HIV Vaccine Efficacy and Immune Correlates of Risk
Robert J. O'Connell and Jean-Louis Excler
Affiliation: US Military HIV Research Program (MHRP), 6720-A Rockledge Drive, Suite 400, Bethesda, MD 20817, USA.
Keywords: Efficacy trial, immune correlates, HIV, prime-boost, V2 antibodies, vaccine.
Although immune correlates of protection for HIV vaccines have remained an intractable question, RV144
provided the first evidence that an HIV vaccine could provide protective efficacy against HIV acquisition. The study of
correlates of risk has opened large and unforeseen avenues of exploration and hope for the most exciting time of HIV
vaccine development. Several elements in the RV144 post-hoc analysis and recent macaque challenge studies suggest that
antibodies directed against the V2 loop of gp120 are functional and may have played a protective role against virus
acquisition. Several protective mechanisms against sexual transmission of HIV are evoked including blocking the gp120-
α4β7 interaction and ADCC although possibly mitigated by high levels of Env-specific IgA, both mechanisms
contributing at least partially to the protective effect. Several questions remain unanswered that will deserve intensive
assessments, in particular, IgG and IgA Env antibodies in mucosal secretions, Env-specific IgG subclasses, cross-reaction
of V2 antibodies, role of T-follicular helper cells, and B-cell memory. Whether RV144 correlates of risk are universal and
apply at least partially to other populations at higher risk for HIV acquisition and other modes of transmission (rectal,
injecting drug users) is unknown and remains to be explored. Future efficacy trials using the same vaccine concept tested
in high-risk heterosexual populations and in men having sex with men may answer this question. In addition, the
determination of early events in the pathogenesis among HIV-infected vaccine recipients based on current correlates
knowledge would offer unprecedented information about correlates biomarkers in the peripheral blood and gut mucosa
during early acute HIV infection.
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