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Two chemoattenuated PfSPZ malaria vaccines induce sterile hepatic immunity
The global decline in malaria has stalled
1
, emphasizing the need for vaccines that induce durable sterilizing immunity. Here we optimized regimens for chemoprophylaxis vaccination (CVac), for which aseptic, purified, cryopreserved, infectious
Plasmodium falciparum
sporozoites (PfSPZ) were inoculated under prophylactic cover with pyrimethamine (PYR) (Sanaria PfSPZ-CVac(PYR)) or chloroquine (CQ) (PfSPZ-CVac(CQ))—which kill liver-stage and blood-stage parasites, respectively—and we assessed vaccine efficacy against homologous (that is, the same strain as the vaccine) and heterologous (a different strain) controlled human malaria infection (CHMI) three months after immunization (
https://clinicaltrials.gov/
, NCT02511054 and NCT03083847). We report that a fourfold increase in the dose of PfSPZ-CVac(PYR) from 5.12 × 10
4
to 2 × 10
5
PfSPZs transformed a minimal vaccine efficacy (low dose, two out of nine (22.2%) participants protected against homologous CHMI), to a high-level vaccine efficacy with seven out of eight (87.5%) individuals protected against homologous and seven out of nine (77.8%) protected against heterologous CHMI. Increased protection was associated with Vδ2 γδ T cell and antibody responses. At the higher dose, PfSPZ-CVac(CQ) protected six out of six (100%) participants against heterologous CHMI three months after immunization. All homologous (four out of four) and heterologous (eight out of eight) infectivity control participants showed parasitaemia. PfSPZ-CVac(CQ) and PfSPZ-CVac(PYR) induced a durable, sterile vaccine efficacy against a heterologous South American strain of
P. falciparum
, which has a genome and predicted CD8 T cell immunome that differs more strongly from the African vaccine strain than other analysed African
P. falciparum
strains.
Two malaria vaccines comprising
Plasmodium falciparum
sporozoites and treatment with either pyrimethamine or chloroquine induced durable protective responses against both the African vaccine strain and a heterologous South American strain of
P. falciparum
.
Journal Article
Safety and Efficacy of Immunization with a Late-Liver-Stage Attenuated Malaria Parasite
Efforts to develop a live-attenuated malaria vaccine are advancing. In this report, an engineered sporozoite-based vaccine is presented in a human challenge model, with associated immunologic assessments.
Journal Article
The fever : how malaria has ruled humankind for 500,000 years
Traces the centuries-long battle to treat and prevent malaria in numerous regions of the world while revealing how hundreds of millions of people are infected annually in spite of available preventions.
Book
Sterile protection against human malaria by chemoattenuated PfSPZ vaccine
Immunization with
Plasmodium falciparum
sporozoites under chemoprophylaxis can protect against controlled human malaria infection with the same strain for at least 10 weeks, and protection correlates with polyfunctional T-cell memory.
The search for a malaria vaccine
The best candidates for a malaria vaccine so far have been radiation-attenuated
Plasmodium falciparum
sporozoites (PfSPZ) inoculated by mosquitos, intravenous injection of radiation-attenuated, cryopreserved PfSPZ, and infectious PfSPZ inoculated by mosquitos in people taking chloroquine or mefloquine. Here Stephen Hoffman, Peter Kremsner and colleagues report that inoculation of volunteers taking chloroquine with direct intravenous injection of aseptic, cryopreserved, non-irradiated PfSPZ can induce protection against infection with the same strain for at least ten weeks. The authors show that protection correlates with polyfunctional T-cell memory.
A highly protective malaria vaccine would greatly facilitate the prevention and elimination of malaria and containment of drug-resistant parasites
1
. A high level (more than 90%) of protection against malaria in humans has previously been achieved only by immunization with radiation-attenuated
Plasmodium falciparum
(Pf) sporozoites (PfSPZ) inoculated by mosquitoes
2
,
3
,
4
; by intravenous injection of aseptic, purified, radiation-attenuated, cryopreserved PfSPZ (‘PfSPZ Vaccine’)
5
,
6
; or by infectious PfSPZ inoculated by mosquitoes to volunteers taking chloroquine
7
,
8
,
9
,
10
or mefloquine
11
(chemoprophylaxis with sporozoites). We assessed immunization by direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated PfSPZ (‘PfSPZ Challenge’
12
,
13
) to malaria-naive, healthy adult volunteers taking chloroquine for antimalarial chemoprophylaxis (vaccine approach denoted as PfSPZ-CVac)
14
. Three doses of 5.12 × 10
4
PfSPZ of PfSPZ Challenge
12
,
13
at 28-day intervals were well tolerated and safe, and prevented infection in 9 out of 9 (100%) volunteers who underwent controlled human malaria infection ten weeks after the last dose (group III). Protective efficacy was dependent on dose and regimen. Immunization with 3.2 × 10
3
(group I) or 1.28 × 10
4
(group II) PfSPZ protected 3 out of 9 (33%) or 6 out of 9 (67%) volunteers, respectively. Three doses of 5.12 × 10
4
PfSPZ at five-day intervals protected 5 out of 8 (63%) volunteers. The frequency of Pf-specific polyfunctional CD4 memory T cells was associated with protection. On a 7,455 peptide Pf proteome array, immune sera from at least 5 out of 9 group III vaccinees recognized each of 22 proteins. PfSPZ-CVac is a highly efficacious vaccine candidate; when we are able to optimize the immunization regimen (dose, interval between doses, and drug partner), this vaccine could be used for combination mass drug administration and a mass vaccination program approach to eliminate malaria from geographically defined areas.
Journal Article
Safety, immunogenicity and efficacy of PfSPZ Vaccine against malaria in infants in western Kenya: a double-blind, randomized, placebo-controlled phase 2 trial
The radiation-attenuated
Plasmodium falciparum
sporozoite (PfSPZ) vaccine provides protection against
P. falciparum
infection in malaria-naïve adults. Preclinical studies show that T cell-mediated immunity is required for protection and is readily induced in humans after vaccination. However, previous malaria exposure can limit immune responses and vaccine efficacy (VE) in adults. We hypothesized that infants with less previous exposure to malaria would have improved immunity and protection. We conducted a multi-arm, randomized, double-blind, placebo-controlled trial in 336 infants aged 5–12 months to determine the safety, tolerability, immunogenicity and efficacy of the PfSPZ Vaccine in infants in a high-transmission malaria setting in western Kenya (
NCT02687373
). Groups of 84 infants each received 4.5 × 10
5
, 9.0 × 10
5
or 1.8 × 10
6
PfSPZ Vaccine or saline three times at 8-week intervals. The vaccine was well tolerated; 52 (20.6%) children in the vaccine groups and 20 (23.8%) in the placebo group experienced related solicited adverse events (AEs) within 28 d postvaccination and most were mild. There was 1 grade 3-related solicited AE in the vaccine group (0.4%) and 2 in the placebo group (2.4%). Seizures were more common in the highest-dose group (14.3%) compared to 6.0% of controls, with most being attributed to malaria. There was no significant protection against
P. falciparum
infection in any dose group at 6 months (VE in the 9.0 × 10
5
dose group = −6.5%,
P
= 0.598, the primary statistical end point of the study). VE against clinical malaria 3 months after the last dose in the highest-dose group was 45.8% (
P
= 0.027), an exploratory end point. There was a dose-dependent increase in antibody responses that correlated with VE at 6 months in the lowest- and highest-dose groups. T cell responses were undetectable across all dose groups. Detection of Vδ2
+
Vγ9
+
T cells, which have been correlated with induction of PfSPZ Vaccine T cell immunity and protection in adults, were infrequent. These data suggest that PfSPZ Vaccine-induced T cell immunity is age-dependent and may be influenced by Vδ2
+
Vγ9
+
T cell frequency. Since there was no significant VE at 6 months in these infants, these vaccine regimens will likely not be pursued further in this age group.
The PfSPZ Vaccine does not protect infants from infection with
Plasmodium falciparum
, the major cause of malaria.
Journal Article
Concentration and avidity of antibodies to different circumsporozoite epitopes correlate with RTS,S/AS01E malaria vaccine efficacy
RTS,S/AS01E has been tested in a phase 3 malaria vaccine study with partial efficacy in African children and infants. In a cohort of 1028 subjects from one low (Bagomoyo) and two high (Nanoro, Kintampo) malaria transmission sites, we analysed IgG plasma/serum concentration and avidity to CSP (NANP-repeat and C-terminal domains) after a 3-dose vaccination against time to clinical malaria events during 12-months. Here we report that RTS,S/AS01E induces substantial increases in IgG levels from pre- to post-vaccination (
p
< 0.001), higher in NANP than C-terminus (2855 vs 1297 proportional change between means), and higher concentrations and avidities in children than infants (
p
< 0.001). Baseline CSP IgG levels are elevated in malaria cases than controls (
p
< 0.001). Both, IgG magnitude to NANP (hazard ratio [95% confidence interval] 0.61 [0.48–0.76]) and avidity to C-terminus (0.07 [0.05–0.90]) post-vaccination are significantly associated with vaccine efficacy. IgG avidity to the C-terminus emerges as a significant contributor to RTS,S/AS01E-mediated protection.
RTS,S/AS01E has been tested in a phase 3 malaria vaccine trial and has shown partial efficacy in children and infants. Here, the authors analyze IgG concentration and avidity to CSP in ~1000 participants and show that IgG avidity to the C-terminus of CSP is significantly associated with vaccine-mediated protection.
Journal Article