February 16, 2023

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Clinical Reports

Intra-Host Evolution Provides for the Continuous Emergence of SARS-CoV-2 Variants
Variants of concern (VOC) in SARS-CoV-2 refer to viruses whose viral genomes differ from the ancestor virus by ≥3 single-nucleotide variants (SNVs) and that show the potential for higher transmissibility and/or worse clinical progression. VOC have the potential to disrupt ongoing public health measures and vaccine efforts. Still, too little is known regarding how frequently new viral variants emerge and under what circumstances. Researchers report a study to determine the degree of SARS-CoV-2 sequence evolution in 94 patients and to estimate the frequency at which highly diverse variants emerge. Two cases accumulated ≥9 SNVs over a 2-week period and one case accumulated 23 SNVs over 3 weeks, including three nonsynonymous mutations in the spike protein (D138H, E554D, D614G). The remainder of the infected patients did not show signs of intra-host evolution. We estimate that in as much as 2% of hospitalized COVID-19 cases, variants with multiple mutations in the spike glycoprotein emerge in as little as 1 month of persistent intra-host virus replication. This suggests the continued local emergence of variants with multiple nonsynonymous SNVs, even in patients without overt immune deficiency. Surveillance by sequencing for (i) viremic COVID-19 patients, (ii) patients suspected of reinfection, and (iii) patients with diminished immune function may offer broad public health benefits.

Antiviral Therapeutics and Vaccines

A Randomized Trial Comparing Omicron-Containing Boosters with the Original Covid-19 Vaccine mRNA-1273
This phase 3, randomized, observer-blind, active-controlled trial in the United Kingdom evaluated the immunogenicity and safety of 50-μg doses of omicron-BA.1-monovalent mRNA-1273.529 and bivalent mRNA-1273.214 booster vaccines compared with 50-μg mRNA-1273 administered as boosters in individuals ≥16 years.The bivalent omicron BA.1 containing booster elicited superior neutralizing antibody responses against omicron BA.1 with acceptable safety results consistent with the BA.1 monovalent vaccine. Incidence rates for Covid-19 were numerically lower in participants who received mRNA-1273.214 compared to the original booster vaccine mRNA-1273, driven by the BA.2 and BA.4 sublineages.
The political polarization of COVID-19 treatments among physicians and laypeople in the United States
In the United States, liberals and conservatives disagree about facts. To what extent does expertise attenuate these disagreements? To study this question, researchers compare the polarization of beliefs about COVID-19 treatments among laypeople and critical care physicians. Researchers find that political ideology predicts both groups’ beliefs about a range of COVID-19 treatments. These associations persist after controlling for a rich set of covariates, including local politics. They study two potential explanations: a) that partisans are exposed to different information and b) that they interpret the same information in different ways, finding evidence for both. Polarization is driven by preferences for partisan cable news but not by exposure to scientific research. Using a set of embedded experiments, researchers demonstrate that partisans perceive scientific evidence differently when it pertains to a politicized treatment (ivermectin), relative to when the treatment is not identified. These results highlight the extent to which political ideology is increasingly relevant for understanding beliefs, even among expert decision makers such as physicians.
Maternal mRNA covid-19 vaccination during pregnancy and delta or omicron infection or hospital admission in infants: test negative design study
To estimate the effectiveness of maternal mRNA covid-19 vaccination during pregnancy against delta and omicron severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and hospital admission in infants. Infants younger than six months of age, born between 7 May 2021 and 31 March 2022, who were tested for SARS-CoV-2 between 7 May 2021 and 5 September 2022. 8809 infants met eligibility criteria, including 99 delta cases (4365 controls) and 1501 omicron cases (4847 controls). Infant vaccine effectiveness from two maternal doses was 95% (95% confidence interval 88% to 98%) against delta infection and 97% (73% to 100%) against infant hospital admission due to delta and 45% (37% to 53%) against omicron infection and 53% (39% to 64%) against hospital admission due to omicron. Vaccine effectiveness for three doses was 73% (61% to 80%) against omicron infection and 80% (64% to 89%) against hospital admission due to omicron. Vaccine effectiveness for two doses against infant omicron infection was highest with the second dose in the third trimester (53% (42% to 62%)) compared with the first (47% (31% to 59%)) or second (37% (24% to 47%)) trimesters. Vaccine effectiveness for two doses against infant omicron infection decreased from 57% (44% to 66%) between birth and eight weeks to 40% (21% to 54%) after 16 weeks of age. Maternal covid-19 vaccination with a second dose during pregnancy was highly effective against delta and moderately effective against omicron infection and hospital admission in infants during the first six months of life. A third vaccine dose bolstered protection against omicron. Effectiveness for two doses was highest with maternal vaccination in the third trimester, and effectiveness decreased in infants beyond eight weeks of age.
SARS-CoV-2 Neutralizing Antibodies After Bivalent vs. Monovalent Booster
Bivalent mRNA vaccine boosters expressing Omicron BA.5 spike and ancestral D614G spike were introduced to attempt to boost waning antibody titers and broaden coverage against emerging SARS-CoV-2 lineages. Previous reports showed that peak serum neutralizing antibody (NAb) titers against SARS-CoV-2 variants following bivalent booster were similar to peak titers following monovalent booster. It remains unknown whether these antibody responses would diverge over time. Researchers assessed serum virus-neutralizing titers in 41 participants who received three monovalent mRNA vaccine doses followed by bivalent booster, monovalent booster, or BA.5 breakthrough infection at one month and three months after the last vaccine dose or breakthrough infection using pseudovirus neutralization assays against D614G and Omicron subvariants (BA.2, BA.5, BQ.1.1, and XBB.1.5). There was no significant difference at one month and three months post-booster for the two booster cohorts. BA.5 breakthrough patients exhibited significantly higher NAb titers at three months against all Omicron subvariants tested compared against monovalent and bivalent booster cohorts. There was a 2-fold drop in mean NAb titers in the booster cohorts between one and three month time points, but no discernible waning of titers in the BA.5 breakthrough cohort over the same period. These results suggest that NAb titers after boosting with one dose of bivalent mRNA vaccine are not higher than boosting with monovalent vaccine. Perhaps inclusion of D614G spike in the bivalent booster exacerbates the challenge posed by immunological imprinting. Hope remains that a second bivalent booster could induce superior NAb responses against emerging variants.
The impacts of SARS-CoV-2 vaccine dose separation and targeting on the COVID-19 epidemic in England
In late 2020, the JCVI (the Joint Committee on Vaccination and Immunisation, which provides advice to the Department of Health and Social Care, England) made two important recommendations for the initial roll-out of the COVID-19 vaccine. The first was that vaccines should be targeted to older and vulnerable people, with the aim of maximally preventing disease rather than infection. The second was to increase the interval between first and second doses from 3 to 12 weeks. Here, researchers re-examine these recommendations through a mathematical model of SARS-CoV-2 infection in England. They show that targeting the most vulnerable had the biggest immediate impact (compared to targeting younger individuals who may be more responsible for transmission). The 12-week delay was also highly beneficial, estimated to have averted between 32-72 thousand hospital admissions and 4-9 thousand deaths over the first ten months of the campaign (December 2020–September 2021) depending on the assumed interaction between dose interval and efficacy.
Real-world use of nirmatrelvir–ritonavir in outpatients with COVID-19 during the era of omicron variants including BA.4 and BA.5 in Colorado, USA: a retrospective cohort study
Among 28,167 patients infected with SARS-CoV-2 between March 26 and Aug 25, 2022, 21 493 met the study inclusion criteria. 9881 patients received treatment with nirmatrelvir–ritonavir and 11 612 were untreated. Nirmatrelvir–ritonavir treatment was associated with reduced 28-day all-cause hospitalization compared with no antiviral treatment. Nirmatrelvir–ritonavir treatment was also associated with reduced 28-day all-cause mortality. Using subsequent emergency department visits as a surrogate for clinically significant relapse, researchers observed a decrease after nirmatrelvir–ritonavir treatment. Real-world evidence reported during a BA.2, BA2.12.1, BA.4, and BA.5 omicron surge showed an association between nirmatrelvir–ritonavir treatment and reduced 28-day all-cause hospitalization, all-cause mortality, and visits to the emergency department. With results that are among the first to suggest effectiveness of nirmatrelvir–ritonavir for non-hospitalized patients during an omicron period inclusive of BA.4 and BA.5 subvariants, these data support nirmatrelvir–ritonavir as an ongoing first-line treatment for adults acutely infected with SARS-CoV-2.
Viral burden rebound in hospitalized patients with COVID-19 receiving oral antivirals in Hong Kong: a population-wide retrospective cohort study
Researchers did a retrospective cohort study of hospitalized patients with a confirmed diagnosis of COVID-19 in Hong Kong, China, for an observation period from Feb 26 to July 3, 2022 (during the omicron BA.2.2 variant wave). Adult patients (age ≥18 years) admitted 3 days before or after a positive COVID-19 test were selected from medical records held by the Hospital Authority of Hong Kong. We included patients with non-oxygen-dependent COVID-19 at baseline receiving either molnupiravir (800 mg twice a day for 5 days), nirmatrelvir–ritonavir (nirmatrelvir 300 mg with ritonavir 100 mg twice a day for 5 days), or no oral antiviral treatment (control group). Researchers found that viral burden rebound rates were similar between patients with antiviral treatment and those without. Importantly, viral burden rebound was not associated with adverse clinical outcomes.
Guidance on the use of convalescent plasma to treat immunocompromised patients with COVID-19
COVID-19 convalescent plasma (CCP) is a safe and effective treatment for COVID-19 in immune compromised (IC) patients. IC patients have a higher risk of persistent infection, severe disease and death from COVID-19. Despite the continued clinical use of CCP to treat IC patients, the optimal dose, frequency/schedule, and duration of CCP treatment has yet to be determined, and related best practices guidelines are lacking. A group of individuals with expertise spanning infectious diseases, virology and transfusion medicine was assembled to render an expert opinion statement pertaining to the use of CCP for IC patients. For optimal effect, CCP should be recently and locally collected to match circulating variant. CCP should be considered for the treatment of IC patients with acute and protracted COVID-19; dosage depends on clinical setting (acute vs protracted COVID-19). CCP containing high-titer SARS-CoV-2 antibodies, retains activity against circulating SARS-CoV-2 variants, which have otherwise rendered monoclonal antibodies ineffective.

Epidemiology

Malawi's cholera death toll crosses 1,300 in its deadliest outbreak on record
The death toll from a cholera outbreak in Malawi has crossed 1,300, a senior Malawian health official said on Thursday, as the southern African country battles its deadliest outbreak yet. As of Wednesday, Malawi had recorded 40,284 cholera cases and 1,316 deaths in an outbreak that started in March 2022, with the country averaging over 500 new cases every day.
Impact of Human Coronavirus Infections on Paediatric Patients at a Tertiary Paediatric Hospital: A Retrospective Study of the Prepandemic Era
Researchers analyzed 450 encounters for 430 different patients, with the majority (85%) being inpatient. OC43 was the most common HCoV. Younger patients (<5 years) had higher probability of hospitalization (aOR 2.2, 95% CI 1.2 – 4.1), requiring HLC (aOR 1.8, 95% CI 1.0 – 3.1), and presence of LRT findings on chest radiographs (aOR 1.7, 95% CI 1.01 – 2.9). Clinical outcomes were not different among HCoV types except LOS that was longer for 229E. Fifty-two (11%) of the encounters were detected after 3 days of hospitalization (median of 25.5), suggesting possible nosocomial infections. HCoVs are important respiratory pathogens in the paediatric population, especially patients <5 years of age who are at increased risk for disease severity. The role of HCoVs as hospital-acquired pathogens may be underappreciated.
Yes, masks reduce the risk of spreading COVID, despite a review saying they don’t
A comprehensive review of the evidence would also include other types of study besides RCTs. For example, a large systematic reviewof 172 various study designs, which included 25,697 patients with SARS-CoV-2, SARS, or MERS, concluded masks were effective in preventing transmission of respiratory viruses. Well-designed real-world studies during the pandemic showed any mask reduces the risk of COVID transmission by 50–80%, with the highest protection offered by N95 respirators. Many lab-based studies have shown respirators are superior to masks at preventing airborne respiratory infections and the incremental superiority from a single to two layered cloth mask to a three-layered surgical mask in blocking respiratory aerosols. There is strong and consistent evidence for the effectiveness of masks and (even more so) respirators in protecting against respiratory infections. Masks are an important protection against serious infections. Current COVID vaccines protect against death and hospitalization, but do not prevent infection well due to waning vaccine immunity and substantial immune escape from new variants.
COVID-19 and Airborne Transmission: Science Rejected, Lives Lost. Can Society Do Better?
This is an account that should be heard of an important struggle: the struggle of a large group of experts who came together at the beginning of the Covid-19 pandemic to warn the world about the risk of airborne transmission and the consequences of ignoring it. Researchers alerted the World Health Organization (WHO) about the potential significance of the airborne transmission of SARS-CoV-2 and the urgent need to control it, but their concerns were dismissed. Here researchers describe how this happened and the consequences. They hope that by reporting this story, they can raise awareness of the importance of interdisciplinary collaboration and the need to be open to new evidence, and to prevent it from happening again. Acknowledgement of an issue and the emergence of new evidence related to it, is the first necessary step towards finding effective mitigation solutions.