***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background Plasmodium vivax is the most geographically widespread human malaria parasite . Cohort studies in Papua New Guinea have identified a rapid onset of immunity against vivax-malaria in children living in highly endemic areas . Although numerous P. vivax merozoite antigens are targets of naturally acquired antibodies , the role of many of these antibodies in protective immunity is yet unknown . Methodology /Principal Findings In a cohort of children aged 1–3 years , antibodies to different  regions of Merozoite Surface Protein 3α ( PvMSP3α ) and Merozoite Surface Protein 9 ( PvMSP9 ) were measured and related to prospect i ve risk of P. vivax malaria during 16 months of active follow-up . Overall , there was a low prevalence of antibodies to PvMSP3α and PvMSP9 proteins ( 9–65 % ) . Antibodies to the PvMSP3α N-terminal , Block I and Block II regions increased significantly with age while antibodies to the PvMSP3α Block I and PvMSP9 N-terminal regions were positively associated with concurrent P. vivax infection . Independent of exposure ( defined as the number of genetically distinct blood-stage infection acquired over time ( molFOB ) ) and age , antibodies specific to both PvMSP3α Block II ( adjusted incidence ratio ( aIRR ) = 0.59 , p = 0.011 ) and PvMSP9 N-terminus ( aIRR = 0.68 , p = 0.035 ) were associated with protection against clinical P. vivax malaria . This protection was most pronounced against high-density infections . For PvMSP3α Block II , the effect was stronger with higher levels of antibodies . Conclusions These results indicate that PvMSP3α Block II and PvMSP9 N-terminus should be further investigated for their potential as P. vivax vaccine antigens . Controlling for molFOB assures that the observed associations are not confounded by individual differences in exposure Individuals residing in malaria-endemic regions acquire protective immunity after repeated infection with malaria parasites ; however , mechanisms of protective immunity and their immune correlates are poorly understood . Blood-stage infection with Plasmodium vivax depends completely on interaction of P. vivax Duffy-binding protein ( PvDBP ) with the Duffy antigen on host erythrocytes . Here , we performed a prospect i ve cohort treatment/reinfection study of children ( 5–14 years ) residing in a P. vivax-endemic region of Papua New Guinea ( PNG ) in which children were cleared of blood-stage infection and then examined biweekly for reinfection for 25 weeks . To test the hypothesis that naturally acquired binding inhibitory antibodies ( BIAbs ) targeting PvDBP region II ( PvDBPII ) provide protection against P. vivax infection , we used a quantitative receptor-binding assay to distinguish between antibodies that merely recognize PvDBP and those that inhibit binding to Duffy . The presence of high-level BIAbs ( > 90 % inhibition of PvDBPII-Duffy binding , n = 18 ) before treatment was associated with delayed time to P. vivax reinfection diagnosed by light microscopy ( P = 0.02 ) , 55 % reduced risk of P. vivax reinfection ( Hazard 's ratio = 0.45 , P = 0.04 ) , and 48 % reduction in geometric mean P. vivax parasitemia ( P < 0.001 ) when compared with children with low-level BIAbs ( n = 148 ) . Further , we found that stable , high-level BIAbs displayed strain-transcending inhibition by reducing reinfection with similar efficiency of PNG P. vivax strains characterized by six diverse PvDBPII haplotypes . These observations demonstrate a functional correlate of protective immunity in vivo and provide support for developing a vaccine against P. vivax malaria based on PvDBPII Background Pfs25 and Pvs25 , surface proteins of mosquito stage of the malaria parasites P. falciparum and P. vivax , respectively , are leading c and i date s for vaccines preventing malaria transmission by mosquitoes . This single blinded , dose escalating , controlled Phase 1 study assessed the safety and immunogenicity of recombinant Pfs25 and Pvs25 formulated with Montanide ISA 51 , a water-in-oil emulsion . Methodology /Principal Findings The trial was conducted at The Johns Hopkins Center for Immunization Research , Washington DC , USA , between May 16 , 2005–April 30 , 2007 . The trial was design ed to enroll 72 healthy male and non-pregnant female volunteers into 1 group to receive adjuvant control and 6 groups to receive escalating doses of the vaccines . Due to unexpected reactogenicity , the vaccination was halted and only 36 volunteers were enrolled into 4 groups : 3 groups of 10 volunteers each were immunized with 5 µg of Pfs25/ISA 51 , 5 µg of Pvs25/ISA 51 , or 20 µg of Pvs25/ISA 51 , respectively . A fourth group of 6 volunteers received adjuvant control ( PBS/ISA 51 ) . Frequent local reactogenicity was observed . Systemic adverse events included two cases of erythema nodosum considered to be probably related to the combination of the antigen and the adjuvant . Significant antibody responses were detected in volunteers who completed the lowest scheduled doses of Pfs25/ISA 51 . Serum anti-Pfs25 levels correlated with transmission blocking activity . Conclusion / Significance It is feasible to induce transmission blocking immunity in humans using the Pfs25/ISA 51 vaccine , but these vaccines are unexpectedly reactogenic for further development . This is the first report that the formulation is associated with systemic adverse events including erythema nodosum . Trial Registration Clinical Trials.gov BACKGROUND Merozoite surface protein ( MSP ) 5 is a c and i date antigen for a malaria vaccine . In cross-sectional and longitudinal studies , we measured MSP5 antibody responses in Papuans with acute Plasmodium falciparum malaria , Plasmodium vivax malaria , and mixed P. falciparum and P. vivax malaria and in those with past exposure . METHODS Enzyme-linked immunosorbant assay ( ELISA ) was used to quantitate antibody responses to P. falciparum MSP5 ( PfMSP5 ) and P. vivax MSP5 ( PvMSP5 ) in 82 subjects with P. falciparum infection , 86 subjects with P. vivax infection , 85 subjects with mixed infection , and 87 asymptomatic individuals . Longitudinal responses through day 28 were tested in 20 persons . Cross-reactivity was tested by competition ELISA . RESULTS PfMSP5 or PvMSP5 immunoglobulin (Ig)Gwas detected in 39%-52 % of subjects , and IgM was detected in 44%-72 % . IgG responses were distributed equally between IgG3 and IgG1 for PfMSP5 but were predominantly IgG3 for PvMSP5 . Although IgG responses were generally specific for PfMSP5 or PvMSP5 , cross-species reactivity was found in 7 of 107 dual-positive responders . No significant difference was seen in the magnitude , frequency , or subclass of PfMSP5 or PvMSP5 IgG antibodies between groups . There was no significant association between antibody responses and therapeutic response . CONCLUSION PfMSP5 and PvMSP5 were frequently recognized by short-lived , species-specific antibodies . Although infrequent , the cross-reactive MSP5 antibodies indicate that an appropriately formulated vaccine may elicit and /or enhance cross-species recognition , which may be very useful in areas where both parasites are endemic Plasmodium vivax is responsible for the majority of malaria cases outside of Africa , and results in substantial morbidity . Transmission blocking vaccines are a potentially powerful component of a multi-faceted public health approach to controlling or eliminating malaria . We report the first phase 1 clinical trial of a P. vivax transmission blocking vaccine  in humans . The Pvs25H vaccine is a recombinant protein derived from the Pvs25 surface antigen of P. vivax ookinetes . The protein was expressed in Saccharomyces cerevisiae , purified , and adsorbed onto Alhydrogel . Ten volunteers in each of three dose groups ( 5 , 20 , or 80 microg ) were vaccinated by intramuscular injection in an open-label study at 0 , 28 and 180 days . No vaccine-related serious adverse events were observed . The majority of adverse events causally related to vaccination were mild or moderate in severity . Injection site tenderness was the most commonly observed adverse event . Anti-Pvs25H antibody levels measured by ELISA peaked after the third vaccination . Vaccine-induced antibody is functionally active as evidence d by significant transmission blocking activity in the membrane feeding assay . Correlation between antibody concentration and degree of inhibition was observed . Pvs25H generates transmission blocking immunity in humans against P. vivax demonstrating the potential of this antigen as a component of a transmission blocking vaccine Background Plasmodium vivax has the potential to infect 2.85 billion individuals worldwide . Nevertheless , the limited number of studies investigating the immune status of individuals living in malaria-endemic areas , as well as the lack of reports investigating serological markers associated with clinical protection , has hampered development of vaccines for P. vivax . It was previously demonstrated that naturally total IgG against the N-terminus of P. vivax merozoite surface protein 1 ( Pv-MSP1 ) was associated with reduced risk of malarial infection . Methods Immune response against Pv-MSP1 ( N-terminus ) of 313 residents of the Rio Pardo rural settlement ( Amazonas State , Brazil ) was evaluated in a cross-sectional and longitudinal follow up over two months ( on site ) wherein gold st and ard diagnosis by thick blood smear and rRNA gene-based nested real-time PCR were used to discriminate symptomless Plasmodium vivax-infected individuals who did not develop clinical symptoms during a 2-months from those uninfected ones or who have had acute malaria . The acquisition of antibodies against Pv-MSP1 was also evaluated as survival analysis by prospect i ve study over a year collecting information of new malaria infections in surveillance data base . Results The majority of P. vivax-infected individuals ( 52 - 67 % ) showed immune recognition of the N-terminus of Pv-MSP1 . Interesting data on infected individuals who have not developed symptoms , total IgG levels against the N-terminus Pv-MSP1 were age-dependent and the IgG3 levels were significantly higher than levels of subjects had acute malaria or those uninfected ones . The total IgG anti ICB2 - 5 was detected to be an important factor of protection against new malaria vivax attacks in survival analysis in a prospect i ve survey ( p = 0.029 ) . Conclusions The study findings illustrate the importance of IgG3 associated to 2-months of symptomless in P. vivax infected individuals and open perspectives for the rationale of malaria vaccine design s capable to sustain high levels of IgG3 against polymorphic malaria antigens The role of naturally acquired circumsporozoite ( CS ) antibodies in protection against falciparum and vivax malaria was evaluated in a group of Thai endemic villagers using a prospect i ve cohort and a case-control study design . There was no evidence of protection by either the presence of positive CS antibody levels at the presumed time of sporozoite exposure or in individuals who persistently had measurable levels of the antibodies . The study defined levels of CS antibodies that were not protective in natural infection We assessed the safety , tolerability , and immunogenicity of a mixture of three synthetic peptides derived from the Plasmodium vivax circumsporozoite protein formulated in Montanide ISA 720 or Montanide ISA 51 .  Forty healthy malaria-naive volunteers were allocated to five experimental groups ( A-E ) : four groups ( A-D ) were immunized intramuscularly with 50 and 100 μg/dose injections of a mixture of N , R , and C peptides formulated in the two different adjuvants at 0 , 2 , and 4 months and one group was administered placebo . Vaccines were immunogenic , safe , well tolerated , and no serious adverse events related to the vaccine occurred . Seroconversion occurred in > 90 % of the vaccines and antibodies recognized the sporozoite protein on immunofluorescent antibody test . Vaccines in Montanide ISA 51 showed a higher sporozoite protein recognition and interferon production . Results encourage further testing of the vaccine protective efficacy ABSTRACT Progress towards the development of a malaria vaccine against Plasmodium vivax , the most widely distributed human malaria parasite , will require a better underst and ing of the immune responses that confer clinical protection to patients in regions where malaria is endemic . The occurrence of clinical protection in P. vivax malaria in Brazil was first reported among residents of the riverine community of Portuchuelo , in Rondônia , western Amazon . We thus analyzed immune sera  from this same human population to determine if naturally acquired humoral immune responses against the merozoite surface protein 1 of P. vivax , PvMSP1 , could be associated with reduced risk of infection and /or clinical protection . Our results demonstrated that this association could be established with 
    Output:
    
Considerable heterogeneity in estimates was observed , but IgG responses to PvCSP , PvMSP-119 , PvMSP-9RIRII , and PvAMA1 were associated with increased odds of P. vivax infection in geographically diverse population s. Potential sources of heterogeneity included study design , different transmission intensities and transmigrant population s. Protective associations were observed for antibodies to PvMSP-119 , PvMSP-1NT , PvMSP-3α and PvMSP-9NT antigens , but only in single geographical locations .
Conclusions This systematic review revealed several antigen-specific antibodies that were associated with active infection and protective immunity , which may be useful biomarkers .