Program for Appropriate Technology in Health

Protection against infection by Plasmodium falciparum sporozoites is mediated in part by antibodies that recognize the repeated (NPNA)3 epitopes of the circumsporozoite protein (CSP). To evaluate the role that the antibody Fc region plays in neutralizing sporozoite infectivity, we assess the protective efficacy of Fab fragments obtained from protective human monoclonal antibodies and use antibodies bearing the LALA and KA mutations known to reduce Fc functions. To determine the impact of multiple-antibody binding to CSP on protection, we use sporozoites from genetically modified P. berghei strains expressing a CSP containing different numbers of (NPNA)3 epitopes. Our results indicate that Fab fragments and Fc-mutated antibodies have a protective efficacy comparable to intact antibodies, indicating a limited role, if any, of Fc functions in sporozoites in this model system. We also determine that antibody binding to multiple adjacent epitopes and the establishment of homotypic interactions between bound antibodies may not be necessary for protection, as binding to one epitope is sufficient to strongly reduce liver burden while only two separate epitopes are needed to achieve sterile protection.

Here we conducted a retrospective evaluation of an electronic medical record-embedded large language model clinical decision support system deployed across 16 primary care clinics in Kenya, between July and September 2024. A panel of trained physicians reviewed 1,469 records. Hallucinations were uncommon, occurring in 50 encounters (3.4%, 95% confidence interval (CI) 2.5-4.5), and most often involved misexpanded acronyms or drug names. Clinical management guidance aligned with local guidelines in almost all cases (1,455; 99%, 95% CI 98.4-99.5). Despite this, clinicians did not modify documentation in 917 encounters (62%, 95% CI 59.9-64.9). Safety assessments identified actively harmful recommendations from the large language model in 115 encounters (7.8%, 95% CI 6.5-9.3), with 67 such recommendations appearing in the final documentation. Conversely, risk present in the clinician's initial notes was fully mitigated in 118 encounters (8.0%, 95% CI 6.7-9.5 overall; 12.1%, 95% CI 9.5-15.2 of amended cases). Overall, the tool showed strong potential to support quality improvement, but the asymmetric adoption of harmful versus beneficial outputs underscores the need for usability optimization, local guardrails and prospective trials to confirm patient-level benefit.

BACKGROUND:Rapid diagnostic tests (RDTs) have improved malaria diagnosis; however, the emergence of hrp2/3 gene deletions threatens the reliability of HRP2-based RDTs. This study evaluated the diagnostic performance of a novel RDT detecting both HRP2 and PfLDH in a single test line. METHOD:A cross-sectional study was conducted at two health centers in Ethiopia, recruiting 1004 study participants. Blood samples were tested using the novel and comparator RDTs, using microscopy and nested polymerase chain reaction (PCR) as the reference standards. Plasmodium falciparum hrp2 and hrp3 genotyping and HRP2 and P. falciparum lactate dehydrogenase (PfLDH) antigen quantification were also conducted. RESULTS:In this study setting, characterized by 80% of P. falciparum infections showing hrp2 or hrp3 deletion, the novel RDT showed a sensitivity of 77.4% and a specificity of 96%, surpassing the HRP2-only comparators Bioline™ Malaria Ag Pf (55.9%) and Bioline™ Malaria Ag Pf/Pv (56.8%). Its performance was comparable to the three-line Bioline™ Malaria Ag Pf/Pf/Pv RDT, which detects HRP2, PfLDH, and PvLDH, at 77.7% sensitivity. Additionally, the novel RDT exhibited the ability to detect P. falciparum cases across a broader range of HRP2 and PfLDH antigen concentrations compared to the comparator RDTs. CONCLUSIONS:The single-line, easy-to-interpret index malaria RDT outperforms conventional HRP2-only RDTs, making it a promising tool for enhancing malaria diagnosis in regions with high hrp2/3 deletion prevalence. Clinical Trial Registration.  The study is registered on ClinicalTrials.gov ID NCT05286359.

Combination vaccine formulations contain distinct components targeting multiple strains of a single pathogen or multiple pathogens. By minimizing the number of separate vaccine administrations required, combination vaccines have been critical in allowing the broad expansion of the number and range of diseases that can now be prevented by immunization. Recent advances in vaccine development and our understanding of the immune system now make it possible to envision how new combination vaccines could play a major role in helping immunization programs address a much wider range of emerging or still problematic pathogens. However, few combinations are currently in the pipeline, in part due to their inherently increased complexity and cost of development compared to standalone formulations. This complexity, in turn, is partly driven by the regulatory requirements surrounding the clinical study program for the combination vaccine, especially the primary clinical endpoints and the required degree of precision around those endpoints, as these ultimately determine the sample size, cost, and duration of the study. As part of a larger effort to facilitate combination vaccine development, vaccine experts at the World Health Organization and PATH coordinated a one-day meeting in March 2025 gathering current and former national regulatory agency staff from a dozen countries, together with vaccine developers, representatives from funding and procurement agencies, and public health and policy officials. The convened participants held spirited discussions on how multiple immune markers and controlled human infection models (CHIM) might contribute to the demonstration of vaccine efficacy. In addition, participants considered the possibility of relying on clinical endpoints when the vaccine components are directed against pathogens causing the same disease syndrome but etiological determination of each component's contribution is not feasible. Regulators welcomed scientifically sound, creative proposals for demonstration of efficacy, and agreed that the benefit-risk of the combination vaccine as a whole should be the primary focus.

Combination vaccines combine several components in a single dose administration. They offer programmatic and public health advantages, particularly as vaccine schedules become increasingly crowded. They are often more expensive to develop and produce, which discourages manufacturer investment without clear market signals. Hence their benefits need to be captured with existing health economic evaluation reference cases used by decision-makers to guide vaccine investments. We propose that the value of combination vaccines can be captured through at least four domains: (1) reductions in tangible and intangible costs to caregivers, (2) operational efficiencies to the health system, (3) opportunity costs of vaccine schedule slots, and (4) more streamlined vaccine schedules. We demonstrate the practicality of our framework by comparing the value of introducing a hypothetical vaccine to a crowded schedule as a standalone formulation, a replacement for a vaccine already in the schedule, or a combination product. The framework could also be applied to estimate the value of reducing the number of separate administrations needed for a standalone vaccine. Applying it in real-world situations could be facilitated by further data collection, particularly on collating results on the value of existing vaccines in the schedule and estimating willingness-to-pay for fewer vaccine administrations.