There is increasing evidence that, in addition to antibodies, protection from blood-stage malaria is determined by the balance of pro and antiinflammatory immune responses induced by the parasite. A clinical trial conducted in the UK aimed to enhance the immunogenicity of RTS,S/AS02A alone by combining it in a prime-boost strategy with MVA that encoded the circumsporozoite protein. T-cell responses as measured by IFN-c ex vivo ELISPOT assays were induced, but the responses were low to moderate, with heterologous boosting yielding only small increments in T-cell immunogenicity and no enhancement in antibody responses. No increase in protection against sporozoite challenge compared to RTS,S/AS02A alone was seen. Nevertheless, as a total of four volunteers, two from each arm of the study, developed sterile protection this trial provided an opportunity to monitor responses to the circumsporozoite antigen before and after vaccination with RTS,S/AS02A in an effort to identify immune correlates of protection. Our group has previously reported an association between the up-regulation of TGF-b1, FoxP3 and the generation of Treg cells along with faster rates of parasitic growth in subjects infected with P. falciparum. We have also demonstrated that MIG, as a marker of bioactive IFN-c, is useful for measuring vaccine induced pro-inflammatory immune responses in line with a previous report.We hypothesised that Niltubacin customer reviews levels of anti-inflammatory and pro-inflammatory cytokines may be associated with vaccine efficacy and we have used real time RT-PCR to monitor changes in TGF-b1, FoxP3, IL-10, IFN-c and MIG in malarianaı ¨ve adults receiving the candidate malaria vaccines RTS,S/ AS02A and MVA-CS in a clinical trial. Although the number of subjects included in the clinical trial with RTS,S/AS02A and MVA-CS was small, such exploratory studies with real time RTPCR may help to guide the selection of immune markers for analysis in larger efficacy trials. Malaria vaccine development is at an exciting stage with both antibody-targeted and T cell-targeted pre-erythrocytic vaccines showing partial protection in humans. However, frustratingly the most effective vaccine candidate RTS,S still only shows about 50% efficacy in the most successful phase IIa efficacy trials, and varying levels of protection in IIb field trials. A better understanding of how some vaccine recipients are better protected than others could be crucial to developing a higher efficacy vaccine. Real time RT-PCR is an emerging method for measuring both pro-inflammatory and anti-inflammatory immune responses in humans and shows real potential for the monitoring of vaccine trials where cell numbers are limited and immune responses are often low. Using real time RT-PCR to monitor changes in gene expression in stored samples from volunteers vaccinated with RTS,S/AS02A and MVA-CS we have found that mRNA expression of pro and anti-inflammatory cytokine responses in unstimulated PBMC are associated with vaccine immunogenicity and protection from malaria.
Vaccinated malarianave populations have underlined the complexity and diversity of T-cell immunity
Leave a reply