Abstract

Background

Plasmodium falciparum and Plasmodium vivax are the most common plasmodium species causing human malaria worldwide. Currently, RTS,S is the first and the only licensed malaria vaccine shown to provide partial protection against malaria in young children in three sub-Saharan African countries [1] The emergence of artemisinin resistance, unfavorable pharmacokinetic or toxicological profile of available drugs and other unmet medical needs highlight the need for new antimalarial drugs with novel mechanisms of action [2]. There are promising antimalarial molecules in clinical development, including KAF156 [3], KAE609 [4], DSM265 [5] and M5717, formerly DDD498 [6]. After successful completion of phase 1 safety and pharmacokinetic studies, phase 2 trials have been undertaken or are being planned in malaria-endemic areas. However, ethical and logistical problems, unknown effects of existing immunity and a reported fall in malaria incidence in endemic areas are hampering the execution of both drug and vaccine trials [2, 7]. As a result, Controlled Human Malaria Infection (CHMI) models are being used as emerging approaches for testing efficacy of investigational medicinal products against malaria.

CHMI entails a deliberate infection of healthy volunteers either by inoculation of plasmodium sporozoites (sporozoite challenge) by mosquito bite or direct injection of Plasmodium falciparum sporozoites (PfSPZ Challenge) or Plasmodium-infected erythrocytes [8]. Since the first deliberate infection of volunteers with malaria as a treatment for neurosyphilis in the 1920s, CHMI has increasingly been used to understand parasite biology and as a framework in the assessment of novel vaccine, drug, and diagnostic candidates [7, 9–11]. Indeed, CHMI studies have become a vital tool to accelerate vaccine and drug development and are integrated into First-in-Human trials. CHMI studies provide a cost-effective way to investigate efficacy and characterize the potential therapeutic dose range in early clinical development to gain exploratory proof of concept [12], and to provide an early alert for clinical safety signals.

Mosquito bite-induced CHMI has been shown to be safe and effective for efficacy testing of anti-malarial drug and vaccine candidates for more than 25 years, including early studies of subunit malaria vaccines and atovaquone efficacy [10]. There is an exponential increase in the use of CHMI models worldwide due to the availability of cryopreserved infectious P. falciparum sporozoites (PfSPZ Challenge), and the need to test more vaccine and drug candidates [11]. Heterogenous study designs and procedures have been used in malaria sporozoite-challenge trials that resulted in variable study outcomes. Moreover, comparative reproducibility of various modalities of sporozoite-challenge trials are lacking in the literature. The objective of this study was, therefore, to conduct a systematic review of current literature on reproducibility of efficacy, such as infection rate, prepatent period, parasitemia and safety clinical endpoints of P. falciparum and P. vivax sporozoite challenge model in humans. In addition, we evaluated the study designs, variables influencing study outcomes, optimal and standardized procedures, ethical and regulatory considerations, and limitations in the conduct of sporozoite challenge studies.

Methods

A systematic review of the literature published between 1990 and 2018 was undertaken using public databases including Pubmed, Scopus, Embase, Cochrane Library, ClinicalTrials.gov and Trialtrove. The search was conducted from 30 September 2018 to 10 November 2018. Randomized or non-randomized and controlled or open-label trials testing efficacy of antimalaria drug and vaccine candidates conducted using P. falciparum or P. vivax sporozoite challenge through mosquito bites or needle injection and sporozoite infectivity human studies were included. Ex-vivo studies, nonclinical studies and studies based on induced blood-stage malaria using infected erythrocytes were excluded. The search was conducted using key words, including sporozoite challenge, sporozoite challenge studies, controlled human malaria infection, clinical trials, human, P. falciparum and P. vivax. Abstracts, articles and conference papers were searched without time restriction. Additionally, the grey literature was used to complement evidence synthesis. Only healthy volunteers receiving placebo but not any of the investigational vaccine or drug, and those who participated in sporozoite infectivity studies were considered for analysis of reproducibility. Infection rate, prepatent period and parasitemia were extracted as efficacy end points, while adverse events and laboratory abnormalities as safety endpoints for sporozoite challenge model. The data were extracted using standardized data extraction forms, and descriptive analysis was conducted for evidence synthesis.

Results

The procedure for screening of articles is shown in Fig. 1. We identified 1488 articles from all searched databases and 70 of them were found to be eligible, out of which 44 were vaccine trials, 19 sporozoite infectivity studies, 5 prophylactic drug trials and 2 assessments of natural immunity. The CHMI trials were conducted from 1990 to 2018 and included a total of 2329 adult healthy volunteers, out of which 1221 were on either placebo treatment used in vaccine and drug efficacy evaluation or in sporozoite infectivity trials. Table ​Table11 summarizes the global landscape of malaria sporozoite challenge trials. The majority of P. falciparum challenge studies were conducted in the USA, the Netherlands, UK, Germany, and Spain; while P. vivax challenge studies were conducted only in Colombia and the USA. Few P. falciparum studies were also carried out in African countries, particularly in Tanzania, Kenya, Mali, Equatorial Guinea and Gabon.

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Fig. 1

Flowchart of search results for sporozoite challenge model based studies from different databases

Analysis of the data by method of infection indicated that 45 (64.3%) studies used P. falciparum-infected mosquito bites (n=1286), 7 (10%) P. vivax-infected mosquito bites (n=189), and 18 (25.7%) injection of cryopreserved P. falciparum sporozoites (n=854). It is of note that only 56% (39/70) of the studies were randomized placebo-controlled trials with blinding. The sporozoite challenge studies were conducted using various P. falciparum strains or clones including NF54, 3D7, NF166.C8, NF135.C10, or 7G8 induced through either sporozoite inoculation or via bite of laboratory-reared mosquitoes (A. Stephensi or A. gambiae). However, only seven sporozoite challenge studies were conducted through the bite of P.vivax -infected mosquitoes (A. dirus or A. albimanu).

Infectivity of malaria sporozoite challenge in healthy volunteers

The analysis of reproducibility of infectivity parameters for sporozoite challenge was done in subjects who received sporozoite challenge as infectivity controls, implemented as part of placebo-controlled vaccine or antimalarial compound efficacy trials. The subjects enrolled in the experimental sporozoite infectivity studies did not receive any investigational compound. Once infectivity of the experimental challenge (parasitemia) was confirmed, all participants had received mandatory rescue medication with confirmation of cure. Table ​Table33 depicts a summary of the efficacy endpoints measured by different methods. A sample size of usually 6 subjects per group (range 2–18) was used in sporozoite challenge studies. The P. falciparum infected mosquito challenge was 100% infective in 88.9% (40/45) of the studies. In 9 studies, the infectivity was, however, came down to 88.3%, whereby one subject per group did not develop parasitemia [9, 19, 24, 28, 36, 44–46].

Table.3

The infectivity, prepatent period and parasitemia measurements in healthy volunteers in malaria sporozoite challenge participated as controls in vaccine or drug trials and in infectivity studies

Plasmodium spp/strain	CHMI type	Infectivity % (n)	TBS-Prepatent period (mean or median) days	PCR-Prepatent period (mean, median) days	PCR-parasitemia (n/µl) Mean or median	References
PfNF54	PfSPZ challenge	100(4/4)	11.7*	7.8	19.55–28.756	[5]
PfNF54	PfSPZ challenge	100(13/13)	11**			[26]
PfNF54	PfSPZ challenge	100 (5/5)	12.7*	10.3	25.6	[71]
PfNF54	PfSPZ challenge	100(6/6)	11.4/12.2*	6.8		[69]
PfNF54	PfSPZ challenge	84(5/6)	13/12.7/13*	10.6/10.3/ 9.9	0.07/0.2	[46]
PfNF54	PfSPZ challenge	100 (28/28)	12.6/11.8/12/ 16.4/13.3/11.9 **			[67]
PfNF54	PfSPZ challenge	100(18/18)	12.5/13/12**		0.5	[27]
PfNF54	PfSPZ challenge	92/91	15.4/13.5**	12.6 /11.1	0.11/0.16	[9]
PfNF54	PfSPZ challenge	100(6/6)	12.7**			[66]
PfNF54	Mosquito bite/PfSPZ	100(6/6)		8.3–9.4**	≥0.25	[14]
PfNF54	PfSPZ challenge	100(9/9)	11.2*			[68]
PfNF54	PfSPZ challenge	64%(7/11) 56(5/9)	16.9/19.1*			[72]
PfNF54	Mosquito bite	100(5/5)	13.5**	7		[54]
Pf3D7	Mosquito bite	100(12/12)				[37]
PfNF54	Mosquito bite	100(6/6)	11.2*	7.5	33.712	[53]
Pf	Mosquito bite	100(15/15)	11.34/ 12.54*	7/6.38	23.92/35.74	[13]
PfNF54	Mosquito bite	100(13/13)	11.2*	–	–	[78]
PfNF54	Mosquito bite	94.4(17/18)	10.9*	7.5		[45]
PfNF54	Mosquito bite	100(19/19)	10.9*	7.5	1.7	[52]
PfNF54	Mosquito bite	100(6/6)	9**	6.7		[30]
Pf3D7	Mosquito bite	100(6/6)	9–13			[79]
PfNF54	Mosquito bite	100(4/4)	9–18			[15]
PfNF54	Mosquito bite	100(4/4)	8.5**	6.3	>0.035	[23]
Pf3D7	Mosquito bite	100(6/6)	9–13		2.7	[16]
Pf3D7	Mosquito bite	100(6/6)	12.8*			[80]
PfNF54	Mosquito bite	100(5/5)	9.2*			[20]
PfNF54	Mosquito bite	100(4/4)	12.5 *	10.8		[17]
Pf3D7	Mosquito bite	100(6/6)	12.3*			[31]
Pf3D7	Mosquito bite	100	10.7			[38]
Pf3D7	Mosquito bite	100(5/5)	11*		>1	[56]
Pf3D7	Mosquito bite	100(6/6)	11.6 *	10.8	>1	[57]
PfNF54	Mosquito bite	80 (4/5)	7–12			[24]
Pf3D7	Mosquito bite	100 (6/6)	12.9*			[81]
Pf3D7	Mosquito bite	100(5/5)	11.8 *			[55]
Pf3D7	Mosquito bite	100% (6/6)	11–13*			[34]
Pf3D7	Mosquito bite	95(22/23)	12			[36]
Pf3D7	Mosquito bite	100(5/5)	12.3*	9		[21]
Pf3D7	Mosquito bite	100(6/6)	9–12*	7		[51]
Pf	Mosquito bite	100(6/6)	11.8*	11.1	>1	[58]
Pf3D7	Mosquito bite	100(6/6)	10.8			[35]
Pf3D7	Mosquito bite	100(16/16)		–	>0.5	[82]
Pf3D7	Mosquito bite	100(11/11)	12.25 **	7.4	>0.5	[41]
Pf3D7/7G8	Mosquito bite	100(4/4)	10–12			[39]
Pf3D7	Mosquito bite	100(36/36)	11–14			[18]
Pf3D7	Mosquito bite	100(11/11)	11–14			[42]
Pf3D7	Mosquito bite	100 (13/13)	13*			[41]
PfNF54/3D7	Mosquito bite	100 (5/5)	11–14			[33]
Pf7G8	Mosquito bite	100(4/4)	9–12			[49]
Pf	Mosquito bite	100(36/36)	10.8/11.8*			[32]
Pf3D7	Mosquito bite	100(6/6)	10.3**	7.5	>0.5	[67]
Pf	Mosquito bite	91(11/12)	7–13			[28]
Pf3D7/Pf7G8	Mosquito bite	100(22/22)	10.9/11.6/11.9**			[29]
PfNF54/NF166.C8/ NF135.C10	Mosquito bite	100(23/23)	10.2/7.2/7.4*	7.5/6.5/6.5		[47]
PfNF135.C10	Mosquito bite	100 (5/5/)	8.5**	-	>0.05	[25]
PfNF54/NF166.C8/ NF135.C10	Mosquito bite	100(15/15)	-	-	>0.1	[22]
NF166.C8/ NF135.C10	Mosquito bite	100(4/4/)	7.5**	-	>0.5	[48]
Pv	Mosquito bite	100(17/17)	12 *	-		[62]
Pv	Mosquito bite	94(15/16)	12.5/12.8 *	9.2–9.4	17.5	[64]
Pv	Mosquito bite	100(2/2)	12–13*	8–11	12.5–1050	[19]
Pv	Mosquito bite	100	11–13	–	–	[83]
Pv	Mosquito bite	94.4(17/18)	11*	9–13		[44]
PV	Mosquito bite	100(6/6)	10.7**			[65]
PV	Mosquito bite	100(18/18)	11, 11, 9 *			[63]

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*Geometric mean, **Median

The infection outcomes of sporozoite challenge studies conducted through either bite of plasmodium- infected mosquito or parenteral injection of purified P. falciparum sporozoites are described below.

Discussion

Our systematic review attempted to establish evidence on the reproducibility of P. falciparum and P. vivax malaria sporozoite challenge model using search of literature from several databases. Seventy studies were identified and used for analysis of data reported. The efficacy endpoints of the sporozoite challenge model were infectivity, prepatent period and parasitemia; while the safety endpoints were adverse events and laboratory abnormalities.

The majority of P. falciparum and P. vivax challenge studies were conducted in developed countries (USA, the Netherlands, UK, Germany, and Spain) while only few P. falciparum challenge studies were also conducted in African countries. The lack of phase 1 clinical trial centers and mosquito laboratory facilities were reasons for the small number of CHMI trials conducted in Africa [9].

Analysis of detection of malaria challenge infections in healthy volunteers indicated that following inoculation of sporozoites, parasitemia was monitored by clinical signs and symptoms, microscopic examination of thick blood smears and PCR techniques. The use of various methodologies with different sensitivity for parasite detection was a source of variability in assessing clinical endpoints. The sensitivity of thick blood film is reported to be 1–10 parasites/µl, which is roughly one-tenth of qPCR [2]. Using qPCR in sporozoite-initiated CHMI has an advantage of shortening the duration of parasitemia due to lower absolute number of parasites so as to avoid or at least reduce the appearance of clinical symptoms in participants [8, 13].

Few studies evaluated chemoprophylactic activity of candidate antimalarial molecules against mosquito-bite- or PfSPZ challenge-induced infections. The studies [5, 14–17] indicate that the variability in chemoprophylactic activity of candidate molecules was observed due to differences in dosing regimen, time of administration, pharmacokinetics and pharmacodynamics of the compounds. Nevertheless, the results reaffirm the use of the sporozoite challenge model for evaluating prophylactic activity of new chemical entities, though work related to standardization remains to be done.

The review of available evidence indicated that sporozoite challenge model has been used to assess the efficacy of several vaccine candidates. The level of protective efficacy of sporozoite-based vaccines varied depending on the type of vaccine-adjuvant system, vaccination regimen, previous exposure status, and type of strain. This model showed positive infectivity in the control arm receiving placebo, although a wide range of protective responses were observed with the different antigens. The reasons for high variability observed in the protective response are largely unknown. Some of them could be directly related to the nature of the sporozoite challenge model, such as the high intensity of the challenge compared to natural infection [30], lack of genetic diversity coverage, and sub-optimal vaccination regimens during the experimental phase. The CHMI model demonstrated its ability to predict efficacy of malaria vaccines in the field as indicated by development of the RTS, S vaccine [7, 31, 32]. However, so far, only limited vaccine candidates have been tested in population at risk of malaria infection. The translation of the results obtained in the CHMI to malaria exposed patients thus remains to be confirmed.

The mosquito-based P. falciparum sporozoite challenge studies were also conducted in well-established research centers in developed nations using parasite clones such as NF54, 3D7, NF135.C10 and NF166.C8. The analysis of efficacy (infectivity) of malaria sporozoite challenge in healthy volunteers shows that P. falciparum infected mosquito challenge was 100% infective in 88.9% of the studies with five mosquito bites resulting in 100% reproducible infections. Although infectivity exhibited a decreasing trend in some studies, the data collectively indicate very good performance of the CHMI experiments. In 84.6% (44/52) of the studies, A. stephensi mosquitoes, a major vector for malaria infections in urban areas and established in laboratories [50, 51], were used for infection with P. falciparum. The outcomes of these studies indicated that optimum infection could be obtained with standardized five bites of P. falciparum infected A. stephensi mosquitoes, regardless of the geographic origin of the infecting parasite, strongly justifying the use of CHMI in testing efficacy of drug and vaccine candidates.

The mean or median prepatent period for P. falciparum infection with TBS was≤12 days in 24 studies, and between 7 and 13 days in all studies. Similarly, the mean prepatent period with qPCR was between 6 and 11 days in 9 studies. PCR detected parasites, on average; 2–6 days earlier than TBS. The parasite detection limits of PCRs ranged from 35 to 100 parasites/mL of blood and average parasite growth rates were also variable. This variability in PCR-detection sensitivity may influence the comparability of study outcomes across trial sites and study designs, justifying the need for standardization of PCR procedures.

The CHMI studies resulted in 100% infectivity through standardized five bites from P. falciparum infected mosquitoes, however, using three aseptically reared mosquitoes also resulted in 100% infectivity. This observation indicates the possibility of setting aseptic model as a new standard for CHMI trials in non-endemic areas with the advantage of reducing adverse events.

Malaria infection with bite of mosquitoes, where the probability of infection increases with the number of infectious bites, reliably reflects the natural infection process. The studies indicated that the pre-patent period depends on strain of parasite, biting dose and number of mosquitoes used. Even though five mosquito bites consistently produced 100% infectivity, impact of the number of sporozoites inoculated in those bites was not clear until recently. Statistical analysis of>1000 experimental infections by Churcher et al. [59] indicated that the probability of infection and pre-patent period depends on the number of residual-sporozoites in salivary glands of mosquitoes. The salivary gland residual-sporozoite load per fed mosquito was scored as 0 (no sporozoites), 1 (1–10), 2 (11–100), 3 (101–1000), 4 (>1000) [60]. However, the number of sporozoites injected into each participant in mosquito bite-initiated CHMI was highly variable. As a result, the number of sporozoites counted in mosquito salivary glands is a poor predictor of the number of sporozoites injected [7].

Few studies on CHMI with P. vivax-infected mosquitoes were conducted on Duffy (+) subjects. The Duffy antigen, a glycosylated membrane protein located on the surface of red blood cells and functioning as a multi-specific receptor for several chemokines, is also the obligate trans-membrane receptor for P. vivax invasion of red blood cells. The low endemicity of P. vivax infection in sub-Saharan Africa is perceived to be due to high prevalence of Duffy (−) phenotype, which confers resistance to P. vivax infection. However, evidence emerging from P. vivax infections confirmed by molecular diagnostic tests in Duffy (−) hosts indicates an additional Duffy-independent -mechanism of transmission across sub-Saharan Africa [61].

There was similar infection outcomes in CHMI with P. vivax with same five mosquito bites however, P. vivax infected mosquitoes appear more potent compared to P. falciparum infection, which requires five bites for reliable infection, although this needs to be validated with more studies.

The standardization of P. vivax challenge is proven to be more difficult, due to unavailability of long-term in-vitro culture, however, an alternative approach has been using fresh gametocytes from infected patients to infect mosquitoes. The P. vivax sporozoites were generated by feeding gametocyte-infected blood to laboratory-reared mosquitoes from residents areas in Colombia and Thailand [7, 8]) or by shipping infected mosquitoes to USA for challenge study [65]. The use of fresh P. vivax isolates may have limitations including variability in drug sensitivity, parasite multiplication rates and prepatent periods [8]. Potential hypnozoite formation and infection relapse are additional complications from P. vivax sporozoite-initiated CHMI studies. In addition, screening for CYP mutations associated with increased metabolism of primaquine is required for CHMI studies involving P. vivax to provide a terminal treatment of liver stages of P. vivax infection. Generally, the current methods for sporozoite challenge through bite of P. vivax-infected mosquitoes is validated for its infectivity and safety in small number of studies. Hence, more studies may be needed for procedures optimization.

Review of PfSPZ challenge-mediated CHMI studies indicated that this method is well established and standardized. The studies have successfully defined the reproducible regimen for administration of PfSPZ challenge resulting in 100% infection rate, with a prepatent period of≤12 days which is 3200 P.falciparum sporozoites given by direct venous inoculation. However, natural adaptive immunity to malaria significantly prolonged the time to parasitemia. Sickle cell trait seemed to prolong it further, whereas 20% (4/20) semi-immunes demonstrated sterile protective immunity. The observed differences in infection outcomes following PfSPZ Challenge injection in Kenyan [67] and Gabonese [72] population could be attributed to population differences in malaria exposure and induction of natural adaptive immunity. However, due to small sample size, more studies in malaria endemic populations are needed to confirm infectivity of PfSPZ challenge in malaria exposed individuals in support of the future use of PfSPZ challenge for testing efficacy of vaccines and anti-malaria drugs.

Analysis of the safety and tolerability of CHMI by Sporozoite challenge indicates local and systemic signs and symptoms and laboratory safety signals that are features of malaria infection which normalize following treatment with antimalarial drugs. The safety profiles following P. falciparum infections by mosquito bites indicated consistent adverse events related to mosquito bite, clinical malaria and its treatment but serious adverse events were rare. Two previous studies [84, 85] reported cardiac-related serious AEs (SAEs) (acute coronary syndrome/myocarditis), whose causality was not definitely established, following a mosquito-bite CHMI study with P. falciparum infection. As a result, CHMI studies recommend assessment of markers for cardiac damage and coagulation such as troponin, lactate dehydrogenase (LDH), platelets, and D-dimer and ECG [9, 43, 46].

The sporozoite infection model with infectious mosquitoes mimics the natural route of infection and allows the occurrence of natural and artificial conditions impacting the development of natural malaria infection, such as naturally or vaccine-induced immunity and drugs. The model has been used in the development and early clinical validation of vaccines [21, 24] and more recently has been established as a translational model for prophylactic drug development [5, 14–17]. Historically, the reliability of the model to support the development of drugs or vaccines has been impaired by the complexity and reproducibility of infective bites by mosquitoes; uncontrolled number of sporozoites inoculated by biting mosquitoes were limiting the interpretation of results from experimental challenge models [7]. The conduct of mosquito-challenge trials was complicated by the need for a mosquito insectary and entomological expertise and risk of adventitious infections [45, 52]. The recent availability of aseptically manufactured PfSPZ Challenge has changed the landscape for CHMI trials with sporozoites and expanded the global capacity to conduct CHMI trials [86], particularly in endemic countries. It also allowed establishing standardized CHMI conditions for drug development [27, 68].

The development of cryopreserved sporozoites helped to produce large scale vaccination in endemic countries following the initial observation that irradiated sporozoites could induce fully protective immune response [87]. With the industrial success of Sanaria Inc to produce large quantity of cryopreserved sporozoites, several CHMI studies have been conducted in malaria endemic countries in Africa to prepare the ground for vaccination campaigns [9, 12, 27, 67, 72–77]. These studies have demonstrated the feasibility of CHMI studies in Africa and allowed to assess the influence of pre-established immunity and malaria related genetic factors such as G6PD and sickle cell trait in the readout of the results [72]. This study indicated that naturally adaptive immunity to malaria and sickle cell trait prolonged prepatent time. The African CHMI studies have also demonstrated the need for addressing the technical and scientific as well as ethical and regulatory challenges [8, 12, 88]. These include prior consultation with key stakeholders, community sensitization, extensive exclusion criteria, consenting issues, challenges of screening of previous exposure, screening asymptomatic parasitemia, confounding of haemoglobinopathies and natural immunity, clinical & laboratory capacity and multitiered system of ethical review.

This systematic review lacks meta-analysis of data on CHMI trials conducted in healthy malaria naïve population and those in endemic countries due to heterogeneous design of trials conducted. However, the data clearly emphasize that these types of experiments can now be conducted in a reliable and systematic manner in well-equipped clinical settings in Africa or other endemic countries. It also provides a comprehensive qualitative evidence on reliability of sporozoite challenge for testing novel therapeutic and prophylactic interventions in healthy volunteers and guide further clinical development. Altogether, the data advocate for further capacity building initiatives to malaria-endemic country based clinical research centers.

Conclusion and future perspectives

Current evidence indicates that mosquito-based sporozoite challenge of healthy volunteers has been validated for several strains of P. falciparum, with five infective mosquito bites being the optimal dose resulting in reproducible infectivity, prepatent period and safety profiles. Mosquito-based sporozoite challenge is a gold standard as it mimics natural infection, however, the method is not yet evaluated in the African setting.

The consistent safety and infectivity of PfSPZ challenge is verified among populations in Europe, America, and Africa. Infective doses are optimized, with DVI of PfSPZ challenge being a new emerging gold standard, including in malaria endemic African population, although there was variability in infection outcomes. Both methods of sporozoite challenge are well characterized for consistent safety profiles. The P. vivax CHMI model using infected mosquitoes has also been validated in few studies, with some limitations including lack of optimization of long-term culture and CHMI procedures.

Sporozoite challenge model is extensively used for testing vaccine efficacy, although few vaccines have been advanced to date. The applicability of the method is also verified in a few prophylactic drug efficacy studies. However, for efficacy studies in African population, PfSPZ challenge is recommended based on current evidence on safety, infectivity and ease of logistical requirement.

The understanding of sporozoite CHMI is advancing, however, gaps in current scientific knowledge to be addressed by future CHMI studies include further assessment of genetic and antigenic diversity of P. falciparum, use of bolus dose of sporozoites in CHMI compared to multiple exposures occurring naturally, comparative studies on wild and lab-cultivated parasites and mosquito vectors, CHMI-mosquito studies in malaria endemic settings in Africa, impact of natural immunity and hemoglobinopathies on CHMI outcomes, development of long-term in-vitro culture of P. vivax and cryopreserved Plasmodium vivax sporozoites (PvSPZ).

Acknowledgements

Abbreviations

Authors' contributions

WS developed proposal, involved in data collection, entry, analysis, and writing the manuscript. WB, OY and AT were involved in proposal development, and read final manuscript. EE was involved in manuscript preparation and editing. CO conceived proposal, and proofread final manuscript. All authors read and approved the final manuscript.

Funding

This study was supported by a grant from European and Developing Countries Clinical Trials Partnership (EDCTP) with Grant Number TMA 2016IF-1778. The study was also supported by Merck Healthcare KGaA, Darmstadt, Germany. The EDCTP did not have a role in the design of the study, collection, analysis, and interpretation of data or in writing the manuscript. The co-authors WB, ÖY, AT and CO are employees of Merck Healthcare KGaA, Darmstadt, Germany or its affiliates who contributed to the study design, analysis, and interpretation of data as well as writing the manuscript.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Footnotes

References