

Comments are closed.