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A phase I randomised, controlled, single blind, dose escalation trial was conducted to evaluate safety and immunogenicity of JAIVAC-1, a recombinant blood stage vaccine candidate against Plasmodium falciparum malaria, composed of a physical mixture of two recombinant proteins, PfMSP-1(19), the 19 kD conserved, C-terminal region of PfMSP-1 and PfF2 the receptor-binding F2 domain of EBA175. Healthy malaria naïve Indian male subjects aged 18-45 years were recruited from the volunteer database of study site. Fifteen subjects in each cohort, randomised in a ratio of 2:1 and meeting the protocol specific eligibility criteria, were vaccinated either with three doses (10 μg, 25 μg and 50 μg of each antigen) of JAIVAC-1 formulated with adjuvant Montanide ISA 720 or with standard dosage of Hepatitis B vaccine. Each subject received the assigned vaccine in the deltoid muscle of the upper arms on Day 0, Day 28 and Day 180. JAIVAC-1 was well tolerated and no serious adverse event was observed. All JAIVAC-1 subjects sero-converted for PfF2 but elicited poor immune response to PfMSP-1(19). Dose-response relationship was observed between vaccine dose of PfF2 and antibody response. The antibodies against PfF2 were predominantly of IgG1 and IgG3 isotype. Sera from JAIVAC-1 subjects reacted with late schizonts in a punctate pattern in immunofluorescence assays. Purified IgG from JAIVAC-1 sera displayed significant growth inhibitory activity against Plasmodium falciparum CAMP strain. Antigen PfF2 should be retained as a component of a recombinant malaria vaccine but PfMSP-1(19) construct needs to be optimised to improve its immunogenicity. Clinical Trial Registry, India CTRI/2010/091/000301.

The antigen, falciparum malaria protein 1 (FMP1), represents the 42-kDa C-terminal fragment of merozoite surface protein-1 (MSP-1) of the 3D7 clone of P. falciparum. Formulated with AS02 (a proprietary Adjuvant System), it constitutes the FMP1/AS02 candidate malaria vaccine. We evaluated this vaccine's safety, immunogenicity, and efficacy in African children. A randomised, double-blind, Phase IIb, comparator-controlled trial.The trial was conducted in 13 field stations of one mile radii within Kombewa Division, Nyanza Province, Western Kenya, an area of holoendemic transmission of P. falciparum. We enrolled 400 children aged 12-47 months in general good health.Children were randomised in a 1ratio1 fashion to receive either FMP1/AS02 (50 microg) or Rabipur(R) rabies vaccine. Vaccinations were administered on a 0, 1, and 2 month schedule. The primary study endpoint was time to first clinical episode of P. falciparum malaria (temperature >/=37.5 degrees C with asexual parasitaemia of >/=50,000 parasites/microL of blood) occurring between 14 days and six months after a third dose. Case detection was both active and passive. Safety and immunogenicity were evaluated for eight months after first immunisations; vaccine efficacy (VE) was measured over a six-month period following third vaccinations. 374 of 400 children received all three doses and completed six months of follow-up. FMP1/AS02 had a good safety profile and was well-tolerated but more reactogenic than the comparator. Geometric mean anti-MSP-1(42) antibody concentrations increased from1.3 microg/mL to 27.3 microg/mL in the FMP1/AS02 recipients, but were unchanged in controls. 97 children in the FMP1/AS02 group and 98 controls had a primary endpoint episode. Overall VE was 5.1% (95% CI: -26% to +28%; p-value = 0.7). FMP1/AS02 is not a promising candidate for further development as a monovalent malaria vaccine. Future MSP-1(42) vaccine development should focus on other formulations and antigen constructs. Clinicaltrials.gov NCT00223990.

Background Plasmodium falciparum merozoite surface proteins 1 (PfMSP1) and 2 (PfMSP2) are potential candidates for malaria vaccine development. However, the genetic diversity of these genes in the global P. falciparum population presents a significant challenge in developing an effective vaccine. Hence, understanding the genetic diversity and evolutionary trends in the global P. falciparum population is crucial. Methods This study analyzed the genetic variations and evolutionary changes of pfmsp1 and pfmsp2 in P. falciparum isolates from the Central Highland and South-Central regions of Vietnam. DNASTAR and MEGA7 programs were utilized for analyses. The polymorphic nature of global pfmsp1 and pfmsp2 was also investigated. Results A total of 337 sequences of pfmsp1 and 289 sequences of pfmsp2 were obtained. The pfmsp1 and pfmsp2 from Vietnam revealed a higher degree of genetic homogeneity compared to those from other malaria-endemic countries. Remarkably, the allele diversity patterns of Vietnam pfmsp1 and pfmsp2 differed significantly from those of neighboring countries in the Greater Mekong Subregion. Declines in allele diversity and polymorphic patterns of Vietnam pfmsp1 and pfmsp2 were observed. Conclusions The Vietnam P. falciparum population might be genetically isolated from the parasite populations in other neighboring GMS countries, likely due to geographical barriers and distinct evolutionary pressures. Furthermore, bottleneck effects or selective sweeps may have contributed to the genetic homogeneity of Vietnam pfmsp1 and pfmsp2 .

•PfRipr is highly conserved target of immunity in Uganda P. falciparum isolates.•Anti-PfRipr IgG inhibited merozoite invasion of heterologous P. falciparum laboratory strains.•PfRipr is a promising candidate for next generation P. falciparum malaria blood-stage vaccine. Genetic variability in Plasmodium falciparum malaria parasites hampers current malaria vaccine development efforts. Here, we hypothesize that to address the impact of genetic variability on vaccine efficacy in clinical trials, conserved antigen targets should be selected to achieve robust host immunity across multiple falciparum strains. Therefore, suitable vaccine antigens should be assessed for levels of polymorphism and genetic diversity. Using a total of one hundred and two clinical isolates from a region of high malaria transmission in Uganda, we analyzed extent of polymorphism and genetic diversity in four recently reported novel blood-stage malaria vaccine candidate proteins: Rh5 interacting protein (PfRipr), GPI anchored micronemal antigen (PfGAMA), rhoptry-associated leucine zipper-like protein 1 (PfRALP1) and Duffy binding-like merozoite surface protein 1 (PfMSPDBL1). In addition, utilizing the wheat germ cell-free system, we expressed recombinant proteins for the four candidates based on P. falciparum laboratory strain 3D7 sequences, immunized rabbits to obtain specific antibodies (Abs) and performed functional growth inhibition assay (GIA). The GIA activity of the raised Abs was demonstrated using both homologous 3D7 and heterologous FVO strains in vitro. Both pfripr and pfralp1 are less polymorphic but the latter is comparatively more diverse, with varied number of regions having insertions and deletions, asparagine and 6-mer repeats in the coding sequences. Pfgama and pfmspdbl1 are polymorphic and genetically diverse among the isolates with antibodies against the 3D7-based recombinant PfGAMA and PfMSPDBL1 inhibiting merozoite invasion only in the 3D7 but not FVO strain. Moreover, although Abs against the 3D7-based recombinant PfRipr and PfRALP1 proteins potently inhibited merozoite invasion of both 3D7 and FVO, the GIA activity of anti-PfRipr was much higher than that of anti-PfRALP1. Thus, PfRipr is regarded as a promising blood-stage vaccine candidate for next-generation vaccines against P. falciparum.

Streptococcus pneumoniae ( Spn ) is the leading cause of community-acquired pneumonia. PspA and PspC are among its most important virulence factors, and these surface proteins carry the proline-rich domain (PRD), whose role was unknown until now. Pneumococcal surface protein A (PspA) and pneumococcal surface protein C (PspC, also called CbpA) are major virulence factors of Streptococcus pneumoniae ( Spn ). These surface-exposed choline-binding proteins (CBPs) function independently to inhibit opsonization, neutralize antimicrobial factors, or serve as adhesins. PspA and PspC both carry a proline-rich domain (PRD) whose role, other than serving as a flexible connector between the N-terminal and C-terminal domains, was up to this point unknown. Herein, we demonstrate that PspA binds to lactate dehydrogenase (LDH) released from dying host cells during infection. Using recombinant versions of PspA and isogenic mutants lacking PspA or specific domains of PspA, this property was mapped to a conserved 22-amino-acid nonproline block (NPB) found within the PRD of most PspAs and PspCs. The NPB of PspA had specific affinity for LDH-A, which converts pyruvate to lactate. In a mouse model of pneumonia, preincubation of Spn carrying NPB-bearing PspA with LDH-A resulted in increased bacterial titers in the lungs. In contrast, incubation of Spn carrying a version of PspA lacking the NPB with LDH-A or incubation of wild-type Spn with enzymatically inactive LDH-A did not enhance virulence. Preincubation of NPB-bearing Spn with lactate alone enhanced virulence in a pneumonia model, indicating exogenous lactate production by Spn -bound LDH-A had an important role in pneumococcal pathogenesis. Our observations show that lung LDH, released during the infection, is an important binding target for Spn via PspA/PspC and that pneumococci utilize LDH-A derived lactate for their benefit in vivo . IMPORTANCE Streptococcus pneumoniae ( Spn ) is the leading cause of community-acquired pneumonia. PspA and PspC are among its most important virulence factors, and these surface proteins carry the proline-rich domain (PRD), whose role was unknown until now. Herein, we show that a conserved 22-amino-acid nonproline block (NPB) found within most versions of the PRD binds to host-derived lactate dehydrogenase A (LDH-A), a metabolic enzyme which converts pyruvate to lactate. PspA-mediated binding of LDH-A increased Spn titers in the lungs and this required LDH-A enzymatic activity. Enhanced virulence was also observed when Spn was preincubated with lactate, suggesting LDH-A-derived lactate is a vital food source. Our findings define a role for the NPB of the PRD and show that Spn co-opts host enzymes for its benefit. They advance our understanding of pneumococcal pathogenesis and have key implications on the susceptibility of individuals with preexisting airway damage that results in LDH-A release.

Background In Burkina Faso, malaria remains the overall leading cause of morbidity and mortality accounting for 35.12% of consultations, 40.83% of hospitalizations and 37.5% of deaths. Genotyping of malaria parasite populations remains an important tool to determine the types and number of parasite clones in an infection. The present study aimed to evaluate the merozoite surface protein 1 ( msp1 ) and merozoite surface protein 2 ( msp2 ) genetic diversity and allele frequencies in Bobo-Dioulasso, Burkina Faso. Method Dried blood spots (DBS) were collected at baseline from patients with uncomplicated malaria in urban health centers in Bobo-Dioulasso. Parasite DNA was extracted using chelex-100 and species were identified using nested PCR. Plamodium falciparum msp1 and msp2 genes were amplified by nested polymerase chain reaction (PCR) and PCR products were analyzed by electrophoresis on a 2.5% agarose gel. Alleles were categorized according to their molecular weight. Results A total of 228 blood samples were analyzed out of which 227 (99.9%) were confirmed as P. falciparum- positive and one sample classified as mixed infection for P. malaria and P. falciparum. In msp1 , the K1 allelic family was predominant with 77.4% (162/209) followed respectively by the MAD20 allelic family with 41.3% and R033 allelic family with 36%. In msp2 , the 3D7 allelic family was the most frequently detected with 93.1 % compared to FC27 with 41.3%. Twenty-one different alleles were observed in msp1 with 9 alleles for K1, 8 alleles for MAD20 and 4 alleles for R033. In msp2 , 25 individual alleles were detected with 10 alleles for FC27 and 15 alleles for 3D7. The mean multiplicity of falciparum infection was 1.95 with respectively 1.8 (1.76–1.83) and 2.1 (2.03–2.16) for msp1 and msp2 ( P = 0.01). Conclusions Our study showed high genetic diversity and allelic frequencies of msp1 and msp2 in Plasmodium falciparum isolates from symptomatic malaria patients in Bobo-Dioulasso.

The carboxyl-terminal fragment of MSP-1 is a potential malaria vaccine candidate, but its limited immunogenicity in humans has slowed clinical progress, needing the optimization of formulation of adjuvant and construct. In this study, the N- and C-terminal fragments of the PyMSP-1 (PyMSP-1 N and PyMSP-1C) were immunized to mice with either incomplete Freund's adjuvant (IFA) plus CpG ODN 1826 or Aluminum salts (Alum) plus CpG, followed by a challenge with Plasmodium yoelii 17XNL to investigate vaccine efficacy. Humoral response and antigen-specific T-cell-derived IFN-γ cytokines were analyzed to compare both fragments. After challenge infection, all mice immunized by PyMSP-1C in IFA plus CpG ODN survived with low-grade parasitemia, while 50 % of mice immunized with PyMSP-1 N in Alum plus CpG ODN died with high levels of parasitemia. Co-immunized with both fragments prevented parasitemia entirely, with IFA plus CpG adjuvants proving more suitable than Alum plus CpG. Both fragments elicited a comparable humoral response when they were formulated with IFA plus CpG ODN but PyMSP-1 N formulated with Alum plus CpG ODN significantly decreased the antigen-specific IgG level. While both IgG1 and IgG2c levels were comparable in two fragments formulated by IFA plus CpG ODN, it was efficient to induce the level of IgG2c of PyMSP-1 N fragment (P < 0.0001). Likewise, IFN-γ from both CD8+ and CD4+ T-cells was significantly lower by PyMSP-1 N than PyMSP-1C formulated in IFA plus CpG ODN (P < 0.0001). In conclusion, the N-terminal fragment of PyMSP-1 protected mice although it showed lower humoral and cellular immune response compared to C-terminal of MSP-1 in IFA plus CpG. The antibody level of PyMSP-1 N was comparable to that of PyMSP-1C when it was formulated with IFA plus CpG.

Malaria caused by Plasmodium parasites remains a large health burden. One approach to combat this disease involves vaccinating individuals with whole sporozoites that have been genetically modified to arrest their development at a specific stage in the liver by targeted gene deletion, resulting in a genetically attenuated parasite (GAP). Through a comprehensive phenotyping screen, we identified the hscb gene, encoding a putative iron-sulfur protein assembly chaperone, as crucial for liver stage development, making it a suitable candidate gene for GAP generation. Parasites lacking Plasmodium berghei HscB ( Pb HscB) exhibited normal sporozoite production in mosquitoes, but their liver stage development was severely impaired, characterized by slow growth and delayed expression of merozoite surface protein 1 (MSP1). In vivo experiments demonstrated that Pb HscB-deficient parasites exhibited a delay in prepatency of 2–4 days, emphasizing the significance of Pb HscB for exo-erythrocytic development. Although knockout of Pb HscB alone allowed breakthrough infections, it is a potent candidate for a dual gene deletion strategy. PlasMei2, an RNA-binding protein, was previously found to be crucial for the completion of liver stage development. We generated a Pb HscB- Pb Mei2-double attenuated parasite line, serving as a late liver stage-arresting replication-competent (LARC) GAP, providing a solid block of liver-to-blood stage transition.

Lyme borreliosis, potentially associated with serious long-term complications, is caused by the species complex Borrelia burgdorferi sensu lato. We investigated a novel Lyme borreliosis vaccine candidate (VLA15) targeting the six most common outer surface protein A (OspA) serotypes 1–6 to prevent infection with pathogenic Borrelia spp prevalent in Europe and North America. This was a partially randomised, observer-masked, phase 1 study in healthy adults older than 18 years to younger than 40 years (n=179) done in trial sites in Belgium and the USA. Following a non-randomised run-in phase, a sealed envelope randomisation method was applied with a 1:1:1:1:1:1 ratio; three dose concentrations of VLA15 (12 μg, 48 μg, and 90 μg) were administered by intramuscular injection on days 1, 29, and 57. The primary outcome was safety (frequency of adverse events up to day 85) assessed in participants who received at least one vaccination. Immunogenicity was a secondary outcome. The trial is registered with ClinicalTrials.gov, NCT03010228, and is complete. Between Jan 23, 2017 and Jan 16, 2019, of 254 participants screened for eligibility, 179 were randomly assigned into six groups: alum-adjuvanted 12 μg (n=29), 48 μg (n=31), or 90 μg (n=31) and non-adjuvanted 12 μg (n=29 participants), 48 μg (n=29), or 90 μg (n=30). VLA15 was safe and well tolerated and the majority of adverse events were mild or moderate. Overall, adverse events were more frequent in the 48 μg and 90 μg groups (range 28−30 participants [94−97%]) when compared with the 12 μg group (25 [86%] participants, 95% CI 69·4–94·5) for adjuvanted and non-adjuvanted groups. Common local reactions were tenderness (151 [84%] participants; 356 events, 95% CI 78·3−89·4) and injection site pain (120 [67%]; 224 events, 59·9–73·5); most frequent systemic reactions were headache (80 [45%]; 112 events, 37·6–52·0), excessive fatigue (45 [25%]; 56 events, 19·4–32·0), and myalgia (45 [25%]; 57 events, 19·4–32·0). A similar safety and tolerability profile was observed between adjuvanted and non-adjuvanted formulations. The majority of solicited adverse events were mild or moderate. VLA15 was immunogenic for all OspA serotypes with higher immune responses induced in the adjuvanted higher dose groups (geometric mean titre range 90 μg with alum 61·3 U/mL–321·7 U/mL vs 23·8 U/mL–111·5 U/mL at 90 μg without alum). This novel multivalent vaccine candidate against Lyme borreliosis was safe and immunogenic and paves the way to further clinical development. Valneva Austria.

Rising Lyme borreliosis incidence rates, potential for severe outcomes, and limitations in accurate and timely diagnosis for treatment initiation suggest the need for a preventive vaccine; however, no vaccine is currently available for human use. We performed two studies in adults to optimise the dose level and vaccination schedule for VLA15, an investigational Lyme borreliosis vaccine targeting outer surface protein A (OspA) serotypes 1–6, which are associated with the most common pathogenic Borrelia species in Europe and North America. Both randomised, observer-blind, placebo-controlled, multicentre phase 2 studies included participants aged 18–65 years without recent history of Lyme borreliosis or tick bites. Study one was conducted at nine clinical research and study centre sites in the USA (n=6), Germany (n=2), and Belgium (n=1); study two was conducted at five of the study one US sites. Based on a randomisation list created by an unmasked statistician for each study, participants were randomly assigned via an electronic case report form randomisation module to receive 90 μg (study one only), 135 μg, or 180 μg VLA15 or placebo by intramuscular injection at months 0, 1, and 2 (study one) or 0, 2, and 6 (study two). Study one began with a run-in phase to confirm safety, after which the Data Safety Monitoring Board recommended the removal of the 90 μg group and continuation of the study. In the study one run-in phase, randomisation was stratified by study site, whereas in the study one main phase and in study two, randomisation was stratified by study site, age group, and baseline B burgdorferi (sensu lato) serostatus. All individuals were masked, other than staff involved in randomisation, vaccine preparation or administration, or safety data monitoring. The primary endpoint for both studies was OspA-specific IgG geometric mean titres (GMTs) at 1 month after the third vaccination and was evaluated in the per-protocol population. Safety endpoints were evaluated in the safety population: all participants who received at least one vaccination. Both studies are registered at ClinicalTrials.gov (study one NCT03769194 and study two NCT03970733) and are completed. For study one, 573 participants were screened and randomly assigned to treatment groups between Dec 21, 2018, and Sept, 26, 2019. For study two, 248 participants were screened and randomly assigned between June 26 and Sept 3, 2019. In study one, 29 participants were assigned to receive 90 μg VLA15, 215 to 135 μg, 205 to 180 μg, and 124 to placebo. In study two, 97 participants were assigned to receive 135 μg VLA15, 100 to 180 μg, and 51 to placebo. At 1 month after the third vaccination (ie, month 3), OspA-specific IgG GMTs in study one ranged from 74·3 (serotype 1; 95% CI 46·4–119·0) to 267·4 units per mL (serotype 3; 194·8–367·1) for 90 μg VLA15, 101·9 (serotype 1; 87·1–119·4) to 283·2 units per mL (serotype 3; 248·2–323·1) for 135 μg, and 115·8 (serotype 1; 98·8–135·7) to 308·6 units per mL (serotype 3; 266·8–356·8) for 180 μg. In study two, ranges at 1 month after the third vaccination (ie, month 7) were 278·5 (serotype 1; 214·9–361·0) to 545·2 units per mL (serotype 2; 431·8–688·4) for 135 μg VLA15 and 274·7 (serotype 1; 209·4–360·4) to 596·8 units per mL (serotype 3; 471·9–754·8) for 180 μg. Relative to placebo, the VLA15 groups had more frequent reports of solicited local adverse events (study one: 94%, 95% CI 91–96 vs 26%, 19–34; study two: 96%, 93–98 vs 35%, 24–49 after any vaccination) and solicited systemic adverse events (study one: 69%, 65–73 vs 43%, 34–52; study two: 74%, 67–80 vs 51%, 38–64); most were mild or moderate. In study one, unsolicited adverse events were reported by 52% (48–57) of participants in the VLA15 groups and 52% (43–60) of those in the placebo groups; for study two these were 65% (58–71) and 69% (55–80), respectively. Percentages of participants reporting serious unsolicited adverse events (study one: 2%, 1–4; study two: 4%, 2–7) and adverse events of special interest (study one: 1%, 0–2; study two: 1%, 0–3) were low across all groups. A single severe, possibly related unsolicited adverse event was reported (worsening of pre-existing ventricular extrasystoles, which resolved after change of relevant concomitant medication); no related serious adverse events or deaths were reported. VLA15 was safe, well tolerated, and elicited robust antibody responses to all six OspA serotypes. These findings support further clinical development of VLA15 using the 180 μg dose and 0-2-6-month schedule, which was associated with the greatest immune responses. Valneva.