Tag: Coronavirus Disease COVID-19

New tARC-seq method enhances precision in tracking SARS-CoV-2 mutations

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In a recent study published in Nature Microbiology, researchers developed a targeted accurate ribonucleic acid (RNA) consensus sequencing (tARC-seq) approach to precisely determine severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutation frequency and types in cell culture and clinical samples.

Study: Targeted accurate RNA consensus sequencing (tARC-seq) reveals mechanisms of replication error affecting SARS-CoV-2 divergence. Image Credit: Andrii Vodolazhskyi/Shutterstock.com

Background

SARS-CoV-2 replicates via RNA-dependent RNA polymerases (RdRp), which are prone to errors. Monitoring replication mistakes is critical to understanding the virus’s development, but existing approaches are insufficient to identify infrequent de novo ribonucleic acid alterations.

During the coronavirus disease 2019 (COVID-19) pandemic, SARS-CoV-2 mutation rates ranged from 10−6 to 10−4 per base per cell. Exonuclease proofreading activity boosts mutation rates, leading to a mean of two mutations in each genome monthly.

About the study

In the present study, researchers created tARC-seq to investigate the mechanisms of replication errors impacting the divergence of SARS-CoV-2.

The tARC-seq approach combines ARC-seq characteristics with hybrid capturing technology to enhance targets, allowing in-depth variant interrogation of these samples.

The researchers used tARC-seq to discover RNA variations in the original SARS-CoV-2 wild-type (WT) strain, SARS-CoV-2 Alpha and Omicron variants, and clinical and Omicron samples.

The researchers sequenced SARS-CoV-2 wild-type RNA following 4.0 infectious cycles, generating 9.0 × 10⁵plaque-forming units (pf.u.) of SARS-CoV-2 RNA. They added E. coli messenger RNA (mRNA) as an enzyme carrier to prepare libraries. Hybrid capture detected E. coli RNA in the genetic library, which the researchers examined individually and used as internal controls.

To further investigate selections in tARC sequencing data, the researchers mapped non-sense-type, synonymous, and non-synonymous variant frequencies identified by tARC sequencing across mon-structural protein 12 (nsp12), a critical gene that encodes SARS-CoV-2 RdRp.

They determined the evolutionary action (EA) scorings and variation frequencies for nonsense-type and non-synonymous single-nucleotide polymorphisms (SNPs) found in SARS-CoV-2 spike (S) and nsp12. They also computed the average mutational frequencies of open reading frames (ORFs) in the wild-type virus, broken down by mutational type and base alterations.

The researchers investigated the random distribution of RNA variants across the SARS-CoV-2 genome using location-based estimations and nucleotide identity analysis. They also used tARC-seq on two clinical samples to look for de novo mutations caused by spontaneous infection.

They matched the top ten most common C>TT and G>AA mutations to known A3A editing sites in the wild-type virus. The researchers examined all SID occurrences with ≥2 nucleotides of complementarity between donor and acceptor sites downstream in WT, Alpha, and Omicron. They investigated the genome-wide prevalence of TC>TT mutations in WT-Vero cells.

Results

Researchers found 2.7 × 10−5 (mean) de novo mistakes per cycle in the SARS-CoV-2 virus, with C>T biases not primarily due to apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC) editing.

They identified cool and hot areas across the genome, according to low or high GC concentration, and highlighted transcription regulatory regions as sites more prone to mistakes. The tARC-seq approach enables the detection of template switches such as deletions, insertions, and complicated alterations.

The WT virus has 1.1 × 10⁻⁴ RNA variations per base, with base substitutions accounting for the majority (8.4 × 10⁻⁵), followed by insertions (2.5 × 10⁻⁶) and deletions (2.1 × 10⁻⁵). The G > A and C > T transitions dominate the viral mutation landscape, contributing 9.0% and 44% of all occurrences.

The mutational spectrum and frequency of wild-type SARS-CoV-2 off-target reads differ from those of E. coli, showing that these mutational events are genuine viral alterations rather than library preparation artifacts.

Random distributions and comparable rates of all three nsp12 mutation types suggest that most RNA variations found by tARC sequencing were de novo-type replication mistakes. The researchers found no differences in variant frequencies between the SNPs with low evolutionary action scores (estimated neutral effects) and those with high EA values (estimated harmful impacts) over the base substitution range, indicating that selection has a limited influence.

Variant rates vary considerably between locations, with 643 loci in WT viral duplicates showing considerably higher base substitution frequencies and 80 recurring throughout both WT replicates.

The researchers found no overlap between the highest-frequency tARC sequencing C>TT hotspots and A3A editing regions in the wild-type virus. The tARC sequencing C>TT frequencies at A3A editing regions were lower than the C>TT frequencies of the highest-frequency tARC sequencing C>TT hotspots by one to two orders of magnitude.

The study highlighted tARC-seq, a specialized sequencing approach, to investigate the replication mistakes that influence SARS-CoV-2 divergence. This approach selectively reads specific RNA molecules to generate a consensus sequence, allowing researchers to detect and evaluate minor differences and mistakes during viral replication.

It may also detect de novo insertions and deletions in SARS-CoV-2 resulting from cell culture infection, corroborating worldwide pandemic sequencing findings.

The study also discovered that SARS-CoV-2 possesses exonuclease proofreading capabilities, which may aid in understanding ExoN’s critical function.

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April 24, 2024
Global study reveals mismatch in COVID-19 treatment guidelines with WHO standards
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In a recent study published in the journal BMJ Global Health, researchers compare coronavirus disease 2019 (COVID-19) management guidelines to those published by the World Health Organization (WHO) among different member states.

Study: Comparison of WHO versus national COVID-19 therapeutic guidelines across the world: not exactly a perfect match. Image Credit: Cryptographer / Shutterstock.com

Global disparities in managing COVID-19

Since the beginning of the COVID-19 pandemic, the therapeutic landscape has changed dramatically, with increasing vaccine coverage, more frequent infections, and viral evolution reducing pathogenicity.

However, the poorest nations have often suffered the worst societal and economic consequences of the pandemic. Variations in treatment recommendations between nations have not been publicly measured or thoroughly investigated, with uneven administration of effective vaccines and medications.

About the study

In the present study, researchers performed a retrospective analysis of each nation’s guidelines (NGs) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection therapy using the Reporting Checklist for Public Versions of Guidelines (RIGHT-PVG) survey checklist and a developed comparison metric based on WHO standards.

Between September and November 2022, data for guidelines compiled by the Ministries of Health, National Infectious Disease websites, COVID-19 Clinical Research Coalition, and key opinion researchers and leaders were analyzed. The most recent national guidelines for SARS-CoV-2 infection therapy were stratified by severity while eliminating local or regional hospital guidelines, vaccination policies, infection control measures, and those without pharmacological recommendations. Any information about COVID-19 complications, such as bacterial pneumonia and thrombosis, was eliminated from the guidelines.

Eight physicians and one clinical nurse extracted information, including publication dates, language, body, illness severity rating, prescribed medications, regulatory status, and regulatory data collected by national-level authorities. Antibiotic suggestions were omitted unless intended for SARS-CoV-2 infection.

Countries were categorized into five areas based on WHO classification, which included the European Region (EUR), the African Region (AFR), the Southeast Asian Region (SEAR), the Region of the Americas (AMR), the Western Pacific, and Eastern Mediterranean Region (EMR). Data on treatment recommendations from the relevant health authorities in each nation were obtained and analyzed.

The alignment between national recommendations and the WHO’s 11^th iteration of recommendations was determined. To this end, positive numeric weights were assigned to suggestions that adhered to WHO criteria, whereas negative weights were assigned to those that discouraged or included non-evidence-based advice. The final score reflected the country’s adherence to WHO recommendations.

Therapeutic suggestions and illness severity categories were evaluated using the World Bank’s gross domestic product (GDP) per capita, Human Development Index, and Global Health Security Index.

Study findings

COVID-19 treatment guidelines were obtained from 109 WHO member countries and exhibited significant variability in recommendations and illness severity categories. Therapeutic advice in some NGs deviated significantly from WHO recommendations. In late 2022, 93% of national guidelines recommended one or more medications that failed randomized trials and were unauthorized by the WHO.

Despite robust evidence of treatment benefits, approximately 10% of NGs did not recommend corticosteroids for severe sickness. Stratifying by yearly GDP, Human Development Index (HDI), and Global Health Security Index (GHS), NGs from low-resource countries showed the highest gap.

The median population of nations with acquired recommendations was 14 million, with 70% of guidelines implemented in EUR, followed by the AFR at 53%. Moreover, 65% of guidelines were released six months before the WHO protocols, with 31% issued or revised over the same period.

About 84% of recommendations did not describe COVID-19 severity according to WHO definitions, with only 9.2% of guidelines incorporating severity criteria equivalent to those used by the WHO. The range of therapies included in the recommendations ranged from one to 22, with the median being five, regardless of severity. Comparatively, WHO guidelines prescribe ten medicines.

In late 2022, several NGs continued to advocate medications that the WHO had previously cautioned against, with some regional variance. Taken together, 105 NGs recommended at least one WHO-approved therapy, with 71% of medications appropriate for the severity of SARS-CoV-2 infection.

Corticosteroids were the most widely recommended medicine, with 92% of NGs using these therapeutics and 80% indicating their use for the same illness severity as the WHO. Moreover, 23% and 79% of the 72 NGs recommended remdesivir and tocilizumab for mild COVID-19, respectively.

Conclusions

Based on the study findings, COVID-19 has resulted in considerable variance in NG recommendations, with many advocating inefficient, costly, and inaccessible remedies, particularly in low-resource areas.

The study findings emphasize the importance of formalizing procedures for generating NGs for infectious diseases to ensure their development based on the best available data. Recommendations provided by NGs varied greatly, some of which did not have any national guidelines, omitted WHO-recommended medicines, proposed untested medications, or used different SARS-CoV-2 infection severity classifications.
Journal reference:

Cokljat, M., Cruz, C. V., Carrara, V. I., et al. (2024). Comparison of WHO versus national COVID-19 therapeutic guidelines across the world: not exactly a perfect match. BMJ Global Health. doi:10.1136/bmjgh-2023-014188
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April 24, 2024
Study reveals how SARS-CoV-2 hijacks lung cells to drive COVID-19 severity

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In a recent study published in the Journal of Experimental Medicine, researchers identified the cellular tropism and transcriptome consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by infecting human lung tissue and using single-cell ribonucleic acid sequencing (scRNA-seq) to rebuild the transcriptional program in “infection pseudotime” for distinct lung cell types.

Lower respiratory infections, such as coronavirus disease 2019 (COVID-19), are a leading cause of death worldwide, producing pneumonia and acute respiratory distress syndrome. Understanding their early phases is difficult. Researchers used classical histopathological approaches and single-cell multi-omic profiling to infer early phases in human pathogenesis from lung lavage, biopsy, or autopsy materials. These approaches reveal a thorough picture of COVID-19 pneumonia at unparalleled cellular and molecular resolution, implying infection models including alveolar epithelium, capillaries, macrophages, and myeloid cells.

Study: Interstitial macrophages are a focus of viral takeover and inflammation in COVID-19 initiation in human lung. Image Credit: Dotted Yeti / Shutterstock

About the study

In the present study, researchers developed an experimental COVID-19 model to investigate early molecular processes and pathogenic mechanisms of SARS-CoV-2 infection at the cellular level in native tissues of the human lung.

The researchers established SARS-CoV-2’s cellular tropism and its unique and dynamic impacts on host cellular gene expression in specific types of lung cells. Prominent targets were lung-resident macrophages, of which one SARS-CoV-2 takes over transcriptomes, inducing a targeted host interferon (IFN) antiviral program, and several chemokines and pro-fibrotic and pro-inflammatory and cytokines signaling to various structural and immunological cells of the lung.

To determine the early stages of COVID-19 in human lungs, the researchers sliced lung tissue obtained from surgical specimens or organ donor individuals into thick sections and used them for tissue culture analysis. Subsequently, they exposed the tissues to the SARS-CoV-2 USA-WA1 2020 strain at 1.0 multiplicity of infection (MOI) for two hours before allowing the SARS-CoV-2 infection to continue for two to three days. They performed a plaque test on culture supernatants.

The researchers separated the slices and examined them by scRNA-seq to evaluate host and viral genetic expression during the SARS-CoV-2 infection. They also examined the viral RNA molecules’ junctional structure and processing by analyzing the scRNA-seq dataset with the SICILIAN framework. They used molecular atlas markers to distinguish lung cell types in healthy lung slices and measure viral RNA levels in infected cells.

The team performed multiplexed single-molecule fluorescence in situ hybridization (smFISH) to confirm lung cell tropism findings and show infected cells. They used single-cell gene expression patterns to identify cellular targets for inflammatory and pro-fibrotic signals elicited by the SARS-CoV-2 infection of a-IMs. They devised a technique for purifying macrophage populations from human lungs with a SARS-CoV-2 spike (S) protein-pseudotyped lentivirus (lenti-S-NLuc-tdT) to investigate lung macrophage entrance routes.

The researchers productively infected human lung slices cultivated ex vivo with SARS-CoV-2, with production rising between 24 and 72 hours of culture. They heat-inactivated, ultraviolet (UV)-treated, or administered 10.0 µM remdesivir, an RNA-dependent RNA polymerase inhibitor used as a COVID-19 therapeutic, to prevent viral stock infection.

Results

The analysis showed that SARS-CoV-2 preferentially infects active interstitial macrophages (IMs), which can amass hundreds of SARS-CoV-2 RNA molecules, comprising >60% of the cell transcriptome and producing dense viral RNA bodies. Infected alveolar macrophages (AMs) exhibit no severe reactions, with spike (S) protein-dependent viral entrance into AMs utilizing angiotensin-converting enzyme 2 (ACE2) and the cluster of differentiation 169 (CD169) and IM entry via CD209.

They found canonical sub-genomic junctions between the unusual sequence reads beyond their 39 terminal regions, indicating canonical-type SARS-CoV-2 messenger RNA (mRNA) production in the pulmonary cultures. They also found hundreds of new subgenomic junctions, showing a wide range of non-canonical and canonical sub-genomic SARS-CoV-2 RNAs produced during pulmonary infection.

Model of initiation, transition, and pathogenesis of COVID-19 and the viral lifecycle in AMs and IMs. (a–d) Model of COVID-19 initiation in the human lung and transition from viral pneumonia to lethal COVID-19 ARDS. (a) SARS-CoV-2 virion dissemination and arrival in the alveoli. Luminal AM encounter virions shed from the upper respiratory tract that enter the lung. AMs can express low to moderate numbers of viral RNA molecules and can propagate the infection but “contain” the viral RNA from taking over the total transcriptome and show only a very limited host cell inflammatory response to viral infection. (b) Replication and epithelial injury. SARS-CoV-2 virions enter AT2 cells through ACE2, its canonical receptor, and “replicate” to high viral RNA levels, producing infectious virions and initiating viral pneumonia. (c) a-IM takeover and inflammation signaling. SARS-CoV-2 virions spread to the interstitial space through either transepithelial release of virions by AT2 cells or injury of the epithelial barrier, and enter a-IMs. Infected a-IMs can express very high levels of viral RNA that dominate (“take over”) the host transcriptome and can propagate the infection. Viral takeover triggers induction of the chemokines and cytokines shown, forming a focus of inflammatory and fibrotic signaling. (d) Endothelial breach and immune infiltration. The a-IM inflammatory cytokine IL6 targets structural cells of the alveolus causing epithelial and endothelial breakdown, and the inflammatory cytokines recruit the indicated immune cells from the interstitium or bloodstream, which flood and infiltrate the alveolus causing COVID-19 ARDS. Local inflammatory molecules are amplified by circulating immune cells, and reciprocally can spread through the bloodstream to cause systemic symptoms of cytokine storm. (e) Comparison of the SARS-CoV-2 viral lifecycle in AMs and IMs. Although both can produce infectious virions, note differences in viral entry receptors (AMs can use ACE2 and CD169/SIGLEC1, whereas IMs use CD209); viral RNA transcription of dsRNA intermediates (greater in AMs); replication of full-length genomic RNA (greater in IMs); viral takeover, formation of RNA bodies, and induction of a robust host cell inflammatory response (only in IMs), and cell destruction/death (only in IMs).

Heat, UV-C inactivation, or remdesivir therapy prevented the development of canonical and non-canonical connections. The team observed SARS-CoV-2 takeover of an activated IM subtype in 176,382 cells with high-quality transcriptomes obtained from infected lung slices of four donor lungs and in 112,359 cells from mock-infected slices (cultured without viral addition) and 95,389 uncultured control cells (directly from freshly cut lung slices). A differential gene expression study of a-IMs over infection pseudotime revealed host gene expression alterations corresponding to SARS-CoV-2 RNA levels.

The study found that COVID-19 pneumonia infection and takeover cause an early antiviral cell response specific to activated interstitial macrophages, resulting in a powerful immunological and fibrotic signaling center. Inflammasome activation is uncommon and only detectable late in a-IM infection. Blocking antibodies against CD169 and CD209 prevented entrance into IMs and AMs. The study also highlighted IMs as the most vulnerable lung target, with initial emphasis on inflammation and fibrosis. Two unique molecular lineages of macrophage targets react differently to SARS-CoV-2, influencing etiology and treatments.

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April 15, 2024
Annual COVID-19 vaccine proves to be a wise investment for personal health and pocketbook
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In a recent study published in The Journal of Infectious Diseases, a team of researchers from the United States (U.S.) attempted to understand whether individuals experienced any economic benefits in getting an annual coronavirus disease 2019 (COVID-19) vaccine, given that the morbidity and mortality rates associated with the disease have decreased and the government no longer covers the vaccine costs.

Study: What is the economic benefit of annual COVID-19 vaccination from the adult individual perspective? Image Credit: eamesBot / Shutterstock

Background

The rapid development of vaccines to combat the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has helped significantly reduce the disease’s severity and limit the transmission of the virus. Although subvariants of SARS-CoV-2 continue to emerge and circulate, the virus’s virulence and transmissibility seem to have reduced due to the protection afforded by large-scale vaccination efforts worldwide.

With the drop in hospitalization and mortality rates, COVID-19 is no longer considered a significant public health risk, leading to a substantial decrease in vaccination rates across the U.S. Furthermore, employment organizations and businesses are no longer mandating booster COVID-19 vaccination shots. With the government no longer funding the cost of the vaccine, individuals have to pay for the COVID-19 booster shots either out-of-pocket or through their insurance. However, the gradual decrease in vaccination coverage and waning of infection-induced immunity could influence the control of viral transmission and disease severity.

About the study

In the present study, the researchers examined the benefits of getting annual COVID-19 vaccines, similar to the influenza vaccine, from an individual perspective instead of from the perspective of a third-party payer or society, which has already been examined in previous studies. The researchers believe that while the findings might not contribute to recommendations and decisions made by governments or insurance companies, they will help individuals assess the merits of an annual COVID-19 vaccination from their perspective.

The study developed and used a Markov computational simulation model to assess the values and trade-offs of getting the annual vaccine. This model used eight mutually exclusive states of SARS-CoV-2 infections and the economic and clinical outcomes for each state.

The state at which an individual begins is the state of no infection with pre-existing protection from previous vaccinations or infections. Based on factors such as risk of infection, probability of clinical outcomes based on age, and pre-existing protection levels, the model calculates the probability of an individual moving to a COVID-19 state. The model also calculates the probabilities of returning to the non-infected state or developing long COVID based on various levels of symptoms ranging from asymptomatic to severe.

These probabilities are calculated twice for each individual, once with and once without the annual COVID-19 vaccination. Minor to severe adverse effects, as well as changing vaccine efficacy, are also factors that are incorporated into the model. The economic measures are calculated based on factors such as loss of productivity due to vaccination absenteeism, mortality, out-of-pocket costs, presenteeism, healthcare visits, and medications. The cost-benefits were calculated for each scenario. Sensitivity analyses were also conducted for varying disease severity based on different SARS-CoV-2 variants.

Results

The results suggested that an individual stood to benefit clinically and economically by getting vaccinated annually against COVID-19. The model showed that adults between the ages of 18 and 49 saved an average of $30 to $603 if they did not have health insurance, while insured individuals of the same age group saved $4 to $437.

These estimates were on the assumption that the efficacy of the vaccine against SARS-CoV-2 started at greater than or equal to 50%, the individuals interacted with about nine people a day, the infection probability was more significant than or equal to 0.2%, the infection prevalence was 10%, and the conditions were for the Omicron variant of SARS-CoV-2 during the winter of 2023-2024.

For individuals between the ages of 50 and 64, the average economic benefits were even higher, with savings of $119 to $1706 and $111 to $1278 for individuals with and without insurance, respectively. Furthermore, in cases where the previous vaccination was nine months ago, and 13.4% of the pre-existing protection remained, the model showed that the risk threshold was greater than or equal to 0.4%.

Conclusions

Overall, the study found that the annual COVID-19 vaccine was economically and clinically beneficial to individuals with or without health insurance. The economic value of getting the COVID-19 vaccine was higher for individuals between 50 and 64 years of age.
Journal reference:

Bartsch, S. M., O’Shea, K. J., Weatherwax, C., Strych, U., Velmurugan, K., John, D. C., Bottazzi, M. E., Hussein, M., Martinez, M. F., Chin, K. L., Ciciriello, A., Heneghan, J., Dibbs, A., Scannell, S. A., Hotez, P. J., & Lee, B. Y. (2024). What is the economic benefit of annual COVID-19 vaccination from the adult individual perspective? The Journal of Infectious Diseases. DOI: 10.1093/infdis/jiae179, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiae179/7641782
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April 11, 2024
Nirmatrelvir fails to shorten COVID-19 symptoms in latest trial
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In a recent study published in The New England Journal of Medicine, researchers evaluate the efficacy of nirmatrelvir in combination with ritonavir against the coronavirus disease 2019 (COVID-19).

Study: Nirmatrelvir for Vaccinated or Unvaccinated Adult Outpatients with Covid-19. Image Credit: Alexsey t17 / Shutterstock.com

A brief history of COVID-19 patient care

Since its emergence at the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, has infected almost 700 million individuals and claimed over seven million lives worldwide. COVID-19 is associated with a wide range of pathologies in different populations, with the very young and elderly at the most significant risk of mortality and morbidity.

Rapid global medical research and vaccination programs have significantly reduced the burden of COVID-19 by attenuating SARS-CoV-2 transmission. Currently, COVID-19 patients are treated symptomatically through general antiviral interventions; however, an extensive search for a COVID-19-specific cure is still in the clinical trials phase.

Nirmatrelvir is an orally administered antiviral agent that inhibits the SARS-CoV-2 main protease (M^pro), which is critical for viral replication. Nirmatrelvir is administered with the pharmacokinetic enhancer ritonavir to inhibit metabolism by CYP3A4.”

One of the most promising antiviral therapies currently in clinical trials is the combination of nirmatrelvir and ritonavir. In unvaccinated adults, phase II and III clinical trials have produced promising results by reducing COVID-19 mortality risk by over 80%. Nevertheless, the anti-COVID-19 benefits of this intervention in vaccinated individuals remain unverified.

About the study

In the current study, researchers evaluate the efficacy and side effects of nirmatrelvir-ritonavir in non-hospitalized patients of various ages, ethnicities, and infection severity.

Data were obtained from the Evaluation of Protease Inhibition for Covid-19 in Standard-Risk Patients (EPIC-SR) trial, which is a randomized, double-blind, and placebo-controlled trial involving adult participants 18 years of age and older with laboratory reverse transcriptase-polymerase chain reaction (RT-PCR)-confirmed COVID-19. Individuals were enrolled in the study between August 2021 and July 2022 if their symptoms initially appeared in the five days prior to study enrollment.

Study participants were randomly assigned to receive either the nirmatrelvir-ritonavir intervention, which comprised 300 mg of nirmatrelvir and 100 mg of ritonavir, or placebo. The dosage was fixed once every 12 hours for five days, thus leading to a final total of 10 doses.

For statistical analyses, randomization was stratified across vaccination status, geographic region, and COVID-19 symptom onset. Data collection included participants’ sociodemographic, anthropometric, and medical records.

Digital diaries were also used to record daily intervention use, COVID-19 symptom severity on a four-point scale, and associated side effects. Efficacy measurements were conducted through day 34.

Sustained alleviation was considered to have occurred on the first of four consecutive days during which all symptoms that had been scored as moderate or severe and as mild or absent at baseline were scored as mild or absent and as absent, respectively.”

Study findings and relevance

Of the 1,296 participants initially enrolled in the study, 1,288 individuals, 654 of whom received nirmatrelvir-ritonavir and 634 placebo, provided completed data and were included in the statistical analyses. The study cohort primarily comprised women and individuals of the White ethnicity at 54% and 78.5%, respectively.

About 57% of the study cohort were vaccinated, with smoking as the most commonly severe COVID-19 risk factor reported among 13.3% of the study participants. Study intervention compliance was high across both cohorts at 94.8% and 96.5% for nirmatrelvir-ritonavir and placebo, respectively.

Efficacy evaluations revealed no statistically different outcomes between nirmatrelvir-ritonavir and placebo treatment cohorts. While the safety evaluation found no statistically significant differences between the side effects reported across trial groups, dysgeusia, diarrhea, and nausea were often reported by those who received nirmatrelvir-ritonavir during the study.

Conclusions

The study findings suggest that nirmatrelvir-ritonavir may not be as effective as suspected in alleviating adverse viral SARS-CoV-2 outcomes, especially in symptomatic, non-hospitalized, vaccinated, or unvaccinated adults. Given the known and study-reported side effects, nirmatrelvir-ritonavir cannot yet be established as a safe and beneficial treatment for severe COVID-19 outpatients, irrespective of prior vaccination status.

Nirmatrelvir–ritonavir was not associated with a significantly shorter time to sustained alleviation of COVID-19 symptoms than placebo, and the usefulness of nirmatrelvir–ritonavir in patients who are not at high risk for severe COVID-19 has not been established.”
Journal reference:

Hammond, J., Fountaine, R. J., Yunis, C., et al. (2024). Nirmatrelvir for Vaccinated or Unvaccinated Adult Outpatients with Covid-19. The New England Journal of Medicine 390(13); 1186-1195. doi:10.1056/nejmoa2309003
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April 9, 2024
COVID-19 shatters decades of global health progress, slashing life expectancy

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A recent study published in The Lancet presented the global burden of 288 mortality causes and life expectancy decomposition.

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has been analyzing causes of human death for over three decades, which has been used to guide policies, monitor/assess health interventions, and reduce risk factors. Assessing cause-specific mortality trends helps inform health policies, which must evolve to account for changes in the global health landscape.

Mortality patterns evolve continually as some areas succeed in reduction efforts while other causes linger in specific locations. Further, there have been improvements in several causes of death in the past three decades, some of which have substantially narrowed geographically and are concentrated in smaller areas.

Study: Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021. Image Credit: tomertu / Shutterstock

About the study

In the present study, researchers presented mortality concentrations and life expectancy decomposition. GBD 2021 provided a comprehensive set of the fatal disease burden for 288 causes by sex and age in 204 countries and territories between 1990 and 2021, an update from previous estimates for 1990–2019. The team calculated years of life lost (YLLs) as the product of death count for each cause, age, sex, year, and location, as well as standard life expectancy at each age.

Cause-specific mortality rates were computed using the causes of death ensemble model for most causes, and alternative strategies were applied to model causes with unusual epidemiology or insufficient data. Diseases and injuries were classified into four levels, with both non-fatal and fatal causes. Level 1 causes included three broad aggregate categories: 1) non-communicable diseases (NCDs), 2) communicable, maternal, neonatal, and nutritional (CMNN) diseases, and 3) injuries.

Level 2 disaggregated these categories into 22 clusters, which were further disaggregated into levels 3 and 4 causes. Life expectancy was decomposed by cause of death, year, and location to explore cause-specific effects on life expectancy between 1990 and 2021. Concentrated causes were estimated using the coefficient of variation and mortality concentration (the fraction of the population affected by 90% of deaths).

Global choropleth maps of COVID-19 (A) and OPRM (B) for 2021 that show sub-national detail where available. OPRM=other pandemic-related mortality.

Findings

During 1990–2019, the annual rate of change in all-cause global mortality ranged between -0.9% and 2.4%. The corresponding rate in age-standardized deaths ranged between -3.3 and 0.4%. Nevertheless, deaths increased by 10.8% worldwide in 2020 compared to 2019. This persisted in 2021, with a 7.5% increase relative to 2020. Likewise, the age-standardized mortality rate showed a similar pattern, increasing 8.1% in 2020 and 5.2% in 2021.

Each row represents the change in life expectancy from 1990 to 2021 for a given GBD region. A bar to the right of 0 represents an increase in life expectancy due to changes in the given cause, and a bar to the left of 0 represents a decrease in life expectancy for a given cause. For readability, labels indicating a change in life expectancy of less than 0·3 years are not shown. CKD=chronic kidney disease. COPD=chronic obstructive pulmonary disease. GBD=Global Burden of Diseases, Injuries, and Risk Factors Study. LRI=lower respiratory infection. NCD=non-communicable disease. OPRM=other pandemic-related mortality. *Does not include war and terrorism. †Does not include natural disasters.

In 2020-21, coronavirus disease 2019 (COVID-19) deaths and other pandemic-related mortality (OPRM) altered mortality patterns for the leading causes of age-standardized death. At level 3, the rankings of the four mortality causes (1. ischemic heart disease, 2. stroke, 3. chronic obstructive pulmonary disease, and 4. lower respiratory infections) with the highest age-standardized rates in 2019 were the same as in 1990.

However, in 2021, stroke became the third leading cause of age-standardized mortality, as COVID-19 eclipsed it as the second leading cause. Besides, OPRM was the fifth leading cause, whereas lower respiratory infections became the seventh leading cause. Although the impact of COVID-19 on age-standardized mortality was similar to that of common obstructive pulmonary disease in 2020, it increased by 60.2% in 2021.

Around 4.8 million and 7.89 million deaths occurred worldwide due to COVID-19 in 2020 and 2021, respectively. Age-standardized rates varied highly among GBD super-regions, with the highest in sub-Saharan Africa and the lowest in Southeast and East Asia and Oceania. OPRM and COVID-19 deaths also varied substantially by age, with older age groups being disproportionately affected.

In 1990, the three leading causes of YLLs globally were CMNN diseases. Further, neonatal disorders remained the leading cause in 2019, but NCDs, viz., ischemic heart disease and stroke, replaced the second and third leading causes, respectively. However, COVID-19 was the second leading cause of YLLs in 2021, with neonatal disorders and ischemic heart disease ranking first and third, respectively.

There have been long-standing positive trends in global life expectancy since the 1990s. Overall, life expectancy increased by 7.8 years between 1990 and 2019. However, during 2019-21, it decreased by 2.2 years due to COVID-19 and OPRM. Despite this decline, there was an overall increase of 6.2 years throughout the study period.

The decrease in mortality from enteric infections (paratyphoid, typhoid, and diarrheal diseases) affected the increase in global life expectancy. The reduction in deaths due to lower respiratory infection had the second most significant impact. All seven super-regions had an increase in life expectancy from 1990 to 2021.

Southeast and East Asia and Oceania had the highest gain (8.3 years), mainly due to lower mortality from chronic respiratory diseases. South Asia had the second largest gain (7.8 years) in life expectancy, mainly due to decreased mortality from enteric infections. Notably, Latin America and the Caribbean superregion had the largest decline in life expectancy (3.6 years) due to COVID-19.

The decline in mortality due to enteric disease substantially impacted global life expectancy. Mortality concentration emerged as 160 countries/territories made progress in CMNN disease mortality. Deaths were more concentrated in some regions or countries. For instance, 90% of deaths due to enteric infections in areas with 63% of the population of children under five years in 1990 reduced to areas with 51% of the population in 2021.

Further, the reduction in lower respiratory infections positively affected life expectancy in regions such as eastern and western sub-Saharan Africa and Andean Latin America. Moreover, reductions in stroke increased life expectancy by 0.8 years. However, stroke deaths were not concentrated. Overall, NCDs did not show a mortality concentration at large.

Conclusions

In sum, the present analysis offered insights into the global disease landscape before and during the two years of the COVID-19 pandemic. The findings showed that, after three decades of life expectancy improvements and reductions in age-standardized mortality rates, COVID-19 disrupted trends in the epidemiological transition, reversing long-standing progress.

COVID-19 was the second leading age-standardized cause of death in 2021, profoundly impacting global life expectancy. It decreased life expectancy approximately as much as reductions in communicable diseases and NCDs have improved over decades. The study suggests that improved life expectancy outcomes could be achieved by leveraging past successes in mortality reduction.

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April 8, 2024
Novel SARS-CoV-2 mutations found in floodwaters near homeless communities
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In a recent study published in the journal Environmental Science & Technology Letters, researchers conducted environmental surveillance to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in two flood control channels in the United States (US), influenced by homeless individuals. They detected SARS-CoV-2 RNA (short for ribonucleic acid) and novel spike gene mutations in the channels during COVID-19 (short for coronavirus disease 2019) outbreaks, emphasizing the efficacy of environmental surveillance for assessing public health in the homeless population.

Study: Environmental Surveillance of Flood Control Infrastructure Impacted by Unsheltered Individuals Leads to the Detection of SARS-CoV-2 and Novel Mutations in the Spike Gene. Image Credit: CROCOTHERY / Shutterstock

Background

During the COVID-19 pandemic, overwhelmed public health laboratories in the US prompted the initiation of the National Wastewater Surveillance System (NWSS) to support traditional surveillance efforts in March 2020. The program could effectively detect SARS-CoV-2 RNA, antimicrobial resistance markers, and emerging variants, offering early detection for public health priorities. Several studies have reported the presence of viruses and human fecal material in flood control channels due to various factors like overflowing sanitary sewers and direct human inputs. In cities where homelessness is common, environmental surveillance of flood control channels can aid in understanding disease transmission among people experiencing homelessness, which is often overlooked in clinical surveillance data.

RNA of SARS-CoV-2 can sustain in water bodies for extended periods, while infected individuals can continue shedding significant amounts of viral RNA in fecal matter for up to seven months. Despite previous research demonstrating the presence of SARS-CoV-2 RNA in surface waters, conducting whole genome sequencing (WGS) from flood control channels for variant identification is less frequent, primarily due to difficulties in collecting and analyzing samples. Researchers in the present study aimed to identify SARS-CoV-2 RNA in environmental water samples from flood control infrastructure impacted by homeless individuals, perform WGS, compare variants with those found in the local community, and potentially reveal any novel mutations.

About the study

In the present study, water sample processing was performed by concentrating primary effluent from wastewater treatment plants (WWTPs) using hollow fiber ultrafiltration, followed by extraction and synthesis of cDNA (short for complementary deoxyribonucleic acid). Environmental water samples from two sources (Flamingo Wash and Tropicana Wash) were processed similarly. A total of 57 samples were collected and analyzed.

SARS-CoV-2 RNA quantification was performed using quantitative polymerase chain reaction (qPCR). Further, library preparation for amplicon-based WGS made use of a SARS-CoV-2 panel and Illumina NextSeq 500. Data analysis included adapter trimming, read alignment, primer masking, variant calling, and determination of variant composition. Low-frequency and novel mutations were identified and validated using various databases.

Results and discussion

SARS-CoV-2 RNA was detected in 15 samples (33% in treated water and 20% in freshwater), with concentrations between 2.8 and 4.8 log10 gc/L. Higher detection frequencies occurred in the first two months of 2022, corresponding to the peak of the first Omicron wave. This aligns with the maximal concentrations observed at the WWTP. PMMoV (short for pepper mild mottle virus), a fecal indicator virus, was detected in almost all samples, with concentrations between 4.0 and 6.3 log10 gc/L, consistent with previous studies. Detection frequencies of PMMoV were slightly higher in this study than in earlier ones, possibly due to the increased sensitivity of sample processing methods or the study of areas with higher densities of unsheltered individuals.

The detected variants were majorly classified as Omicron, Delta, and Alpha, especially in environmental water samples. Notably, Alpha detection in freshwater indicated potential persistent shedding or low circulation levels. Delta variant signals were observed, correlating with shedding timelines, suggesting variable loadings could influence variant composition in environmental samples.

Previously unreported mutations of the SARS-CoV-2 spike protein, including Tyr636Phe, Ser943Thr, and Phe1103Val, were identified in the samples. These mutations, not residing in the receptor-binding domain (RBD), were observed more than once, with Tyr636Phe being the most frequently detected. While the origin and significance of these mutations remain uncertain, their presence suggests potential circulation within the local community rather than being unique to flood control channels or municipal wastewater.

The findings suggest that COVID-19 transmission within unsheltered populations may reflect trends in the general community. However, a direct comparison of variant prevalence could not be made due to limited clinical surveillance data for unsheltered individuals.

Conclusion

In conclusion, the study found that the SARS-CoV-2 variants detected in environmental water samples influenced by human waste from homeless individuals were like those circulating in the broader community, as observed through wastewater and clinical surveillance. The highest concentrations of SARS-CoV-2 RNA coincided with the peak of the initial Omicron surge, followed by a decline correlating with decreased wastewater concentrations and confirmed case counts. The study emphasizes the utility of environmental surveillance for understanding public health conditions and infectious disease transmission, particularly among vulnerable homeless populations.
Journal reference:

Environmental Surveillance of Flood Control Infrastructure Impacted by Unsheltered Individuals Leads to the Detection of SARS-CoV-2 and Novel Mutations in the Spike Gene. Anthony Harrington et al., Environmental Science & Technology Letters (2024), DOI: 10.1021/acs.estlett.3c00938, https://pubs.acs.org/doi/10.1021/acs.estlett.3c00938
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April 5, 2024
Molnupiravir influences SARS-CoV-2 evolution in immunocompromised patients

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In a recent study published in The Lancet Microbe, researchers investigated the effects of molnupiravir on the evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in immunocompromised patients.

Persistent SARS-CoV-2 infection in individuals who are immunocompromised offers genomic variation and has been linked to viral evolution. Antiviral therapy is recommended in immunocompromised patients with acute infection to prevent severe disease. Molnupiravir is the only alternative when first-line therapies (remdesivir and ritonavir-boosted nirmatrelvir) are not feasible, available, or appropriate.

Study: Effect of molnupiravir on SARS-CoV-2 evolution in immunocompromised patients: a retrospective observational study. Image Credit: creativeneko / Shutterstock

Molnupiravir has been used worldwide in hospital and community settings as well as for immunocompromised patients. Nevertheless, it has been ineffective at reducing coronavirus disease 2019 (COVID-19) hospitalization and mortality rates in high-risk groups, and consequently, it has been designated a third-line therapeutic option. The drug triggers mutagenesis by introducing β-D-N4-hydroxycytidine, the prodrug, into the viral ribonucleic acid (RNA).

The viral RNA polymerase uses this modified RNA as the template, and an error catastrophe occurs, inhibiting the viral replication. During RNA synthesis, molnupiravir behaves like a cytosine (C) and pairs with guanine (G); however, once incorporated, it transforms into a tautomer analogous to uracil (U), leading to G-to-A mutations in the subsequent round of replication. Likewise, it can induce C-to-U (or -thymine [T]) mutations during the synthesis of the positive-sense genome.

Reverse T-to-C and A-to-G mutations are also possible but are less frequent. G-to-A mutations indicate molnupiravir treatment; distinctive mutational profiles with extensive G-to-A mutations have been found in global sequences and phylogenetic trees. This is linked to the use of molnupiravir as countries showing long G-to-A branches had increased use of the drug. Contrastingly, countries with infrequent G-to-A branches have not authorized molnupiravir.

About the study

In the present study, researchers analyzed the sequencing data from immunocompromised patients with SARS-CoV-2 infection to assess the effects of molnupiravir on viral evolution. The team sequenced around 100 genomes weekly from December 2021 to September 2022, specifically focusing on samples from reinfections, hospitalized patients, overseas travelers, and suspected residential care- and healthcare-related infections.

Immunocompromised patients with protracted infection were also covered. The team selected nine patients with the same variant with multiple samples (from distinct time points). Four patients (controls) were tested before molnupiravir was available, and five were sampled pre- and post-molnupiravir treatment. All molnupiravir recipients and two controls were immunocompromised. Seven patients received ≥ two vaccine doses, and two were non-vaccinated.

Patients’ prior infection status was unknown. Patients infected with similar variants and high-quality genomes were selected for group comparisons across time points. Accumulated mutations were compared between groups. The ultrafast sample placement on existing trees (UShER) pipeline and the University of California Santa Cruz genome viewer were leveraged to compare variants from patients with global reference sequences and visualize the locations of mutations.

Findings

The team noted that SARS-CoV-2 genomes acquired an average of 30 new low/mid frequency variants by 10 days post-molnupiravir treatment. These changes in viral diversity were not observed in patients who did not receive molnupiravir. On average, 3.3 mutations were acquired per day in the molnupiravir group.

The probability of observing no mutations among controls during the study period was extremely low. Non-synonymous mutations were common in the spike protein, and subsequent samples indicated that some mutations were fixed. In one patient, 10 non-synonymous mutations were fixed by 35 days post-treatment.

Accrued mutations were scattered throughout the genome, including those not detected in global Omicron genomes. Mutations acquired in the spike protein clustered at two locations, and their functional relevance was unclear. No known drug-resistance mutations were observed; however, non-synonymous mutations in the open reading frame 1b (ORF1b) were noted.

The UShER analysis revealed potentially rare/novel mutations in the sequences following treatment. Some samples could not be placed on the global SARS-CoV-2 phylogeny as many mutations were phylogenetically distinct. Mutational profiles post-treatment revealed dominant G-to-A and C-to-T mutations, representing 70% of mutations, which persisted up to 44 days post-treatment.

Conclusions

In sum, the findings showed that molnupiravir use in immunocompromised patients modified the patterns of viral evolution, with effects lasting beyond the five-day treatment period. This highlights the risks of treating this subgroup of patients with an error-generating antiviral. The evolution rate in molnupiravir recipients exceeded that observed in non-recipients in this study and globally. Overall, the researchers provided more evidence of the causal link between molnupiravir and the altered mutational landscape of SARS-CoV-2.

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March 26, 2024
Certain genes slash severity and death risk in older men
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In a recent study published in The Journal of Infectious Diseases, researchers investigated the inflammation outcomes of three different Interleukin-1 receptor antagonist gene (IL1RN) single-nucleotide variants (SNVs) in acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection patients. Their retrospective study included almost 2,600 confirmed severe coronavirus disease 2019 (COVID-19) patients and showed that the IL1RN CTA haplotype and its rs419598 C/C SNV dramatically attenuated COVID-19-associated hyperinflammation, a characteristic of severe SARS-CoV-2 infections.

Observed outcomes were substantially improved in men compared to women, with men depicting 15% reduced mortality over women with the same SNV. These findings were most extreme for older men, with patients with the rs419598 C/C SNV above the age of 74 presenting 80% less mortality risk than their non-SNV-expressing age-matched counterparts. This study is one of the first to elucidate the genetic determinants of COVID-19 pathology and may form the basis for personalized future interventions against the disease.

Study: Interleukin-1 Receptor Antagonist Gene (IL1RN) Variants Modulate the Cytokine Release Syndrome and Mortality of COVID-19. Image Credit: Adao / Shutterstock

COVID-19 and the dangers of CRS

The coronavirus disease 2019 (COVID-19) represents one of the worst pandemics in human history, responsible for almost 7 million deaths worldwide and leaving hundreds of millions of survivors with long-lasting clinical symptoms. In severe cases, the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may result in multiorgan failure, acute respiratory distress syndrome (ARDS), and even death in 10-20% of affected patients.

Research has shown that severe COVID-19 symptoms are often associated with elevated plasma cytokine levels, especially those of interleukin 1β (IL-1β), IL-2, and IL-6. Unfortunately, a number of immunotherapy drugs, including those used to treat COVID-19, have been implicated in the overexpression of these ILs, a condition similar to cytokine release syndrome (CRS). Previous work by the present research group identified that IL1RN haplotypes containing the rs419598, rs315952, and rs9005 single-nucleotide variants (SNVs) could alter osteoarthritis and rheumatoid arthritis severity by attenuating hyperinflammation.

Unfortunately, the role of genetics in COVID-19 pathology remains poorly understood. The present study aims to shine a light on this knowledge gap by investigating the role of IL1RN SNP in moderate-to-severe COVID-19 infections.

About the study

Previous research by the current group identified the associations of IL1RN genetic variants with osteoarthritis and rheumatoid arthritis outcomes. It revealed that three SNVs (rs419598, rs315952, and rs9005) improved disease outcomes via hyperinflammation reduction mechanisms. The present study aims to investigate if the same genetic variants could improve COVID-19 outcomes due to the central role of hyperinflammation in severe COVID-19 pathology.

The study is a retrospective, observational study comprising data from adult (19+) patients admitted to Tisch Hospital, New York, United States, between March 2010 and March 2021. The cytokine profiles of these patients were compared against healthy age, sex, and body mass index (BMI)-matched controls without a clinical history of COVID-19 exposure. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assays were used to confirm COVID-19 status and severity. Data sources comprised sociodemographic (sex, age, race, and ethnicity) and medical data obtained from hospital records and discarded COVID-19 blood samples (for plasma extraction). Data generation included whole-genome sequences (low coverage) of participants’ blood. The gencove.org database was used to annotate common SNV genotypes for each sequenced sample.

Three IL1RN genotypes, namely rs419598, rs315952, and rs9005, formed the focus of this study and were extracted from patients’ plasma samples during routine COVID-19 care. However, since multiple cytokines of interest were not included in routine care, plasma samples from 359 randomly selected study participants and their demography-matched controls were additionally extracted and subjected to a multiplex enzyme-linked immunosorbent assay (ELISA) assay.

“Plasma cytokines IL-1β, IL-2, and IL-6 were determined by a test developed by ARUP Laboratories (Salt Lake City, UT) and approved by the New York State Department of Health.”

Summary statistics were used to collate and analyze demographic variables and mortality statuses categorized by sex, race/ethnicity, and age. Univariate parametric tests were computed to evaluate CRS and mortality outcomes for each category. Comparisons between the mortality risks of different genotypes were conducted using multivariate logistic regressions, adjusting for sex and age.

Study findings

The present study included records from 2,589 hospitalized patients and an equal number of age, sex, and BMI-matched controls. Study participants presented a mean age of 61.2 years, an average BMI of 30.43, and comprised 53.3% male individuals.

“IL1RN rs419598, rs315952, and rs9005 genotype data were available for all patients. Biomarkers noted in the clinical electronic hospital record (EHR) for IL-1β, IL-2, and IL-6 were available for 642, 645, and 1229 subjects, respectively, whereas other plasma inflammatory markers were available for more than 2000 subjects.”

ELISA and cytokine analyses revealed that, compared to healthy control, COVID-19 patients displayed significantly elevated levels of cytokines (IL-1α, IL-5, IL-8, IL-17, IL-1β, IL-2, IL-1Ra, IL-6, tumor necrosis factor-α [TNF-α], interferon-α, and vascular endothelial growth factor [VEGF]). Alarmingly, levels of IL-6, IL-1Ra, IL-8, and IL-10 were found to be more than 10 times higher than baseline controls’ values. Inflammatory markers, including CRP, procalcitonin, D-dimer, and ferritin, were similarly heightened.

Of the included patients, 397 (15.3%) died during treatment, with age (direct), sex (male at higher risk), and BMI (direct) showing associations with COVID-19-associated mortality.

“RS-associated inflammatory biomarkers were elevated in both patients who survived and died; however, deceased patients had significantly higher levels of IL-6, CRP, procalcitonin, ferritin, and D-dimer, as well as reduced levels of complement components C3 and C4.”

Surprisingly, carriers of the IL1RN CTA-1/2 haplotype (either or two copies of the CTA haplotype) displayed substantially reduced inflammatory marker concentrations (except IL-1Ra, which was increased in these patients) compared to patients without the genotype. Encouragingly, the CTA haplotype was found to confer a 40% reduction in COVID-19-associated mortality risk in men above the age of 74. However, no associations with BMI were revealed. When evaluating each IL1RN CTA SNV individually, rs419598 C/C SNV patients exhibited substantially reduced inflammatory marker concentrations compared to their C/T or T/T counterparts.

Comparison between men and women reveals that, while most biomarker and mortality outcomes are indistinguishable across the sexes, IL1RN rs419598 C/C SNV was found to be associated with a decreased trend in mortality in men of all included age groups. In men above the age of 74, especially, this genotype was associated with an 80% decline in mortality, highlighting the role of hyperinflammation in severe COVID-19 progression.

Conclusions

The present study highlights that the IL1RN CTA haplotype, especially in combination with the rs419598 C/C genotype, substantially reduced CRS in patients (irrespective of sex) in severe COVID-19 infections and substantially reduced mortality in men.

“We show that concomitant with decreased proinflammatory cytokine production, the IL1RN CTA haplotype and rs419598 C/C SNV are associated with increased levels of its anti-inflammatory gene product IL-1Ra. Our data provide genetic evidence that activation of the inflammasome and the IL-1 pathway is proximal in the systemic cytokine inflammatory cascade. Its regulation by IL-1Ra, an endogenous anti-inflammatory protein, and potential crosstalk with IFN require further elucidation to advance the understanding and treatment of SARS-CoV-2 infection.”
Journal reference:

Attur, M., Petrilli, C., Adhikari, S., Iturrate, E., Li, X., Tuminello, S., Hu, N., Chakravarti, A., Beck, D., & Abramson, S. B. Interleukin-1 Receptor Antagonist Gene (IL1RN) Variants Modulate the Cytokine Release Syndrome and Mortality of COVID-19. The Journal of Infectious Diseases, DOI – 10.1093/infdis/jiae031, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiae031/7625543
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March 19, 2024
Impact of intensive delivery initiative
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In response to the coronavirus disease 2019 (COVID-19) pandemic, several vaccines were produced and rolled out at an unprecedented rate—however, access and cost issues limited vaccine delivery in many parts of the developing world.

A new study in the journal Nature reports on the success of Sierra Leone’s immunization program against COVID-19, which is based on a simple, cost-effective, and scalable intervention that enhances access to vaccines.

Study: Last-mile delivery increases vaccine uptake in Sierra Leone. Image Credit: Media Lens King / Shutterstock.com

COVID-19 vaccine inequity

COVID-19 vaccines were first rolled out in December 2020. However, by March 2022, only 15% of the population in low-income countries (LIC) had received at least one dose compared to 80% in high-income countries (HICs).

The hazards associated with low vaccine coverage include the possibility of new surges and subsequent lockdowns, unemployment, loss of income, food insecurity, and the emergence of dangerous new variants and subvariants.

By March 2022, only one-third of Africa’s population received a single COVID-19 vaccine dose. In Sierra Leone, previous research showed that, on average, a person had to travel seven hours to access one dose of the vaccine and that the cost of access to the vaccine was equivalent to a week’s wages.

The intervention

In partnership with the Sierra Leone Ministry of Health and Sanitation (MoHS) and international non-governmental organization (NGO) Concern Worldwide, the authors of the current study designed and executed an intervention aimed at distributing vaccines to remote villages. The permission of the local community was first sought, followed by efforts to mobilize the community in the vaccination initiative.

The current intervention was a randomized controlled trial (RCT) in rural Sierra Leone that included 150 villages. All of these were outside the five-kilometer radius of primary health units (PHUs) offering COVID-19 vaccines in the area. Of these, 100 villages were involved in the intervention, with 50 serving as controls.

The villages were small, with about 200 individuals for each village, with a total of just over 20,000 individuals participating in the trial. The mean age of these individuals was 22 years, with approximately 75% of households headed by men. Farming was the primary occupation of the head of the household in 86% of cases.

The first day of the intervention involved community mobilization with all village elders and political, youth, and religious leaders, with the help of MoHS volunteers. That night, a community meeting was held to educate the people about the vaccine, its safety, effectiveness, and importance, as well as answer questions.

The next day was devoted to setting up the temporary vaccination site with vaccine delivery workers, MoHS staff for data collection, and vaccine doses. Vaccines were available for the next two to three days, from sunrise to sunset, and community mobilization continued. Individual, door-to-door, small group or randomly selected houses were some of the tested outreach strategies.

The results

Daily vaccination uptake increased from nine to 55 people in two to three days, with the vaccination rate rising by 26 percentage points. The initiative attracted large numbers of people from neighboring areas and transients. Overall, about 5,000 people were vaccinated.

At baseline, the average vaccination rate was 6% and 9% in control and treatment villages, respectively. After the intervention, treatment villages reported a 30% vaccination rate, which rose to over 70% by December 2022, with nearly eight million doses delivered by March 2023.

About 65% of those who attended the meetings took the vaccine, compared to 40% among non-attendees. Conversely, about 53% of attendees who were initially unwilling to take the vaccine did so after attending the meetings, compared to only 14% of non-attendees.

The cost for each administered vaccine dose was about $33. If repeated with the same vetted and trained volunteers, this cost would reduce to about $23 for each person, thereby facilitating large-scale or nationwide efforts.

Compared to over 200 similar interventions offered during 144 RCTs, including financial and other incentives, social motivation, and community engagement, the intervention discussed in the current study produced a more significant effect size than 95% of the others at a lower cost.

These results suggest that low vaccination rates are related to deficiencies in access and that a cost-effective intervention is capable of overcoming that deficiency.”

What this means for the future

The approach employed in the current study could have significant impacts on public health around the world by encouraging delivery programs to immunize remote communities if these individuals cannot reach vaccine delivery centers. In Bangladesh, similar efforts have increased the infant vaccination rate from 1% during the early 1980s to over 70% by the 1990s.

Bundling interventions to improve maternal and child health could also reduce healthcare delivery costs, as transport to remote locations accounted for a significant portion of associated costs. Thus, providing access to remote locations in LICs is fundamental in promoting vaccination of the first 50% of the population.

Prominent behavioral scientists have recently acknowledged our excessive focus on individual behavioural peculiarities (‘i-frame’) at the expense of systemic solutions (‘s-frame’).”

The current study demonstrates the striking efficiency and cost-effectiveness of a community-based vaccine intervention that benefited the local community and neighboring and migrant populations. Future applications of the approach employed in this study have the potential to improve vaccine uptake rates and ensure near-universal coverage to ultimately increase vaccine equity.
Journal reference:

Meriggi, N. F., Voors, M., Levine, M. et al. (2024). Last-mile delivery increases vaccine uptake in Sierra Leone. Nature. doi:10.1038/s41586-024-07158-w.
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March 15, 2024