BACKGROUND: Globally, malaria continues to pose a major health challenge, with approximately 247 million cases of the illness and 627,000 deaths reported in 2021. However, the threat is particularly pronounced in sub-Saharan African countries, where pregnant women and children under the age of five face heightened vulnerability to the disease. As a result, the imperative to develop malaria vaccines especially for these vulnerable populations, remains crucial in the pursuit of malaria eradication. However, despite decades of research, effective vaccine development faces technical challenges, including the rapid spread of drug-resistant parasite strains, the complex parasite lifecycle, the development of liver hypnozoites with potential for relapse, and evasion of the host immune system. This review aims to discuss the different malaria vaccine candidates in the pipeline, highlighting different approaches used for adjuvating these candidates, their benefits, and outcomes, and summarizing the progress of these vaccine candidates under development.
METHODS: A comprehensive web-based search for peer-reviewed journal articles published in SCOPUS, MEDLINE (via PubMed), Science Direct, WHO, and Advanced Google Scholar databases was conducted from 1990 to May 2022. Context-specific keywords such as \"Malaria\", \"Malaria Vaccine\", \"Malaria Vaccine Candidates\", \"Vaccine Development\", \"Vaccine Safety\", \"Clinical Trials\", \"mRNA Vaccines\", \"Viral Vector Vaccines\", \"Protein-based Vaccines\", \"Subunit Vaccines\", \"Vaccine Adjuvants\", \"Vaccine-induced Immune Responses\", and \"Immunogenicity\" were emphatically considered. Articles not directly related to malaria vaccine candidates in preclinical and clinical stages of development were excluded.
RESULTS: Various approaches have been studied for malaria vaccine development, targeting different parasite lifecycle stages, including the pre-erythrocytic, erythrocytic, and sexual stages. The RTS, S/AS01 vaccine, the first human parasite vaccine reaching WHO-listed authority maturity level 4, has demonstrated efficacy in preventing clinical malaria in African children. However, progress was slow in introducing other safe, and feasible malaria vaccines through clinical trials . Recent studies highlight the potential effectiveness of combining pre-erythrocytic and blood-stage vaccines, along with the advantages of mRNA vaccines for prophylaxis and treatment, and nonstructural vaccines for large-scale production.
CONCLUSIONS: Malaria vaccine candidates targeting different lifecycle stages of the parasite range from chemoprophylaxis vaccination to cross-species immune protection. The use of a multi-antigen, multi-stage combinational vaccine is therefore essential in the context of global health. This demands careful understanding and critical consideration of the long-term multi-faceted interplay of immune interference, co-dominance, complementary immune response, molecular targets, and adjuvants affecting the overall vaccine-induced immune response. Despite challenges, advancements in clinical trials and vaccination technology offer promising possibilities for novel approaches in malaria vaccine development.

Malaria remains a significant global health challenge, with Plasmodium parasites transmitted by Anopheles mosquitoes causing substantial morbidity and mortality. Despite historical efforts, malaria continues to affect millions worldwide, particularly in tropical regions. This systematic review aimed to assess the acceptability of the RTS, S/AS01 malaria vaccine among diverse populations. A comprehensive search strategy was employed across databases such as Cochrane Library, Embase, Google Scholar, and Medline. Studies were included based on specific criteria, including observational and cross-sectional designs involving adults. Data extraction and analysis were conducted meticulously, encompassing key variables related to vaccine acceptance rates and influencing factors. Analysis of 18 studies involving 18,561 participants revealed an overall malaria vaccine acceptance rate of 87.51%, ranging from 32.26% to 99.30%. Significant variations were observed based on demographics, with Ghana and Nigeria reporting high acceptance rates. Factors influencing acceptance included knowledge levels, past vaccination experiences, community preferences, and engagement in malaria prevention behaviors. Concerns about adverse reactions and regional disparities were noted as potential barriers to acceptance. This review highlights the importance of understanding public perceptions and concerns regarding malaria vaccines to enhance vaccine coverage and uptake. Tailored communication strategies, advocacy efforts, and targeted education interventions are crucial for addressing misconceptions and increasing vaccine acceptance. Policy recommendations should consider demographic and regional factors to ensure effective implementation of malaria vaccination programs, ultimately contributing to global malaria prevention efforts and public health initiatives.

BACKGROUND: In 2021 and 2023, the World Health Organization approved RTS,S/AS01 and R21/Matrix M malaria vaccines, respectively, for routine immunization of children in African countries with moderate to high transmission. These vaccines are made of Plasmodium falciparum circumsporozoite protein (PfCSP), but polymorphisms in the gene raise concerns regarding strain-specific responses and the long-term efficacy of these vaccines. This study assessed the Pfcsp genetic diversity, population structure and signatures of selection among parasites from areas of different malaria transmission intensities in Mainland Tanzania, to generate baseline data before the introduction of the malaria vaccines in the country.
METHODS: The analysis involved 589 whole genome sequences generated by and as part of the MalariaGEN Community Project. The samples were collected between 2013 and January 2015 from five regions of Mainland Tanzania: Morogoro and Tanga (Muheza) (moderate transmission areas), and Kagera (Muleba), Lindi (Nachingwea), and Kigoma (Ujiji) (high transmission areas). Wright\'s inbreeding coefficient (Fws), Wright\'s fixation index (FST), principal component analysis, nucleotide diversity, and Tajima\'s D were used to assess within-host parasite diversity, population structure and natural selection.
RESULTS: Based on Fws (< 0.95), there was high polyclonality (ranging from 69.23% in Nachingwea to 56.9% in Muheza). No population structure was detected in the Pfcsp gene in the five regions (mean FST = 0.0068). The average nucleotide diversity (π), nucleotide differentiation (K) and haplotype diversity (Hd) in the five regions were 4.19, 0.973 and 0.0035, respectively. The C-terminal region of Pfcsp showed high nucleotide diversity at Th2R and Th3R regions. Positive values for the Tajima\'s D were observed in the Th2R and Th3R regions consistent with balancing selection. The Pfcsp C-terminal sequences revealed 50 different haplotypes (H_1 to H_50), with only 2% of sequences matching the 3D7 strain haplotype (H_50). Conversely, with the NF54 strain, the Pfcsp C-terminal sequences revealed 49 different haplotypes (H_1 to H_49), with only 0.4% of the sequences matching the NF54 strain (Hap_49).
CONCLUSIONS: The findings demonstrate high diversity of the Pfcsp gene with limited population differentiation. The Pfcsp gene showed positive Tajima\'s D values, consistent with balancing selection for variants within Th2R and Th3R regions. The study observed differences between the intended haplotypes incorporated into the design of RTS,S and R21 vaccines and those present in natural parasite populations. Therefore, additional research is warranted, incorporating other regions and more recent data to comprehensively assess trends in genetic diversity within this important gene. Such insights will inform the choice of alleles to be included in the future vaccines.

Malaria remains a public health challenge. Since many control strategies have proven ineffective in eradicating this disease, new strategies are required, among which the design of a multivalent vaccine stands out. However, the effectiveness of this strategy has been hindered, among other reasons, by the genetic diversity observed in parasite antigens. In Plasmodium vivax, the Erythrocyte Binding Protein (PvEBP, also known as DBP2) is an alternate ligand to Duffy Binding Protein (DBP); given its structural resemblance to DBP, EBP/DBP2 is proposed as a promising antigen for inclusion in vaccine design. However, the extent of genetic diversity within the locus encoding this protein has not been comprehensively assessed. Thus, this study aimed to characterize the genetic diversity of the locus encoding the P. vivax EBP/DBP2 protein and to determine the evolutionary mechanisms modulating this diversity. Several intrapopulation genetic variation parameters were estimated using 36 gene sequences of PvEBP/DBP2 from Colombian P. vivax clinical isolates and 186 sequences available in databases. The study then evaluated the worldwide genetic structure and the evolutionary forces that may influence the observed patterns of genetic variation. It was found that the PvEBP/DBP2 gene exhibits one of the lowest levels of genetic diversity compared to other vaccine-candidate antigens. Four major haplotypes were shared worldwide. Analysis of the protein\'s 3D structure and epitope prediction identified five regions with potential antigenic properties. The results suggest that the PvEBP/DBP2 protein possesses ideal characteristics to be considered when designing a multivalent effective antimalarial vaccine against P. vivax.

Efficacy data on two malaria vaccines, RTS,S and R21, targeting Plasmodium falciparum circumsporozoite protein (PfCSP), are encouraging. Efficacy may be improved by induction of additional antibodies to neutralizing epitopes outside of the central immunodominant repeat domain of PfCSP. We designed four rPfCSP-based vaccines in an effort to improve the diversity of the antibody response. We also evaluated P. falciparum merozoite surface protein 8 (PfMSP8) 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, rPfCSP (#1) or the chimeric rPfCSP/8 (#2), markedly increased the breadth of B cell epitopes recognized covering the N-terminal domain, junctional region, and central repeat. Both rPfCSP (#1) and rPfCSP/8 (#2) also elicited a high proportion of antibodies to conformation-dependent epitopes in the C-terminus of PfCSP. Fusion of PfCSP to PfMSP8 shifted the specificity of the T cell response away from PfCSP toward PfMSP8 epitopes. Challenge studies with transgenic Plasmodium yoelii sporozoites expressing PfCSP demonstrated high and consistent sterile protection following rPfCSP/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 PfCSP can drive responses to protective, repeat, and non-repeat B cell epitopes and that PfMSP8 is an effective carrier for induction of high-titer, durable anti-PfCSP antibodies.

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.

BACKGROUND: There are giant steps taken in the introduction of the novel malaria vaccine poised towards reducing mortality and morbidity associated with malaria.
OBJECTIVE: This study aimed to determine the knowledge of malaria vaccine and factors militating against willingness to accept the vaccine among mothers presenting in nine hospitals in Enugu metropolis.
METHODS: This was a cross-sectional study carried out among 491 mothers who presented with their children in nine hospitals in Enugu metropolis, South-East Nigeria. A pre-tested and interviewer-administered questionnaire was used in this study.
RESULTS: A majority of the respondents, 72.1% were aware of malaria vaccine. A majority of the respondents, 83.1% were willing to receive malaria vaccine. Similarly, a majority of the mothers, 92.9%, were willing to vaccinate baby with the malaria vaccine, while 81.1% were willing to vaccinate self and baby with the malaria vaccine. The subjects who belong to the low socio-economic class were five times less likely to vaccinate self and baby with malaria vaccine when compared with those who were in the high socio-economic class (AOR = 0.2, 95% CI 0.1-0.5). Mothers who had good knowledge of malaria vaccination were 3.3 times more likely to vaccinate self and baby with malaria vaccine when compared with those who had poor knowledge of malaria vaccination (AOR = 3.3, 95% CI 1-6-6.8).
CONCLUSIONS: Although the study documented a high vaccine acceptance among the mothers, there exists a poor knowledge of the malaria vaccine among them.

UNASSIGNED: Malaria is a leading cause of death among children under 5 years of age in sub-Saharan Africa. The malaria vaccine is an important preventive measure introduced by the World Health Organization to reduce malaria and its associated mortality and morbidity. We aimed to assess the acceptance of the malaria vaccine among next of kin of children under 5 years of age in Gulu City, Northern Uganda.
UNASSIGNED: Between October and December 2023, we conducted a cross-sectional study in Pece-Laroo division, Gulu City, Uganda. Socio-demographic, vaccine profile and health system factors were collected. Multivariable logistic regression was performed using STATA 16 to determine factors associated with acceptance of the malaria vaccine among next of kin of children under 5 years.
UNASSIGNED: A total of 432 participants were enrolled. Of these, the majority were female (72.5%, n = 313) with most aged 30 years and above (51.2%, n = 221). Overall, 430 (99.5%) participants had good knowledge about malaria. The majority (91.4%, n = 395) had good acceptance of the malaria vaccine. Factors independently associated with acceptance of the malaria vaccine were knowing a child who died of malaria [adjusted prevalence ratio (aPR): 1.07, 95% confidence interval (CI): 1.01-1.13, p = 0.022] and preferring the injection route for a malaria vaccine (aPR: 1.1, 95% CI: 1.06-1.22, p < 0.001). All 395 participants with good knowledge of malaria had good acceptance of the malaria vaccine (p = 0.007).
UNASSIGNED: There was a high acceptance of the malaria vaccine in Laroo-Pece division, Gulu, Uganda. However, there is a need for further health education to achieve universal acceptability of the malaria vaccine in preparation for the malaria vaccine implementation program in Uganda.

BACKGROUND: Malaria remains a significant global health burden affecting millions of people, children under 5 years and pregnant women being most vulnerable. In 2019, the World Health Organization (WHO) endorsed the introduction of RTS,S/AS01 malaria vaccine as Phase IV implementation evaluation in three countries: Malawi, Kenya and Ghana. Acceptability and factors influencing vaccination coverage in implementing areas is relatively unknown. In Malawi, only 60% of children were fully immunized with malaria vaccine in Nsanje district in 2021, which is below 80% WHO target. This study aimed at exploring factors influencing uptake of malaria vaccine and identify approaches to increase vaccination.
METHODS: In a cross-sectional study conducted in April-May, 2023, 410 mothers/caregivers with children aged 24-36 months were selected by stratified random sampling and interviewed using a structured questionnaire. Vaccination data was collected from health passports, for those without health passports, data was collected using recall history. Regression analyses were used to test association between independent variables and full uptake of malaria vaccine.
RESULTS: Uptake of malaria vaccine was 90.5% for dose 1, but reduced to 87.6%, 69.5% and 41.2% for dose 2, 3, and 4 respectively. Children of caregivers with secondary or upper education and those who attended antenatal clinic four times or more had increased odds of full uptake of malaria vaccine [OR: 2.43, 95%CI 1.08-6.51 and OR: 1.89, 95%CI 1.18-3.02], respectively. Children who ever suffered side-effects following immunization and those who travelled long distances to reach the vaccination centre had reduced odds of full uptake of malaria vaccine [OR: 0.35, 95%CI 0.06-0.25 and OR: 0.30, 95%CI 0.03-0.39] respectively. Only 17% (n = 65) of mothers/caregivers knew the correct schedule for vaccination and 38.5% (n = 158) knew the correct number of doses a child was to receive.
CONCLUSIONS: Only RTS,S dose 1 and 2 uptake met WHO coverage targets. Mothers/caregivers had low level of information regarding malaria vaccine, especially on numbers of doses to be received and dosing schedule. The primary modifiable factor influencing vaccine uptake was mother/caregiver knowledge about the vaccine. Thus, to increase the uptake Nsanje District Health Directorate should strengthen communities\' education about malaria vaccine. Programmes to strengthen mother/caregiver knowledge should be included in scale-up of the vaccine in Malawi and across sub-Saharan Africa.

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