Unexpectedly Higher Morbidity and Mortality of Hospitalized Elderly Patients Associated with Rhinovirus Compared with Influenza Virus Respiratory Tract Infection

Rhinovirus is a common cause of upper and lower respiratory tract infections in adults, especially among the elderly and immunocompromised. Nevertheless, its clinical characteristics and mortality risks have not been well described. A retrospective analysis on a prospective cohort was conducted in a single teaching hospital center over a one-year period. We compared adult patients hospitalized for pneumonia caused by rhinovirus infection with those hospitalized for influenza infection during the same period. All recruited patients were followed up for at least 3 months up to 15 months. Independent risk factors associated with mortality for rhinovirus infection were identified. Between 1 March 2014 and 28 February 2015, a total of 1946 patients were consecutively included for analysis. Of these, 728 patients were hospitalized for rhinovirus infection and 1218 patients were hospitalized for influenza infection. Significantly more rhinovirus patients were elderly home residents and had chronic lung diseases (p < 0.001), whereas more influenza patients had previous stroke (p = 0.02); otherwise, there were no differences in the Charlson comorbidity indexes between the two groups. More patients in the rhinovirus group developed pneumonia complications (p = 0.03), required oxygen therapy, and had a longer hospitalization period (p < 0.001), whereas more patients in the influenza virus group presented with fever (p < 0.001) and upper respiratory tract symptoms of cough and sore throat (p < 0.001), and developed cardiovascular complications (p < 0.001). The 30-day (p < 0.05), 90-day (p < 0.01), and 1-year (p < 0.01) mortality rate was significantly higher in the rhinovirus group than the influenza virus group. Intensive care unit admission (odds ratio (OR): 9.56; 95% confidence interval (C.I.) 2.17–42.18), elderly home residents (OR: 2.60; 95% C.I. 1.56–4.33), requirement of oxygen therapy during hospitalization (OR: 2.62; 95% C.I. 1.62–4.24), and hemoglobin level <13.3 g/dL upon admission (OR: 2.43; 95% C.I. 1.16–5.12) were independent risk factors associated with 1-year mortality in patients hospitalized for rhinovirus infection. Rhinovirus infection in the adults was associated with significantly higher mortality and longer hospitalization when compared with influenza virus infection. Institutionalized older adults were particularly at risk. More stringent infection control among health care workers in elderly homes could lower the infection rate before an effective vaccine and antiviral become available

Repurposing of Miltefosine as an Adjuvant for Influenza Vaccine

We previously reported that topical imiquimod can improve the immunogenicity of the influenza vaccine. This study investigated another FDA-approved drug, miltefosine (MTF), as a vaccine adjuvant. Mice immunized with an influenza vaccine with or without MTF adjuvant were challenged by a lethal dose of influenza virus 3 or 7 days after vaccination. Survival, body weight, antibody response, histopathological changes, viral loads, cytokine levels, and T cell frequencies were compared. The MTF-adjuvanted vaccine (MTF-VAC) group had a significantly better survival rate than the vaccine-only (VAC) group, when administered 3 days (80% vs. 26.7%, p = 0.0063) or 7 days (96% vs. 65%, p = 0.0041) before influenza virus challenge. Lung damage was significantly ameliorated in the MTF-VAC group. Antibody response was significantly augmented in the MTF-VAC group against both homologous and heterologous influenza strains. There was a greater T follicular helper cell (TFH) response and an enhanced germinal center (GC) reaction in the MTF-VAC group. MTF-VAC also induced both TH1 and TH2 antigen-specific cytokine responses. MTF improved the efficacy of the influenza vaccine against homologous and heterologous viruses by improving the TFH and antibody responses. Miltefosine may also be used for other vaccines, including the upcoming vaccines for COVID-19

Attenuated SARS-CoV-2 variants with deletions at the S1/S2 junction

The emergence of SARS-CoV-2 has led to the current global coronavirus pandemic and more than one million infections since December 2019. The exact origin of SARS-CoV-2 remains elusive, but the presence of a distinct motif in the S1/S2 junction region suggests the possible acquisition of cleavage site(s) in the spike protein that promoted cross-species transmission. Through plaque purification of Vero-E6 cultured SARS-CoV-2, we found a series of variants which contain 15-30-bp deletions (Del-mut) or point mutations respectively at the S1/S2 junction. Examination of the original clinical specimen from which the isolate was derived, and 26 additional SARS-CoV-2 positive clinical specimens, failed to detect these variants. Infection of hamsters shows that one of the variants (Del-mut-1) which carries deletion of 10 amino acids (30bp) does not cause the body weight loss or more severe pathological changes in the lungs that is associated with wild type virus infection. We suggest that the unique cleavage motif promoting SARS-CoV-2 infection in humans may be under strong selective pressure, given that replication in permissive Vero-E6 cells leads to the loss of this adaptive function. It would be important to screen the prevalence of these variants in asymptomatic infected cases. The potential of the Del-mut variants as an attenuated vaccine or laboratory tool should be evaluated

Spike mutations contributing to the altered entry preference of SARS-CoV-2 Omicron BA.1 and BA.2

SARS-CoV-2 B.1.1.529.1 (Omicron BA.1) emerged in November 2021 and quickly became the predominant circulating SARS-CoV-2 variant globally. Omicron BA.1 contains more than 30 mutations in the spike protein, which contribute to its altered virological features when compared to the ancestral SARS-CoV-2 or previous SARS-CoV-2 variants. Recent studies by us and others demonstrated that Omicron BA.1 is less dependent on transmembrane serine protease 2 (TMPRSS2), less efficient in spike cleavage, less fusogenic, and adopts an altered propensity to utilize the plasma membrane and endosomal pathways for virus entry. Ongoing studies suggest that these virological features of Omicron BA.1 are in part retained by the subsequent Omicron sublineages. However, the exact spike determinants that contribute to these altered features of Omicron remain incompletely understood. In this study, we investigated the spike determinants for the observed virological characteristics of Omicron. By screening for the individual changes on Omicron BA.1 and BA.2 spike, we identify that 69-70 deletion, E484A, and H655Y contribute to the reduced TMPRSS2 usage while 25-27 deletion, S375F, and T376A result in less efficient spike cleavage. Among the shared spike mutations of BA.1 and BA.2, S375F and H655Y reduce spike-mediated fusogenicity. Interestingly, the H655Y change consistently reduces serine protease usage while increases the use of endosomal proteases. In keeping with these findings, the H655Y substitution alone reduces plasma membrane entry and facilitates endosomal entry when compared to SARS-CoV-2 WT. Overall, our study identifies key changes in Omicron spike that contributes to our understanding on the virological determinant and pathogenicity of Omicron.</p