September 14, 2023

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Clinical Reports

Genome-wide Association Study of Susceptibility to Respiratory Syncytial Virus Hospitalization in Young Children <5 Years of Age
Worldwide, respiratory syncytial virus (RSV) infections are among the most common causes of infant hospitalization. Host genetic factors influencing the risk and severity of RSV infection are not well known. Researchers conducted a genome-wide association study (GWAS) to investigate single-nucleotide polymorphisms (SNPs) associated with severe RSV infections using a nested case-control design based on 2 Danish cohorts. Researchers compared SNPs from 1786 children hospitalized with RSV to 45 060 controls without an RSV-coded hospitalization. Researchers performed gene-based testing, tissue enrichment, gene-set enrichment, and a meta-analysis of the 2 cohorts. Finally, an analysis of potential associations between the severity of RSV infection and genetic markers was performed. Researchers did not detect any significant genome-wide associations between SNPs and RSV infection or the severity of RSV. We did find potential loci associated with RSV infections on chromosome 5 in 1 cohort but failed to replicate any signals in both cohorts. Despite being the largest GWAS of severe RSV infection, we did not detect any genome-wide significant loci. This may be an indication of a lack of power or an absence of signal. Future studies might include mild illness and need to be larger to detect any significant associations.

Antiviral Therapeutics and Vaccines

Immunogenicity and Reactogenicity of Coadministration of COVID-19 and Influenza Vaccines
This prospective cohort study included health care workers at a large tertiary medical center in Israel who received the Influvac Tetra (Abbott) influenza vaccine (2022/2023), the Omicron BA.4/BA.5–adapted bivalent (Pfizer/BioNTech) vaccine, or both. Vaccination began in September 2022, and data were collected until January 2023. Vaccines were offered to all employees and were coadministered or given separately. Adverse reaction questionnaires were sent, and serologic samples were also collected. The main outcomes for the reactogenicity analysis were symptoms following vaccine receipt, assessed by a digital questionnaire: any local symptoms; fever; weakness or fatigue; any systemic symptoms; and their duration. The immunogenicity analysis’ outcome was postvaccination anti-spike IgG titer. This study included 2 cohorts for 2 separate analyses. The reactogenicity analysis included 588 participants (of 649 questionnaire responders): 85 in the COVID-19 vaccine–alone group (median [IQR] age, 71 [58-74] years; 56 [66%] female); 357 in the influenza vaccine–alone group (median [IQR] age, 55 [40-65] years; 282 [79%] female); and 146 in the coadministration group (median [IQR] age, 61 [50-71] years; 81 [55%] female). The immunogenicity analysis included 151 participants: 74 participants in the COVID-19 vaccine group (median [IQR] age, 67 [56-73] years; 45 [61%] female) and 77 participants in the coadministration group (median [IQR] age, 60 [49-73] years; 42 [55%] female). Compared with COVID-19 vaccination alone, the risk of systemic symptoms was similar in the coadministration group (odds ratio, 0.82; 95% CI, 0.43-1.56). Geometric mean titers in the coadministration group were estimated to be 0.84 (95% CI, 0.69-1.04) times lower than in the COVID-19 vaccine–alone group. In this cohort study of health care workers who received a COVID-19 vaccine, an influenza vaccine, or both, coadministration was not associated with substantially inferior immune response or to more frequent adverse events compared with COVID-19 vaccine administration alone, supporting the coadministration of these vaccines.
Interim Effectiveness Estimates of 2023 Southern Hemisphere Influenza Vaccines in Preventing Influenza-Associated Hospitalizations
The 2023 Southern Hemisphere seasonal influenza vaccine reduced the risk for influenza-associated hospitalizations by 52%. Circulating influenza viruses were genetically similar to those targeted by the 2023–24 Northern Hemisphere influenza vaccine formulation. This vaccine might offer similar protection if these viruses predominate during the coming Northern Hemisphere influenza season. Vaccination remains one of the most effective ways to protect against influenza-associated complications. In anticipation of Northern Hemisphere influenza virus circulation, CDC recommends that health authorities encourage U.S. health care providers to administer seasonal influenza vaccine to all eligible persons aged ≥6 months.
Safety and Immunogenicity of XBB.1.5-Containing mRNA Vaccines
In this ongoing, phase 2/3 study participants were randomized 1:1 to receive 50-µg doses of mRNA-1273.815 monovalent (50-µg omicron XBB.1.5 spike mRNA) or mRNA-1273.231 bivalent (25-µg omicron XBB.1.5 and 25-µg omicron BA.4/BA.5 spike mRNAs) vaccines, administered as 5th doses, to adults who previously received a primary series and 3rd dose of an original mRNA coronavirus disease 2019 (Covid-19) vaccine, and a 4th dose of a bivalent (omicron BA.4/BA.5 and original SARS-CoV-2) vaccine. Interim safety and immunogenicity data 15 days post-vaccination are presented. In April 2023, participants received mRNA-1273.815 (n=50) and mRNA-1273.231 (n=51). The median intervals from the prior dose of BA.4/BA.5-containing bivalent vaccine were 8.2 and 8.3 months for the mRNA-1273.815 and mRNA-1273.231 groups, respectively. Both vaccines increased neutralizing antibody (nAb) geometric mean titers against all variants tested at day 15 post-booster nAb compared to pre-booster levels. Geometric mean fold-rises from pre-booster titers after the monovalent booster were numerically higher against XBB.1.5, XBB.1.16 and SARS-CoV-2 (D614G) than those of the bivalent booster and were comparable against BA.4/BA.5 and BQ1.1 variants for both vaccines. The monovalent vaccine also elicited nAb responses against omicron XBB.2.3.2, EG.5.1, FL.1.5.1 and BA.2.86 that were similar to those against XBB.1.5 in a subset (n=20) of participants. The occurrence of solicited adverse reactions and unsolicited adverse events were overall similar to those previously reported for the original mRNA-1273 50-µg and omicron BA.4/BA.5-containing bivalent mRNA-1273 vaccines. In this interim analysis, XBB.1.5-containing monovalent and bivalent vaccines elicited potent neutralizing responses against variants of the omicron XBB-lineage (XBB.1.5, XBB.1.6, XBB.2.3.2, EG.5.1, and FL.1.5.1) as well as the recently emerged BA.2.86 variant. The safety profile of the XBB.1.5-containing vaccine was consistent with those of prior vaccines. These results overall indicate that the XBB.1.5-containing mRNA-1273.815 vaccine has the potential to provide protection against these emerging variants and support the Covid-19 vaccine update in 2023-2024 to a monovalent XBB.1.5-containing vaccine.
The C.D.C. Director Explains Why You Should Get the Latest Covid Booster
While we would all love to leave Covid-19 in the rearview mirror for good, the virus is still here. And it will probably always be with us. The good news is that we have the tools to help people avoid serious illness, hospitalization, death and long Covid symptoms. We can minimize the virus’s damage to our lives by using one of our most effective tools in combating the virus: updated Covid-19 vaccines. Some viruses, however, change over time. This coronavirus is one of them. It finds ways to evade our immune systems by constantly evolving. That’s why our vaccines need to be updated to match the changed virus. Even though many Americans have been exposed to previous versions of the virus because they’ve been infected, that protection decreases over time. This is partly why you can get Covid more than once and why you can still get very sick even if you had it before. Covid-19 continues to pose a health threat, especially to older Americans. From January to July 2023, 88 percent of deaths from Covid-19 were among people who were age 65 years or older. Those with certain underlying health conditions — approximately 70 percent of American adults — and weakened immune systems also are at greater risk than younger, healthier Americans. What’s more, anyone who gets infected with Covid can develop long Covid… studies have found that the people who may be more likely than others to get long Covid were unvaccinated against the virus. If you get Covid-19, remember that treatment is available. Paxlovid, pills you take twice a day for five days, can help reduce the severity of illness and may help prevent long Covid. It works best when taken soon after symptoms begin. That’s why people with Covid symptoms should get tested and ask their doctor about treatment. The more people who get the shots, the bigger difference it can make in how many Americans are sick and the ability of our health care system to handle influxes of patients. As a doctor, a mother and the head of the C.D.C., I would not recommend anything to others that I wouldn’t recommend for my own family. My 9- and 11-year-old daughters, my husband, my parents and I will all be rolling up our sleeves to get our updated Covid-19 vaccines along with our flu shots soon. I hope you and the people you care about will do the same.

Diagnostics

Performance of Rapid Antigen Tests to Detect Symptomatic and Asymptomatic SARS-CoV-2 Infection : A Prospective Cohort Study
The sensitivity of Ag-RDTs was measured on the basis of testing once (same-day), twice (after 48 hours), and thrice (after a total of 96 hours). The analysis was repeated for different days past index PCR positivity (DPIPPs) to approximate real-world scenarios where testing initiation may not always coincide with DPIPP 0. Results were stratified by symptom status. Among 154 participants who tested positive for SARS-CoV-2, 97 were asymptomatic and 57 had symptoms at infection onset. Serial testing with Ag-RDTs twice 48 hours apart resulted in an aggregated sensitivity of 93.4% (95% CI, 90.4% to 95.9%) among symptomatic participants on DPIPPs 0 to 6. When singleton positive results were excluded, the aggregated sensitivity on DPIPPs 0 to 6 for 2-time serial testing among asymptomatic participants was lower at 62.7% (CI, 57.0% to 70.5%), but it improved to 79.0% (CI, 70.1% to 87.4%) with testing 3 times at 48-hour intervals. Participants tested every 48 hours; therefore, these data cannot support conclusions about serial testing intervals shorter than 48 hours. The performance of Ag-RDTs was optimized when asymptomatic participants tested 3 times at 48-hour intervals and when symptomatic participants tested 2 times separated by 48 hours.

Epidemiology

Optimal Duration of Systemic Corticosteroids in Coronavirus Disease 2019 Treatment: A Systematic Review and Meta-analysis
Corticosteroids confer a survival benefit in individuals hospitalized with coronavirus disease 2019 (COVID-19) who require oxygen. This meta-analysis seeks to determine the duration of corticosteroids needed to optimize this mortality benefit. Electronic databases were searched to 9 March 2022, for studies reporting corticosteroid versus no corticosteroid treatment in hospitalized COVID-19 patients. Researchers estimated the effect of corticosteroids on mortality by random-effects meta-analyses. Subgroup analyses and meta-analyses were conducted to assess the optimal duration of corticosteroid treatment while adjusting for the severity of disease, age, duration of symptoms, and proportion of control group given steroids. Researchers identified 27 eligible studies consisting of 13 404 hospitalized COVID-19 patients. Seven randomized controlled trials and 20 observational studies were included in the meta-analysis of mortality, which suggested a protective association with corticosteroid therapy (risk ratio [RR], 0.71 [95% confidence interval {CI}, .58–.87]). Pooled analysis of 18 studies showed the greatest survival benefit for a treatment duration up to 6 days (RR, 0.54 [95% CI, .39–.74]). Survival benefit was 0.65 (95% CI, .51–.83) up to 7 days, and no additional survival benefit was observed beyond 7 days of treatment (RR, 0.64 [95% CI, .44–.93]). The survival benefit was not confounded by severity of disease, age, duration of symptoms, or proportion of control group given steroids. In this meta-analysis, optimal duration of corticosteroid treatment for hospitalized COVID-19 patients was up to 6 days, with no additional survival benefit with >7 days of treatment.
Timing and Predictors of Loss of Infectivity among Healthcare Workers with Mild Primary and Recurrent COVID-19: a Prospective Observational Cohort Study
There is a need to understand the duration of infectivity of primary and recurrent COVID-19 and identify predictors of loss of infectivity. Prospective observational cohort study with serial viral culture, rapid antigen detection test (RADT) and RT-PCR on nasopharyngeal specimens of healthcare workers with COVID-19. The primary outcome was viral culture positivity as indicative of infectivity. Predictors of loss of infectivity were determined using multivariate regression model. The performance of the US CDC criteria (fever resolution, symptom improvement and negative RADT) to predict loss of infectivity was also investigated. 121 participants (91 female [79.3%]; average age, 40 years) were enrolled. Most (n=107, 88.4%) had received ≥3 SARS-CoV-2 vaccine doses, and 20 (16.5%) had COVID-19 previously. Viral culture positivity decreased from 71.9% (87/121) on day 5 of infection to 18.2% (22/121) on day 10. Participants with recurrent COVID-19 had a lower likelihood of infectivity than those with primary COVID-19 at each follow-up (day 5 OR, 0.14; p<0.001]; day 7 OR, 0.04; p=0.003]) and were all non-infective by day 10 (p=0.02). Independent predictors of infectivity included prior COVID-19 (adjusted OR [aOR] on day 5, 0.005; p=0.003), a RT-PCR Ct value <23 (aOR on day 5, 22.75; p<0.001), but not symptom improvement or RADT result. The CDC criteria would identify 36% (24/67) of all non-infectious individuals on Day 7. However, 17% (5/29) of those meeting all the criteria had a positive viral culture. Infectivity of recurrent COVID-19 is shorter than primary infections. Loss of infectivity algorithms could be optimized.
Effect of famotidine on cognitive and behavioral dysfunctions induced in post-COVID-19 infection: A randomized, double-blind, and placebo-controlled study
There is a need to understand the duration of infectivity of primary and recurrent COVID-19 and identify predictors of loss of infectivity. Prospective observational cohort study with serial viral culture, rapid antigen detection test (RADT) and RT-PCR on nasopharyngeal specimens of healthcare workers with COVID-19. The primary outcome was viral culture positivity as indicative of infectivity. Predictors of loss of infectivity were determined using multivariate regression model. The performance of the US CDC criteria (fever resolution, symptom improvement and negative RADT) to predict loss of infectivity was also investigated. 121 participants (91 female [79.3%]; average age, 40 years) were enrolled. Most (n=107, 88.4%) had received ≥3 SARS-CoV-2 vaccine doses, and 20 (16.5%) had COVID-19 previously. Viral culture positivity decreased from 71.9% (87/121) on day 5 of infection to 18.2% (22/121) on day 10. Participants with recurrent COVID-19 had a lower likelihood of infectivity than those with primary COVID-19 at each follow-up (day 5 OR, 0.14; p<0.001]; day 7 OR, 0.04; p=0.003]) and were all non-infective by day 10 (p=0.02). Independent predictors of infectivity included prior COVID-19 (adjusted OR [aOR] on day 5, 0.005; p=0.003), a RT-PCR Ct value <23 (aOR on day 5, 22.75; p<0.001), but not symptom improvement or RADT result. The CDC criteria would identify 36% (24/67) of all non-infectious individuals on Day 7. However, 17% (5/29) of those meeting all the criteria had a positive viral culture. Infectivity of recurrent COVID-19 is shorter than primary infections. Loss of infectivity algorithms could be optimized.