ABSTRACT
Rationale: Historically, Hispanics are underrepresented in research which reduces the generalizability of research findings. Patient engagement in research can support more relevant research through better alignment with patients' and clinicians' real-world needs and concerns. A virtual conference series for the Hispanic community was held to gain insights to better engage Hispanic patients in research. Methods: A Patient Advisory Group (PAG) comprised of Hispanic patients diagnosed with COVID-19 and/or asthma and a Faith-based leader developed a six-month virtual series (objectives, platform, theme, agendas, and identification of presenters), pre-and-post knowledge surveys, polling questions, and session evaluations. Based on the PAG feedback, messaging, promotion and handouts were offered in English and Spanish. Results: Between October 2021- March 2022, 2200 people attended over the 6 virtual sessions. Attendees identifying as Hispanic patients or caregivers increased by 6.7%, and 19% requested content in Spanish. Overall knowledge was gained for sessions 2-6. 66.4% of attendees agreed they would be willing to be a research subject in an asthma study, while 15.6% did not agree and 18% would if their doctor thought it was a good idea. When asked about willingness to be a patient partner/advisor for an asthma study, 77.6% agreed, while only 3.2% did not agree and the remaining 20% were either unsure or participation would depend on whether their doctor thought it was a good idea. Conclusions: This bilingual virtual series engaged patients/caregivers to learn about COVID-19 and asthma, and tools used to participate in research with the goal to increase representation of Hispanics in research.
ABSTRACT
Background. The SARS-CoV-2 pandemic continues, with new variants of concern fueling periodic increases in COVID-19 cases. Authorized vaccines have provided protection against severe disease but less so for incident cases. Boosts with these vaccines have demonstrated waning protection. New vaccines, including those which induce immunity against more conserved regions outside of Spike, may improve upon these and be key to long-term protection and may be a useful approach against novel coronaviruses. Methods. GO-009 (CORAL-Boost, NCT05148962) is an open-label study, conducted in the UK, of a self-amplifying mRNA vaccine encoding for Wuhan Spike (S) and highly conserved non-S T cell epitopes (GRT-R910;R910). R910 is given as 1 or 2 doses after vaccination with an authorized adenovirus or mRNA SARS-CoV-2 vaccine. The first two cohorts assessed 10mug and 30mug doses of R910 in older (>=60y) adults who had previously received ChAdOx1. Subsequent cohorts assess two boost doses in older and younger adults who have received an adenovirus or mRNAvaccine. Primary objectives are safety and reactogenicity and secondary objectives include cellular and humoral immunogenicity. Results. Ten and seven adults received 10 or 30mug (cohorts 1 and 2) of R910, respectively. Reactogenicity and unsolicited adverse events were mostly mild/moderate and transient. The majority of severe events (malaise, fatigue, myalgia, Inj. site pain/ tenderness/swelling) after dose 1 were experienced by 1 subject in cohort 2. Analysis of both IgG binding and neutralizing antibodies demonstrated a boost of anti-S antibodies after one dose of R910;geomean ID50 titers from 92 to 2370 and 99 to 1553 for 10 and 30mug, respectively. ELISpot analyses demonstrated that R910 boosted and broadened T cell responses to S and non-S T cell epitopes. Conclusion. R910 was well tolerated. One R910 boost vaccination increased existing humoral and cellular immunity against S while inducing a broad T cell response against non-S SARS-CoV-2 proteins. A 10mug R910 boost increased neutralizing antibody titers comparable to a 10-fold higher dose (100mug) with authorized mRNA vaccines in a similar population (Munro et al 2021). A 10mug dose was selected for further study. Data post mRNA primary series will also be presented.
ABSTRACT
The immunogenicity and efficacy of RNA-based vaccine platforms has been abundantly shown through their application in prophylactic SARS-CoV2 vaccines. Contrasting to mRNA based vectors, self amplifying mRNA platforms may offer dose-sparing and superior induction of T cell responses, and may also trigger distinct innate immune pathways, which may exert adjuvanting or inhibiting effects on vaccine-induced immunity. Optimal dosing for a novel self-amplifying mRNA (SAM) in a heterologous prime-boost vaccination approach consisting of Chimpanzee Adenovirus (ChAd) prime and SAM boosts was evaluated in two first-in-human phase 1/2 clinical trials assessing personalized neoantigen vaccines in patients with metastatic cancer (NCT03639714, NCT03953235). SAM vaccine dose escalation was performed to assess safety, tolerability, and immunogenicity, including administration of up to 8 SAM doses at 30, 100, or 300μg following a fixed dose of ChAd (1012 vp) over the course of a year. SAM was safe and well tolerated at all 3 dose levels, with no evidence of increasing reactogenicity with sequential doses. However, while immune monitoring via IFNγ ELISpot revealed that the 30μg SAM dose boosted T cell responses induced by the ChAd prime, the 100μg and 300μg SAM doses resulted in maintenance of T cell levels, without a clear T cell boost, suggesting a non-linear and likely bell-shaped dose-response curve to SAM in humans. Follow-up studies in non-human primates (NHPs) using a model antigen revealed dose-dependent increases in serum IFNa levels following administration of increasing SAM doses. Similarly, while multiple inflammatory cytokines were transiently increased following both ChAd and SAM administration in patients, serum IFNa levels were only increased 24h post SAM administration and correlated positively with SAM dose. Increased IFNa levels post SAM dosing suggested activation of mRNA-sensing innate immune pathways that may reduce the amplification of, and/or antigen expression by, the SAM vector and thus blunt T cell boosting at higher SAM doses. In addition, analysis of T cell responses in patients and NHPs showed increased boosting of T cell responses with longer intervals. These data lead to a reduction of the SAM dose to 30μg and adjusting SAM dosing intervals to 8 weeks in the Phase 2 portion of these clinical studies. Multiple patients have been dosed with the adjusted vaccine regimen, and preliminary data suggest robust boosting of ChAd-induced neoantigen-specific T cell responses with the selected SAM dosing regimen and the 30μg dose. We anticipate that this translational approach of adjusting clinical vaccine regimens based on strong translational immune data will increase the potency of our heterologous neoantigen vaccine, and subsequently provide more durable clinical benefit to patients with cancer.
ABSTRACT
The heterogeneous disease course of COVID-19 is unpredictable, ranging from mild self-limiting symptoms to cytokine storms, acute respiratory distress syndrome (ARDS), multi-organ failure and death. Identification of high-risk cases will enable appropriate intervention and escalation. This study investigates the routine laboratory tests and cytokines implicated in COVID-19 for their potential application as biomarkers of disease severity, respiratory failure and need of higher-level care. From analysis of 203 samples, CRP, IL-6, IL-10 and LDH were most strongly correlated with the WHO ordinal scale of illness severity, the fraction of inspired oxygen delivery, radiological evidence of ARDS and level of respiratory support (p ≤ 0.001). IL-6 levels of ≥3.27 pg/ml provide a sensitivity of 0.87 and specificity of 0.64 for a requirement of ventilation, and a CRP of ≥37 mg/l of 0.91 and 0.66. Reliable stratification of high-risk cases has significant implications on patient triage, resource management and potentially the initiation of novel therapies in severe patients.