Vaccine Efficacy Research Articles

A convolution neural network integrating climate variables and spatial-temporal properties to predict influenza trends

The spread of influenza is contingent upon a multitude of outbreak-related factors, including viral mutation, climate conditions, acquisition of immunity, crowded environments, vaccine efficacy, social gatherings, and the health and age profiles of individuals in contact with infected individuals. An epidemic in the region impacted by spatial transmission risk from adjacent regions. A few influenzas epidemic models start highlighting the spatial correlations between influenza patients and geographically adjacent regions. The proposed model is based on the concept of climatic, immunization, and spatial correlations which are represented by a convolution neural network (CNN) for influenza epidemic forecasting. This study presents an integration of three determinants for predicting influenza outbreaks, multivariate climate data, spatial data on influenza vaccination, and spatial-temporal data of historical influenza patients. The performance of three comparison models, CNN, recurrent neural network (RNN), and long short-term memory (LSTM) was compared by the root mean squared error metric (RMSE). The findings revealed that the CNN model represents human interaction at intervals of 12, 16, 20, 24, and 28 weeks resulting in the best effectiveness of the lowest RMSE=0.00376 with learning rate=0.0001.

Cross-Neutralization Activities of Antibodies against 18 Lyssavirus Glycoproteins.

Some lyssaviruses, including the rabies virus (RABV), cause lethal neurological symptoms in humans. However, the efficacy of commercial vaccines has only been evaluated against RABV. To assess cross-reactivity among lyssaviruses, including RABV, sera from rabbits inoculated with human and animal RABV vaccines and polyclonal antibodies from rabbits immunized with expression plasmids of the glycoproteins of all 18 lyssaviruses were prepared, and cross-reactivity was evaluated via virus-neutralization tests using Duvenhage lyssavirus (DUVV), European bat lyssavirus-1 (EBLV-1), Mokola lyssavirus (MOKV), Lagos bat lyssavirus (LBV), and RABV. The sera from rabbits inoculated with RABV vaccines showed cross-reactivity with EBLV-1 and DUVV, both belonging to phylogroup I. However, reactivity with MOKV and LBV in phylogroup II was notably limited or below the detection level. Next, we compared the cross-reactivity of the polyclonal antibodies against all lyssavirus glycoproteins. Polyclonal antibodies had high virus-neutralization titers against the same phylogroup but not different phylogroups. Our findings indicate that a new vaccine should be developed for pre- and post-exposure prophylaxis against lyssaviral infections.

Management of intraspecific aggression in two bull giraffes (Giraffa camelopardalis ssp. rothschildi).

Maintaining nonbreeding individuals in zoological collections may sometimes necessitate housing bachelor groups. In turn, intact cohabiting males may express increased intraspecific agonistic behaviors, and management intervention may be indicated. Where castration is deemed inappropriate (e.g., future breeding, or anesthesia and surgery-related risk), the immune contraceptive gonadotrophin-releasing hormone (GnRH) is increasingly used as an alternative. When intraspecific aggression (sparring) in two bull giraffes housed as a bachelor pair at Knowsley Safari, UK, escalated in frequency and intensity (despite management interventions), further mediation was warranted to moderate sparring behaviors. The Ex situ Program recommendation was for one giraffe, the (slightly) older, outwardly mature (darker, strong musth) individual, to be treated with the GnRH vaccine Improvac® (Zoetis). To gauge the efficacy of vaccination, behavioral observations were conducted during each vaccination phase to identify changes in the frequency of sparring behaviors. In addition, fecal samples were collected by keepers and sent to Chester Zoo's Endocrine Diagnostic Laboratory for analysis to compare androgen levels between the pre- and postvaccination phases. Testicular atrophy was investigated using both visual inspection and photographic images. The GnRH vaccine Improvac® initially appeared to be associated with reduced aggressive behaviors in the two bull giraffes. Sparring behaviors decreased in frequency after each vaccination phase, although these did not significantly diminish until phase 4. Physiological markers were inconclusive as testosterone concentrations varied throughout the phases, although levels remained low after the fourth vaccination phase. Approximately 8 months following the initial vaccination with Improvac®, the unvaccinated bull exhibited heightened aggression, resulting in physical aggression and injury to the vaccinated bull. As a result, both bulls are now on an Improvac® vaccination schedule, which has enabled them to remain housed together as a bachelor pair.

Efficient signal sequence of mRNA vaccines enhances the antigen expression to expand the immune protection against viral infection

The signal sequence played a crucial role in the efficacy of mRNA vaccines against virus pandemic by influencing antigen translation. However, limited research had been conducted to compare and analyze the specific mechanisms involved. In this study, a novel approach was introduced by substituting the signal sequence of the mRNA antigen to enhance its immune response. Computational simulations demonstrated that various signal peptides differed in their binding capacities with the signal recognition particle (SRP) 54 M subunit, which positively correlated with antigen translation efficiency. Our data revealed that the signal sequences of tPA and IL-6-modified receptor binding domain (RBD) mRNA vaccines sequentially led to higher antigen expression and elicited more robust humoral and cellular immune protection against the SARS-CoV-2 compared to the original signal sequence. By highlighting the importance of the signal sequence, this research provided a foundational and safe approach for ongoing modifications in signal sequence-antigen design, aiming to optimize the efficacy of mRNA vaccines.

Genetic substructure and host-specific natural selection trend across vaccine-candidate ORF-2 capsid protein of hepatitis-E virus.

Hepatitis E virus is a primary cause of acute hepatitis worldwide. The present study attempts to assess the genetic variability and evolutionary divergence among HEV genotypes. A vaccine promising capsid-protein coding ORF-2 gene sequences of HEV was evaluated using phylogenetics, model-based population genetic methods and principal component analysis. The analyses unveiled nine distinct clusters as subpopulations for six HEV genotypes. HEV-3 genotype samples stratified into four different subgroups, while HEV-4 stratified into three additional subclusters. Rabbit-infectious HEV-3ra samples constitute a distinct cluster. Pairwise analysis identified marked genetic distinction of HEV-4c and HEV-4i subgenotypes compared to other genotypes. Numerous admixed, inter and intragenotype recombinant strains were detected. The MEME method identified several ORF-2 codon sites under positive selection. Some selection signatures lead to amino acid substitutions within ORF-2, resulting in altered physicochemical features. Moreover, a pattern of host-specific adaptive signatures was identified among HEV genotypes. The analyses conclusively depict that recombination and episodic positive selection events have shaped the observed genetic diversity among different HEV genotypes. The significant genetic diversity and stratification of HEV-3 and HEV-4 genotypes into subgroups, as identified in the current study, are noteworthy and may have implications for the efficacy of anti-HEV vaccines.

Feasibility of Using a Type I IFN-Based Non-Animal Approach to Predict Vaccine Efficacy and Safety Profiles

Feasibility of Using a Type I IFN-Based Non-Animal Approach to Predict Vaccine Efficacy and Safety Profiles

Effect of methotrexate hold on COVID-19 vaccine response in the patients with autoimmune inflammatory disorders: a systematic review and meta-analysis.

Immunosuppressants, such as methotrexate (MTX), can suppress the COVID-19 vaccine response in patients with autoimmune diseases. Thus, this study aims to evaluate the effects of MTX hold following COVID-19 vaccination on vaccine efficacy response. A systematic review and meta-analysis of relevant studies retrieved from Web of Science, SCOPUS, PubMed, and CENTRAL from inception until Oct 1, 2023, was conducted. Covidence was used to screenthe eligible articles, and all relevant outcomes data were synthesized using risk ratios (RRs) or standardized mean differences (SMDs) with 95% confidence intervals (CIs) in meta-analysis models within RevMan 5.4. PROSPERO ID: CRD42024511628. Four studies with a total of 762 patients with autoimmune inflammatory disorders were included. Holding MTX following the COVID-19 vaccination for approximately 2 weeks was associated with significantly higher antibody titer (SMD: 0.70,95% CI [0.54, 0.87], P < 0.00001). However, the flare rate was significantly higher in the MTX hold group based on CDAI > 10 or DAS28-CRP > 1.2 either after 1st dose (RR: 2.49 with 95% CI [1.39, 4.47], P = 0.002) or 2nd dose (RR: 2.16 with 95% CI [1.37, 3.41], P = 0.0009) and self-reported disease flare (RR: 1.71 with 95% CI [1.35, 2.17], P < 0.00001). Holding MTX for 2 weeks after the COVID-19 vaccination resulted in significantly higher antibody titer but also had a higher disease flare rate, necessitating cautious clinical monitoring during this period. There is still a need to investigate safer MTX hold duration, considering patients' vulnerability to COVID-19, disease status, and demographics while adopting this strategy.

Mycobacterium smegmatis enhances shikonin-induced immunogenic cell death-an efficient in situ tumor vaccine strategy.

Tumor vaccines are a promising avenue in cancer immunotherapy. Despite the progress in targeting specific immune epitopes, tumor cells lacking them can evade treatment. Here, we aimed to construct an efficient in situ tumor vaccine Vac-SM, utilizing shikonin (SKN) to induce immunogenic cell death (ICD) and Mycobacterium smegmatis ( M. smegmatis) as an immune adjuvant to enhance in situ tumor vaccine efficacy. SKN demonstrated a dose-dependent and time-dependent cytotoxic effect on the tumor cell line as seen using the CCK-8 assay and induced ICD in tumor cells by detecting the expression of relevant indicators respectively. Compared to that in the control groups, in situ Vac-SM injection in mouse subcutaneous metastatic tumors significantly inhibited tumor growth and distant tumor growth and improved survival rates. M. smegmatis effectively induced bone marrow-derived dendritic cells (DC) maturation and activation and in vivo tumor-draining lymph nodes showed increased maturation of DC and a higher proportion of effector memory T-cell subsets with Vac-SM treatment, based on flow cytometry analysis results.Collectively, Vac-SM vaccine effectively induces ICD, improves antigen presentation by DC, activates a specific systemic antitumor T-cell immune response, exhibits favorable safety profile, and holds promise for clinical translation for local tumor immunotherapy.

Plasmonic Nanograin Metasurface with Disorder‐Enhanced Biosensing for SARS‐CoV‐2 Variant and Antibodies

AbstractRecently, the concept of introducing disorder into ordered metasurfaces or periodic metastructures has shown great potential in improving their performance for light extraction, scattering, reflection, and radiation. However, its use in optical biosensing enhancement is still barely reported. Here, a kind of plasmonic biosensors based on disorder‐enhanced nanograin metasurfaces (DENMs) are proposed, and utilized for high‐sensitivity detection of SARS‐CoV‐2 Omicron variant and vaccine‐induced total antibodies. With the aim to elucidate the physics of short‐range‐disordered meta‐elements in long‐range‐ordered metastructures, the meta‐atom evolution is deduced from periodic nanohole metasurfaces to DENMs and totally disordered nanograin metasurfaces. It is found that the disorder of nanograin plays a critical role in elevating the DENM surface sensitivity of biomolecules. The DENM‐based biosensing demonstrates an extremely high diagnostic specificity with the probability P &lt; 0.0001 on distinguishing the Omicron variant from other respiratory viruses. Moreover, these biosensors are used as a convenient tool to monitor vaccine efficacy for inoculators with the third booster injections. This study implies the promise of disorder‐enhanced metasurfaces on biomedical detection and will guide their applications on virus early discovery and prevention for future mobile healthcare.

Design, Synthesis, and Biological Evaluation of New 2,6,7-Substituted Purine Derivatives as Toll-like Receptor 7 Agonists for Intranasal Vaccine Adjuvants.

TLR7/8 agonists are versatile immune stimulators capable of treating various diseases such as viral infections, autoimmune, and cancer. Despite the structural similarity of TLR7/8, their immune stimulation mechanisms and time-course responses significantly differ. In this study, a new series of TLR7-selective agonists was synthesized utilizing the economical building block 2,6-dichloropurine. Compound 27b showed the most potent activity on hTLR7 with an EC50 of 17.53 nM and demonstrated high hTLR7 selectivity (224 folds against TLR8). 27b effectively stimulated the secretion of proinflammatory cytokines in mouse macrophages and enhanced intranasal vaccine efficacy against influenza A virus in vivo. Assessment of humoral and mucosal antibody titers confirmed that 27b elevates IgG and IgA levels, protecting against both homologous and heterologous influenza viral infections. These findings suggest that 27b is a promising candidate as a vaccine adjuvant to prevent viral infections or as a robust immunomodulator with prolonged activity for treating immune-suppressed diseases.

Vaccine Designing Technology against Leishmaniasis: Current Challenges and Implication.

Leishmaniasis, a debilitating disease caused by protozoan parasites of the genus Leishmania and transmitted by the bite of a female sandfly, continues to present significant challenges despite ongoing research and collaboration in vaccine development. The intricate interaction between the parasite's life cycle stages and the host's immunological response, namely the promastigote and amastigote forms, adds complexity to vaccine design. The quest for a potent vaccine against Leishmaniasis demands a comprehensive understanding of the immune mechanisms that confer long-lasting protection, which necessitates extensive research efforts. In this pursuit, innovative approaches such as reverse vaccinology and computer-aided design offer promising avenues for unraveling the intricacies of host-pathogen interactions and identifying effective vaccine candidates. However, numerous obstacles, including limited treatment options, the need for sustained antigenic presence, and the prevalence of co-infections, particularly with HIV, impede progress. Nevertheless, through persistent research endeavours and collaborative initiatives, the goal of developing a highly efficacious vaccine against Leishmaniasis can be achieved, offering hope through the latest Omics data development with immunoinformatics approaches for effective vaccine design for the prevention of this disease.

#2434 Literature review on the burden of herpes zoster in patients with kidney disease—a need for earlier prevention

Abstract Background and Aims Kidney disease (KD), including end stage renal disease (ESRD), is a global health problem. Both are associated with impaired immune systems, which can lead to infections. Complications such as cardiovascular disease and various infections are leading causes of morbidity and mortality in KD patients. Notably, patients with KD have an increased risk of herpes zoster (HZ). While the link between ESRD and renal transplant with increased HZ risk is understood, knowledge gaps regarding the burden of HZ across the KD spectrum still exist. This review aims to describe the risk and impact of HZ across the KD spectrum in order to guide preventive care strategies for patients with renal diseases. Method A structured literature review was conducted in PubMed using a combination of keywords and Medical Subject Heading (MeSH) terms to identify studies related to HZ risk in adult KD patients aged ≥18 years published in the English language between 01/11/2003–31/10/2023. Data extracted from published studies included the burden of HZ infection in patients with KD (risk of HZ and related complications), impact of HZ on underlying KD, and the efficacy/effectiveness of HZ vaccines among patients with KD. Results A total of 47 studies were identified (Randomized controlled trials [RCT] = 2; observational studies = 45) in this review (Fig. 1). Included studies presented evidence from regions in Europe (n = 18), Asia (n = 17), North America (n = 7), South America (n = 1), multinational (n = 2) and Australia (n = 1); country not reported in one study. Evidence from observational studies (n = 37) reported a high risk of HZ infection and related complications, such as disseminated HZ, and recurrent HZ across the KD spectrum, including chronic KD, polycystic KD, hemodialysis, peritoneal dialysis and kidney transplant patients. Infection with HZ was reported to accelerate KD progression and increased the risk of ESRD and cardiovascular events. In general, for ESRD patients with an inpatient HZ diagnosis, mortality increased with age, followed by malnutrition and bacteremia/septicemia. Studies reporting vaccine efficacy (n = 2) and effectiveness results (n = 8) suggest that HZ vaccination was associated with a reduced risk of HZ when compared to unvaccinated individuals. Furthermore, the recombinant zoster vaccine (RZV) was found to be immunogenic in kidney transplant recipients, with immunogenicity persisting through 12 months post-vaccination. An RCT post-hoc analysis showed high vaccine efficacy in patients aged ≥50 years with medical conditions at enrollment, including KD, which was consistent with the overall population. A favorable benefit-risk profile was reported in randomized and observational studies. Studies evaluating the effectiveness of the zoster live-attenuated vaccine (ZVL) found a lower risk of HZ in patients with ESRD immunized against HZ compared to unvaccinated individuals. In many countries, vaccination guidelines specifically recommended immunization of people with KD to protect against HZ. However, ZVL is contraindicated for immunocompromised (e.g. kidney transplant) patients. Conclusion Findings indicate that HZ has a significant HZ burden across the KD spectrum, which may negatively impact renal disease progression. With effective vaccines offering durable protection against HZ and its complications, the immunization of renal patients at earlier stages could enhance healthcare management and patient outcomes.

#1635 In hemodialysis patients, COVID-19 vaccination mitigates the variability of clinical and laboratory variables

Abstract Background and Aims Despite prior studies on the clinical impact of COVID-19 and the documented efficacy of COVID-19 vaccinations in hemodialysis (HD) patients, the exact effects of COVID-19 vaccinations on various clinical biomarkers before and after the diagnosis of COVID-19 have not been established. In particular, the longitudinal trajectories of clinical and laboratory parameters remain unknown. We aim to investigate clinical and laboratory variables around the time of COVID-19 diagnosis and how vaccination impacts population trajectories. Method We studied 53,223 HD patients from Fresenius Kidney Care, a large U.S. dialysis organization, who received COVID-19 vaccination between January 1, 2021 and August 2, 2021. Depending on whether or not COVID-19 diagnosis happened after the first dose of vaccination for Johnson &amp; Johnson or after the second dose for all other vaccines, we created two patient cohorts comprising patients infected before (N = 47,443) and after (N = 5780) full vaccination. A nonparametric cubic spline model for flexibility was fitted to the patient data averaged for each day between 60 days before and 60 days after the COVID-19 diagnosis. Clinical parameters include ones that are recorded at each HD treatment (pre-HD temperature, TEMP; pre-HD systolic blood pressure, SBP; pre-HD weight, WT; pre-HD pulse rate, PULSE; intradialytic weight gain, IDWG) and ones that are recorded less frequently (hemoglobin, HGB; white blood cell, WBC; neutrophil-lymphocyte ratio, NLR; platelet count, PLA; albumin, ALB). Results All longitudinal trajectory patterns undergo changes in the days before and after the diagnosis of COVID-19. In both the vaccinated and unvaccinated cohorts, there is an initial increase in TEMP, PULSE, and NLR up to 14 days preceding the diagnosis of COVID-19, followed by a subsequent decrease. Conversely, WT and IDWG exhibit a decline up to 14 days before the diagnosis of COVID-19 and an increase thereafter. ALB maintains a decreasing trend from 14 days prior until 20 days after before increasing again. In the unvaccinated cohort, SBP and WBC start decreasing up to 20 days ahead of diagnosis of COVID-19, whereas the unvaccinated cohort maintains a steady trend, increasing for SBP and decreasing for WBC. The lasting effects of COVID-19 can be found up to 60 days after diagnosis, e.g., WT, PULSE, and HGB. Variations in trend shapes are evident between the vaccinated and unvaccinated cohorts across all variables. Notably, all variables in the vaccinated cohort demonstrate smaller changes around the days of COVID-19 diagnosis. Conclusion We discovered trend changes in multiple variables in the days leading up to COVID-19 diagnosis, corroborating earlier findings. This finding lays the foundation for early detection ahead of regular COVID-19 tests. Prior COVID-19 vaccination mitigates the effect of COVID-19 on several important clinical and laboratory indicators, supporting the need for continued vaccination efforts. Lasting effects from infection are prevalent, extending beyond 60 days after confirmation. Further research is warranted to understand their long-term impact.

#477 Risk factors for the mortality among hemodialysis patients with COVID-19 infection in 28 hemodialysis centers, South Korea

Abstract Background and Aims Understanding mortality risk factors in hemodialysis patients with COVID-19 is critical for effective management. This study aimed to identify the factors influencing mortality risk and to evaluate the efficacy of COVID-19 vaccines in this specific population. Method This retrospective study analyzed clinical data from patients with COVID-19 who underwent hemodialysis at 28 affiliated centers of the Yeolin Medical Foundation between January 2020 and December 2022. Risk factors contributing to mortality were assessed through comparative analysis between survivors and deceased patients using R statistics. Results Of the 1,983 (ive study analyzed clinical data from patients with COVID-19 who underwent hemodialysis at 28 affiliated centers of the Yeolin analysis comparing survivors and deceased individuals revealed significant associations between mortality risk and several factors such as the omicron dominance period, age om patients with COVID-19 who underwent hemodialysis at 28 affiliated centers of tation, except for one dose, showed a decreasing trend in mortality risk with increasing doses. In the multivariable analysis, age ≥65 years(OR 1.04;95% CI[1.00 - 1.09],p=0.028), dyspnea(OR1.13;95% CI [1.07 - 1.19],p&amp;lt;0.001), and multiple doses of COVID-19 vaccination{2 doses(OR 0.91;CI[0.86 - 0.96],p=0.001), 3 doses(OR 0.88;CI[0.84- 0.92],p&amp;lt;0.001), 4 doses(OR 0.88;CI [0.84 - 0.93],p&amp;lt;0.001), 5 doses(OR 0.87;CI[0.81 - 0.93],p&amp;lt;0.001)} retained significance. Mortality did not appear to be significantly affected by sex, duration of ESRD, BMI, pneumococcal vaccination status, type and total number of comorbidities, or use of immunosuppressants. Conclusion Hemodialysis patients with COVID-19 infection have a high mortality rate per se, and comorbidity had no effect on mortality. Age(&amp;gt;65) and dyspnea were associated with higher mortality rates, and the lower ORs with increasing number of vaccines suggest that vaccination is a crucial protective factor in dialysis patients.

Incidence of SARS-CoV-2 infection among healthcare workers before and after COVID-19 vaccination in a tertiary paediatric hospital in Warsaw: A retrospective cohort study.

A retrospective observational study was conducted among healthcare workers (HCWs) in a tertiary paediatric hospital. The study covered the period before and after implementation of the vaccination programme and evaluated the incidence of new SARS-CoV-2 infections in both periods. Risk factors of the new SARS-CoV-2 infection and COVID-19 vaccine effectiveness was also assessed in a real-world setting. The overall incidence of SARS-CoV-2 infections among HCWs in the study period was 19.4% with a high proportion of asymptomatic individuals (45.1%). The incidence before vaccination was 16.6% and nurses had a higher risk of infection, while physicians had a reduced risk (OR 1.80, 95% CI 1.29-2.52; and OR 0.45, 95% CI 0.30-0.68). Within two months of implementation, the programme achieved a high (88.9%) vaccination coverage in our cohort, although some disparities in vaccination rates were observed. In particular, older individuals, physicians, those working in clinical settings, and those previously uninfected were more likely to be vaccinated. The overall incidence of SARS-CoV-2 infection after vaccination deployment was 6.4% (40.0% in unvaccinated individuals and 3.2% in individuals vaccinated with at least one dose). The estimated vaccine efficacy was high (95.0%) in fully vaccinated HCWs and similar to those observed previously in clinical trials and real-world settings.

Immunogenicity and efficacy of CNA25 as a potential whole-cell vaccine against systemic candidiasis.

Disseminated fungal infections account for ~1.5 million deaths per year worldwide, and mortality may increase further due to a rise in the number of immunocompromised individuals and drug-resistance fungal species. Since an approved antifungal vaccine is yet to be available, this study explored the immunogenicity and vaccine efficacy of a DNA polymerase mutant strain of Candida albicans. CNA25 is a pol32ΔΔ strain that exhibits growth defects and does not cause systemic candidiasis in mice. Immunized mice with live CNA25 were fully protected against C. albicans and C. parapsilosis but partially against C. tropicalis and C. glabrata infections. CNA25 induced steady expression of TLR2 and Dectin-1 receptors leading to a faster recognition and clearance by the immune system associated with the activation of protective immune responses mostly mediated by neutrophils, macrophages, NK cells, B cells, and CD4+ and CD8+ T cells. Molecular blockade of Dectin-1, IL-17, IFNγ, and TNFα abolished resistance to reinfection. Altogether, this study suggested that CNA25 collectively activates innate, adaptive, and trained immunity to be a promising live whole-cell vaccine against systemic candidiasis.

SARS-CoV-2 Viral Load in the Nasopharynx at Time of First Infection Among Unvaccinated Individuals

SARS-CoV-2 viral load (VL) in the nasopharynx is difficult to quantify and standardize across settings, but it may inform transmission potential and disease severity. To characterize VL at COVID-19 diagnosis among previously uninfected and unvaccinated individuals by evaluating the association of demographic and clinical characteristics, viral variant, and trial with VL, as well as the ability of VL to predict severe disease. This secondary cross-protocol analysis used individual-level data from placebo recipients from 4 harmonized, phase 3 COVID-19 vaccine efficacy trials sponsored by Moderna, AstraZeneca, Janssen, and Novavax. Participants were SARS-CoV-2 negative at baseline and acquired COVID-19 during the blinded phase of the trials. The setting included the US, Brazil, South Africa, Colombia, Argentina, Peru, Chile, and Mexico; start dates were July 27, 2020, to December 27, 2020; data cutoff dates were March 26, 2021, to July 30, 2021. Statistical analysis was performed from November 2022 to June 2023. Linear regression was used to assess the association of demographic and clinical characteristics, viral variant, and trial with polymerase chain reaction-measured log10 VL in nasal and/or nasopharyngeal swabs taken at the time of COVID-19 diagnosis. Among 1667 participants studied (886 [53.1%] male; 995 [59.7%] enrolled in the US; mean [SD] age, 46.7 [14.7] years; 204 [12.2%] aged 65 years or older; 196 [11.8%] American Indian or Alaska Native, 150 [9%] Black or African American, 1112 [66.7%] White; 762 [45.7%] Hispanic or Latino), median (IQR) log10 VL at diagnosis was 6.18 (4.66-7.12) log10 copies/mL. Participant characteristics and viral variant explained only 5.9% of the variability in VL. The independent factor with the highest observed differences was trial: Janssen participants had 0.54 log10 copies/mL lower mean VL vs Moderna participants (95% CI, 0.20 to 0.87 log10 copies/mL lower). In the Janssen study, which captured the largest number of COVID-19 events and variants and used the most intensive post-COVID surveillance, neither VL at diagnosis nor averaged over days 1 to 28 post diagnosis was associated with COVID-19 severity. In this study of placebo recipients from 4 randomized phase 3 trials, high variability was observed in SARS-CoV-2 VL at the time of COVID-19 diagnosis, and only a fraction was explained by individual participant characteristics or viral variant. These results suggest challenges for future studies of interventions seeking to influence VL and elevates the importance of standardized methods for specimen collection and viral load quantitation.

Replicon particle vaccination induces non-neutralizing anti-nucleoprotein antibody-mediated control of Crimean-Congo hemorrhagic fever virus

Crimean-Congo hemorrhagic fever virus (CCHFV) can cause severe human disease and is considered a WHO priority pathogen due to the lack of efficacious vaccines and antivirals. A CCHF virus replicon particle (VRP) has previously shown protective efficacy in a lethal Ifnar-/- mouse model when administered as a single dose at least 3 days prior to challenge. Here, we determine that non-specific immune responses are not sufficient to confer short-term protection, since Lassa virus VRP vaccination 3 days prior to CCHFV challenge was not protective. We also investigate how CCHF VRP vaccination confers protective efficacy by examining viral kinetics, histopathology, clinical analytes and immunity early after challenge (3 and 6 days post infection) and compare to unvaccinated controls. We characterize how these effects differ based on vaccination period and correspond to previously reported CCHF VRP-mediated protection. Vaccinating Ifnar-/- mice with CCHF VRP 28, 14, 7, or 3 days prior to challenge, all known to confer complete protection, significantly reduced CCHFV viral load, mucosal shedding, and markers of clinical disease, with greater reductions associated with longer vaccination periods. Interestingly, there were no significant differences in innate immune responses, T cell activation, or antibody titers after challenge between groups of mice vaccinated a week or more before challenge, but higher anti-NP antibody avidity and effector function (ADCD) were positively associated with longer vaccination periods. These findings support the importance of antibody-mediated responses in VRP vaccine-mediated protection against CCHFV infection.

From virus to immune system: Harnessing membrane-derived vesicles to fight COVID-19 by interacting with biological molecules.

Emerging and re-emerging viral pandemics have emerged as a major public health concern. Highly pathogenic coronaviruses, which cause severe respiratory disease, threaten human health and socioeconomic development. Great efforts are being devoted to the development of safe and efficacious therapeutic agents and preventive vaccines to combat them. Nevertheless, the highly mutated virus poses a challenge to drug development and vaccine efficacy, and the use of common immunomodulatory agents lacks specificity. Benefiting from the burgeoning intersection of biological engineering and biotechnology, membrane-derived vesicles have shown superior potential as therapeutics due to their biocompatibility, design flexibility, remarkable bionics, and inherent interaction with phagocytes. The interactions between membrane-derived vesicles, viruses, and the immune system have emerged as a new and promising topic. This review provides insight into considerations for developing innovative antiviral strategies and vaccines against SARS-CoV-2. First, membrane-derived vesicles may provide potential biomimetic decoys with a high affinity for viruses to block virus-receptor interactions for early interruption of infection. Second, membrane-derived vesicles could help achieve a balanced interplay between the virus and the host's innate immunity. Finally, membrane-derived vesicles have revealed numerous possibilities for their employment as vaccines.

Phase I/II Study of a Vascular Endothelial Growth Factor Receptor Vaccine in Patients With NF2-Related Schwannomatosis.

The humanized antivascular endothelial growth factor (VEGF) antibody bevacizumab (Bev) is efficacious for the treatment of NF2-related schwannomatosis (NF2), previously known as neurofibromatosis type 2. This study evaluated the safety and efficacy of a VEGF receptor (VEGFR) vaccine containing VEGFR1 and VEGFR2 peptides in patients with NF2 with progressive schwannomas (jRCTs031180184). VEGFR1 and VEGFR2 peptides were injected subcutaneously into infra-axillary and inguinal regions, once a week for 4 weeks and then once a month for 4 months. The primary end point was safety. Secondary end points included tolerability, hearing response, imaging response, and immunologic response. Sixteen patients with NF2 with progressive schwannomas completed treatment and were assessed. No severe vaccine-related adverse events occurred. Among the 13 patients with assessable hearing, word recognition score improved in five patients at 6 months and two at 12 months. Progression of average hearing level of pure tone was 0.168 dB/mo during the year of treatment period, whereas long-term progression was 0.364 dB/mo. Among all 16 patients, a partial response was observed in more than one schwannoma in four (including one in which Bev had not been effective), minor response in 5, and stable disease in 4. Both VEGFR1-specific and VEGFR2-specific cytotoxic T lymphocytes (CTLs) were induced in 11 patients. Two years after vaccination, a radiologic response was achieved in nine of 20 assessable schwannomas. This study demonstrated the safety and preliminary efficacy of VEGFR peptide vaccination in patients with NF2. Memory-induced CTLs after VEGFR vaccination may persistently suppress tumor progression.