Covid19-Sources

„Zunehmende Hinweise deuten auf signifikante und lang anhaltende neurologische Manifestationen von COVID-19 hin. Etwa vier von fünf Patienten, die an … — Ralf Wittenbrink (@RWittenbrink)

Nature Communications - Macrophages drive inflammation associated with severe COVID-19 but it is less clear whether they can be infected. Here, the authors show efficient antibody-mediated...

Scientific Reports - Impact of COVID-19 pandemic on acute stroke care in a tertiary stroke centre

Scientific Reports - Heart rate variability parameters indicate altered autonomic tone in subjects with COVID-19

Scientific Reports - Impact of COVID-19 on heart rate variability in post-COVID individuals compared to a control group

Scientific Reports - Assessing COVID-19 transmission through school and family networks using population-level registry data from the Netherlands

XEC and KP.3.1.1 have surpassed KP.3 to become the globally dominant lineages due to their unique NTD mutations. However, several emerging JN.1 sublineages, such as LF.7.2.1, MC.10.1, NP.1, and, especially, LP.8.1, have demonstrated superior growth advantages compared to XEC. It is critical to access the virological and antigenic characteristics of these emerging SARS-CoV-2 variants. Here, we found that LF.7.2.1 is significantly more immune invasive than XEC, primarily due to the A475V mutation, which enabled the evasion of Class 1 neutralizing antibodies. However, LF.7.2.1's weak ACE2 binding affinity substantially impaired its fitness. Likewise, MC.10.1 and NP.1 exhibited strong antibody immune evasion due to the A435S mutation, but their limited ACE2 engagement efficiency restricted their growth advantage, suggesting that A435S may regulate the Spike conformation, similar to the NTD glycosylation mutations found in KP.3.1.1 and XEC. Most importantly, we found that LP.8.1 showed comparable humoral immune evasion to XEC but demonstrated much increased ACE2 engagement efficiency, supporting its rapid growth. These findings highlight the trade-off between immune evasion and ACE2 engagement efficiency in SARS-CoV-2 evolution, and underscore the importance of monitoring LP.8.1 These findings highlight the trade-off between immune evasion and ACE2 engagement efficiency in SARS-CoV-2 evolution, and underscore the importance of monitoring LP.8.1 and its descend lineages. ### Competing Interest Statement Y.C. has provisional patent applications for the BD series antibodies (WO2024131775A9 and WO2023151312A1), and is the founder of Singlomics Biopharmaceuticals. The other authors declare no competing interests.

A landmark paper[1] entitled, “Fibrin drives thrombo-inflammation and neuropathology in COVID-19,” was published in August 2024 that concluded the mechanism of the thrombotic and neurological symptoms following a SARS-CoV-2 infection, often called “long COVID,” is attributable to the binding of fibrin to discrete portions of the spike protein, specifically three N-terminal domains. This paper is a high impact publication with 110,000 views, placing it in the 99th percentile of articles published contemporaneously. Here I examine the regions of the spike protein that bind to fibrin, fibrinogen, or both. The N-terminus of the spike protein contains the three strongest binding peptides and surprisingly, these regions are also the three insertions in the protein sequence that are unique to SARS-CoV-2 and not found in natural sarbecoviruses. All pre-pandemic sarbecoviruses have either a partial deletion in these regions or have protein amino acid substitutions that are non-conserved and therefore would not support fibrin binding. In addition, the three inserts also correspond to regions of the spike protein that have been shown previously to have high sequence homology with the HIV gp120 protein. GP120 is an HIV surface protein that binds to a host cell surface receptor on CD4+ T-cells and facilitates cell entry to begin infections.  In comparing the immunological and clinical presentation of HIV and COVID-19 patients, the commonality of D-dimer production, CD4+ lymphopenia, neurotropism, and IL-10 expression strongly suggests that these protein sequence homologies are clinically relevant. A conclusion that the pathophysiology of long COVID is based on the insertion of spike protein motifs with sequence homology that mimic the HIV gp120 protein motif properties, and that these SARS-CoV-2 motifs are not found in the sarbecovirus subgenus strongly suggests that these inserts were design features in the synthetic assembly of SARS-CoV-2. [1] Ryu, J.K., Yan, Z., Montano, M. et al. Fibrin drives thromboinflammation and neuropathology in COVID-19. Nature 633, 905–913 (2024). https://doi.org/10.1038/s41586-024-07873-4

Scientific Reports - The association between baseline viral load and long-term risk in patients with COVID-19 in Hong Kong: a territory-wide study

Exposure to the virus in utero may have affected children’s development, according to a UCLA study, adding to a list of health problems emerging in the wake of the global pandemic.

Elevated incidence of type 2 diabetes after COVID-19 is greater, and persists for longer, in people who were hospitalised with COVID-19 than in those who were not, and is markedly less apparent in people who have been vaccinated against COVID-19. Testing for type 2 diabetes after severe COVID-19 and the promotion of vaccination are important tools in addressing this public health problem.

Intra-host diversity is an intricate phenomenon related to immune evasion, antiviral resistance, and evolutionary leaps along transmission chains. SARS-CoV-2 intra-host variation has been well-evidenced from respiratory samples. However, data on systemic dissemination and diversification are relatively scarce and come from immunologically impaired patients. Here, the presence and variability of SARS-CoV-2 were assessed among 71 tissue samples obtained from multiple organs including lung, intestine, heart, kidney, and liver from 15 autopsies with positive swabs and no records of immunocompromise. The virus was detected in most organs in the majority of autopsies. All organs presented intra-host single nucleotide variants (iSNVs) with low, moderate, and high abundances. The iSNV abundances observed within different organs indicate that the virus can mutate at one host site and subsequently spread to other parts of the body. In agreement with previous data from respiratory samples, our lung samples presented no more than 10 iSNVs each. But interestingly, when analyzing different organs we were able to detect between 11 and 45 iSNVs per case. Our results indicate that SARS-CoV-2 can replicate, and evolve in a compartmentalized manner, in different body sites, which agrees with the "viral reservoir" theory. We elaborate on how compartmentalized evolution in multiple organs may contribute to SARS-CoV-2 evolving so rapidly despite the virus having a proofreading mechanism.

To determine the proportion of individuals with detectable antigen in plasma or serum after SARS-CoV-2 infection and the association of antigen detect…

Persistent symptoms among some individuals who develop COVID-19 have led to the hypothesis that SARS-CoV-2 might, in some form or location, persist for long periods following acute infection.1,2 Studies on SARS-CoV-2 persistence to date, however, have been limited by small and non-representative study populations, short durations since acute infection, unclear documentation of vaccination and reinfection histories, and the absence of a true negative comparator group to assess assay specificity (appendix p 2). To address these limitations, we evaluated the presence of SARS-CoV-2 antigens in once-thawed plasma from a well characterised group of 171 adults (appendix pp 3, 9) at several timepoints in the 14 months following RNA-confirmed SARS-CoV-2 infection, most of whom were studied before vaccination or reinfection (so-called pandemic-era participants).3 To understand the specificity of our findings, we compared them to 250 adults (appendix pp 3, 9) whose plasma was collected before 2020, who, by definition, were not infected with SARS-CoV-2 (pre-pandemic era). We used the Simoa (Quanterix) single molecule array detection platform to measure SARS-CoV-2 spike, S1, and nucleocapsid antigens (appendix p 4).4,5 Of 660 pandemic-era specimens tested, 61 (9·2%) specimens from 42 participants (25% of the group), had one or more detectable SARS-CoV-2 antigens (figure A). The most commonly detected antigen was spike (n=33, 5·0%), followed by S1 (n=15, 2·3%) and N (n=15, 2·3%). Compared with the pre-pandemic era participants who had 2% assay positivity, detection of any SARS-CoV-2 antigen was significantly more frequent among the pandemic-era participants at all three timepoints in the post-acute phase of infection (figure B–E). The absolute difference in SARS-CoV-2 plasma antigen prevalence was +10·6% (95% CI +5·0 to +16·2) at 3·0–6·0 months post-onset of COVID-19; +8·7% (+3·1 to +14·3) at 6·1–10·0 months; and +5·4% (+0·42 to +10·3) at 10·1–14·1 months (appendix p 11).

ownload PDF Cite Share Set Alert Get Rights Reprints Previous article Next article mRNA-based vaccines, as shown by licensed COVID-19 vaccines, are immunogenic and can offer protection from severe disease with high efficacy.1,2 With the recent approval of a novel mRNA-based vaccine against human respiratory syncytial virus (mRESVIA; Moderna, Cambridge, MA, USA) by the US Food and Drug Administration and European Medical Agency, it is clear that mRNA-based vaccines will remain part of the future vaccine landscape. A self-amplifying RNA-based vaccine targeting ancestral SARS-CoV-2 was immunogenic as both a priming and booster vaccine in phase 3 trials.3,4 In a direct comparison with an mRNA-based vaccine, ARCT-154 induced superior neutralising antibody concentrations to omicron BA.5,4 highlighting the potential of self-amplifying RNA-based vaccines to induce stronger and broader antibody responses. In a follow-up report, Oda and colleagues5 showed that neutralising antibodies persist for at least 6 months after booster vaccination with a self-amplifying RNA-based vaccine. Both features are especially relevant as new, antigenically distinct SARS-CoV-2 variants continue to emerge and vaccine updates are required. In The Lancet Infectious Diseases, Yusuke Okada and colleagues6 report the results of a phase 3 trial evaluating an updated bivalent self-amplifying mRNA-based vaccine (ARCT-2301), targeting both the ancestral SARS-CoV-2 and the omicron BA.4/5 variant. In this double-blind, randomised, controlled, phase 3 clinical trial, the immunogenicity of booster vaccination with ARCT-2301 was compared with that of an mRNA-based BA.4/5 bivalent vaccine in fully vaccinated adults (ie, at least three previous vaccinations with mRNA-based vaccines; a total of 930 participants aged 19–80 years). 28 days after the booster vaccination, ARCT-2301-boosted individuals had superior neutralising antibody concentrations against ancestral SARS-CoV-2 and omicron BA.4/5 and higher neutralising antibody concentrations against omicron XBB.1.5 compared with those boosted with the mRNA-based vaccine. Compared with conventional mRNA-based vaccines, self-amplifying mRNA-based vaccines have the advantage of being immunogenic when administered at a low dose. In this trial, ARCT-2301 was administered at a 5-μg RNA dose, whereas the mRNA-based vaccine was given at 30 μg. The strong induction of neutralising antibodies by ARCT-2301, despite this lower dose, was probably caused by prolonged antigen production.7 The possibility of using lower doses with self-amplifying mRNA-based vaccines, combined with high-throughput production platforms, could substantially contribute to pandemic preparedness by allowing wider and more equitable distribution. Despite the proven immunogenicity of self-amplifying mRNA-based vaccines in multiple phase 3 clinical trials, even at a low dose, some questions remain unanswered. Most importantly, the clinical relevance of slightly higher neutralising antibody concentrations after self-amplifying mRNA-based vaccination is unclear, and efficacy studies have yet to be done. Additionally, in contrast to the well characterised antibody response, the cellular immune response induced by self-amplifying mRNA-based vaccines has been minimally characterised. It is unclear if mRNA-based and self-amplifying mRNA-based vaccines are mechanistically different in the way that immune responses are induced, or if the observed differences are mainly due to a difference in dose and antigen persistence. Follow-up studies comparing mRNA-based and self-amplifying mRNA-based vaccines would benefit from more in-depth immunological characterisation. Due to emergence of antigenically distinct SARS-CoV-2 variants, WHO currently recommends the use of updated monovalent COVID-19 vaccine formulations that are based on the circulating variant. Monovalent vaccines are preferred over bivalent formulations to prevent boosting of the immune response to ancestral SARS-CoV-2 and direct the immune response to the circulating variant.8 However, Okada and colleagues6 evaluated a bivalent formulation, and describe neutralising antibody concentrations to three SARS-CoV-2 variants, limiting insight into the breadth of the antibody response induced by the ARCT-2301 booster. It is essential to evaluate whether updated monovalent self-amplifying mRNA-based vaccines are capable of inducing SARS-CoV-2-specific immune responses to antigenically distinct variants, and whether these vaccines can redirect B-cell responses to novel variants by overcoming immune imprinting. Global acceptance rates of mRNA-based vaccines have varied since their introduction during the COVID-19 pandemic but are generally lower than those of conventional vaccines.9 The addition of a self-amplifying component to the vaccine landscape might further reduce acceptance rates of these vaccine types. With multiple self-amplifying mRNA-based vaccines in development6,10 it will be crucial to study acceptance rates of such vaccines and factors affecting those rates to maximise their potential. The combined clinical trials3,4,6 done by Arcturus Therapeutics with self-amplifying mRNA-based constructs show that these vaccines are immunogenic and can outperform mRNA-based vaccines when measuring neutralising antibody concentrations. It remains to be determined whether this finding is due to differences in dose and antigen persistence, or underlying mechanistical differences. However, the possibility to administer these vaccines at a low dose, combined with their adaptability, makes self-amplifying mRNA-based vaccines an attractive platform for emergency use. Confirming that self-amplifying mRNA-based vaccines have clinical efficacy and understanding the public acceptance of vaccines that contain self-amplifying nucleic acids could be the last steps towards licensure and widespread use.

In adults who had previously received three doses of an mRNA COVID-19 vaccine, immune responses 28 days after an ARCT-154 booster dose were non-inferior to those observed after a BNT162b2 booster dose for the Wuhan-Hu-1 strain of SARS-CoV-2 and superior for the Omicron BA.4/5 variant. Increased immune responses at 28 days might provide increased likelihood of protection against these strains during this period and could also result in longer duration of protection. Further studies will assess the immunogenicity induced against more recent SARS-CoV-2 variants.

Boosting mRNA-immunised adults with ARCT-2301 induced superior immunogenicity compared with Comirnaty BA.4-5 against both Wuhan-Hu-1 and omicron BA.4/5 variant COVID-19, and elicited a higher response against omicron XBB.1.5. Both vaccines had similar tolerability profiles. Self-amplifying mRNA vaccines could provide a substantial contribution to pandemic preparedness and response, inducing robust immune responses with a lower dose of mRNA to allow wider and more equitable distribution.

ownload PDF Cite Share Set Alert Get Rights Reprints Previous article Next article Of the many effective vaccines developed to combat the COVID-19 pandemic, the most notable were novel mRNA vaccines. Despite their high efficacy against the original Wuhan-Hu-1 strain and early SARS-CoV-2 variants, mRNA vaccines elicit a relatively short duration of immunity, exacerbated by immune evasion by variants leading to lower efficacy;1 for example, mRNA vaccine effectiveness against omicron declined to below 20% within 6 months of vaccination.2 Additionally, new variants are continuing to emerge,3 so the ongoing risk of COVID-19 outbreaks due to persistent viral circulation necessitates ongoing development of new vaccines to prolong vaccine-induced immunity, ideally for at least 1 year to meet new annual immunisation recommendations.3 We recently reported that a booster dose of the novel mRNA vaccine, ARCT-154 (Arcturus Therapeutics Holdings, San Diego, CA, USA), a self-amplifying mRNA (saRNA) vaccine based on the SARS-CoV-2 D614G variant (B.1), induced superior immunogenicity than BNT162b2 (Comirnaty; Pfizer–BioNTech) in BNT162b2-primed adults 1 month after administration.4 Commenting on our Article, Herfst and de Vries5 noted that “whether this [improvement in RNA vaccine technology] leads to better and longer-lasting immunity warrants further investigation”. In response, we present available ARCT-154 and BNT162b2 immunogenicity data at 3-months and 6-months post-booster until data showing responses at 12 months becomes available. In our study, Japanese adults who had been primed with two doses of mRNA vaccine and a booster dose of BNT162b2 at least 3 months earlier were randomly assigned equally to receive a second booster of either ARCT-154 (n=420) or BNT162b2 (n=408).4 In this extension analysis, we progressively excluded any participant who displayed seropositivity on days 1, 29, 91, or 181 for SARS-CoV-2 N-protein, considered to be indicative of COVID-19 infection, leaving 332 in the ARCT-154 group and 313 participants in the BNT162b2 group eligible for inclusion at the 6-month timepoint (appendix). Both groups had similar geometric mean surrogate virus neutralising titres (GMT) at baseline (GMT ratios were 0·94 for both Wuhan-Hu-1 and Omicron BA.4/5 SARS-CoV-2 variants). 1 month post-booster, the ARCT-154 group had the previously reported superior immunogenicity against both strains (figure A); GMTs against Wuhan-Hu-1 in the ARCT-154 group was 5390 (95% CI 4899–5931, n=378) and in the BNT162b2 group was 3738 (3442–4060, n=367), with a GMT ratio of 1·44 (95% CI 1·27–1·64). 3 months post-booster GMTs were 5928 (5414–6491, n=369) in the ARCT-154 group and 2899 (2648–3175, n=356) in the BNT162b2 group, a higher GMT ratio of 2·04 (1·80–2·32). Day 91 titres were equal to or greater than day 29 titres in 205 of 369 (55·6% [95% CI 50·3–60·7]) ARCT-154 recipients, but in only 108 of 356 (30·3% [25·6–35·4]) BNT162b2 recipients. Due to different rates of antibody waning by day 181 GMTs were 4119 (95% CI 3723–4557, n=332) in the ARCT-154 group and 1861 (1667–2078, n=313) in the BNT162b2 group, maintaining a GMT ratio of 2·21 (1·91–2·57) between vaccine groups. GMTs against Wuhan-Hu-1 remained higher 180 days after ARCT-154 than GMTs observed 28 days after the BNT162b2 booster.

Der CHMP hat zum Jahresende noch einige Arzneimittel zur Zulassung empfohlen, darunter zwei, die COVID-19 angehen: So gab der Ausschuss grünes Licht für Zapomeran (Kostaive), einen sich selbst verstärkenden mRNA-Impfstoff. Zudem empfahl er, den monoklonalen Antikörper Sipavibart (Kavigale) zur Vorbeugung von symptomatischem COVID-19 bei immungeschwächten Personen ab 12 Jahren zuzulassen.

This review investigates the therapeutic potential of vagal nerve stimulation (VNS) in managing long COVID, a condition marked by persistent symptoms …

Fra i programmi CCM nati nel periodo della pandemia, quello qui presentato analizza gli effetti a lungo termine del COVID-19. Tramite uno studio di coorte, viene definita la dimensione del fenomeno, viene steso un documento di riferimento e definito un sistema di sorveglianza ad hoc.

ABSTRACTIntroduction. The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on physical fitness in previously healthy adults

Journal of Neurology - SARS-CoV-2 antibodies in the cerebrospinal fluid (CSF) of COVID-19 patients possibly reflect blood-cerebrospinal fluid barrier (BCB) disruption due to systemic inflammation....

A positive-sense single-stranded RNA virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused the coronavirus disease 2019 (COVID-19) pandemic that devastated the world. While this is a respiratory virus, one feature of the SARS-CoV-2 infection was recognized to cause pathogenesis of other organs. Because the membrane fusion protein of SARS-CoV-2, the spike protein, binds to its major host cell receptor angiotensin-converting enzyme 2 (ACE2) that regulates a critical mediator of cardiovascular diseases, angiotensin II, COVID-19 is largely associated with vascular pathologies. In fact, we have previous reported that postmortem lung tissues collected from patients who died of COVID-19 exhibited thickened pulmonary vascular walls and reduced vascular lumen. The present study extended these findings by further characterizing the pulmonary vasculature of COVID-19 patients using larger sample sizes and providing mechanistic information through histological observations. The examination of 56 autopsy lung samples showed thickened vascular walls of small pulmonary arteries after 14 days of disease compared to H1N1 influenza patients who died before COVID-19 pandemic started. Pulmonary vascular remodeling in COVID-19 patients was associated with hypertrophy of the smooth muscle layer, perivascular fibrosis, edema and lymphostasis, inflammatory infiltration, perivascular hemosiderosis and neoangiogenesis. We found a correlation between the duration of hospital stay and the thickness of the muscular layer of pulmonary arterial walls. These results further confirm that COVID-19 affects the pulmonary vasculature and warrants an evaluation of patients that survived COVID-19 for possible future development of pulmonary arterial hypertension. ### Competing Interest Statement The authors have declared no competing interest.

This study examined the associations between psychopathy dimensions (triarchic phenotypes and classical factors), empathy domains (cognitive and affective), ...

A lack of empathy, and particularly its affective components, is a core symptom of behavioural variant frontotemporal dementia (bvFTD). Visual exposure to images of a needle pricking a hand (pain condition) and Q-tips touching a hand (control ...

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Nature Reviews Microbiology - In this Review, Sigal et al. explore SARS-CoV-2 persistence mechanisms, the frequency of persistent infections, their role in accelerated evolution and their link to...

Molecular Neurobiology - It has been more than three years since COVID-19 impacted the lives of millions of people, many of whom suffer from long-term effects known as long-haulers. Notwithstanding...