Tag: SARS

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
Pioneering vaccine strategy promises to outmaneuver antimicrobial resistance
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In a recent study published in the journal Npj Vaccines, researchers presented the method of Reverse Vaccine Development, which provides an opportunity to determine the correlates of protection in the early stages of clinical trials for vaccines against pathogens that are resistant to antimicrobial agents to prevent problems such as significant phase-III clinical trial failures, loss of investment in vaccine development, and populations being exposed to ineffective vaccines.

Perspective: Reverse development of vaccines against antimicrobial-resistant pathogen. Image Credit: Kateryna Kon / Shutterstock

Background

The development of antimicrobial resistance in pathogens is rapidly becoming a public health concern of the same or possibly higher magnitude as malaria or human immunodeficiency virus (HIV). However, the process of developing vaccines is tedious and expensive, and in the case of antimicrobial-resistant pathogens, it is made worse by inadequate information on correlates of protection.

In the case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the process of vaccine development was significantly accelerated by the discovery of antibodies that could bind to the spike protein of the virus, preventing it from binding to the host angiotensin-converting enzyme-2 receptor. This discovery also indicated that neutralizing antibody titers could be used as correlates of protection since they indicated the clinical efficacy of the vaccine.

For most antimicrobial-resistant pathogens, the mechanisms through which vaccines can protect the host remain unknown. While immunomics, proteomics, and genomics are being extensively used to develop vaccines against antimicrobial-resistant pathogens, the dearth of information on correlates of protection continues to present the risk of jeopardizing late-stage clinical trials.

About the study

In the present study, the researchers presented a method of Reverse Vaccine Development, a new paradigm for vaccine development that requires information on the efficacy of the vaccine and the immune responses to be generated much earlier in the vaccine development process so that the correlates of protection can be identified early on instead of closer to phase III trials. They also implemented this paradigm to evaluate a vaccine against the antimicrobial bacteria Staphylococcus aureus.

The process is called Reverse Vaccine Development since the order of information procurement on vaccine efficacy is reversed as compared to the typical procedure of vaccine development. This information is obtained from populations that are already experiencing a high incidence of antimicrobial-resistant pathogenic infections instead of the population that will eventually get vaccinated.

Paradigm clinical trial design (phase 1/2) in Reverse Vaccine Development: S. aureus vaccine in subjects at high risk of SSTI.

Given that animal models have not been unreliable in vaccine development against antimicrobial-resistant pathogens, using high-risk populations helps compare the immune responses of unprotected and protected individuals, which can provide data on correlates of protection.

The efforts to develop vaccines against S. aureus have yielded four candidate vaccines that target various antigens and use four different protection mechanisms. Based on the results from animal model studies and in-vitro assays, the vaccines were advanced to phase I and II clinical trials. The vaccines passed the safety assessments and elicited satisfactory antibody titers. However, the phase III efficacy trials for these vaccines failed, indicating a lack of adequate information on correlates of protection.

To circumvent such problems, the researchers in this study applied the paradigm of Reverse Vaccine Development to design a randomized, observer-blinded, placebo-controlled phase I and II trials to assess the immunogenicity, safety, and efficacy of the candidate vaccine developed against S. aureus by GSK.

Results

The study discussed how Reverse Vaccine Development differs from the traditional vaccine development process by beginning in phase I or II trials that evaluate the efficacy, immunogenicity, and safety of the vaccine instead of efficacy evaluation in phase III trials. This ensures that potential problems associated with correlates of protection are identified early in the vaccine development process and do not result in the failure of the vaccine towards the end stages when considerable resources have been invested in the process.

Phase I safety trials with and without adjuvant are often conducted if the vaccine is being developed for the first time for humans, and based on the results of the phase I safety assessments, the trial proceeds into phase II to evaluate the efficacy and immunogenicity. Comparing the immune responses elicited by the vaccine among unprotected and protected groups can help identify correlates of protection, which can then be used to formulate, schedule, and facilitate vaccine efficacy assessments in the general populations and refine the vaccine dosage.

The researchers discussed in detail the various parameters that need to be evaluated when correlates of protection are being explored. These included serology, cellular responses, immunological signals, transcriptional profiles, memory immune cell responses, and background immunity.

Conclusions

To summarize, the study described a novel vaccine development paradigm that involves conducting phase I and II trials in populations that are at high risk of contracting the target antimicrobial-resistant pathogen to understand the correlates of protection before the development process progresses to phase III trials and risks failure. This method could circumvent grave problems in vaccine development, such as exposure to inefficacious vaccines and the loss of resource investment.
Journal reference:

Bagnoli, F., Galgani, I., Kumaran, V. V., & Phogat, S. (2024). Reverse development of vaccines against antimicrobial-resistant pathogens. Npj Vaccines, 9(1), 71. 10.1038/s41541024008584, https://www.nature.com/articles/s41541-024-00858-4
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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
Wastewater surveillance reveals COVID-19 transmission patterns in unsheltered encampments

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To better understand COVID-19’s spread during the pandemic, public health officials expanded wastewater surveillance. These efforts track SARS-CoV-2 levels and health risks among most people, but they miss people who live without shelter, a population particularly vulnerable to severe infection. To fill this information gap, researchers reporting in ACS’ Environmental Science & Technology Letters tested flood-control waterways near unsheltered encampments, finding similar transmission patterns as in the broader community and identifying previously unseen viral mutations.

In recent years, testing untreated wastewater for SARS-CoV-2 incidence and dominant viral variants, as well as other pathogens, has been vital to helping public health officials determine infectious disease transmission in local communities. Yet, this monitoring only captures information on viruses shed from human feces and urine in buildings that are connected to local sewage infrastructure. Beyond the pandemic’s impact on human health, it also exacerbated socioeconomic difficulties and increased the number of people experiencing homelessness and living in open-air encampments without access to indoor bathrooms. To understand the prevalence of COVID-19 among people who live unsheltered, Edwin Oh and colleagues tested for SARS-CoV-2 in waterways near encampments outside Las Vegas from December 2021 through July 2022.

Using quantitative polymerase chain reaction, the researchers identified SARS-CoV-2 RNA in more than 25% of the samples tested from two flood-control channels. The highest detection frequency over the study period aligned with Las Vegas’ first wave of omicron variant infections, as confirmed through parallel testing at a local wastewater treatment plant. The researchers say these results suggest a similar level of transmission was occurring within the unsheltered community as it was among the general population. Then the researchers conducted whole genome sequencing to identify the SARS-CoV-2 variants in the waterways. These samples largely contained the same variants identified in the broader community. Deeper computational analysis of the viral sequences identified three novel viral spike protein mutations in some waterway samples, but the researchers have not yet examined what impact these mutations might have on viral function or clinical outcomes. Regardless, the ability to detect and identify SARS-CoV-2 in environmental water samples could help improve public health measures for a community that is often underrepresented in current surveillance methods. The researchers also say monitoring waterways could warn health officials of unexpected variants circulating in the community.

Source:

American Chemical Society

Journal reference:

Harrington, A., et al. (2024) 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. Environmental Science & Technology Letters. doi.org/10.1021/acs.estlett.3c00938.

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April 3, 2024
New study reveals increased risk of allergic diseases after COVID-19 infection
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A recent study published in Nature Communications explored the association of COVID-19 with long-term allergic conditions.

Study: Incident allergic diseases in post-COVID-19 condition: multinational cohort studies from South Korea, Japan and the UK. Image Credit: wavebreakmedia/Shutterstock.com

Background

The severe respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019, and led to the declaration of a coronavirus disease 2019 (COVID-19) pandemic in March 2020. It caused over seven million deaths and many times that number of infections and hospitalizations.

Additionally, nearly half of COVID-19 cases have to deal with delayed or chronic morbidity, which may have set in during or after the acute phase of infection. These are called post-COVID-19 conditions or post-acute sequelae of COVID-19 (PASC), otherwise known as long COVID.

Symptoms of PASC, in some cases, include immunologic phenomena that may cause allergic conditions of various kinds.

About the study

The study aimed to investigate how ethnicity affects allergic conditions following COVID-19. Researchers formed a synthetic group comprising over 22 million individuals from South Korea, Japan, and the UK, drawing participants from multinational studies to represent these ethnic backgrounds. S

pecifically, the South Korean segment included more than 800,000 people with an average age of 48. From the UK and Japan, the cohorts included over 325,000 and 2.5 million participants, respectively.

Within these groups, approximately 150,000 participants from South Korea, 77,000 from the UK, and 542,000 from Japan had been infected with SARS-CoV-2. This large-scale analysis aimed to shed light on the ethnic variations in post-COVID-19 allergic reactions.

What were the findings?

After adjusting for all known variables that could affect the outcome, the researchers discovered that individuals infected with SARS-CoV-2 showed a 20% higher occurrence of allergic diseases compared to those not infected.

This increased risk was consistent for infections from both the original and Delta variants of the virus. Specifically, the likelihood of developing asthma in those infected was more than double, at 2.25 times that in non-infected individuals.

The chance of getting allergic rhinitis was 25% higher in the infected group, though no significant increase was observed for food allergies or atopic dermatitis.

Moreover, while the risk for allergic diseases decreased over time after the infection, it didn’t disappear entirely. This decrease in risk varied from country to country.

Severity of infection and allergy risk

Moderate-to-severe COVID-19 was linked to a 50% higher risk of overall allergy, compared to 14% among those with mild disease.

COVID-19 vaccination and allergy risk

Those who had received the vaccine had a 44% higher risk of allergy (with one dose). This was reduced by 20% after two doses of the vaccine. The two-dose cohort had comparable allergy risk as the controls, both overall and for the various allergy subgroups.

Other factors like coexisting morbidity, drinking, body mass index, exercise, and the SARS-CoV-2 strain responsible for the infection, did not show significant correlation with allergy risk.

Conclusions

“This is the first study that provides comprehensive evidence for the association between SARS-CoV-2 infection and subsequent incident allergic outcomes.”

It emphasizes the relationship between COVID-19, especially moderate to severe, and subsequent allergy onset. It also indicates that COVID-19 vaccination with at least two doses weakens the risk of new allergies.

The findings broadly corroborate earlier research, but there is a need for more studies on the allergic sequelae of COVID-19 on a larger and more multinational scale.

Multiple pathways have been proposed to account for the observed correlations, including T cell disruption, regulatory T cell (Treg) disturbances, and the cytokine storm in acute severe COVID-19.

Over time, the virus may be slowly cleared from the host, especially if adaptive immunity has been strengthened by vaccination against the virus.

The study underlines “a need for persistent health policies to manage the severity of SARS-CoV-2 infection.” People with a history of COVID-19 should be aware that they are at higher risk for allergic manifestations in the short-term future, at least.
Journal reference:

Oh, J., Lee, M., Kim, M., et al. Incident allergic diseases in post-COVID-19 condition: multinational cohort studies from South Korea, Japan and the UK. Nature Communications. doi: https://doi.org/10.1038/s41467-024-47176-w.
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April 3, 2024
WHO’s global network for coronavirus expertise

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WHO has launched a new network for coronaviruses, CoViNet, to facilitate and coordinate global expertise and capacities for early and accurate detection, monitoring and assessment of SARS-CoV-2, MERS-CoV and novel coronaviruses of public health importance.

CoViNet expands on the WHO COVID-19 reference laboratory network established during the early days of the pandemic. Initially, the lab network was focused on SARS-CoV-2, the virus that causes COVID-19, but will now address a broader range of coronaviruses, including MERS-CoV and potential new coronaviruses. CoViNet is a network of global laboratories with expertise in human, animal and environmental coronavirus surveillance.

The network currently includes 36 laboratories from 21 countries in all 6 WHO regions.

Representatives of the laboratories met in Geneva on 26 – 27 March to finalize an action plan for 2024-2025 so that WHO Member States are better equipped for early detection, risk assessment, and response to coronavirus-related health challenges.

The CoViNet meeting brings together global experts in human, animal, and environmental health, embracing a comprehensive One Health approach to monitor and assess coronavirus evolution and spread. The collaboration underscores the importance of enhanced surveillance, laboratory capacity, sequencing, and data integration to inform WHO policies and support decision-making.

Coronaviruses have time and again demonstrated their epidemic and pandemic risk. We thank our partners from around the world who are working to better understand high threat coronaviruses like SARS, MERS and COVID-19 and to detect novel coronaviruses. This new global network for coronaviruses will ensure timely detection, monitoring and assessment of coronaviruses of public health importance.”

Dr. Maria Van Kerkhove, Acting Director of WHO’s Department of Epidemic and Pandemic Preparedness and Prevention

Data generated through CoViNet’s efforts will guide the work of WHO’s Technical Advisory Groups on Viral Evolution (TAG-VE) and Vaccine Composition (TAG-CO-VAC) and others, ensuring global health policies and tools are based on the latest scientific information.

Source:

The World Health Organization

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March 29, 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
Inflammatory responses fuel cardiovascular complications

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In a recent study published in the journal Circulation, researchers investigate the inflammatory response to acute respiratory distress syndrome (ARDS) within the heart.

Study: Virus-Induced Acute Respiratory Distress Syndrome Causes Cardiomyopathy Through Eliciting Inflammatory Responses in the Heart. Image Credit: Kateryna Kon / Shutterstock

The link between respiratory viral infections and CVD

Seasonal viral infections can range in severity from mild flu-like symptoms to potentially lethal ARDS. For example, despite being primarily a respiratory tract infection, coronavirus disease of 2019 (COVID-19) can lead to ARDS and other severe cardiovascular disease outcomes with high mortality rates.

Circulating immune cells may respond to COVID-19 by upregulating cytokine release, which can lead to myocardial injury. Cardiac macrophages, immune cells responsible for the myocardial inflammatory response, are increasingly being investigated for their role in ARDS. Recent evidence indicates that macrophage expansion, which can be accompanied by changes in the population size and relative abundances of various cardiac macrophages, is a characteristic feature of ARDS.

The main two types of cardiac macrophages include C-C chemokine receptor type 2 negative (CCR2^–) and CCR2⁺ macrophages. Further research is needed to determine the viral-induced contributions of these macrophages to adverse cardiac outcomes.

These data would allow clinicians to make informed intervention decisions and elucidate whether these outcomes are COVID-19-induced or if observed inflammation is a systemic immune response to viral infection. Furthermore, this information could support the development of future therapies to prevent cardiovascular disease (CVD) following recovery from COVID-19.

About the study

In the present study, researchers investigate the role of viral- and non-viral-induced ARDS-associated immune signals in altering cardiac macrophage populations, thereby impacting CVD parameters, including systemic inflammation.

This study was conducted at Massachusetts General Hospital and involved 33 control samples obtained from patients who died between September and December 2019, prior to the onset of COVID-19, as well as 21 samples obtained between May and July 2020 from patients who died from COVID-19-associated complications. Samples consisted of autopsy tissue excised from the left ventricular or septal region.

Simultaneously, in vivo studies involved a daily intratracheal administration of an ARDS cocktail of immunostimulatory agents to mice, which included resiquimod, imiquimod, lipopolysaccharide (LPS), and angiotensin-converting enzyme 2 (ACE2) inhibitor MLN-4760. This model allowed the researchers to reproduce clinical ARDS features in mice without the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Patient data included results obtained from electrocardiogram (ECG), echocardiography, lung computed tomography (CT) scan, blood gas analyses, body temperature evaluation, bronchoalveolar lavage fluid (BALF) characterization, blood pressure measurements, and flow cytometry. Both human and murine autopsy samples were processed using ribonucleic acid (RNA) isolation, real-time polymerase chain reaction (PCR) assay, and enzyme-linked immunosorbent assays (ELISAs) for protein and gene expression determinations.

Similar immune responses in non-viral- and SARS-CoV-2-associated ARDS

In the absence of viral infection, mice treated with the ARDS cocktail exhibited significant weight loss over the five-day cocktail treatment period. This was accompanied by hypothermia, a common feature of both ARDS and septic shock, as well as a mortality rate of over 40% by day five.

Mice with ARDS exhibited bilateral opacities and immune cell infiltrations within their lungs, as well as reduced blood oxygenation. Furthermore, increased D-dimer, neutrophil, and monocyte levels were observed, as well as reduced blood pressure and lower heart rates in ARDS mice. Other inflammatory pathways that were activated in ARDS mice included increased levels of interleukin 6 (IL-6), IL-1ß, tumor-necrosis factor α (TNF-α), and interferon y (IFN-y), all of which are also associated with SARS-CoV-2 infection.

In both non-infected ARDS and SARS-CoV-2-infected mice, an increased infiltration of interstitial macrophages and reduced levels of alveolar macrophages were observed. Although both mouse models exhibited increased levels of cardiac macrophages, this immune response was more pronounced in infected mice. Nevertheless, both models’ subsets of cardiac macrophages were altered to similar levels.

Upon comparison of control and COVID-19 patient myocardium samples, SARS-CoV-2 infection recruited a more significant number of CCR2+ CD68+ macrophages, thus indicating that a robust immune response is elicited after severe infection compared to other life-threatening diseases.

“Our findings indicate that systemic and myocardial inflammatory signals elicited by virally induced ARDS may contribute to the cardiovascular complications and high mortality rates of this condition. In addition, our study confirms previous reports that SARS-CoV-2 infection increases overall macrophage numbers in hearts.”

The cardiac benefits of TNF-α immune therapy

TNF-α neutralizing antibodies were also administered to mice to evaluate their effects on immune activation during ARDS. To this end, TNF-α immune therapy reduced weight loss, improved body temperature, increased blood oxygenation, and led to better survival rates. Histological analysis indicated that ARDS mice receiving anti-TNF-α therapy exhibited reduced macrophages, Cxcl2, IL-1ß, and IL-6 expression within the lungs.

TNF-α therapy also improved systolic dysfunction, cardiomyocyte apoptosis, and monocyte infiltration in ARDS mice. Total cardiac macrophage counts and reduced expression of IL-1ß, IL-6, and TNF-α within the myocardium were also observed, thus demonstrating the anti-inflammatory benefits associated with TNF-α immune therapy in the lungs and hearts of mice with ARDS.

Conclusions

The study findings demonstrate that SARS-CoV-2 infection leads to significant alterations in cardiac macrophage subset levels, particularly increased levels of CCR2+ macrophages, in both mice and humans. Even in the absence of SARS-CoV-2 or another virus, the immune response to ARDS-like injury is capable of inducing significant alterations in heart macrophage levels, which may increase the risk of cardiovascular complications and mortality associated with ARDS.

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March 24, 2024
Antibiotics can effectively target gut bacteria that harbor COVID-19 virus, study shows

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New research indicates that antibiotics can effectively target bacteria in the gut that harbor the virus that causes COVID-19 and produce toxin-like peptides that contribute to COVID-19-related symptoms. In the study, which involved 211 participants and was published in the Journal of Medical Virology, individuals who received early antibiotic treatment after having COVID-19 recovered more quickly than those who did not receive antibiotics.

The authors had already evaluated the efficacy of certain antibiotics in SARS-CoV-2-infected bacterial cultures in vitro, and this new study demonstrates promising results with the use of the combination of 2 antibiotics (amoxicillin and rifaximin) within the first 3 days.

Furthermore, a significant number of patients who received antibiotics within the first 3 days and for a duration of 7 days during the acute phase of COVID-19 did not develop long COVID.

Our findings suggest that antibiotics should be considered in acute infection and Long COVID. The study also lays the foundation for additional vaccine strategies.”

Marina Piscopo, PhD, co-corresponding author of the University of Naples Federico, Italy

Source:

Journal reference:

Brogna, C., et al. (2024) A retrospective cohort study on early antibiotic use in vaccinated and unvaccinated COVID-19 patients. Journal of Medical Virology. doi.org/10.1002/jmv.29507.

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March 21, 2024