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JCI Insight Apr 2024A systems analysis was conducted to determine the potential molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical... (Randomized Controlled Trial)
Randomized Controlled Trial
A systems analysis was conducted to determine the potential molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical trial of the radiation-attenuated whole-sporozoite PfSPZ vaccine in African infants. Innate immune activation and myeloid signatures at prevaccination baseline correlated with protection from P. falciparum parasitemia in placebo controls. These same signatures were associated with susceptibility to parasitemia among infants who received the highest and most protective PfSPZ vaccine dose. Machine learning identified spliceosome, proteosome, and resting DC signatures as prevaccination features predictive of protection after highest-dose PfSPZ vaccination, whereas baseline circumsporozoite protein-specific (CSP-specific) IgG predicted nonprotection. Prevaccination innate inflammatory and myeloid signatures were associated with higher sporozoite-specific IgG Ab response but undetectable PfSPZ-specific CD8+ T cell responses after vaccination. Consistent with these human data, innate stimulation in vivo conferred protection against infection by sporozoite injection in malaria-naive mice while diminishing the CD8+ T cell response to radiation-attenuated sporozoites. These data suggest a dichotomous role of innate stimulation for malaria protection and induction of protective immunity by whole-sporozoite malaria vaccines. The uncoupling of vaccine-induced protective immunity achieved by Abs from more protective CD8+ T cell responses suggests that PfSPZ vaccine efficacy in malaria-endemic settings may be constrained by opposing antigen presentation pathways.
Topics: Malaria Vaccines; Immunity, Innate; Humans; Animals; Malaria, Falciparum; Plasmodium falciparum; Mice; Vaccines, Attenuated; Sporozoites; CD8-Positive T-Lymphocytes; Infant; Protozoan Proteins; Antibodies, Protozoan; Female; Parasitemia; Immunoglobulin G; Vaccine Efficacy
PubMed: 38687615
DOI: 10.1172/jci.insight.167408 -
Frontiers in Cellular and Infection... 2024
Topics: Antigens, Protozoan; Malaria; Humans; Plasmodium; Animals; Malaria Vaccines
PubMed: 38686096
DOI: 10.3389/fcimb.2024.1408366 -
NPJ Systems Biology and Applications Apr 2024Malaria vaccine development is hampered by extensive antigenic variation and complex life stages of Plasmodium species. Vaccine development has focused on a small number...
Malaria vaccine development is hampered by extensive antigenic variation and complex life stages of Plasmodium species. Vaccine development has focused on a small number of antigens, many of which were identified without utilizing systematic genome-level approaches. In this study, we implement a machine learning-based reverse vaccinology approach to predict potential new malaria vaccine candidate antigens. We assemble and analyze P. falciparum proteomic, structural, functional, immunological, genomic, and transcriptomic data, and use positive-unlabeled learning to predict potential antigens based on the properties of known antigens and remaining proteins. We prioritize candidate antigens based on model performance on reference antigens with different genetic diversity and quantify the protein properties that contribute most to identifying top candidates. Candidate antigens are characterized by gene essentiality, gene ontology, and gene expression in different life stages to inform future vaccine development. This approach provides a framework for identifying and prioritizing candidate vaccine antigens for a broad range of pathogens.
Topics: Plasmodium falciparum; Malaria Vaccines; Antigens, Protozoan; Malaria, Falciparum; Machine Learning; Humans; Proteomics; Vaccine Development; Protozoan Proteins; Computational Biology
PubMed: 38678051
DOI: 10.1038/s41540-024-00365-1 -
Vaccines Apr 2024Two novel vaccines against malaria are proposed as a complementary control tool to prevent and reduce related disease and death in under-five children from moderate to...
Socio-Demographic Factors Influencing Malaria Vaccine Acceptance for Under-Five Children in a Malaria-Endemic Region: A Community-Based Study in the Democratic Republic of Congo.
Two novel vaccines against malaria are proposed as a complementary control tool to prevent and reduce related disease and death in under-five children from moderate to high malaria transmission regions. The Democratic Republic of Congo (DRC) has committed to eradicate malaria by 2030, and significant efforts have been deployed to strengthen control and elimination measures. We aimed to understand factors influencing the malaria vaccine acceptability among the general population in eastern DRC. We conducted a survey among adult Congolese in Bukavu in March 2022. The questionnaire was adapted from the Behavioral and Social Drivers of vaccine uptake (BeSD) framework and was administered online and physically. Multivariate logistic regressions were built, and estimates were represented as adjusted odds ratios (aOR) and corresponding 95% confidence intervals (95%CI). Out of 1612 adults (median age: 39 years, 46.15% female) surveyed, only 7.26% were aware of the malaria vaccine. However, 46.53% expressed willingness to vaccinate themselves, and 52.60% were open to vaccinating their under-five children. Adjusting for confounding factors, non-student/non-healthcare worker professions (aOR = 0.58, 95%CI [0.42-0.78]) and middle-income status (aOR = 1.87, 95%CI [1.25-2.80]) were significantly associated with self-vaccination acceptance. Age played a role in under-five child vaccination acceptability, with 25 to over 64 years showing increased acceptability compared to the 18-24 age group. Additionally, non-student/non-healthcare worker professions (aOR = 1.88, 95%CI [1.37-2.59]), medium education levels (aOR = 2.64, 95%CI [1.29-5.79]), and residing in semi-rural areas (aOR = 1.63, 95%CI [1.27-2.10]) were predictors of under-five child vaccination acceptance. The acceptability of the malaria vaccine for self and for under-five children was suboptimal for effective malaria control in this community in the DRC. Our study constitutes a call for the Expanded Program on Immunization to closely work with various stakeholders to strengthen risk communication for community engagement prior to and during the introduction of this novel and lifesaving tool, malaria vaccination.
PubMed: 38675762
DOI: 10.3390/vaccines12040380 -
Vaccines Mar 2024Efficacy data on two malaria vaccines, RTS,S and R21, targeting circumsporozoite protein (CSP), are encouraging. Efficacy may be improved by induction of additional...
Efficacy data on two malaria vaccines, RTS,S and R21, targeting circumsporozoite protein (CSP), are encouraging. Efficacy may be improved by induction of additional antibodies to neutralizing epitopes outside of the central immunodominant repeat domain of CSP. We designed four rCSP-based vaccines in an effort to improve the diversity of the antibody response. We also evaluated merozoite surface protein 8 (MSP8) as a malaria-specific carrier protein as an alternative to hepatitis B surface antigen. We measured the magnitude, specificity, subclass, avidity, durability, and efficacy of vaccine-induced antibodies in outbred CD1 mice. In comparison to N-terminal- or C-terminal-focused constructs, immunization with near full-length vaccines, rCSP (#1) or the chimeric rCSP/8 (#2), markedly increased the breadth of B cell epitopes recognized covering the N-terminal domain, junctional region, and central repeat. Both rCSP (#1) and rCSP/8 (#2) also elicited a high proportion of antibodies to conformation-dependent epitopes in the C-terminus of CSP. Fusion of CSP to MSP8 shifted the specificity of the T cell response away from CSP toward MSP8 epitopes. Challenge studies with transgenic sporozoites expressing CSP demonstrated high and consistent sterile protection following rCSP/8 (#2) immunization. Of note, antibodies to conformational C-terminal epitopes were not required for protection. These results indicate that inclusion of the N-terminal domain of CSP can drive responses to protective, repeat, and non-repeat B cell epitopes and that MSP8 is an effective carrier for induction of high-titer, durable anti-CSP antibodies.
PubMed: 38675734
DOI: 10.3390/vaccines12040351 -
Vaccines Mar 2024Vaccines are an effective tool to reduce the disease burden from infectious diseases on a population, infrastructural, and individual level. Before vaccines can be... (Review)
Review
Vaccines are an effective tool to reduce the disease burden from infectious diseases on a population, infrastructural, and individual level. Before vaccines can be administered to populations at large, they must go through rigorous testing in the form of clinical trials. While vaccine trials can be used to assess the efficacy of interventions on a local populace as well as target local endemic diseases, most clinical trials are sponsored and conducted by companies in high-income countries (HICs). This can lead to vaccines that are not optimized for low- and middle-income countries (LMICs) and that often neglect to address diseases specific to the local population. This narrative review aims to explore the factors leading to discrepancies in the execution of and access to vaccine trials between HICs and LMICs, thus guiding future efforts in confronting them. This review was written using the literature sourced from the PubMed database and supplemented with articles from Google Scholar along with grey literature. Several themes are highlighted including poorly defined regulatory and ethical guidelines, staff shortages, lack of research infrastructure, and logistical barriers. We discuss how these challenges have affected vaccine development in various capacities through case examples of SARS-CoV-2, poliovirus, and malaria. Many challenges remain in equitable vaccine clinical trial development and implementation. Facilitating the implementation of locally sponsored vaccine clinical trials in LMICs may be one avenue to address these challenges. In doing so, LMICs can become active stakeholders in the health of their citizens by addressing endemic diseases, tailoring vaccine specifications based on local needs, and implementing wide-scale vaccine access and delivery.
PubMed: 38675731
DOI: 10.3390/vaccines12040348 -
Vaccines Mar 2024Cameroon introduced the malaria vaccine in its routine immunization program on 22 January 2024 in the 42 districts out of 200 that are among the most at risk of malaria....
Cameroon introduced the malaria vaccine in its routine immunization program on 22 January 2024 in the 42 districts out of 200 that are among the most at risk of malaria. A cross-sectional analysis of the data on key vaccine events in the introduction roadmap and the vaccine uptake during the first 30 days was conducted. In addition to available gray literature related to the introduction of the malaria vaccine, data on the malaria vaccine uptake by vaccination session, collected through a digital platform, were analyzed. A total of 1893 reports were received from 22 January 2024 to 21 February 2024 from 766 health facilities (84% of overall completeness). Two regions out of ten recorded less than 80% completeness. As of 21 February 2024, 13,811 children had received the first dose of the malaria vaccine, including 7124 girls (51.6%) and 6687 boys (48.4%). In total, 36% of the children were vaccinated through outreach sessions, while 61.5% were vaccinated through sessions in fixed posts. The overall monthly immunization coverage with the first dose was 37%. Early results have shown positive attitudes towards and acceptance of malaria vaccines. Suboptimal completeness of data reporting and a low coverage highlight persistent gaps and challenges in the vaccine rollout.
PubMed: 38675729
DOI: 10.3390/vaccines12040346 -
Scientific Reports Apr 2024Merozoite surface protein 3 of Plasmodium vivax (PvMSP3) contains a repertoire of protein members with unique sequence organization. While the biological functions of...
Merozoite surface protein 3 of Plasmodium vivax (PvMSP3) contains a repertoire of protein members with unique sequence organization. While the biological functions of these proteins await elucidation, PvMSP3 has been suggested to be potential vaccine targets. To date, studies on natural immune responses to this protein family have been confined to two members, PvMSP3α and PvMSP3β. This study analyzed natural IgG antibody responses to PvMSP3γ recombinant proteins derived from two variants: one containing insert blocks (CT1230nF) and the other without insert domain (NR25nF). The former variant was also expressed as two subfragment proteins: one encompassing variable domain I and insert block A (CT1230N) and the other spanning from insert block B to conserved block III (CT1230C). Serum samples were obtained from 246 symptomatic vivax malaria patients in Tak (n = 50) and Ubon Ratchathani (n = 196) Provinces. In total, 176 (71.5%) patients could mount antibodies to at least one recombinant PvMSP3γ antigen. IgG antibodies directed against antigens CT1230nF, CT1230N, CT1230C and NR25nF occurred in 96.6%, 61.4%, 71.6% and 68.2% of samples, respectively, suggesting the widespread occurrence of B-cell epitopes across PvMSP3γ. The rates of seropositivity seemed to correlate with the number of previous malaria episodes. Isotype analysis of anti-PvMSP3γ antibodies has shown predominant cytophilic subclass responses, accounting for 75.4-81.7% for IgG1 and 63.6-77.5% for IgG3. Comparing with previous studies in the same cohort, the numbers of serum samples reactive to antigens derived from P. vivax merozoite surface protein 9 (PvMSP9) and thrombospondin-related anonymous protein (PvTRAP) were higher than those to PvMSP3γ, being 92.7% and 87.0% versus 71.5%, respectively. Three (1.22%) serum samples were nonresponsive to all these malarial proteins. Nevertheless, the relevance of naturally acquired antibodies to PvMSP3γ in host protection requires further studies.
Topics: Plasmodium vivax; Humans; Malaria, Vivax; Protozoan Proteins; Antigens, Protozoan; Antibodies, Protozoan; Immunoglobulin G; Male; Adult; Female; Middle Aged; Adolescent; Young Adult; Recombinant Proteins; Child
PubMed: 38671033
DOI: 10.1038/s41598-024-59153-w -
Frontiers in Immunology 2024Conventionally, immunity in humans has been classified as innate and adaptive, with the concept that only the latter type has an immunological memory/recall response... (Review)
Review
Conventionally, immunity in humans has been classified as innate and adaptive, with the concept that only the latter type has an immunological memory/recall response against specific antigens or pathogens. Recently, a new concept of trained immunity (a.k.a. innate memory response) has emerged. According to this concept, innate immune cells can exhibit enhanced responsiveness to subsequent challenges, after initial stimulation with antigen/pathogen. Thus, trained immunity enables the innate immune cells to respond robustly and non-specifically through exposure or re-exposure to antigens/infections or vaccines, providing enhanced resistance to unrelated pathogens or reduced infection severity. For example, individuals vaccinated with BCG to protect against tuberculosis were also protected from malaria and SARS-CoV-2 infections. Epigenetic modifications such as histone acetylation and metabolic reprogramming (e.g. shift towards glycolysis) and their inter-linked regulations are the key factors underpinning the immune activation of trained cells. The integrated metabolic and epigenetic rewiring generates sufficient metabolic intermediates, which is crucial to meet the energy demand required to produce proinflammatory and antimicrobial responses by the trained cells. These factors also determine the efficacy and durability of trained immunity. Importantly, the signaling pathways and regulatory molecules of trained immunity can be harnessed as potential targets for developing novel intervention strategies, such as better vaccines and immunotherapies against infectious (e.g., sepsis) and non-infectious (e.g., cancer) diseases. However, aberrant inflammation caused by inappropriate onset of trained immunity can lead to severe autoimmune pathological consequences, (e.g., systemic sclerosis and granulomatosis). In this review, we provide an overview of conventional innate and adaptive immunity and summarize various mechanistic factors associated with the onset and regulation of trained immunity, focusing on immunologic, metabolic, and epigenetic changes in myeloid cells. This review underscores the transformative potential of trained immunity in immunology, paving the way for developing novel therapeutic strategies for various infectious and non-infectious diseases that leverage innate immune memory.
Topics: Animals; Humans; Epigenesis, Genetic; Immunity, Innate; Immunologic Memory; Myeloid Cells; Trained Immunity
PubMed: 38665915
DOI: 10.3389/fimmu.2024.1365127 -
Journal of Biomedical Semantics Apr 2024Pathogenic parasites are responsible for multiple diseases, such as malaria and Chagas disease, in humans and livestock. Traditionally, pathogenic parasites have been...
BACKGROUND
Pathogenic parasites are responsible for multiple diseases, such as malaria and Chagas disease, in humans and livestock. Traditionally, pathogenic parasites have been largely an evasive topic for vaccine design, with most successful vaccines only emerging recently. To aid vaccine design, the VIOLIN vaccine knowledgebase has collected vaccines from all sources to serve as a comprehensive vaccine knowledgebase. VIOLIN utilizes the Vaccine Ontology (VO) to standardize the modeling of vaccine data. VO did not model complex life cycles as seen in parasites. With the inclusion of successful parasite vaccines, an update in parasite vaccine modeling was needed.
RESULTS
VIOLIN was expanded to include 258 parasite vaccines against 23 protozoan species, and 607 new parasite vaccine-related terms were added to VO since 2022. The updated VO design for parasite vaccines accounts for parasite life stages and for transmission-blocking vaccines. A total of 356 terms from the Ontology of Parasite Lifecycle (OPL) were imported to VO to help represent the effect of different parasite life stages. A new VO class term, 'transmission-blocking vaccine,' was added to represent vaccines able to block infectious transmission, and one new VO object property, 'blocks transmission of pathogen via vaccine,' was added to link vaccine and pathogen in which the vaccine blocks the transmission of the pathogen. Additionally, our Gene Set Enrichment Analysis (GSEA) of 140 parasite antigens used in the parasitic vaccines identified enriched features. For example, significant patterns, such as signal, plasma membrane, and entry into host, were found in the antigens of the vaccines against two parasite species: Plasmodium falciparum and Toxoplasma gondii. The analysis found 18 out of the 140 parasite antigens involved with the malaria disease process. Moreover, a majority (15 out of 54) of P. falciparum parasite antigens are localized in the cell membrane. T. gondii antigens, in contrast, have a majority (19/24) of their proteins related to signaling pathways. The antigen-enriched patterns align with the life cycle stage patterns identified in our ontological parasite vaccine modeling.
CONCLUSIONS
The updated VO modeling and GSEA analysis capture the influence of the complex parasite life cycles and their associated antigens on vaccine development.
Topics: Biological Ontologies; Animals; Parasites; Protozoan Vaccines; Humans; Vaccines; Models, Biological
PubMed: 38664818
DOI: 10.1186/s13326-024-00307-0