RV144 HIV Vaccine Trial Research Articles

Humoral immune response profiling with peptide microarrays

Background In a case-controlled analysis designed to identify immune correlates of infection risk in the RV144 HIV vaccine trial, 2/6 primary variables showed significant correlation. One, the binding of IgG antibodies to the V1/V2 loop of HIV-1 env protein appears to protect against HIV-1 infection. Consequently, data from a detailed mapping of antibody reactivities in response to vaccination on a sub-protein level might be a predictor for vaccine efficacy. In contrast to assays relying on whole antigens, peptide microarrays are efficient tools to deliver such information. Besides, complex peptide libraries can cover the HIV sequence diversity. We present peptide microarray data from a human clinical trial.

Vaccine-elicited systemic and mucosal humoral responses of lactating rhesus monkeys vaccinated with the transmitted/founder HIV Envelope 1086C

Background We previously demonstrated that vaccination of lactating rhesus monkeys with a DNA prime/ vector boost strategy induces strong SIV-specific cellular immune responses, but limited Envelope-specific humoral responses in breast milk. Therefore, we sought to improve vaccine-elicited Envelope-specific antibody responses in the milk compartment by using a transmitted/founder (T/F) HIV Envelope immunogen in a prime-boost strategy modeled after that of the moderately-successful RV144 HIV vaccine trial. Methods

Natural Killer cells present in gut mucosa as potential ADCC effector cells

Background Data from the RV144 HIV vaccine trial showed a moderate protection from HIV infection in the absence of neutralizing antibodies or CTL activity. In contrast, all vaccinees mounted robust HIV-specific binding antibodies, that may have provided some level of protection through their capacity to recruit antibody dependent cellular cytotoxicity (ADCC). The capacity of an antibody to recruit ADCC relies on its ability to interact with the Fc-receptor, FCgRIII (CD16), expressed on Natural Killer (NK) cells. However, little is known about innate immune effector cells present within mucosa, and whether they have the capacity to be harnessed by ADCC inducing antibodies should they be elicited by a vaccine. Here we hypothesized that abundant numbers of CD16+ NK cells line the gut mucosa, providing a robust effector arm that could be harnessed by ADCC inducing antibodies. Methods The frequency and function of CD16+ cells in the colon was assessed by flow cytometry following enzymatic digestion of intestinal resections from HIV-uninfected subjects.

Profiling immunity to HIV vaccines with systems biology

The recent modest success of the RV144 HIV vaccine trial in Thailand has shown that development of an HIV vaccine is possible. Designing a vaccine that achieves better protection, however, will require a more complete understanding of vaccine mechanisms of action and correlates of protection. Systems biology approaches enable integration of large datasets from a variety of assays and offer new approaches to understanding how vaccine-induced immune responses are coordinately regulated. In this review, we discuss the recent advances in clinical trial design, specimen collection, and assay standardization that will generate datasets for systems analyses of immune responses to HIV vaccines. Several recently published HIV vaccine trials have shown that different HIV vaccine prime/boost combinations can greatly affect the immune response generated, but mechanistic insights into their modes of action are lacking. Novel systems biology studies of efficacious, licensed vaccines provide a new template for analysis of HIV vaccines. To generate datasets appropriate for systems analysis, current HIV vaccine clinical trials are undergoing design modifications and increased standardization of specimen collection and immune response assays. Systems biology approaches to HIV vaccine evaluation are driving new methods of HIV vaccine immune response profiling in clinical trials and will hopefully lead to new improved HIV vaccines in the near future.

Emerging Concepts on the Role of Innate Immunity in the Prevention and Control of HIV Infection

While neutralizing antibodies can provide sterilizing protection from HIV infection via their variable domains, the antibody constant domain provides a functional link between innate and adaptive immunity and offers a means to harness the potent antiviral properties of a wide spectrum of innate immune effector cells. There has been a growing appreciation of the role of these effector mechanisms across fields from cancer immunotherapy to autoimmunity and infectious disease, as well as speculation that this mechanism may be responsible for the protection observed in the RV144 HIV vaccine trial. This review summarizes these extraneutralizing humoral immune activities, progress in defining the importance of these effector mechanisms during progression in HIV infection, and the potential impact that such vaccine-induced immune responses may have on protection from infection.

Comparative Immunogenicity of HIV-1 Clade C Envelope Proteins for Prime/Boost Studies

BackgroundPrevious clinical efficacy trials failed to support the continued development of recombinant gp120 (rgp120) as a candidate HIV vaccine. However, the recent RV144 HIV vaccine trial in Thailand showed that a prime/boost immunization strategy involving priming with canarypox vCP1521 followed by boosting with rgp120 could provide significant, although modest, protection from HIV infection. Based on these results, there is renewed interest in the development of rgp120 based antigens for follow up vaccine trials, where this immunization approach can be applied to other cohorts at high risk for HIV infection. Of particular interest are cohorts in Africa, India, and China that are infected with clade C viruses.Methodology/Principal FindingsA panel of 10 clade C rgp120 envelope proteins was expressed in 293 cells, purified by immunoaffinity chromatography, and used to immunize guinea pigs. The resulting sera were collected and analyzed in checkerboard experiments for rgp120 binding, V3 peptide binding, and CD4 blocking activity. Virus neutralization studies were carried out with two different assays and two different panels of clade C viruses. A high degree of cross reactivity against clade C and clade B viruses and viral proteins was observed. Most, but not all of the immunogens tested elicited antibodies that neutralized tier 1 clade B viruses, and some sera neutralized multiple clade C viruses. Immunization with rgp120 from the CN97001 strain of HIV appeared to elicit higher cross neutralizing antibody titers than the other antigens tested.Conclusions/SignificanceWhile all of the clade C antigens tested were immunogenic, some were more effective than others in eliciting virus neutralizing antibodies. Neutralization titers did not correlate with rgp120 binding, V3 peptide binding, or CD4 blocking activity. CN97001 rgp120 elicited the highest level of neutralizing antibodies, and should be considered for further HIV vaccine development studies.