Sustainable Sciences Institute

Immune imprinting1 or original antigenic sin2 is a phenomenon whereby the immune system preferentially recalls its initial response to a related, often evolving pathogen after subsequent exposure. Despite its important implications for vaccine development, the causes of imprinting remain unclear. Here, to understand the basis and impact of imprinting by influenza A viruses, we characterized the B cell responses of young children after consecutive first infections with divergent H1N1 and H3N2 strains of influenza. Children had a primary but otherwise similar B cell response to that of adults. Adult B cells commonly cross-reacted with past strains using more stereotyped and mutated immunoglobulin genes, indicating substantial homosubtypic imprinting. In children, after consecutive heterosubtypic primary infections, up to 6% of memory B cells are H1/H3 cross-reactive and bind to the highly conserved central stalk epitope-a lead target for broadly protective vaccine candidates. Over 90% of these B cells had a higher affinity for the imprinting H3N2 strain, resulting in reduced breadth and neutralization potency against H1N1 strains. Mechanistically, the imprinting H3 strains and affected H1 strains shared a residue change in the stalk epitope (D46N) that was central to the nearly universal shift in reactivity, despite differing by only a single atomic group. In conclusion, imprinting by influenza viruses can cause a deleterious shift of nearly the entire memory recall response against key, conserved epitopes.

BackgroundThe four dengue virus serotypes (DENV1-4), Zika virus (ZIKV) and chikungunya virus (CHIKV) have similar epidemiology and transmission cycles and are the most prevalent arthropod-borne viruses in humans, with half the world’s population at risk of infection. Although these infections share overlapping clinical presentations, the immune mechanisms that distinguish these infections, particularly in children, remain poorly defined. We aimed to characterize the immune responses to DENV, ZIKV, and CHIKV in a pediatric population and to define the specific immune signatures associated with each virus.MethodsWe characterized the immune responses to DENV, ZIKV and CHIKV by measuring cytokine/chemokine/growth-factor profiles in plasma/serum samples, and immune-cell profiles in peripheral blood mononuclear cells, collected from children during acute (~1–3 and ~4-6 days) primary infection with DENV1/DENV3 (n=32), ZIKV (n=50) or CHIKV (n=45), and during infection recovery (~14–25 days). ResultsThe innate immune responses to CHIKV and DENV were similar in terms of acute cytokine concentrations and monocyte frequencies. The innate immune response to ZIKV was mild, and the adaptive response was delayed, showing much lower concentrations of inflammatory cytokines and delayed T cell/B cell activation. Overall, the immune response to CHIKV and DENV were most similar than DENV and ZIKV, despite DENV and ZIKV belonging to the same flavivirus genus. The immune response to ZIKV was the most distinct, showing rapid B cell expansion but attenuated/delayed B cell activation. ConclusionThese findings reveal that early immune responses to arboviruses are defined more by infection-specific dynamics than by viral taxonomy, underscoring distinct immunological signatures for each virus.

Latin American countries have faced limited access to new scientific technologies for many years due to restricted budgets for research programs, which has hindered local scientific development. These research disparities became especially evident during the COVID-19 pandemic, as lower-middle-income countries (LMICs) like Ecuador and Nicaragua had restricted access to genomic surveillance protocols, sequencing technologies, and adequate infrastructure, compromising global pandemic preparedness and response. In response to the urgent need for SARS-CoV-2 research capabilities in these countries, the Asian-American Center for Arbovirus Research and Enhanced Surveillance led the initiative, collaborating with the NGO Sustainable Sciences Institute and LMIC stakeholders, including universities and Ministries of Health, to develop pandemic-related research programs, provide resources, and conduct peer training workshops for local health scientists. Over the past five years, collaborative efforts have enabled teams in Ecuador and Nicaragua to establish sustainable research capacity and technology-sharing initiatives, as showcased by the institutionalization of government-led genomic surveillance efforts. This has opened new research opportunities in genomic surveillance for other emerging and reemerging pathogens and strengthening South-South collaboration.

Ae. aegypti is the primary vector of dengue, chikungunya, and Zika viruses, traditionally associated with urban environments. However, its presence and abundance in rural settings remain understudied. This study compares Ae. aegyptipopulations between rural and urban communities in Managua, Nicaragua, across different seasons over multiple years. Entomological surveys were conducted in 500 randomly selected households (250 rural, 250 urban) during the rainy and dry seasons of 2022 and 2023. Immature mosquitoes were collected from water-holding containers, and adult mosquitoes were sampled using aspirators. Entomological indices, including Stegomyia, pupal, and adult indices, were compared across seasons and localities. All entomological indices were significantly higher in rural communities than in urban areas across both years and seasons. Rural households had greater mosquito densities, with pupal productivity concentrated in large water storage containers. Adult mosquito collections confirmed a greater Ae. aegypti presence in rural areas, suggesting sustained transmission risk. We observed pupal thresholds in water-holding containers for female adult collections. Contrary to the conventional view of Ae. aegypti as an urban mosquito, our findings highlight its substantial presence in rural settings, likely driven by water storage practices and environmental conditions. These results align with findings from other regions reporting high mosquito abundance in rural areas, challenging assumptions about urban dominance. Rural areas play a crucial role in sustaining Ae. aegypti populations. Vector control strategies should target both rural and urban communities, with seasonally tailored interventions to mitigate disease transmission risks.

Communication between immune cells through direct contact is a critical feature of immune responses. Here, we developed a novel high-throughput method to study the transcriptome and adaptive immune receptor repertoire of single cells forming complexes without needing bioinformatic deconvolution. We found that T cells and monocytes forming complexes in blood during active tuberculosis (TB) and dengue hold unique transcriptomic signatures indicative of TCR/MCH-II immune synapses. Additionally, T cells in complexes showed enrichment for effector phenotypes, imaging and transcriptomic features of active TCR signaling, and increased immune activity at diagnosis compared to after anti-TB therapy. We also found evidence for bidirectional RNA exchange between T cells and monocytes, since complexes were markedly enriched for “dual-expressing” cells (i.e., co-expressing T cell and monocyte genes). Thus, studying immune cell complexes at a single-cell resolution offers novel perspectives on immune synaptic interactions occurring in blood during infection.

Tailings generated during ore processing may host significant residual contents of valuable commodities, including critical metals. The particle properties of the tailings, such as mineralogy, particle size, and the surface liberation of ore minerals, strongly control processing behaviour. This study explores a novel combination of methods for incorporating particle data, derived from automated mineralogy, into geometallurgical models of tailings deposits to better understand their reprocessing potential and the economic feasibility of re-mining. This was achieved through binning of different particle types, geostatistical modelling of particle bin frequencies, and bootstrap resampling to reconstruct particle populations. The spatial distributions of processing-relevant particle properties throughout the tailings deposit were predicted with corresponding uncertainties. There are clear systematic trends in the spatial distributions of different particle types, resulting from the sedimentary-style deposition of the tailings. For instance, the tailings nearer the dam walls comprise coarser, silicate-rich particles, while fine-grained and well-liberated sulphide mineral particles are more abundant in the centre of the tailings deposit. As a result, robust models could be developed for the spatial distributions of particle size and mineralogy, which strongly control the sorting of particles during deposition, and other related properties, such as sulphide mineral grain sizes. Finally, a bulk sulphide flotation process was simulated and acid mine drainage potential estimated using the interpolated particle data. Around 58% of the sulphide minerals present could be recoverable by flotation, with the recoverable sulphide portion decreasing towards the centre of the TSF due to the fine-grained nature of the sulphide minerals. The acid mine drainage potential of the tailings is estimated to be moderate to high, indicating that the carbonate minerals present are not sufficient to neutralise the high acid-generating potential of the sulphide minerals. Overall, this study demonstrates how particle-based geometallurgical models can be developed and utilised for practical applications, with the aim of improving the accuracy of resource and reserve estimations of tailings deposits and the sustainable and responsible management of anthropogenic resources. The methodology proposed here can be easily transferred to other tailings deposits.

BackgroundZIKV has neuroinvasive properties, and in utero exposure can cause birth defects, but little is known about the neurological and neurocognitive impacts of acquired ZIKV infection, particularly in children.MethodsWe assessed neurological symptoms frequency among ZIKV-infected children within one year after ZIKV infection. Three to 5 years post-infection, these children and a matched group of uninfected children were assessed via questionnaires, neurological exams, and neuropsychological testing to evaluate the association between prior ZIKV infection and subsequent neurological symptoms, and cognitive-behavioral function.ResultsAmong 194 ZIKV-infected children, 3 reported asthenia, 4 reported neck pain, and 10 reported back pain within one year post-infection. At follow-up, clinician-observed cranial nerve abnormalities were significantly more common among ZIKV-infected vs. uninfected children (16 vs. 3; p < 0.01), with vestibulocochlear nerve abnormalities observed most frequently. While ZIKV-infected children scored better than uninfected on cognitive measures, this difference was not clinically meaningful.ConclusionsNeurological signs, including paresthesia and cranial nerve abnormalities, were observed among ZIKV-infected participants in our study. However, we did not observe a meaningful link between acquired ZIKV infection and subsequent neurological, cognitive, or behavioral outcomes in a representative sample. An exception may be hearing impairment and loss, which should be explored further in future studies.ImpactNeurological symptoms, though rare, were observed and reported more frequently among ZIKV-infected vs. uninfected children. These included: asthenia, neck pain, back pain, paresthesia, and cranial nerve abnormalities.Neurocognitive and behavioral test scores were similar among ZIKV-infected and uninfected children.Our study suggests that ZIKV-infected children should be monitored for neurological symptoms and cranial neuropathy to better understand the full burden of acquired ZIKV infection among children.

Few data are available on antibody response for some SARS-CoV-2 vaccines, and there is a lack of ability to compare vaccine responses in the same population. This cross-sectional study conducted in Nicaragua examines the SARS-CoV-2 antibody responses in individuals, previously exposed to high infection rates who have received various vaccines. The vaccines under comparison include well-known ones like Pfizer (BNT162b2) and AstraZeneca (ChAdOx1-S), alongside less-studied vaccines including Soberana (Soberana 02), Abdala (CIGB-66), and Sputnik V/Sputnik Light. Overall, 3195 individuals participated, with 2862 vaccinated and 333 unvaccinated. We found that 95% of the unvaccinated were seropositive, with much lower titers than the vaccinated. Among the vaccinated, we found that Soberana recipients mounted the highest anti-spike response (mean difference (MD) = 36,498.8 [20,312.2, 52,685.5]), followed by Abdala (MD = 25,889.9 [10,884.1, 40,895.7]), BNT162b2 (MD = 12,967.2 [7543.7, 18,390.8]) and Sputnik with AstraZeneca as the reference group, adjusting for age, sex, vaccine status, days after last dose, and self-reported COVID-19. In addition, we found that subjects with complete vaccination series had higher antibody magnitude than those with incomplete series. Overall, we found no evidence of waning in the antibody magnitude across vaccines. Our study supports the conclusion that populations with high infection rates still benefit substantially from vaccination.

Sequential infection with multiple dengue virus (DENV) serotypes is thought to induce enduring protection against dengue disease. However, long-term antibody waning has been observed after repeated DENV infection. Here, we provide evidence that highly immune Nicaraguan children and adults (n = 4478) experience boosting and waning of antibodies during and after major Zika and dengue epidemics. We develop a susceptible-infected-recovered-susceptible (SIRS-type) model that tracks immunity by titer rather than number of infections to show that boosts in highly immune individuals can contribute to herd immunity, delaying their susceptibility to transmissible infection. In contrast, our model of lifelong immunity in highly immune individuals, as previously assumed, results in complete disease eradication after introduction. Periodic epidemics under this scenario can only be sustained with a constant influx of infected individuals into the population or a high basic reproductive number. We also find that Zika virus infection can boost DENV immunity and produce delays and then surges in dengue epidemics, as observed with real epidemiological data. This work provides insight into factors shaping periodicity in dengue incidence and may inform vaccine efforts to maintain population immunity.