In vitro production of infectious Plasmodium falciparum sporozoites.

An effective vaccine is needed for the prevention and elimination of malaria. The only immunogens that have been shown to have a protective efficacy of more than 90% against human malaria are Plasmodium falciparum (Pf) sporozoites (PfSPZ) manufactured in mosquitoes (mPfSPZ)1-7. The ability to produce PfSPZ in vitro (iPfSPZ) without mosquitoes would substantially enhance the production of PfSPZ vaccines and mosquito-stage malaria research, but this ability is lacking. Here we report the production of hundreds of millions of iPfSPZ. iPfSPZ invaded human hepatocytes in culture and developed to mature liver-stage schizonts expressing P. falciparum merozoite surface protein 1 (PfMSP1) in numbers comparable to mPfSPZ. When injected into FRGhuHep mice containing humanized livers, iPfSPZ invaded the human hepatocytes and developed to PfMSP1-expressing late liver stage parasites at 45% the quantity of cryopreserved mPfSPZ. Human blood from FRGhuHep mice infected with iPfSPZ produced asexual and sexual erythrocytic-stage parasites in culture, and gametocytes developed to PfSPZ when fed to mosquitoes, completing the P. falciparum life cycle from infectious gametocyte to infectious gametocyte without mosquitoes or primates.

Understanding referral of patients with cancer in rural Ethiopia: a qualitative study.

BACKGROUND: Cancer incidence is increasing in Ethiopia mainly due to increased life expectancy, while oncological capacities remain limited. Strong referral linkages between different levels of the healthcare system are key to provide timely access to cancer care. In this qualitative study, we assessed limitations and potential of cancer patient referral in the rural Southwest of Ethiopia. METHODS: We held four focus group discussions (FGD) with health professionals at one primary and three secondary hospitals and conducted eight in-depth interviews (IDI) with the hospitals´ medical executives and local health bureau representatives. Data was analysed inductively using thematic analysis and emerging themes were categorized within the revised concept of access by Penchansky and Saurman. RESULTS: The inevitable referral of patients with cancer in the rural Southwest of Ethiopia is characterized by the absence of clear communication protocols and the lack of formal referral linkages. The newly implemented hub-system has improved emergency referrals and could be expanded to non-emergency referrals, sensitive to the needs of advanced oncological care. Liaison officers can pave the way but need to be trained and equipped adequately. Referred patients struggle with inadequate transportation systems, the lack of accommodation close to specialized facilities as well as the inability to navigate at those sites due to language barriers, illiteracy, and stigmatization. Few Non-Governmental Organizations (NGOs) help but cannot compensate the limited governmental support. The shortage of medications at public hospitals leads to patients being directed to costly private pharmacies. In the light of those challenges, cancer remains to be perceived as a "death sentence" within the rural communities. CONCLUSIONS: Standardized referral linkages and a multi-faceted support network throughout the cancer care continuum are necessary to make oncology care accessible to Ethiopia´s large rural population.

PfSPZ-CVac efficacy against malaria increases from 0% to 75% when administered in the absence of erythrocyte stage parasitemia: A randomized, placebo-controlled trial with controlled human malaria infection.

PfSPZ-CVac combines 'PfSPZ Challenge', which consists of infectious Plasmodium falciparum sporozoites (PfSPZ), with concurrent antimalarial chemoprophylaxis. In a previously-published PfSPZ-CVac study, three doses of 5.12x104 PfSPZ-CVac given 28 days apart had 100% vaccine efficacy (VE) against controlled human malaria infection (CHMI) 10 weeks after the last immunization, while the same dose given as three injections five days apart had 63% VE. Here, we conducted a dose escalation trial of similarly condensed schedules. Of the groups proceeding to CHMI, the first study group received three direct venous inoculations (DVIs) of a dose of 5.12x104 PfSPZ-CVac seven days apart and the next full dose group received three DVIs of a higher dose of 1.024x105 PfSPZ-CVac five days apart. CHMI (3.2x103 PfSPZ Challenge) was performed by DVI 10 weeks after the last vaccination. In both CHMI groups, transient parasitemia occurred starting seven days after each vaccination. For the seven-day interval group, the second and third vaccinations were therefore administered coincident with parasitemia from the prior vaccination. Parasitemia was associated with systemic symptoms which were severe in 25% of subjects. VE in the seven-day group was 0% (7/7 infected) and in the higher-dose, five-day group was 75% (2/8 infected). Thus, the same dose of PfSPZ-CVac previously associated with 63% VE when given on a five-day schedule in the prior study had zero VE here when given on a seven-day schedule, while a double dose given on a five-day schedule here achieved 75% VE. The relative contributions of the five-day schedule and/or the higher dose to improved VE warrant further investigation. It is notable that administration of PfSPZ-CVac on a schedule where vaccine administration coincided with blood-stage parasitemia was associated with an absence of sterile protective immunity. Clinical trials registration: NCT02773979.

Determinants of willingness to pay for community-based health insurance scheme among households in rural community of southern Ethiopia.

BACKGROUND: Community-based health insurance programs are being acknowledged as effective strategies to attain universal health coverage and mitigate the financial catastrophic shock of the community. Even though Ethiopia has been focusing on the implementation and expansion of a community-based health insurance (CBHI) program since 2011, only a small number of people are enrolled, which might be attributed to a lack of willingness towards the program. The purpose of this study is to determine the willingness to pay for community-based health insurance and associated factors among households in the rural community of Gombora District, Hadiya Zone, southern Ethiopia. METHODS: Using the multistage systematic random sampling technique, a sample of 421 households was chosen for a community-based cross-sectional study. The desired information was gathered using a pre-tested, structured, interviewer-administered questionnaire. The data was entered using Epi-Data V3.1 and exported to SPSS version 24.0 for statistical analysis. Bivariable and multivariable logistic regression analyses were performed to determine the variables associated with the willingness to pay for community-based health insurance. RESULTS: The study showed that 67.1% of respondents expressed a willingness to pay for community-based health insurance. The mean amount of money they are willing to pay for the scheme is 178.41 (± 57.21) Ethiopian Birr (ETB), or 6.43 (± 2.06) USD per household per annum in 2020. Based on multiple logistic regression analysis, belonging to Rich household compared to poor (AOR: 2.78, 95% CI: 1.54, 5.03), having a household head who can read and write (AOR: 2.90, 95% CI: 1.39, 6.05), family size greater than five (AOR: 1.76, 95% CI: 1.06, 2.92), indigenous community insurance (iddir) participation (AOR: 2.83, 95% CI: 1.61, 4.96), and the presence of chronic illness (AOR: 1.94, 95% CI: 1.21, 3.12), were significantly associated with the willingness to pay for a CBHI scheme. CONCLUSION: Households' willingness to pay for a CBHI scheme was found to be significantly influenced by poor household wealth status, household heads who cannot read and write, households with less than or equal to five family members, households who participate in greater or equal to two indigenous community insurance participations, and the absence of chronic illness within the household. Therefore, factors affecting households' willingness to pay should be considered and massive community mobilization needs to be done to strengthen and increase household membership during the implementation of the CBHI scheme, especially in rural areas.

"Magnitude of community-based health insurance utilization and associated factors in Bassona Worena District, North Shoa Zone, Ethiopia: a community-based cross-sectional study".

INTRODUCTION: The health insurance system has been proven to offer effective and efficient health care for the community, particularly community-based health insurance is expected to ensure health care access for people with low economic status and vulnerable groups. Despite the significance of evidence-based systems and implementation, there is a limited report about the magnitude of CBHI utilization. Therefore, this study was done to assess factors associated with community-based health insurance utilization in Basona Worena District, North Shewa Zone, Ethiopia. METHOD: A community-based cross-sectional study was employed. We have included 530 households from 6 randomly selected kebeles. The data was entered using Epi-Data V 3.1 and exported to SPSS version 20.0 for statistical analysis. Bi-variable and multivariable logistic regression analyses were computed to determine factors associated with community-based health insurance utilization. RESULT: The study finding shows that 58.6% of the respondents were members of community-based health insurance. Respondents who had primary and secondary education levels were 2 times more likely to be members than those who had no formal education. As compared to those who had awareness, respondents who had no awareness about CBHI were 0.27 times less likely to be insured. Respondents who did not experience illness were 0.27 times less likely to be members than respondents who experienced illness. CONCLUSION: Educational status, awareness about CBHI, perception of CBHI scheme and illness experience of family influence CBHI utilization. There is a need to strengthen awareness creation to improve the CBHI utilization.

Serologic Markers of Previous Malaria Exposure and Functional Antibodies Inhibiting Parasite Growth Are Associated With Parasite Kinetics Following a Plasmodium falciparum Controlled Human Infection.

BACKGROUND: We assessed the impact of exposure to Plasmodium falciparum on parasite kinetics, clinical symptoms, and functional immunity after controlled human malaria infection (CHMI) in 2 cohorts with different levels of previous malarial exposure. METHODS: Nine adult males with high (sero-high) and 10 with low (sero-low) previous exposure received 3200 P. falciparum sporozoites (PfSPZ) of PfSPZ Challenge by direct venous inoculation and were followed for 35 days for parasitemia by thick blood smear (TBS) and quantitative polymerase chain reaction. Endpoints were time to parasitemia, adverse events, and immune responses. RESULTS: Ten of 10 (100%) volunteers in the sero-low and 7 of 9 (77.8%) in the sero-high group developed parasitemia detected by TBS in the first 28 days (P = .125). The median time to parasitemia was significantly shorter in the sero-low group than the sero-high group (9 days [interquartile range {IQR} 7.5-11.0] vs 11.0 days [IQR 7.5-18.0], respectively; log-rank test, P = .005). Antibody recognition of sporozoites was significantly higher in the sero-high (median, 17.93 [IQR 12.95-24] arbitrary units [AU]) than the sero-low volunteers (median, 10.54 [IQR, 8.36-12.12] AU) (P = .006). Growth inhibitory activity was significantly higher in the sero-high (median, 21.8% [IQR, 8.15%-29.65%]) than in the sero-low group (median, 8.3% [IQR, 5.6%-10.23%]) (P = .025). CONCLUSIONS: CHMI was safe and well tolerated in this population. Individuals with serological evidence of higher malaria exposure were able to better control infection and had higher parasite growth inhibitory activity. CLINICAL TRIALS REGISTRATION: NCT03496454.

Safety, Tolerability, and Immunogenicity of Plasmodium falciparum Sporozoite Vaccine Administered by Direct Venous Inoculation to Infants and Young Children: Findings From an Age De-escalation, Dose-Escalation, Double-blind, Randomized Controlled Study in Western Kenya.

BACKGROUND: The whole Plasmodium falciparum sporozoite (PfSPZ) vaccine is being evaluated for malaria prevention. The vaccine is administered intravenously for maximal efficacy. Direct venous inoculation (DVI) with PfSPZ vaccine has been safe, tolerable, and feasible in adults, but safety data for children and infants are limited. METHODS: We conducted an age de-escalation, dose-escalation randomized controlled trial in Siaya County, western Kenya. Children and infants (aged 5-9 years, 13-59 months, and 5-12 months) were enrolled into 13 age-dose cohorts of 12 participants and randomized 2:1 to vaccine or normal saline placebo in escalating doses: 1.35 × 105, 2.7 × 105, 4.5 × 105, 9.0 × 105, and 1.8 × 106 PfSPZ, with the 2 highest doses given twice, 8 weeks apart. Solicited adverse events (AEs) were monitored for 8 days after vaccination, unsolicited AEs for 29 days, and serious AEs throughout the study. Blood taken prevaccination and 1 week postvaccination was tested for immunoglobulin G antibodies to P. falciparum circumsporozoite protein (PfCSP) using enzyme-linked immunosorbent assay. RESULTS: Rates of AEs were similar in vaccinees and controls for solicited (35.7% vs 41.5%) and unsolicited (83.9% vs 92.5%) AEs, respectively. No related grade 3 AEs, serious AEs, or grade 3 laboratory abnormalities occurred. Most (79.0%) vaccinations were administered by a single DVI. Among those in the 9.0 × 105 and 1.8 × 106 PfSPZ groups, 36 of 45 (80.0%) vaccinees and 4 of 21 (19.0%) placebo controls developed antibodies to PfCSP (P < .001). CONCLUSIONS: PfSPZ vaccine in doses as high as 1.8 × 106 can be administered to infants and children by DVI, and was safe, well tolerated, and immunogenic. CLINICAL TRIALS REGISTRATION: NCT02687373.

Increase of Dose Associated With Decrease in Protection Against Controlled Human Malaria Infection by PfSPZ Vaccine in Tanzanian Adults.

BACKGROUND: A vaccine would be an ideal tool for reducing malaria's impact. PfSPZ Vaccine (radiation attenuated, aseptic, purified, cryopreserved Plasmodium falciparum [Pf] sporozoites [SPZ]) has been well tolerated and safe in >1526 malaria-naive and experienced 6-month to 65-year-olds in the United States, Europe, and Africa. When vaccine efficacy (VE) of 5 doses of 2.7 × 105 PfSPZ of PfSPZ Vaccine was assessed in adults against controlled human malaria infection (CHMI) in the United States and Tanzania and intense field transmission of heterogeneous Pf in Mali, Tanzanians had the lowest VE (20%). METHODS: To increase VE in Tanzania, we increased PfSPZ/dose (9 × 105 or 1.8 × 106) and decreased numbers of doses to 3 at 8-week intervals in a double blind, placebo-controlled trial. RESULTS: All 22 CHMIs in controls resulted in parasitemia by quantitative polymerase chain reaction. For the 9 × 105 PfSPZ group, VE was 100% (5/5) at 3 or 11 weeks (P < .000l, Barnard test, 2-tailed). For 1.8 × 106 PfSPZ, VE was 33% (2/6) at 7.5 weeks (P = .028). VE of dosage groups (100% vs 33%) was significantly different (P = .022). Volunteers underwent repeat CHMI at 37-40 weeks after last dose. 6/6 and 5/6 volunteers developed parasitemia, but time to first parasitemia was significantly longer than controls in the 9 × 105 PfSPZ group (10.89 vs 7.80 days) (P = .039), indicating a significant reduction in parasites in the liver. Antibody and T-cell responses were higher in the 1.8 × 106 PfSPZ group. CONCLUSIONS: In Tanzania, increasing the dose from 2.7 × 105 to 9 × 105 PfSPZ increased VE from 20% to 100%, but increasing to 1.8 × 106 PfSPZ significantly reduced VE. CLINICAL TRIALS REGISTRATION: NCT02613520.

Dose-Dependent Infectivity of Aseptic, Purified, Cryopreserved Plasmodium falciparum 7G8 Sporozoites in Malaria-Naive Adults.

Direct venous inoculation of 3.2 × 103 aseptic, purified, cryopreserved, vialed Plasmodium falciparum (Pf) strain NF54 sporozoites, PfSPZ Challenge (NF54), has been used for controlled human malaria infection (CHMI) in the United States, 4 European countries, and 6 African countries. In nonimmune adults, this results in 100% infection rates. We conducted a double-blind, randomized, dose-escalation study to assess the infectivity of the 7G8 clone of Pf (PfSPZ Challenge [7G8]). Results showed dose-dependent infectivity from 43% for 8 × 102 PfSPZ to 100% for 4.8 × 103 PfSPZ. PfSPZ Challenge (7G8) will allow for more complete assessment by CHMI of antimalarial vaccines and drugs.

Trends and barriers of emergency medical service use in Addis Ababa; Ethiopia.

BACKGROUND: The increasing burdens of trauma and time sensitive non-communicable disease in Addis Ababa necessitate a robust emergency medical care system. The objectives of this study were to assess the proportion of patients who used emergency medical services (EMS) and to quantitatively and qualitatively assess barriers to EMS utilization in Addis Ababa. METHODS: A cross-sectional quantitative and qualitative study was conducted on patients who visited five selected public hospitals in Addis Ababa with specific emergency conditions. Data were collected by trained nurses using a standardized questionnaire. Descriptive statistics and logistic regression was done on cleaned and coded quantitative data using SPSS version 20. Thematic analysis was performed on the qualitative data. Ethical approval was obtained prior to the study. RESULTS: A total of 429 participants completed the survey with a non-response rate of 5.1%. The most common emergency scene was the home (n = 222, 51.8%) followed by road side (n = 159, 37.1%). Only 87(20.3%) patients arrived by ambulance, though a majority (53.4%) of participants recalled at least one access number for an ambulance service and 96.3% stated that ambulances were an important part of the continuum of care for their emergency condition. A higher proportion of participants believed that ambulance transportation is generally safer (n = 341, 78.5%) and faster (n = 298, 69.5%) than emergency transport by taxi or private car. Patients who were non-Amharic speaking had a negative association with arriving by ambulance (P = 0.001, OR 0.47; C.I, 0.31, 0.71). The median acceptable time to get the ambulance (according to respondent's perception) was 16 min but actually perceived ambulance waiting time was 40 min. CONCLUSION: EMS utilization in Addis Ababa is relatively low and emergency patients are instead being transported by taxi or private car. Perceived longer ambulance waiting time and language barriers may have contributed for low utilization. Findings of this study suggest an action to improve access by improving ambulance availability while simultaneously enhancing the public's knowledge and perception of EMS in Addis Ababa.

Epidemiology of ambulance utilized patients in Addis Ababa, Ethiopia.

BACKGROUND: Well organized and appropriately utilized pre-hospital emergency services play a critical role in augmenting emergency care systems. The primary objective of this study was to understand the demographic and clinical profile of patients who used ambulances in Addis Ababa. The secondary objectives were to assess ambulance response time, transport time and reasons for referral amongst inter-facility transported patients in Addis Ababa. METHODS: The study was designed as a cross-sectional retrospective chart review of ambulance transported patients using ambulance station records from Addis Ababa Fire and Emergency Prevention and Control Authority. With IRB approval, simple random sampling and manual review of six months of clinical records was performed. Data were collected by trained data collectors and descriptive analysis was done using SPSS version 20. RESULTS: Female patients used ambulance services more often than males (female to male ratio of 3:1) and the mean age of the patients was 26 years. The most commonly transported age group was 16-30 years, followed by 31-50 years and neonatal patients (i.e. < 1 month). The majority of the patients had pregnancy related illnesses (n = 492, 61.4%), followed by general medical issues (n = 210, 26.2%) and injury secondary to trauma (n = 99, 12.3%). Most patients (n = 702, 87.6%) were transported for inter-facility transfers, while only 12.4% (n = 99) were primary responses (i.e. from the scene). Prolonged labor was the most common reason (n = 103, 23.4%) for inter-facility transfer of pregnant patients, followed by premature rupture of the amniotic membrane (n = 60, 13.6%). The mean dispatch to scene time interval was 10.1 min, and mean scene to facility time interval was 17.2 min. CONCLUSION: Inter-facility transfers accounted for the largest proportion of ambulance utilization and dispatch in Addis Ababa. Ambulance transport time was twice as long compared to international recommendations of less than eight minutes for emergent transports. The most common reasons for ambulance dispatch were Obstetric. We recommend urgent action to decrease the transport times and to dedicate further pre-hospital resources to address the high burden of inter-facility transfers.

Ambulance use is not associated with patient acuity after road traffic collisions: a cross-sectional study from Addis Ababa, Ethiopia.

BACKGROUND: Africa accounts for one sixth of global road traffic deaths-most in the pre-hospital setting. Ambulance transport is expensive relative to other modes of pre-hospital transport, but has advantages in time-sensitive, high-acuity scenarios. Many countries, including Ethiopia, are expanding ambulance fleets, but clinical characteristics of patients using ambulances remain ill-defined. METHODS: This is a cross-sectional study of 662 road traffic collisions (RTC) patients arriving to a single trauma referral center in Addis Ababa, Ethiopia, over 7 months. Emergency Department triage records were used to abstract clinical and arrival characteristics, including acuity. The outcome of interest was ambulance arrival. Secondary outcomes of interest were inter-facility referral and referral communication. Descriptive and multivariable statistics were computed to identify factors independently associated with outcomes. RESULTS: Over half of patients arrived with either high (13.1%) or moderate (42.2%) acuity. Over half (59.0%) arrived by ambulance, and nearly two thirds (65.9%) were referred. Among referred patients, inter-facility communication was poor (57.7%). Patients with high acuity were most likely to be referred (aOR 2.20, 95%CI 1.16-4.17), but were not more likely to receive ambulance transport (aOR 1.56, 95%CI 0.86-2.84) or inter-facility referral communication (aOR 0.98, 95%CI 0.49-1.94) than those with low acuity. Nearly half (40.2%) of all patients were referred by ambulance despite having low acuity. CONCLUSIONS: Despite ambulance expansion in Addis Ababa, ambulance use among RTC patients remains heavily concentrated among those with low-acuity. Inter-facility referral appears a primary contributor to low-acuity ambulance use. In other contexts, similar routine ambulance monitoring may help identify low-value utilization. Regional guidelines may help direct ambulance use where most valuable, and warrant further evaluation.

Robust, reproducible, industrialized, standard membrane feeding assay for assessing the transmission blocking activity of vaccines and drugs against Plasmodium falciparum.

BACKGROUND: A vaccine that interrupts malaria transmission (VIMT) would be a valuable tool for malaria control and elimination. One VIMT approach is to identify sexual erythrocytic and mosquito stage antigens of the malaria parasite that induce immune responses targeted at disrupting parasite development in the mosquito. The standard Plasmodium falciparum membrane-feeding assay (SMFA) is used to assess transmission-blocking activity (TBA) of antibodies against candidate immunogens and of drugs targeting the mosquito stages. To develop its P. falciparum sporozoite (SPZ) products, Sanaria has industrialized the production of P. falciparum-infected Anopheles stephensi mosquitoes, incorporating quantitative analyses of oocyst and P. falciparum SPZ infections as part of the manufacturing process. METHODS: These capabilities were exploited to develop a robust, reliable, consistent SMFA that was used to assess 188 serum samples from animals immunized with the candidate vaccine immunogen, Pfs25, targeting P. falciparum mosquito stages. Seventy-four independent SMFAs were performed. Infection intensity (number of oocysts/mosquito) and infection prevalence (percentage of mosquitoes infected with oocysts) were compared between mosquitoes fed cultured gametocytes plus normal human O(+) serum (negative control), anti-Pfs25 polyclonal antisera (MRA39 or MRA38, at a final dilution in the blood meal of 1:54 as positive control), and test sera from animals immunized with Pfs25 (at a final dilution in the blood meal of 1:9). RESULTS: SMFA negative controls consistently yielded high infection intensity (mean = 46.1 oocysts/midgut, range of positives 3.7-135.6) and infection prevalence (mean = 94.2%, range 71.4-100.0) and in positive controls, infection intensity was reduced by 81.6% (anti-Pfs25 MRA39) and 97.0% (anti-Pfs25 MRA38), and infection prevalence was reduced by 12.9 and 63.5%, respectively. A range of TBAs was detected among the 188 test samples assayed in duplicate. Consistent administration of infectious gametocytes to mosquitoes within and between assays was achieved, and the TBA of anti-Pfs25 control antibodies was highly reproducible. CONCLUSIONS: These results demonstrate a robust capacity to perform the SMFA in a medium-to-high throughput format, suitable for assessing large numbers of experimental samples of candidate antibodies or drugs.

Evaluation of surveillance system and response for maternal and perinatal mortalities in Meda Welabu District, Ethiopia, 2023.

The weekly disease surveillance system (WDSS) serves as a precursor to possible public health emergencies. The Meda Welabu Woreda Bale Zone in Ethiopia has reporting rates of 87% overall timeliness and 88% completeness in 2023, falling short of the 100% objective. Low reporting rates could mean that epidemics in the province are only discovered later. In the Meda Welabu Woreda Bale Zone of Ethiopia, the study was carried out to assess the WDSS maternal and perinatal death surveillance response (MPDSR). Using the most recent Centers for Disease Control (CDC) criteria for assessing public health monitoring systems, we carried out a descriptive cross-sectional analysis. Data from the health workers were gathered through key informant interviews and questionnaires given by the interviewer. Using checklists, the availability of resources was evaluated. Twenty-two health personnel and twelve Health Extension Workers were questioned; of them, 15 (44%) were females. Nurses made up 18 (53%) of the health personnel. Only sixteen (47%) of the respondents were aware of the WDSS goals, compared to thirty-four (53%) who were aware of the deadlines for submitting data to the next level. A total of eight (24%) responders received training in using the WDSS. 26(76%) respondents said they would be willing to continue participating in the WDSS, whereas 6 (18%) respondents said they had analyzed the data from the WDSS. Of the health facilities, seven (50%) reported having issues with the district public health emergency officer. However, low attention to immediately report on maternal and perinatal death (42.9%). It was concluded that the WDSS was adaptable, reasonable, and easy to use. That was erratic and premature, though. We suggest that healthcare professionals in the province receive training on maternal and perinatal death surveillance response. In Meda Welabu Woreda Bale Zone conducted an evaluation in 2023 of the weekly disease surveillance system, maternal and perinatal death surveillance response. Launched in 1998, the system tracks weekly trends of diseases under surveillance to provide an early warning of any dangers to public health, but maternal and perinatal death surveillance were included on 2013. On the other hand, in 2023, the overall completion and timeliness of reports was 88%, falling short of the 100% aim. Low rates of reporting could mean that outbreaks and quality of service in the province were discovered later than expected. Using current centers for disease control criteria and interviewer-administered data, a descriptive cross-sectional study was undertaken.

Repeat controlled human Plasmodium falciparum infections delay bloodstream patency and reduce symptoms.

Resistance to clinical malaria takes years to develop even in hyperendemic regions and sterilizing immunity has rarely been observed. To evaluate the maturation of the host response against controlled repeat exposures to P. falciparum (Pf) NF54 strain-infected mosquitoes, we systematically monitored malaria-naïve participants through an initial exposure to uninfected mosquitoes and 4 subsequent homologous exposures to Pf-infected mosquitoes over 21 months (n = 8 males) (ClinicalTrials.gov# NCT03014258). The primary outcome was to determine whether protective immunity against parasite infection develops following repeat CHMI and the secondary outcomes were to track the clinical signs and symptoms of malaria and anti-Pf antibody development following repeat CHMI. After two exposures, time to blood stage patency increases significantly and the number of reported symptoms decreases indicating the development of clinical tolerance. The time to patency correlates positively with both anti-Pf circumsporozoite protein (CSP) IgG and CD8 + CD69+ effector memory T cell levels consistent with partial pre-erythrocytic immunity. IFNγ levels decrease significantly during the participants' second exposure to high blood stage parasitemia and could contribute to the decrease in symptoms. In contrast, CD4-CD8 + T cells expressing CXCR5 and the inhibitory receptor, PD-1, increase significantly after subsequent Pf exposures, possibly dampening the memory response and interfering with the generation of robust sterilizing immunity.

Implementation of a Randomized, Placebo-Controlled Trial of Live Attenuated Malaria Sporozoite Vaccines in an Indonesian Military Study Population.

Malaria eradication efforts prioritize safe and efficient vaccination strategies, although none with high-level efficacy against malaria infection are yet available. Among several vaccine candidates, Sanaria® PfSPZ Vaccine and Sanaria PfSPZ-CVac are, respectively, live radiation- and chemo-attenuated sporozoite vaccines designed to prevent infection with Plasmodium falciparum, the leading cause of malaria-related morbidity and mortality. We are conducting a randomized normal saline placebo-controlled trial called IDSPZV1 that will analyze the safety, tolerability, immunogenicity, and efficacy of PfSPZ Vaccine and PfSPZ-CVac administered pre-deployment to malaria-naive Indonesian soldiers assigned to temporary duties in a high malaria transmission area. We describe the manifold challenges of enrolling and immunizing 345 soldier participants at their home base in western Indonesia before their nearly 6,000-km voyage to eastern Indonesia, where they are being monitored for incident P. falciparum and Plasmodium vivax malaria cases during 9 months of exposure. The unique regulatory, ethical, and operational complexities of this trial demonstrate the importance of thorough planning, frequent communication, and close follow-up with stakeholders. Effective engagement with the military community and the ability to adapt to unanticipated events have proven key to the success of this trial.

Safety and protective efficacy of PfSPZ Vaccine administered to HIV-negative and -positive Tanzanian adults.

BACKGROUNDSanaria PfSPZ Vaccine, composed of attenuated Plasmodium falciparum (Pf) sporozoites (SPZ), protects against malaria. We conducted this clinical trial to assess the safety and efficacy of PfSPZ Vaccine in HIV-positive (HIV+) individuals, since the HIV-infection status of participants in mass vaccination programs may be unknown.METHODSThis randomized, double-blind, placebo-controlled trial enrolled 18- to 45-year-old HIV-negative (HIV-) and well-controlled HIV+ Tanzanians (HIV viral load <40 copies/mL, CD4 counts >500 cells/µL). Participants received 5 doses of PfSPZ Vaccine or normal saline (NS) over 28 days, followed by controlled human malaria infection (CHMI) 3 weeks later.RESULTSThere were no solicited adverse events in the 9 HIV- and 12 HIV+ participants. After CHMI, 6 of 6 NS controls, 1 of 5 HIV- vaccinees, and 4 of 4 HIV+ vaccinees were Pf positive by quantitative PCR (qPCR). After immunization, anti-Pf circumsporozoite protein (anti-PfCSP) (isotype and IgG subclass) and anti-PfSPZ antibodies, anti-PfSPZ CD4+ T cell responses, and Vδ2+ γδ CD3+ T cells were nonsignificantly higher in HIV- than in HIV+ vaccinees. Sera from HIV- vaccinees had significantly higher inhibition of PfSPZ invasion of hepatocytes in vitro and antibody-dependent complement deposition (ADCD) and Fcγ3B binding by anti-PfCSP and ADCD by anti-cell-traversal protein for ookinetes and SPZ (anti-PfCelTOS) antibodies.CONCLUSIONSPfSPZ Vaccine was safe and well tolerated in HIV+ vaccinees, but not protective. Vaccine efficacy was 80% in HIV- vaccinees (P = 0.012), whose sera had significantly higher inhibition of PfSPZ invasion of hepatocytes and enrichment of multifunctional PfCSP antibodies. A more potent PfSPZ vaccine or regimen is needed to protect those living with HIV against Pf infection in Africa.TRIAL REGISTRATIONClinicalTrials.gov NCT03420053.FUNDINGEquatorial Guinea Malaria Vaccine Initiative (EGMVI), made up of the Government of Equatorial Guinea Ministries of Mines and Hydrocarbons, and Health and Social Welfare, Marathon Equatorial Guinea Production Limited, Noble Energy, Atlantic Methanol Production Company, and EG LNG; Swiss government, through ESKAS scholarship grant no. 2016.0056; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH; NIH grant 1U01AI155354-01.

Antituberculosis Drug Nonadherence and Its Associated Factors: Evidence from Debre Berhan Town, North Shewa Zone, Ethiopia.

Introduction: Tuberculosis is a bacterial disease caused by the Mycobacterium tuberculosis. Regardless of many efforts made to control tuberculosis, the disease remains to be a major public health problem. Nonadherence to antituberculosis treatment poses a challenge to the disease treatment as it potentially increases the risk of drug resistance, mortality, relapse, and extended infectiousness. The North Shewa Zone had a poor performed on TB control status, so this study assessed the prevalence of antituberculosis drug nonadherence and its associated factors at governmental health institutions in Debre Berhan town, North Shewa Zone, Ethiopia, 2020. Methods: An institution-based cross-sectional study design was employed. A total of 180 tuberculosis patients were included in the study. The data was entered using EpiData version 3.1 and exported to SPSS version 20.0 for statistical analysis. Bivariable and multivariable logistic regression analyses were computed to determine factor associated with antituberculosis drug nonadherence. Result: Study finding shows that 26.0% respondents were nonadherent to their antituberculosis treatment. Respondents who were married were less likely to be nonadherent than who were single (AOR = 0.307; 95%CI = 0.120, 0.788). Respondents who have primary and secondary education were less likely to be nonadherent than those who had no formal education (AOR = 0.313; 95%CI = 0.100, 0.976). Respondents who experienced drug side effects were two times more likely to be nonadherent than those who did not experience drug side effects (AOR = 2.379; 95%CI = 1.008, 5.615). In addition, respondents who do not screen for HIV were four times more likely to be nonadherent than their counterparts (AOR = 4.620; 95%CI = 11.135, 18.802). Conclusion: The antituberculosis drug nonadherence is high. Marital status, educational status, drug side effects, HIV screening status of the patients, and availability of medication were the variables that influence drug nonadherence. There is a need to strengthen awareness creation and improve quality of the TB treatment services and anti-TB drug availability.

Anti-merozoite antibodies induce natural killer cell effector function and are associated with immunity against malaria.

Natural killer (NK) cells are potent immune effectors that can be activated via antibody-mediated Fc receptor engagement. Using multiparameter flow cytometry, we found that NK cells degranulate and release IFN-γ upon stimulation with antibody-opsonized Plasmodium falciparum merozoites. Antibody-dependent NK (Ab-NK) activity was largely strain transcending and enhanced invasion inhibition into erythrocytes. Ab-NK was associated with the successful control of parasitemia after experimental malaria challenge in African adults. In an independent cohort study in children, Ab-NK increased with age, was boosted by concurrent P. falciparum infections, and was associated with a lower risk of clinical episodes of malaria. Nine of the 14 vaccine candidates tested induced Ab-NK, including some less well-characterized antigens: P41, P113, MSP11, RHOPH3, and Pf_11363200. These data highlight an important role of Ab-NK activity in immunity against malaria and provide a potential mechanism for evaluating vaccine candidates.

Sporozoite immunization: innovative translational science to support the fight against malaria.

INTRODUCTION: Malaria, a devastating febrile illness caused by protozoan parasites, sickened 247,000,000 people in 2021 and killed 619,000, mostly children and pregnant women in sub-Saharan Africa. A highly effective vaccine is urgently needed, especially for Plasmodium falciparum (Pf), the deadliest human malaria parasite. AREAS COVERED: Sporozoites (SPZ), the parasite stage transmitted by Anopheles mosquitoes to humans, are the only vaccine immunogen achieving >90% efficacy against Pf infection. This review describes >30 clinical trials of PfSPZ vaccines in the U.S.A., Europe, Africa, and Asia, based on first-hand knowledge of the trials and PubMed searches of 'sporozoites,' 'malaria,' and 'vaccines.' EXPERT OPINION: First generation (radiation-attenuated) PfSPZ vaccines are safe, well tolerated, 80-100% efficacious against homologous controlled human malaria infection (CHMI) and provide 18-19 months protection without boosting in Africa. Second generation chemo-attenuated PfSPZ are more potent, 100% efficacious against stringent heterologous (variant strain) CHMI, but require a co-administered drug, raising safety concerns. Third generation, late liver stage-arresting, replication competent (LARC), genetically-attenuated PfSPZ are expected to be both safe and highly efficacious. Overall, PfSPZ vaccines meet safety, tolerability, and efficacy requirements for protecting pregnant women and travelers exposed to Pf in Africa, with licensure for these populations possible within 5 years. Protecting children and mass vaccination programs to block transmission and eliminate malaria are long-term objectives.