From trauma to transmission: exploring the intersection of adversity, substance use, and HIV risk in women's life histories.

BACKGROUND: At increased risk for poor health outcomes, physical and/or sexual violence, and onward transmission of HIV, women who use drugs and are living with HIV (WWUDHIV) are vulnerable and in need of services. Understanding the role of trauma across their life history may offer insights into HIV and drug use prevention and opportunities for intervention. We explored trauma and drug use among WWUDHIV in Dar es Salaam, Tanzania. METHODS: We conducted in-depth interviews with 30 WWUDHIV from January-March 2019. Interviewers used semi-structured interview guides and asked questions about the life history as related to drug use. Interviews were audio recorded, transcribed, translated, coded, and life histories charted. We utilized content analysis. RESULTS: Participants described death of family members as traumatic catalysts for drug use. Sexual partners early in their life history were often the point of introduction to drugs and source of HIV acquisition. Death of partners was present across many life histories and was a traumatic event negatively influencing life trajectories, including start of sex work for survival or to support drug use. Sex work in-turn often led to traumatic events including sexual and/or physical violence. HIV diagnosis for many participants followed the start of drug use, frequently occurred during pregnancy or severe illness and was described by most participants as a trauma. Despite this, particularly during pregnancy, HIV diagnosis was a turning point for some participant's desire to engage in drug use treatment. Traumatic events were often cumulative and regularly described as catalysts for poor mental health that could lead to new or increased drug use for coping. CONCLUSIONS: These findings suggest trauma is common in the life history of WWUDHIV and has negative impacts on drug use and HIV vulnerability. Our life history charting highlights the cumulative and cyclical nature of trauma and drug use in this population. This study allows for better understanding of trauma, drug use, and HIV prevention, which offers opportunities for intervention among a group with limited access to services: during adolescence for orphaned youth, following the death of a child or partner, and when vulnerable women engage with the health system (HIV diagnosis, pregnancy, illness).

A third dose of SARS-CoV-2 vaccine increases neutralizing antibodies against variants of concern in solid organ transplant recipients.

Vaccine-induced SARS-CoV-2 antibody responses are attenuated in solid organ transplant recipients (SOTRs) and breakthrough infections are more common. Additional SARS-CoV-2 vaccine doses increase anti-spike IgG in some SOTRs, but it is uncertain whether neutralization of variants of concern (VOCs) is enhanced. We tested 47 SOTRs for clinical and research anti-spike IgG, pseudoneutralization (ACE2 blocking), and live-virus neutralization (nAb) against VOCs before and after a third SARS-CoV-2 vaccine dose (70% mRNA, 30% Ad26.COV2.S) with comparison to 15 healthy controls after two mRNA vaccine doses. We used correlation analysis to compare anti-spike IgG assays and focused on thresholds associated with neutralization. A third SARS-CoV-2 vaccine dose increased median total anti-spike (1.6-fold), pseudoneutralization against VOCs (2.5-fold vs. Delta), and neutralizing antibodies (1.4-fold against Delta). However, neutralization activity was significantly lower than healthy controls (p < .001); 32% of SOTRs had zero detectable nAb against Delta after third vaccination compared to 100% for controls. Correlation with nAb was seen at anti-spike IgG >4 Log10 (AU/ml) on the Euroimmun ELISA and >4 Log10 (AU/ml) on the MSD research assay. These findings highlight benefits of a third vaccine dose for some SOTRs and the need for alternative strategies to improve protection in a significant subset of this population.

Integrated cell-free DNA and cytokine analysis uncovers distinct tissue injury and immune response patterns in solid organ transplant recipients with COVID-19.

COVID-19 pathogenesis is associated with an exuberant inflammatory response. However, the tissue injury pattern and immune response in solid-organ transplant recipients (SOTRs) taking immunosuppressive therapy have not been well characterized. Here, we perform both cfDNA and cytokine profiling on plasma samples to map tissue damage, including allograft injury and delineate underlying immunopathology. We identified injuries from multiple-tissue types, including hematopoietic cells, vascular endothelium, hepatocyte, adipocyte, pancreas, kidney, heart, and lung in SOTRs with COVID-19 that correlates with disease severity. SOTRs with COVID-19 have higher plasma levels of cytokines such as IFN-λ1, IFN-γ, IL-15, IL-18 IL-1RA, IL-6, MCP-2, and TNF-α as compared to healthy controls, and the levels of GM-CSF, IL-15, IL-6, IL-8, and IL-10 were associated with disease severity in SOTRs. Strikingly, IFN-λ and IP-10 were markedly increased in SOTRs compared to immunocompetent patients with COVID-19. Correlation analyses showed a strong association between monocyte-derived cfDNA and inflammatory cytokines/chemokines in SOTRs with COVID-19. Moreover, compared to other respiratory viral infections, COVID-19 induced pronounced injury in hematopoietic, vascular endothelial and endocrine tissues. Allograft injury, measured as donor-derived cfDNA was elevated in SOTRs with COVID-19, including allografts distant from the primary site of infection. Allograft injury correlated with inflammatory cytokines and cfDNA from immune cells. Furthermore, longitudinal analysis identified a gradual decrease of cfDNA and inflammatory cytokine levels in patients with a favorable outcome. Our findings highlight distinct tissue injury and cytokine features in SOTRs with COVID-19 that correlate with disease severity.

A Third Dose of SARS-CoV-2 Vaccine Increases Neutralizing Antibodies Against Variants of Concern in Solid Organ Transplant Recipients.

Vaccine-induced SARS-CoV-2 antibody responses are attenuated in solid organ transplant recipients (SOTRs) and breakthrough infections are more common. Additional SARS-CoV-2 vaccine doses increase anti-spike IgG in some SOTRs, but it is uncertain whether neutralization of variants of concern (VOCs) is enhanced. We tested 47 SOTRs for clinical and research anti-spike IgG, pseudoneutralization (ACE2 blocking), and live-virus neutralization (nAb) against VOCs before and after a third SARS-CoV-2 vaccine dose (70% mRNA, 30% Ad26.COV2.S) with comparison to 15 healthy controls after two mRNA vaccine doses. We used correlation analysis to compare anti-spike IgG assays and focused on thresholds associated with neutralizing activity. A third SARS-CoV-2 vaccine dose increased median anti-spike (1.6-fold) and receptor-binding domain (1.5-fold) IgG, as well as pseudoneutralization against VOCs (2.5-fold versus Delta). However, IgG and neutralization activity were significantly lower than healthy controls (p<0.001); 32% of SOTRs had zero detectable nAb against Delta after third vaccination. Correlation with nAb was seen at anti-spike IgG >4 AU on the clinical assay and >10^4 AU on the research assay. These findings highlight benefits of a third vaccine dose for some SOTRs and the need for alternative strategies to improve protection in a significant subset of this population.