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1.
Cancer Research ; 82(12), 2022.
Article in English | EMBASE | ID: covidwho-1986491

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.

2.
Journal of the American College of Cardiology ; 79(9):2150-2150, 2022.
Article in English | Web of Science | ID: covidwho-1849291
3.
Journal of the American College of Cardiology ; 79(9):1493-1493, 2022.
Article in English | Web of Science | ID: covidwho-1848891
4.
PubMed; 2020.
Preprint in English | PubMed | ID: ppcovidwho-333583

ABSTRACT

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a whole-blood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferon-stimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and auto-directed antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense. ONE SENTENCE SUMMARY: In severe COVID-19 patients, the immune system fails to generate cells that define mild disease;antibodies in their serum actively prevents the successful production of those cells.

5.
Circulation ; 144:2, 2021.
Article in English | Web of Science | ID: covidwho-1710981
6.
Circulation ; 144(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1637784

ABSTRACT

Introduction: Acute myocarditis after coronavirus disease 2019 (COVID-19) mRNA vaccination is not well described. Recent public reports have signaled that this is an entity that requires ongoing surveillance. The goal of this study is to investigate myocarditis incidence following COVID-19 mRNA vaccination, and to report the clinical course and outcomes. Methods: This is a retrospective population-based cohort study performed at Kaiser Permanente Southern California (KPSC), an integrated health care system in California. Patients who received at least one dose of BNT162b2 (Pfizer) or mRNA-1273 (Moderna) mRNA vaccine were included. Clinically significant cases of acute myocarditis within 10 days of COVID-19 mRNA vaccination were identified between 12/14/2020 and 5/31/2021. Key demographic, clinical, laboratory, diagnostic data, and clinical course were obtained from medical record review. Results: Of 1,776,608 KPSC members who received at least one dose of COVID-19 mRNA vaccines, 12 developed acute myocarditis within 10 days following vaccination, for an estimated incidence of 6.6 cases per 1 million patients. All patients were relatively healthy White or Hispanic men between the ages of 18 and 40 years. Patients reported chest pain two to eight days after vaccine administration (Moderna N=5;Pfizer N=7). Eleven patients developed myocarditis after the second dose, and one after the first dose. Troponin I elevations ranged from 1.53-32.30 ng/mL. All cases were self-limited, with troponin peaking within 24-48 hours of admission and symptom resolution prior to discharge. None of the patients had evidence of decompensated heart failure. Length of stay was 1-4 days, with all patients discharged home and no recurrence, readmission, or major adverse cardiac events. Conclusions: Acute myocarditis after COVID-19 mRNA vaccination is a rare and self-limited event that warrants further description and investigation.

7.
Chinese Journal of Applied Clinical Pediatrics ; 36(18):1368-1372, 2021.
Article in Chinese | Scopus | ID: covidwho-1481061

ABSTRACT

Severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)infection is still worldwide.As a vulnerable group, severe and dead pediatric cases are also reported.Under this severe epidemic situation, children should be well protected.With the widespread vaccination of SARS-CoV-2 vaccine in adults, the infection rate have decreased.Therefore, SARS-CoV-2 vaccine inoculation for children groups step by step is of great significance to the protection of children and the prevention and control of corona virus disease 2019(COVID-19) as a whole.But the safety of children vaccinated with SARS-CoV-2 vaccine is a main concern of parents.Therefore, in order to ensure the safety of vaccination and the implementation of vaccination work, National Clinical Research Center for Respiratory Diseases, National Center for Children's Health and the Society of Pediatrics, Chinese Medical Association organized experts to interpret the main issue of parents about SARS-CoV-2 vaccine for children, in order to answer the doubts of parents. Copyright © 2021 by the Chinese Medical Association.

8.
Chinese Journal of Applied Clinical Pediatrics ; 36(18):1361-1367, 2021.
Article in Chinese | Scopus | ID: covidwho-1481060

ABSTRACT

At present, severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)infection is still rampant worldwide.As of September 10, 2021, there were about 222 million confirmed cases of corona virus disease 2019(COVID-19)and more than 4.6 million deaths worldwide.With the development of COVID-19 vaccines and the gradual vaccination worldwide, the increasing number of cases in children and unvaccinated young people has drawn attention.According to World Health Organization surveillance data, the proportion of COVID-19 infection cases in children gradually increased, and the proportion of cases in the age groups of under 5 years and 5-14 years increased from 1.0% and 2.5% in January 2020 to 2.0% and 8.7% in July 2021, respectively.At present, billions of adults have been vaccinated with various COVID-19 vaccines worldwide, and their protective effects including reducing infection and transmission, reducing severe disease and hospitalization, and reducing death, as well as high safety have been confirmed.Canada, the United States, Europe and other countries have approved the emergency COVID-19 vaccination in children and adolescents aged 12 to 17 years, and China has also approved the phased vaccination of COVID-19 vaccination in children and adolescents aged 3 to 17 years. For smooth advancement and implementation of COVID-19 vaccination in children, academic institutions, including National Clinical Research Center for Respiratory Diseases, National Center for Children's Health, and The Society of Pediatrics, Chinese Medical Association organized relevant experts to reach this consensus on COVID-19 vaccination in children. Copyright © 2021 by the Chinese Medical Association.

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