Despite having the highest risk of progressing to severe disease due to lack of acquired immunity, the youngest children living in areas of highly intense malaria transmission have long been observed to be infected at lower rates than older children. Whether this observation is due to reduced exposure to infectious mosquito bites from behavioral and biological factors, maternally transferred immunity, genetic factors, or enhanced innate immunity in the young child has intrigued malaria researchers for over half a century. Recent evidence suggests that maternally transferred immunity may be limited to early infancy and that the young child's own immune system may contribute to control of malarial symptoms early in life and prior to the development of more effective adaptive immunity. Prospective studies of active and passive detection of Plasmodium falciparum blood-stage infections have identified young children (<5 years old) who remain uninfected through a defined surveillance period despite living in settings of highly intense malaria transmission. Yet, little is known about the potential immunological basis for this ‘aparasitemic’ phenotype. In this review, we summarize the observational evidence for this phenotype in field studies and examine potential reasons why these children escape detection of parasitemia, covering factors that are either extrinsic or intrinsic to their developing immune system. We discuss the challenges of distinguishing malaria protection from lack of malaria exposure in field studies. We also identify gaps in our knowledge regarding cellular immunity in the youngest age group and propose directions that researchers may take to address these gaps.

Malaria, caused by Plasmodium parasites that are transmitted to humans by Anopheles mosquitos, affects over 230 million people globally each year, resulting in over 600 000 deaths [1]. The vast majority of these deaths occur in African children under 5 years of age suffering from severe Plasmodium falciparum malaria [1]. Despite having the highest risk of progressing to severe disease due to lack of acquired immunity, the youngest children living in areas of high malaria transmission have long been observed to be infected at lower rates than older children [2–4]. The factors underlying the reduced prevalence of malaria infection observed in children with immature and inexperienced immune systems have intrigued malaria researchers for decades [2,4–7]. From an evolutionary perspective, enhanced innate protection against malaria infection early in life, even if imperfect and short-lived, would still reduce the total number of potentially life-threatening malaria episodes prior to the acquisition of more effective adaptive immunity, especially in rural settings in sub-Saharan Africa where entomological inoculation rates (EIRs) average 144 infective bites per person per year [8]. The increased prevalence of symptomatic malaria, which prompts treatment and parasite clearance by anti-malarials, among the youngest children may partially explain reduced infection prevalence observed in cross-sectional studies [9,10]. However, other explanations that are extrinsic or intrinsic to the young host have been postulated as contributing to these observations [2,5,6]. Longitudinal cohort studies conducted in malaria-endemic communities have sought to identify predictors of sterile or clinical protection by correlating specific factors measured at baseline to prospective risk of Plasmodium infection or symptomatic malaria episodes, respectively (Figure 1A). These studies employ active and passive case detection, and protection is measured as either the absence of events or a delay in time to event. Depending on the study objectives, an event can be either detectable parasitemia (identified by blood smear or PCR) or clinical malaria (parasitemia above a pre-defined density threshold plus malarial symptoms, usually documented fever). Thus, malaria risk can be reported in terms of binary outcomes (absence or occurrence of any infection or clinical malaria episode during the surveillance period) or as continuous variables (time-to-infection or time-to-clinical-malaria). Interestingly, prospective cohort studies that assess time-to-infection have shown that a fraction of young children remain parasite negative during a defined surveillance period despite high malaria transmission [10,12,14,15]. Given the lack of evidence for naturally acquired immunity to P. falciparum infection even as immunity to clinical malaria is clearly acquired in individuals who experience years of intense transmission [10], one possible explanation is that elite innate immunity early in life either prevents liver-stage infection or controls blood-stage parasitemia to undetectable levels. Yet little is known about the cellular immune responses that may contribute to the apparent resistance to malaria infection in these children. In this review, we summarize the evidence to date for a subset of young children living in settings of intense malaria transmission with an ‘aparasitemic’ phenotype, which we define as the continued absence of detectable P. falciparum parasites in the blood despite active longitudinal surveillance for asexual blood-stage infection during a specified time period. We examine potential reasons why these children escape detectable parasitemia, covering factors extrinsic and intrinsic to their developing immune system and identifying gaps in our knowledge regarding cellular immunity in this population. We also discuss the challenges of distinguishing protection from detectable infection or clinical malaria from lack of malaria exposure in field studies and how researchers may address this.

Surveillance of malaria infections in prospective cohort studies.

Figure 1.
Surveillance of malaria infections in prospective cohort studies.

(A) Design of a prototypical prospective cohort study with passive and active detection of malaria episodes and P. falciparum infections. Figure adapted from [11]. Participant blood samples are collected at the start of the study to allow biological assessments that can be linked to prospective risk of clinical malaria or P. falciparum infection. Plasma/serum collected at the end of the surveillance period can be used to evaluate seroconversion of P. falciparum stage-specific antibodies as a surrogate of malaria exposure. PBMCs, peripheral blood mononuclear cells. Hypothetical infection cumulative incidence plots showing the fraction of young children escaping parasite detection for (B) an observational cohort study of natural P. falciparum infections in children and (C) a pre-erythrocytic malaria vaccine trial in infants aged 5–12 months. These conceptual plots were modeled after unpublished and published data from the Kalifabougou cohort study [10] and the KSPZV1 malaria vaccine trial [12,13], respectively.

Figure 1.
Surveillance of malaria infections in prospective cohort studies.

(A) Design of a prototypical prospective cohort study with passive and active detection of malaria episodes and P. falciparum infections. Figure adapted from [11]. Participant blood samples are collected at the start of the study to allow biological assessments that can be linked to prospective risk of clinical malaria or P. falciparum infection. Plasma/serum collected at the end of the surveillance period can be used to evaluate seroconversion of P. falciparum stage-specific antibodies as a surrogate of malaria exposure. PBMCs, peripheral blood mononuclear cells. Hypothetical infection cumulative incidence plots showing the fraction of young children escaping parasite detection for (B) an observational cohort study of natural P. falciparum infections in children and (C) a pre-erythrocytic malaria vaccine trial in infants aged 5–12 months. These conceptual plots were modeled after unpublished and published data from the Kalifabougou cohort study [10] and the KSPZV1 malaria vaccine trial [12,13], respectively.

Close modal

Infants and young children have been observed to have decreased rates of P. falciparum infection by blood smear relative to older children up to 15 years of age [2–4,9,16–19]. Studies that used more sensitive molecular parasite detection have also found decreased parasite prevalence in the youngest children when compared with school-aged children [16–18,20,21]. Such differences appear to be most pronounced in areas of high malaria transmission intensity [22]. These cross-sectional community prevalence studies have generally captured pre-symptomatic and truly asymptomatic malaria infections. Thus, the increased prevalence in school-aged children reflects, to a large degree, acquisition of clinical immunity to parasitemia after several years cumulative malaria exposure [10,23]. However, period prevalence and incidence rates measured by rapid diagnostic tests (RDT) in treatment-seeking, febrile patients at health facilities on the Kenyan coast, where overall RDT infection prevalence was 9.9%, also increased with age from infancy to ∼9 years of age before decreasing towards adulthood [24]. Evidence for decreased malaria infection rates in the youngest children can also be found in longitudinal cohorts. A 500-participant cohort study in an area of Mali where malaria transmission is seasonal and intense showed that the 1-year longitudinal prevalence of P. falciparum, measured by PCR, was highest in individuals aged 9–16 years when compared with those aged 1–4 years or >17 years [25]. In a longitudinal study of 114 Malawian children living in an area of intense perennial transmission, children <5 years of age had fewer incident P. falciparum infections by PCR per child relative to children aged 5–15 years [26]. Even within a narrow age range, infants aged 6–11 months appear to be more protected than older children aged 12–24 months in areas of Uganda with high malaria incidence rates (6.41 vs. 7.24 cases per person-years at risk, respectively) [27]. Thus, there is considerable evidence that, in areas of high malaria endemicity, the youngest children are infected at lower rates when compared with older children despite having relatively less acquired immunity to the parasite.

Further evidence for decreased rates of incident P. falciparum clinical episodes and infection in infants and young children can be found in prospective studies of both active and passive malaria surveillance in high malaria transmission settings. In a longitudinal study in Kenya, more children were observed to have no clinical malaria episodes during a 5-year surveillance period than what otherwise would be expected based on a fitted Poisson distribution, particularly among children <5 years of age [28]. In a prospective cohort study of children and adults conducted in Mali, P. falciparum infections were determined over the course of a 6-month malaria-transmission season by retrospective PCR analysis of dried blood spots collected every 2 weeks and at sick visits [10]. The main finding of this study was that the infection risk did not decrease with increasing years of malaria exposure, providing evidence that naturally acquired sterile immunity to P. falciparum does not occur even in high malaria transmission settings. Interestingly, 10% of children in the youngest age group (4–6 years) in the published study remained uninfected at the end of 6 months of intense malaria transmission compared with <5% in the older age groups [10]. In unpublished data from the same year of the cohort, ∼25% of children aged 3 months to 3 years remained uninfected during the first year of intensive surveillance but eventually had detectable parasitemia during the ensuing malaria seasons (Peter Crompton, personal communication, conceptualized in Figure 1B). A longitudinal study of 264 Papua New Guinean children aged 0.9–3.2 years reported that 13% remained free of PCR-detectable P. falciparum infections despite up to 69 weeks of follow-up that included active surveillance for malaria morbidity every 2 weeks and infections every 8–9 weeks as well as passive malaria case detection [29]. A longitudinal birth cohort study in a high malaria transmission area of Tanzania reported 63 children aged 1–3.5 years (9.2% of the cohort) who had no blood smear-positive slides despite 2 years of biweekly active parasitological surveillance [15]. In a study of Ugandan children residing in an area of high transmission intensity, a subset of 16 children for whom longitudinal infection histories were shown through their first 5 years of life, two children experienced infection-free periods of at least ∼18 months despite surveillance by monthly blood smears and symptom-triggered visits [30]. Additional evidence can be found in the control arms of malaria vaccine studies. In a phase 2b trial of the pre-erythrocytic vaccine RTS,S/AS02 conducted in Mozambican children aged 1–4 years (‘cohort 2’), of the 146 children in the control arm who completed the trial, 10 (6.8%) remained free of parasitemia during 6 months of intensive surveillance that consisted of at least monthly blood smears and passive surveillance [14]. More recently, a clinical trial of the radiation-attenuated P. falciparum sporozoite (PfSPZ) vaccine conducted in Kenyan infants aged 5–12 months, ∼34% of infants in the normal saline placebo arm who completed the protocol remained uninfected despite 6 months of monthly blood smears and passive surveillance (conceptualized in Figure 1C) [12,13]. That such a high proportion of infants remained ‘aparasitemic’ is made more remarkable by the highly intense malaria transmission that occurs in Siaya county, where the trial was conducted, with EIR reaching as high as 29.9 infective bites per person per month during peak transmission [31]. These studies suggest that a subset of infants and young children somehow escape detectable parasitemia for a finite time period despite living in areas of highly intense malaria transmission.

Numerous explanations have been proposed for the observation of reduced infection in infants and young children. Behavioral measures such as swaddling of infants and increased used of insecticide-treated nets for the youngest children may reduce exposure to infectious mosquito bites [32]. Young children are bitten by mosquitoes less frequently than older children and adults, a finding that has been correlated to body surface area [19,33,34]. Fetal hemoglobin has been suggested as being malaria protective based on in vitro experiments [35,36] and a modest association with protection in the youngest children [37], especially in presence of hemoglobin AA [38]. Host genetic variants, especially erythrocyte polymorphisms and hemoglobinopathies, can confer protection against malaria [39]. However, little evidence exists for protective synergy between younger age and host polymorphisms. Although sickle cell trait (HbAS) protects against all-cause mortality, severe malarial anemia, and high-density parasitemia in the highest risk group of young children aged 2–16 months [40], the protection afforded by HbAS against molecular force of P. falciparum infection and mild clinical malaria actually increases with age up to 8–10 years [41,42].

Placentally transferred maternal anti-malarial IgG antibodies have been proposed as one mechanism to explain malaria-resistance in infants [5]. However, the evidence that maternal antibodies protect against malaria infection and clinical malaria has been mixed and may be dependent on the specific malaria antigen and IgG subclass [6]. For example, neither IgM nor IgG antibodies specific for pre-erythrocytic and erythrocytic antigens were associated with time-to-first P. falciparum infection or the number of infections during the first year of life in a longitudinal study of Cameroonian infants [43]. However, a birth cohort study in Burkina Faso showed that high level maternal IgG to P. falciparum erythrocytic antigens EBA140, EBA175, MSP142, and MSP5 independently predicted protection from clinical malaria during the first year of life [44]. Notably, any malaria-protective effect of maternal IgG specific to such antigens diminishes rapidly after these antibodies wane [45], which is usually by 6 months [6,46–48]. Thus, malaria-specific maternal antibodies likely would not explain reduced malaria infections in children older than 6 months.

Breast milk has been hypothesized to provide protection against malaria in the breastfed infant. While breastfeeding can confer non-malaria specific benefits to the developing infant immune system [49,50], evidence that breast milk derived maternal antimalarial antibodies protects against malaria infection of clinical malaria is lacking [5]. In mice, maternal IgG from breast milk can be transferred from the gut lumen to serum of pups via neonatal Fc receptors [51]. However, in humans, a recent case series of mothers given therapeutic monoclonal IgG1 antibodies for chronic inflammatory rheumatic conditions revealed minimal transfer of these antibodies to breastmilk with undetectable levels in the blood of their breastfed infants [52]. It must be noted that the WHO-recommended practice of exclusive breast feeding in infants under 6 months of age ranges widely from 31% to 84% across sub-Saharan African countries [53,54], with the majority of mothers stopping breastfeeding their child all together by 24 months of age [55]. Thus, any effect of breastfeeding on reducing malaria in young children would be geographically variable.

Despite being immature, the host immune response early in life can potentially thwart malaria infection at the pre-erythrocytic stage, control parasitemia and disease after establishment of blood-stage infection, or prime adaptive responses. Mosquito bites can provoke innate immune responses and affect T cell responses [56,57] which have been associated with reduced parasite burden in mouse models [58], but there is little evidence that host responses to bites by Anopheles mosquitoes can lead to protection against either malaria infection or clinical malaria in human studies. The children described as ‘malaria-resistant’ in the aforementioned Tanzanian birth cohort study by Nash and colleagues had higher levels of pro-inflammatory cytokines, particularly IL-1β, in the cord blood compared with susceptible children [15]. In another prospective study conducted in Benin, TLR-mediated IL-10 responses from whole blood obtained at birth were associated with increased risk of P. falciparum infection [59]. A birth cohort study of mother-infant pairs in Burkina Faso showed a mixed picture in terms of the association of inflammatory cytokine responses of TLR-agonist stimulated cord blood and malaria risk during the first year of life [60]. Note that studies that used cord blood or samples obtained at birth may be confounded by prenatal exposure to P. falciparum (i.e. placental malaria), which not only affects the neonatal immune response [7] but is also associated with increased risk of malaria in the first years of life that is itself confounded by relative differences in malaria exposure between mother-infant pairs [61–63]. Despite this caveat, the limited evidence to date seems to suggest that pro-inflammatory responses detected at birth are modestly associated with protection from P. falciparum infection but not necessarily clinical malaria once infected.

Recent studies of immune responses assessed after birth but early in life (<5 years) have provided further insight into potential roles of innate and early adaptive immunity in mitigating malaria risk. IgM antibodies to the α-gal glycan, which is expressed by pathogens including Plasmodium spp. and higher organisms except for birds, fish, and humans, can specifically inhibit hepatocyte invasion by Plasmodium sporozoites and have been shown to have an association with protection from clinical malaria, but not P. falciparum infection, in infants [64,65]. Higher production of pro-inflammatory cytokines, particular TNF, by P. falciparum-stimulated peripheral blood mononuclear cells isolated from Mozambican children up to 2 years of age was associated with reduced incidence of clinical malaria during the following 2 years of follow up [66]. In a systems vaccinology analysis of the PfSPZ malaria vaccine trial conducted in Kenyan infants mentioned above, we observed that innate immune activation and myeloid blood signatures at study baseline were associated with protection from P. falciparum parasitemia in placebo controls through 3 months of active and passive surveillance [13]. Despite being relatively immature, the malaria-specific antibody responses of very young children can control parasitemia and symptomatic malaria to some extent. IgM+ B cells specific for P. falciparum isolated from young Malian children aged 0–4 years have been shown to proliferate in response to acute malaria, and IgM isolated from these children can inhibit parasite growth in vitro [67]. In a longitudinal cohort of Papa New Guinean children aged 1–3 years, antibodies to PfEMP1 Group 2 DBLα variants were associated with reduced prospective risk of clinical malaria [68].

Age-dependent changes in circulating innate cells may partially explain the observed decreased risk of parasitemia in the youngest children. A subset of γδ T cells called Vγ9Vδ2+ T cells (or Vδ2+ T cells) respond to phosphoantigens produced by bacteria and parasites, including Plasmodium, and rapidly proliferate immediately after birth [69]. In a high-malaria transmission setting in Uganda, Vδ2+ T cell counts sharply decline after this initial expansion until ∼4 years of age, but both the frequency and function of these Vδ2+ T cells were observed to correlate with protection from P. falciparum infection [70]. Additional studies are needed to confirm these findings and further assess whether other innate responses early in life correlate with reduced prospective risk of P. falciparum infection. However, such studies are difficult to conduct as they are resource intensive. Blood samples must be collected longitudinally at frequent intervals (e.g. every 2 weeks) followed by retrospective molecular analysis of samples to determine time-to-first infection (Figure 1A). Additionally, there are ethical and practical considerations that restrict the frequency and volume of blood obtained from young children. However, as multiomic technologies become more democratized, systems-based approaches would allow researchers to maximize the use of limited samples obtained from the youngest and most vulnerable children, potentially providing greater insight in the cellular immune response against the establishment of blood-stage infection early in life.

As noted in the Introduction, prospective field studies that define malaria protection as absence of P. falciparum infection or clinical malaria can potentially misclassify individuals as protected when they were either never exposed to infectious mosquito bites or malaria events were not fully captured due to insensitive detection or insufficient sampling [71]. For clinical episodes, this can be addressed by measuring the time from incident parasitemia to malarial symptoms in individuals with documented parasitemia and serves as a more reliable assessment of blood-stage immunity [47,72]. However, assessing pre-erythrocytic immunity in field studies poses additional challenges. In time-to-infection studies, not only can the non-malaria exposed be misclassified as protected, but the time-to-infection metric is, in essence, a time-to-detectable parasitemia metric and cannot distinguish between pre-erythrocytic and early blood-stage immunity [73]. In fact, it has been suggested that differences in time-to-detectable parasitemia can be largely attributable to acquisition of immunity that inhibits blood-stage growth [73]. Highly sensitive molecular detection of asexual parasites using larger blood volumes combined with more frequent sampling can address these issues to some extent but are resource intensive and thus impractical for large-scale field studies. A more scalable approach would be to confirm malaria exposure by measuring increases in antibodies specific for antigens from either Anopheles salivary glands [74] or the pre-erythrocytic or erythrocytic stages of the parasite [75,76] during the surveillance period. The application of down-selected protein microarrays containing hundreds of P. falciparum antigens from multiple stages would facilitate such studies [77,78].

The biology of malaria transmission, infection, and disease is undoubtedly complex given the Plasmodium parasite's requirement for both mosquito and vertebrate hosts. Studying human immunity to the malaria infection in the field is made even more complex by the myriad of factors extrinsic to the host that may confound our interpretation of what constitutes protection against liver-stage infection, elite control of blood-stage growth, and lack of malaria exposure. The ‘aparasitemic’ phenotype described in this review can only be identified in prospective studies with high-resolution active infection surveillance, ideally using sensitive molecular detection of parasitemia. Such studies would require at least 200 children, as this unique phenotype represents only a small proportion of children when followed for more than a year, such was the case for the Tanzanian cohort noted above, where only 9.2% remained free of parasitemia [15]. Computational advances have allowed us to address complex biological questions using unbiased approaches that considers not only high-dimensional molecular and cellular features from the host's peripheral blood (e.g. bulk and single-cell transcriptomics, metabolomics, functional antibody profiling) but also individual and population-level metadata such as exposure history and transmission intensity. Moving forward, integrated and comprehensive systems-based analyses that attempt to evaluate as many intrinsic and extrinsic features available would allow researchers to maximize the use of limited samples obtained from the youngest and most vulnerable children. This would potentially provide greater insight in the cellular immune response against the establishment of P. falciparum blood-stage infection early in life and generate new hypotheses that could be validated in other cohorts or experimentally using animal and in vitro cell culture models.

  • The observation that infants and young children living in settings of intense malaria transmission have less malaria infections than what would otherwise be expected for their level of immunity has long intrigued researchers.

  • Although factors extrinsic to the young host's immune system have been proposed as explanations for this observation, including reduced malaria exposure and maternally transferred immune factors, more recent evidence has suggested that innate and early adaptive immune responses contribute to protection from clinical malaria.

  • Moving forward, unbiased systems-based approaches would maximize the use of limited samples obtained from the youngest and most vulnerable children, potentially provide greater insight in the cellular immune response against the establishment of P. falciparum blood-stage infection early in life.

The authors declare that there are no competing interests associated with the manuscript.

This work was supported by NIH NIAID grants R21AI156443, K08AI125682, and R01AI158719.

EIR

entomological inoculation rate

PfSPZ

P. falciparum sporozoite

RDT

rapid diagnostic tests

1
World Health Organization
. (
2023
)
World Malaria Report 2023
,
World Health Organization
,
Geneva, Switzerland
.
2
Pringle
,
G.
(
1964
)
Some factors affecting the detection of residual transmission in malaria eradication schemes in Africa
.
Bull. World Health Organ.
30
,
858
862
3
Pringle
,
G.
,
Draper
,
C.C.
and
Clyde
,
D.F.
(
1960
)
A new approach to the measurement of residual transmission in a malaria control scheme in East Africa
.
Trans. R. Soc. Trop. Med. Hyg.
54
,
434
438
4
Macdonald
,
G.
(
1950
)
The analysis of malaria parasite rates in infants
.
Trop. Dis. Bull.
47
,
915
938
5
Riley
,
E.M.
,
Wagner
,
G.E.
,
Akanmori
,
B.D.
and
Koram
,
K.A.
(
2001
)
Do maternally acquired antibodies protect infants from malaria infection?
Parasite Immunol.
23
,
51
59
6
Dobbs
,
K.R.
and
Dent
,
A.E.
(
2016
)
Plasmodium malaria and antimalarial antibodies in the first year of life
.
Parasitology
143
,
129
138
7
Feeney
,
M.E.
(
2020
)
The immune response to malaria in utero
.
Immunol. Rev.
293
,
216
229
8
Doumbe-Belisse
,
P.
,
Kopya
,
E.
,
Ngadjeu
,
C.S.
,
Sonhafouo-Chiana
,
N.
,
Talipouo
,
A.
,
Djamouko-Djonkam
,
L.
et al. (
2021
)
Urban malaria in sub-Saharan Africa: dynamic of the vectorial system and the entomological inoculation rate
.
Malar. J.
20
,
364
9
Yaro
,
J.B.
,
Tiono
,
A.B.
,
Ouedraogo
,
A.
,
Lambert
,
B.
,
Ouedraogo
,
Z.A.
,
Diarra
,
A.
et al. (
2022
)
Risk of Plasmodium falciparum infection in south-west Burkina Faso: potential impact of expanding eligibility for seasonal malaria chemoprevention
.
Sci. Rep.
12
,
1402
10
Tran
,
T.M.
,
Li
,
S.
,
Doumbo
,
S.
,
Doumtabe
,
D.
,
Huang
,
C.Y.
,
Dia
,
S.
et al. (
2013
)
An intensive longitudinal cohort study of Malian children and adults reveals no evidence of acquired immunity to Plasmodium falciparum infection
.
Clin. Infect. Dis.
57
,
40
47
11
Tran
,
T.M.
,
Guha
,
R.
,
Portugal
,
S.
,
Skinner
,
J.
,
Ongoiba
,
A.
,
Bhardwaj
,
J.
et al. (
2019
)
A molecular signature in blood reveals a role for p53 in regulating malaria-induced inflammation
.
Immunity
51
,
750
765 e10
12
Oneko
,
M.
,
Steinhardt
,
L.C.
,
Yego
,
R.
,
Wiegand
,
R.E.
,
Swanson
,
P.A.
,
Kc
,
N.
et al. (
2021
)
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.
27
,
1636
1645
13
Senkpeil
,
L.
,
Bhardwaj
,
J.
,
Little
,
M.R.
,
Holla
,
P.
,
Upadhye
,
A.
,
Fusco
,
E.M.
et al. (
2024
)
Innate immune activation restricts priming and protective efficacy of the radiation-attenuated PfSPZ malaria vaccine
.
JCI Insight
e167408
14
Alonso
,
P.L.
,
Sacarlal
,
J.
,
Aponte
,
J.J.
,
Leach
,
A.
,
Macete
,
E.
,
Milman
,
J.
et al. (
2004
)
Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial
.
Lancet
364
,
1411
1420
15
Nash
,
S.D.
,
Prevots
,
D.R.
,
Kabyemela
,
E.
,
Khasa
,
Y.P.
,
Lee
,
K.L.
,
Fried
,
M.
et al. (
2017
)
A malaria-resistant phenotype with immunological correlates in a Tanzanian birth cohort exposed to intense malaria transmission
.
Am. J. Trop. Med. Hyg.
96
,
1190
1196
16
Okell
,
L.C.
,
Bousema
,
T.
,
Griffin
,
J.T.
,
Ouedraogo
,
A.L.
,
Ghani
,
A.C.
and
Drakeley
,
C.J.
(
2012
)
Factors determining the occurrence of submicroscopic malaria infections and their relevance for control
.
Nat. Commun.
3
,
1237
17
Amoah
,
L.E.
,
Donu
,
D.
,
Abuaku
,
B.
,
Ahorlu
,
C.
,
Arhinful
,
D.
,
Afari
,
E.
et al. (
2019
)
Probing the composition of Plasmodium species contained in malaria infections in the Eastern region of Ghana
.
BMC Public Health
19
,
1617
18
Salgado
,
C.
,
Ayodo
,
G.
,
Macklin
,
M.D.
,
Gould
,
M.P.
,
Nallandhighal
,
S.
,
Odhiambo
,
E.O.
et al. (
2021
)
The prevalence and density of asymptomatic Plasmodium falciparum infections among children and adults in three communities of western Kenya
.
Malar. J.
20
,
371
19
Goncalves
,
B.P.
,
Kapulu
,
M.C.
,
Sawa
,
P.
,
Guelbeogo
,
W.M.
,
Tiono
,
A.B.
,
Grignard
,
L.
et al. (
2017
)
Examining the human infectious reservoir for Plasmodium falciparum malaria in areas of differing transmission intensity
.
Nat. Commun.
8
,
1133
20
Gul
,
D.
,
Rodriguez-Rodriguez
,
D.
,
Nate
,
E.
,
Auwan
,
A.
,
Salib
,
M.
,
Lorry
,
L.
et al. (
2021
)
Investigating differences in village-level heterogeneity of malaria infection and household risk factors in Papua New Guinea
.
Sci. Rep.
11
,
16540
21
Coalson
,
J.E.
,
Cohee
,
L.M.
,
Buchwald
,
A.G.
,
Nyambalo
,
A.
,
Kubale
,
J.
,
Seydel
,
K.B.
et al. (
2018
)
Simulation models predict that school-age children are responsible for most human-to-mosquito Plasmodium falciparum transmission in southern Malawi
.
Malar. J.
17
,
147
22
Wu
,
L.
,
van den Hoogen
,
L.L.
,
Slater
,
H.
,
Walker
,
P.G.
,
Ghani
,
A.C.
,
Drakeley
,
C.J.
et al. (
2015
)
Comparison of diagnostics for the detection of asymptomatic Plasmodium falciparum infections to inform control and elimination strategies
.
Nature
528
,
S86
S93
23
Langhorne
,
J.
,
Ndungu
,
F.M.
,
Sponaas
,
A.M.
and
Marsh
,
K.
(
2008
)
Immunity to malaria: more questions than answers
.
Nat. Immunol.
9
,
725
732
24
Kamau
,
A.
,
Mtanje
,
G.
,
Mataza
,
C.
,
Mwambingu
,
G.
,
Mturi
,
N.
,
Mohammed
,
S.
et al. (
2020
)
Malaria infection, disease and mortality among children and adults on the coast of Kenya
.
Malar. J.
19
,
210
25
Adomako-Ankomah
,
Y.
,
Chenoweth
,
M.S.
,
Durfee
,
K.
,
Doumbia
,
S.
,
Konate
,
D.
,
Doumbouya
,
M.
et al. (
2017
)
High Plasmodium falciparum longitudinal prevalence is associated with high multiclonality and reduced clinical malaria risk in a seasonal transmission area of Mali
.
PLoS One
12
,
e0170948
26
Buchwald
,
A.G.
,
Sorkin
,
J.D.
,
Sixpence
,
A.
,
Chimenya
,
M.
,
Damson
,
M.
,
Wilson
,
M.L.
et al. (
2019
)
Association between age and Plasmodium falciparum infection dynamics
.
Am. J. Epidemiol.
188
,
169
176
27
Bigira
,
V.
,
Kapisi
,
J.
,
Clark
,
T.D.
,
Kinara
,
S.
,
Mwangwa
,
F.
,
Muhindo
,
M.K.
et al. (
2014
)
Protective efficacy and safety of three antimalarial regimens for the prevention of malaria in young Ugandan children: a randomized controlled trial
.
PLoS Med.
11
,
e1001689
28
Mwangi
,
T.W.
,
Fegan
,
G.
,
Williams
,
T.N.
,
Kinyanjui
,
S.M.
,
Snow
,
R.W.
and
Marsh
,
K.
(
2008
)
Evidence for over-dispersion in the distribution of clinical malaria episodes in children
.
PLoS One
3
,
e2196
29
Mueller
,
I.
,
Schoepflin
,
S.
,
Smith
,
T.A.
,
Benton
,
K.L.
,
Bretscher
,
M.T.
,
Lin
,
E.
et al. (
2012
)
Force of infection is key to understanding the epidemiology of Plasmodium falciparum malaria in Papua New Guinean children
.
Proc. Natl Acad. Sci. U.S.A.
109
,
10030
10035
30
Rodriguez-Barraquer
,
I.
,
Arinaitwe
,
E.
,
Jagannathan
,
P.
,
Boyle
,
M.J.
,
Tappero
,
J.
,
Muhindo
,
M.
et al. (
2016
)
Quantifying heterogeneous malaria exposure and clinical protection in a cohort of Ugandan children
.
J. Infect. Dis.
214
,
1072
1080
31
The PMI Vector Link Project
. (
2020
)
Kenya Annual Entomological Monitoring Report. October 2018–September 2019.
Abt Associates Inc.
Available from:
https://d1u4sg1s9ptc4z.cloudfront.net/uploads/2021/03/kenya-2019-entomological-monitoring-final-report-1.pdf
32
Apinjoh
,
T.O.
,
Anchang-Kimbi
,
J.K.
,
Mugri
,
R.N.
,
Njua-Yafi
,
C.
,
Tata
,
R.B.
,
Chi
,
H.F.
et al. (
2015
)
Determinants of infant susceptibility to malaria during the first year of life in South Western cameroon
.
Open Forum Infect. Dis.
2
,
ofv012
33
Muirhead-Thomson
,
R.C.
(
1951
)
The distribution of anopheline mosquito bites among different age groups; a new factor in malaria epidemiology
.
Br. Med. J.
1
,
1114
1117
34
Boreham
,
P.F.L.
,
Bryan
,
J.H.
and
Port
,
G.R.
(
1980
)
The relationship of host size to feeding by mosquitoes of the Anopheles gambiae Giles complex (Diptera: Culicidae)
.
Bull. Entomol. Res.
70
,
133
144
35
Amaratunga
,
C.
,
Lopera-Mesa
,
T.M.
,
Brittain
,
N.J.
,
Cholera
,
R.
,
Arie
,
T.
,
Fujioka
,
H.
et al. (
2011
)
A role for fetal hemoglobin and maternal immune IgG in infant resistance to Plasmodium falciparum malaria
.
PLoS One
6
,
e14798
36
Pasvol
,
G.
,
Weatherall
,
D.J.
and
Wilson
,
R.J.
(
1977
)
Effects of foetal haemoglobin on susceptibility of red cells to Plasmodium falciparum
.
Nature
270
,
171
173
37
Kangoye
,
D.T.
,
Nebie
,
I.
,
Yaro
,
J.B.
,
Debe
,
S.
,
Traore
,
S.
,
Ouedraogo
,
O.
et al. (
2014
)
Plasmodium falciparum malaria in children aged 0-2 years: the role of foetal haemoglobin and maternal antibodies to two asexual malaria vaccine candidates (MSP3 and GLURP)
.
PLoS One
9
,
e107965
38
Mmbando
,
B.P.
,
Mgaya
,
J.
,
Cox
,
S.E.
,
Mtatiro
,
S.N.
,
Soka
,
D.
,
Rwezaula
,
S.
et al. (
2015
)
Negative epistasis between sickle and foetal haemoglobin suggests a reduction in protection against malaria
.
PLoS One
10
,
e0125929
39
Kariuki
,
S.N.
and
Williams
,
T.N.
(
2020
)
Human genetics and malaria resistance
.
Hum. Genet.
139
,
801
811
40
Aidoo
,
M.
,
Terlouw
,
D.J.
,
Kolczak
,
M.S.
,
McElroy
,
P.D.
,
ter Kuile
,
F.O.
,
Kariuki
,
S.
et al. (
2002
)
Protective effects of the sickle cell gene against malaria morbidity and mortality
.
Lancet
359
,
1311
1312
41
Williams
,
T.N.
,
Mwangi
,
T.W.
,
Roberts
,
D.J.
,
Alexander
,
N.D.
,
Weatherall
,
D.J.
,
Wambua
,
S.
et al. (
2005
)
An immune basis for malaria protection by the sickle cell trait
.
PLoS Med.
2
,
e128
42
Gong
,
L.
,
Maiteki-Sebuguzi
,
C.
,
Rosenthal
,
P.J.
,
Hubbard
,
A.E.
,
Drakeley
,
C.J.
,
Dorsey
,
G.
et al. (
2012
)
Evidence for both innate and acquired mechanisms of protection from Plasmodium falciparum in children with sickle cell trait
.
Blood
119
,
3808
3814
43
Tassi Yunga
,
S.
,
Siriwardhana
,
C.
,
Fouda
,
G.G.
,
Bobbili
,
N.
,
Sama
,
G.
,
Chen
,
J.J.
et al. (
2022
)
Characterization of the primary antibody response to Plasmodium falciparum antigens in infants living in a malaria-endemic area
.
Malar. J.
21
,
346
44
Natama
,
H.M.
,
Moncunill
,
G.
,
Vidal
,
M.
,
Rouamba
,
T.
,
Aguilar
,
R.
,
Santano
,
R.
et al. (
2023
)
Associations between prenatal malaria exposure, maternal antibodies at birth, and malaria susceptibility during the first year of life in Burkina Faso
.
Infect. Immun.
91
,
e0026823
45
Reynaldi
,
A.
,
Dent
,
A.E.
,
Schlub
,
T.E.
,
Ogolla
,
S.
,
Rochford
,
R.
and
Davenport
,
M.P.
(
2019
)
Interaction between maternally derived antibodies and heterogeneity in exposure combined to determine time-to-first Plasmodium falciparum infection in Kenyan infants
.
Malar. J.
18
,
19
46
Dobano
,
C.
,
Santano
,
R.
,
Vidal
,
M.
,
Jimenez
,
A.
,
Jairoce
,
C.
,
Ubillos
,
I.
et al. (
2019
)
Differential patterns of IgG subclass responses to Plasmodium falciparum antigens in relation to malaria protection and RTS,S vaccination
.
Front. Immunol.
10
,
439
47
Tran
,
T.M.
,
Ongoiba
,
A.
,
Coursen
,
J.
,
Crosnier
,
C.
,
Diouf
,
A.
,
Huang
,
C.Y.
et al. (
2014
)
Naturally acquired antibodies specific for Plasmodium falciparum reticulocyte-binding protein homologue 5 inhibit parasite growth and predict protection from malaria
.
J. Infect. Dis.
209
,
789
798
48
Bustamante
,
L.Y.
,
Powell
,
G.T.
,
Lin
,
Y.C.
,
Macklin
,
M.D.
,
Cross
,
N.
,
Kemp
,
A.
et al. (
2017
)
Synergistic malaria vaccine combinations identified by systematic antigen screening
.
Proc. Natl Acad. Sci. U.S.A.
114
,
12045
12050
49
Bermejo-Haro
,
M.Y.
,
Camacho-Pacheco
,
R.T.
,
Brito-Perez
,
Y.
and
Mancilla-Herrera
,
I.
(
2023
)
The hormonal physiology of immune components in breast milk and their impact on the infant immune response
.
Mol. Cell. Endocrinol.
572
,
111956
50
Koren
,
O.
,
Konnikova
,
L.
,
Brodin
,
P.
,
Mysorekar
,
I.U.
and
Collado
,
M.C.
(
2024
)
The maternal gut microbiome in pregnancy: implications for the developing immune system
.
Nat. Rev. Gastroenterol. Hepatol.
21
,
35
45
51
Zheng
,
W.
,
Zhao
,
W.
,
Wu
,
M.
,
Song
,
X.
,
Caro
,
F.
,
Sun
,
X.
et al. (
2020
)
Microbiota-targeted maternal antibodies protect neonates from enteric infection
.
Nature
577
,
543
548
52
Bosshard
,
N.
,
Zbinden
,
A.
,
Eriksson
,
K.K.
and
Forger
,
F.
(
2021
)
Rituximab and canakinumab use during lactation: no detectable serum levels in breastfed infants
.
Rheumatol. Ther.
8
,
1043
1048
53
Bhattacharjee
,
N.V.
,
Schaeffer
,
L.E.
,
Marczak
,
L.B.
,
Ross
,
J.M.
,
Swartz
,
S.J.
,
Albright
,
J.
et al. (
2019
)
Mapping exclusive breastfeeding in Africa between 2000 and 2017
.
Nat. Med.
25
,
1205
1212
54
Wako
,
W.G.
,
Wayessa
,
Z.
and
Fikrie
,
A.
(
2022
)
Effects of maternal education on early initiation and exclusive breastfeeding practices in sub-Saharan Africa: a secondary analysis of Demographic and Health Surveys from 2015 to 2019
.
BMJ Open
12
,
e054302
55
Appiah
,
P.K.
,
Amu
,
H.
,
Osei
,
E.
,
Konlan
,
K.D.
,
Mumuni
,
I.H.
,
Verner
,
O.N.
et al. (
2021
)
Breastfeeding and weaning practices among mothers in Ghana: a population-based cross-sectional study
.
PLoS One
16
,
e0259442
56
Guerrero
,
D.
,
Vo
,
H.T.M.
,
Lon
,
C.
,
Bohl
,
J.A.
,
Nhik
,
S.
,
Chea
,
S.
et al. (
2022
)
Evaluation of cutaneous immune response in a controlled human in vivo model of mosquito bites
.
Nat. Commun.
13
,
7036
57
Arora
,
G.
,
Chuang
,
Y.M.
,
Sinnis
,
P.
,
Dimopoulos
,
G.
and
Fikrig
,
E.
(
2023
)
Malaria: influence of Anopheles mosquito saliva on Plasmodium infection
.
Trends Immunol.
44
,
256
265
58
Donovan
,
M.J.
,
Messmore
,
A.S.
,
Scrafford
,
D.A.
,
Sacks
,
D.L.
,
Kamhawi
,
S.
and
McDowell
,
M.A.
(
2007
)
Uninfected mosquito bites confer protection against infection with malaria parasites
.
Infect. Immun.
75
,
2523
2530
59
Gbedande
,
K.
,
Varani
,
S.
,
Ibitokou
,
S.
,
Houngbegnon
,
P.
,
Borgella
,
S.
,
Nouatin
,
O.
et al. (
2013
)
Malaria modifies neonatal and early-life toll-like receptor cytokine responses
.
Infect. Immun.
81
,
2686
2696
60
Natama
,
H.M.
,
Moncunill
,
G.
,
Rovira-Vallbona
,
E.
,
Sanz
,
H.
,
Sorgho
,
H.
,
Aguilar
,
R.
et al. (
2018
)
Modulation of innate immune responses at birth by prenatal malaria exposure and association with malaria risk during the first year of life
.
BMC Med.
16
,
198
61
Cairns
,
M.
,
Gosling
,
R.
and
Chandramohan
,
D.
(
2009
)
Placental malaria increases malaria risk in the first 30 months of life: not causal
.
Clin. Infect. Dis.
48
,
497
498
; author reply 8–9
62
Sylvester
,
B.
,
Gasarasi
,
D.B.
,
Aboud
,
S.
,
Tarimo
,
D.
,
Massawe
,
S.
,
Mpembeni
,
R.
et al. (
2016
)
Prenatal exposure to Plasmodium falciparum increases frequency and shortens time from birth to first clinical malaria episodes during the first two years of life: prospective birth cohort study
.
Malar. J.
15
,
379
63
Schwarz
,
N.G.
,
Adegnika
,
A.A.
,
Breitling
,
L.P.
,
Gabor
,
J.
,
Agnandji
,
S.T.
,
Newman
,
R.D.
et al. (
2008
)
Placental malaria increases malaria risk in the first 30 months of life
.
Clin. Infect. Dis.
47
,
1017
1025
64
Aguilar
,
R.
,
Ubillos
,
I.
,
Vidal
,
M.
,
Balanza
,
N.
,
Crespo
,
N.
,
Jimenez
,
A.
et al. (
2018
)
Antibody responses to alpha-Gal in African children vary with age and site and are associated with malaria protection
.
Sci. Rep.
8
,
9999
65
Yilmaz
,
B.
,
Portugal
,
S.
,
Tran
,
T.M.
,
Gozzelino
,
R.
,
Ramos
,
S.
,
Gomes
,
J.
et al. (
2014
)
Gut microbiota elicits a protective immune response against malaria transmission
.
Cell
159
,
1277
1289
66
Dobano
,
C.
,
Nhabomba
,
A.J.
,
Manaca
,
M.N.
,
Berthoud
,
T.
,
Aguilar
,
R.
,
Quinto
,
L.
et al. (
2019
)
A balanced proinflammatory and regulatory cytokine signature in young African children is associated with lower risk of clinical malaria
.
Clin. Infect. Dis.
69
,
820
828
67
Hopp
,
C.S.
,
Sekar
,
P.
,
Diouf
,
A.
,
Miura
,
K.
,
Boswell
,
K.
,
Skinner
,
J.
et al. (
2021
)
Plasmodium falciparum-specific IgM B cells dominate in children, expand with malaria, and produce functional IgM
.
J. Exp. Med.
218
,
e20200901
68
Tessema
,
S.K.
,
Nakajima
,
R.
,
Jasinskas
,
A.
,
Monk
,
S.L.
,
Lekieffre
,
L.
,
Lin
,
E.
et al. (
2019
)
Protective immunity against severe malaria in children is associated with a limited repertoire of antibodies to conserved PfEMP1 variants
.
Cell Host Microbe
26
,
579
590 e5
69
Ravens
,
S.
,
Fichtner
,
A.S.
,
Willers
,
M.
,
Torkornoo
,
D.
,
Pirr
,
S.
,
Schoning
,
J.
et al. (
2020
)
Microbial exposure drives polyclonal expansion of innate gammadelta T cells immediately after birth
.
Proc. Natl Acad. Sci. U.S.A.
117
,
18649
18660
70
Jagannathan
,
P.
,
Lutwama
,
F.
,
Boyle
,
M.J.
,
Nankya
,
F.
,
Farrington
,
L.A.
,
McIntyre
,
T.I.
et al. (
2017
)
Vdelta2+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure
.
Sci. Rep.
7
,
11487
71
Bejon
,
P.
,
Warimwe
,
G.
,
Mackintosh
,
C.L.
,
Mackinnon
,
M.J.
,
Kinyanjui
,
S.M.
,
Musyoki
,
J.N.
et al. (
2009
)
Analysis of immunity to febrile malaria in children that distinguishes immunity from lack of exposure
.
Infect. Immun.
77
,
1917
1923
72
Greenhouse
,
B.
,
Ho
,
B.
,
Hubbard
,
A.
,
Njama-Meya
,
D.
,
Narum
,
D.L.
,
Lanar
,
D.E.
et al. (
2011
)
Antibodies to Plasmodium falciparum antigens predict a higher risk of malaria but protection from symptoms once parasitemic
.
J. Infect. Dis.
204
,
19
26
73
Pinkevych
,
M.
,
Chelimo
,
K.
,
Vulule
,
J.
,
Kazura
,
J.W.
,
Moormann
,
A.M.
and
Davenport
,
M.P.
(
2015
)
Time-to-infection by Plasmodium falciparum is largely determined by random factors
.
BMC Med.
13
,
19
74
Kearney
,
E.A.
,
Agius
,
P.A.
,
Chaumeau
,
V.
,
Cutts
,
J.C.
,
Simpson
,
J.A.
and
Fowkes
,
F.J.I.
(
2021
)
Anopheles salivary antigens as serological biomarkers of vector exposure and malaria transmission: a systematic review with multilevel modelling
.
Elife
10
,
e73080
75
Yman
,
V.
,
Tuju
,
J.
,
White
,
M.T.
,
Kamuyu
,
G.
,
Mwai
,
K.
,
Kibinge
,
N.
et al. (
2022
)
Distinct kinetics of antibodies to 111 Plasmodium falciparum proteins identifies markers of recent malaria exposure
.
Nat. Commun.
13
,
331
76
Helb
,
D.A.
,
Tetteh
,
K.K.
,
Felgner
,
P.L.
,
Skinner
,
J.
,
Hubbard
,
A.
,
Arinaitwe
,
E.
et al. (
2015
)
Novel serologic biomarkers provide accurate estimates of recent Plasmodium falciparum exposure for individuals and communities
.
Proc. Natl Acad. Sci. U.S.A.
112
,
E4438
E4447
77
Furtado
,
R.
,
Paul
,
M.
,
Zhang
,
J.
,
Sung
,
J.
,
Karell
,
P.
,
Kim
,
R.S.
et al. (
2023
)
Cytolytic circumsporozoite-specific memory CD4(+) T cell clones are expanded during Plasmodium falciparum infection
.
Nat. Commun.
14
,
7726
78
Obeng-Adjei
,
N.
,
Portugal
,
S.
,
Tran
,
T.M.
,
Yazew
,
T.B.
,
Skinner
,
J.
,
Li
,
S.
et al. (
2015
)
Circulating Th1-cell-type Tfh cells that exhibit impaired B cell help are preferentially activated during acute malaria in children
.
Cell Rep.
13
,
425
439
This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).