Publications by authors named "James G Beeson"

210 Publications

Novel Virus-Like Particle Vaccine Encoding the Circumsporozoite Protein of Is Immunogenic and Induces Functional Antibody Responses in Mice.

Front Immunol 2021 17;12:641421. Epub 2021 Mar 17.

Life Sciences, Burnet Institute, Melbourne, VIC, Australia.

RTS,S is the leading malaria vaccine in development, but has demonstrated only moderate protective efficacy in clinical trials. RTS,S is a virus-like particle (VLP) that uses the human hepatitis B virus as scaffold to display the malaria sporozoite antigen, circumsporozoite protein (CSP). Particle formation requires four-fold excess scaffold antigen, and as a result, CSP represents only a small portion of the final vaccine construct. Alternative VLP or nanoparticle platforms that reduce the amount of scaffold antigen and increase the amount of the target CSP antigen present in particles may enhance vaccine immunogenicity and efficacy. Here, we describe the production and characterization of a novel VLP that uses the small surface antigen (dS) of duck hepatitis B virus to display CSP. The CSP-dS fusion protein successfully formed VLPs without the need for excess scaffold antigen, and thus CSP represented a larger portion of the vaccine construct. CSP-dS formed large particles approximately 31-74 nm in size and were confirmed to display CSP on the surface. CSP-dS VLPs were highly immunogenic in mice and induced antibodies to multiple regions of CSP, even when administered at a lower vaccine dosage. Vaccine-induced antibodies demonstrated relevant functional activities, including Fc-dependent interactions with complement and Fcγ-receptors, previously identified as important in malaria immunity. Further, vaccine-induced antibodies had similar properties (epitope-specificity and avidity) to monoclonal antibodies that are protective in mouse models. Our novel platform to produce VLPs without excess scaffold protein has wide implications for the future development of vaccines for malaria and other infectious diseases.
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http://dx.doi.org/10.3389/fimmu.2021.641421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010251PMC
March 2021

Mechanisms and targets of Fcγ-receptor mediated immunity to malaria sporozoites.

Nat Commun 2021 03 19;12(1):1742. Epub 2021 Mar 19.

Burnet Institute for Medical Research and Public Health, Melbourne, VIC, Australia.

A highly protective vaccine will greatly facilitate achieving and sustaining malaria elimination. Understanding mechanisms of antibody-mediated immunity is crucial for developing vaccines with high efficacy. Here, we identify key roles in humoral immunity for Fcγ-receptor (FcγR) interactions and opsonic phagocytosis of sporozoites. We identify a major role for neutrophils in mediating phagocytic clearance of sporozoites in peripheral blood, whereas monocytes contribute a minor role. Antibodies also promote natural killer cell activity. Mechanistically, antibody interactions with FcγRIII appear essential, with FcγRIIa also required for maximum activity. All regions of the circumsporozoite protein are targets of functional antibodies against sporozoites, and N-terminal antibodies have more activity in some assays. Functional antibodies are slowly acquired following natural exposure to malaria, being present among some exposed adults, but uncommon among children. Our findings reveal targets and mechanisms of immunity that could be exploited in vaccine design to maximize efficacy.
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http://dx.doi.org/10.1038/s41467-021-21998-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979888PMC
March 2021

Framework for Characterizing Longitudinal Antibody Response in Children After Infection.

Front Immunol 2021 2;12:617951. Epub 2021 Mar 2.

Malaria Branch, Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, Atlanta, GA, United States.

Human infection produces a robust adaptive immune response. Time courses for 104 children followed for 42 days after initiation of chemotherapy were assayed for antibody levels to the five isotypes of human immunoglobulins (Ig) and 4 subclasses of IgG for 32 antigens encompassing all 4 parasite stages of human infection. IgD and IgE against these antigens were undetectable at 1:100 serum concentration, but other Ig isotypes and IgG subclasses were consistently observed against all antigens. Five quantitative parameters were developed to directly compare Ig response among isotypes and antigens: C, maximum antibody level; Δ, difference between C and the antibody level at Day 0; t, time in days to reach C; t, Ig signal half-life in days; t, estimated number of days until complete loss of Ig signal. Classical Ig patterns for a bloodborne pathogen were seen with IgM showing early t and IgG production highest among Ig isotypes. However, some unexpected trends were observed such as IgA showing a biphasic pattern for many antigens. Variability among these dynamics of Ig acquisition and loss was noted for different antigens and able to be compared both quantitatively and statistically. This parametrization methodology allows direct comparison of Ig isotypes produced against various antigens following malaria infection, and the same methodology could be applied to other longitudinal serologic studies from or different pathogens. Specifically for seroepidemiological studies, reliable and quantitative estimates regarding the IgG dynamics in human populations can better optimize modeling efforts for serological outputs.
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http://dx.doi.org/10.3389/fimmu.2021.617951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960919PMC
March 2021

HIV infection and placental malaria reduce maternal transfer of multiple antimalarial antibodies in Mozambican women.

J Infect 2021 04 23;82(4):45-57. Epub 2021 Feb 23.

ISGlobal, Hospital Clínic - Universitat de Barcelona, Carrer Rosselló 153, E-08036, Barcelona, Catalonia, Spain; Centro de Investigação em Saúde de Manhiça (CISM), Rua 12, Cambeve, Vila de Manhiça, CP 1929, Maputo, Mozambique. Electronic address:

Objectives: Maternal Plasmodium falciparum-specific antibodies may contribute to protect infants against severe malaria. Our main objective was to evaluate the impact of maternal HIV infection and placental malaria on the cord blood levels and efficiency of placental transfer of IgG and IgG subclasses.

Methods: In a cohort of 341 delivering HIV-negative and HIV-positive mothers from southern Mozambique, we measured total IgG and IgG subclasses in maternal and cord blood pairs by quantitative suspension array technology against eight P. falciparum antigens: Duffy-binding like domains 3-4 of VAR2CSA from the erythrocyte membrane protein 1, erythrocyte-binding antigen 140, exported protein 1 (EXP1), merozoite surface proteins 1, 2 and 5, and reticulocyte-binding-homologue-4.2 (Rh4.2). We performed univariable and multivariable regression models to assess the association of maternal HIV infection, placental malaria, maternal variables and pregnancy outcomes on cord antibody levels and antibody transplacental transfer.

Results: Maternal antibody levels were the main determinants of cord antibody levels. HIV infection and placental malaria reduced the transfer and cord levels of IgG and IgG1, and this was antigen-dependent. Low birth weight was associated with an increase of IgG2 in cord against EXP1 and Rh4.2.

Conclusions: We found lower maternally transferred antibodies in HIV-exposed infants and those born from mothers with placental malaria, which may underlie increased susceptibility to malaria in these children.
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http://dx.doi.org/10.1016/j.jinf.2021.02.024DOI Listing
April 2021

Mycoplasma genitalium and Other Reproductive Tract Infections in Pregnant Women, Papua New Guinea, 2015-2017.

Emerg Infect Dis 2021 Mar;27(3):894-904

Much about the range of pathogens, frequency of coinfection, and clinical effects of reproductive tract infections (RTIs) among pregnant women remains unknown. We report on RTIs (Mycoplasma genitalium, Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Treponema pallidum subspecies pallidum, bacterial vaginosis, and vulvovaginal candidiasis) and other reproductive health indicators in 699 pregnant women in Papua New Guinea during 2015-2017. We found M. genitalium, an emerging pathogen in Papua New Guinea, in 12.5% of participants. These infections showed no evidence of macrolide resistance. In total, 74.1% of pregnant women had >1 RTI; most of these infections were treatable. We detected sexually transmitted infections (excluding syphilis) in 37.7% of women. Our findings showed that syndromic management of infections is greatly inadequate. In total, 98.4% of women had never used barrier contraception. These findings will inform efforts to improve reproductive healthcare in Papua New Guinea.
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http://dx.doi.org/10.3201/eid2703.201783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920647PMC
March 2021

Impact of a Rapid Decline in Malaria Transmission on Antimalarial IgG Subclasses and Avidity.

Front Immunol 2020 27;11:576663. Epub 2021 Jan 27.

Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom.

Understanding how immunity to malaria is affected by declining transmission is important to aid vaccine design and understand disease resurgence. Both IgG subclasses and avidity of antigen-specific responses are important components of an effective immune response. Using a multiplex bead array assay, we measured the total IgG, IgG subclasses, and avidity profiles of responses to 18 blood stage antigens in samples from 160 Ugandans collected at two time points during high malaria transmission and two time points following a dramatic reduction in transmission. Results demonstrated that, for the antigens tested, (i) the rate of decay of total IgG following infection declined with age and was driven consistently by the decrease in IgG3 and occasionally the decrease in IgG1; (ii) the proportion of IgG3 relative to IgG1 in the absence of infection increased with age; (iii) the increase in avidity index (the strength of association between the antibody and antigen) following infection was largely due to a rapid loss of non-avid compared to avid total IgG; and (iv) both avid and non-avid total IgG in the absence of infection increased with age. Further studies are required to understand the functional differences between IgG1 and IgG3 in order to determine their contribution to the longevity of protective immunity to malaria. Measuring changes in antibody avidity may be a better approach of detecting affinity maturation compared to avidity index due to the differential expansion and contraction of high and low avidity total IgG.
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http://dx.doi.org/10.3389/fimmu.2020.576663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873448PMC
January 2021

Risk factors and knowledge associated with high unintended pregnancy rates and low family planning use among pregnant women in Papua New Guinea.

Sci Rep 2021 Jan 13;11(1):1222. Epub 2021 Jan 13.

Burnet Institute, 85 Commercial Rd, Melbourne, VIC, 3004, Australia.

Unintended pregnancy is a major driver of poor maternal and child health in resource-limited settings. Data on pregnancy intention and use of family planning (FP) is scarce in Papua New Guinea (PNG), but are needed to inform public health strategies to improve FP accessibility and uptake. Data from a facility-based cross-sectional sample of 699 pregnant women assessed prevalence and predictors of unintended pregnancy and modern FP use among pregnant women in East New Britain Province, PNG. More than half (55%) the women reported their pregnancy as unintended. Few (18%) reported ever having used a modern FP method, and knowledge of different methods was low. Being single, separated or divorced (AOR 9.66; 95% CI 3.27-28.54), educated to a tertiary or vocational level (AOR 1.78 CI 1.15-2.73), and gravidity > 1 (AOR 1.43 for each additional pregnancy CI 1.29-1.59) were associated with unintended pregnancy; being accompanied by a male partner to ANC was associated with a reduced unintended pregnancy (0.46 CI 0.30-0.73). Factors associated with modern FP use included male partner involvement (AOR 2.26 CI 1.39-3.67) and gravidity > 1 (AOR 1.54 for each additional pregnancy CI 1.36-1.74). FP use also varied by the facility women attended. Findings highlight an urgent need for targeted interventions to improve FP knowledge, uptake and access, and male partner involvement, to reduce unintended pregnancies and their complications.
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http://dx.doi.org/10.1038/s41598-020-79103-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806862PMC
January 2021

Complement Factors in COVID-19 Therapeutics and Vaccines.

Trends Immunol 2021 02 13;42(2):94-103. Epub 2020 Dec 13.

Burnet Institute, Melbourne, Australia; Department of Immunology and Pathology, Monash University, Melbourne, Australia; Central Clinical School and Department of Microbiology, Monash University, Melbourne, Australia; Department of Medicine, The University of Melbourne, Parkville, Australia. Electronic address:

Complement is integral to a healthy functioning immune system and orchestrates various innate and adaptive responses against viruses and other pathogens. Despite its importance, the potential beneficial role of complement in immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been overshadowed by reports of extensive complement activation in severe coronavirus disease 2019 (COVID-19) patients. Here, we hypothesize that complement may also have a protective role and could function to enhance virus neutralization by antibodies, promote virus phagocytosis by immune cells, and lysis of virus. These functions might be exploited in the development of effective therapeutics and vaccines against SARS-CoV-2.
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http://dx.doi.org/10.1016/j.it.2020.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733687PMC
February 2021

Th2-like T Follicular Helper Cells Promote Functional Antibody Production during Infection.

Cell Rep Med 2020 Dec 22;1(9):100157. Epub 2020 Dec 22.

Life Sciences, Burnet Institute, Melbourne, VIC 3004, Australia.

CD4 T follicular helper cells (Tfh) are key drivers of antibody development. During malaria in children, the activation of Tfh is restricted to the Th1 subset and not associated with antibody levels. To identify Tfh subsets that are associated with antibody development in malaria, we assess Tfh and antibodies longitudinally in human volunteers with experimental infection. Tfh cells activate during infection, with distinct dynamics in different Tfh subsets. Th2-Tfh cells activate early, during peak infection, while Th1-Tfh cells activate 1 week after peak infection and treatment. Th2-Tfh cell activation is associated with the functional breadth and magnitude of parasite antibodies. In contrast, Th1-Tfh activation is not associated with antibody development but instead with plasma cells, which have previously been shown to play a detrimental role in the development of long-lived immunity. Thus, our study identifies the contrasting roles of Th2 and Th1-Tfh cells during experimental malaria.
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http://dx.doi.org/10.1016/j.xcrm.2020.100157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762767PMC
December 2020

RTS,S/AS01 malaria vaccine induces IgA responses against CSP and vaccine-unrelated antigens in African children in the phase 3 trial.

Vaccine 2021 01 25;39(4):687-698. Epub 2020 Dec 25.

ISGlobal, Hospital Clínic, Universitat de Barcelona, Carrer Rosselló 153 CEK Building, E-08036 Barcelona, Catalonia, Spain; Centro de Investigação em Saúde de Manhiça (CISM), Rua 12, Cambeve, Vila de Manhiça, CP 1929 Maputo, Mozambique. Electronic address:

Background: The evaluation of immune responses to RTS,S/AS01 has traditionally focused on immunoglobulin (Ig) G antibodies that are only moderately associated with protection. The role of other antibody isotypes that could also contribute to vaccine efficacy remains unclear. Here we investigated whether RTS,S/AS01 elicits antigen-specific serum IgA antibodies to the vaccine and other malaria antigens, and we explored their association with protection.

Methods: Ninety-five children (age 5-17 months old at first vaccination) from the RTS,S/AS01 phase 3 clinical trial who received 3 doses of RTS,S/AS01 or a comparator vaccine were selected for IgA quantification 1 month post primary immunization. Two sites with different malaria transmission intensities (MTI) and clinical malaria cases and controls, were included. Measurements of IgA against different constructs of the circumsporozoite protein (CSP) vaccine antigen and 16 vaccine-unrelated Plasmodium falciparum antigens were performed using a quantitative suspension array assay.

Results: RTS,S vaccination induced a 1.2 to 2-fold increase in levels of serum/plasma IgA antibodies to all CSP constructs, which was not observed upon immunization with a comparator vaccine. The IgA response against 13 out of 16 vaccine-unrelated P. falciparum antigens also increased after vaccination, and levels were higher in recipients of RTS,S than in comparators. IgA levels to malaria antigens before vaccination were more elevated in the high MTI than the low MTI site. No statistically significant association of IgA with protection was found in exploratory analyses.

Conclusions: RTS,S/AS01 induces IgA responses in peripheral blood against CSP vaccine antigens and other P. falciparum vaccine-unrelated antigens, similar to what we previously showed for IgG responses. Collectively, data warrant further investigation of the potential contribution of vaccine-induced IgA responses to efficacy and any possible interplay, either synergistic or antagonistic, with protective IgG, as identifying mediators of protection by RTS,S/AS01 immunization is necessary for the design of improved second-generation vaccines.

Clinical Trial Registration: ClinicalTrials.gov: NCT008666191.
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http://dx.doi.org/10.1016/j.vaccine.2020.12.038DOI Listing
January 2021

Sero-epidemiological evaluation of malaria transmission in The Gambia before and after mass drug administration.

BMC Med 2020 11 13;18(1):331. Epub 2020 Nov 13.

Faculty of Infectious Tropical Diseases, Department of Infection Biology, London School of Hygiene and Tropical Medicine (LSHTM), London, WC1E 7HT, UK.

Background: As The Gambia aims to achieve malaria elimination by 2030, serological assays are a useful surveillance tool to monitor trends in malaria incidence and evaluate community-based interventions.

Methods: Within a mass drug administration (MDA) study in The Gambia, where reduced malaria infection and clinical disease were observed after the intervention, a serological sub-study was conducted in four study villages. Spatio-temporal variation in transmission was measured with a panel of recombinant Pf antigens on a multiplexed bead-based assay. Village-level antibody levels were quantified as under-15 sero-prevalence, sero-conversion rates, and age-adjusted antibody acquisition rates. Antibody levels prior to MDA were assessed for association with persistent malaria infection after community chemoprophylaxis.

Results: Seasonal changes in antibodies to Etramp5.Ag1 were observed in children under 15 years in two transmission settings-the West Coast and Upper River Regions (4.32% and 31.30% Pf prevalence, respectively). At the end of the malaria season, short-lived antibody responses to Etramp5.Ag1, GEXP18, HSP40.Ag1, EBA175 RIII-V, and Rh2.2030 were lower amongst 1-15 year olds in the West Coast compared to the Upper River, reflecting known differences in transmission. Prior to MDA, individuals in the top 50th percentile of antibody levels had two-fold higher odds of clinical malaria during the transmission season, consistent with previous findings from the Malaria Transmission Dynamics Study, where individuals infected before the implementation of MDA had two-fold higher odds of re-infection post-MDA.

Conclusions: Serological markers can serve dual functions as indicators of malaria exposure and incidence. By monitoring age-specific sero-prevalence, the magnitude of age-stratified antibody levels, or identifying groups of individuals with above-average antibody responses, these antigens have the potential to complement conventional malaria surveillance tools. Further studies, particularly cluster randomised trials, can help establish standardised serological protocols to reliably measure transmission across endemic settings.
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http://dx.doi.org/10.1186/s12916-020-01785-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664049PMC
November 2020

Epitope masking may limit antibody boosting to malaria vaccines.

Immunol Cell Biol 2021 Feb 5;99(2):126-129. Epub 2020 Nov 5.

Burnet Institute, Melbourne, VIC, Australia.

We discuss the study by McNamara et al., who report that low levels of antigen-specific antibodies in serum can limit the boosting of antibody and B-cell responses following immunization with live attenuated malaria sporozoites.
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http://dx.doi.org/10.1111/imcb.12415DOI Listing
February 2021

Retargeting azithromycin analogues to have dual-modality antimalarial activity.

BMC Biol 2020 09 29;18(1):133. Epub 2020 Sep 29.

Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, 5005, Australia.

Background: Resistance to front-line antimalarials (artemisinin combination therapies) is spreading, and development of new drug treatment strategies to rapidly kill Plasmodium spp. malaria parasites is urgently needed. Azithromycin is a clinically used macrolide antibiotic proposed as a partner drug for combination therapy in malaria, which has also been tested as monotherapy. However, its slow-killing 'delayed-death' activity against the parasite's apicoplast organelle and suboptimal activity as monotherapy limit its application as a potential malaria treatment. Here, we explore a panel of azithromycin analogues and demonstrate that chemical modifications can be used to greatly improve the speed and potency of antimalarial action.

Results: Investigation of 84 azithromycin analogues revealed nanomolar quick-killing potency directed against the very earliest stage of parasite development within red blood cells. Indeed, the best analogue exhibited 1600-fold higher potency than azithromycin with less than 48 hrs treatment in vitro. Analogues were effective against zoonotic Plasmodium knowlesi malaria parasites and against both multi-drug and artemisinin-resistant Plasmodium falciparum lines. Metabolomic profiles of azithromycin analogue-treated parasites suggested activity in the parasite food vacuole and mitochondria were disrupted. Moreover, unlike the food vacuole-targeting drug chloroquine, azithromycin and analogues were active across blood-stage development, including merozoite invasion, suggesting that these macrolides have a multi-factorial mechanism of quick-killing activity. The positioning of functional groups added to azithromycin and its quick-killing analogues altered their activity against bacterial-like ribosomes but had minimal change on 'quick-killing' activity. Apicoplast minus parasites remained susceptible to both azithromycin and its analogues, further demonstrating that quick-killing is independent of apicoplast-targeting, delayed-death activity.

Conclusion: We show that azithromycin and analogues can rapidly kill malaria parasite asexual blood stages via a fast action mechanism. Development of azithromycin and analogues as antimalarials offers the possibility of targeting parasites through both a quick-killing and delayed-death mechanism of action in a single, multifactorial chemotype.
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http://dx.doi.org/10.1186/s12915-020-00859-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526119PMC
September 2020

Antibody responses to a suite of novel serological markers for malaria surveillance demonstrate strong correlation with clinical and parasitological infection across seasons and transmission settings in The Gambia.

BMC Med 2020 09 25;18(1):304. Epub 2020 Sep 25.

Faculty of Infectious Tropical Diseases, Department of Infection Biology, London School of Hygiene and Tropical Medicine (LSHTM), London, WC1E 7HT, UK.

Background: As malaria transmission declines, sensitive diagnostics are needed to evaluate interventions and monitor transmission. Serological assays measuring malaria antibody responses offer a cost-effective detection method to supplement existing surveillance tools.

Methods: A prospective cohort study was conducted from 2013 to 2015 in 12 villages across five administrative regions in The Gambia. Serological analysis included samples from the West Coast Region at the start and end of the season (July and December 2013) and from the Upper River Region in July and December 2013 and April and December 2014. Antigen-specific antibody responses to eight Plasmodium falciparum (P. falciparum) antigens-Etramp5.Ag1, GEXP18, HSP40.Ag1, Rh2.2030, EBA175 RIII-V, PfMSP1, PfAMA1, and PfGLURP.R2-were quantified using a multiplexed bead-based assay. The association between antibody responses and clinical and parasitological endpoints was estimated at the individual, household, and population level.

Results: Strong associations were observed between clinical malaria and concurrent sero-positivity to Etramp5.Ag1 (aOR 4.60 95% CI 2.98-7.12), PfMSP1 (aOR 4.09 95% CI 2.60-6.44), PfAMA1 (aOR 2.32 95% CI 1.40-3.85), and PfGLURP.R2 (aOR 3.12, 95% CI 2.92-4.95), while asymptomatic infection was associated with sero-positivity to all antigens. Village-level sero-prevalence amongst children 2-10 years against Etramp5.Ag1, HSP40.Ag1, and PfMSP1 showed the highest correlations with clinical and P. falciparum infection incidence rates. For all antigens, there were increased odds of asymptomatic P. falciparum infection in subjects residing in a compound with greater than 50% sero-prevalence, with a 2- to 3-fold increase in odds of infection associated with Etramp5.Ag1, GEXP18, Rh2.2030, PfMSP1, and PfAMA1. For individuals residing in sero-positive compounds, the odds of clinical malaria were reduced, suggesting a protective effect.

Conclusions: At low transmission, long-lived antibody responses could indicate foci of malaria transmission that have been ongoing for several seasons or years. In settings where sub-patent infections are prevalent and fluctuate below the detection limit of polymerase chain reaction (PCR), the presence of short-lived antibodies may indicate recent infectivity, particularly in the dry season when clinical cases are rare. Serological responses may reflect a persistent reservoir of infection, warranting community-targeted interventions if individuals are not clinically apparent but have the potential to transmit. Therefore, serological surveillance at the individual and household level may be used to target interventions where there are foci of asymptomatically infected individuals, such as by measuring the magnitude of age-stratified antibody levels or identifying areas with clustering of above-average antibody responses across a diverse range of serological markers.
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http://dx.doi.org/10.1186/s12916-020-01724-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517687PMC
September 2020

Structure-Activity Studies of Truncated Latrunculin Analogues with Antimalarial Activity.

ChemMedChem 2021 Feb 10;16(4):679-693. Epub 2020 Nov 10.

Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.

Malarial parasites employ actin dynamics for motility, and any disruption to these dynamics renders the parasites unable to effectively establish infection. Therefore, actin presents a potential target for malarial drug discovery, and naturally occurring actin inhibitors such as latrunculins are a promising starting point. However, the limited availability of the natural product and the laborious route for synthesis of latrunculins have hindered their potential development as drug candidates. In this regard, we recently described novel truncated latrunculins, with superior actin binding potency and selectivity towards P. falciparum actin than the canonical latrunculin B. In this paper, we further explore the truncated latrunculin core to summarize the SAR for inhibition of malaria motility. This study helps further understand the binding pattern of these analogues in order to develop them as drug candidates for malaria.
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http://dx.doi.org/10.1002/cmdc.202000399DOI Listing
February 2021

Evaluation of the effectiveness of topical repellent distributed by village health volunteer networks against Plasmodium spp. infection in Myanmar: A stepped-wedge cluster randomised trial.

PLoS Med 2020 08 20;17(8):e1003177. Epub 2020 Aug 20.

Burnet Institute, Victoria, Australia, and Yangon, Myanmar.

Background: The World Health Organization has yet to endorse deployment of topical repellents for malaria prevention as part of public health campaigns. We aimed to quantify the effectiveness of repellent distributed by the village health volunteer (VHV) network in the Greater Mekong Subregion (GMS) in reducing malaria in order to advance regional malaria elimination.

Methods And Findings: Between April 2015 and June 2016, a 15-month stepped-wedge cluster randomised trial was conducted in 116 villages in Myanmar (stepped monthly in blocks) to test the effectiveness of 12% N,N-diethylbenzamide w/w cream distributed by VHVs, on Plasmodium spp. infection. The median age of participants was 18 years, approximately half were female, and the majority were either village residents (46%) or forest dwellers (40%). No adverse events were reported during the study. Generalised linear mixed modelling estimated the effect of repellent on infection detected by rapid diagnostic test (RDT) (primary outcome) and polymerase chain reaction (PCR) (secondary outcome). Overall Plasmodium infection detected by RDT was low (0.16%; 50/32,194), but infection detected by PCR was higher (3%; 419/13,157). There was no significant protection against RDT-detectable infection (adjusted odds ratio [AOR] = 0.25, 95% CI 0.004-15.2, p = 0.512). In Plasmodium-species-specific analyses, repellent protected against PCR-detectable P. falciparum (adjusted relative risk ratio [ARRR] = 0.67, 95% CI 0.47-0.95, p = 0.026), but not P. vivax infection (ARRR = 1.41, 95% CI 0.80-2.47, p = 0.233). Repellent effects were similar when delayed effects were modelled, across risk groups, and regardless of village-level and temporal heterogeneity in malaria prevalence. The incremental cost-effectiveness ratio was US$256 per PCR-detectable infection averted. Study limitations were a lower than expected Plasmodium spp. infection rate and potential geographic dilution of the intervention.

Conclusions: In this study, we observed apparent protection against new infections associated with the large-scale distribution of repellent by VHVs. Incorporation of repellent into national strategies, particularly in areas where bed nets are less effective, may contribute to the interruption of malaria transmission. Further studies are warranted across different transmission settings and populations, from the GMS and beyond, to inform WHO public health policy on the deployment of topical repellents for malaria prevention.

Trial Registration: Australian and New Zealand Clinical Trials Registry (ACTRN12616001434482).
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http://dx.doi.org/10.1371/journal.pmed.1003177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444540PMC
August 2020

Identifying and combating the impacts of COVID-19 on malaria.

BMC Med 2020 07 30;18(1):239. Epub 2020 Jul 30.

Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Australia.

Background: The COVID-19 pandemic has resulted in millions of infections, hundreds of thousands of deaths and major societal disruption due to lockdowns and other restrictions introduced to limit disease spread. Relatively little attention has been paid to understanding how the pandemic has affected treatment, prevention and control of malaria, which is a major cause of death and disease and predominantly affects people in less well-resourced settings.

Main Body: Recent successes in malaria control and elimination have reduced the global malaria burden, but these gains are fragile and progress has stalled in the past 5 years. Withdrawing successful interventions often results in rapid malaria resurgence, primarily threatening vulnerable young children and pregnant women. Malaria programmes are being affected in many ways by COVID-19. For prevention of malaria, insecticide-treated nets need regular renewal, but distribution campaigns have been delayed or cancelled. For detection and treatment of malaria, individuals may stop attending health facilities, out of fear of exposure to COVID-19, or because they cannot afford transport, and health care workers require additional resources to protect themselves from COVID-19. Supplies of diagnostics and drugs are being interrupted, which is compounded by production of substandard and falsified medicines and diagnostics. These disruptions are predicted to double the number of young African children dying of malaria in the coming year and may impact efforts to control the spread of drug resistance. Using examples from successful malaria control and elimination campaigns, we propose strategies to re-establish malaria control activities and maintain elimination efforts in the context of the COVID-19 pandemic, which is likely to be a long-term challenge. All sectors of society, including governments, donors, private sector and civil society organisations, have crucial roles to play to prevent malaria resurgence. Sparse resources must be allocated efficiently to ensure integrated health care systems that can sustain control activities against COVID-19 as well as malaria and other priority infectious diseases.

Conclusion: As we deal with the COVID-19 pandemic, it is crucial that other major killers such as malaria are not ignored. History tells us that if we do, the consequences will be dire, particularly in vulnerable populations.
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http://dx.doi.org/10.1186/s12916-020-01710-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391033PMC
July 2020

Antibody responses to the RTS,S/AS01 vaccine and antigens after a booster dose within the phase 3 trial in Mozambique.

NPJ Vaccines 2020 4;5:46. Epub 2020 Jun 4.

ISGlobal, Hospital Clínic-Universitat de Barcelona, Barcelona, Catalonia Spain.

The RTS,S/AS01 vaccine has shown consistent but partial vaccine efficacy in a pediatric phase 3 clinical trial using a 3-dose immunization schedule. A fourth-dose 18 months after the primary vaccination was shown to restore the waning efficacy. However, only total IgG against the immunodominant malaria vaccine epitope has been analyzed following the booster. To better characterize the magnitude, nature, and longevity of the immune response to the booster, we measured levels of total IgM, IgG, and IgG subclasses against three constructs of the circumsporozoite protein (CSP) and the hepatitis B surface antigen (HBsAg, also present in RTS,S) by quantitative suspension array technology in 50 subjects in the phase 3 trial in Manhiça, Mozambique. To explore the impact of vaccination on naturally acquired immune responses, we measured antibodies to antigens not included in RTS,S. We found increased IgG, IgG1, IgG3 and IgG4, but not IgG2 nor IgM, levels against vaccine antigens 1 month after the fourth dose. Overall, antibody responses to the booster dose were lower than the initial peak response to primary immunization and children had higher IgG and IgG1 levels than infants. Higher anti-Rh5 IgG and IgG levels were detected after the booster dose, suggesting that RTS,S partial protection could increase some blood stage antibody responses. Our work shows that the response to the RTS,S/AS01 booster dose is different from the primary vaccine immune response and highlights the dynamic changes in subclass antibody patterns upon the vaccine booster and with acquisition of adaptive immunity to malaria.
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http://dx.doi.org/10.1038/s41541-020-0192-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272643PMC
June 2020

Iron deficiency is associated with reduced levels of Plasmodium falciparum-specific antibodies in African children.

Clin Infect Dis 2020 Jun 7. Epub 2020 Jun 7.

Kenya Medical Research Institute (KEMRI) Centre for Geographic Medicine Coast, KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.

Background: Iron deficiency (ID) and malaria are common causes of ill-health and disability among children living in sub-Saharan Africa. Although iron is critical for the acquisition of humoral immunity, little is known about the effects of ID on antibody responses to Plasmodium falciparum malaria.

Methods: The study included 1,794 Kenyan and Ugandan children aged 0-7 years. We measured biomarkers of iron and inflammation, and antibodies to P falciparum antigens including apical merozoite antigen 1 (anti-AMA-1) and merozoite surface antigen 1 (anti-MSP-1) in cross-sectional and longitudinal studies.

Results: The overall prevalence of ID was 31%. ID was associated with lower anti-AMA-1 and anti-MSP-1 antibody levels in pooled analyses adjusted for age, gender, study site, inflammation and P falciparum parasitemia (adjusted mean difference on a log-transformed scale (β) -0.46; 95 CI -0.66, -0.25 P <0.0001; β -0.33; 95 CI -0.50, -0.16 P <0.0001, respectively). Additional covariates for malaria exposure index, previous malaria episodes, and time since last malaria episode, were available for individual cohorts. Meta-analysis was used to allow for these adjustments giving β -0.34; -0.52, -0.16 for anti-AMA-1 antibodies and β -0.26; -0.41, -0.11 for anti-MSP-1 antibodies. Low transferrin saturation was similarly associated with reduced anti-AMA1 antibody levels. Lower AMA-1 and MSP-1 specific antibody levels persisted over time in iron-deficient children.

Conclusions: Reduced levels of P. falciparum-specific antibodies in iron-deficient children might reflect impaired acquisition of immunity to malaria and/or reduced malaria exposure. Strategies to prevent and treat ID may influence antibody responses to malaria for children living in sub-Saharan Africa.
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http://dx.doi.org/10.1093/cid/ciaa728DOI Listing
June 2020

Selection of Antibody Responses Associated With Infections in the Context of Malaria Elimination.

Front Immunol 2020 15;11:928. Epub 2020 May 15.

Department of Infection Biology, London School of Hygiene & Tropical Medicine, London, United Kingdom.

In our aim to eliminate malaria, more sensitive tools to detect residual transmission are quickly becoming essential. Antimalarial antibody responses persist in the blood after a malaria infection and provide a wider window to detect exposure to infection compared to parasite detection metrics. Here, we aimed to select antibody responses associated with recent and cumulative exposure to malaria using cross-sectional survey data from Haiti, an elimination setting. Using a multiplex bead assay, we generated data for antibody responses (immunoglobulin G) to 23 targets in 29,481 participants across three surveys. This included one community-based survey in which participants were enrolled during household visits and two sentinel group surveys in which participants were enrolled at schools and health facilities. First, we correlated continuous antibody responses with age (Spearman) to determine which showed strong age-related associations indicating accumulation over time with limited loss. AMA-1 and MSP-1 antibody levels showed the strongest correlation with age (0.47 and 0.43, < 0.001) in the community-based survey, which was most representative of the underlying age structure of the population, thus seropositivity to either of these antibodies was considered representative of cumulative exposure to malaria. Next, in the absence of a gold standard for recent exposure, we included antibody responses to the remaining targets to predict highly sensitive rapid diagnostic test (hsRDT) status using receiver operating characteristic curves. For this, only data from the survey with the highest hsRDT prevalence was used (7.2%; 348/4,849). The performance of the top two antigens in the training dataset (two-thirds of the dataset; = 3,204)-Etramp 5 ag 1 and GLURP-R0 (area-under-the-curve, AUC, 0.892 and 0.825, respectively)-was confirmed in the test dataset (remaining one-third of the dataset; = 1,652, AUC 0.903 and 0.848, respectively). As no further improvement was seen by combining seropositivity to GLURP-R0 and Etramp 5 ag 1 ( = 0.266), seropositivity to Etramp 5 ag 1 alone was selected as representative of current or recent exposure to malaria. The validation of antibody responses associated with these exposure histories simplifies analyses and interpretation of antibody data and facilitates the application of results to evaluate programs.
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http://dx.doi.org/10.3389/fimmu.2020.00928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243477PMC
April 2021

Multi-functional antibodies are induced by the RTS,S malaria vaccine and associated with protection in a phase I/IIa trial.

J Infect Dis 2020 Mar 31. Epub 2020 Mar 31.

Burnet Institute, Melbourne, Australia.

Background: RTS,S is the leading malaria vaccine candidate, but only confers partial efficacy against malaria in children. RTS,S is based on the major Plasmodium falciparum sporozoite surface antigen, circumsporozoite protein (CSP). The induction of anti-CSP antibodies is important for protection, however, it is unclear how these protective antibodies function.

Methods: We quantified the induction of functional anti-CSP antibody responses in healthy malaria-naïve adults (N=45) vaccinated with RTS,S/AS01. This included the ability to mediate effector functions via the fragment crystallizable (Fc) region, such as interacting with human complement proteins and Fcγ-receptors (FcγRs) that are expressed on immune cells, which promote various immunological functions.

Results: Our major findings were i) RTS,S-induced antibodies mediate Fc-dependent effector functions, ii) functional antibodies were generally highest after the second vaccine dose; iii) functional antibodies targeted multiple regions of CSP, iv) participants with higher levels of functional antibodies had a reduced probability of developing parasitemia following homologous challenge (p<0.05); v) non-protected subjects had higher levels of anti-CSP IgM.

Conclusions: Our data suggests a role for Fc-dependent antibody effector functions in RTS,S-induced immunity. Enhancing the induction of these functional activities may be a strategy to improve the protective efficacy of RTS,S or other malaria vaccines.
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http://dx.doi.org/10.1093/infdis/jiaa144DOI Listing
March 2020

Strengthening routine immunization in Papua New Guinea: a cross-sectional provincial assessment of front-line services.

BMC Public Health 2020 Jan 23;20(1):100. Epub 2020 Jan 23.

Burnet Institute, Melbourne, Australia.

Background: Routine immunization programs face many challenges in settings such as Papua New Guinea with dispersed rural populations, rugged geography and limited resources for transport and health. Low routine coverage contributes to disease outbreaks such as measles and the polio that re-appeared in 2018. We report on an in-depth local assessment that aimed to document immunization service provision so as to review a new national strategy, and consider how routine immunization could be better strengthened.

Methods: In East New Britain Province, over 2016 and 17, we carried out a cross-sectional assessment of 12 rural health facilities, staff and clients. The study was timed to follow implementation of a new national strategy for strengthening routine immunization. We used interview, structured observation, and records review, informed by theory-based evaluation, a World Health Organization quality checklist, and other health services research tools.

Results: We documented strengths and weaknesses across six categories of program performance relevant to national immunization strategy and global standards. We found an immunization service with an operational level of staff, equipment and procedures in place; but one that could reach only half to two thirds of its target population. Stronger routine services require improvement in: understanding of population catchments, tracking the unvaccinated, reach and efficiency of outreach visits, staff knowledge of vaccination at birth and beyond the first year of life, handling of multi-dose vials, and engagement of community members. Many local suggestions to enhance national plans, included more reliable on-demand services, integration of other family health services and increased involvement of men.

Conclusions: The national strategy addresses most local gaps, but implementation and resourcing requires greater commitment. Long-term strengthening requires a major increase in centrally-allocated resources, however there are immediate locally feasible steps within current resources that could boost coverage and quality of routine immunization especially through better population-based local planning, and stronger community engagement. Our results also suggest areas where vaccination campaigns in PNG can contribute to routine immunization services.
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http://dx.doi.org/10.1186/s12889-020-8172-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979348PMC
January 2020

Complement in malaria immunity and vaccines.

Immunol Rev 2020 01 26;293(1):38-56. Epub 2019 Sep 26.

Burnet Institute, Melbourne, Vic., Australia.

Developing efficacious vaccines for human malaria caused by Plasmodium falciparum is a major global health priority, although this has proven to be immensely challenging over the decades. One major hindrance is the incomplete understanding of specific immune responses that confer protection against disease and/or infection. While antibodies to play a crucial role in malaria immunity, the functional mechanisms of these antibodies remain unclear as most research has primarily focused on the direct inhibitory or neutralizing activity of antibodies. Recently, there is a growing body of evidence that antibodies can also mediate effector functions through activating the complement system against multiple developmental stages of the parasite life cycle. These antibody-complement interactions can have detrimental consequences to parasite function and viability, and have been significantly associated with protection against clinical malaria in naturally acquired immunity, and emerging findings suggest these mechanisms could contribute to vaccine-induced immunity. In order to develop highly efficacious vaccines, strategies are needed that prioritize the induction of antibodies with enhanced functional activity, including the ability to activate complement. Here we review the role of complement in acquired immunity to malaria, and provide insights into how this knowledge could be used to harness complement in malaria vaccine development.
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http://dx.doi.org/10.1111/imr.12802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972673PMC
January 2020

Malaria vaccine candidates displayed on novel virus-like particles are immunogenic and induce transmission-blocking activity.

PLoS One 2019 10;14(9):e0221733. Epub 2019 Sep 10.

Burnet Institute, Life Sciences, Melbourne, VIC, Australia.

The development of effective malaria vaccines remains a global health priority. Currently, the most advanced vaccine, known as RTS,S, has only shown modest efficacy in clinical trials. Thus, the development of more efficacious vaccines by improving the formulation of RTS,S for increased efficacy or to interrupt malaria transmission are urgently needed. The RTS,S vaccine is based on the presentation of a fragment of the sporozoite antigen on the surface of virus-like particles (VLPs) based on human hepatitis B virus (HBV). In this study, we have developed and evaluated a novel VLP platform based on duck HBV (known as Metavax) for malaria vaccine development. This platform can incorporate large and complex proteins into VLPs and is produced in a Hansenula cell line compatible with cGMP vaccine production. Here, we have established the expression of leading P. falciparum malaria vaccine candidates as VLPs. This includes Pfs230 and Pfs25, which are candidate transmission-blocking vaccine antigens. We demonstrated that the VLPs effectively induce antibodies to malaria vaccine candidates with minimal induction of antibodies to the duck-HBV scaffold antigen. Antibodies to Pfs230 also recognised native protein on the surface of gametocytes, and antibodies to both Pfs230 and Pfs25 demonstrated transmission-reducing activity in standard membrane feeding assays. These results establish the potential utility of this VLP platform for malaria vaccines, which may be suitable for the development of multi-component vaccines that achieve high vaccine efficacy and transmission-blocking immunity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221733PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736250PMC
March 2020

Display of malaria transmission-blocking antigens on chimeric duck hepatitis B virus-derived virus-like particles produced in Hansenula polymorpha.

PLoS One 2019 4;14(9):e0221394. Epub 2019 Sep 4.

ARTES Biotechnology GmbH, Langenfeld, Germany.

Background: Malaria caused by Plasmodium falciparum is one of the major threats to human health globally. Despite huge efforts in malaria control and eradication, highly effective vaccines are urgently needed, including vaccines that can block malaria transmission. Chimeric virus-like particles (VLP) have emerged as a promising strategy to develop new malaria vaccine candidates.

Methods: We developed yeast cell lines and processes for the expression of malaria transmission-blocking vaccine candidates Pfs25 and Pfs230 as VLP and VLP were analyzed for purity, size, protein incorporation rate and expression of malaria antigens.

Results: In this study, a novel platform for the display of Plasmodium falciparum antigens on chimeric VLP is presented. Leading transmission-blocking vaccine candidates Pfs25 and Pfs230 were genetically fused to the small surface protein (dS) of the duck hepatitis B virus (DHBV). The resulting fusion proteins were co-expressed in recombinant Hansenula polymorpha (syn. Pichia angusta, Ogataea polymorpha) strains along with the wild-type dS as the VLP scaffold protein. Through this strategy, chimeric VLP containing Pfs25 or the Pfs230-derived fragments Pfs230c or Pfs230D1M were purified. Up to 100 mg chimeric VLP were isolated from 100 g dry cell weight with a maximum protein purity of 90% on the protein level. Expression of the Pfs230D1M construct was more efficient than Pfs230c and enabled VLP with higher purity. VLP showed reactivity with transmission-blocking antibodies and supported the surface display of the malaria antigens on the native VLP.

Conclusion: The incorporation of leading Plasmodium falciparum transmission-blocking antigens into the dS-based VLP scaffold is a promising novel strategy for their display on nano-scaled particles. Competitive processes for efficient production and purification were established in this study.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221394PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726142PMC
March 2020

Induction and Kinetics of Complement-Fixing Antibodies Against Plasmodium vivax Merozoite Surface Protein 3α and Relationship With Immunoglobulin G Subclasses and Immunoglobulin M.

J Infect Dis 2019 11;220(12):1950-1961

Menzies School of Health Research, Darwin, Australia.

Background: Complement-fixing antibodies are important mediators of protection against Plasmodium falciparum malaria. However, complement-fixing antibodies remain uncharacterized for Plasmodium vivax malaria. P. vivax merozoite surface protein 3α (PvMSP3α) is a target of acquired immunity and a potential vaccine candidate.

Methods: Plasma from children and adults with P. vivax malaria in Sabah, Malaysia, were collected during acute infection, 7 and 28 days after drug treatment. Complement-fixing antibodies and immunoglobulin M and G (IgM and IgG), targeting 3 distinctive regions of PvMSP3α, were measured by means of enzyme-linked immunosorbent assay.

Results: The seroprevalence of complement-fixing antibodies was highest against the PvMSP3α central region (77.6%). IgG1, IgG3, and IgM were significantly correlated with C1q fixation, and both purified IgG and IgM were capable of mediating C1q fixation to PvMSP3α. Complement-fixing antibody levels were similar between age groups, but IgM was predominant in children and IgG3 more prevalent in adults. Levels of functional antibodies increased after acute infection through 7 days after treatment but rapidly waned by day 28.

Conclusion: Our study demonstrates that PvMSP3α antibodies acquired during P. vivax infection can mediate complement fixation and shows the important influence of age in shaping these specific antibody responses. Further studies are warranted to understand the role of these functional antibodies in protective immunity against P. vivax malaria.
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http://dx.doi.org/10.1093/infdis/jiz407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834073PMC
November 2019

RTS,S/AS01E immunization increases antibody responses to vaccine-unrelated Plasmodium falciparum antigens associated with protection against clinical malaria in African children: a case-control study.

BMC Med 2019 08 14;17(1):157. Epub 2019 Aug 14.

ISGlobal, Hospital Clínic - Universitat de Barcelona, Carrer Rosselló 153, E-08036, Barcelona, Catalonia, Spain.

Background: Vaccination and naturally acquired immunity against microbial pathogens may have complex interactions that influence disease outcomes. To date, only vaccine-specific immune responses have routinely been investigated in malaria vaccine trials conducted in endemic areas. We hypothesized that RTS,S/A01E immunization affects acquisition of antibodies to Plasmodium falciparum antigens not included in the vaccine and that such responses have an impact on overall malaria protective immunity.

Methods: We evaluated IgM and IgG responses to 38 P. falciparum proteins putatively involved in naturally acquired immunity to malaria in 195 young children participating in a case-control study nested within the African phase 3 clinical trial of RTS,S/AS01E (MAL055 NCT00866619) in two sites of different transmission intensity (Kintampo high and Manhiça moderate/low). We measured antibody levels by quantitative suspension array technology and applied regression models, multimarker analysis, and machine learning techniques to analyze factors affecting their levels and correlates of protection.

Results: RTS,S/AS01E immunization decreased antibody responses to parasite antigens considered as markers of exposure (MSP1, AMA1) and levels correlated with risk of clinical malaria over 1-year follow-up. In addition, we show for the first time that RTS,S vaccination increased IgG levels to a specific group of pre-erythrocytic and blood-stage antigens (MSP5, MSP1 block 2, RH4.2, EBA140, and SSP2/TRAP) which levels correlated with protection against clinical malaria (odds ratio [95% confidence interval] 0.53 [0.3-0.93], p = 0.03, for MSP1; 0.52 [0.26-0.98], p = 0.05, for SSP2) in multivariable logistic regression analyses.

Conclusions: Increased antibody responses to specific P. falciparum antigens in subjects immunized with this partially efficacious vaccine upon natural infection may contribute to overall protective immunity against malaria. Inclusion of such antigens in multivalent constructs could result in more efficacious second-generation multistage vaccines.
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http://dx.doi.org/10.1186/s12916-019-1378-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693200PMC
August 2019

Understanding the interactions between iron supplementation, infectious disease and adverse birth outcomes is essential to guide public health recommendations.

BMC Med 2019 08 5;17(1):153. Epub 2019 Aug 5.

Maternal and Child Health Program, Burnet Institute, Melbourne, VIC, 3004, Australia.

Pregnant women are highly susceptible to anaemia and iron deficiency due to the increased demands of pregnancy as well as other factors. Iron supplementation is recommended in pregnancy, yet the benefits on newborn outcomes are variable between populations, most likely due to the heterogeneity in the prevalence of iron deficiency, detrimental birth outcomes and infectious diseases. Furthermore, there are concerns regarding iron supplementation in malaria-endemic areas due to reports of increased risk of malaria in those receiving iron. This is compounded by limited knowledge of how iron deficiency, anaemia, malaria, and other infections may interact to influence birth outcomes. In a recent cohort study in Papua New Guinea, where there is a high burden of infections and iron deficiency, we found that iron deficiency in pregnancy was associated with a reduced risk of adverse birth outcomes. However, this effect could not be wholly explained by interactions between iron deficiency and malaria. We proposed that iron deficiency may confer a degree of protection against other infectious pathogens, which in turn caused improvements in birthweight. We argue that further studies in multiple populations are crucial to elucidate interactions between iron status, iron supplementation and birthweight as well as to understand the context-specific benefits of iron supplementation in pregnancy and inform public policy. Focus should be given to haematological studies on anaemia, haemodilution and iron absorption, as well as investigating infectious diseases and other nutritional deficiencies. This is a particular priority in resource-constrained settings where the prevalence of iron deficiency, poor nutrition, infections and poor birth outcomes are high. While current recommendations of iron supplementation and malaria prophylaxis to reduce the burden of poor pregnancy outcomes should be supported, the strength of evidence underpinning these must be improved and new insights should be garnered in order to maximise improvements in maternal and child health.Please see related article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-018-1146-z .Please see related article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1375-9 .
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http://dx.doi.org/10.1186/s12916-019-1376-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681473PMC
August 2019

Antibody Reactivity to Merozoite Antigens in Ghanaian Adults Correlates With Growth Inhibitory Activity Against in Culture.

Open Forum Infect Dis 2019 Jul 28;6(7):ofz254. Epub 2019 May 28.

West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Legon, Accra, Ghana.

Background: uses a repertoire of merozoite-stage proteins for invasion of erythrocytes. Antibodies against some of these proteins halt the replication cycle of the parasite by preventing erythrocyte invasion and are implicated as contributors to protective immunity against malaria.

Methods: We assayed antibody reactivity against a panel of 9 recombinant antigens based on erythrocyte-binding antigen (EBA) and reticulocyte-like homolog (Rh) proteins in plasma from children with malaria and healthy adults residing in 3 endemic areas in Ghana using enzyme-linked immunosorbent assay. Purified immunoglobulin (Ig)G from adult plasma samples was also tested for invasion inhibition against 7 different culture lines, including clinical isolates.

Results: Antibodies against the antigens increased in an age-dependent manner in children. Breadth of reactivity to the different antigens was strongly associated with in vitro parasite growth inhibitory activity of IgG purified from the adults. The strongest predictors of breadth of antibody reactivity were age and transmission intensity, and a combination of reactivities to Rh2, Rh4, and Rh5 correlated strongly with invasion inhibition.

Conclusions: Growth inhibitory activity was significantly associated with breadth of antibody reactivity to merozoite antigens, encouraging the prospect of a multicomponent blood-stage vaccine.
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http://dx.doi.org/10.1093/ofid/ofz254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611546PMC
July 2019