Immune response and reactogenicity after immunization with two-doses of an experimental COVID-19 vaccine (CVnCOV) followed by a third-fourth shot with a standard mRNA vaccine (BNT162b2): RescueVacs multicenter cohort study

Background: There is no evidence to date on immunogenic response among individuals who participated in clinical trials of COVID-19 experimental vaccines redirected to standard national vaccination regimens. Methods: This multicentre, prospective controlled cohort study included subjects who received a COVID-19 experimental vaccine (CVnCoV)(test group, TG) - and unvaccinated subjects (control group, CG), selected among individuals to be vaccinated according to the Spanish vaccination program. All study subjects received BNT162b2 as a standard national vaccination schedule, except 8 (from CG) who received mRNA-1273 and were excluded from immunogenicity analyses. Anti-RBD antibodies level and neutralising titres (NT50) against G614, Beta, Mu, Delta and Omicron variants were analysed. Reactogenicity was also assessed. Findings: 130 participants (TG:92; CG:38) completed standard vaccination. In TG, median (IQR) of anti-RBD antibodies after first BNT162b2 dose were 10740·0 BAU/mL (4466·0-12500) compared to 29·8 BAU/mL (14·5-47·8) in CG (p <0·0001). Median NT50 (IQR) of G614 was 2674·0 (1865·0-3997·0) in TG and 63·0 (16·0-123·1) in CG (p <0·0001). After second BNT162b2 dose, anti-RBD levels increased to ≥12500 BAU/mL (11625·0-12500) in TG compared to 1859·0 BAU/mL (915·4-3820·0) in CG (p <0·0001). NT50 was 2626·5 (1756·0-5472·0) and 850·4 (525·1-1608·0), respectively (p <0·0001). Variant-specific (Beta, Mu, Omicron) response was also assessed. Most frequent adverse reactions were headache, myalgia, and local pain. No severe AEs were reported. Interpretation: Heterologous BNT162b2 as third and fourth doses in previously suboptimal immunized individuals elicit stronger immune response than that obtained with two doses of BNT162b2. This apparent benefit was also observed in variant-specific response. No safety concerns arose.This work is partially funded by Institute of Health Carlos III (Instituto de Salud Carlos III − ISCIII −), (grants PI19CIII/00004 −JA- and PI21CIII/00025 −MPO, JG-), and COVID-19 FUND (grants COV20/00679 −MPO- and COV20/00072 −JA-) and CIBERINFEC, co-financed by the European Regional Development Fund (FEDER) “A way to make Europe”. Instituto de Salud Carlos III is a Spanish public body assigned to the Ministry of Science and Innovation that manages and promotes public clinical research related to public health. The authors thank Esther Prieto, MD (cited with consent) for editorial assistance and writing support (funded by the Research Foundation of HCSC).S

Immunogenic dynamics and SARS-CoV-2 variant neutralisation of the heterologous ChAdOx1-S/BNT162b2 vaccination: Secondary analysis of the randomised CombiVacS study

Background: The CombiVacS study was designed to assess immunogenicity and reactogenicity of the heterologous ChAdOx1-S/BNT162b2 combination, and 14-day results showed a strong immune response. The present secondary analysis addresses the evolution of humoral and cellular response up to day 180. Methods: Between April 24 and 30, 2021, 676 adults primed with ChAdOx1-S were enrolled in five hospitals in Spain, and randomised to receive BNT162b2 as second dose (interventional group [IG]) or no vaccine (control group [CG]). Individuals from CG received BNT162b2 as second dose and also on day 28, as planned based on favourable results on day 14. Humoral immunogenicity, measured by immunoassay for SARS-CoV-2 receptor binding domain (RBD), antibody functionality using pseudovirus neutralisation assays for the reference (G614), Alpha, Beta, Delta, and Omicron variants, as well as cellular immune response using interferon-γ and IL-2 immunoassays were assessed at day 28 after BNT162b2 in both groups, at day 90 (planned only in the interventional group) and at day 180 (laboratory data cut-off on Nov 19, 2021). This study was registered with EudraCT (2021-001978-37) and ClinicalTrials.gov (NCT04860739). Findings: In this secondary analysis, 664 individuals (441 from IG and 223 from CG) were included. At day 28 post vaccine, geometric mean titres (GMT) of RBD antibodies were 5616·91 BAU/mL (95% CI 5296·49-5956·71) in the IG and 7298·22 BAU/mL (6739·41-7903·37) in the CG (p 1:100 at day 180 (19% and 22%, respectively). Interpretation: Titres of RBD antibodies decay over time, similar to homologous regimes. Our findings suggested that delaying administration of the second dose did not have a detrimental effect after vaccination and may have improved the response obtained. Lower neutralisation was observed against Omicron and Beta variants at day 180.Funded by Instituto de Salud Carlos III (ISCIII). AMB, AJC, JO, and JF are members of the VACCELERATE (European Corona Vaccine Trial Accelerator Platform) Network, which aims to facilitate and accelerate the design and implementation of COVID-19 phase 2 and 3 vaccine trials. JO is a member of the INsTRuCT (Innovative Training in Myeloid Regulatory Cell Therapy) Consortium, a network of European scientists from academia and industry focused on developing innovative immunotherapies. This work is funded by Instituto de Salud Carlos III, a Spanish public body assigned to the Ministry of Science and Innovation that manages and promotes public clinical research related to public health. The Spanish Clinical Trials Platform is a public network funded by the Instituto de Salud Carlos III (grant numbers PTC20/00018 and PT17/0017), the State Plan for Research, Development, and Innovation 2013−16, the State Plan for Scientific and Technical Research and Innovation 2017−20, and the Subdirectorate General for Evaluation and Promotion of Research, Instituto de Salud Carlos III, cofinanced with FEDER funds. CombiVacS was designed under the umbrella of the VACCELERATE project. VACCELER ATE and INsTRuCT received funding from the EU’s Horizon 2020 Research and Innovation Programme (grant agreement numbers 101037867 and 860003). The Instituto de Salud Carlos III is the Spanish partner in the VACCELERATE project. This work is partially funded by Institute of Health Carlos III (Instituto de Salud Carlos III − ISCIII −), (grants PI19CIII/00004 to JA and PI21CIII/00025 to MPO and JGP), and COVID-19 FUND (grants COV20/00679 and COV20/00072 to MPO and JA) and CIBERINFEC, co-financed by the European Regional Development Fund (FEDER) “A way to make Europe”. The authors thank all trial participants, the international data safety monitoring board (Appendix 1 p 23), and the trial steering committee (Appendix 1 pp 24−25). The authors thank Esther Prieto for editorial assistance and writing support (employed by Hospital Universitario La Paz; funded by the Instituto de Salud Carlos III, grant number PCT20/00018) and María Castillo-de la Osa (PEJ2018-004557-A) for excellent technical assistance.S

Reacciones adversas a medicamentos en cirugía pediátrica

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Enfermería, Fisioterapia y Podología, leída el 16-06-2023La población pediátrica presenta unas diferencias fisiológicas y fisiopatológicas, ligadas al crecimiento y al desarrollo, que distan significativamente dela población adulta. Estas diferencias sustentan, en gran medida, por qué no debería realizarse una extrapolación de los resultados de seguridad, ligados a la utilización de medicamentos, de los adultos a los niños. Por otra parte, el bajo interés de la industria en conducir ensayos clínicos en esta población, unido a las implicaciones éticas de la inclusión de niños en ensayos de fases tempranas, ha obstaculizado el desarrollo de estudios que avalen la seguridad y eficacia de los medicamentos en los niños. Como consecuencia, existe una baja disponibilidad de fármacos que hayan probado estos aspectos (seguridad y eficacia) en población pediátrica. Esta situación ha obligado a los clínicos a tener que recurrir a la utilización off-label de medicamentos, pese a las implicaciones que esto pueda tener, en el desarrollo de Reacciones Adversas a Medicamentos (RAM). Por otra parte, el ámbito quirúrgico se plantea como una atmósfera ideal para el desarrollo de RAM debido, fundamentalmente, al elevado número de fármacos que se emplean durante este periodo y a las similitudes farmacocinéticas y farmacodinámicas de estos productos, que con frecuencia interaccionan entre sí. Por todo esto, si la población que va a ser sometida a un acto quirúrgico es la pediátrica, nos encontramos ante un escenario perfecto para la aparición de RAM y, en consecuencia, evaluar su magnitud se plantea una necesidad de primer orden...The paediatric population's physiological and pathophysiological characteristics are significantly different from the adult one, what largely support why drug use safety results should not be extrapolated from adults to children. Also, the scarce interest of pharmaceutical companies in conducting clinical trials in this population, and the ethical complexity of enrolling children in early phase clinical trials, have hindered the development of studies that support drug's safety and efficacy evidences in children. As a consequence, few drugs adequately studied in children are available, what has forced clinicians to off-label use of medicines despite the implications that this may have in the development of adverse drug reactions (ADRs). Considering the conditions surrounding surgical practice are ideal for the development of ADRs due to the high number of potentially interacting drugs used during surgery, if the population who undergo surgery is paediatric, we are faced with a perfect scenario for the appearance of adverse drug reactions and, consequently, evaluating their magnitude becomes a first-order care need...Fac. de Enfermería, Fisioterapia y PodologíaTRUEunpu