Diversification of the VH3-53 immunoglobulin gene segment by somatic hypermutation results in neutralization of SARS-CoV-2 virus variants.

COVID-19 induces re-circulating long-lived memory B cells (MBC) that, upon re-encounter with the pathogen, are induced to mount immunoglobulin responses. During convalescence, antibodies are subjected to affinity maturation, which enhances the antibody binding strength and generates new specificities that neutralize virus variants. Here, we performed a single-cell RNA sequencing analysis of spike-specific B cells from a SARS-CoV-2 convalescent subject. After COVID-19 vaccination, matured infection-induced MBC underwent recall and differentiated into plasmablasts. Furthermore, the transcriptomic profiles of newly activated B cells transiently shifted toward the ones of atypical and CXCR3+ B cells and several B-cell clonotypes massively expanded. We expressed monoclonal antibodies (mAbs) from all B-cell clones from the largest clonotype that used the VH3-53 gene segment. The in vitro analysis revealed that some somatic hypermutations enhanced the neutralization breadth of mAbs in a putatively stochastic manner. Thus, somatic hypermutation of B-cell clonotypes generates an anticipatory memory that can neutralize new virus variants.

Simulation Study of Surveillance Strategies for Faster Detection of Novel SARS-CoV-2 Variants.

Earlier global detection of novel SARS-CoV-2 variants gives governments more time to respond. However, few countries can implement timely national surveillance, resulting in gaps in monitoring. The United Kingdom implemented large-scale community and hospital surveillance, but experience suggests it might be faster to detect new variants through testing England arrivals for surveillance. We developed simulations of emergence and importation of novel variants with a range of infection hospitalization rates to the United Kingdom. We compared time taken to detect the variant though testing arrivals at England borders, hospital admissions, and the general community. We found that sampling 10%-50% of arrivals at England borders could confer a speed advantage of 3.5-6 weeks over existing community surveillance and 1.5-5 weeks (depending on infection hospitalization rates) over hospital testing. Directing limited global capacity for surveillance to highly connected ports could speed up global detection of novel SARS-CoV-2 variants.

Effectiveness of Naturally Acquired and Vaccine-Induced Immune Responses to SARS-CoV-2 Mu Variant.

SARS-CoV-2 Mu variant emerged in Colombia in 2021 and spread globally. In 49 serum samples from vaccinees and COVID-19 survivors in Colombia, neutralization was significantly lower (p<0.0001) for Mu than a parental strain and variants of concern. Only the Omicron variant of concern demonstrated higher immune evasion.

Humoral immune response after different SARS-CoV-2 vaccination regimens.

BACKGROUND: The humoral immune response after primary immunisation with a SARS-CoV-2 vector vaccine (AstraZeneca AZD1222, ChAdOx1 nCoV-19, Vaxzevria) followed by an mRNA vaccine boost (Pfizer/BioNTech, BNT162b2; Moderna, m-1273) was examined and compared with the antibody response after homologous vaccination schemes (AZD1222/AZD1222 or BNT162b2/BNT162b2). METHODS: Sera from 59 vaccinees were tested for anti-SARS-CoV-2 immunoglobulin G (IgG) and virus-neutralising antibodies (VNA) with three IgG assays based on (parts of) the SARS-CoV-2 spike (S)-protein as antigen, an IgG immunoblot (additionally contains the SARS-CoV-2 nucleoprotein (NP) as an antigen), a surrogate neutralisation test (sVNT), and a Vero-cell-based virus-neutralisation test (cVNT) with the B.1.1.7 variant of concern (VOC; alpha) as antigen. Investigation was done before and after heterologous (n = 30 and 42) or homologous booster vaccination (AZD1222/AZD1222, n = 8/9; BNT162b2/BNT162b2, n = 8/8). After the second immunisation, a subgroup of 26 age- and gender-matched sera (AZD1222/mRNA, n = 9; AZD1222/AZD1222, n = 9; BNT162b2/BNT162b2, n = 8) was also tested for VNA against VOC B.1.617.2 (delta) in the cVNT. The strength of IgG binding to separate SARS-CoV-2 antigens was measured by avidity. RESULTS: After the first vaccination, the prevalence of IgG directed against the (trimeric) SARS-CoV-2 S-protein and its receptor binding domain (RBD) varied from 55-95% (AZD1222) to 100% (BNT162b2), depending on the vaccine regimen and the SARS-CoV-2 antigen used. The booster vaccination resulted in 100% seroconversion and the occurrence of highly avid IgG, which is directed against the S-protein subunit 1 and the RBD, as well as VNA against VOC B.1.1.7, while anti-NP IgGs were not detected. The results of the three anti-SARS-CoV-2 IgG tests showed an excellent correlation to the VNA titres against this VOC. The agreement of cVNT and sVNT results was good. However, the sVNT seems to overestimate non- and weak B.1.1.7-neutralising titres. The anti-SARS-CoV-2 IgG concentrations and the B.1.1.7-neutralising titres were significantly higher after heterologous vaccination compared to the homologous AZD1222 scheme. If VOC B.1.617.2 was used as antigen, significantly lower VNA titres were measured in the cVNT, and three (33.3%) vector vaccine recipients had a VNA titre < 1:10. CONCLUSIONS: Heterologous SARS-CoV-2 vaccination leads to a strong antibody response with anti-SARS-CoV-2 IgG concentrations and VNA titres at a level comparable to that of a homologous BNT162b2 vaccination scheme. Irrespective of the chosen immunisation regime, highly avid IgG antibodies can be detected just 2 weeks after the second vaccine dose indicating the development of a robust humoral immunity. The reduction in the VNA titre against VOC B.1.617.2 observed in the subgroup of 26 individuals is remarkable and confirms the immune escape of the delta variant.

Estimating SARS-CoV-2 variant fitness and the impact of interventions in England using statistical and geo-spatial agent-based models.

The SARS-CoV-2 epidemic has been extended by the evolution of more transmissible viral variants. In autumn 2020, the B.1.177 lineage became the dominant variant in England, before being replaced by the B.1.1.7 (Alpha) lineage in late 2020, with the sweep occurring at different times in each region. This period coincided with a large number of non-pharmaceutical interventions (e.g. lockdowns) to control the epidemic, making it difficult to estimate the relative transmissibility of variants. In this paper, we model the spatial spread of these variants in England using a meta-population agent-based model which correctly characterizes the regional variation in cases and distribution of variants. As a test of robustness, we additionally estimated the relative transmissibility of multiple variants using a statistical model based on the renewal equation, which simultaneously estimates the effective reproduction number R. Relative to earlier variants, the transmissibility of B.1.177 is estimated to have increased by 1.14 (1.12-1.16) and that of Alpha by 1.71 (1.65-1.77). The vaccination programme starting in December 2020 is also modelled. Counterfactual simulations demonstrate that the vaccination programme was essential for reopening in March 2021, and that if the January lockdown had started one month earlier, up to 30 k (24 k-38 k) deaths could have been prevented. This article is part of the theme issue 'Technical challenges of modelling real-life epidemics and examples of overcoming these'.

Synergistic Antiviral Activity of Pamapimod and Pioglitazone against SARS-CoV-2 and Its Variants of Concern.

The SARS-CoV-2 pandemic remains a major public health threat, especially due to newly emerging SARS-CoV-2 Variants of Concern (VoCs), which are more efficiently transmitted, more virulent, and more able to escape naturally acquired and vaccine-induced immunity. Recently, the protease inhibitor Paxlovid® and the polymerase inhibitor molnupiravir, both targeting mutant-prone viral components, were approved for high-risk COVID-19 patients. Nevertheless, effective therapeutics to treat COVID-19 are urgently needed, especially small molecules acting independently of VoCs and targeting genetically stable cellular pathways which are crucial for viral replication. Pamapimod is a selective inhibitor of p38 Mitogen-Activated Protein Kinase alpha (p38 MAPKα) that has been extensively clinically evaluated for the treatment of rheumatoid arthritis. Signaling via p38 has recently been described as a key pathway for the replication of SARS-CoV-2. Here, we reveal that the combination of pamapimod with pioglitazone, an anti-inflammatory and approved drug for the treatment of type 2 diabetes, possesses potent and synergistic activity to inhibit SARS-CoV-2 replication in vitro. Both drugs showed similar antiviral potency across several cultured cell types and similar antiviral activity against SARS-CoV-2 Wuhan type, and the VoCs Alpha, Beta, Gamma, Delta, and Omicron. These data support the combination of pamapimod and pioglitazone as a potential therapy to reduce duration and severity of disease in COVID-19 patients, an assumption currently evaluated in an ongoing phase II clinical study.

COVID-WideNet-A capsule network for COVID-19 detection.

Ever since the outbreak of COVID-19, the entire world is grappling with panic over its rapid spread. Consequently, it is of utmost importance to detect its presence. Timely diagnostic testing leads to the quick identification, treatment and isolation of infected people. A number of deep learning classifiers have been proved to provide encouraging results with higher accuracy as compared to the conventional method of RT-PCR testing. Chest radiography, particularly using X-ray images, is a prime imaging modality for detecting the suspected COVID-19 patients. However, the performance of these approaches still needs to be improved. In this paper, we propose a capsule network called COVID-WideNet for diagnosing COVID-19 cases using Chest X-ray (CXR) images. Experimental results have demonstrated that a discriminative trained, multi-layer capsule network achieves state-of-the-art performance on the COVIDx dataset. In particular, COVID-WideNet performs better than any other CNN based approaches for diagnosis of COVID-19 infected patients. Further, the proposed COVID-WideNet has the number of trainable parameters that is 20 times less than that of other CNN based models. This results in fast and efficient diagnosing COVID-19 symptoms and with achieving the 0.95 of Area Under Curve (AUC), 91% of accuracy, sensitivity and specificity respectively. This may also assist radiologists to detect COVID and its variant like delta.

Deformed wing virus type a and b in managed honeybee colonies of Argentina.

Apis mellifera is infected by more than 24 virus species worldwide, mainly positive-sense, single-stranded RNA viruses of the Dicistroviridae and Iflaviridae families. Among the viruses that infect honey bees, Deformed wing virus is the most prevalent and is present as three master variants DWV-A, B, and C. Given that the ectoparasitic mite Varroa destructor vectors these virus variants, recombination events between them are expected, and variants and their recombinants can co-exist in mites and honeybees at the same time. In this study, we detect, through RT-qPCR, the presence of DWV-A and B in the same samples of adult bees from colonies of Argentina. Total RNA was extracted from pools of ten adult bees from 45 apiaries distributed across the main beekeeping Provinces of Argentina (Buenos Aires, Santa Fe, Córdoba, Santiago del Estero, Río Negro, and Mendoza); then RT-qPCR reactions were performed to detect DWV-A and B, with specific primer pairs. After the amplifications, PCR products (204 and 660 bp amplicons for DWV-B, and ~250 bp for DWV-A) were purified and sequenced to verify that they corresponded to reported sequences, analyzing them using the Blast software. Of the 45 samples analyzed by RT-qPCR, over 90% were infected with DWV-A and 47% were also positive for DWV-B, where it was found in high prevalence specifically in colonies of A. mellifera of the Buenos Aires Province. Future studies will determine the impact of this type of the virus and its ability to recombine with the other DWV types in the apiaries of our country.

[COVID-19: epidemiology and mutations : An update]. / COVID-19: Epidemiologie und Mutationen : Ein Update.

Mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can enhance the spread and the infectiousness and decrease the protective effect of antibodies present after infection, vaccination or antibody treatment. The alpha variant (B.1.1.7), first seen in Kent/United Kingdom, has increased the R­value and therefore the infectiousness by 75%; however, the effectiveness of the vaccines against SARS-CoV­2 available in Germany seems to be only slightly impaired by these mutations. In the case of the beta variant (B.1.351), first described in South Africa, the neutralization ability of antibodies towards SARS-CoV­2 is decreased. The monoclonal antibodies bamlanivimab and etesivimab, which are used therapeutically, are ineffective. The AstraZeneca vaccine offers almost no protection against mild or moderate disease caused by the beta variant. The gamma variant (P.1 or B.1.1.28.1), which was first found in Brazil, is probably 1.7-2.6 times more transmissible than previous virus strains circulating in Brazil. In addition to the infectiousness, the mortality risk of the gamma variant also seems to be increased between 1.2 and 1.9-fold in adults and between 5 and 8-fold in young persons. The delta variant (B.1.617), first described in India, is now dominant in most countries. It is 50% more infectious than the alpha variant, and the protective effect of vaccinations against symptomatic disease can be decreased (Biontech: delta variant 88%, alpha variant 93.7%; AstraZeneca: delta variant 67%, alpha variant 74.5%). Furthermore, the course of the disease with the delta variant is often more severe than with the wild type. Disease courses with the delta variant are less severe in vaccinated than in nonvaccinated persons, and fatal outcomes are substantially rarer. A high vaccination rate is essential in order to approach herd immunity and to bring the pandemic under control. Even where the protective effect towards mild or moderate disease is decreased, as a rule, vaccination still offers excellent protection against life-threatening and fatal disease courses.

Iota-Carrageenan Inhibits Replication of SARS-CoV-2 and the Respective Variants of Concern Alpha, Beta, Gamma and Delta.

The COVID-19 pandemic continues to spread around the world and remains a major public health threat. Vaccine inefficiency, vaccination breakthroughs and lack of supply, especially in developing countries, as well as the fact that a non-negligible part of the population either refuse vaccination or cannot be vaccinated due to age, pre-existing illness or non-response to existing vaccines intensify this issue. This might also contribute to the emergence of new variants, being more efficiently transmitted, more virulent and more capable of escaping naturally acquired and vaccine-induced immunity. Hence, the need of effective and viable prevention options to reduce viral transmission is of outmost importance. In this study, we investigated the antiviral effect of iota-, lambda- and kappa-carrageenan, sulfated polysaccharides extracted from red seaweed, on SARS-CoV-2 Wuhan type and the spreading variants of concern (VOCs) Alpha, Beta, Gamma and Delta. Carrageenans as part of broadly used nasal and mouth sprays as well as lozenges have the potential of first line defense to inhibit the infection and transmission of SARS-CoV-2. Here, we demonstrate by using a SARS-CoV-2 spike pseudotyped lentivirus particles (SSPL) system and patient-isolated SARS-CoV-2 VOCs to infect transgenic A549ACE2/TMPRSS2 and Calu-3 human lung cells that all three carrageenan types exert antiviral activity. Iota-carrageenan exhibits antiviral activity with comparable IC50 values against the SARS-CoV-2 Wuhan type and the VOCs. Altogether, these results indicate that iota-carrageenan might be effective for prophylaxis and treatment of SARS-CoV-2 infections independent of the present and potentially future variants.

Authentic Patient-Derived Hepatitis C Virus Infects and Productively Replicates in Primary CD4+ and CD8+ T Lymphocytes In Vitro.

Accumulated evidence indicates that immune cells can support the replication of hepatitis C virus (HCV) in infected patients and in culture. However, there is a scarcity of data on the degree to which individual immune cell types support HCV propagation and on characteristics of virus assembly. We investigated the ability of authentic, patient-derived HCV to infect in vitro two closely related but functionally distinct immune cell types, CD4+ and CD8+ T lymphocytes, and assessed the properties of the virus produced by these cells. The HCV replication system in intermittently mitogen-stimulated T cells was adapted to infect primary human CD4+ or CD8+ T lymphocytes. HCV replicated in both cell types although at significantly higher levels in CD4+ than in CD8+ T cells. Thus, the HCV RNA replicative (negative) strand was detected in CD4+ and CD8+ cells at estimated mean levels ± standard errors of the means of 6.7 × 102 ± 3.8 × 102 and 1.2 × 102 ± 0.8 × 102 copies/µg RNA, respectively (P < 0.0001). Intracellular HCV NS5a and/or core proteins were identified in 0.9% of CD4+ and in 1.2% of CD8+ T cells. Double staining for NS5a and T cell type-specific markers confirmed that transcriptionally competent virus replicated in both cell types. Furthermore, an HCV-specific protease inhibitor, telaprevir, inhibited infection in both CD4+ and CD8+ cells. The emergence of unique HCV variants and the release of HCV RNA-reactive particles with biophysical properties different from those of virions in plasma inocula suggested that distinct viral particles were assembled, and therefore, they may contribute to the pool of circulating virus in infected patients.IMPORTANCE Although the liver is the main site of HCV replication, infection of the immune system is an intrinsic characteristic of this virus independent of whether infection is symptomatic or clinically silent. Many fundamental aspects of HCV lymphotropism remain uncertain, including the degree to which different immune cells support infection and contribute to virus diversity. We show that authentic, patient-derived HCV productively replicates in vitro in two closely related but functionally distinct types of T lymphocytes, CD4+ and CD8+ cells. The display of viral proteins and unique variants, the production of virions with biophysical properties distinct from those in plasma serving as inocula, and inhibition of replication by an antiviral agent led us to ascertain that both T cell subtypes supported virus propagation. Infection of CD4+ and CD8+ T cells, which are central to adaptive antiviral immune responses, can directly affect HCV clearance, favor virus persistence, and decisively influence the development and progression of hepatitis C.

A computational model of epidemic process with three variants on a synthesized human interaction network.

Virus mutations give rise to new variants that cause multiple waves of pandemics and escalate the infected number of individuals. In this paper, we develop both a simple random network that we define as a synthesized human interaction network and an epidemiological model based on the microscopic process of disease spreading to describe the epidemic process with three variants in a population with some features of social structure. The features of social structure we take into account in the model are the average number of degrees and the frequency of contacts. This paper shows many computational results from several scenarios both in varying network structures and epidemiological parameters that cannot be obtained numerically by using the compartmental model.

A mathematical model for the within-host (re)infection dynamics of SARS-CoV-2.

Interactions between SARS-CoV-2 and the immune system during infection are complex. However, understanding the within-host SARS-CoV-2 dynamics is of enormous importance for clinical and public health outcomes. Current mathematical models focus on describing the within-host SARS-CoV-2 dynamics during the acute infection phase. Thereby they ignore important long-term post-acute infection effects. We present a mathematical model, which not only describes the SARS-CoV-2 infection dynamics during the acute infection phase, but extends current approaches by also recapitulating clinically observed long-term post-acute infection effects, such as the recovery of the number of susceptible epithelial cells to an initial pre-infection homeostatic level, a permanent and full clearance of the infection within the individual, immune waning, and the formation of long-term immune capacity levels after infection. Finally, we used our model and its description of the long-term post-acute infection dynamics to explore reinfection scenarios differentiating between distinct variant-specific properties of the reinfecting virus. Together, the model's ability to describe not only the acute but also the long-term post-acute infection dynamics provides a more realistic description of key outcomes and allows for its application in clinical and public health scenarios.

Dissecting the dynamics of SARS-CoV-2 reinfections in blood donors with pauci- or asymptomatic COVID-19 disease course at initial infection.

BACKGROUND: Understanding the dynamics of SARS-CoV-2 reinfections is crucial for public health policy, vaccine development, and long-term disease management. However, data on reinfections in the general population remains scarce. OBJECTIVES: This study aimed to investigate SARS-CoV-2 antibody dynamics among Austrian blood donors, representing healthy adults, over two years following primary infection and to evaluate the reinfection risk. METHODS: 117,895 blood donations were analysed for SARS-CoV-2 total anti-N levels from June 2020 to December 2023. We examined anti-N and anti-S antibody dynamics and in vitro functionality in 230 study participants at five defined times during 24 months, assessing associations with demographics, vaccination status, and reinfection awareness. RESULTS: The seroprevalence of SARS-CoV-2 infection-derived anti-N antibodies increased over time, reaching 90% by February 2023 and remaining at that level since then. According to serological screenings, we found an 88% reinfection rate, which is in contrast to participants' reports indicating a reinfection rate of 59%. Our data further reveal that about 26% of reinfections went completely unnoticed. Antibody dynamics were independent of age, sex, and ABO blood group. Interestingly, individuals with multiple reinfections reported symptoms more frequently during their primary infection. Our results further show that vaccination modestly affected reinfection risk and disease course. CONCLUSION: SARS-CoV-2 reinfections were uncommon until the end of 2021 but became common with the advent of Omicron. This study highlights the underestimation of reinfection rates in healthy adults and underscores the need for continued surveillance, which is an important support for public health policies and intervention strategies.

COVID-19 throughout pandemic waves and virus variants: a real-life experience in an Italian hospital.

New therapies and vaccines changed the management of COVID-19. The aim of this retrospective study was to describe characteristics, in-hospital mortality and its predictors in patients with moderate/severe COVID-19, considering the 4 different pandemic waves and viral variants' prevalence from February 2020 to January 2022. Among 1135 patients included, 873 (77%) had at least one comorbidity, 177 (16%) were immunocompromised. From waves 1 to 4, patients with severe respiratory failure and ICU admission decreased over time (p < 0.001), like the length of in-hospital stay (p < 0.001). Despite a reduction of in-hospital mortality from 19% to 11%, increased risk of death was related to older age and immunocompromising conditions, especially during the 4th wave (HR = 5.07 and HR = 10.86, p < 0.001 respectively) while remdesivir treatment in the 3rd wave (HR = 0.41, p = 0.010) and positive serology (aHR = 0.66, p = 0.027) were protective for survival. These data support the need for tailoring vaccine campaign for future COVID-19 waves.

CavitOmiX Drug Discovery: Engineering Antivirals with Enhanced Spectrum and Reduced Side Effects for Arboviral Diseases.

Advancing climate change increases the risk of future infectious disease outbreaks, particularly of zoonotic diseases, by affecting the abundance and spread of viral vectors. Concerningly, there are currently no approved drugs for some relevant diseases, such as the arboviral diseases chikungunya, dengue or zika. The development of novel inhibitors takes 10-15 years to reach the market and faces critical challenges in preclinical and clinical trials, with approximately 30% of trials failing due to side effects. As an early response to emerging infectious diseases, CavitOmiX allows for a rapid computational screening of databases containing 3D point-clouds representing binding sites of approved drugs to identify candidates for off-label use. This process, known as drug repurposing, reduces the time and cost of regulatory approval. Here, we present potential approved drug candidates for off-label use, targeting the ADP-ribose binding site of Alphavirus chikungunya non-structural protein 3. Additionally, we demonstrate a novel in silico drug design approach, considering potential side effects at the earliest stages of drug development. We use a genetic algorithm to iteratively refine potential inhibitors for (i) reduced off-target activity and (ii) improved binding to different viral variants or across related viral species, to provide broad-spectrum and safe antivirals for the future.

SARS-CoV-2 antigen rapid detection tests: test performance during the COVID-19 pandemic and the impact of COVID-19 vaccination.

BACKGROUND: SARS-CoV-2 antigen rapid detection tests (RDTs) emerged as point-of-care diagnostics alongside reverse transcription polymerase chain reaction (RT-qPCR) as reference. METHODS: In a prospective performance assessment from 12 November 2020 to 30 June 2023 at a single centre tertiary care hospital, the sensitivity and specificity (primary endpoints) of RDTs from three manufacturers (NADAL®, Panbio™, MEDsan®) were compared to RT-qPCR as reference standard among patients, accompanying persons and staff aged ≥ six month in large-scale, clinical screening use. Regression models were used to assess influencing factors on RDT performance (secondary endpoints). FINDINGS: Among 78,798 paired RDT/RT-qPCR results analysed, overall RDT sensitivity was 34.5% (695/2016; 95% CI 32.4-36.6%), specificity 99.6% (76,503/76,782; 95% CI 99.6-99.7%). Over the pandemic course, sensitivity decreased in line with a lower rate of individuals showing typical COVID-19 symptoms. The lasso regression model showed that a higher viral load and typical COVID-19 symptoms were directly significantly correlated with the likelihood of a positive RDT result in SARS-CoV-2 infection, whereas age, sex, vaccination status, and the Omicron VOC were not. INTERPRETATION: The decline in RDT sensitivity throughout the pandemic can primarily be attributed to the reduced prevalence of symptomatic infections among vaccinated individuals and individuals infected with Omicron VOC. RDTs remain valuable for detecting SARS-CoV-2 in symptomatic individuals and offer potential for detecting other respiratory pathogens in the post-pandemic era, underscoring their importance in infection control efforts. FUNDING: German Federal Ministry of Education and Research (BMBF), Free State of Bavaria, Bavarian State Ministry of Health and Care.

Chronological development of in-patient oncology in times of COVID-19: a retrospective analysis of hospitalized oncology and COVID-19 patients of a German University Hospital.

PURPOSE: The goal of this study is to examine the chronological development of hospitalized oncology and COVID-19 patients, and compare effects on oncology sub-disciplines for pre-pandemic (2017-19) and pandemic (2020-21) years in the setting of a German university maximum care provider. METHODS: Data were retrospectively retrieved from the hospital performance controlling system for patient collectives with oncological main (nOnco) and COVID-19 secondary diagnosis (nCOVID-19). Data analysis is based on descriptive statistical assessment. RESULTS: The oncology patient collective (nOnco = 27,919) shows a decrease of hospitalized patients for the whole pandemic (- 4% for 2020 and - 2,5% for 2021 to 2019). The number of hospitalized COVID-19 patients increases from first to second pandemic year by + 106.71% (nCOVID-19 = 868). Maximum decline in monthly hospitalized oncology patients amounts to - 19% (May 2020) during the first and - 21% (December 2020) during the second lockdown. Relative monthly hospitalization levels of oncology patients reverted to pre-pandemic levels from February 2021 onwards. CONCLUSION: The results confirm a decline in hospitalized oncology patients for the entire pandemic in the setting of a maximum care provider. Imposed lockdown and contact restrictions, rising COVID-19 case numbers, as well as discovery of new virus variants have a negative impact on hospitalized treated oncological patients.

Potential option for rabies post-exposure prophylaxis: New vaccine with PIKA adjuvant against diverse Chinese rabies strains.

Rabies is a fatal zoonotic disease caused by the rabies virus. Despite existing vaccines, failures still persist. Complete protection relies on improving vaccination for delayed antibody response and weak cellular immunity. A more effective and secure vaccine is necessary for rabies prevention. For this purpose, we employed the use of PIKA adjuvant, a stabilized double-stranded RNA that interacts with TLR3, as an enhancer for the rabies immunization. Testing on mice infected with seven rabies strains prevalent in China showed over 80% protective efficacy without immunoglobulin. In contrast, the PIKA rabies vaccine exhibited a more significant enhancement in neutralizing antibody levels just 5 days post-vaccination, surpassing the immune response induced by licensed rabies vaccines. Furthermore, the administration of the PIKA rabies vaccine resulted in a significant augmentation in the population of T cells that produce IFN-γ in response to the antigen. Additionally, elevated levels of IL-1ß, IL-6, CCL-2, and TNF-α were observed at the injection site. Furthermore, an increase in the levels of chemotactic proteins and pro-inflammatory molecules in the serum was observed following administration of the PIKA rabies vaccine. Confirmation of the mechanism of action of PIKA was further established by testing it on TLR3-knockout mice, proving that its adjuvant function is dependent on the TLR3 pathway. Taken together, these results indicate that the PIKA vaccine for rabies shows potential as a highly efficacious approach, resulting in a significant enhancement of the efficacy of rabies vaccines.

Understanding the mechanisms for COVID-19 vaccine's protection against infection and severe disease.

INTRODUCTION: Multiple COVID-19 vaccines have been approved and employed in the fight against the pandemic. However, these vaccines have limited long-term effectiveness against severe cases and a decreased ability to prevent mild disease. AREAS COVERED: This review discusses the relevant factors influencing the efficacy of the vaccines against mild and severe infection, analyzes the possible underlying mechanisms contributing to the different outcomes in terms of vaccine function and disease progression, and proposes improvements for the next generation of vaccines. EXPERT OPINION: The reduced efficacy of the COVID-19 vaccine in the prevention of viral infection is closely related to the emergence of novel SARS-CoV-2 variants and their rapid transmission ability. Fundamentally, the immune responses induced by COVID-19 vaccines cannot effectively halt virus replication in the upper respiratory tract because only a limited number of specific antibodies reach these areas and decrease in concentration over time. However, the established immune response can provide sufficient protection against severe diseases by blocking viral infection of the lower respiratory tract or lung owing to sufficient antibody repertoires and memory responses. Considering this situation, future COVID-19 vaccines should have the potential to replenish the mucosal immune response in the respiratory tract to prevent viral infection.