Models of Successful Vaccination?

Because of challenges to the development of a fully preventive vaccine, which would require the induction of potent and broadly directed neutralizing antibodies, the field has in part focused on development of T-cell-based vaccines. These would be intended not to prevent infection, but rather to prevent disease progression when a person becomes infected, by limiting the production of progeny virions from infected cells (Figure 3).

Enthusiasm for such an approach comes from the observation that a small fraction of persons who become HIV infected are able spontaneously to control HIV replication and maintain normal CD4 + cell counts without medications – some now for more than 30 years after the initial infection (for a review, see Ref). This group of persons has been termed "HIV controllers", and consists of both elite controllers, who maintain plasma viremia less than 50 RNA copies ml^-1, as well as viremic controllers who maintain viral loads between 50 and 2000 copies, a level at which the likelihood of progression and of transmission are markedly reduced.

Figure 1.3 The theory behind T-cell vaccination. T-cell vaccines would be expected not to prevent infection, but rather to modulate the viral load after infection, reducing it to a level at which the likelihood of disease progression and transmission would be markedly reduced. This level is thought to be around 1000–2000 RNA copies per ml plasma.

Most studies suggest that durable HIV control occurs in less than 1% of infected individuals, and may be as low as one in 300. So far, no epidemiologic factors have been associated with complete or near-complete HIV control in vivo. Gender does not seem to determine the ability to contain the infection, as both male and female HIV controllers are defined. Controllers have been identified within multiple ethnicities, infected with different virus subtypes, and via different routes of HIV acquisition. This leads to the assumption that race, geographic location, and/or viral subtype independently are not impacting immunologic and virologic outcomes.

Although the mechanisms by which elite controllers are able to contain viral replication are still being defined, there are emerging data which indicate that it is immunologically mediated. There is an overrepresentation of certain HLA class I alleles in these individuals, particularly HLA B57 and B27, and recent studies have shown that circulating CD8 + T-cells from these individuals are able to potently suppress viral replication in an in vitro assay.

Most information is available for the subset of elite controllers who express HLA B[1]5701, in whom it has been shown that CTL responses select for mutations unique to those with elite control, which markedly impair viral fitness, while at the same time eliciting de novo CTL responses to the variant virus. The results of recent studies have also suggested that the specificity of responses may be critical for the durable control of HIV infection, with multiple studies showing that preferential targeting of Gag is associated with a better outcome.

This observation may be at least partially explained by immuneinduced mutations, which would be expected to have a greater impact on viral fitness when arising in key structural or functional proteins, as opposed to the envelope protein, which is able to accommodate extensive sequence variation. Durable control of AIDS virus infection has also been achieved with live attenuated vaccines, which by far have had the most impressive effect of any vaccine tested.

So far, a live attenuated SIV represents the most successful nonhuman primate vaccine approach, and has consistently protected rhesus macaques against challenge with a homologous, pathogenic SIV. Whilst this is a critical model to understand in terms of the correlates of immune protection, thus far it remains unclear how such protection is achieved. Moreover, even this approach potentially falls short of what would be required, given the need for protection against heterologous strains of virus. The protective effect of this vaccine against a heterologous SIV challenge has been addressed in only a few smaller studies, with mixed results.

Source :     -    Aids and Tuberculosis : A Deadly Liaison – (Books)

                        Edited by Stefan H. E. Kaufmann and Bruce D. Walker