Introduction

Malaria is prevalent in Africa and poses a significant public health threat with substantial morbidity and mortality [1]. Despite concerted efforts to curb the disease, its persistence can be attributed to socioeconomic inequality, inadequate infrastructure, and the emergence and spread of drug-resistant strains [2]. Control measures such as insecticide-treated nets (ITNs), indoor residual spraying (IRS), and antimalarial drugs are critical, but additional complementary interventions are needed. One of the promising emergent strategies is vaccination, which has been identified as a potentially pivotal measure in the fight against malaria [3].

Developing a malaria vaccine has been an arduous journey, complicated by the inherent complexity of the Plasmodium parasite's life cycle and its diverse antigenic characteristics [4]. Despite these challenges, there has been substantial progress. One particular advancement in this field is the RTS,S/AS01 and the R21/Matrix-M vaccines. These vaccines demonstrated protective efficacy in large-scale clinical trials, and have been recommended by the World Health Organization (WHO) for use in regions with moderate to high P. falciparum transmission, particularly Sub-Saharan Africa [5].

Malaria vaccine clinical trials have provided important knowledge and insights to support the implementation of large-scale vaccination programs. Mokuolo et al. [6] offered several key learnings from these trials, stressing the significance of robust local regulatory and ethical frameworks, effective community engagement and communication, as well as vigilant monitoring for potential disease enhancement or rebound morbidity following temporary interruptions of clinical infections. A critical factor in the success of vaccine implementation is community acceptance. A recent review of the literature suggests high acceptance of the RTS,S malaria vaccine across low- and middle-income countries (LMICs), with an average acceptance rate of 95.3% [7]. However, acceptance rates vary and appear to be impacted by socio-demographic factors and community apprehensions about safety, efficacy, and vaccine awareness [8, 9].

In light of the success of the RTS,S and R21 vaccines, the need for greater global resources for malaria vaccine research and logistics in vaccine implementation cannot be over-emphasized. This study sought to address a current gap in understanding by using an in-depth scoping review to summarize recent empirical evidence on malaria vaccine efficacy, safety, and community perceptions in Africa.

Methods

A scoping review was conducted using the methodological framework outlined by Arksey and O’Malley [10], incorporated quality recomendations [11], and reported using the PRISMA extension for scoping reviews (PRISMA-ScR), as outlined in Appendix 1 [12]. The review protocol was registered at Open Science Framework (OSF) at https://doi.org/https://doi.org/10.17605/OSF.IO/D54YC.

Eligibility criteria

Studies were included if they evaluated the efficacy, safety, or community perception of a malaria vaccine; were published after 2011; were primary/empirical research; conducted in malaria-endemic African countries; and included the general public as participants (e.g., caregivers, parents, children, or adults). Studies published from 2012 were included as a previous review that have explored malaria vaccine research prior to 2012 [13]. Studies were excluded if the participants were outside Africa, were not primary research (reviews, opinions, editorial, commentaries), and if they evaluated immunogenicity without safety or efficacy as a construct.

Information sources

Five primary databases were searched to identify relevant studies in any language: African Journals Online (AJOL), Academic Search Complete, Medline, CINAHL and PsychInfo. The initial search was conducted in January 2023 for articles published from 2012 to 2022. An update search was conducted in June 2023 for articles published from 2022 to June 2023. The search was supplemented with two gray literature sources; AfricArxiv (Achieve for African Research) and OPUS (Open Publication of UTS Scholars) to identify relevant preprints and thesis/dissertations respectively. Additionally, the reference list of articles that met the inclusion criteria was searched manually and forward literature search on Google Scholar was conducted to identify potentially missing articles. Peer review identified three additional studies published after June 2023 and those studies have also been included.

Search

A combination of MeSh and index terms were formulated based on the PICO framework to aid the search process: Population (P)—African communities, Intervention (I)—malaria vaccine, Comparator (C)—none, and Outcome (O)—efficacy, safety, community perception. The EBSCOhost interface (including Academic Search Complete, CINAHL, Medline with full-text and PsychInfo) and the AJOL database were searched. The full search terms are reported in supplemental Table S1. The EBSCOhost interface was expanded to; ‘Apply related words’ and ‘Apply equivalent subjects’.

For gray literature sources, the term 'malaria vaccine' was used to search for preprints papers on AfricArxiv, and any relevant thesis/publication on OPUS.

Selection of studies

Two reviewers (MC and KA) screened potentially eligible studies using the eligibility criteria. First, exact duplicates were removed in EBSCOhost and the search was narrowed to studies published from January 2012. Search results were then exported to Endnote. The duplicate screening was conducted in Endnote. The remaining articles were independently screened by 2 reviewers based on the title and abstract. The full text of all potentially relevant articles was then retrieved and screened independently by MC and UMB in-line with the eligibility criteria.

Data charting process

A data extraction form was developed by three authors (MC, UMB, DS) and included study characteristics such as the citation, year of publication, study design, and study setting. Data related to the study findings varied based on the focus of the study and included the study methods, the type of malaria vaccine assessed, the outcome assessments used, and the major findings. Two reviewers (KA and MAK) independently conducted the data extraction. Differences were resolved through discussion between the two reviewers and a third reviewer (MC).

Critical appraisal of included studies

The quality of the included studies was assessed using Joanna Briggs Institute (JBI) appraisal tools [14] and the Mixed Methods Appraisal Tool (MMAT) [15]. The appraisal was conducted independently by 2 reviewers (KKD and PB) and differences were resolved by a third reviewer (UMB). No study was excluded based on quality appraisal, but the quality of the study was considered when reaching key conclusions. JBI and MMAT do not provide a scoring guideline, therefore, studies were considered ‘above-average quality’ when they met at least half (average) of the quality criteria assessed in the specific study design. Therefore, the terms ‘below-average quality’ or ‘above-average quality’ were used to refer to study quality in the results.

Data items

Efficacy was operationally defined as the vaccine’s estimated effect on all malaria episodes (clinical, severe, or hospitalization). Efficacy was based on Intention-To-Treat (ITT) or According-To-Protocol/Per Protocol (ATP) analyses. Where ITT and ATP analyses were unavailable, efficacy was based on Hazard Ratio (HR), or any other percentage/proportion estimates reported in the studies. Safety was defined based on the presence or absence of Adverse Event (AE) and/or Serious Adverse Event (SAE). Community perception was defined as the different views of communities (general population) about malaria vaccines.

Synthesis of results

Results were synthesized narratively by summarizing the descriptive numerical data followed by a summary of the textual data. The synthesis considered the nature of the research (e.g., design), the type of malaria vaccine (for efficacy and safety), and the quality of the research studies.

Overall efficacy was classified as positive, none/negative or mixed. A result was considered as having positive efficacy if the Confidence Intervals (CI) were within the positive range; mixed efficacy if the CI ranged from negative to positive; and negative efficacy if the CI was within the negative range to zero. Similarly, safety issues were classified based on the number of subjects presenting with at least one SAE, AE, or none. Where the number of affected subjects were not available, a total number of events/incidents was reported. AEs can be solicited, unsolicited or unexpected, and the cumulative number/range was reported based on available information. For community perception, results were synthesized thematically by reporting the overall quantitative results followed by a summary of qualitative results as applicable. Overall percentages/proportions were reported with a range when available. Community perception was further classified based on 3 components: nature of the vaccine (e.g., risks, effect), systems (e.g., mistrust, logistics), or personal reasons (encompassing anything else). N refers to the number of studies reporting the same finding, while n refers to the number of participants reporting a finding in a study in this review.

Results

We initially found 1299 articles (Fig. 1) from the five databases, and 661 underwent title/abstract screening. Two non-English articles, in Danish and French, were evaluated and excluded as they were secondary research. In total, 66 studies (N) were included (61 from the main search, 2 from the updated search, and 3 were identified during peer review) [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78].

Fig. 1
figure 1

PRISMA flow diagram indicating screening process

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Characteristics of included studies

The 66 included studies incorporated 47 Randomized Controlled Trials/clinical trials (71.4%), a case–control study (1.6%), and 17 surveys (27.0%). Sixteen African countries were included, with 64 of the 66 studies (97.0%) being above-average quality (Table S2). Further details are presented in Table S3.

Efficacy of malaria vaccines

Half of the included studies (50%, N = 33) reported vaccine efficacy. At 12 months post-vaccination, the R21 vaccine showed the highest overall efficacy at 77% (N = 1, n = 146), compared to the RTS,S vaccine at 55% (N = 1, n = 273). Both of these studies were of above-average quality (Table S2). R21 further demonstrated an efficacy of 79% among younger children (5–17 months compared to 18–36 month-olds) at 12 months [86] and 80% (N = 1, n = 137) at 12 months after a booster dose [78]. Similarly, RTS,S vaccine showed an efficacy of 56% among children aged 5–17 months at 12 months following vaccination [62]. PfSPZ, though tested on only five individuals, demonstrated an efficacy of 100% at three- or eleven-weeks post-vaccination. This efficacy rose from 20 to 100% at 3 weeks when PfSPZ's dosage regimen was adjusted [39]. The combined use of RTS,S/AS01 with chemoprevention yielded efficacy between 59.6 to 60.1% against clinical malaria and outperformed the vaccine in isolation against severe malaria and related deaths [25]. Other vaccines' efficacies varied significantly (Table 1).

Table 1 Efficacy of malaria vaccine
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Two studies [55, 73] evaluated the long-term (up to 7 years) efficacy of RTS,S on severe and clinical malaria. While the study by Tinto et al. [73] demonstrated a decrease in severe malaria cases over time, there was a rebound against clinical malaria among older children (5–7 years). Oluto et al. [55] identified that vaccine efficacy (clinical malaria) waned over time, including negative efficacy among children with higher exposure to the malaria parasite. Similarly, a negative efficacy of ChAd63/MVA ME-TRAP for an adjusted severe malaria cohort was found [74]. Vaccine effectiveness was maintained when co-administered with malaria chemoprevention [24, 25, 27] or other childhood vaccinations [20].

Safety of malaria vaccines

Thirty-six studies (54.5%, N = 36) investigated the safety of the malaria vaccines, all employing Randomized Controlled Trial design with above-average quality (Table S2). Each study reported one or more AEs (N = 28) or SAEs (N = 23). The reported AEs and SAEs ranged broadly across various vaccines; RTS,S (AEs: 1.6–87.5%, N = 6; SAEs: 2.8–92.2%, N = 12, vaccine-related SAEs: 0.1–1%, N = 7), BK-SE36 (AEs: 5.6–94.4%, N = 1; SAEs: 4.4–5.6%, N = 2), ChAd63/MVA (AEs: 0–100%, N = 6; SAE: 0.4–8.9%, N = 2), FMP2.1/AS02A (SAE: 4%, N = 1), GMZ2 (AEs: 23–100%, N = 2; SAEs: 49–54.5%, N = 2), PfPZ (AEs: 1.6–83.9%, N = 7; SAEs: 1.6%, N = 1), PfAMA1 (AEs: 5–60%, N = 1), PfSPZ-CVac (AEs: 19.4%, N = 1), Pfs25H-EPA (AEs: 100%, N = 1, SAEs: 1.7%, N = 1) and R21 (AEs 0.7–24.6%, N = 1, SAEs: 2.1%, N = 1).

The local and systemic AEs that were typically reported included injection site pain and fever among other symptoms including redness, warmth, discoloration, bruising, erythema, blistering, pruritis, swelling and induration; headache; allergic rash,; drowsiness; irritability; loss of appetite; fatigue; dizziness; abdominal pain; chills; myalgia; diarrhea; nausea and vomiting [18, 20, 30, 31, 37,38,39, 45, 46, 52, 56, 57, 59, 61,62,63,64, 66,67,68,69,70, 72, 74, 75, 77, 86,87,88]. Most AEs subsided within 1–7 days [18, 46, 52, 74, 86].

Commonly reported SAEs were acute gastritis, anemia, bronchitis, cerebral malaria, severe malaria, dehydration, convulsion, febrile convulsion, gastroenteritis, seizures, meningitis, paralytic ileus, pyrexia, pneumonia, respiratory distress, and death. However, most SAEs were.

deemed unrelated to the vaccination (Table 2) and were associated with malaria infection [29, 87]. Only 0.1–1% and 4.3% of SAEs were possibly linked to vaccines, mainly febrile convulsion/seizures, associated with RTS,S vaccine [25, 35, 58, 61,62,63, 66] and R21 vaccine [86] respectively. Malaria vaccine safety when co-administered with other routine childhood immunization was identified [20, 46].

Table 2 Safety of malaria vaccine
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Community perception of malaria vaccine

Seventeen studies (27.0%, N = 17) assessed community perception of malaria vaccines, with a mix of below and above-average quality studies (Table S2). The overall perception of participants has been summarized in addition to five key issues that emerged from the studies: acceptance, availability, knowledge/awareness, logistics, and misconceptions about the vaccines (Table 3).

Table 3 Community perception of malaria vaccine
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Overall perception

Ten of the seventeen studies that assessed community perception (58.8%) reported their overall perception of malaria vaccines (Table 3), and were of below and above-average quality (Table S2). Community members agreed that it was essential to have a malaria vaccine [44] and that the vaccine is necessary for malaria control [33]. More than three-quarters of participants from each study reported overall positive perceptions [26, 36, 47, 48], identified malaria as a risk for their children [36], and identified that the vaccine will keep children healthy [23, 44] even though the efficacy of the vaccine may not be 100% [47]. A significant positive association between positive perception and intent to comply with vaccination was reported [26]. More than half of respondents recommend the vaccine to others [48] and were part of the National Program on Immunisation [33, 48]. The majority of participants preferred vaccines to malaria drugs/vector control [28, 34]. There was a mixed reaction between oral and injectable vaccines in Ghana [44], while in Tanzania, participants were open to all modes of administration [60]. The limited side effects experienced by participants in the RTS,S/AS01 vaccine trial reinforced participants’ beliefs about its safety in Nigeria [28].

Acceptance

Of the studies examined, 88.2%, (N = 15) reported acceptance of malaria vaccines (Table 3), and most studies were above-average quality (Table S2). Acceptance rates varied from 32.3% in Ethiopia [21] to 96% in Sierra Leone [43]. Acceptance increased to 98.9% in malaria-endemic areas in Kenya [53]. Key drivers for acceptance were the high risk of malaria in children [17, 41], the desire for self-protection and prevention [41, 43], and incentives such as free consultations and medication [17].

The impact of religion on vaccine acceptance was inconsistent [36, 47, 71]. Some findings showed that Christian mothers were more likely to accept the vaccine than Muslim mothers in Tanzania [47], while in Ghana [36] and Nigeria [71], Christian mothers showed lower odds of accepting the vaccine. Free provision significantly increased vaccine acceptance [41, 43], while increased costs decreased acceptance [41, 76].

Fear of adverse events and unsuccessful intravenous vaccination attempts were linked to vaccine refusal [23, 43, 44, 71]. Factors such as marital status, region, knowledge of vaccine, tribe, education level, prior vaccination experience, satisfaction with healthcare services, and parent age influenced willingness to accept vaccination [21, 33, 41, 47, 53, 76].

Availability

Two of the studies (11.8%) reported concerns associated with the availability of malaria vaccines (Table 3). The need to provide malaria vaccine to adults in addition to children was reported in Mozambique [23]. The importance of an adequate supply chain to promote availability was documented from a key informant interview in Sierra Leone [43].

Knowledge/awareness

Nine of the studies (52.9%) reported knowledge of participants about malaria vaccines (Table 3). The percentage of participants having awareness of malaria vaccines ranged from 11% in Tanzania [60] to 60% in Nigeria [33]. Additionally, there was a low willingness to learn more about the vaccine in Mozambique [23]. Confusion and delays related to trial designs were seen to discourage participation in a malaria vaccine trial in Kenya [17]. The use of mass media, particularly Television, radio, and phones were identified as good sources of information by participants [23, 26, 44]. Information vans, health talks, and information from trusted community members [44] or health professionals were important but were rated equally with internet sources [71]. Awareness of vaccines was higher in older people when compared to younger people [36] and in mothers of Christian children compared to the Islamic faith [36]. There was evidence of confusion about malaria vaccines and other childhood vaccines in Ghana [44].

Logistics

Four of the studies (23.5%) reported findings related to the logistics associated with malaria vaccine enrolments (Table 3). The need for community outreach by community health workers, including malaria vaccine campaigns alongside existing vector control programs to encourage participation was reported [43]. Negative attitudes of health staff were reported and shown to discourage participation in malaria vaccine trials [17]. Similarly, the system’s capacity to train staff for intravenous administration was noted as important [17].

Parents’ willingness to pay for the malaria vaccine was reported as a barrier [26, 28, 43]. Although, affordability was noted as a concern in a number of studies [26, 28, 41, 76], some participants suggested that the provision of malaria vaccines was the sole responsibility of the government [28].

Misconceptions

Four of the studies (23.5%) reported misconceptions about potential malaria vaccines. Rumors of blood ‘theft and selling’ were linked to early withdrawal from malaria vaccine trials in Kenya [17]. Similarly, a widespread belief that newborns should have minimum exposure to adults and that the presence of a vaccine scar signifies a nurse had sexual intercourse with the child hindered vaccination programs in Mozambique [23]. The ideology that vaccines are harmful and can cause sickness was reported as a fear preventing vaccinations [23, 43]. Furthermore, rumors of vaccines causing infertility and system mistrust were cited as critical reasons for hesitancy to receive the malaria vaccine [43, 71].

Discussion

This paper summarizes recent evidence on the efficacy, safety, and perception of malaria vaccines in Africa. All vaccines studied showed some degree of protection in terms of reducing the risk of contracting malaria and/or eliciting an antibody response. Overall efficacy varied; the highest overall efficacy (77%) was observed with R21 [30], which increased to 80% with a booster dose [78]. Increasing the dosage regimen of PfSPZ may also lead to an increase in efficacy from 20 to 100% [39]. Vaccination efficacy decreases over time with the highest efficacy expected up to one year after the last dose [55, 73]. R21 showed increased efficacy between six months (74%) to one year (77%) after vaccination [30]. RTS,S, was the most-studied vaccine. RTS,S showed good efficacy (55%) up to one year after vaccination, but this decreased over time [24, 55], with efficacy around zero after four years and negative in areas with high malaria exposure at five years of follow-up [55]. RTS,S was found to prevent clinical malaria cases in infants and children over three to four years and was further enhanced by administering a booster dose [63]. Emerging evidence suggests that the efficacy of vaccines like RTS,S increases when combined with seasonal malaria chemoprophylaxis [63]. The concomitant use of malaria vaccines with other control measures is therefore seen to be an important mitigation strategy in areas of high transmission.

Adverse events were reported in all studies. The most common adverse events were injection site pain and fever. Most adverse events were reported to subside within one week of appearance. Serious adverse events were rare (0.1–1%). Serious adverse events can occur following vaccinations, with about 1% of participants developing events such as febrile convulsions following malaria vaccines [23, 25, 35, 58, 61,62,63]. This was particularly observed in children within 2–3 days of receiving the RTS,S vaccine [35]. It is therefore possible that adverse events may arise following vaccination; however, further research is required.

Fear of unknown side effects associated with vaccines, especially newly developed ones, are often associated with low levels of acceptance [79]. Willingness to accept the malaria vaccine ranges from 32.3% in Ethiopia to 96% in Sierra Leone [21, 26]. However, a number of factors are likely to affect the use of malaria vaccines in many African communities, including inadequate knowledge, misconceptions, availability of vaccines, and logistics.

This review has identified that knowledge about malaria vaccines is not widespread throughout Africa. Vaccine awareness was slightly lower than vaccine acceptance; however, people may have been reluctant to accept the newly developed malaria vaccines because of generalized vaccine hesitancy in some parts of Africa. Vaccine hesitancy has been reported in the literature as a consequence of misinformation about vaccine origin, efficacy, and safety, and psychological factors such as anxiety [80, 81]. In addition to these factors, political influences, religious beliefs, and low perception of risk combine to contribute to vaccination rates in sub-Saharan Africa [79, 80]. The extent of vaccination hesitancy may vary according to people's commitment to health protection and risk culture and their trust in conventional medicine and public health authorities. Evidence from the literature suggests that the lack of willingness to vaccinate may be due to a lack of knowledge, indifference, and irregular vaccination behavior [82]. Public education campaigns on vaccination programs are therefore important to support behavior change.

The findings of this review could assist public health experts and policymakers in Africa to develop and implement strategies to address the low acceptance and use of malaria vaccines. Wide-spread adoption of malaria vaccines is possible if awareness campaigns provide adequate factual explanations to counter rumors and mis-information [6, 83]. Increasing local vaccine production within the African continent may further promote the use of malaria vaccines. Local production may help reduce mistrust through technology transfer. To raise awareness about vaccination, it is important to take a context-specific approach involving community and religious leaders [84, 85]. The provision of credible information to communities by trusted sources is an important strategy to promote vaccination uptake.

There are some limitations to this review. Due to recent advances in malaria vaccines and the recommendations of Schwartz et al. [9] only studies published since 2012 were included. The scope of this review summarizes the existing evidence and highlights areas for more in-depth analysis in the future.

Conclusion

Different types of malaria vaccines have different efficacy levels, and combining seasonal malaria prophylaxis with a malaria vaccine might increase effectiveness. A variable degree of protection from malaria infection is provided by malaria vaccines with severe adverse events only occurring rarely. Many African communities have a high perception of malaria vaccines, but knowledge of the vaccine is relatively low. Further research and community involvement are needed to respectively improve vaccine efficacy and ensure successful widespread use in African communities.