Institut Pasteur de Dakar

BACKGROUND:WHO recommends fractional dose vaccination to address yellow fever vaccine shortages during outbreaks. In adults, a 500 IU dose has recently been shown to be non-inferior to the full standard dose, but the minimum effective dose for children is unknown. METHODS:We conducted a randomised, double-blind, non-inferiority trial at two centres in Kenya and Uganda, including infants aged 9-12 months with no previous yellow fever vaccination or infection. Participants were randomly assigned 1:1 in blocks of variable sizes of four, six, or eight to receive either the standard dose (>13 000 IU) or 500 IU of the Institut Pasteur de Dakar (Dakar, Senegal) 17D-204 yellow fever vaccine, co-administered with the measles-rubella vaccine. The primary outcome was seroconversion 28 days post-vaccination, defined as a four-fold or greater increase in antibody titre at day 28 from baseline (day 0), as measured by the 50% plaque reduction neutralisation test. Non-inferiority was shown if the lower bound of the 95% CI for the difference in seroconversion rates between doses exceeded -10 percentage points. Safety was assessed in the safety population, which included all participants who received a study vaccine dose. This study is registered with ClinicalTrials.gov (NCT04059471) and is complete. FINDINGS:Between Oct 7, 2021, and June 14, 2023, 420 infants were enrolled and randomly assigned (210 participants in each group). The seroconversion rate at day 28 was 99% (95% CI 96-100; 177 of 179 infants) for the standard dose and 93% (88-96; 166 of 179 infants) for the 500 IU dose in the per-protocol population. The difference in seroconversion rate was -6·15 percentage points (95% CI -10·27 to -2·02); therefore, non-inferiority was not met for the 500 IU dose. 12 serious adverse events were reported in the study (eight in the 500 IU dose group and four in the standard dose group), but all were considered unrelated to vaccination. INTERPRETATION:Compared with the standard yellow fever vaccine dose, a dose of 500 IU did not meet the non-inferiority criterion, suggesting that minimum dose requirements in adults are not generalisable to infants. Therefore, standard yellow fever doses should be used for infants in the routine WHO Expanded Programme on Immunization. FUNDING:European and Developing Countries Clinical Trials Partnership and the Wellcome Trust.

The advent of multiplexing technologies, allowing antibodies to hundreds of antigens to be measured in a single test, has led to enormous increases in the amount of data generated by serological surveys. New modelling methods are required to exploit this data. This study extends serocatalytic models to consider up to three antibody responses targeting the same pathogen simultaneously. These models were fitted to data from cross-sectional serological surveys of Plasmodium falciparum malaria in the Senegalese villages of Dielmo and Ndiop, and model predictions were validated against 22 years of longitudinal epidemiological data. The most accurate reconstruction of historical clinical incidence of P. falciparum was provided by a combination of antibodies to Apical Membrane Antigen 1 (PfAMA1) and Glutamate-Rich Protein (PfGlurpR2). This model estimated a 76% (95% CrI: 61% - 86%) drop in transmission in 2004 (95% CrI: 2001 - 2008) coinciding with changing anti-malarial treatment. Multiplex serocatalytic models provided more accurate estimates of past clinical incidence than singleplex serocatalytic models, with the most accurate multiplex model (PfAMA1 + PfGlurpR2) outperforming all singleplex models (KruskalWallis p < 0.01). Finally, models with three antigens did not provide more accurate estimation than models with two antigens.

RH5-interacting protein (RIPR) is essential for the invasion of Plasmodium into host red blood cells and is currently being studied as a novel malaria vaccine candidate in Phase 1a clinical trials. To study the genetic diversity of RIPR, deep amplicon sequencing was used to identify RIPR mutations in Plasmodium falciparum clinical isolates (n = 89) collected in Kédougou, a high malaria transmission region of Senegal. We identified non-synonymous single-nucleotide polymorphisms (SNPs) in 64/89 (71.9%) of samples. In total, 26 non-synonymous SNPs were identified, including 15 novel SNPs. Sixteen of 26 SNPs could be threaded onto existing PfRIPR crystal structures to predict the effects of SNPs on RIPR stability. Seven of 16 mutations were predicted to destabilize PfRIPR, while two of 16 were predicted to increase the stability of RIPR. Additionally, we identified 3 SNPs (Q737K, T738K, and V840L) in the EGF5-8 domains of PfRIPR where neutralizing antibodies are known to bind.

Arboviruses such as dengue virus (DENV) and chikungunya virus (CHIKV) pose major global health threats. To support serological surveillance and study cross-reactivity, an in-house multiplex bead-based immunoassay was developed to measure IgG responses against a wide panel of orthoflavivirus and alphavirus antigens. Samples from Senegal, France, the Philippines, and Bangladesh enabled analyses to be carried out in endemic and non-endemic regions. IgG kinetics following DENV1 and CHIKV infections revealed virus-specific temporal profiles and identified antigens, such as CHIKV E2 and VLP, as well as DENV1 EDIII and SNAP-tagged EDIII, as promising markers for serosurveillance. A two-step Random Forest model was used to classify PRNT-positive samples and predict PRNT titers. CHIKV showed a strong correlation between IgG and PRNT titers (R2 = 0.71), while DENV1 showed weaker performance (R2 = 0.42). These results support the use of multiplex serology for arbovirus surveillance and highlight the limitations of using binding antibodies to predict neutralisation, particularly for orthoflaviviruses. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Yes ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Bangladesh study was approved by the ethical review board at icddr,b (protocol #PR-14058) and Institut Pasteur (protocol #2015-074). The Senegalese samples were collected as part of the ongoing Dielmo and Ndiop project which was approved by the Senegalese National Health Research Ethics Committee (CNERS Sénégal). Approval to measure antibodies in these samples was granted by CNERS Sénégal (N 00000007 MSAS/CNERS/Sec). The Philippines study was approved by the ethical review boards at Vicente Sotto Memorial Medical Center in Cebu City, Philippines and Walter Reed Army Institute of Research Human Subjects Protection Branch (protocol #1833). Negative samples were obtained from the COVID-Oise study, which was registered with ClinicalTrials.gov ([NCT04644159][1]) and received ethical approval from the Comité de Protection des Personnes Nord Ouest IV. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study are openly available in the Supplementary information. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04644159&atom=%2Fmedrxiv%2Fearly%2F2025%2F11%2F02%2F2025.10.31.25339243.atom