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Background: To evaluate the influence of previous physical activity (PA) during childhood, adolescence, and current PA practice on the production of antibodies and inflammatory response between the first and second doses of the COVID-19 vaccine. Methods: Fifty-nine men and 56 women were evaluated before the first vaccine, and 12 weeks later, blood samples were taken to quantify production of anti-severe acute respiratory syndrome coronavirus-2 immunoglobulin G antibodies and cytokines. Previous PA during childhood and adolescence was self-referred, and current PA was assessed using the International Physical Activity Questionnaire. Results: A positive and significant association was observed only between PA practice during adolescence and an increase in antibody production in adulthood (β = 2012.077, 95% confidence interval, 257.7953–3766.358, P =.025). Individuals who practiced PA during adolescence showed higher production of antibodies between the first and second vaccine dose compared to nonpractitioners (P =.025) and those that accumulated ≥150 minutes per week of current moderate–vigorous PA (MVPA), and presented higher antibody production in relation to who did <150 minutes per week of MVPA (P =.046). Individuals that were practitioners during childhood produced higher G-CSF (P =.047), and those that accumulated ≥150 minutes per week of current MVPA demonstrated lower IP-10 levels (P =.033). However, PA practitioners during adolescence presented higher G-CSF (P =.025), IL-17 (P =.038), IL-1RA (P =.005), IL-1β (P =.020), and IL-2 (P =.026) levels. Conclusion: Our results suggest that adults that accumulated at least 150 minutes of MVPA per week or practiced PA during adolescence developed an improved immune and inflammatory response against COVID-19 vaccination. [ABSTRACT FROM AUTHOR]

How human genetic variation contributes to vaccine effectiveness in infants is unclear, and data are limited on these relationships in populations with African ancestries. We undertook genetic analyses of vaccine antibody responses in infants from Uganda (n = 1391), Burkina Faso (n = 353) and South Africa (n = 755), identifying associations between human leukocyte antigen (HLA) and antibody response for five of eight tested antigens spanning pertussis, diphtheria and hepatitis B vaccines. In addition, through HLA typing 1,702 individuals from 11 populations of African ancestry derived predominantly from the 1000 Genomes Project, we constructed an imputation resource, fine-mapping class II HLA-DR and DQ associations explaining up to 10% of antibody response variance in our infant cohorts. We observed differences in the genetic architecture of pertussis antibody response between the cohorts with African ancestries and an independent cohort with European ancestry, but found no in silico evidence of differences in HLA peptide binding affinity or breadth. Using immune cell expression quantitative trait loci datasets derived from African-ancestry samples from the 1000 Genomes Project, we found evidence of differential HLA-DRB1 expression correlating with inferred protection from pertussis following vaccination. This work suggests that HLA-DRB1 expression may play a role in vaccine response and should be considered alongside peptide selection to improve vaccine design.

In pandemic scenarios involving novel human pathogenic viruses, it is highly desirable that vaccines induce strong neutralizing antibodies as quickly as possible. However, current vaccine strategies require multiple immunization doses to produce high titers of neutralizing antibodies and are poorly protective after a single vaccination. We therefore wished to design a vaccine candidate that would induce increased protective immune responses following the first vaccine dose. We hypothesized that antibodies against the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein could be increased by drawing upon immunity to a previous infection. We generated a fusion protein containing the influenza H1N1 PR8 virus nucleoprotein (NP) and the SARS-CoV-2 spike RBD. Mice with or without preexisting immunity to PR8 were then vaccinated with NP/RBD. We observed significantly increased SARS-CoV-2 neutralizing antibodies in mice with PR8 immunity compared to mice without preexisting PR8 immunity. Vaccination with NP/RBD protected mice from SARS-CoV-2-induced morbidity and mortality after a single dose. Additionally, we compared SARS-CoV-2 virus titers in the lungs and nasal turbinates 4 days post-challenge of mice vaccinated with NP/RBD. SARS-CoV-2 virus was detectable in the lungs and nasal turbinate of mice without preexisting PR8 immunity, while SARS-CoV-2 virus was completely undetectable in mice with preexisting PR8 immunity. We also found that CD4-positive T cells in mice with preexisting immunity to PR8 play an essential role in producing the increased antibody response against RBD. This vaccine strategy potentially can be modified to target other pathogens of concern and offers extra value in future pandemic scenarios.IMPORTANCEIncreased globalization and changes in human interactions with wild animals has increased the likelihood of the emergence of novel viruses with pandemic potential. Vaccines can be effective in preventing severe disease caused by pandemic viruses. However, it takes time to develop protective immunity via prime-boost vaccination. More effective vaccine designs should quickly induce protective immunity. We propose leveraging preexisting immunity to a different pathogen to boost protection against emerging viruses. We targeted SARS-CoV-2 as a representative pandemic virus and generated a fusion protein vaccine that combines the nucleoprotein from influenza A virus and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Our vaccine design significantly increased the production of RBD-specific antibodies in mice that had previously been exposed to influenza virus, compared to those without previous exposure. This enhanced immunity reduced SARS-CoV-2 replication in mice. Our results offer a vaccine design that could be valuable in a future pandemic setting.

Malaria sterile immunity has been reproducibly induced by immunization with Plasmodium radiation-attenuated sporozoites (RAS). Analyses of sera from RAS-immunized individuals allowed the identification of P. falciparum antigens, such as the circumsporozoite protein (CSP), the basis for the RTS, S and R21Matrix-M vaccines. Similar advances in P. vivax (Pv) vaccination have been elusive. We previously reported 42% (5/12) of sterile protection in malaria-unexposed, Duffy-positive (Fy +) volunteers immunized with PvRAS followed by a controlled human malaria infection (CHMI). Using a custom protein microarray displaying 515 Pv antigens, we found a significantly higher reactivity to PvCSP and one hypothetical protein (PVX_089630) in volunteers protected against P. vivax infection. In mock-vaccinated Fy + volunteers, a strong antibody response to CHMI was also observed. Although the Fy- volunteers immunized with non-irradiated Pv-infected mosquitoes (live sporozoites) did not develop malaria after CHMI, they recognized a high number of antigens, indicating the temporary presence of asexual parasites in peripheral blood. Together, our findings contribute to the understanding of the antibody response to P. vivax infection and allow the identification of novel parasite antigens as vaccine candidates.Trial registration: ClinicalTrials.gov number: NCT01082341.

BACKGROUND: Despite immunization, patients on antineoplastic and immunomodulating agents have a heightened risk of COVID-19 infection. However, accurately attributing this risk to specific medications remains challenging. METHODS: An observational cohort study from December 11, 2020 to September 22, 2022, within a large healthcare system in San Diego, California, USA was designed to identify medications associated with greatest risk of postimmunization SARS-CoV-2 infection. Adults prescribed WHO Anatomical Therapeutic Chemical (ATC) classified antineoplastic and immunomodulating medications were matched (by age, sex, race, and number of immunizations) with control patients not prescribed these medications yielding a population of 26 724 patients for analysis. From this population, 218 blood samples were collected from an enrolled subset to assess serological response and cytokine profile in relation to immunization. RESULTS: Prescription of WHO ATC classified antineoplastic and immunomodulatory agents was associated with elevated postimmunization SARS-CoV-2 infection risk (HR 1.50, 95% CI 1.38 to 1.63). While multiple immunization doses demonstrated a decreased association with postimmunization SARS-CoV-2 infection risk, antineoplastic and immunomodulatory treated patients with four doses remained at heightened risk (HR 1.23, 95% CI 1.06 to 1.43). Risk variation was identified among medication subclasses, with PD-1/PD-L1 inhibiting monoclonal antibodies, calcineurin inhibitors, and CD20 monoclonal antibody inhibitors identified to associate with increased risk of postimmunization SARS-CoV-2 infection. Antineoplastic and immunomodulatory treated patients also displayed a reduced IgG antibody response to SARS-CoV-2 epitopes alongside a unique serum cytokine profile. CONCLUSIONS: Antineoplastic and immunomodulating medications associate with an elevated risk of postimmunization SARS-CoV-2 infection in a drug-specific manner. This comprehensive, unbiased analysis of all WHO ATC classified antineoplastic and immunomodulating medications identifies medications associated with greatest risk. These findings are crucial in guiding and refining vaccination strategies for patients prescribed these treatments, ensuring optimized protection for this susceptible population in future COVID-19 variant surges and potentially for other RNA immunization targets.

BACKGROUND: Our previous study established a 2-dose regimen of high-dose trivalent influenza vaccine (HD-TIV) to be immunogenically superior compared to a 2-dose regimen of standard-dose quadrivalent influenza vaccine (SD-QIV) in pediatric allogeneic hematopoietic cell transplant (HCT) recipients. However, the durability of immunogenicity and the role of time post-HCT at immunization as an effect modifier are unknown. METHODS: This phase II, multi-center, double-blinded, randomized controlled trial compared HD-TIV to SD-QIV in children 3-17 years old who were 3-35 months post-allogeneic HCT, with each formulation administered twice, 28-42 days apart. Hemagglutination inhibition (HAI) titers were measured at baseline, 28-42 days following each dose, and 138-222 days after the second dose. Using linear mixed effects models, we estimated adjusted geometric mean HAI titer ratios (aGMR: HD-TIV/SD-QIV) to influenza antigens. Early and late periods were defined as 3-5 and 6-35 months post-HCT, respectively. RESULTS: During 3 influenza seasons (2016-2019), 170 participants were randomized to receive HD-TIV (n = 85) or SD-QIV (n = 85). HAI titers maintained significant elevations above baseline for both vaccine formulations, although the relative immunogenic benefit of HD-TIV to SD-QIV waned during the study. A 2-dose series of HD-TIV administered late post-HCT was associated with higher GMTs compared to the early post-HCT period (late group: A/H1N1 aGMR = 2.16, 95% confidence interval [CI] = [1.14-4.08]; A/H3N2 aGMR = 3.20, 95% CI = [1.60-6.39]; B/Victoria aGMR = 1.91, 95% CI = [1.01-3.60]; early group: A/H1N1 aGMR = 1.03, 95% CI = [0.59-1.80]; A/H3N2 aGMR = 1.23, 95% CI = [0.68-2.25]; B/Victoria aGMR = 1.06, 95% CI = [0.56-2.03]). CONCLUSIONS: Two doses of HD-TIV were more immunogenic than SD-QIV, especially when administered ≥6 months post-HCT. Both groups maintained higher titers compared to baseline throughout the season. CLINICAL TRIALS REGISTRATION: NCT02860039.

Human humoral immune responses to SARS-CoV-2 vaccines exhibit substantial inter-individual variability and have been linked to vaccine efficacy. To elucidate the underlying mechanism behind this variability, we conducted a genome-wide association study (GWAS) on the anti-spike IgG serostatus of UK Biobank participants who were previously uninfected by SARS-CoV-2 and had received either the first dose (n = 54,066) or the second dose (n = 46,232) of COVID-19 vaccines. Our analysis revealed significant genome-wide associations between the IgG antibody serostatus following the initial vaccine and human leukocyte antigen (HLA) class II alleles. Specifically, the HLA-DRB1∗13:02 allele (MAF = 4.0%, OR = 0.75, p = 2.34e-16) demonstrated the most statistically significant protective effect against IgG seronegativity. This protective effect was driven by an alteration from arginine (Arg) to glutamic acid (Glu) at position 71 on HLA-DRβ1 (p = 1.88e-25), leading to a change in the electrostatic potential of pocket 4 of the peptide binding groove. Notably, the impact of HLA alleles on IgG responses was cell type specific, and we observed a shared genetic predisposition between IgG status and susceptibility/severity of COVID-19. These results were replicated within independent cohorts where IgG serostatus was assayed by two different antibody serology tests. Our findings provide insights into the biological mechanism underlying individual variation in responses to COVID-19 vaccines and highlight the need to consider the influence of constitutive genetics when designing vaccination strategies for optimizing protection and control of infectious disease across diverse populations.

BACKGROUND: Dexamethasone is routinely administered to horses but its effect on the antibody response to a commercial EIV/EHV vaccine is unclear. HYPOTHESIS: Horses receiving dexamethasone will have lower postvaccination antibody levels against EIV and EHV-1 than vaccinated controls. ANIMALS: Fifty-five healthy adult research horses. METHODS: Randomized cohort study. Control (no vaccine, group 1), vaccination only (EIV/EHV-1/EHV-4, Prestige 2, Merck Animal Health, group 2), vaccination and concurrent single intravenous dose of dexamethasone (approximately .05 mg/kg, group 3), vaccination and 3 intravenous doses of dexamethasone at 24 hours intervals (group 4). Serum SAA levels were measured on day 1 and day 3. Antibody levels against EIV (hemagglutination inhibition assay, Kentucky 2014 antigen) and EHV-1 (multiplex ELISA targeting total IgG and IgG 4/7) were measured on day 1 and day 30. RESULTS: Significantly increased mean antibody titers after vaccination were only noted against EIV and only after the vaccination alone (n = 14, prevaccine mean [prvm] 166.9, SD 259.6, 95% CI 16.95-316.8; postvaccine mean [povm] 249.1, SD 257.2, 95% confidence interval [CI] 100.6-397.6, P = .02) and the single dose dexamethasone (n = 14, prvm 93.14, SD 72.2, CI 51.45-134.8; povm 185.1, SD 118, CI 116.7-253.6, P = .01), but not after multiple doses of dexamethasone (n = 14, prvm 194.3, SD 258.3, CI 45.16-343.4; povm 240.0, SD 235.7, CI 103.9-376.1, P > .05). CONCLUSION: The effect of dexamethasone on the postvaccine antibody response varies depending on the dosing frequency and the antigen-specific antibody type.

Background: Natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or vaccination triggers antibody production against key viral antigens. However, there is limited evidence on the levels of antibodies produced in naturally infected individuals compared to those vaccinated in Ethiopia. Therefore, we aimed to detect and compare SARS-CoV-2 antibodies produced by naturally infected and vaccinated individuals. Materials and methods: We conducted a multicenter cross-sectional study among a total of 355 naturally infected and 355 vaccinated individuals from November 2022 to April 2023 at 10 selected health facilities in Addis Ababa, Ethiopia. We enrolled the participants consecutively upon their arrival at health facilities until the required sample size was achieved. We used a structured questionnaire to collect data on the demographic and clinical characteristics of the participants. We also collected 3–5 ml of blood samples from all participants and tested for anti-Spike (anti-S) and anti-nucleocapsid (anti-N) antibodies using Cobas 6000. We utilized frequency, mean, or median to describe the data, the Mann-Whitney U test to compare groups, and a generalized linear regression model to assess factors associated with anti-S antibody concentration. We analyzed the data with SPSS version 26, and the level of significance was set at P-value < 0.05. Results: Of the naturally infected participants, 352 (99.5%) had anti-S antibodies and all (100%) had anti-N antibodies, whereas among vaccinated participants, all (100%) had anti-S antibodies, while 323 (91.6%) had anti-N antibodies. Anti-S antibodies produced by vaccinated individuals were significantly (P < 0.001) higher than those produced as a result of natural infection. Being young (P = 0.004), having hypertension (P < 0.001), and having diabetes (P < 0.001) were significantly associated with lower anti-S antibody levels, while being recently vaccinated and having a higher number of vaccine doses were significantly associated with higher anti-S antibody concentrations in vaccinated participants. Having diabetes (P < 0.001) were significantly associated with lower anti-S concentrations in participants who were naturally infected. Conclusion: There is a high seropositivity rate in both naturally infected and vaccinated individuals. However, vaccinated individuals had higher levels of SARS-CoV-2 antibodies than those who were naturally infected, which highlights the significant contribution of vaccination in increasing the protection of COVID-19 in Ethiopia. [ABSTRACT FROM AUTHOR]

Malaria blood‐stage parasite is a critical pathogenic stage responsible for serious adverse outcomes in pregnant women and their neonates. Immunoglobulin G (IgG) antibody responses specific to various asexual blood‐stage antigens were well reported in non‐pregnant individuals. However, little is still known during placental malaria. To assess the antibody responses specific to Plasmodium falciparum‐derived MSP3 and UB05 malaria vaccine candidates in mother‐neonate couples, mother's peripheral blood and neonate's cord blood samples were collected at delivery. After malaria diagnostic, plasma levels of IgG and IgG subclass responses specific to UB05, MSP3 and UB05‐MSP3 were determined using ELISA. As outcomes, both mothers and neonates had significantly higher IgG responses to UB05 and UB05‐MSP3 compared to anti‐MSP3 IgG (p < 0.05), irrespective of malaria status. Significant negative correlations were observed between IgG levels specific to the three antigens and parasitaemia (p < 0.01). Anti‐UB05 and anti‐UB05‐MSP3 IgG levels in neonates showed a significant positive correlation with the corresponding mothers' antibodies (rs = 0.25 with p = 0.04; rs = 0.31 with p = 0.01, respectively). UB05MSP3‐specific IgG3 and IgG1 subclass responses were significantly higher than the IgG4 subclass (p < 0.01). The neonates IgG1 and IgG3 levels positively correlated with the corresponding antibody subclasses of mothers. These findings suggest an association between UB05 and UB05‐MSP3‐specific antibody responses and malaria control during pregnancy. Maternal–foetal transfer of MSP3 and UB05‐specific IgG occurs during pregnancy, suggesting the interest in the future malaria vaccination strategies in pregnant women to generate early protective immunity in baby against malaria. [ABSTRACT FROM AUTHOR]

Summary The human genome harbors hundreds of thousands of integrations of ancient retroviruses, amassed over millions of years of evolution. To reduce further amplification in the genome, the host prevents transcription of these now endogenous retroviruses (ERVs) through epigenetic repression and, with evolutionary time, ERVs are incapacitated by accumulating mutations and deletions. However, several members of recently endogenized ERV groups still retain the capacity to produce viral RNA, retroviral proteins, and higher order structures, including virions. The retention of viral characteristics, combined with the reversible nature of epigenetic repression, particularly as seen in cancer, allow for immunologically unanticipated ERV expression, perceived by the adaptive immune system as a genuine retroviral infection, to which it has to respond. Accordingly, antibodies reactive with ERV antigens have been detected in diverse disorders and, occasionally, in healthy individuals. Although they are part of self, the retroviral legacy of ERV antigens, and association with and, possibly, causation of disease states may set them apart from typical self‐antigens. Consequently, the pathogenic or, indeed, host‐protective capacity of antibodies targeting ERV antigens is likely to be context‐dependent. Here, we review the immunogenicity of typical ERV proteins, with emphasis on the antibody response and its potential disease implications. [ABSTRACT FROM AUTHOR]

Background The emergence of rapidly evolving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, coupled with waning vaccine-induced immunity, has contributed to the rise of vaccine breakthrough infections. It is crucial to understand how vaccine-induced protection is mediated. Methods We examined 2 prospective cohorts of mRNA vaccinated and boosted individuals during the Omicron wave of infection in Singapore. Results We found that individuals who remain uninfected over the follow-up period had a higher variant-specific IgA, but not IgG, antibody response at 1 month after booster vaccination, compared with individuals who became infected. Conclusions We conclude that IgA may have a potential contributory role in protection against Omicron infection. Clinical Trials Registration. NCT05142319. [ABSTRACT FROM AUTHOR]

Background Factors influencing susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain to be resolved. Using data from the Swiss HIV Cohort Study on 6270 people with human immunodeficiency virus (HIV) and serologic assessment for SARS-CoV-2 and circulating human coronavirus (HCoV) antibodies, we investigated the association of HIV-related and general parameters with SARS-CoV-2 infection. Methods We analyzed SARS-CoV-2 polymerase chain reaction test results, COVID-19–related hospitalizations, and deaths reported to the Swiss HIV Cohort Study between 1 January 2020 and 31 December 2021. Antibodies to SARS-CoV-2 and HCoVs were determined in prepandemic (2019) and pandemic (2020) biobanked plasma samples and compared with findings in HIV-negative individuals. We applied logistic regression, conditional logistic regression, and bayesian multivariate regression to identify determinants of SARS-CoV-2 infection and antibody responses to SARS-CoV-2 in people with HIV. Results No HIV-1–related factors were associated with SARS-CoV-2 acquisition. High prepandemic HCoV antibodies were associated with a lower risk of subsequent SARS-CoV-2 infection and with higher SARS-CoV-2 antibody responses on infection. We observed a robust protective effect of smoking on SARS-CoV-2 infection risk (adjusted odds ratio, 0.46 [95% confidence interval,.38–.56]; P <.001), which occurred even in previous smokers and was highest for heavy smokers. Conclusions Our findings of 2 independent protective factors, smoking and HCoV antibodies, both affecting the respiratory environment, underscore the importance of the local immune milieu in regulating susceptibility to SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Background MF59-adjuvanted gB subunit (gB/MF59) vaccine demonstrated approximately 50% efficacy against human cytomegalovirus (HCMV) acquisition in multiple clinical trials, suggesting that efforts to improve this vaccine design might yield a vaccine suitable for licensure. Methods A messenger RNA (mRNA)–based vaccine candidate encoding HCMV gB and pentameric complex (PC), mRNA-1647, is currently in late-stage efficacy trials. However, its immunogenicity has not been compared to the partially effective gB/MF59 vaccine. We assessed neutralizing and Fc-mediated immunoglobulin G (IgG) effector antibody responses induced by mRNA-1647 in both HCMV-seropositive and -seronegative vaccinees from a first-in-human clinical trial through 1 year following third vaccination using a systems serology approach. Furthermore, we compared peak anti-gB antibody responses in seronegative mRNA-1647 vaccinees to that of seronegative gB/MF59 vaccine recipients. Results mRNA-1647 vaccination elicited and boosted HCMV-specific IgG responses in seronegative and seropositive vaccinees, respectively, including neutralizing and Fc-mediated effector antibody responses. gB-specific IgG responses were lower than PC-specific IgG responses. gB-specific IgG and antibody-dependent cellular phagocytosis responses were lower than those elicited by gB/MF59. However, mRNA-1647 elicited higher neutralization and antibody-dependent cellular cytotoxicity (ADCC) responses. Conclusions Overall, mRNA-1647 vaccination induced polyfunctional and durable HCMV-specific antibody responses, with lower gB-specific IgG responses but higher neutralization and ADCC responses compared to the gB/MF59 vaccine. Clinical Trials Registration NCT03382405 (mRNA-1647) and NCT00133497 (gB/MF59). [ABSTRACT FROM AUTHOR]

Nipah virus (NiV) is a highly pathogenic paramyxovirus. The Syrian hamster model recapitulates key features of human NiV disease and is a critical tool for evaluating antivirals and vaccines. Here we describe longitudinal humoral immune responses in NiV-infected Syrian hamsters. Samples were obtained 1–28 days after infection and analyzed by ELISA, neutralization, and Fc-mediated effector function assays. NiV infection elicited robust antibody responses against the nucleoprotein and attachment glycoprotein. Levels of neutralizing antibodies were modest and only detectable in surviving animals. Fc-mediated effector functions were mostly observed in nucleoprotein-targeting antibodies. Antibody levels and activities positively correlated with challenge dose. [ABSTRACT FROM AUTHOR]

Objective: The current study aimed to investigate the baseline immune and inflammatory features and in-hospital outcomes of patients infected with the Omicron variant (PIWO) who presented with different disease severities during the first wave of mass Omicron infections in the Chinese population has occurred. Method: A cross‐sectional study was conducted on 140 hospitalized PIWO between December 11, 2022, and February 16, 2023. The clinical features, antibodies against SARS-CoV-2, immune cells, and inflammatory cytokines among mildly, severely, and critically ill PIWO at baseline and during follow-up period were compared. Result: Patients with severe (n = 49) and critical (n = 35) disease were primarily male, needed invasive mechanical ventilation treatment, and exhibited higher mortality than those with mild disease (n = 56). During acute infection, SARS-CoV-2-specific antibody levels fluctuated with disease severity, serum antibodies increased and the incidence of severe cases decreased in critically ill PIWO over time. Antibody titers in severe or critical PIWO with no antibody responses at baseline did not increase significantly over time. Meanwhile, CD4+T cell, CD8+T cell, and natural killer cell counts were negatively correlated with disease severity, whereas interleukin (IL)-6 and IL-10 levels were positively correlated. In addition, combined diabetes, immunosuppressive therapy before infection, serum amyloid A, IL-10 and neutrophil counts were independently associated with severe and critical illness in PIWO. Among the 11 nonsurvivors, 8, 2, 1 died of respiratory failure, sudden cardiac death, and renal failure, respectively. Compared with survivors, nonsurvivors exhibited lower seropositivity of SARS-CoV-2-specific antibody, reduced CD3+T and CD4+T cell counts, and higher IL-2R, IL-6, IL-8, and IL-10 levels. Of note, lactate dehydrogenase was a significant risk factor of death in severe or critically ill PIWO. Conclusion: This present study assessed the dynamic changes of SARS-CoV-2-specific antibodies, immune cells and inflammatory indexes between severely and critically ill PIWO. Critical and dead PIWO featured compromised humoral immune response and excessive inflammation, which broadened the understanding of the pathophysiology of Omicron infection and provides warning markers for severe disease and poor prognosis. Highlights : 1. Specific anti-SARS-CoV-2 antibodies showed a trend of increasing first and then decreasing with the progression of disease severity. 2. The severity of infection decreased and the levels of the four antibodies against SARS-CoV-2 increased in critically ill PIWO over time. 3. Negative antibodies in severe/critical PIWO at baseline did not increase significantly with therapeutic intervention. 4. Dead PIWO exhibited disordered features of immunocompromised, hyperinflammatory, abnormal coagulation and myocardial injury. 5. Combined diabetes, immunosuppressive therapy before infection, high levels of SAA, IL-10 and neutrophil counts were the risk factors for severe/critical illness. 6. High LDH was related to death event in severely/critically ill PIWO. [ABSTRACT FROM AUTHOR]

Antigen‐specific B and T cell responses play a critical role in vaccine‐mediated protection against infectious diseases, but these responses are highly variable between individuals and vaccine immunogenicity is frequently sub‐optimal in infants, the elderly and in people living in low‐ and middle‐income countries. Although many factors such as nutrition, age, sex, genetics, environmental exposures, and infections may all contribute to variable vaccine immunogenicity, mounting evidence indicates that the gut microbiota is an important and targetable factor shaping optimal immune responses to vaccination. In this review, we discuss evidence from human, preclinical and experimental studies supporting a role for a healthy gut microbiota in mediating optimal vaccine immunogenicity, including the immunogenicity of COVID‐19 vaccines. Furthermore, we provide an overview of the potential mechanisms through which this could occur and discuss strategies that could be used to target the microbiota to boost vaccine immunogenicity where it is currently sub‐optimal. [ABSTRACT FROM AUTHOR]

The recent emergence and rapid response to severe acute respiratory syndrome coronavirus 2 was enabled by prototype pathogen and vaccine platform approaches, driven by the preemptive application of RNA vaccine technology to the related Middle East respiratory syndrome coronavirus. Recently, the National Institutes of Allergy and Infectious Diseases identified nine virus families of concern, eight enveloped virus families and one nonenveloped virus family, for which vaccine generation is a priority. Although RNA vaccines have been described for a variety of enveloped viruses, a roadmap for their use against nonenveloped viruses is lacking. Enterovirus D68 was recently designated a prototype pathogen within the family Picornaviridae of nonenveloped viruses because of its rapid evolution and respiratory route of transmission, coupled with a lack of diverse anti-enterovirus vaccine approaches in development. Here, we describe a proof-of-concept approach using a clinical stage RNA vaccine platform that induced robust enterovirus D68–neutralizing antibody responses in mice and nonhuman primates and prevented upper and lower respiratory tract infections and neurological disease in mice. In addition, we used our platform to rapidly characterize the antigenic diversity within the six genotypes of enterovirus D68, providing the necessary data to inform multivalent vaccine compositions that can elicit optimal breadth of neutralizing responses. These results demonstrate that RNA vaccines can be used as tools in our pandemic-preparedness toolbox for nonenveloped viruses. Editor's summary: mRNA vaccines have been shown to be successful for many enveloped viruses, including SARS-CoV-2 and RSV. However, their ability to confer protection against nonenveloped viruses, such as picornaviruses, remains to be seen. Here, Warner et al. developed and tested a series of self-amplifying mRNA vaccines targeting different subclades of enterovirus D68 (EV-D68). The authors found that the vaccines elicited antibodies that could neutralize their homologous subclade, with some evidence of heterologous protection. These data, coupled with a series of immunogenicity and challenge studies in mice and nonhuman primates, suggest that multivalent EV-D68 vaccines may confer broad protection against this prototype pathogen. —Courtney Malo [ABSTRACT FROM AUTHOR]

Tick-borne encephalitis virus (TBEV) vaccine breakthrough (VBT) infections are not uncommon in endemic areas. The clinical and immunological outcomes have been poorly investigated. We assessed the magnitude and specificity of virus-specific antibody and T cell responses after TBE in previously vaccinated subjects and compared the results with those of unvaccinated TBE patients and study subjects that received vaccination without VBT infection. Symptomatic TBEV infection of unvaccinated study subjects induced virus-specific antibody responses to the E protein and non-structural protein 1 (NS1) as well as T cell responses to structural and other non-structural (NS) proteins. After VBT infections, significantly impaired NS1-specific antibody responses were observed, while the virus-specific T cell responses to the NS proteins were relatively strong. VBT infection caused predominantly moderate to severe disease during hospitalization. The level of TBEV EDIII- and NS1-specific antibodies in unvaccinated convalescent patients inversely correlated with TBE severity and neurological symptoms early after infection. [ABSTRACT FROM AUTHOR]

Single B-cell antibody generation technology is an advanced method that offers several advantages, including rapid production, high efficiency, and high yield. The antibodies generated via this technique retain their natural conformation and are well suited for applications in pathogen diagnosis, disease treatment, and investigations of virus cross-species transmission mechanisms. Our study aimed to establish a platform for generating single B-cell antibodies specifically targeting the foot-and-mouth disease virus (FMDV) 146S antigen in mice. Female BALB/c mice were immunized with inactivated O-type FMDV 146S antigen, and spleen cells were collected for further analysis. Flow cytometric sorting was performed using a biotin-labeled O-type FMDV 146S antigen as a decoy to identify and select CD19 + /CD21/35 + /CD43-/IgM-/Biotin + antigen-specific individual B cells. The gene sequences encoding the variable regions of the heavy and light chains of the murine IgG antibodies were obtained via single-cell nested PCR amplification. Separate constructs were created for the heavy and light chain plasmids to ensure the proper expression of intact IgG antibodies. These plasmids were cotransfected into human embryonic kidney 293T (HEK293T) cells, leading to the successful production and purification of 15 specific monoclonal antibodies (mAbs), 10 which exhibited activity in ELISA tests, and six antibodies that displayed activity in IFA tests. These findings highlight the successful development of a method for generating mouse-derived single B-cell antibodies that target FMDV. This achievement provides a solid foundation for diagnostic techniques and the analysis of antigenic structural variations. [ABSTRACT FROM AUTHOR]

This study reports on the immunogenicity and biodistribution of H5 hemagglutinin (HA)-based self-amplifying (sa) mRNA vaccines in mice. Four sa-mRNA vaccines encoding either a secreted full-length HA, a secreted HA head domain, a secreted HA stalk domain, or a full-length membrane-anchored HA were investigated. All vaccines elicited an adaptive immune response. However, the full-length HA sa-RNA vaccines demonstrated superior performance compared to head and stalk domain vaccines. The antibody titers positively correlated with the vaccine dose. Cellular immune responses and antigen-specific IgA antibodies in the lungs were also observed. The comparison of the sa-mRNA vaccines encoding the secreted and membrane-anchored full-length HA revealed that anchoring of the HA to the membrane significantly enhanced the antibody and cellular responses. In addition to the injection site, the intramuscularly injected sa-mRNA-LNPs were also detected in the draining lymph nodes, spleen, and to a lesser extent, in the lung, kidney, liver, and heart. [ABSTRACT FROM AUTHOR]

Avian influenza poses a severe threat to poultry production and global food security, prompting the development of vaccination programs in numerous countries. Modified live virus (MLV) vaccines, with their potential for mass application, offer a distinct advantage over existing options. However, concerns surrounding reversion, recombination, and unintended transmission have hindered the progress of MLV development for avian influenza in poultry. To address these concerns, we engineered reassortment-impaired, non-transmissible, safe, immunogenic, and protective MLVs through the rearrangement of internal gene segments and additional modifications to the surface gene segments HA and NA. The unique peptide marker aspartic acid-arginine-proline-alanine-valine-isoleucine-alanine-asparragine (DRPAVIAN) was incorporated into HA, while NA was modified to encode the chicken interleukin-18 (ckIL18) gene (MLV-H9N2-IL). In vitro, the MLV-H9N2 and MLV-H9N2-IL candidates demonstrated stability and virus titers comparable to the wild-type H9N2 strain. In chickens, the MLV-H9N2 and MLV-H9N2-IL candidates did not transmit via direct contact. Co-infection studies with wild-type virus confirmed that the altered HA and NA segments exhibited fitness disadvantages and did not reassort. Vaccinated chickens showed no clinical signs upon vaccination, all seroconverted, and the inclusion of ckIL18 in the MLV-H9N2-IL vaccine enhanced neutralizing antibody production. A significant decrease in viral loads post-challenge underscored the protective effect of the MLVs. The MLV-H9N2-IL vaccine, administered via drinking water, proved immunogenic in chickens in a dose-dependent manner, generating protective levels of neutralizing antibodies upon aggressive homologous virus challenge. In summary, this study lays the groundwork for safe MLVs against avian influenza suitable for mass vaccination efforts. [ABSTRACT FROM AUTHOR]

Mammalian cell line stability is an important consideration when establishing a biologics manufacturing process in the biopharmaceutical and in vitro diagnostics (IVD) industries. Traditional Chinese hamster ovary (CHO) cell line development methods use a random integration approach that requires transfection, selection, optional amplification, screenings, and single-cell cloning to select clones with acceptable productivity, product quality, and genetic stability. Site-specific integration reduces these disadvantages, and new technologies have been developed to mitigate risks associated with genetic instability. In this study, we applied the Leap-In® transposase-mediated expression system from ATUM to generate stable CHOK1 pools for the production of four recombinant antibody reagents for IVD immunoassays. CHO cell line stability is defined by consistent antibody production over time. Three of the CHOK1 pools maintained productivity suitable for manufacturing, with high antibody yields. The productivity of the remaining CHOK1 pool decreased over time; however, derivative clones showed acceptable stability. l-glutamine had variable effects on CHOK1 cell line or stable pool stability and significantly affected antibody product titer. Compared with traditional random integration methods, the ATUM Leap-In system can reduce the time needed to develop new immunoassays by using semi site-specific integration to generate high-yield stable pools that meet manufacturing stability requirements. [ABSTRACT FROM AUTHOR]

Summary: Immune responses to primary COVID‐19 vaccination were investigated in 58 patients with follicular lymphoma (FL) as part of the PETReA trial of frontline therapy (EudraCT 2016–004010‐10). COVID‐19 vaccines (BNT162b2 or ChAdOx1) were administered before, during or after cytoreductive treatment comprising rituximab (depletes B cells) and either bendamustine (depletes CD4+ T cells) or cyclophosphamide‐based chemotherapy. Blood samples obtained after vaccine doses 1 and 2 (V1, V2) were analysed for antibodies and T cells reactive to the SARS‐CoV‐2 spike protein using the Abbott Architect and interferon‐gamma ELISpot assays respectively. Compared to 149 healthy controls, patients with FL exhibited lower antibody but preserved T‐cell responses. Within the FL cohort, multivariable analysis identified low pre‐treatment serum IgA levels and V2 administration during induction or maintenance treatment as independent determinants of lower antibody and higher T‐cell responses, and bendamustine and high/intermediate FLIPI‐2 score as additional determinants of a lower antibody response. Several clinical scenarios were identified where dichotomous immune responses were estimated with >95% confidence based on combinations of predictive variables. In conclusion, the immunogenicity of COVID‐19 vaccines in FL patients is influenced by multiple disease‐ and treatment‐related factors, among which B‐cell depletion showed differential effects on antibody and T‐cell responses. [ABSTRACT FROM AUTHOR]

Background: The use of mammalian target of rapamycin inhibitors (mTORis) in kidney transplantation increases the risk of donor-specific human leukocyte antigen (HLA) antibody formation and rejection. Here, we investigated the long-term consequences of early mTORi treatment compared to calcineurin inhibitor (CNI) treatment. Methods: In this retrospective single-center analysis, key outcome parameters were compared between patients participating in randomized controlled immunosuppression trials between 1998 and 2011, with complete follow-up until 2018. The outcomes of eligible patients on a CNI-based regimen (n = 384) were compared with those of patients randomized to a CNI-free mTORi-based regimen (n = 81) and 76 patients randomized to a combination of CNI and mTORi treatments. All data were analyzed according to the intention-to-treat (ITT) principle. Results: Deviation from randomized immunosuppression for clinical reasons occurred significantly more often and much earlier in both mTORi-containing regimens than in the CNI treatment. Overall patient survival, graft survival, and death-censored graft survival did not differ between the treatment groups. Donor-specific HLA antibody formation and BPARs were significantly more common in both mTORi regimens than in the CNI-based immunosuppression. Conclusions: The tolerability and efficacy of the mTORi treatment in kidney graft recipients are inferior to those of CNI-based immunosuppression, while the long-term patient and graft survival rates were similar. [ABSTRACT FROM AUTHOR]

BACKGROUND: Nine-valent human papillomavirus (9vHPV) vaccines can be administered in 2 doses 6 to 12 months apart in adolescents. The impact of extended dose intervals is unknown. We report immunogenicity and safety data in adolescents of a second 9vHPV vaccine dose administered ≥1 year after the first. METHODS: This open-label safety and immunogenicity study (NCT04708041) assessed extended-interval 2-dose regimens of 9vHPV vaccine among adolescents (10 to 15 years) who received 2 9vHPV vaccine doses: the first ≥1 year before enrollment, and second, at enrollment (day 1). We measured serologic responses to vaccine-targeted human papillomavirus (HPV) types at enrollment day 1 (pre-dose 2) and 1 month post-dose 2 (month 1) using a competitive LuminexV® immunoassay. We estimated effects of dose interval on geometric mean titers (GMTs) using regression modeling. Participants reported adverse events (AEs) through 15 days after vaccination. RESULTS: We enrolled 146 adolescents (mean age 13.3 years) with median 25 months since first 9vHPV vaccine dose (range: 12-53 months). Across vaccine-targeted HPV types, GMTs increased from day 1 to month 1; seropositivity at month 1 was 100%. Anti-HPV GMTs at month 1 were not affected by differences in dose interval of 12 to 53 months, based on regression modeling. The most common AEs were mild-to-moderate injection site reactions; no serious AEs were reported. CONCLUSIONS: Extending the interval between first and second 9vHPV vaccine doses to 12 to 53 months did not affect antibody responses, with favorable safety profile. These results support feasibility of extended interval regimens for 9vHPV vaccine. [ABSTRACT FROM AUTHOR]

Vaccination and infection elicit antibodies with Fc-effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Fc-effector functions are more stable than neutralization in convalescent individuals. Hybrid immunity generates higher levels of Fc-effector functions than vaccination alone. Fc-effector functions play a protective role against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in different animal models. Caution should be used when selecting assays to measure Fc-effector functions. Major efforts were deployed to study the antibody response against SARS-CoV-2. Antibodies neutralizing SARS-CoV-2 have been extensively studied in the context of infections, vaccinations, and breakthrough infections. Antibodies, however, are pleiotropic proteins that have many functions in addition to neutralization. These include Fc-effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Although important to combat viral infections, these Fc-effector functions were less studied in the context of SARS-CoV-2 compared with binding and neutralization. This is partly due to the difficulty in developing reliable assays to measure Fc-effector functions compared to antibody binding and neutralization. Multiple assays have now been developed and can be used to measure different Fc-effector functions. Here, we review these assays and what is known regarding anti-SARS-CoV-2 Fc-effector functions. Overall, this review summarizes and updates our current state of knowledge regarding anti-SARS-CoV-2 Fc-effector functions. [ABSTRACT FROM AUTHOR]

Since pregnant women were excluded from clinical trials for vaccines against SARS-CoV-2, the novel coronavirus disease 2019 (COVID-19), there is limited data on the safety and efficacy of vaccines in this population. This systematic review explored the safety and efficacy of mRNA vaccines in pregnant women. A literature search was performed using Ovid databases through November 2021 for all studies evaluated efficacy and safety of mRNA COVID-19 vaccines in pregnant women. A total of five studies including 42,782 women were included in the systematic review. Humoral immunity to COVID-19 was detected in pregnant women who received the vaccine and no differences found in spike-specific T-cell responses. Incidence of high-grade chronic villitis is higher in the unvaccinated group with adjusted odds ratio of.31 (.1-.97), P <.05. Vaccination in pregnant women resulted in 12.6% spontaneous abortions (SAB) with 92.3% occurring in the first trimester,.1% stillbirth (> 20 weeks gestation), 9.4% preterm birth (<37 weeks gestation), and 2.2% congenital abnormalities. The mRNA COVID-19 vaccines are immunogenic in pregnant women and no obvious safety concerns observed. There is no increased incidence of adverse reactions in pregnant women. Our finding supports that pregnant women should receive the vaccination at their earliest convenience regardless of trimester. [ABSTRACT FROM AUTHOR]

Human Chorionic Gonadotropin (hCG) plays a crucial role in embryo implantation and in maintenance of pregnancy. An immuno-contraceptive approach involves the use of a recombinant hCGβ-LTB vaccine formulated with adjuvant Mycobacterium indicus pranii (MIP), to prevent pregnancy without disturbing ovulation, hormonal profiles, and menstrual cycles in women. The present work in mice was designed to address issues encountered in clinical trials conducted with hCGβ-LTB vaccine, with focus on two primary concerns. Firstly, it aimed to determine the optimal vaccine dosage required to induce a high level of anti-hCG antibodies. Secondly, it aimed to assess the safety profile of the vaccine, specifically injection site reactions in the form of nodules, observed in some of the subjects. Studies undertaken indicate that a 2 µg dose of the protein version of the vaccine, administered in mice through the intramuscular route, can induce high anti-hCG titres. Furthermore, administering a booster dose enhances the antibody response. Our findings suggest that the concentration and frequency of administration of the adjuvant MIP can also be reduced without compromising vaccine efficacy. The issue of nodule formation at the injection site can be mitigated either by administering the vaccine along with MIP intramuscularly or injecting hCG vaccine and MIP at separate intradermal sites. Thus, protein vaccine administered at a 2µg dose via the intramuscular route addresses both efficacy and safety concerns. The Phase I/II clinical trials initiated with the recombinant hCG vaccine in women revealed inadequate antibody titres in all subjects, alongside the development of nodules at the injection sites in some participants. Studies were undertaken in mice to propose potential strategies for mitigating injection site reactions and enhancing the antibody response. It was concluded that the optimum dose of the protein version of the vaccine to get high antibody titres, is 2 µg administered intramuscularly while upholding safety standards. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study is to assess long-term immunogenicity of the recombinant adenoviruses 26 and 5 vector-based COVID-19 vaccine Gam-COVID-Vac (Sputnik V, developed by N. F. Gamaleya National Research Centre, Russia) in patients receiving maintenance hemodialysis (HD) compared to healthy subjects. Materials & methods: A prospective cohort study included patients treated with maintenance HD (n=23) and healthy volunteers (n=28). The levels of anti-severe acute respiratory syndrome coronavirus-2 specific IgG as well as specific T-cell responses were quantified in all participants at two time points: one and six months after complete vaccination. All participates were adults, had been vaccinated twice with Gam-COVID-Vac and had no prior history of confirmed COVID-19. Results: In both groups, IgG levels decreased from month one to six, however, antibodies did not decline more rapidly in HD group (analysis of variance p=0.7214 for the "time×group" interaction, non-adjusted model). At the end of the study, 48.0% of non-HD and 67.0% of HD participants showed T-cell positivity. T-spot counts dropped over time in non-HD controls, but not in HD subjects (p=0.0080 and p=0.1800, respectively). Conclusions: Patients receiving HD maintain significant long-term humoral response after Gam-COVID-Vac vaccination, which is comparable to that in subjects with normal kidney function. Cellular response turned up to be more sustained over time in HD group. [ABSTRACT FROM AUTHOR]

Stress has been associated with less effective vaccine responses in adults. This review aims to investigate the evidence for a similar association in children. A systematic review search was conducted in January 2021 in three databases: Medline, Embase and PsycInfo. An updated search of the Medline database was systematically conducted until the most recent update on September 25th, 2023, to ensure the inclusion of the most current research available. Keywords related to stress, vaccines and children were used, and a total of 7263 (+1528) studies were screened by two independent investigators. Six studies met the inclusion criteria for data extraction and analysis. For quality assessment of the studies, the risk of bias in non‐randomized studies—of interventions (ROBINS‐I) tool was applied. Most of the studies suggest a negative role of stress on vaccine responses. However, the scarcity of studies, lack of confirmatory studies, risk of bias and heterogeneity according to age, type of vaccine, measures of stress and vaccine responses prevent a clear conclusion. Future studies should emphasize the use of as strict study designs as possible, including well‐defined stress metrics and thorough examination of both pre‐ and post‐vaccination responses. Systematic review registration: Prospero CRD42021230490. [ABSTRACT FROM AUTHOR]

Data on the safety and antibody response of the BNT162b2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine in children aged 5–11 years with underlying diseases are limited. Thus, our study aimed to address this gap. This prospective observational study investigated the antibody titers for SARS-CoV-2 spike protein receptor-binding domain (S-IgG) and nucleocapsid protein (N-IgG) in patients aged 5–11 years with chronic underlying diseases following two doses of BNT162b2. Additionally, a questionnaire was used to assess adverse events (AEs) arising within 7 days after each dose. Data on severe AEs arising within 28 days after each dose were extracted from the patients' electronic medical records. Among 122 patients, 24.6% (30/122) were immunocompromised. Furthermore, 79 patients experienced at least one AE following vaccination, but all recovered without sequelae, including one severe case after the first dose. The seropositivity rate after the second dose was 99.1% (116/117). Excluding 19 N-IgG-positive patients, the geometric mean antibody titer (GMT) was significantly higher in immunocompetent patients than in immunocompromised patients (1496 U/mL [95% confidence interval 1199–1862] vs. 472 U/mL [200−1119], p = 0.035). Additionally, the GMT of S-IgG was higher in N-IgG-positive patients than in N-IgG-negative patients (8203 [5847–11482] U/mL vs. 1127 [855–1486] U/mL, p < 0.001). BNT162b2 is acceptably safe and immunogenic for children aged 5–11 years with underlying diseases. Although seroconversion was satisfactory in immunocompromised patients, the titers were lower than in immunocompetent patients. [ABSTRACT FROM AUTHOR]

Objective: To investigate polymerase chain reaction (PCR) confirmed symptomatic coronavirus disease-2019 (COVID-19) infection incidence in vaccinated older adults. Materials and Methods: This prospective study comprised 483 adults aged 60 years and older, all vaccinated with 2 doses of inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. All participants had their anti-SARS-CoV-2 immunoglobulin G antibody titers checked and were simultaneously evaluated by comprehensive geriatric assessment, including frailty. We defined the overall survival time as the period from the date of blood collection for antibody responses through the event date [i.e., PCR confirmed (COVID-19) diagnosis] (if any), the time of the last visit or at the termination of data collection (November 25, 2021), whichever occurred first. Individuals who were vaccinated with the 3rd dose of any type were censored at the time of vaccination and removed from further follow-up. Results: The incidence of symptomatic COVID-19 was significantly higher in the frail group, with a cumulative incidence of 7.1% and 2.2% in the frail and non-frail groups, respectively (p=0.02). In Cox regression analysis, the clinical frailty scale (CFS) score was found to be a significant predictor for breakthrough COVID-19 infection [hazard ratio: 3.2 (95% confidence interval: 1.0-9.9), p=0.04]. Conclusion: High CFS scores among vaccinated older adults should be considered as an easy-to-assess, high-risk marker for predicting breakthrough COVID-19 infection. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to determine how the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) inactivated vaccine antibody response and vitamin D levels in the older population are related. Materials and Methods: This study included people over the age of 60 who received their second dose of the SARS-CoV-2 inactivated vaccine after 28 days. Immunoglobulin G antibodies against SARS-CoV-2 spikes were measured; levels equal to or greater than 1 U/mL were classified as seropositive, and levels below 1 U/mL were classified as seronegative. Serum 25-hydroxyvitamin D levels were evaluated in the participants; levels below 30 nmol/L were classified as low, and levels above 30 nmol/L were classified as normal. Results: A total of 188 patients were included. A total of 152 people (80.9%) were found to be positive for the antibodies. The median [interquartile range (IQR)] age of the seropositive individuals was 71 (60-94) and the median (IQR) age of seronegative individuals was 72 (64-86) (p=0.272). While the vitamin D level was below 30 in 115 (75.6%) of the seropositive group, the vitamin D level was below 30 in 26 (70.9%) patients in the seronegative group (p=0.822). Conclusion: In this study, we examined the association between vitamin D levels and seroconversion rate after the second dose of SARS-CoV-2 inactivated vaccine. There were no differences between the seropositive and seronegative groups in terms of vitamin D levels. In another context, it was discovered that vitamin D level has no effect on antibody response. [ABSTRACT FROM AUTHOR]

Over the past century, the field of antibody discovery has undergone significant evolution, excluding the current exploration stage of artificial intelligence‐based antibody generation and the often overlooked non‐animal sourced antibody discovery, which typically requires mature in vitro affinity and the selection of high‐quality antigen formulations. This journey has traversed various stages, from methods involving serum‐based antibody acquisition, the isolation of B cells capable of perpetual antibody production through hybridoma technology, to the in‐depth exploration of genetic material using the phage display system, and the current stage involving diverse single B cell screening techniques. Additionally, the emergence of machine learning has brought impressive scientific and technological breakthroughs across research domains, proving to be a powerful application in the field of antibody discovery. However, each technique comes with its limitations, such as variability and control challenges in serum‐based acquisition, lengthy and difficult hybridoma‐derived antibody development, potential limitations in sequence and epitope diversity due to immunization biases in phage display techniques, and costly single B cell screening. Protein mass spectrometry sequencing, with shorter acquisition time and lower costs, is seen as a shortcut by diagnostic companies, impacting traditional antibody development. In diagnostic antibody development, methodological differences in downstream assays and the impact of constant regions outside the Fv core are often neglected. This paper deeply analyzes challenges, proposing innovative strategies for the next generation of diagnostic antibody development. Aimed at moving closer to the gold standard of antibody discovery, these strategies enhance the competitiveness of diagnostic reagent products. [ABSTRACT FROM AUTHOR]

Background: The examination of anti-double stranded DNA (ds-DNA) IgG antibody is of great significance for the diagnosis, differential diagnosis, assessment of disease activity, and prognosis of disease recurrence in SLE. Methods: We used a chemiluminescence method to detect ds-DNA IgG and found that the levels of ds-DNA IgG antibody in the patient's serum were significantly increased and the indirect immunofluorescence (IIF) test result was negative. Laboratory tests show that the patient's RF level far exceeds the upper limit of their reference range. Results: RF 110.6 IU/mL, ds-DNA IgG 753 IU/mL; After PEG6000 treatment, the RF was 108.7 IU/mL, and then the ds-DNA IgG was measured at 23.5 IU/mL. Conclusions: The RF IgM subtype is the main cause of RF interference in IgG antibody detection, mainly due to the binding of the Fc region of RF to the Fab segment of IgG. Combining with capture antibodies and labeled antibodies leads to the formation of non-specific detection signals, or directly reacting with the detected substance, resulting in false positive test results. [ABSTRACT FROM AUTHOR]

Genetic variants of the OX40 ligand (OX40L) locus are associated with the risk of systemic lupus erythematosus (SLE), it is unclear how the OX40L blockade delays the lupus phenotype. Therefore, we examined the effects of an anti‐OX40L antibody in MRL/Lpr mice. Next, we investigated the effect of anti‐OX40L on immunosuppression in keyhole limpet hemocyanin‐immunized C57BL/6J mice. In vitro treatment of anti‐OX40L in CD4+ T and B220+ B cells was used to explore the role of OX40L in the pathogenesis of SLE. Anti‐OX40L alleviated murine lupus nephritis, accompanied by decreased production of anti‐dsDNA and proteinuria, as well as lower frequencies of splenic T helper (Th) 1 and T‐follicular helper cells (Tfh). In keyhole limpet hemocyanin‐immunized mice, decreased levels of immunoglobulins and plasmablasts were observed in the anti‐OX40L group. Anti‐OX40L reduced the number and area of germinal centers. Compared with the control IgG group, anti‐OX40L downregulated CD4+ T‐cell differentiation into Th1 and Tfh cells and upregulated CD4+ T‐cell differentiation into regulatory T cells in vitro. Furthermore, anti‐OX40L inhibited toll‐like receptor 7‐mediated differentiation of antibody‐secreting cells and antibody production through the regulation of the SPIB‐BLIMP1‐XBP1 axis in B cells. These results suggest that OX40L is a promising therapeutic target for SLE. [ABSTRACT FROM AUTHOR]

Purpose: In contrast to adults, immune protection against SARS-CoV-2 in children and adolescents with natural or hybrid immunity is still poorly understood. The aim of this study was to analyze different immune compartments in different age groups and whether humoral immune reactions correlate with a cellular immune response. Methods: 72 children and adolescents with a preceding SARS-CoV-2 infection were recruited. 37 were vaccinated with an RNA vaccine (BNT162b2). Humoral immunity was analyzed 3–26 months (median 10 months) after infection by measuring Spike protein (S), nucleocapsid (NCP), and neutralizing antibodies (nAB). Cellular immunity was analyzed using a SARS-CoV-2-specific interferon-γ release assay (IGRA). Results: All children and adolescents had S antibodies; titers were higher in those with hybrid immunity (14,900 BAU/ml vs. 2118 BAU/ml). NCP antibodies were detectable in > 90%. Neutralizing antibodies (nAB) were more frequently detected (90%) with higher titers (1914 RLU) in adolescents with hybrid immunity than in children with natural immunity (62.5%, 476 RLU). Children with natural immunity were less likely to have reactive IGRAs (43.8%) than adolescents with hybrid immunity (85%). The amount of interferon-γ released by T cells was comparable in natural and hybrid immunity. Conclusion: Spike antibodies are the most reliable markers to monitor an immune reaction against SARS-CoV-2. High antibody titers of spike antibodies and nAB correlated with cellular immunity, a phenomenon found only in adolescents with hybrid immunity. Hybrid immunity is associated with markedly higher antibody titers and a higher probability of a cellular immune response than a natural immunity. [ABSTRACT FROM AUTHOR]

Under the dual pressure of emerging zoonoses and the difficulty in eliminating conventional zoonoses, the strategic management of bird diseases through vaccination represents a highly efficacious approach to disrupting the transmission of zoonotic pathogens to humans. Immunization with a DNA vaccine yielded limited protection against avian pathogen infection. To improve its immunogenicity, the extracellular domain of duck-derived CD40L (designated as dusCD40L) was employed as a bio-adjuvant. Our findings unequivocally established the evolutionary conservation of dusCD40L across avian species. Notably, dusCD40L exhibited a compelling capacity to elicit robust immune responses from both B and T lymphocytes. Furthermore, when employed as an adjuvant, dusCD40L demonstrated a remarkable capacity to significantly augment the titers of neutralizing antibodies and the production of IFNγ elicited by a DNA vaccine encoding the prM-E region of an avian flavivirus, namely, the Tembusu virus (TMUV). Moreover, dusCD40L could strengthen virus clearance of the prM-E DNA vaccine in ducks post-TMUV challenge. This research study presents a highly effective adjuvant for advancing the development of DNA vaccines targeting TMUV in avian hosts. Additionally, it underscores the pivotal role of duCD40L as a potent adjuvant in the context of vaccines designed to combat zoonotic infections in avian species. [ABSTRACT FROM AUTHOR]

The aim of the present research was to evaluate the probiotic activity of Lactobacillus acidophilus in broilers of the ARBOR ACRE strain. The probiotic was administered in drinking water at a rate of 50 ml per 1000 chicks every 7 days during the breeding period. Growth performance, the effect on endogenous flora and on the structure of the gut and the bursa of Fabricius, as well as the immune response, were recorded at 20 and 37 days. We evaluated the effectiveness of Lactobacillus acidophilus added to broiler diets, a zootechnical study (mortality, growth rate, index of growth) and a clinical survey, homogeneity and antibody production. Zootechnical studies revealed that the best growth performances were achieved by the probiotic-treated chickens, with significant differences (p<0.05). which concluded with a positive effect on zootechnical performance compared with the controls. Similarly, the study of the organism's reaction showed a good response from the birds supplemented with Lactobacillus acidophilus in the animal's digestive tract, with interactions with the endogenous flora, compared with the control subjects (P<0.05). Antibody titration showed that the Lactobacillus acidophilus-based diet had a positive effect on antibody levels, resulting in a coverage rate higher than the average indicated by the baseline (1000-2500) and also higher than the control batch antibodies. [ABSTRACT FROM AUTHOR]

Understanding SARS-CoV-2 vaccine-induced antibody responses in varied antigenic and serological prior exposures can guide optimal vaccination strategies for enhanced immunogenicity. We evaluated spike (S)-directed IgG, IgM, and IgA antibody optical densities (ODs) and concentrations to the two-dose ChAdOx1-S Oxford-AstraZeneca (ChAdOx1-S, Covishield) SARS-CoV-2 vaccine in 67 Ugandans, categorised by prior infection and baseline S-IgG histories: uninfected and S-IgG-negative (n = 12); previously infected yet S-IgG-negative (n = 17); and previously infected with S-IgG-positive status (n = 38). Antibody dynamics were compared across eight timepoints from baseline till nine months. S-IgG antibodies remained consistently potent across all groups. Individuals with prior infections maintained robust S-IgG levels, underscoring the endurance of hybrid immunity. In contrast, those without prior exposure experienced an initial surge in S-IgG after the primary dose but no subsequent significant increase post-boost. However, they reached levels parallel to the previously exposed groups. S-IgM levels remained moderate, while S-IgA persisted in individuals with prior antigen exposure. ChAdOx1-S, Covishield vaccine elicited robust and sustained antibody responses in recipients, irrespective of their initial immune profiles. Hybrid immunity showed higher responses, aligning with global observations. Early post-vaccination antibody levels could predict long-term immunity, particularly in individuals without virus exposure. These findings can inform vaccine strategies and pandemic management. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a systemic autoimmune disease driven by highly active autoantibody‐producing B cells. Activation of B cells is maintained within ectopic germinal centres found in affected joints. Fibroblast‐like synoviocytes (FLS) present in inflamed joints support B‐cell survival, activation, and differentiation. CD27+ memory B cells and naive B cells show very different responses to activation, particularly by CD40 ligand (CD40L). We show that FLS‐dependent activation of human B cells is dependent on interleukin‐6 (IL‐6) and CD40L. FLS have been shown to activate both naive and memory B cells. Whether the activating potential of FLS is different for naive and memory B cells has not been investigated. Our results suggest that FLS‐induced activation of B cells is dependent on IL‐6 and CD40L. While FLS are able to induce plasma cell differentiation, isotype switching, and antibody production in memory B cells, the ability of FLS to activate naive B cells is significantly lower. [ABSTRACT FROM AUTHOR]

The interference of direct‐acting antiviral agents (DAAs) within various steps of the life cycle of hepatitis C virus (HCV) results in a high cure rate for chronic HCV infection. To accurately quantify the effect of DAAs on treatment and to achieve an optimal drug combination for treatment, we formulate an age‐structured multiscale HCV model. This model incorporates intracellular virus RNA replication process corresponding to the mechanism of drug action, two modes of extracellular virus transmission (virus‐to‐cell infection and cell‐to‐cell infection), and antibody immune response. We prove that the threshold dynamics of the pre‐treatment model is completely determined by the basic reproduction number R0$$ {\mathcal{R}}_0 $$ and the antibody immune reproduction number RW$$ {\mathcal{R}}_W $$. Under reasonable assumptions, we obtain long‐term and short‐term approximations for post‐treatment viral loads and identify which approximation performs better under various scenarios. Numerical simulations show that the infection mode of cells mainly affects the reduction of viral load in the third stage, while the antibody immune response is mainly manifested in the clearance of viral particles in the first stage of viral load decrease. With effective treatments, blocking cell‐to‐cell infection and enhancing the antibody immune response can effectively reduce the viral load in a short time period achieving the eradication of infection. Our findings suggest that the HCV infection is highly dynamic post‐DAAs treatment, and early monitoring of viral load decline contributes to the implementation of subsequent treatment regimens. [ABSTRACT FROM AUTHOR]

• Immunogenicity data for single versus 2-dose JYNNEOS regimens were previously limited. • We evaluate OPXV-specific serologic responses in individuals without rash presenting for JYNNEOS mpox vaccination. • IgG antibody responses increased during the 41 days post vaccination followed by a decline by 180 days but continued to remain IgG seropositive. • Serologic response did not vary by age, sex, or HIV status, but did vary by vaccine administration route. We assessed early antibody responses after two doses of JYNNEOS (IMVANEX) mpox vaccine in the District of Columbia (D.C.) in persons at high risk for mpox without characteristic lesions or rash. Participants with PCR mpox negative specimens (oral swab, blood, and/or rectal swab) on the day of receipt of the first vaccine dose and who provided a baseline (day 0) serum sample and at least one serum sample at ∼28, ∼42–56 days, or 180 days post vaccination were included in this analysis. Orthopoxvirus (OPXV)-specific IgG and IgM ELISAs and neutralizing antibody titers were performed, and longitudinal serologic responses were examined. Based on participants' IgG and IgM antibody levels at baseline, they were categorized as naïve or non-naïve. Linear mixed effects regression models were conducted to determine if IgG antibody response over time varied by age, sex, HIV status, and route of administration for both naïve and non-naïve participants. Among both naïve and non-naïve participants IgG seropositivity rates increased until day 42–56, with 89.4 % of naïve and 92.1 % of non-naïve participants having detectable IgG antibodies. The proportion of naive participants with detectable IgG antibodies declined by day 180 (67.7 %) but remained high among non-naïve participants (94.4 %). Neutralizing antibody titers displayed a similar pattern, increasing initially post vaccination but declining by day 180 among naïve participants. There were no significant serologic response differences by age, sex, or HIV status. Serologic response did vary by route of vaccine administration, with those receiving a combination of intradermal and subcutaneous doses displaying significantly higher IgG values than those receiving both doses intradermally. These analyses provide initial insights into the immunogenicity of a two-dose JYNNEOS PEP regimen in individuals at high risk of mpox exposure in the United States. [ABSTRACT FROM AUTHOR]

The rates of nasopharyngeal meningococcal carriage in healthcare workers are unknown. Meningococcal vaccine is recommended for risk groups but healthcare workers are not included in risk groups for many countries. Herein, we aimed to investigate the nasopharyngeal meningococcal carriage rates, basal and after one dose of Men-ACWY-DT vaccine response on the 30th day by evaluating meningococcus IgG antibody levels and decolonization at month six after vaccination among the detected carriers. Nasopharyngeal swab samples were taken before vaccination to evaluate meningococcal carriage in healthcare workers. All participants received a single dose of Men-ACWY-DT vaccine. Serum samples were collected immediately before vaccination and again on day 30 post-vaccination. Antibodies in the stored sera were analyzed using the ELISA method. Participants who were determined to carry meningococci at the initial visit underwent another round of nasopharyngeal swab tests six months post-vaccination to check for decolonization. Between November 2020 and May 2021, we evaluated samples from 100 physicians [52 % females, 28.28 ± 4.45 (min: 24, max: 49)]. The majority of the physicians worked in the emergency department (45 %), followed by the infectious diseases clinic (14 %). Fifty-eight physicians had a history of at least one contact with a meningococcus-infected patient, and 53 (91.4 %) had used prophylactic antibiotics at least once due to this exposure. None of the study group nasopharyngeal swab cultures were positive for Neisseria meningitidis. Before the Men-ACWY-DT vaccine, anti-meningococcus IgG positivity was detected in the serum samples of only 3 (3 %) participants. By day 30 after vaccination, 48 % of participants showed positive for antibodies. As we didn't detect nasopharyngeal carriage in any participants, we didn't evaluate decolonization among carriers six months post-vaccination. Notably, detection of antibodies was evident in about half of the participants on day 30 after receiving a single dose of the Men-ACWY-DT vaccine. [ABSTRACT FROM AUTHOR]

• Homologous and heterologous Ad26.COV2.S boosters elicited neutralizing antibodies. • Responses were durable against SARS-CoV-2 reference strain and variants of concern. • Ad26 pre-existing immunity does not impact vaccine-elicited immune responses. COVID-19 vaccine boosters may optimize durability of protection against variants of concern (VOCs). In this randomized, double-blind, phase 2 trial, participants received 3 different dose levels of an Ad26.COV2.S booster (5 × 1010 vp [viral particles], 2.5 × 1010 vp, or 1 × 1010 vp) ≥6 months post–primary vaccination with either single-dose Ad26.COV2.S (homologous boost; n = 774) or 2-dose BNT162b2 (heterologous boost; n = 758). Primary endpoints were noninferiority of neutralizing antibody responses at Day 15 post-boost versus Day 29 post–primary vaccination. Secondary endpoints included reactogenicity/safety and neutralizing antibody responses to VOCs. All primary endpoints passed prespecified hierarchical noninferiority criteria by Day 15 post-boost. Geometric mean increases in neutralizing antibody titers against the D614G reference strain ranged from 5.5 to 6.8 at Day 15 for homologous boosting and 12.6 to 22.0 for heterologous boosting. For VOCs, heterologous boosting elicited higher neutralizing antibody responses than homologous boosting. Neutralizing antibody responses were dose-dependent and durable for ≥6 months post-boost. More solicited systemic adverse events occurred following heterologous versus homologous boosting. Trial Registration: ClinicalTrials.gov Identifier: NCT04999111. [ABSTRACT FROM AUTHOR]

Background: Elevated systemic antibody responses against gut microbiota flagellins are observed in both Crohn's disease (CD) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggesting potential serological biomarkers for diagnosis. However, flagellin-specific antibody repertoires and functional roles in the diseases remain incompletely understood. Bacterial flagellins can be categorized into three types depending on their interaction with toll-like receptor 5 (TLR5): (1) "stimulator" and (2) "silent" flagellins, which bind TLR5 through a conserved N-terminal motif, with only stimulators activating TLR5 (involving a C-terminal domain); (3) "evader" flagellins of pathogens, which entirely circumvent TLR5 activation via mutations in the N-terminal TLR5 binding motif. Results: Here, we show that both CD and ME/CFS patients exhibit elevated antibody responses against distinct regions of flagellins compared to healthy individuals. N-terminal binding to Lachnospiraceae flagellins was comparable in both diseases, while C-terminal binding was more prevalent in CD. N-terminal antibody-bound flagellin sequences were similar across CD and ME/CFS, resembling "stimulator" and "silent" flagellins more than evaders. However, C-terminal antibody-bound flagellins showed a higher resemblance to the stimulator than to silent flagellins in CD, which was not observed in ME/CFS. Conclusions: These findings suggest that antibody binding to the N-terminal domain of stimulator and silent flagellins may impact TLR5 activation in both CD and ME/CFS patients. Blocking this interaction could lead commensal bacteria to be recognized as pathogenic evaders, potentially contributing to dysregulation in both diseases. Furthermore, elevated antibody binding to the C-terminal domain of stimulator flagellins in CD may explain pathophysiological differences between the diseases. Overall, these results highlight the diagnostic potential of these antibody responses and lay a foundation for deeper mechanistic studies of flagellin/TLR5 interactions and their impact on innate/adaptive immunity balance. 3dk6-s1stA6fneys_e7fgX Video Abstract [ABSTRACT FROM AUTHOR]

Background: Trichothiodystrophy-1 (TTD1) is an autosomal-recessive disease and caused by mutations in ERCC2, a gene coding for a subunit of the TFIIH transcription and nucleotide-excision repair (NER) factor. In almost half of these patients infectious susceptibility has been reported but the underlying molecular mechanism leading to immunodeficiency is largely unknown. Objective: The aim of this study was to perform extended molecular and immunological phenotyping in patients suffering from TTD1. Methods: Cellular immune phenotype was investigated using multicolor flow cytometry. DNA repair efficiency was evaluated in UV-irradiation assays. Furthermore, early BCR activation events and proliferation of TTD1 lymphocytes following DNA damage induction was tested. In addition, we performed differential gene expression analysis in peripheral lymphocytes of TTD1 patients. Results: We investigated three unrelated TTD1 patients who presented with recurrent infections early in life of whom two harbored novel ERCC2 mutations and the third patient is a carrier of previously described pathogenic ERCC2 mutations. Hypogammaglobulinemia and decreased antibody responses following vaccination were found. TTD1 B-cells showed accumulation of g-H2AX levels, decreased proliferation activity and reduced cell viability following UV irradiation. mRNA sequencing analysis revealed significantly downregulated genes needed for B-cell development and activation. Analysis of B-cell subpopulations showed low numbers of naïve and transitional B-cells in TTD1 patients, indicating abnormal B-cell differentiation in vivo. Conclusion: In summary, our analyses confirmed the pathogenicity of novel ERCC2 mutations and show that ERCC2 deficiency is associated with antibody deficiency most likely due to altered B-cell differentiation resulting from impaired BCR-mediated B-cell activation and activation-induced gene transcription. [ABSTRACT FROM AUTHOR]

Antibody responses require the proliferative expansion of B cells controlled by affinity-dependent signals. Yet, proliferative bursts are heterogeneous, varying between 0 and 8 divisions in response to the same stimulus. NFκB cRel is activated in response to immune stimulation in B cells and is genetically required for proliferation. Here, we asked whether proliferative heterogeneity is controlled by natural variations in cRel abundance. We developed a fluorescent reporter mTFP1-cRel for the direct observation of cRel in live proliferating B cells. We found that cRel is heterogeneously distributed among naïve B cells, which are enriched for high expressors in a heavy-tailed distribution. We found that high cRel expressors show faster activation of the proliferative program, but do not sustain it well, with population expansion decaying earlier. With a mathematical model of the molecular network, we showed that cRel heterogeneity arises from balancing positive feedback by autoregulation and negative feedback by its inhibitor IKBG, confirmed by mouse knockouts. Using live-cell fluorescence microscopy, we showed that increased cRel primes B cells for early proliferation via higher basal expression of the cell cycle driver cMyc. However, peak cMyc induction amplitude is constrained by incoherent feedforward regulation, decoding the fold change of cRel activity to terminate the proliferative burst. This results in a complex nonlinear, nonmonotonic relationship between cRel expression and the extent of proliferation. These findings emphasize the importance of direct observational studies to complement gene knockout results and to learn about quantitative relationships between biological processes and their key regulators in the context of natural variations. [ABSTRACT FROM AUTHOR]

Summary Despite the near ubiquitous presence of Ig‐based antibodies in vertebrates, IgE is unique to mammals. How and why it emerged remains mysterious. IgE expression is greatly constrained compared to other IgH isotypes. While other IgH isotypes are relatively abundant, soluble IgE has a truncated half‐life, and IgE plasma cells are mostly short‐lived. Despite its rarity, IgE is consequential and can trigger life‐threatening anaphylaxis. IgE production reflects a dynamic steady state with IgG memory B cells feeding short‐lived IgE production. Emerging evidence suggests that IgE may also potentially be produced in longer‐lived plasma cells as well, perhaps as an aberrancy stemming from its evolutionary roots from an antibody isotype that likely functioned more like IgG. As a late derivative of an ancient systemic antibody system, the benefits of IgE in mammals likely stems from the antibody system's adaptive recognition and response capability. However, the tendency for massive, systemic, and long‐lived production, common to IgH isotypes like IgG, were likely not a good fit for IgE. The evolutionary derivation of IgE from an antibody system that for millions of years was good at antigen de‐sensitization to now functioning as a highly specialized antigen‐sensitization function required heavy restrictions on antibody production—insufficiency of which may contribute to allergic disease. [ABSTRACT FROM AUTHOR]