Humoral and cellular immune responses after 6 months of a heterologous SARS-CoV-2 booster with the protein-based PHH-1V vaccine in a phase IIb trial (preprint)

The HIPRA-HH-2 was a multicentre, randomized, active-controlled, double-blind, non-inferiority phase IIb clinical trial to compare the immunogenicity and safety of a heterologous booster with PHH-1V adjuvanted recombinant vaccine versus a homologous booster with mRNA vaccine. Interim results showed a strong humoral and cellular immune response against the SARS-CoV-2 Wuhan-Hu-1 strain and the Beta, Delta, and Omicron BA.1 variants up to day 98 after dosing. Here we report that these humoral and cellular responses after PHH-1V dosing are sustained up to 6 months. These results are observed both when including or not participants who reported SARS-CoV-2 infection and in a high-risk population ([≥]65 years). Additional analysis revealed a non-inferiority of PHH-1V booster in eliciting neutralizing antibodies also for SARS-CoV-2 Omicron XBB.1.5 when compared to mRNA vaccine after 6 months. The PHH-1V vaccine provides long-lasting protection against a wide variety of SARS-CoV-2 emerging variants to prevent severe COVID-19. ClinicalTrials.gov Identifier: NCT05142553

Safety and immunogenicity of the protein-based PHH-IV compared to BNT162b2 as a heterologous SARS-CoV-2 booster vaccine in adults vaccinated against COVID-19: a multicentre, randomised, double-blind, non-inferiority phase IIb trial (preprint)

Summary 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 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 endpoints were humoral immunogenicity measured by changes in levels of neutralizing antibodies against the ancestral Wuhan-Hu-1 strain and different variants of SARS-CoV-2 after the PHH-1V or the BNT162b2 boost, the T-cell responses towards the SARS-CoV-2 spike glycoprotein peptides and the safety and tolerability of PHH-1V as a boost. 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 and 98, shown as BNT162b2 active control versus PHH-1V, was, respectively, 1·68 (p<0·0001) and 0·87 (p=0·43) for the ancestral Wuhan-Hu-1 strain; 0·61 (p<0·0001) and 0·57 (p=0·0064) for the beta variant; 1·01 (p=0·89) and 0·52 (p=0·0003) for the delta variant; and 0·59 (p=<0·0001) and 0·56 (p=0·0026) for the omicron variant. Additionally, PHH-1V as a booster dose induced a significant increase of CD4 + and CD8 + T-cells expressing IFN-γ 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, elicits a strong and sustained neutralizing antibody response against Wuhan-Hu-1 strain, and a superior one concerning the previous circulating beta and delta SARS-CoV-2 variants, as well as the currently circulating omicron. 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.

Tocilizumab efficacy in COVID-19 patients is associated with respiratory severity-based stages (preprint)

Background: Tocilizumab treatment is investigated, and effectiveness in ICU-admitted COVID-19 patients has been reported. Although controversy exists regarding the efficacy of tocilizumab treatment, it has been suggested that tocilizumab might show positive results depending on patient severity status. We examined an association between tocilizumab and distinct disease severity stages. Methods and Findings: From March 3 to March 23 2020, 494 consecutively admitted COVID-19 patients received tocilizumab or standard treatment alone. Data were obtained retrospectively. Clinical respiratory severity (CRS) stages were defined by patient oxygenation status and were also associated to scores of WHO clinical progression scale. We categorized patients in three stages, mild/moderate CRS1 (FiSpO2<0.35; WHO score 5), moderate/severe CRS2 (FiO2=0.5/high flow mask; WHO score 6) and severe/critical CRS3 (FiO2<80%/high flow/prone position or mechanical ventilation; score>6). The primary outcome was the composite of death or ICU admission in patients of stages CRS1, CRS2, and CRS3, as well as in total patients. We also addressed mortality alone in total patients. Kaplan-Maier curves, Cox proportional regression and inverse probability weighting marginal structural models were used. We conducted the study from March 3 to April 7 2020 with broad-ranged severity patients; 167 tocilizumab-treated and 327 untreated. CRS1 patients showed no apparent benefit after treatment, while the risk of the primary outcome was greatly reduced in CRS2 treated participants ((HR=0.22; 95% CI (0.16-0.44)). Moreover, tocilizumab treatment was associated with significantly decreased CRS2 patient proportion that reached the outcome compared to non-treated controls (27.8.0% vs. 65.4%; p<0.001). Severe/critical CRS3 patients, also showed benefit after treatment (HR=0.38; 95% CI (0.16-90)), although not as robust as was that of CRS2 treated individuals. Tocilizumab was associated with reduced outcome risk in total patients (HR=0.42; 95% CI (0.26-0.66)) after CRS adjustment, but not if CRS classification was not accounted as confounding factor (HR=1.19; 95% CI (0.84-1.69)). The outcome of mortality alone upon tocilizumab treatment was significant (HR=0.58; 95% CI (0.35-0.96)) after accounting for CRS classification. Conclusions: Tocilizumab treatment is associated with reduced COVID-19 escalation in CRS2 patients, suggesting efficacy in moderate/severe non-ICU-admitted patients. CRS classification could represent an essential confounding factor in evaluating tocilizumab in studies of broad-ranged severity patients.

Prevalence and risk factors for mortality related to COVID-19 in a severely affected area of Madrid, Spain (preprint)

BACKGROUND: The coronavius disease 2019 (COVID-9) caused by the severe acute respiratory syndrome coronavirus 2 reached Spain by 31 January 2020, in April 2020, the Comunidad de Madrid suffered one of the world's highest crude mortality rate ratios. This study aimed to detect risk factors for mortality in patients with COVID-19. METHODS: Our cohort were all consecutive adult patients with laboratory-confirmed COVID-19 at a secondary hospital in Madrid, March 3-16, 2020. Clinical and laboratory data came from electronic clinical records and were compared between survivors and non-survivors, with outcomes followed up until April 4. Univariable and multivariable logistic regression methods allowed us to explore risk factors associated with in-hospital death. FINDINGS: The cohort comprised 562 patients with COVID-19. Clinical records were available for evaluation for 392 patients attended at the emergency department of our hospital, of whom 199 were discharged, 85 remained hospitalized and 108 died during hospitalization. Among 311 of the hospitalized patients, 34.7% died. Of the 392 patients with records, the median age was 71.5 years (50.6-80.7); 52.6% were men. 252 (64.3%) patients had a comorbidity, hypertension being the most common: 175 (44.6%), followed by other cardiovascular disease: 102 (26.0%) and diabetes: 97 (24.7%). Multivariable regression showed increasing odds of in-hospital death associated with age over 65 (odds ratio 8.32, 95% CI 3.01-22.96; p<0.001), coronary heart disease (2.76, 1.44-5.30; 0.002), and both lower lymphocyte count (0.34, 0.17-0.68; 0.002) and higher LDH (1.25, 1.05-1.50; 0.012) per 1-unit increase and per 100 units respectively. INTERPRETATION: COVID-19 was associated in our hospital at the peak of the pandemic with a crude mortality ratio of 19.2% and a mortality ratio of 34.7% in admitted patients, considerably above most of the ratios described in the Chinese series. These results leave open the question as to which factors, epidemiological or intrinsically viral, apart from age and comorbidities, can explain this difference in excess mortality. FUNDING: None.