Predicting the Impact of a Nonsterilizing Vaccine against Human Immunodeficiency Virus

Abstract

Studies of human immunodeficiency virus (HIV) vaccines in animal modelssuggest that it is difficult to induce complete protection from infection (sterilizing immunity) but that it is possible to reduce the viral load and to slow or prevent disease progression following infection. We have developed an age-structured epidemiological model of the effects of a disease-modifying HIV vaccine that incorporates the intrahost dynamics of infection, a transmission rate and host mortality that depend on the viral load, the possible evolution and transmission of vaccine escape mutant viruses, a finite duration of vaccine protection, and possible changes in sexual behavior. Using this model, we investigated the long-term outcome of a disease-modifying vaccine and utilized uncertainty analysis to quantify the effects of our lack of precise knowledge of various parameters. Our results suggest that the extent of viral load reduction in vaccinated infected individuals (compared to unvaccinated individuals) is the key predictor of vaccine efficacy. Reductions in viral load of about 1 log 10 copies ml ؊1

Understanding the Failure of CD8+T-Cell Vaccination against Simian/Human Immunodeficiency Virus

“…SIV indeed expands faster than the specific CD8 ϩ T-cell immune response, with estimated growth rates of 1.8 day Ϫ1 and 0.9 day Ϫ1 , respectively (21). During the initial expansion phase, the effector/target ratio at the local site of infection is apparently too low to control the pathogen.…”

“…Despite equal initial replication rates, the peak viral loads that are obtained in vaccinated monkeys can be 10-fold lower than those in naive monkeys (12,21,22,32,86). CD8 ϩ T cells are known to be important around the time of the peak, because in their absence, there is hardly any decrease in the viral load after the peak, i.e., a high viral set point is approached (85).…”

“…Vaccinated monkeys indeed approach lower viral set points (12,86) and better preserve central memory CD4 ϩ T cells (54,61). After the peak, the viral load contracts, with a half-life of about a day, and surprisingly, this half-life is largely unaffected by the presence of large numbers of specific CD8 ϩ T cells in vaccinated animals (1,21,22). This 1-day half-life is similar to the classical half-life of productively infected cells during chronic infection (42,74,95).…”

“…This similarity has been quantified in a number of studies estimating initial viral replication rates. In both naive and vaccinated animals, the virus grows uncontrolled for a few weeks, with a replication rate of about 1.5 day Ϫ1 (21,22,57,71). Such a failure of memory CD8 ϩ T-cell responses to reduce initial viral replication rates is not unique to SIV/HIV and has also been found in other experimental models of rapidly replicating viruses (7,29,34).…”

“…Several authors have argued that the specific CD8 ϩ T-cell response to SIV (or HIV) is "too late and too little" for effective control during acute infection (1,21,22,81,93). The late arrival of CD8 ϩ effector cells at the local site of infection is partly explained by the high antigen densities required for the recruitment of large memory CD8 ϩ T-cell populations (22).…”