https://orcid.org/0009-0001-3810-9074
Figures
Abstract
Objective
For more than a century, developing novel and effective vaccines against malaria and Tuberculosis (TB) infections has been a challenge. This review sought to investigate the reasons for the slow progress of malaria and TB vaccine candidates in sub-Saharan African clinical trials.
Methods
The systematic review protocol was registered on PROSPERO on July 26, 2023 (CRD42023445166). The research articles related to the immunogenicity, efficacy, or safety of malaria or TB vaccines that were published between January 1, 2012, and August 31, 2023, were searched on three databases: Web of Science (WoS), PubMed, and ClinicalTrials.gov.
Results
A total of 2342 articles were obtained, 50 of which met the inclusion criteria. 28 (56%) articles reported on malaria vaccine attributes, while 22 (44%) articles reported on TB vaccines. In both cases, the major challenges in sub-Saharan African clinical trials were immunogenicity and efficacy, rather than safety.
Citation: Hamisi MA, Asri NAM, Yassim ASM, Suppian R (2025) A systematic review on malaria and Tuberculosis (TB) vaccine challenges in sub-Saharan African clinical trials. PLoS ONE 20(1): e0317233. https://doi.org/10.1371/journal.pone.0317233
Editor: Luzia H. Carvalho, Fundação Oswaldo Cruz Centro de Pesquisas René Rachou: Fundacao Oswaldo Cruz Instituto Rene Rachou, BRAZIL
Received: April 2, 2024; Accepted: December 25, 2024; Published: January 24, 2025
Copyright: © 2025 Hamisi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the article and its supporting information files.
Funding: This study was supported by the Strategic Research Fund (SRF) under the Ministry of Science, Technology, and Innovation (MOSTI), Malaysia (Grant number: 305.PPSK.614503).
Competing interests: The authors declare that there are no financial and non-financial conflicts of interests.
1. Introduction
Malaria and Tuberculosis (TB) are among the top ten causes of death in low- and middle-income countries, the majority of which are sub-Saharan countries [1]. Malaria is a plasmodium-borne infection that is spread by female Anopheles mosquitoes [2]. Plasmodium falciparum species are the dominant cause of human malaria [3]. In 2021, 619,000 deaths were caused by malaria worldwide, 95% of which occurred in sub-Saharan Africa [4]. The favourable environment for P. falciparum species [5] and healthcare systems for instance, poor hospitals, treatments, and poor drug stewardships contribute to this prevalence [6]. In contrast, human TB is an airborne disease caused by Mycobacterium tuberculosis (Mtb). TB spreads through respiratory system encounters active Mtb-containing air droplets [7]. TB infections were the leading cause of human deaths prior to COVID-19 [7]. Human TB causes 10.6 million cases and 1.6 deaths, 90% of which occurred in sub-Saharan Africa [7].
Currently, chemical drugs, as well as vaccines, are used for the control of malaria [8] and TB [7]. However, the development of resistant strains has made drug use inefficient and costly. Vaccines are the most effective options for these diseases, and they can help to prevent the spread of resistance. Despite not being fully certified, the malaria RTS, S/AS01, was recommended for the pilot vaccination of 5- to 17-month-old children living in high-endemic areas [9]. Unlike malaria, BCG is the only certified TB vaccine. Both RTS, S/AS01 [10], and BCG [11] share similar limitations: they provide protection but limited to young age groups. Different groups of malaria vaccine candidates have been tested in sub-Saharan African clinical trials. Some of these include subunit vaccines [12–16], viral-like particle vaccines [17–20], and whole attenuated vaccines [21–23]. Like malaria vaccine candidates, TB vaccine candidates include subunit vaccines [24–33], inactivated vaccines [34], and whole attenuated vaccines [11,35,36]. Nevertheless, the progress of malaria and TB vaccine development in sub-Saharan Africa has been arduous and frequently regarded as sluggish. The aim of this study was to elucidate the barriers that hinder the rapid advancement of efficacious malaria and TB vaccines, with a specific emphasis on immunogenicity, effectiveness, and safety in sub-Saharan Africa.
2. Methodology
The review protocol was registered on PROSPERO (CRD42023445166). In brief, this review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [37]. The keywords and review questions were formulated based on PICO: Sub-Saharan Africans (population), malaria and TB vaccine candidates (intervention), non-vaccinated, placebo, or any control setting (control), immunogenicity, efficacy, and safety (outcomes). The review question was “What are the challenges that hinder the rapid development of malaria and TB vaccines in sub-Saharan African clinical trials?”.
2.1 Article identification
The review began with the identification of keywords and their respective synonyms by the first and second authors (HM and NA, respectively). The keywords and synonyms used to formulate the search strategy were based on the PICO formulation, which includes Sub-Saharan Africans (population), malaria and TB vaccine candidates (intervention), non-vaccinated, placebo, or any control setting (control), immunogenicity, efficacy, and safety (outcomes) as summarized in Table 1. The search was performed between the 1st of August 2023 and the 31st of August 2023 on three databases, Web of Science, PubMed, and ClinicalTrials.gov, with some refinement to meet the inclusion criteria.
2.2 Article screening and eligibility
Two authors, HM, and NA screened the articles obtained independently. Malaria or TB vaccine candidate studies that reported immunogenicity, efficacy, safety, or a combination, involved a sub-Saharan population, were randomised clinical trials, published in English between January 1, 2012, and August 31, 2023, were included. Studies not meeting these criteria were excluded. The discrepancies occurred were resolved by involving the third and fourth authors (AS and RS). The duplicate and irrelevant articles were removed using Mendeley software (2.107.0, 2023).
2.3 Assessment of study quality
The risk of bias in the eligible studies was analysed by the first author (HM) using the Cochrane risk of bias tool (RoB 2) [37]. The other three co-authors confirmed the findings (NA, AS, and RS). Each randomised controlled trial was rated as “high,” “low,” or “some concerns” for bias in five domains: randomization process, deviation from intervention, missing outcome data, measurement of outcomes, and selection of reported outcomes.
2.4 Data extraction and synthesis
Data were extracted and compiled from all eligible articles on the standard data collection table. The first author’s surname, publication year, population, region (country), clinical trial phase, intervention, control, and number of doses were retrieved for the articles. We then performed a narrative synthesis of the literature using our outcome keywords immunogenicity, efficacy, and safety.
3. Results
3.1 Study selection
The search yielded 2342 publications S1 Table. 1791 (76.5%) articles were from Web of Sciences, 497 (21.2%) from PubMed, and 54 (2.3%) from ClincalTrials.gov. The ClincalTrials.gov database contained 54 articles from 11 studies (55%) of 20 search projects. To minimise bias, nine (45%) studies had no publications and were excluded from this review. The 2342 published studies were reduced to 92 (3.9%) duplicates and 2179 (93%) irrelevant. 17 (23.9%) studies were removed after screening titles and abstracts of 71 (3.0%). After full-text screening, 4 (7.4%) of 54 (76.1%) studies were removed. Fifty studies were eligible for review; 28 (56%) were malaria vaccines and 22 (44%) were TB vaccines. The flowchart of this study was summarized in Fig 1 and Table 2.
3.2 Quality assessment
The overall quality of all 50 eligible studies was good. 47 (94%) studies received “low risk” overall status for causing bias, 3 (6%) studies received “some concerns” status [13,18,47], and there were no articles with “high risk” overall status Fig 2.
(A) Dot plot showing quality of each article. (B) Overall report summary of all included articles.
3.3 Immunogenicity
In general, this review revealed that most malaria and TB vaccine candidates were immunogenic. However, the immune responses varied in terms of either magnitude, type of immune responses, or durability. For example, most malaria vaccine candidates had seven times the immunogenicity of humoral immune cells compared to CD4+ and CD8+ cells, which appeared only two times (7.14%). Conversely, TB vaccine candidates were more immunogenic to CD4+ T cells (72.7%) than CD8+ T cells (45.50%). However, in most cases, these immune responses were induced simultaneously. For example, CD4+ and CD8+ cells only [24,28,34,36,42,44,46], followed by CD4+, CD8+ cells, and antibodies only [27,29,30,40], and CD4+ cells and antibodies only [31,41]. Furthermore, few vaccine candidates induced only CD4+ cells [11,25,39], and none induced CD8+ cells only. Despite this diversity in both cases, challenges such as insignificant level of immune responses [40], lack of protection efficacy correlation [56], and poor durability [26,35,55] were observed. These findings demonstrate the immunogenic diversity of both malaria and TB vaccine candidates and the need for tailored vaccine design and evaluation.
3.4 Efficacy
Like in immunogenicity, efficacy differed based on the respective study. For instance, this review revealed that out of 28 malaria-related studies, only the R21/MM vaccine candidate (3.8%) had the highest vaccine efficacy (VE) of 77% [55], followed by RTS, S/AS01, 50.3% VE [61], 46% VE [48], 45% VE [50], 28% VE [20], 27% VE [48], 12% VE [51], and 18% VE [20], as well as 8% VE [58] in adults. Other malaria-related studies reported vaccine efficacy qualitatively [22,62,63]. On the other hand, the M72/AS01E TB vaccine candidate showed the highest vaccine efficacy, 54.0% VE [32], followed by 49.7% VE [38], 45.4% VE, and 30.5% VE [43]. In addition to the insignificant efficacy shown in both cases, other challenges such as lack of protection correlation [24,45,58] and the tendency of waning over time [15,50,57] were observed. These observations demonstrate that efficacy is not durable and thus requires continued research and development.
3.5 Safety
This review revealed that both malaria and TB vaccine candidates had no safety issues that resulted in the termination of the studies. However, adverse effects (AEs) like localized injection site swelling (9, 32.14%) and pains (8, 28.6%), whereas the systemic AEs included headache (12, 42.9%), myalgia, fever, and nausea (8, 28.6%) were reported in different malaria studies. Also in some cases, severe adverse effects (SAEs) such as malaria (8, 28.6%), meningitis, and febrile convulsion (7, 25%) were observed. Unlike in malaria vaccine candidates, injection site pains (5, 22.7%) and systemic abdominal pains (11, 50.0%) were the common AEs associated with TB vaccine candidates. Also, common SAE associated with TB vaccine candidates was found to be gastroenteritis (3, 13.6%) was the only common SAE. These results demonstrate that vaccine candidates’ safety issues are not the big challenges towards achieving the potent vaccines in sub-Saharan clinical trials.
4. Discussion
The systematic review of 50 studies highlights immunogenicity and efficacy as major challenges in sub-Saharan African malaria and TB vaccine clinical trials. However, safety should not be ignored in new vaccine development against these diseases since it is influenced by factors like dose [23,33,51,64], vaccine type [43], age group [54], and health status [27]. It is critical to evaluate the factors that contribute to variations in immunogenicity and efficacy during the development of vaccines against malaria and TB, especially in clinical trial settings. Complexities on vaccine candidates’ immunogenicity and efficacy arise because of factors such as population attributes, nature of vaccine candidates, vaccination strategy, and pathogen genetic diversity. Due to these complexities, drawing general conclusions on a particular vaccine candidate becomes hard, hence resulting in slow progress in sub-Saharan clinical trials.
In general, we discovered that population characteristics such as naturally acquired immunity, health status and socioeconomic factors affect greatly the drawing of general conclusions on vaccine candidate performance in clinical trials. Natural acquired immunity was found to influence the vaccine candidates’ performance antagonistically. For example, Kimani et al. showed that vaccine candidate performance was better in naïve adults than semi-immune adults [13]. Non-cytophilic and naturally acquired antibodies correlated with an increase in malaria infections and a reduction in the immunogenicity and efficacy of vaccine candidates [60]. This may explain why malaria is more common in older people [65]. Ideally, older age groups might have more non-cytophilic and naturally acquired antibodies than younger age groups due to the longer exposure time. Contrary to this ideology, many studies show that vaccine candidates’ performance is better in older ages than young ages [15,20,54,57] despite being variable among vaccinees of similar age groups [15,20,50]. These observations agree with those of the study conducted in Brazil that observed that naturally acquired antibodies were protective against parasites [66].
This review also observed that the health and socioeconomic status of the vaccinees played important roles in the vaccine candidates’ immunogenicity and efficacy. In general, HIV infections affected negatively the performance of both malaria and TB vaccine candidates regardless of the age group [24,27,49]. These findings are consistent with a previous study in which the vaccine candidate’s performance was low in comparison to the healthy group [19]. The reduced immune responses in HIV-infected participants might be due to the ability of HIV to cause immune response dysfunction. These differences complicate the drawing of general conclusions for a particular group. However, the effects of the coinfecting infection can be reduced by its respective chemotherapy [19,63]. Also, the socioeconomic status (SES) of the participating population played an important role in the vaccine candidates’ performance. For example, Gyaase et al. discovered that the decrease in vaccine efficacy was associated with a decrease in SES [62]. Since, poor SES may act as the precursor of higher malaria transmission intensity [62]. Studies show that higher infection transmission intensity reduces vaccine candidate performance [50] due to the rebound effect [10]. This condition of heightening naturally acquired immunity increases while vaccine-induced protection diminishes. The decrease in vaccine efficacy due to infection exposure was also reported by Olotu et al. [67]. This is contradictory to the studies that showed better vaccine candidate performance in older age groups than in young groups. Infection transmission intensity can also be facilitated by ecological factors such as vegetation [52] and wet season [57].
The vaccination strategy, such as the number of doses, vaccination timepoints, and routes of administration, influences significantly the immunogenicity and effectiveness of vaccine candidates. This review observed that BCG vaccinations in infants at different time points resulted in mixed observations. For example, vaccination at birth results in more distinct cellular immune responses than vaccination at 6 weeks [42] or vaccination at 14 weeks [35]. However, these differences were not observed when infants were vaccinated at birth and at 8 weeks after delivery [39]. Also, vaccine candidates may have different attributes due to the number of doses and route of administration. This review observed that most studies included employed multiple doses to keep up immunogenicity and efficacy steady [10,17,28,31,52,55]. In some cases, natural acquired immunity played a priming role [33]. However, other studies showed that number of doses had no effects on immunogenicity or efficacy [40,41,57]. The multiple doses strategy is worthy of recovering the diminishing protection. Despite this, the strategy may be an embargo to the accessibility of vaccines in low- or middle-income countries (LMICs), such as Sub-Saharan Africa, due to poverty.
This review revealed that the inferior performance of the vaccine candidates was associated with either poor immunogenicity or a narrow range of immune response inductions [30,43]. The low or missing of some immune responses may result in poor protection since immunogenicity is often related to the vaccine efficacy. Possibility, the nature, and formulations of the vaccine candidates were responsible. For example, CSP-based malaria vaccine candidates induced more anti-NANP antibodies than anti-C-terminal antibodies [53,55]. This might be because the NANP region is more conserved than the C-terminus, which can be reduced by removing antigen parts responsible for the induction of non-neutralizing antibodies [68]. However, the immune response distribution induced by Ad.35.CS.01 was influenced by CSP and Ad35 antigens [12]. Anti-CSP and anti-HB-specific IgG as well as IgM antibodies defined the efficacy of the RTS and S/AS01 vaccine candidates [60]. Despite being different from one endemic region to another, the failure to induce anti-HB antibodies decreased the vaccine candidate efficacy [17]. Also, the lack of PfSPZ vaccine candidate efficacy at 6 months postimmunization was associated with the lack of induction of cellular T immune responses [51]. This shows that multiple immune responses are needed for robust protection. Also, adjuvant formulations contributed to complexity in drawing conclusions. For example, the comparative studies that employed pairs of RTS, S/AS01 and RTS, S/AS02A [50], GMZ2/alum [15] and GMZ2/Alhydrogel/liposomes [16], and AMA1-DiCo GLA-SE and AMA1-DiCo Alhydrogel [14] resulted in different vaccine performance. However, similar differences were not observed during the GMZ2 Alhydorgel and GMZ2 CFA01 studies [16]. This underscores the need for pre-evaluation of adjuvants for conjugation.
Furthermore, pathogen genetic diversity is common in sub-Saharan Africa. This increases allelic mismatches between vaccine antigens and natural pathogens, which may affect vaccine efficacy [61]. The vaccine candidate might be immunogenic, but the immune responses would be non-specific to the natural parasite antigens. Surprisingly, studies show that allelic mismatches are more than 90% in Sub-Saharan Africa. This might be another major reason for the immunogenic vaccine candidates that failed to protect the vaccinees from the infection challenges.
Regardless of the disease, all vaccination studies included in this review employed only parenteral administration routes. This may have limited the induction of immune responses as well as protection efficacy. The mimicking of infection natural route plays an important role in effective protection against such infection. For example, the mucosal MVA85A immunization against TB in the United Kingdom induced strong immunogenicity, which was not observed after being administered through parenteral routes in South Africa [69]. This might be because of the ability of mucosal routes to induce speedy localized and systemic immune responses. Even though the malaria infections do not occur through mucosal surfaces, mucosal immunization against malaria protected the mice [70]. In addition to the immunological point of view, mucosal routes may be more economical than parenteral routes because they do not require trained personnel and needles and hence are appropriate in resource-limited sub-Saharan Africa.
The review acknowledges the missing of some publications as limitations of the review processes. These publications might have increased the scope of our results. However, the possibility to change the conclusion seems to be negligible due to being significantly small. Also, the absence of consistency in observations across studies has been a big challenge. This underscores the need for a comprehensive evaluation of the roles played by administration routes, vaccination timing, dosage, and the existence of confounding variables such as infection exposure, natural acquired immunity, age groups, infection transmission intensity, environments, as well as socioeconomic factors.
Despite this, WHO has recommended two malaria vaccines such as RTS, S/AS01E and R21/Matrix-M for vaccination of young children in sub-Saharan Africa after meeting some of the important WHO preferred product characteristics (PPCs) for malaria vaccines. Such characteristics include being safe, protective throughout the malaria season with the ability to reduce clinical malaria by 90%, and strongly immunogenic [71]. Unlike malaria, none of the novel TB vaccine candidates has been recommended for human vaccination. However, vaccine candidates like M72/AS01E have been shown to meet the PPCs for TB vaccines. In addition to the other two malaria PPCs, a novel TB vaccine must have at least 50% protection efficacy [72]. The vaccine candidate clinical trials show variability in immunogenicity and efficacy, as well as waning tendency. The ineffectiveness of specific vaccine candidates can be attributed to their inadequate immunogenicity, which means they elicit a restricted spectrum of immune responses. This underscores the criticality of refining the process of vaccine development and assessment. The review emphasizes the importance of comprehensive immune responses, which comprise humoral and cellular components, to provide strong protection against malaria and TB. Further investigation is warranted to tackle the identified obstacles, including but not limited to optimizing dosing regimens, enhancing the immunogenicity of vaccines that is specific to certain endemic regions and population groups, and investigating alternative delivery routes such as mucosal administration to enhance vaccine efficacy, particularly in settings with limited resources like sub-Saharan Africa.
5. Conclusion
This review revealed that immunogenicity and efficacy are the major challenges for both malaria and TB vaccine candidates. The challenges were orchestrated by population characteristics, vaccination strategies, and pathogen genetic diversity. This review suggests that the continued neglect of these factors could lengthen the journey toward robust vaccines, that mucosal routes may improve vaccine candidate performance, and that the development of endemic region-based vaccines is worthwhile.
Supporting information
S1 Table. List of all articles identified and reasons for exclusion of some articles.
https://doi.org/10.1371/journal.pone.0317233.s001
(DOCM)
S2 Table. Eligible studies, extracted data, extractors, period of data extraction, and reasons for inclusion.
https://doi.org/10.1371/journal.pone.0317233.s002
(DOCX)
References
- 1.
https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death. The top 10 causes of death.
- 2. Vinicius de Araújo R, Silva Santos S, Missfeldt Sanches L, Giarolla J, El Seoud O, Igne Ferreira E. Malaria and tuberculosis as diseases of neglected populations: state of the art in chemotherapy and advances in the search for new drugs. Mem Inst Oswaldo Cruz. 2020.
- 3.
Ashley EA, Pyae Phyo A, Woodrow CJ. Malaria. Vol. 391, The Lancet. Lancet Publishing Group; 2018. p. 1608–21.
- 4.
WHO. World malaria report 2022 [Internet]. 2022. Available from: https://www.who.int/teams/global-malaria-programme
- 5. Rossati A, Bargiacchi O, Kroumova V, Zaramella M, Caputo A, Garavelli PL. Climate, environment and transmission of malaria. Infezioni in Medicina. 2016;24(2):93–104. pmid:27367318
- 6.
CDC. CDC—Malaria—Malaria Worldwide—Impact of Malaria. 2021.
- 7.
WHO. Global Tuberculosis report 2022 [Internet]. 2022. Available from: http://apps.who.int/bookorders.
- 8.
WHO. Artemisinin resistance and artemisinin-based combination therapy efficacy. 2018.
- 9.
WHO. World malaria report 2016. 2016. 148 p.
- 10. Bell GJ, Goel V, Essone P, Dosoo D, Adu B, Mensah BA, et al. Malaria Transmission Intensity Likely Modifies RTS, S/AS01 Efficacy Due to a Rebound Effect in Ghana, Malawi, and Gabon. Journal of Infectious Diseases. 2022;226(9):1646–56. pmid:35899811
- 11. Tameris M, Mearns H, Penn-Nicholson A, Gregg Y, Bilek N, Mabwe S, et al. Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial. Lancet Respir Med. 2019 Oct;7(9):757–70. pmid:31416768
- 12. Ouédraogo A, Tiono AB, Kargougou D, Yaro JB, Ouédraogo E, Kaboré Y, et al. A phase 1b randomized, controlled, double-blinded dosage-escalation trial to evaluate the safety, reactogenicity and immunogenicity of an adenovirus type 35 based circumsporozoite malaria vaccine in burkinabe healthy adults 18 to 45 years of age. PLoS One. 2013 Oct;8(11). pmid:24244339
- 13. Kimani D, Jagne YJ, Cox M, Kimani E, Bliss CM, Gitau E, et al. Translating the Immunogenicity of Prime-boost Immunization with ChAd63 and MVA ME-TRAP From Malaria Naive to Malaria-endemic Populations. MOLECULAR THERAPY. 2014;22(11):1992–2003. pmid:24930599
- 14. Sirima SB, Durier C, Kara L, Houard S, Gansane A, Loulergue P, et al. Safety and immunogenicity of a recombinant Plasmodium falciparum AMA1-DiCo malaria vaccine adjuvanted with GLA-SE or Alhydrogel® in European and African adults: A phase 1a/1b, randomized, double-blind multi-centre trial. Vaccine. 2017 Oct;35(45):6218–27.
- 15. Dassah S, Adu B, Sirima SB, Mordmüller B, Ngoa UA, Atuguba F, et al. Extended follow-up of children in a phase2b trial of the GMZ2 malaria vaccine. Vaccine. 2021 Oct;39(31):4314–9. pmid:34175127
- 16. Dejon-Agobe JC, Ateba-Ngoa U, Lalremruata A, Homoet A, Engelhorn J, Nouatin OP, et al. Controlled Human Malaria Infection of Healthy Adults with Lifelong Malaria Exposure to Assess Safety, Immunogenicity, and Efficacy of the Asexual Blood Stage Malaria Vaccine Candidate GMZ2. Clinical Infectious Diseases [Internet]. 2019 Sep 27;69(8):1377–84. Available from: https://academic.oup.com/cid/article/69/8/1377/5252072 pmid:30561539
- 17. Partnership. A Phase 3 Trial of RTS, S/AS01 Malaria Vaccine in African Infants. New England Journal of Medicine. 2012 Oct;367(24):2284–95. pmid:23136909
- 18. Moncunill G, Rosa SC De, Ayestaran A, Nhabomba AJ, Mpina M, Cohen KW, et al. RTS, S/AS01E Malaria Vaccine Induces Memory and Polyfunctional T Cell Responses in a Pediatric African Phase III Trial. Front Immunol. 2017;8.
- 19. Otieno L, Oneko M, Otieno W, Abuodha J, Owino E, Odero C, et al. Safety and immunogenicity of RTS, S/AS01 malaria vaccine in infants and children with WHO stage 1 or 2 HIV disease: a randomised, double-blind, controlled trial. www.thelancet.com/infection [Internet]. 2016;16. Available from: pmid:27394191
- 20. RTS SCTP, Tinto H, D’Alessandro U, Sorgho H, Valea I, Tahita MC, et al. Efficacy and safety of RTS, S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. LANCET. 2015;386(9988):31–45. pmid:25913272
- 21. Jongo SA, Shekalaghe SA, Church LWP, Ruben AJ, Schindler T, Zenklusen I, et al. Safety, immunogenicity, and protective efficacy against controlled human malaria infection of plasmodium falciparum sporozoite vaccine in Tanzanian adults. American Journal of Tropical Medicine and Hygiene. 2018;99(2):338–49. pmid:29943719
- 22. Sissoko MS, Healy SA, Katile A, Omaswa F, Zaidi I, Gabriel EE, et al. Safety and efficacy of PfSPZ Vaccine against Plasmodium falciparum via direct venous inoculation in healthy malaria-exposed adults in Mali: a randomised, double-blind phase 1 trial. Lancet Infect Dis. 2017 Oct;17(5):498–509. pmid:28216244
- 23. Shekalaghe S, Rutaihwa M, Billingsley PF, Chemba M, Daubenberger CA, James ER, et al. Controlled human malaria infection of Tanzanians by intradermal injection of aseptic, purified, cryopreserved plasmodium falciparum sporozoites. American Journal of Tropical Medicine and Hygiene. 2014 Oct;91(3):471–80. pmid:25070995
- 24. Ndiaye BP, Thienemann F, Ota M, Landry BS, Camara M, Dièye S, et al. Safety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: A randomised, placebo-controlled, phase 2 trial. Lancet Respir Med. 2015 Oct;3(3):190–200. pmid:25726088
- 25. Odutola AA, Owolabi OA, Owiafe PK, McShane H, Ota MOC. A new TB vaccine, MVA85A, induces durable antigen-specific responses 14 months after vaccination in African infants. Vaccine. 2012 Oct;30(38):5591–4. pmid:22749600
- 26. Nemes E, Hesseling AC, Tameris M, Mauff K, Downing K, Mulenga H, et al. Safety and immunogenicity of newborn MVA85A vaccination and selective, delayed bacille calmette-guerin for infants of human immunodeficiency virus-infected mothers: A phase 2 randomized, controlled trial. Clinical Infectious Diseases. 2018 Feb 15;66(4):554–63. pmid:29028973
- 27. Churchyard GJ, Snowden MA, Hokey D, Dheenadhayalan V, McClain JB, Douoguih M, et al. The safety and immunogenicity of an adenovirus type 35-vectored TB vaccine in HIV-infected, BCG-vaccinated adults with CD4+ T cell counts >350 cells/mm3. Vaccine. 2015 Oct;33(15):1890–6.
- 28. Kagina BMN, Tameris MD, Geldenhuys H, Hatherill M, Abel B, Hussey GD, et al. The novel tuberculosis vaccine, AERAS-402, is safe in healthy infants previously vaccinated with BCG, and induces dose-dependent CD4 and CD8T cell responses. Vaccine. 2014 Oct;32(45):5908–17. pmid:25218194
- 29. Walsh DS, Owira V, Polhemus M, Otieno L, Andagalu B, Ogutu B, et al. Adenovirus type 35-vectored tuberculosis vaccine has an acceptable safety and tolerability profile in healthy, BCG-vaccinated, QuantiFERON®-TB Gold (+) Kenyan adults without evidence of tuberculosis. Vaccine. 2016 Oct;34(21):2430–6.
- 30. Bekker LG, Dintwe O, Fiore-Gartland A, Middelkoop K, Hutter J, Williams A, et al. A phase lb randomized study of the safety and immunological responses to vaccination with H4:IC31, H56:IC31, and BCG revaccination in Mycobacterium tuberculosis-uninfected adolescents in Cape Town, South Africa. EClinicalMedicine. 2020;21.
- 31. Idoko OT, Owolabi OA, Owiafe PK, Moris P, Odutola A, Bollaerts A, et al. Safety and immunogenicity of the M72/AS01 candidate tuberculosis vaccine when given as a booster to BCG in Gambian infants: An open label randomized controlled trial. Tuberculosis. 2014 Oct;94(6):564–78. pmid:25305000
- 32. Meeren O Van Der, Hatherill M, Nduba V, Wilkinson RJ, Muyoyeta M, Brakel E Van, et al. Phase 2b Controlled Trial of M72/AS01 E Vaccine to Prevent Tuberculosis. New England Journal of Medicine. 2018 Oct;379(17):1621–34. pmid:30280651
- 33. Penn-Nicholson A, Geldenhuys H, Burny W, van der Most R, Day CL, Jongert E, et al. Safety and immunogenicity of candidate vaccine M72/AS01E in adolescents in a TB endemic setting. Vaccine. 2015 Oct;33(32):4025–34. pmid:26072017
- 34. Nell AS, D’Lom E, Bouic P, Sabaté M, Bosser R, Picas J, et al. Safety, tolerability, and immunogenicity of the novel antituberculous vaccine RUTI: Randomized, placebo-controlled phase II clinical trial in patients with latent tuberculosis infection. PLoS One. 2014 Oct;9(2). pmid:24586912
- 35. Hesseling AC, Jaspan HB, Black GF, Nene N, Walzl G. Immunogenicity of BCG in HIV-exposed and non-exposed infants following routine birth or delayed vaccination. International Journal of Tuberculosis and Lung Disease. 2015 Oct;19(4):454–62. pmid:25860002
- 36. Loxton AG, Knaul JK, Grode L, Gutschmidt A, Meller C, Eisele B, et al. Safety and immunogenicity of the recombinant mycobacterium bovis BCG vaccine VPM1002 in HIV-unexposed newborn infants in South Africa. Clinical and Vaccine Immunology. 2017 Oct;24(2). pmid:27974398
- 37. Page MJ, Mckenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. Updating guidance for reporting systematic reviews: development of the PRISMA 2020 statement What is new? J Clin Epidemiol [Internet]. 2021; 134:103–12. Available from: https://doi.org/10.1016/j.jclinepi.2021.02.003
- 38. Tait DR, Hatherill M, Meeren O Van Der, Ginsberg AM, Brakel E Van, Salaun B, et al. Final Analysis of a Trial of M72/AS01 E Vaccine to Prevent Tuberculosis. New England Journal of Medicine. 2019 Oct;381(25):2429–39. pmid:31661198
- 39. Tchakoute CT, Hesseling AC, Kidzeru EB, Gamieldien H, Passmore JAS, Jones CE, et al. Delaying BCG vaccination until 8 weeks of age results in robust BCG-specific T-cell responses in HIV-exposed infants. Journal of Infectious Diseases. 2015 Oct;211(3):338–46. pmid:25108027
- 40. Tameris M, Hokey DA, Nduba V, Sacarlal J, Laher F, Kiringa G, et al. A double-blind, randomised, placebo-controlled, dose-finding trial of the novel tuberculosis vaccine AERAS-402, an adenovirus-vectored fusion protein, in healthy, BCG-vaccinated infants. Vaccine. 2015 Oct;33(25):2944–54. pmid:25936724
- 41. Penn-Nicholson A, Tameris M, Smit E, Day TA, Musvosvi M, Jayashankar L, et al. Safety and immunogenicity of the novel tuberculosis vaccine ID93 + GLA-SE in BCG-vaccinated healthy adults in South Africa: a randomised, double-blind, placebo-controlled phase 1 trial. Lancet Respir Med. 2018 Oct;6(4):287–98.
- 42. Lutwama F, Kagina BM, Wajja A, Waiswa F, Mansoor N, Kirimunda S, et al. Distinct T-Cell Responses When BCG Vaccination Is Delayed from Birth to 6 Weeks of Age in Ugandan Infants. JOURNAL OF INFECTIOUS DISEASES. 2014;209(6):887–97. pmid:24179111
- 43. Nemes E, Geldenhuys H, Rozot V, Rutkowski KT, Ratangee F, Bilek N, et al. Prevention of M. tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination. New England Journal of Medicine [Internet]. 2018 Jul 12;379(2):138–49. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1714021 pmid:29996082
- 44. Suliman S, Geldenhuys H, Johnson JL, Hughes JE, Smit E, Murphy M, et al. Bacillus Calmette–Guérin (BCG) Revaccination of Adults with Latent Mycobacterium tuberculosis Infection Induces Long-Lived BCG-Reactive NK Cell Responses. The Journal of Immunology. 2016 Oct;197(4):1100–10.
- 45. Tameris MD, Hatherill M, Landry BS, Scriba TJ, Snowden MA, Lockhart S, et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: A randomised, placebo-controlled phase 2b trial. The Lancet. 2013;381(9871):1021–8. pmid:23391465
- 46. Geldenhuys HD, Mearns H, Foster J, Saxon E, Kagina B, Saganic L, et al. A randomized clinical trial in adults and newborns in South Africa to compare the safety and immunogenicity of bacille Calmette-Guérin (BCG) vaccine administration via a disposable-syringe jet injector to conventional technique with needle and syringe. Vaccine. 2015 Oct;33(37):4719–26.
- 47. Hatherill M, Geldenhuys H, Pienaar B, Suliman S, Chheng P, Debanne SM, et al. Safety and reactogenicity of BCG revaccination with isoniazid pretreatment in TST positive adults. Vaccine. 2014 Oct;32(31):3982–8. pmid:24814553
- 48. Agnandji ST, Lell B, Fernandes JF, Abossolo BP, Kabwende AL, Adegnika AA, et al. Efficacy and Safety of the RTS, S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at 11 African Sites. PLoS Med. 2014;11(7). pmid:25072396
- 49. Otieno L, Guerra Mendoza Y, Adjei S, Agbenyega T, Agnandji ST, Aide P, et al. Safety and immunogenicity of the RTS, S/AS01 malaria vaccine in infants and children identified as HIV-infected during a randomized trial in sub-Saharan Africa. Vaccine [Internet]. 2020 Jan;38(4):897–906. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0264410X19314665 pmid:31708182
- 50. Bejon P, White MT, Olotu A, Bojang K, Lusingu JPA, Salim N, et al. Efficacy of RTS, S malaria vaccines: individual-participant pooled analysis of phase 2 data. Lancet Infectious Diseases. 2013;13(4):319–27. pmid:23454164
- 51. Oneko M, Steinhardt LC, Yego R, Wiegand RE, Swanson PA, KC N, et al. Safety, immunogenicity and efficacy of PfSPZ Vaccine against malaria in infants in western Kenya: a double-blind, randomized, placebo-controlled phase 2 trial. Nat Med [Internet]. 2021 Sep 13;27(9):1636–45. Available from: pmid:34518679
- 52. Bell GJ, Loop MS, Mvalo T, Juliano JJ, Mofolo I, Kamthunzi P, et al. Environmental modifiers of RTS, S/AS01 malaria vaccine efficacy in Lilongwe, Malawi. BMC Public Health. 2020;20(1). pmid:32532234
- 53. Dobaño C, Sanz H, Sorgho H, Dosoo D, Mpina M, Ubillos I, et al. Concentration and avidity of antibodies to different circumsporozoite epitopes correlate with RTS, S/AS01E malaria vaccine efficacy. Nat Commun [Internet]. 2019 May 15;10(1):2174. Available from: https://www.nature.com/articles/s41467-019-10195-z pmid:31092823
- 54. Mendoza Y, Garric E, Leach A, Lievens M, Ofori-Anyinam O, Pirçon JY, et al. Safety profile of the RTS, S/AS01 malaria vaccine in infants and children: additional data from a phase III randomized controlled trial in sub-Saharan Africa. Hum Vaccin Immunother. 2019 Oct;15(10):2386–98. pmid:31012786
- 55. Datoo MS, Natama MH, Some A, Traore O, Rouamba T, Bellamy D, et al. Efficacy of a low-dose candidate malaria vaccine, R21 in adjuvant Matrix-M, with seasonal administration to children in Burkina Faso: a randomised controlled trial. Lancet. 2021;397(10287):1809–18. pmid:33964223
- 56. Berry AA, Gottlieb ER, Kouriba B, Diarra I, Thera MA, Dutta S, et al. Immunoglobulin G subclass and antibody avidity responses in Malian children immunized with Plasmodium falciparum apical membrane antigen 1 vaccine candidate FMP2.1/AS02(A). Malar J. 2019;18.
- 57. Han L, Hudgens MG, Emch ME, Juliano JJ, Keeler C, Martinson F, et al. RTS, S/AS01 Malaria Vaccine Efficacy is Not Modified by Seasonal Precipitation: Results from a Phase 3 Randomized Controlled Trial in Malawi. Sci Rep. 2017 Oct;7(1). pmid:28775306
- 58. Mensah VA, Gueye A, Ndiaye M, Edwards NJ, Wright D, Anagnostou NA, et al. Safety, immunogenicity and efficacy of prime-Boost vaccination with chad63 and mva encoding me-trap against plasmodium falciparum infection in adults in senegal. PLoS One. 2016 Oct;11(12). pmid:27978537
- 59. Thera MA, Coulibaly D, Kone AK, Guindo AB, Traore K, Sall AH, et al. Phase 1 randomized controlled trial to evaluate the safety and immunogenicity of recombinant Pichia pastoris-expressed Plasmodium falciparum apical membrane antigen 1 (PfAMA1-FVO [25–545]) in healthy Malian adults in Bandiagara. Malar J. 2016 Oct;15(1). pmid:27577237
- 60. Ubillos I, Ayestaran A, Nhabomba AJ, Dosoo D, Vidal M, Jiménez A, et al. Baseline exposure, antibody subclass, and hepatitis B response differentially affect malaria protective immunity following RTS, S/AS01E vaccination in African children. BMC Med. 2018 Oct;16(1). pmid:30376866
- 61. Neafsey DE, Juraska M, Bedford T, Benkeser D, Valim C, Griggs A, et al. Genetic Diversity and Protective Efficacy of the RTS, S/AS01 Malaria Vaccine. New England Journal of Medicine [Internet]. 2015 Nov 19;373(21):2025–37. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1505819 pmid:26488565
- 62. Gyaase S, Asante KP, Adeniji E, Boahen O, Cairns M, Owusu-Agyei S. Potential effect modification of RTS, S/AS01 malaria vaccine efficacy by household socio-economic status. BMC Public Health. 2021;21(1). pmid:33509156
- 63. Chandramohan D, Zongo I, Sagara I, Cairns M, Yerbanga RS, Diarra M, et al. Seasonal Malaria Vaccination with or without Seasonal Malaria Chemoprevention. New England Journal of Medicine. 2021;385(11):1005–17. pmid:34432975
- 64. Datoo MS, Natama HM, Somé A, Bellamy D, Traoré O, Rouamba T, et al. Efficacy and immunogenicity of R21/Matrix-M vaccine against clinical malaria after 2 years’ follow-up in children in Burkina Faso: a phase 1/2b randomised controlled trial. Lancet Infect Dis [Internet]. 2022 Dec 1 [cited 2024 Oct 19];22(12):1728–36. Available from: http://www.thelancet.com/article/S147330992200442X/fulltext pmid:36087586
- 65. Tinto H, Otieno W, Gesase S, Sorgho H, Otieno L, Liheluka E, et al. Long-term incidence of severe malaria following RTS, S/AS01 vaccination in children and infants in Africa: an open-label 3-year extension study of a phase 3 randomised controlled trial. Lancet Infect Dis. 2019 Aug 1;19(8):821–32. pmid:31300331
- 66. Baptista BO, de Souza ABL, Riccio EKP, Bianco-Junior C, Totino PRR, Martins da Silva JH, et al. Naturally acquired antibody response to a Plasmodium falciparum chimeric vaccine candidate GMZ2.6c and its components (MSP-3, GLURP, and Pfs48/45) in individuals living in Brazilian malaria-endemic areas. Malar J [Internet]. 2022 Dec 1 [cited 2024 Oct 16];21(1):1–16. Available from: https://malariajournal.biomedcentral.com/articles/ pmid:34983540
- 67. Olotu A, Fegan G, Wambua J, Nyangweso G, Awuondo KO, Leach A, et al. Four-Year Efficacy of RTS, S/AS01E and Its Interaction with Malaria Exposure. New England Journal of Medicine [Internet]. 2013 Mar 21 [cited 2024 Oct 18];368(12):1111–20. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa1207564 pmid:23514288
- 68. Langowski MD, Khan FA, Savransky S, Brown DR, Balasubramaniyam A, Harrison WB, et al. Restricted valency (NPNA)n repeats and junctional epitope-based circumsporozoite protein vaccines against Plasmodium falciparum. NPJ Vaccines. 2022 Dec 1;7(1). pmid:35087099
- 69. Riste M, Marshall JL, Satti I, Harris SA, Wilkie M, Ramon RL, et al. Phase i trial evaluating the safety and immunogenicity of candidate tb vaccine mva85a, delivered by aerosol to healthy m.Tb-infected adults. Vaccines (Basel). 2021;9(4). pmid:33923628
- 70. Saveria T, Parthiban C, Seilie AM, Brady C, Martinez A, Manocha R, et al. Needle-free, spirulina-produced Plasmodium falciparum circumsporozoite vaccination provides sterile protection against pre-erythrocytic malaria in mice. NPJ Vaccines. 2022 Dec 1;7(1). pmid:36195607
- 71.
WHO. Malaria vaccines: Preferred product characteristics and development considerations. 2022.
- 72.
WHO. WHO Preferred Product Characteristics for Therapeutic Vaccines to Improve Tuberculosis Treatment Outcomes. 2019 [cited 2024 Oct 19]; Available from: http://apps.who.int/bookorders.