Protein Potential (United States)

Abstract Potent protection against malaria can be induced by attenuated live-immunization withPlasmodium falciparum(Pf) sporozoites (SPZ). However, a better understanding of the critical processes involved in the establishment of protective immunity is needed. We explored the safety and vaccine efficacy of early chemo-attenuation of PfSPZ under atovaquone-proguanil (AP). AP caused early arrest ofP. bergheiliver stages. Despite the absence of replication, robust protection in mice correlated with parasite-specific effector-memory CD8+T-cell responses. In a phase I clinical trial a single dose of AP prevented Pf infections in the liver of adult, human subjects who received three doses of 5.12x104or 1.5x105PfSPZ by direct venous inoculation combined with oral AP. However, only 2 of 8 (25%) and 2 of 10 (20%), respectively, were protected against controlled human malaria infection (CHMI) 10 weeks after the last vaccine dose, despite levels of IgG antibodies to the Pf circumsporozoite protein (PfCSP) comparable to those achieved in fully protected volunteers after immunization with 5.12x104PfSPZ with chloroquine chemoprophylaxis active only against subsequent blood stages. We identify lower IgG recognition of the secreted liver stage-specific antigens LISP2 and LSA1 and the multi-stage antigen MSP5 as immune signatures of inferior vaccine efficacy compared to PfSPZ with chloroquine chemoprophylaxis. In conclusion, we show that immune signatures of liver stage antigens, but neither an established rodent malaria model nor concentrations of antibodies against the major surface protein of sporozoites, permit prediction of vaccine efficacy. Thus, this study provides a clear rationale for the development of live sporozoite vaccination protocols that boost exposure to Pf liver stage antigens.Significance StatementOur research demonstrates that attenuation of liver infection of high doses ofPlasmodium falciparumsporozoites by concomitant single-dose administration of atovaquone-proguanil is safe in humans. However, vaccine efficacy was modest when compared to an identical protocol using chloroquine that acts only on the subsequent blood infection. Immune signatures of secretedP. falciparumliver stage antigens, but neither an established rodent malaria model nor concentrations of sporozoite antibodies, permit prediction of vaccine efficacy.

It is a stiff known fact that in chauvinistic society, a female has been taken as a suppressed commodity. The ultimate dependence is the main factor in the marginalization of females in society. Although, in a country where the female population is more than men’s, such topics of female subjugation can be traced from the shared history. This study aims at the various factors through which the main character of the movie and novel “Orlando” has gone through the acute transformation from a weaker position to being in command and strong. This paper is based on the qualitative methodology and it will probe traces through which the protagonist is viewed through the lens of Simon de Beauvoir’s Second Sex and gender differences (Beauvoir, 1993). Complete analysis in terms of the body language from being submissive to outrageous, from vulnerable to gaining strength, this research will significantly try to scan all the aspects through which a character is transformed. This paper will also try to probe the socio-psychological factors through which an individual suffers through the anguish (Ranjan, 2019 ). The protagonist's anguish has been depicted and will be analyzed in the light of famous feminist theorist Simon de Beauvoir's “The Second Sex” (Beauvoir, 1976). While engaging and clashing for the dependability this investigation likewise examines the complexities agonized over the opportunity of enunciation of the protagonist from the two portrayals that are film and text. This examination will open vistas to contemplate the grievance forced by the financial components that pressurises a person, as far as possible, where one has to decide between giving up or revolting against the shackles of society. By the execution of Beauvoir's idea on the screen transformation of "Orlando" composed by Virginia Woolf (Woolf, 1993), the spitting image of women in Elizabethan civilization and her insurrection is illustrated. This paper is a significant effort to highlight the cobwebs encapsulating an individual and their strife to survive and breathe in the same existing world.
 

Consistent, high-level, vaccine-induced protection against human malaria has only been achieved by inoculation of Plasmodium falciparum (Pf) sporozoites (SPZ) by mosquito bites. We report that the PfSPZ Vaccine--composed of attenuated, aseptic, purified, cryopreserved PfSPZ--was safe and well tolerated when administered four to six times intravenously (IV) to 40 adults. Zero of six subjects receiving five doses and three of nine subjects receiving four doses of 1.35 × 10(5) PfSPZ Vaccine and five of six nonvaccinated controls developed malaria after controlled human malaria infection (P = 0.015 in the five-dose group and P = 0.028 for overall, both versus controls). PfSPZ-specific antibody and T cell responses were dose-dependent. These data indicate that there is a dose-dependent immunological threshold for establishing high-level protection against malaria that can be achieved with IV administration of a vaccine that is safe and meets regulatory standards.

Our goal is to develop a vaccine that sustainably prevents Plasmodium falciparum (Pf) malaria in ≥80% of recipients. Pf sporozoites (PfSPZ) administered by mosquito bites are the only immunogens shown to induce such protection in humans. Such protection is thought to be mediated by CD8(+) T cells in the liver that secrete interferon-γ (IFN-γ). We report that purified irradiated PfSPZ administered to 80 volunteers by needle inoculation in the skin was safe, but suboptimally immunogenic and protective. Animal studies demonstrated that intravenous immunization was critical for inducing a high frequency of PfSPZ-specific CD8(+), IFN-γ-producing T cells in the liver (nonhuman primates, mice) and conferring protection (mice). Our results suggest that intravenous administration of this vaccine will lead to the prevention of infection with Pf malaria.

BackgroundPolymorphism of the Duffy Antigen Receptor for Chemokines (DARC) is associated with susceptibility to and the severity of Plasmodium vivax malaria in humans. P. vivax uses DARC to invade erythrocytes. Individuals lacking DARC are ‘resistant’ to P. vivax erythrocytic infection. However, susceptibility to P. vivax in DARC+ individuals is reported to vary between specific DARC genotypes. We hypothesized that the natural acquisition of antibodies to P. vivax blood stages may vary with the host genotype and the level of DARC expression. Furthermore, high parasitemia has been reported to effect the acquisition of immunity against pre-erythrocytic parasites. We investigated the correlation between host DARC genotypes and the frequency and magnitude of antibodies against P. vivax erythrocytic stage antigens.Methodology/FindingsWe assessed the frequencies and magnitudes of antibody responses against P. vivax and P. falciparum sporozoite and erythrocytic antigens in Colombian donors from malaria-endemic regions. The frequency and level of naturally-acquired antibodies against the P. vivax erythrocytic antigens merozoite surface protein 1 (PvMSP1) and Duffy binding protein (PvDBP) varied with the host DARC genotypes. Donors with one negative allele (FY*B/FY*Bnull and FY*A/FY*Bnull) were more likely to have anti-PvMSP1 and anti-PvDBP antibodies than those with two positive alleles (FY*B/FY*B and FY*A/FY*B). The lower IgG3 and IgG1 components of the total IgG response may account for the decreased responses to P. vivax erythrocytic antigens with FY*A/FY*B and FY*B/FY*B genotypes. No such association was detected with P. falciparum erythrocytic antigens, which does not use DARC for erythrocyte invasion.Conclusion/SignificanceIndividuals with higher DARC expression, which is associated with higher susceptibility to P. vivax infection, exhibited low frequencies and magnitudes of P. vivax blood-stage specific antibody responses. This may indicate that one of the primary mechanisms by which P. vivax evades host immunity is through DARC indirectly down-regulating humoral responses against erythrocytic invasion and development.