Development of an improved blood-stage malaria vaccine targeting the essential RH5-CyRPA-RIPR invasion complex.

Reticulocyte-binding protein homologue 5 (RH5), a leading blood-stage Plasmodium falciparum malaria vaccine target, interacts with cysteine-rich protective antigen (CyRPA) and RH5-interacting protein (RIPR) to form an essential heterotrimeric "RCR-complex". We investigate whether RCR-complex vaccination can improve upon RH5 alone. Using monoclonal antibodies (mAbs) we show that parasite growth-inhibitory epitopes on each antigen are surface-exposed on the RCR-complex and that mAb pairs targeting different antigens can function additively or synergistically. However, immunisation of female rats with the RCR-complex fails to outperform RH5 alone due to immuno-dominance of RIPR coupled with inferior potency of anti-RIPR polyclonal IgG. We identify that all growth-inhibitory antibody epitopes of RIPR cluster within the C-terminal EGF-like domains and that a fusion of these domains to CyRPA, called "R78C", combined with RH5, improves the level of in vitro parasite growth inhibition compared to RH5 alone. These preclinical data justify the advancement of the RH5.1 + R78C/Matrix-M™ vaccine candidate to Phase 1 clinical trial.

Functional Comparison of Blood-Stage Plasmodium falciparum Malaria Vaccine Candidate Antigens.

The malaria genome encodes over 5,000 proteins and many of these have also been proposed to be potential vaccine candidates, although few of these have been tested clinically. RH5 is one of the leading blood-stage Plasmodium falciparum malaria vaccine antigens and Phase I/II clinical trials of vaccines containing this antigen are currently underway. Its likely mechanism of action is to elicit antibodies that can neutralize merozoites by blocking their invasion of red blood cells (RBC). However, many other antigens could also elicit neutralizing antibodies against the merozoite, and most of these have never been compared directly to RH5. The objective of this study was to compare a range of blood-stage antigens to RH5, to identify any antigens that outperform or synergize with anti-RH5 antibodies. We selected 55 gene products, covering 15 candidate antigens that have been described in the literature and 40 genes selected on the basis of bioinformatics functional prediction. We were able to make 20 protein-in-adjuvant vaccines from the original selection. Of these, S-antigen and CyRPA robustly elicited antibodies with neutralizing properties. Anti-CyRPA IgG generally showed additive GIA with anti-RH5 IgG, although high levels of anti-CyRPA-specific rabbit polyclonal IgG were required to achieve 50% GIA. Our data suggest that further vaccine antigen screening efforts are required to identify a second merozoite target with similar antibody-susceptibility to RH5.

The Long Road to an Effective Vaccine for Meningococcus Group B (MenB).

Neisseria meningitidis infection can cause life-threatening meningitis and meningococcal septicaemia. Over the past 40 years, vaccines against most of the main meningococcal serogroups have offered increasingly good protection from disease, with one major exception in the developed world: serogroup B meningococcus (MenB). In the United States, MenB accounts for about a quarter of cases of meningococcal meningitis, with the bulk of the rest caused by meningococcus serogroups C (MenC) and Y (MenY). In the UK, where a vaccine against MenC is widely used, MenB is now responsible for nearly 90% of cases of invasive meningococcal disease. Recent attempts to create a universal MenB vaccine have been thwarted by the variability of the surface proteins of MenB and by the similarity of the MenB capsule to human glycoproteins. This review discusses current meningococcal vaccine strategies and their limitations with regard to MenB, and examines a promising new strategy for the rational design of a MenB vaccine. Thanks to a fusion of a rational reverse genetics approach and a membrane vesicle approach, a MenB vaccine, 4CMenB (Bexsero(®)), has finally gained regulatory approval in Europe and could be in clinical use by the end of 2013.