Antigenic diversity has posed a critical barrier to vaccine development against the pathogenic blood-stage infection of the human malaria parasite Plasmodium falciparum. To date, only strain-specific ...protection has been reported by trials of such vaccines in nonhuman primates. We recently showed that P. falciparum reticulocyte binding protein homolog 5 (PfRH5), a merozoite adhesin required for erythrocyte invasion, is highly susceptible to vaccine-inducible strain-transcending parasite-neutralizing antibody. In vivo efficacy of PfRH5-based vaccines has not previously been evaluated. Here, we demonstrate that PfRH5-based vaccines can protect Aotus monkeys against a virulent vaccine-heterologous P. falciparum challenge and show that such protection can be achieved by a human-compatible vaccine formulation. Protection was associated with anti-PfRH5 antibody concentration and in vitro parasite-neutralizing activity, supporting the use of this in vitro assay to predict the in vivo efficacy of future vaccine candidates. These data suggest that PfRH5-based vaccines have potential to achieve strain-transcending efficacy in humans.
Display omitted
•Vaccines based on the P. falciparum merozoite antigen PfRH5 were tested in Aotus monkeys•PfRH5-based vaccines afforded protection against heterologous strains of P. falciparum•Protection correlated with anti-PfRH5 IgG concentration and in vivo neutralization
Antigenic diversity has hindered development of vaccines against the pathogenic blood-stage of Plasmodium falciparum. Douglas et al. demonstrate that human-compatible PfRH5-based vaccines can protect Aotus monkeys against vaccine-heterologous P. falciparum challenge. Protection correlated with anti-PfRH5 antibody concentration and parasite-neutralizing activity. PfRH5-based vaccines have potential to achieve strain-transcending efficacy in humans.
Malaria vaccine design and prioritization has been hindered by the lack of a mechanistic correlate of protection. We previously demonstrated a strong association between protection and ...merozoite-neutralizing antibody responses following vaccination of non-human primates against Plasmodium falciparum reticulocyte binding protein homolog 5 (PfRH5). Here, we test the mechanism of protection. Using mutant human IgG1 Fc regions engineered not to engage complement or FcR-dependent effector mechanisms, we produce merozoite-neutralizing and non-neutralizing anti-PfRH5 chimeric monoclonal antibodies (mAbs) and perform a passive transfer-P. falciparum challenge study in Aotus nancymaae monkeys. At the highest dose tested, 6/6 animals given the neutralizing PfRH5-binding mAb c2AC7 survive the challenge without treatment, compared to 0/6 animals given non-neutralizing PfRH5-binding mAb c4BA7 and 0/6 animals given an isotype control mAb. Our results address the controversy regarding whether merozoite-neutralizing antibody can cause protection against P. falciparum blood-stage infections, and highlight the quantitative challenge of achieving such protection.
The
protein, apical membrane antigen 1 forms a complex with another parasite protein, rhoptry neck protein 2, to initiate junction formation with the erythrocyte and is essential for merozoite ...invasion during the blood stage of infection. Consequently, apical membrane antigen 1 has been a target of vaccine development but vaccination with apical membrane antigen 1 alone in controlled human malaria infections failed to protect and showed limited efficacy in field trials. Here we show that vaccination with AMA1-RON2L complex in Freund's adjuvant protects
monkeys against a virulent
infection. Vaccination with AMA1 alone gave only partial protection, delaying infection in one of eight animals. However, the AMA1-RON2L complex vaccine completely protected four of eight monkeys and substantially delayed infection (>25 days) in three of the other four animals. Interestingly, antibodies from monkeys vaccinated with the AMA1-RON2L complex had significantly higher neutralizing activity than antibodies from monkeys vaccinated with AMA1 alone. Importantly, we show that antibodies from animals vaccinated with the complex have significantly higher neutralization activity against non-vaccine type parasites. We suggest that vaccination with the AMA1-RON2L complex induces functional antibodies that better recognize AMA1 as it appears complexed with RON2 during merozoite invasion. These data justify progression of this next generation AMA1 vaccine towards human trials.
The present study was designed to determine whether the treatment with an ethanolic extract of pomegranate (EEP) (Punica granatum) can be useful for the treatment of the deleterious effect of lead ...acetate (LA) administration on sperm production in rats. The effects of EEP were compared with those of ascorbic acid (AA) that is a strong antioxidant and has been shown to reverse lead-induced damage on the reproductive system.
The rats were divided into five different groups: those received distilled water (control group), LA, LA with EEP, LA with AA, and EEP alone, respectively.
LA administration inhibited spermatogenesis by reducing the length of the stages related to spermiation (VII and VIII) and onset of mitosis (IX-XI). LA-treated rats also showed a reduction in epididymal sperm number and daily sperm production (DSP). Administration of EEP or AA resulted in longer VIII and IX-XI stages when compared with LA-treated rats. Moreover, EEP and AA administration reduced the deleterious effect of LA on DSP and epididymal sperm number. EEP showed an antioxidant activity similar to that of AA. EEP prevented LA-induced spermatogenic disruption in rats and its antioxidant activity could explain its capacity to reverse the damage produced by LA on spermatogenesis.
PDF
