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Background: A SARS-CoV-2 protein-based heterodimer vaccine, PHH-1V, has been shown to be safe and well-tolerated in healthy young adults in a first-in-human, Phase I/IIa study dose-escalation trial. Here, we report the interim results of the Phase IIb HH-2, where the immunogenicity and safety of a heterologous booster with PHH-1V is assessed versus a homologous booster with BNT162b2 at 14, 28 and 98 days after vaccine administration. Methods: The HH-2 study is an ongoing multicentre, randomised, active-controlled, double-blind, non-inferiority Phase IIb trial, where participants 18 years or older who had received two doses of BNT162b2 were randomly assigned in a 2:1 ratio to receive a booster dose of vaccine -either heterologous (PHH-1V group) or homologous (BNT162b2 group)- in 10 centres in Spain. Eligible subjects were allocated to treatment stratified by age group (18-64 versus [≥]65 years) with approximately 10% of the sample enrolled in the older age group. The primary endpoints were humoral immunogenicity measured by changes in levels of neutralizing antibodies (PBNA) against the ancestral Wuhan-Hu-1 strain after the PHH-1V or the BNT162b2 boost, and the safety and tolerability of PHH-1V as a boost. The secondary endpoints were to compare changes in levels of neutralizing antibodies against different variants of SARS-CoV-2 and the T-cell responses towards the SARS-CoV-2 spike glycoprotein peptides. The exploratory endpoint was to assess the number of subjects with SARS-CoV-2 infections [≥]14 days after PHH-1V booster. This study is ongoing and is registered with ClinicalTrials.gov, NCT05142553. Findings: From 15 November 2021, 782 adults were randomly assigned to PHH-1V (n=522) or BNT162b2 (n=260) boost vaccine groups. The geometric mean titre (GMT) ratio of neutralizing antibodies on days 14, 28 and 98, shown as BNT162b2 active control versus PHH-1V, was, respectively, 1.68 (p<0.0001), 1.31 (p=0.0007) and 0.86 (p=0.40) for the ancestral Wuhan-Hu-1 strain; 0.62 (p<0.0001), 0.65 (p<0.0001) and 0.56 (p=0.003) for the Beta variant; 1.01 (p=0.92), 0.88 (p=0.11) and 0.52 (p=0.0003) for the Delta variant; and 0.59 (p=<0.0001), 0.66 (p<0.0001) and 0.57 (p=0.0028) for the Omicron BA.1 variant. Additionally, PHH-1V as a booster dose induced a significant increase of CD4+ and CD8+ T-cells expressing IFN-{gamma} on day 14. There were 458 participants who experienced at least one adverse event (89.3%) in the PHH-1V and 238 (94.4%) in the BNT162b2 group. The most frequent adverse events were injection site pain (79.7% and 89.3%), fatigue (27.5% and 42.1%) and headache (31.2 and 40.1%) for the PHH-1V and the BNT162b2 groups, respectively. A total of 52 COVID-19 cases occurred from day 14 post-vaccination (10.14%) for the PHH-1V group and 30 (11.90%) for the BNT162b2 group (p=0.45), and none of the subjects developed severe COVID-19. Interpretation: Our interim results from the Phase IIb HH-2 trial show that PHH-1V as a heterologous booster vaccine, when compared to BNT162b2, although it does not reach a non-inferior neutralizing antibody response against the Wuhan-Hu-1 strain at days 14 and 28 after vaccination, it does so at day 98. PHH-1V as a heterologous booster elicits a superior neutralizing antibody response against the previous circulating Beta and Delta SARS-CoV-2 variants, as well as the currently circulating Omicron BA.1. Moreover, the PHH-1V boost also induces a strong and balanced T-cell response. Concerning the safety profile, subjects in the PHH-1V group report significantly fewer adverse events than those in the BNT162b2 group, most of mild intensity, and both vaccine groups present comparable COVID-19 breakthrough cases, none of them severe. Funding: HIPRA SCIENTIFIC, S.L.U.
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BackgroundAlmost two years since the onset of the COVID-19 pandemic no predictive algorithm has been generally adopted, nor new tests identified to improve the prediction and management of SARS-CoV-2 infection. MethodsRetrospective observational analysis of the predictive performance of clinical parameters and laboratory tests in hospitalised patients with COVID-19. Outcomes were 28-day survival and maximal severity in a cohort of 1,579 patients and two validation cohorts of 598 and 434 patients. A pilot study conducted in a patient subgroup measured 17 cytokines and 27 lymphocyte phenotypes to explore additional predictive laboratory tests. Findings1) Despite a strong association of 22 clinical and laboratory variables with the outcomes, their joint prediction power was limited due to redundancy. 2) Eight variables: age, comorbidity index, oxygen saturation to fraction of inspired oxygen ratio, neutrophil-lymphocyte ratio, C-reactive protein, aspartate aminotransferase/alanine aminotransferase ratio, fibrinogen, and glomerular filtration rate captured most of the statistical predictive power. 3) The interpretation of clinical and laboratory variables was improved by grouping them in categories. 4) Age and organ damage-related tests were the best predictors of survival, and inflammatory-related tests were the best predictors of severity. 5) The pilot study identified several immunological tests (including chemokine ligand 10, chemokine ligand 2, and interleukin 1 receptor antagonist), that performed better than currently used tests. ConclusionsCurrently used tests for clinical management of COVID-19 patients are of limited predictive value due to redundancy, as all measure aspects of two major processes: inflammation, and organ damage. There are no independent predictors based on the quality of the nascent adaptive immune response. Understanding the limitations of current tests would improve their interpretation and simplify clinical management protocols. A systematic search for better biomarkers is urgent and feasible. This study was funded by Instituto de Salud Carlos III, Madrid, Spain, grants COV20/00416, Cov20/00654 and COV20/00388 to R.P-B, ATS and JBM respectively and co-financed by the European Regional Development Fund (ERDF). DA-S is recipient of a doctoral fellowship from the Vall dHebron Research Institute, Barcelona, Spain. ASM was supported by a postdoctoral grant "Juan Rodes" (JR18/00022) from Instituto de Salud Carlos III through the Ministry of Economy and Competitiveness, Spain
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OBJETIVO: Describir el uso de carbapenémicos en pacientes pediátricos hospitalizados fuera de las unidades de cuidados intensivos y oncohematología, y evaluar la adecuación de su prescripción a un protocolo terapéutico. PACIENTES Y MÉTODOS: Estudio retrospectivo observacional, entre enero de 2009 y diciembre de 2010, sobre la utilización de carbapenémicos en niños hospitalizados, por patología infecciosa comunitaria y relacionada con asistencia sanitaria, en el área infantil del Hospital Universitari Vall d'Hebrón, en Barcelona, excluyendo las unidades de cuidados intensivos, neonatología y oncohematología. Se recogieron datos clínicos y de consumo de antibióticos, facilitados por el Servicio de Farmacia. RESULTADOS: Cumplían los criterios de inclusión 51 episodios. En el 31,4% se indicó un carbapenémico como tratamiento empírico inicial; en el resto fue como tratamiento de rescate. Se adecúan a las indicaciones del protocolo el 70,6% de las prescripciones empíricas y el 87,5% de las dirigidas. Globalmente, el 77,6% de las prescripciones de un carbapenémico se ajustaron a las indicaciones del protocolo. En los pacientes con un ingreso previo o una enfermedad de base la prescripción empírica tiene una mejor adecuación. Factores como el diagnóstico al ingreso, la edad o la antibioterapia previa al ingreso no mostraron ninguna tendencia respecto a la indicación empírica de un carbapenémico. CONCLUSIONES: La existencia de un protocolo de indicaciones de tratamiento con carbapenémicos establecido desde 2007 en el hospital ha permitido unos resultados de adecuación de la prescripción significativamente superiores a los obtenidos en otros estudios
OBJECTIVE: To describe the use of carbapenems in children hospitalised outside intensive care and onco-haematology units, and assess adherence to a therapeutic protocol. PATIENTS AND METHODS: A retrospective observational study was conducted on the use of carbapenems between January 2009 and December 2010. The study included children with a community-acquired infectious disease or a health care-associated infectious disease, and who were admitted to paediatric areas of the Vall d'Hebron University Hospital (Barcelona, Spain), other than intensive care, neonatology and onco-haematology units. Clinical data were collected and antibiotic consumption data were provided by the Pharmacy Department. RESULTS: A total of 51 episodes fulfilled the inclusion criteria. Carbapenem as initial empirical treatment was indicated in 31.4%, and applied as rescue therapy in the remainder. The instructions of the protocol were adhered to in 70.6% of the empirical and 87.5% of the targeted prescriptions (77.6% overall). A better match was found for empirical carbapenem in patients with a previous admission or underlying condition. Factors such as diagnosis, age or antibiotic use prior to admission did not affect the empirical indication of carbapenem. CONCLUSIONS: The establishment of a treatment protocol with carbapenem indications in our centre since 2007 has yielded significantly better results on the appropriateness of the prescription than those obtained in other studies
