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.
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•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.
Plasmodium vivax represents the most geographically widespread human malaria parasite affecting civilian and military populations in endemic areas. Targeting the pre-erythrocytic (PE) stage of the ...parasite life cycle is especially appealing for developing P. vivax vaccines as it would prevent disease and transmission. Here, naturally acquired immunity to a panel of P. vivax PE antigens was explored, which may facilitate vaccine development and lead to a better understanding of naturally acquired PE immunity.
Twelve P. vivax PE antigens orthologous to a panel of P. falciparum antigens previously identified as highly immunogenic in protected subjects after immunization with radiation attenuated sporozoites (RAS) were used for evaluation of humoral and cellular immunity by ELISA and IFN-γ ELISpot. Samples from P. vivax infected individuals (n = 76) from a low endemic malaria region in the Peruvian Amazon Basin were used.
In those clinical samples, all PE antigens evaluated showed positive IgG antibody reactivity with a variable prevalence of 58-99% in recently P. vivax diagnosed patients. The magnitude of the IgG antibody response against PE antigens was lower compared with blood stage antigens MSP1 and DBP-II, although antibody levels persisted better for PE antigens (average decrease of 6% for PE antigens and 43% for MSP1, p < 0.05). Higher IgG antibodies was associated with one or more previous malaria episodes only for blood stage antigens (p < 0.001). High IgG responders across PE and blood stage antigens showed significantly lower parasitaemia compared to low IgG responders (median 1,921 vs 4,663 par/µl, p < 0.05). In a subgroup of volunteers (n = 17),positive IFN-γ T cell response by ELISPOT was observed in 35% vs 9-35% against blood stage MSP1 and PE antigens, respectively, but no correlation with IgG responses.
These results demonstrate clear humoral and T cell responses against P. vivax PE antigens in individuals naturally infected with P. vivax. These data identify novel attractive PE antigens suitable for use in the potential development and selection of new malaria vaccine candidates which can be used as a part of malaria prevention strategies in civilian and military populations living in P. vivax endemic areas.
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.
To better understand the ecology of
in the northeastern Peruvian Amazon, we evaluated the prevalence of
and other trypanosomatids in four orders of wild mammals hunted and consumed by inhabitants of ...three remote indigenous communities in the Peruvian Amazon. Of 300 wild mammals sampled, 115 (38.3%) were infected with trypanosomatids and 15 (5.0%) with
The prevalence of
within each species was as follows: large rodents (
, 5.5%;
spp., 2.6%), edentates (
, 4.2%), and carnivores with higher prevalence (
, 18.8%). The high prevalence of
and other trypanosomatids in frequently hunted wild mammals suggests a sizeable
sylvatic reservoir in remote Amazonian locations.
In the Peruvian North Coast (PNC), the number of
malaria cases increased steadily from 2007 to 2010 despite a significant decline in the overall number of cases in Peru during the same period. To ...better understand the transmission dynamics of
populations in the PNC and the neighboring Ecuadorian Amazon Basin (EAB), we studied the genetic variability and population structure of
in these areas. One hundred and twenty
isolates (58 from Piura and 37 from Tumbes in the PNC collected from 2008 to 2010 and 25 from the EAB collected in Pastaza from 2001 to 2004) were assessed by five polymorphic microsatellite markers. Genetic variability was determined by expected heterozygosity (
) and population structure by Bayesian inference cluster analysis. We found very low genetic diversity in the PNC (
= 0-0.32) but high genetic diversity in the EAB (
= 0.43-0.70). Population structure analysis revealed three distinct populations in the three locations. Six of 37 (16%) isolates from Tumbes had an identical haplotype to that found in Piura, suggesting unidirectional flow from Piura to Tumbes. In addition, one haplotype from Tumbes showed similarity to a haplotype found in Pastaza, suggesting that this could be an imported case from EAB. These findings strongly suggest a minimal population flow and different levels of genetic variability between these two areas divided by the Andes Mountains. This work presents molecular markers that could be used to increase our understanding of regional malaria transmission dynamics, which has implications for the development of strategies for
control.
We determined the prevalence rate and risk of infection of
Trypanosoma cruzi
and other trypanosomatids in Peruvian non-human primates (NHPs) in the wild (
n
= 126) and in different captive ...conditions (
n
= 183). Blood samples were collected on filter paper, FTA cards, or EDTA tubes and tested using a nested PCR protocol targeting the 24Sα rRNA gene. Main risk factors associated with trypanosomatid and
T. cruzi
infection were genus and the human–animal context (wild
vs
captive animals). Wild NHPs had higher prevalence of both trypanosomatids (64.3 vs 27.9%,
P
< 0.001) and
T. cruzi
(8.7 vs 3.3%,
P
= 0.057), compared to captive NHPs, suggesting that parasite transmission in NHPs occurs more actively in the sylvatic cycle. In terms of primate family, Pitheciidae had the highest trypanosomatid prevalence (20/22, 90.9%) and Cebidae had the highest
T. cruzi
prevalence (15/117, 12.8%).
T. cruzi
and trypanosomatids are common in Peruvian NHPs and could pose a health risk to human and animals that has not been properly studied.
Two Plasmodium vivax recurrences in a Peruvian sailor with weight above the 60 kg (cap for primaquine dosage) highlight the importance of adequate radical cure weight dosage for patient treatment and ...control efforts, particularly within the military.
Objetivo: Comparar la capacidad de sellado de dos materiales para obturación retrógrada en dientes permanentes unirradiculares: el agregado de trióxido mineral (MTA®) y el silicato tricálcico ...(Biodentine®). Materiales y métodos: Se seleccionaron 38 dientes permanentes unirradiculares con cierre apical completo, los cuales fueron divididos aleatoriamente en dos grupos experimentales (n = 15): Grupo 1: MTA®, Grupo 2: Biodentine®. Además, se usaron controles positivos y negativos. El tratamiento radicular se realizó con el sistema rotatorio Mtwo y la obturación mediante el sistema termoplástico de onda continua (Beefill), y se usó como sellador el cemento tipo Grossman. Se realizó la apicectomía del extremo apical, luego la preparación de cavidades retroapicales estandarizadas y las respectivas obturaciones con MTA® y Biodentine®, según grupo. Posteriormente, los especímenes se sometieron a un proceso de filtración apical de tinta china y de transparentación, mientras que la filtración apical fue evaluada por medio de un microscopio estereoscópico. Los datos fueron analizados con la prueba U de Mann-Whitney. Resultados: El análisis inferencial mostró que Biodentine® tuvo una menor microfiltración que el MTA®, con una diferencia estadísticamente significativa al 95% (p < 0,034). Conclusión: El cemento Biodentine® mostró una mayor capacidad de sellado a nivel apical que el cemento MTA® en obturaciones retrógradas de dientes unirradiculares ex vivo.
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