Abstract
Trials testing the RTS,S candidate malaria vaccine and radiation-attenuated sporozoites (RAS) have shown that protective immunity against malaria can be induced and that an effective vaccine is not out of reach. However, longer-term protection and higher protection rates are required to eradicate malaria from the endemic regions. It implies that there is still a need to explore new vaccine strategies. Lentiviral vectors are very potent at inducing strong immunological memory. However their integrative status challenges their safety profile. Eliminating the integration step obviates the risk of insertional oncogenesis. Providing they confer sterile immunity, nonintegrative lentiviral vectors (NILV) hold promise as mass pediatric vaccine by meeting high safety standards. In this study, we have assessed the protective efficacy of NILV against malaria in a robust pre-clinical model. Mice were immunized with NILV encoding Plasmodium yoelii Circumsporozoite Protein (Py CSP) and challenged with sporozoites one month later. In two independent protective efficacy studies, 50% (37.5–62.5) of the animals were fully protected (p = 0.0072 and p = 0.0008 respectively when compared to naive mice). The remaining mice with detectable parasitized red blood cells exhibited a prolonged patency and reduced parasitemia. Moreover, protection was long-lasting with 42.8% sterile protection six months after the last immunization (p = 0.0042). Post-challenge CD8+ T cells to CSP, in contrast to anti-CSP antibodies, were associated with protection (r = −0.6615 and p = 0.0004 between the frequency of IFN-g secreting specific T cells in spleen and parasitemia). However, while NILV and RAS immunizations elicited comparable immunity to CSP, only RAS conferred 100% of sterile protection. Given that a better protection can be anticipated from a multi-antigen vaccine and an optimized vector design, NILV appear as a promising malaria vaccine.
Highlights
Plasmodium is the causative agent of malaria, a life-threatening disease affecting 216 million people worldwide and responsible for 655 000 deaths in 2010 according to the World malaria report 2011
They only differ by the D64V substitution in the catalytic domain of the HIV-1 integrase encoded by Pol, blocking the DNA cleaving and joining reactions of the integration step as previously described [59] (Figure 1)
The lower immunogenicity of nonintegrative lentiviral vectors (NILV) compared to integrative LV (ILV) was not dependent on Circumsporozoite protein (CSP), as this was observed with an unrelated Ag, SIV GAG (Figure S2); and it could be compensated by increasing the dose of vector particles (5E+08TU/mouse) (Figure 2B)
Summary
Plasmodium is the causative agent of malaria, a life-threatening disease affecting 216 million people worldwide and responsible for 655 000 deaths in 2010 according to the World malaria report 2011. Immunizations with radiation-attenuated sporozoites (RAS), which interrupt their development inside hepatocytes, can confer sterile protection against malaria in humans [5] and rodents [6]. This strategy is not applicable to large-scale approaches because of major technical and logistical limitations, and was sub-optimally immunogenic and protective in a recent phase I/IIa trial following subcutaneous and intradermal injections [7]. It was shown to substantially reduce clinical and severe Pf malaria episodes in infants from seven countries in sub-Saharan Africa in a large phase III clinical trial yet without completely preventing infection [13]. Longer-term protection needs to be documented and higher rates of protection are likely required to achieve eradication of malaria in endemic zones [14]
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