SARS-CoV-2 vaccination and phase 1 cancer clinical trials.
Ontology highlight
ABSTRACT:
SUBMITTER: Yap TA
PROVIDER: S-EPMC7906739 | biostudies-literature | 2021 Mar
REPOSITORIES: biostudies-literature
Publications
SARS-CoV-2 vaccination and phase 1 cancer clinical trials.
Yap Timothy A TA Siu Lillian L LL Calvo Emiliano E Lolkema Martijn P MP LoRusso Patricia M PM Soria Jean-Charles JC Plummer Ruth R de Bono Johann S JS Tabernero Josep J Banerji Udai U
The Lancet. Oncology 20210208 3
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Project description:Immune memory plays a critical role in the development of durable antimicrobial immune responses. How precisely mRNA vaccines train innate immune cells to shape protective host defence mechanisms remains unknown. Here we show that SARS-CoV-2 mRNA vaccination significantly establishes histone H3 lysine 27 acetylation (H3K27ac) at promoters of human monocyte-derived macrophages, suggesting epigenetic memory. However, we found that two consecutive vaccinations were required for persistence of H3K27ac, which matched with proinflammatory innate immune-associated transcriptional changes and antigen-mediated cytokine secretion. H3K27ac at promoter regions were preserved for six months and a single mRNA booster vaccine potently restored their levels and release of macrophage-derived cytokines. Interestingly, we found that H3K27ac at promoters is enriched for G-quadruplex DNA secondary structure-forming sequences in macrophage-derived nucleosome-depleted regions, linking epigenetic memory to nucleic acid structure. Collectively, these findings reveal that mRNA vaccines induce a highly dynamic and persistent training of innate immune cells enabling a sustained pro-inflammatory immune response.
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Project description:IntroductionThe COVID-19 pandemic is a global public health problem. Patients with end-stage renal disease on hemodialysis are at a higher risk of infection and mortality than the general population. Worldwide, a vaccination campaign has been developed that has been shown to reduce severe infections and deaths in the general population. However, there are currently limited data on the clinical efficacy of vaccinations in the hemodialysis population.MethodsA national multicenter observational cohort was performed in Chile to evaluate the clinical efficacy of anti-SARS-CoV-2 vaccination in end-stage renal disease patients on chronic hemodialysis from February 2021 to August 2021. In addition, the BNT162b2 (Pfizer-BioNTech) and CoronaVac (Sinovac) vaccines were evaluated. The efficacy of vaccination in preventing SARS-CoV-2 infection, hospitalizations, and deaths associated with COVID-19 was determined.ResultsA total of 12,301 patients were evaluated; 10,615 (86.3%) received a complete vaccination (2 doses), 490 (4.0%) received incomplete vaccination, and 1196 (9.7%) were not vaccinated. During follow-up, 1362 (11.0%) patients developed COVID-19, and 150 died (case fatality rate: 11.0%). The efficacy of the complete vaccination in preventing infection was 18.1% (95% confidence interval [CI]:11.8-23.8%), and prevention of death was 66.0% (95% CI:60.6-70.7%). When comparing both vaccines, BNT162b2 and CoronaVac were effective in reducing infection and deaths associated with COVID-19. Nevertheless, the BNT162b2 vaccine had higher efficacy in preventing infection (42.6% vs. 15.0%) and deaths (90.4% vs. 64.8%) compared to CoronaVac.ConclusionThe results of our study suggest that vaccination against SARS-CoV-2 in patients on chronic hemodialysis was effective in preventing infection and death associated with COVID-19.
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2021-08-11 | GSE173567 | GEO
Project description:BackgroundNew vaccines are being developed to fight the ongoing COVID-19 pandemic. In our study we compared the efficacy of COVID-19 vaccines to prevent COVID-19-related infections and mortality.Methods17 randomized clinical trials of COVID-19 vaccines were included after search in databases. We compared COVID-19 vaccines based on symptomatic and severe infections, number of deaths and hospitalizations related to COVID-19. Also, we analyzed the efficacy of COVID-19 against different variants of SARS-CoV-2 as well as according to different age groups. Random effects model using Mantel-Haenzeal method was used to pool relative risk (RR).ResultsOur meta-analysis shows that full vaccination could decrease not only the risk of symptomatic or severe COVID-19, the risk of hospitalization and death caused by COVID-19. COVID-19 vaccines were also effective against variants of SARS-CoV-2 (RR = 0.36; 95% CI [0.25; 0.53], p < 0.0001). However, efficacy of vaccination varied in COVID-19 variant-dependent manner. Moreover, the analysis in different age groups showed that COVID-19 vaccines had the similar results: the risk was slightly lower in adults compared to elderly cohort [Formula: see text] 65 years): (RR = 0.16, 95% CI [0.11; 0.23]) and (RR = 0.19, 95% CI [0.12; 0.30]), respectively.ConclusionsData obtained from clinical trials of COVID-19 vaccines looks promising, in order to fully investigate efficacy of the vaccines further clinical examination is required especially considering new SARS-CoV-2 variants.
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Project description:The sudden outbreak of 2019 novel coronavirus (2019-nCoV, later named SARS-CoV-2) in Wuhan, China, which rapidly grew into a global pandemic, marked the third introduction of a virulent coronavirus into the human society, affecting not only the healthcare system, but also the global economy. Although our understanding of coronaviruses has undergone a huge leap after two precedents, the effective approaches to treatment and epidemiological control are still lacking. In this article, we present a succinct overview of the epidemiology, clinical features, and molecular characteristics of SARS-CoV-2. We summarize the current epidemiological and clinical data from the initial Wuhan studies, and emphasize several features of SARS-CoV-2, which differentiate it from SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), such as high variability of disease presentation. We systematize the current clinical trials that have been rapidly initiated after the outbreak of COVID-19 pandemic. Whereas the trials on SARS-CoV-2 genome-based specific vaccines and therapeutic antibodies are currently being tested, this solution is more long-term, as they require thorough testing of their safety. On the other hand, the repurposing of the existing therapeutic agents previously designed for other virus infections and pathologies happens to be the only practical approach as a rapid response measure to the emergent pandemic, as most of these agents have already been tested for their safety. These agents can be divided into two broad categories, those that can directly target the virus replication cycle, and those based on immunotherapy approaches either aimed to boost innate antiviral immune responses or alleviate damage induced by dysregulated inflammatory responses. The initial clinical studies revealed the promising therapeutic potential of several of such drugs, including favipiravir, a broad-spectrum antiviral drug that interferes with the viral replication, and hydroxychloroquine, the repurposed antimalarial drug that interferes with the virus endosomal entry pathway. We speculate that the current pandemic emergency will be a trigger for more systematic drug repurposing design approaches based on big data analysis.
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Project description:Durable cell-mediated immune responses require efficient innate immune signaling and the release of pro-inflammatory cytokines. How precisely mRNA vaccines trigger innate immune cells for shaping antigen specific adaptive immunity remains unknown. Here we show that SARS-CoV-2 mRNA vaccination primes human monocyte derived macrophages for activation of the NLRP3 inflammasome. Spike protein exposed macrophages undergo NLRP3 driven pyroptotic cell death and subsequently secrete mature interleukin-1β. These effects depend on activation of spleen tyrosine kinase (SYK) coupled to C-type lectin receptors. Using autologous co-cultures, we show that SYK and NLRP3 orchestrate macrophage driven activation of effector memory T cells. Furthermore, vaccination induced macrophage priming can be enhanced with repetitive antigen exposure providing a rationale for prime-boost concepts to augment innate immune signaling in SARS-CoV-2 vaccination. Collectively, these findings identify SYK as a regulatory node capable of differentiating between primed and unprimed macrophages, which modulate spike protein specific T cell responses.
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Project description: Not available
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Project description:BackgroundSOBERANA 02 is a COVID-19 vaccine based on SARS-CoV-2 recombinant RBD conjugated to tetanus toxoid (TT). SOBERANA Plus antigen is dimeric-RBD. Here we report safety and immunogenicity from phase I and IIa clinical trials using two-doses of SOBERANA 02 and three-doses (homologous) or heterologous (with SOBERANA Plus) protocols.MethodWe performed an open-label, sequential and adaptive phase I to evaluate safety and explore the immunogenicity of SOBERANA 02 in two formulations (15 or 25 μg RBD-conjugated to 20 μg of TT) in 40 subjects, 19-59-years-old. Phase IIa was open-label including 100 volunteers 19-80-years, receiving two doses of SOBERANA 02-25 μg. In both trials, half of volunteers were selected to receive a third dose of the corresponding SOBERANA 02 and half received a heterologous dose of SOBERANA Plus. Primary outcome was safety. The secondary outcome was immunogenicity evaluated by anti-RBD IgG ELISA, molecular neutralization of RBD:hACE2 interaction, live-virus-neutralization and specific T-cells response.ResultsThe most frequent adverse event (AE) was local pain, other AEs had frequencies ≤ 5%. No serious related-AEs were reported. Phase IIa confirmed the safety in 60 to 80-years-old subjects. In phase-I SOBERANA 02-25 µg elicited higher immune response than SOBERANA 02-15 µg and progressed to phase IIa. Phase IIa results confirmed the immunogenicity of SOBERANA 02-25 µg even in 60-80-years. Two doses of SOBERANA02-25 µg elicited an immune response similar to that of the Cuban Convalescent Serum Panel and it was higher after the homologous and heterologous third doses. The heterologous scheme showed a higher immunological response. Anti-RBD IgG neutralized the delta variant in molecular assay, with a 2.5-fold reduction compared to D614G neutralization.ConclusionsSOBERANA 02 was safe and immunogenic in persons aged 19-80 years, eliciting neutralizing antibodies and specific T-cell response. Highest immune responses were obtained in the heterologous three doses protocol.Trial registryhttps://rpcec.sld.cu/trials/RPCEC00000340, https://rpcec.sld.cu/trials/RPCEC00000347.
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