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Controlled human malaria infection (CHMI) involves the intentional infection of healthy individuals with malaria parasites, close observation of the volunteers, and clearance of the parasite at a predetermined endpoint. Depending on the need, CHMI can be initiated by either sporozoites or the administration of parasite-infected erythrocytes, with each of the two systems offering different advantages and caveats. Among other uses, CHMI has proven to be a useful tool for the evaluation of new malaria interventions, particularly vaccines and drugs. The majority of CHMI studies have been conducted in Europe, the USA and Australia, with only a handful of studies conducted in malaria-endemic countries. The slow adoption of CHMI in malaria-endemic countries may be attributed to a lack of infrastructure and expertise to conduct studies in malaria-endemic countries and the risk of undue influence and coercion as a result of volunteers' vulnerability due to a lack of education and financial situation. With the need to generate results relevant to the target populations, there has recently been an increase in CHMI studies that are being conducted in malaria-endemic countries. The use of CHMI models for the evaluation of preerythrocytic and blood-stage malaria interventions has been attempted in malaria-endemic countries with great success. There is a need for the adoption of a CHMI model for the evaluation of transmission-blocking interventions in malaria-endemic countries. The establishment of such a model in malaria-endemic countries will facilitate the selection of potential transmission-blocking intervention (TBI) candidates and accelerate their development. Here is an overview of CHMI, key challenges and ethical considerations in adopting CHMI for the evaluation of malaria transmission-blocking interventions in malaria-endemic countries.

Malaria control relies heavily on the use of anti-malarial drugs and insecticides against malaria parasites and mosquito vectors. Drug and insecticide resistance threatens the effectiveness of conventional malarial interventions; alternative control approaches are, therefore, needed. The development of malaria transmission-blocking vaccines that target the sexual stages in humans or mosquito vectors is among new approaches being pursued. Here, the immunological mechanisms underlying malaria transmission blocking, status of Pfs25-based vaccines are viewed, as well as approaches and capacity for first in-human evaluation of a transmission-blocking candidate vaccine Pfs25-IMX313/Matrix-M administered to semi-immune healthy individuals in endemic settings. It is concluded that institutions in low and middle income settings should be supported to conduct first-in human vaccine trials in order to stimulate innovative research and reduce the overdependence on developed countries for research and local interventions against many diseases of public health importance.

Background For blood-stage malaria vaccine development, the in vitro growth inhibition assay (GIA) has been widely used to evaluate functionality of vaccine-induced antibodies (Ab), and Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is a leading blood-stage antigen. However, precision, also called “error of assay (EoA)”, in GIA readouts and the source of EoA has not been evaluated systematically. Methods In the Main GIA experiment, 4 different cultures of P. falciparum 3D7 parasites were prepared with red blood cells (RBC) collected from 4 different donors. For each culture, 7 different anti-RH5 Ab (either monoclonal or polyclonal Ab) were tested by GIA at two concentrations on three different days (168 data points). To evaluate sources of EoA in % inhibition in GIA (%GIA), a linear model fit was conducted including donor (source of RBC) and day of GIA as independent variables. In addition, 180 human anti-RH5 polyclonal Ab were tested in a Clinical GIA experiment, where each Ab was tested at multiple concentrations in at least 3 independent GIAs using different RBCs (5,093 data points). The standard deviation (sd) in %GIA and in GIA 50 (Ab concentration that gave 50%GIA) readouts, and impact of repeat assays on 95% confidence interval (95%CI) of these readouts was estimated. Results The Main GIA experiment revealed that the RBC donor effect was much larger than the day effect, and an obvious donor effect was also observed in the Clinical GIA experiment. Both %GIA and log-transformed GIA 50 data reasonably fit a constant sd model, and sd of %GIA and log-transformed GIA 50 measurements were calculated as 7.54 and 0.206, respectively. Taking the average of three repeat assays (using three different RBCs) reduces the 95%CI width in %GIA or in GIA 50 measurements by ~ half compared to a single assay. Conclusions The RBC donor effect (donor-to-donor variance on the same day) in GIA was much bigger than the day effect (day-to-day variance using the same donor’s RBC) at least for the RH5 Ab evaluated in this study; thus, future GIA studies should consider the donor effect. In addition, the 95%CI for %GIA and GIA 50 shown here help when comparing GIA results from different samples/groups/studies; therefore, this study supports future malaria blood-stage vaccine development.

Transmission-blocking vaccines are among the novel tools under development for malaria control and elimination. Understanding the human immune response to the sexual stages of Plasmodium falciparum is essential for progressing transmission-blocking vaccine development. A serosurvey was conducted in Tanzania, from May to August 2022 among 290 participants, consisting of 114 children (5–12 years), 44 adolescents (13–17 years), and 132 adults (18–45 years). The participants were tested for malaria parasites using quantitative polymerase chain reaction, and standardized enzyme-linked immunosorbent assays were performed to detect the presence of IgG antibodies against transmission-blocking target antigens—Pfs230D1M, Pfs48/45, and Pfs25. A set of 10 plasma samples that were reactive to Pfs230DIM and/or Pfs48/45 were tested individually for transmission-reducing activity via standard membrane feeding assays. Of the participants tested, 56% (157/281) had detectable Pfs230D1M antibodies, and 49% (141/290) were positive for Pfs48/45 IgG. Approximately 30% were seropositive for both. However, Pfs25 IgG was not detected in any of the 117 participants tested. The seroprevalence for Pfs230D1M and Pfs48/45 IgG increased significantly with participants’ age, with adults more likely to have antibodies than children: Pfs230D1M (adjusted odds ratio: 3.16, 95% confidence interval: 1.81–5.53, p -value ≤ 0.0001) and Pfs45/48 (OR: 3.06, 95% CI: 1.79–5.25, p ≤ 0.0001). There was no significant difference in antibody titers for Pfs230D1M and Pfs48/45 antibodies across age groups. A significant transmission-reducing activity was observed in 2/10 participants, who were highly reactive to Pfs230D1M and Pfs48/45. Naturally acquired antibody responses to both full-length Pfs48/45 and Pfs230D1M proteins are prevalent and appeared to be stable, suggesting that semi-immune populations may be ideal to evaluate boosting transmission-blocking vaccine candidates.

There is great interest in combining the licensed pre-erythrocytic malaria vaccine R21/Matrix-M® and the blood-stage candidate vaccine RH5.1/Matrix-M® to maximise efficacy against malaria. As protection is understood to be antibody-mediated for both vaccines, the success of a multistage vaccination strategy will be aided by understanding factors that impact the cellular drivers of humoral immunity, e.g. dosing regimen, exposure to malaria, and age. Prior analyses of adult vaccinees showed higher RH5-specific memory B cell responses with delayed fractional versus monthly booster dosing (50-50-10μg at 0-1-6months and 10-10-10μg at 0-1-2months, respectively), but the B cell impact of delayed booster regimens has not yet been evaluated in the target paediatric population. There have also not yet been NANP-specific B cell immunogenicity analyses with R21/Matrix-M. Here, pre- and post-vaccination PBMC from two Phase 1b clinical trials with R21/Matrix-M® (NCT03580824;Kenya) and RH5.1/Matrix-M® (NCT04318002; Tanzania) were analysed by flow cytometry for antigen-specific memory B cell and total (R21) or antigen-specific (RH5) circulating Tfh (cTfh) cell responses. For R21, higher frequencies of NANP-specific activated memory IgG B cells were detected in infants versus adults, and also with a higher Matrix-M® dose (50μg versus 25μg). Both NANP-specific IgG memory B cells and total cTfh cells correlated with anti-NANP serum IgG. For RH5.1, higher previous malaria exposure was associated with increased RH5- specific cTfh and cTfh2 cell frequencies. RH5-specific IgG memory B cell responses were greatest with delayed booster dosing (10-10-10μg at 0-1-6months) compared to monthly or delayed fractional regimens, and correlated with both peak and late time point serum antibody (2-years after final vaccination). Interestingly, while late time point anti-RH5.1 serum IgG concentrations in delayed booster children vaccinees matched previous reports with RH5.1/AS01 delayed fractional dosing in adults (NCT02927145; UK), IgG durability and relationship to RH5-specific B cells differed between these two cohorts. While our conclusions would be strengthened by further analyses in larger clinical trials, our data indicate that age, adjuvant dose, vaccine dose, and timing of final booster vaccination impact antigen-specific cellular responses to malaria vaccines and could thus inform the development of next-generation multi-stage malaria vaccination strategies.

We have previously reported primary endpoints of a clinical trial testing two vaccine platforms for the delivery of Plasmodium vivax malaria DBPRII: viral vectors (ChAd63, MVA), and protein/adjuvant (PvDBPII with 50µg Matrix-M™ adjuvant). Delayed boosting was necessitated due to trial halts during the pandemic and provides an opportunity to investigate the impact of dosing regimens. Here, using flow cytometry – including agnostic definition of B cell populations with the clustering tool CITRUS – we report enhanced induction of DBPRII-specific plasma cell and memory B cell responses in protein/adjuvant versus viral vector vaccinees. Within protein/adjuvant groups, delayed boosting further improved B cell immunogenicity compared to a monthly boosting regimen. Consistent with this, delayed boosting also drove more durable anti-DBPRII serum IgG. In an independent vaccine clinical trial with the P. falciparum malaria RH5.1 protein/adjuvant (50µg Matrix-M™) vaccine candidate, we similarly observed enhanced circulating B cell responses in vaccinees receiving a delayed final booster. Notably, a higher frequency of vaccine-specific (putatively long-lived) plasma cells was detected in the bone marrow of these delayed boosting vaccinees by ELISPOT and correlated strongly with serum IgG. Finally, following controlled human malaria infection with P. vivax parasites in the DBPRII trial, in vivo growth inhibition was observed to correlate with DBPRII-specific B cell and serum IgG responses. In contrast, the CD4+ and CD8+ T cell responses were impacted by vaccine platform but not dosing regimen and did not correlate with in vivo growth inhibition in a challenge model. Taken together, our DBPRII and RH5 data suggest an opportunity for protein/adjuvant dosing regimen optimisation in the context of rational vaccine development against pathogens where protection is antibody-mediated.

A blood-stage Plasmodium falciparum malaria vaccine would provide a second line of defence to complement partially effective or waning immunity conferred by the approved pre-erythrocytic vaccines. RH5.1 is a soluble protein vaccine candidate for blood-stage P falciparum, formulated with Matrix-M adjuvant to assess safety and immunogenicity in a malaria-endemic adult and paediatric population for the first time. We did a non-randomised, phase 1b, single-centre, dose-escalation, age de-escalation, first-in-human trial of RH5.1/Matrix-M in Bagamoyo, Tanzania. We recruited healthy adults (aged 18–45 years) and children (aged 5–17 months) to receive the RH5.1/Matrix-M vaccine candidate in the following three-dose regimens: 10 μg RH5.1 at 0, 1, and 2 months (Adults 10M), and the higher dose of 50 μg RH5.1 at 0 and 1 month and 10 μg RH5.1 at 6 months (delayed-fractional third dose regimen; Adults DFx). Children received either 10 μg RH5.1 at 0, 1, and 2 months (Children 10M) or 10 μg RH5.1 at 0, 1, and 6 months (delayed third dose regimen; Children 10D), and were recruited in parallel, followed by children who received the dose-escalation regimen (Children DFx) and children with higher malaria pre-exposure who also received the dose-escalation regimen (High Children DFx). All RH5.1 doses were formulated with 50 μg Matrix-M adjuvant. Primary outcomes for vaccine safety were solicited and unsolicited adverse events after each vaccination, along with any serious adverse events during the study period. The secondary outcome measures for immunogenicity were the concentration and avidity of anti-RH5.1 serum IgG antibodies and their percentage growth inhibition activity (GIA) in vitro, as well as cellular immunogenicity to RH5.1. All participants receiving at least one dose of vaccine were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT04318002, and is now complete. Between Jan 25, 2021, and April 15, 2021, we recruited 12 adults (six [50%] in the Adults 10M group and six [50%] in the Adults DFx group) and 48 children (12 each in the Children 10M, Children 10D, Children DFx, and High Children DFx groups). 57 (95%) of 60 participants completed the vaccination series and 55 (92%) completed 22 months of follow-up following the third vaccination. Vaccinations were well-tolerated across both age groups. There were five serious adverse events involving four child participants during the trial, none of which were deemed related to vaccination. RH5-specific T cell and serum IgG antibody responses were induced by vaccination and purified total IgG showed in vitro GIA against P falciparum. We found similar functional quality (ie, GIA per μg RH5-specific IgG) across all age groups and dosing regimens at 14 days after the final vaccination; the concentration of RH5.1-specific polyclonal IgG required to give 50% GIA was 14·3 μg/mL (95% CI 13·4–15·2). 11 children were vaccinated with the delayed third dose regimen and showed the highest median anti-RH5 serum IgG concentration 14 days following the third vaccination (723 μg/mL [IQR 511–1000]), resulting in all 11 who received the full series showing greater than 60% GIA following dilution of total IgG to 2·5 mg/mL (median 88% [IQR 81–94]). The RH5.1/Matrix-M vaccine candidate shows an acceptable safety and reactogenicity profile in both adults and 5–17-month-old children residing in a malaria-endemic area, with all children in the delayed third dose regimen reaching a level of GIA previously associated with protective outcome against blood-stage P falciparum challenge in non-human primates. These data support onward efficacy assessment of this vaccine candidate against clinical malaria in young African children. The European and Developing Countries Clinical Trials Partnership; the UK Medical Research Council; the UK Department for International Development; the National Institute for Health and Care Research Oxford Biomedical Research Centre; the Division of Intramural Research, National Institute of Allergy and Infectious Diseases; the US Agency for International Development; and the Wellcome Trust.

Background Malaria transmission depends on the presence of gametocytes in the peripheral blood of infected human hosts. Understanding malaria infectious reservoirs enables transmission-blocking interventions to target the most important hosts for the disease. This study characterized the distribution of gametocyte carriage as a baseline for the clinical evaluation of a Pfs25-based transmission-blocking vaccine candidate in Bagamoyo, Tanzania. Methods A malaria survey was conducted in five locations from May to August 2022. A total of 467 participants—192 children (5–12 years), 65 adolescents (13–17 years) and 210 adults (18–45 years)—were enrolled. Malaria was detected using three methods: rapid diagnostic tests, light microscopy and quantitative polymerase chain reaction. The geometric mean of the gametocyte density, and weighted arithmetic mean of the gametocytes sex ratio were estimated. Results Overall, 23.5% (110/467) of the participants tested positive for malaria parasites, with the majority of positives (> 92%) being Plasmodium falciparum. The overall gametocytaemia was 5.6%, with a percent positivity of 6.8% (13/192), 6.2% (4/65) and 4.3% (9/210), in children, adolescents, and adults, respectively. The geometric mean gametocyte density (gametocytes/μL) was greater in adults (124.6) than in children (71.7) and adolescents (50.5). Regression analysis revealed that gametocytes were more likely to be present among male participants than among female participants [ORa: 2.79 (95% CI: 1.19 – 6.59) p = 0.019]. The gametocyte sex ratio in children and adult gametocyte carriers was similar but greater than that in adolescents . Conclusion The observed gametocyte densities and distribution across age groups suggest the need for malaria transmission-blocking interventions to target all populations in heterogeneous transmission settings. The implication of targeting only children may leave residual malaria transmission and reinfection from the left-out groups. Graphical abstract

For blood-stage malaria vaccine development, the in vitro growth inhibition assay (GIA) has been widely used to evaluate functionality of vaccine-induced antibodies (Ab), and Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is a leading blood-stage antigen. However, precision, also called \"error of assay (EoA)\", in GIA readouts and the source of EoA has not been evaluated systematically. In the Main GIA experiment, 4 different cultures of P. falciparum 3D7 parasites were prepared with red blood cells (RBC) collected from 4 different donors. For each culture, 7 different anti-RH5 Ab (either monoclonal or polyclonal Ab) were tested by GIA at two concentrations on three different days (168 data points). To evaluate sources of EoA in % inhibition in GIA (%GIA), a linear model fit was conducted including donor (source of RBC) and day of GIA as independent variables. In addition, 180 human anti-RH5 polyclonal Ab were tested in a Clinical GIA experiment, where each Ab was tested at multiple concentrations in at least 3 independent GIAs using different RBCs (5,093 data points). The standard deviation (sd) in %GIA and in GIA.sub.50 (Ab concentration that gave 50%GIA) readouts, and impact of repeat assays on 95% confidence interval (95%CI) of these readouts was estimated. The Main GIA experiment revealed that the RBC donor effect was much larger than the day effect, and an obvious donor effect was also observed in the Clinical GIA experiment. Both %GIA and log-transformed GIA.sub.50 data reasonably fit a constant sd model, and sd of %GIA and log-transformed GIA.sub.50 measurements were calculated as 7.54 and 0.206, respectively. Taking the average of three repeat assays (using three different RBCs) reduces the 95%CI width in %GIA or in GIA.sub.50 measurements by half compared to a single assay. The RBC donor effect (donor-to-donor variance on the same day) in GIA was much bigger than the day effect (day-to-day variance using the same donor's RBC) at least for the RH5 Ab evaluated in this study; thus, future GIA studies should consider the donor effect. In addition, the 95%CI for %GIA and GIA.sub.50 shown here help when comparing GIA results from different samples/groups/studies; therefore, this study supports future malaria blood-stage vaccine development.

Abstract Background Malaria transmission depends on the presence of gametocytes in the peripheral blood of infected human hosts. Understanding malaria infectious reservoirs enables transmission-blocking interventions to target the most important hosts for the disease. This study characterized the distribution of gametocyte carriage as a baseline for the clinical evaluation of a Pfs25-based transmission-blocking vaccine candidate in Bagamoyo, Tanzania. Methods A malaria survey was conducted in five locations from May to August 2022. A total of 467 participants—192 children (5–12 years), 65 adolescents (13–17 years) and 210 adults (18–45 years)—were enrolled. Malaria was detected using three methods: rapid diagnostic tests, light microscopy and quantitative polymerase chain reaction. The geometric mean of the gametocyte density, and weighted arithmetic mean of the gametocytes sex ratio were estimated. Results Overall, 23.5% (110/467) of the participants tested positive for malaria parasites, with the majority of positives (> 92%) being Plasmodium falciparum. The overall gametocytaemia was 5.6%, with a percent positivity of 6.8% (13/192), 6.2% (4/65) and 4.3% (9/210), in children, adolescents, and adults, respectively. The geometric mean gametocyte density (gametocytes/μL) was greater in adults (124.6) than in children (71.7) and adolescents (50.5). Regression analysis revealed that gametocytes were more likely to be present among male participants than among female participants [ORa: 2.79 (95% CI: 1.19 – 6.59) p = 0.019]. The gametocyte sex ratio in children and adult gametocyte carriers was similar but greater than that in adolescents. Conclusion The observed gametocyte densities and distribution across age groups suggest the need for malaria transmission-blocking interventions to target all populations in heterogeneous transmission settings. The implication of targeting only children may leave residual malaria transmission and reinfection from the left-out groups. Graphical abstract