ABSTRACT
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.
ABSTRACT
BackgroundSevere coronavirus disease 2019 (COVID-19) is characterized, in part, by an excessive inflammatory response. Evidence from animal and human studies suggests that vagus nerve stimulation can lead to reduced levels of various pro-inflammatory cytokines. We conducted a prospective randomized controlled study (SAVIOR-I) to assess the feasibility, efficacy, and safety of non-invasive vagus nerve stimulation (nVNS) for the treatment of respiratory symptoms and inflammatory markers among patients who were hospitalized for COVID-19 (ClinicalTrials.gov identifier: NCT04368156). MethodsParticipants were randomly assigned in a 1:1 allocation to receive either the standard of care (SoC) alone or nVNS therapy plus the SoC. The nVNS group received 2 consecutive 2-minute doses of nVNS 3 times daily as prophylaxis. Efficacy and safety were evaluated via the incidence of specific clinical events, inflammatory biomarker levels, and the occurrence of adverse events. ResultsOf the 110 participants who were enrolled and randomly assigned, 97 (nVNS, n=47; SoC, n=50) had sufficient available data and comprised the evaluable population. C-reactive protein (CRP) levels decreased from baseline to a significantly greater degree in the nVNS group than in the SoC group at day 5 and overall (ie, all postbaseline data points collected through day 5, combined). Procalcitonin level also showed significantly greater decreases from baseline to day 5 in the nVNS group than in the SoC group. D-dimer levels were decreased from baseline for the nVNS group and increased from baseline for the SoC group at day 5 and overall, although the difference between the treatment groups did not reach statistical significance. No significant treatment differences were seen for clinical respiratory outcomes or any of the other biochemical markers evaluated. No serious nVNS-related adverse events occurred during the study. ConclusionsnVNS therapy led to significant reductions in levels of inflammatory markers, specifically CRP and procalcitonin. Because nVNS has multiple mechanisms of action that may be relevant to COVID-19, additional research into its potential to be used earlier in the course of COVID-19 and possibly mitigate some of the symptoms associated with post-acute COVID-19 syndrome is warranted.
ABSTRACT
There is limited information on SARS-CoV-2 T-cell immune responses in patients with Covid-19. Both CD4+ and CD8+ T cells may be instrumental in the resolution of and protection from SARS-CoV-2 infection. Here, we tested 25 hospitalized patients with either microbiologically documented Covid-19 (n=19) or highly suspected of having the disease (n=6) for the presence of SARS-CoV-2-reactive-CD69+-expressing interferon--producing-(IFN-) CD8+ T cells by a flow-cytometry for intracelular cytokine staining assay. Two sets of overlapping peptides encompassing the SARS-CoV-2 Spike glycoprotein N-terminal 1-643 amino acid sequence and the entire sequence of SARS-CoV-2 M protein were used simultaneously as antigenic stimulus. Ten patients (40%) had detectable responses, displaying frequencies ranging from 0.15 to 2.7% (median of 0.57 cells/L; range, 0.43-9.98 cells/L). The detection rate of SARS-CoV-2-reactive IFN-{gamma} CD8+ T cells in patients admitted to intensive care was comparable (P=0.28) to that in patients hospitalized in other medical wards. No correlation was found between SARS-CoV-2-reactive IFN-{gamma} CD8+ T-cell counts and SARS-CoV-2 S-specific antibody levels. Likewise, no correlation was observed between either SARS-CoV-2-reactive IFN-{gamma} CD8+ T cells or S-specific IgG-antibody titers and blood cell count or levels of inflammatory biomarkers. In summary, in this descriptive, preliminary study we showed that SARS-CoV-2-reactive IFN-{gamma} CD8+ T cells can be detected in a non-negligible percentage of patients with moderate to severe forms of Covid-19. Further studies are warranted to determine whether quantitation of these T-cell subsets may provide prognostic information on the clinical course of Covid-19.
ABSTRACT
There is scarce information on the frequency of co-detection of respiratory pathogens (RP) in patients with Covid-19. Documentation of coinfections in Covid-19 pneumonia patients may be relevant for appropriate clinical and therapeutic management of patients. Between March 4th and March 28th, 2020, a total of 183 adult patients testing positive by SARS CoV-2 RT-PCR on respiratory specimens were hospitalized with interstitial pneumonia at our center, of whom 103 were tested for other RP by a multiplexed PCR assay. Three patients had a positive result for either one (n=2; Coronavirus HKU1 or Mycoplasma pneumoniae) or two targets (n=1; Influenza virus A (H3) and Respiratory syncytial virus B). Twenty-three patients testing negative by SARS CoV-2 RT-PCR and presentig with clinical, laboratory findings and imaging compatibe with Covid-19 pneumonia underwent RP screening. Of these, 6 (26%) had a positive result for a single RP. Our data indicate that despite the apparent rarity of coinfections in patients with Covid-19 pneumonia, routine testing for RP should be advised, since agents for which specific therapy can be prescribed may be detected.
