The candidate MVA and FP HIV-1 vaccines were well tolerated in HIV-infected young adults on HAART. Prior trials of MVA vaccines in HIV-1 infected individuals have also demonstrated favorable safety profiles [1
]. While these trials used different products and doses, the collective experience suggests that MVA and FP vaccines can be safely used in HIV positive individuals.
Based on recent reports linking attenuated vaccinia immunizations with cardiac toxicities in healthy volunteers, study participants were carefully monitored for potential cardiac toxicity. The MVA used for this vaccine is further attenuated, and in spite of intensive monitoring, we found no significant cardiac events among study participants. Given the large numbers of normal variants that are often reported as abnormalities, the level of surveillance employed in this study was very labor intensive and not practical or feasible for larger studies.
Immune correlates of protection from HIV-1 disease progression are incompletely defined, however cellular immune responses are considered critical in limiting viral replication. HIV-1–specific CD4 T-cell proliferative responses have been correlated inversely with PVL and disease progression [22
]. CD4 T-cells that produce both IFN and IL-2 in response to peptide stimuli also have an inverse relationship with PVL [24
]. We observed significant augmentation of proliferative and IL-2 producing HIV-1 specific CD4 T-cell responses after immunizations. The enhancement of proliferative responses, in particular, appeared to be quite durable providing evidence that these vaccines may provide some long-term benefit.
The frequencies and functional profiles of vaccinia-specific CD8 T-cell responses were similar to those of healthy MVA recipients [18
]. Augmentation of HIV-1 specific CD4 and CD8 T-cell responses in the context of new responses to poxvirus epitopes suggests specific boosting by the vaccines. The candidate vaccines elicited a different hierarchy of responses (Gag>Pol>Nef>Env) in this trial than observed in a trial of the same vaccine regimen in HIV-1 uninfected adults (Env=Gag>Pol>Nef) [25
]. This suggests that vaccination of the HIV-1 positive individuals may have resulted in the expansion of CD8 T-cells that were previously primed by natural infection. The larger magnitude of the HIV-1 specific responses compared with vaccinia-specific responses also suggests prior priming. The increased breadth of detectable HIV-1 specific CD8+ T cell responses () may represent de novo responses or amplification of pre-existing low-level responses.
While the magnitude of vaccine-specific CD4 and CD8 T cell responses is likely to relate to vaccine effectiveness, functional properties of vaccine-elicited responses may also be important. In our studies, significant increases in CD4 T cell proliferation and CD8 T cell IFNγ production were detected. Direct comparisons of the frequencies and magnitude of vaccine-elicited responses are difficult due to differences in methodologies amongst therapeutic immunization trials. Nevertheless, the increases in response frequencies, as well as in the magnitude of responses, are similar to those previously reported from several trials. For example, the CD8 T cell IFNγ responses in the current study are of the same order of magnitude as those reported from a study of similar design [26
]. However, there are no clear quantitative thresholds that define effective responses at this time. Future therapeutic vaccine studies that incorporate a period of HAART discontinuation following immunization could help to us to better understand whether the increased frequencies, or particular functional properties of vaccine-elicited responses are associated with improved control of viral replication.
It is generally accepted that potent (highly “functional”) responses against conserved viral epitopes with functional constraints on mutability would be most effective at controlling viral replication. HIV-specific CD8+ T-cells detected in infected individuals tend to produce fewer cytokines in response to their cognate antigens than those specific for antigens of other viruses [18
]. It is therefore of note that we observed increased functionality of some HIV-1 epitope-specific CD8+ T-cells in several individuals after immunization.
In a recent trial of live recombinant adenoviral HIV vaccinations, increased susceptibility to infection was observed in individuals with pre-existing adenoviral immunity. In this context, our results and those of others suggest that future development of poxvirus based vaccines may deserve greater attention [27
]. Broad segments of the population at risk for HIV infection lack pre-existing immunity to poxviruses, so are more likely to respond and perhaps less likely to display enhancement of infection.
In summary, this and other studies demonstrate the safety and immunogenicity of recombinant poxviruses, even in HIV-infected individuals [1
]. While this particular recombinant vaccine is not likely to move forward in development, therapeutic trials of other poxvirus-based vaccines have been proposed or are in progress for HIV. Published results from early trials indicate that poxvirus-based vaccines are safe and immunogenic in adults with pre-existing immunity to tuberculosis and malaria [30
]. Our results demonstrating broad boosting of CD4 and CD8 T-cell responses following vaccination are consistent with data from prior studies and support further evaluation of poxvirus-based vaccines.