Coordinated expansion of memory T follicular helper and B cells mediates spontaneous clearance of HCV reinfection.

Introduction: Follicular helper T cells are essential for helping in the maturation of B cells and the production of neutralizing antibodies (NAbs) during primary viral infections. However, their role during recall responses is unclear. Here, we used hepatitis C virus (HCV) reinfection in humans as a model to study the recall collaborative interaction between circulating CD4 T follicular helper cells (cTfh) and memory B cells (MBCs) leading to the generation of NAbs. Methods: We evaluated this interaction longitudinally in subjects who have spontaneously resolved primary HCV infection during a subsequent reinfection episode that resulted in either another spontaneous resolution (SR/SR, n = 14) or chronic infection (SR/CI, n = 8). Results: Both groups exhibited virus-specific memory T cells that expanded upon reinfection. However, early expansion of activated cTfh (CD4+CXCR5+PD-1+ICOS+FoxP3-) occurred in SR/SR only. The frequency of activated cTfh negatively correlated with time post-infection. Concomitantly, NAbs and HCV-specific MBCs (CD19+CD27+IgM-E2-Tet+) peaked during the early acute phase in SR/SR but not in SR/CI. Finally, the frequency of the activated cTfh1 (CXCR3+CCR6-) subset correlated with the neutralization breadth and potency of NAbs. Conclusion: These results underscore a key role for early activation of cTfh1 cells in helping antigen-specific B cells to produce NAbs that mediate the clearance of HCV reinfection.

In Vivo Evolution of a Klebsiella pneumoniae Capsule Defect With wcaJ Mutation Promotes Complement-Mediated Opsonophagocytosis During Recurrent Infection.

BACKGROUND: Klebsiella pneumoniae carbapenemase-producing K pneumoniae (KPC-Kp) bloodstream infections are associated with high mortality. We studied clinical bloodstream KPC-Kp isolates to investigate mechanisms of resistance to complement, a key host defense against bloodstream infection. METHODS: We tested growth of KPC-Kp isolates in human serum. In serial isolates from a single patient, we performed whole genome sequencing and tested for complement resistance and binding by mixing study, direct enzyme-linked immunosorbent assay, flow cytometry, and electron microscopy. We utilized an isogenic deletion mutant in phagocytosis assays and an acute lung infection model. RESULTS: We found serum resistance in 16 of 59 (27%) KPC-Kp clinical bloodstream isolates. In 5 genetically related bloodstream isolates from a single patient, we noted a loss-of-function mutation in the capsule biosynthesis gene, wcaJ. Disruption of wcaJ was associated with decreased polysaccharide capsule, resistance to complement-mediated killing, and surprisingly, increased binding of complement proteins. Furthermore, an isogenic wcaJ deletion mutant exhibited increased opsonophagocytosis in vitro and impaired in vivo control in the lung after airspace macrophage depletion in mice. CONCLUSIONS: Loss of function in wcaJ led to increased complement resistance, complement binding, and opsonophagocytosis, which may promote KPC-Kp persistence by enabling coexistence of increased bloodstream fitness and reduced tissue virulence.

Long-lived central memory γδ T cells confer protection against murine cytomegalovirus reinfection.

The involvement of γδ TCR-bearing lymphocytes in immunological memory has gained increasing interest due to their functional duality between adaptive and innate immunity. γδ T effector memory (TEM) and central memory (TCM) subsets have been identified, but their respective roles in memory responses are poorly understood. In the present study, we used subsequent mouse cytomegalovirus (MCMV) infections of αß T cell deficient mice in order to analyze the memory potential of γδ T cells. As for CMV-specific αß T cells, MCMV induced the accumulation of cytolytic, KLRG1+CX3CR1+ γδ TEM that principally localized in infected organ vasculature. Typifying T cell memory, γδ T cell expansion in organs and blood was higher after secondary viral challenge than after primary infection. Viral control upon MCMV reinfection was prevented when masking γδ T-cell receptor, and was associated with a preferential amplification of private and unfocused TCR δ chain repertoire composed of a combination of clonotypes expanded post-primary infection and, more unexpectedly, of novel expanded clonotypes. Finally, long-term-primed γδ TCM cells, but not γδ TEM cells, protected T cell-deficient hosts against MCMV-induced death upon adoptive transfer, probably through their ability to survive and to generate TEM in the recipient host. This better survival potential of TCM cells was confirmed by a detailed scRNASeq analysis of the two γδ T cell memory subsets which also revealed their similarity to classically adaptive αß CD8 T cells. Overall, our study uncovered memory properties of long-lived TCM γδ T cells that confer protection in a chronic infection, highlighting the interest of this T cell subset in vaccination approaches.

Specific immunological characteristics and risk factor of XBB variants re-infection in nasopharyngeal carcinoma patients after BA.5 infection.

OBJECTIVES: The specific humoral immune response resulting from inactivated vaccination following by BA.5 infection, and predictors of XBB variants re-infection in BA.5 infection-recovered nasopharyngeal carcinoma (BA.5-RNPC) patients, were explored. METHODS: Serum SARS-CoV-2 specific antibody levels were assessed using enzyme-linked-immunosorbent-assay. Univariate and multivariate binary logistic regression analyses were conducted to identify factors associated with the magnitude of specific humoral immunity and susceptibility to re-infection by XBB variants. RESULTS: Our data demonstrates that SARS-CoV-2 specific antibody levels were comparable between BA.5-RNPC patients and BA.5 infection-recovered-non-cancerous (BA.5-RNC) individuals. Specifically, serum levels of anti-ancestral-S1-IgG, anti-ancestral-nucleocapsid-protein (NP)-IgG, anti-BA.5-receptor binding domain (RBD)-IgG and anti-XBB.1.1.6-RBD-IgG were higher in BA.5-RNPC patients compared to those without a prior infection. Compared to BA.5-RNPC patients without vaccination, individuals who received inactivated vaccination exhibited significantly higher levels of anti-ancestral-S1-IgG and anti-XBB.1.16-RBD-IgG. Multivariate logistic regression analysis revealed that inactivated vaccination was the most significant predictor of all tested SARS-CoV-2 specific antibodies response. Subsequent analysis indicated that a low globulin level is an independent risk factor for XBB re-infection in BA.5-RNPC patients. CONCLUSIONS: The SARS-CoV-2 specific antibodies have been improved in vaccinated BA.5-RNPC patients. However, the baseline immunity status biomarker IgG is an indicators of XBB variant re-infection risk in BA.5-RNPC patients.

The serological IgG and neutralizing antibody of SARS-CoV-2 omicron variant reinfection in Jiangsu Province, China.

Background: It is important to figure out the immunity of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) reinfection to understand the response of humans to viruses. A serological survey for previously infected populations in Jiangsu Province was conducted to compare the antibody level of SARS-CoV-2 in reinfection by Omicron or not. Methods: Reinfection with SARS-CoV-2 was defined as an individual being infected again after 90 days of the initial infection. Telephone surveys and face-to-face interviews were implemented to collect information. Experimental and control serum samples were collected from age-sex-matched reinfected and non-reinfected cases, respectively. IgG anti-S and neutralizing antibodies (Nab) concentrations were detected by the Magnetism Particulate Immunochemistry Luminescence Method (MCLIA). Antibody titers were log(2)-transformed and analyzed by a two-tailed Mann-Whitney U test. Subgroup analysis was conducted to explore the relationship between the strain type of primary infection, SARS-Cov-2 vaccination status, and antibody levels. Multivariate linear regression models were used to identify associations between reinfection with IgG and Nab levels. Results: Six hundred thirty-one individuals were enrolled in this study, including 327 reinfected cases and 304 non-reinfected cases. The reinfection group had higher IgG (5.65 AU/mL vs. 5.22 AU/mL) and Nab (8.02 AU/mL vs. 7.25 AU/mL) levels compared to the non-reinfection group (p < 0.001). Particularly, individuals who had received SARS-CoV-2 vaccination or were initially infected with the Wild type and Delta variant showed a significant increase in antibody levels after reinfection. After adjusting demographic variables, vaccination status and the type of primary infection together, IgG and Nab levels in the reinfected group increased by log(2)-transformed 0.71 and 0.64 units, respectively (p < 0.001). This revealed that reinfection is an important factor that affects IgG and Nab levels in the population. Conclusion: Reinfection with Omicron in individuals previously infected with SARS-CoV-2 enhances IgG and Nab immune responses.

Vaccine Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection by Type and Frequency of Vaccine: A Community-Based Case-Control Study.

BACKGROUND: Although guidelines recommend vaccination for individuals who have recovered from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to prevent reinfection, comprehensive evaluation studies are limited. We aimed to evaluate vaccine effectiveness against SARS-CoV-2 reinfection according to the primary vaccination status, booster vaccination status, and vaccination methods used. METHODS: This population-based case-control study enrolled all SARS-CoV-2-infected patients in Seoul between January 2020 and February 2022. Individuals were categorized into case (reinfection) and control (no reinfection) groups. Data were analyzed using conditional logistic regression after adjusting for underlying comorbidities using multiple regression. RESULTS: The case group included 7,678 participants (average age: 32.26 years). In all vaccinated individuals, patients who received the first and second booster doses showed reduced reinfection rates compared with individuals who received basic vaccination (odds ratio [OR] = 0.605, P < 0.001 and OR = 0.002, P < 0.001). Patients who received BNT162b2 or mRNA-1273, NVX-CoV2373 and heterologous vaccination showed reduced reinfection rates compared with unvaccinated individuals (OR = 0.546, P < 0.001; OR = 0.356, P < 0.001; and OR = 0.472, P < 0.001). However, the ChAdOx1-S or Ad26.COV2.S vaccination group showed a higher reinfection rate than the BNT162b2 or mRNA-1273 vaccination group (OR = 4.419, P < 0.001). CONCLUSION: In SARS-CoV-2-infected individuals, completion of the basic vaccination series showed significant protection against reinfection compared with no vaccination. If the first or second booster vaccination was received, the protective effect against reinfection was higher than that of basic vaccination; when vaccinated with BNT162b2 or mRNA-1273 only or heterologous vaccination, the protective effect was higher than that of ChAdOx1-S or Ad26.COV2.S vaccination only.

A longitudinal study on SARS-CoV-2 seroconversion, reinfection and neutralisation spanning several variant waves and vaccination campaigns, Heinsberg, Germany, April 2020 to November 2022.

BackgroundSince its emergence in December 2019, over 700 million people worldwide have been infected with SARS-CoV-2 up to May 2024. While early rollout of mRNA vaccines against COVID-19 has saved many lives, there was increasing immune escape of new virus variants. Longitudinal monitoring of population-wide SARS-CoV-2 antibody responses from regular sample collection irrespective of symptoms provides representative data on infection and seroconversion/seroreversion rates.AimTo examine adaptive and cellular immune responses of a German SARS-CoV-2 outbreak cohort through several waves of infection with different virus variants.MethodsUtilising a 31-month longitudinal seroepidemiological study (n = 1,446; mean age: 50 years, range: 2-103) initiated during the first SARS-CoV-2 superspreading event (February 2020) in Heinsberg, Germany, we analysed acute infection, seroconversion and virus neutralisation at five follow-up visits between October 2020 and November 2022; cellular and cross-protective immunity against SARS-CoV-2 Omicron variants were also examined.ResultsSARS-CoV-2 spike (S)-specific IgAs decreased shortly after infection, while IgGs remained stable. Both increased significantly after vaccination. We predict an 18-month half-life of S IgGs upon infection. Nucleocapsid (N)-specific responses declined over 12 months post-infection but increased (p < 0.0001) during Omicron. Frequencies of SARS-CoV-2-specific TNF-alpha+/IFN-gamma+ CD4+ T-cells declined over 12 months after infection (p < 0.01). SARS-CoV-2 S antibodies and neutralisation titres were highest in triple-vaccinated participants infected between April 2021 and November 2022 compared with infections between April 2020 and January 2021. Cross neutralisation against Omicron BQ.1.18 and XBB.1.5 was very low in all groups.ConclusionInfection and/or vaccination did not provide the population with cross-protection against Omicron variants.

CD4+ T cells display a spectrum of recall dynamics during re-infection with malaria parasites.

Children in malaria-endemic regions can experience repeated Plasmodium infections over short periods of time. Effects of re-infection on multiple co-existing CD4+ T cell subsets remain unresolved. Here, we examine antigen-experienced CD4+ T cells during re-infection in mice, using scRNA-seq/TCR-seq and spatial transcriptomics. TCR transgenic TEM cells initiate rapid Th1/Tr1 recall responses prior to proliferating, while GC Tfh counterparts are refractory, with TCM/Tfh-like cells exhibiting modest non-proliferative responses. Th1-recall is a partial facsimile of primary Th1-responses, with no upregulated effector-associated genes being unique to recall. Polyclonal, TCR-diverse, CD4+ T cells exhibit similar recall dynamics, with individual clones giving rise to multiple effectors including highly proliferative Th1/Tr1 cells, as well as GC Tfh and Tfh-like cells lacking proliferative capacity. Thus, we show substantial diversity in recall responses mounted by multiple co-existing CD4+ T cell subsets in the spleen, and present graphical user interfaces for studying gene expression dynamics and clonal relationships during re-infection.

Primary infection enhances neutrophil-mediated host defense by educating HSPCs.

Hematopoietic stem and progenitor cells (HSPCs) can give rise to all kinds of immune cells including neutrophils. Neutrophils are the first line of defense in the innate immune system with a short lifespan, due to which it is well-accepted that neutrophils have no immune memory. However, recent reports showed that the changes in HSPCs induced by primary stimulation could last a long time, which contributes to enhancing response to subsequent infection by generating more monocytes or macrophages equipped with stronger anti-bacterial function. Here, we used the reinfection mice model to reveal that primary infection could improve neutrophil-mediated host defense by training neutrophil progenitors in mammals, providing a new idea to enhance neutrophil number and improve neutrophil functions, which is pretty pivotal for patients with compromised or disordered immunity.

Immune responses and reinfection of SARS-CoV-2 Omicron variant in patients with lung cancer.

A significant Omicron wave emerged in China in December 2022. To explore the duration of humoral and cellular response postinfection and the efficacy of hybrid immunity in preventing Omicron reinfection in patients with lung cancer, a total of 447 patients were included in the longitudinal study after the Omicron wave from March 2023 to August 2023. Humoral responses were measured at pre-Omicron wave, 3 months and 7 months postinfection. The detected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specific antibodies including total antibodies, anti-receptor binding domain (RBD) specific IgG, and neutralizing antibodies against SARS-CoV-2 wild type (WT) and BA.4/5 variant. T cell responses against SARS-CoV-2 WT and Omicron variant were evaluated in 101 patients by ELISpot at 3 months postinfection. The results showed that Omicron-infected symptoms were mild, while fatigue (30.2%), shortness of breath (34.0%) and persistent cough (23.6%) were long-lasting, and vaccines showed efficacy against fever in lung cancer patients. Humoral responses were higher in full or booster vaccinated patients than those unvaccinated (p < .05 for all four antibodies), and the enhanced response persisted for at least 7 months. T cell response to Omicron was higher than WT peptides (21.3 vs. 16.0 SFUs/106 PBMCs, p = .0093). Moreover, 38 (9.74%) patients were reinfected, which had lower antibody responses than non-reinfected patients (all p < .05), and those patients of unvaccinated at late stage receiving anti-cancer immunotherapy alone were at high risk of reinfection. Collectively, these data demonstrate the Omicron infection induces a high and durable immune response in vaccinated patients with lung cancer, which protects vaccinated patients from reinfection.

Dynamics of SARS-CoV-2 antibodies after natural infection: insights from a study on Pasteur Institute of Tunis employees.

This study aimed to assess the kinetics of antibodies against the SARS-CoV-2, following natural infection in a cohort of employees of the Institut Pasteur de Tunis (IPT) and to assess the risk of reinfection over a 12-months follow-up period. A prospective study was conducted among an open cohort of IPT employees with confirmed SARS-CoV-2 infection that were recruited between September 2020 and March 2021. Sera samples were taken at 1, 3, 6, 9 and 12 months after confirmation of COVID-19 infection and tested for SARS-CoV-2-specific immunoglobulin G (IgG) antibodies to the spike (S-RBD) protein (IgG anti-S-RBD) and for neutralizing antibodies. Participants who had an initial decline of IgG anti-S-RBD and neutralizing antibodies followed by a subsequent rise in antibody titers as well as those who tested positive for SARS-CoV-2 by RT-PCR after at least 60 days of follow up were considered as reinfected. In total, 137 individuals were included with a mean age of 44.7 ± 12.3 years and a sex-ratio (Male/Female) of 0.33. Nearly all participants (92.7%) were symptomatic, and 2.2% required hospitalization. Among the 70 participants with three or more prospective blood samples, 32.8% were reinfected among whom 11 (47.8%) reported COVID-19 like symptoms. Up to 12 months of follow up, 100% and 42.9% of participants had detectable IgG anti-S-RBD and neutralizing antibodies, respectively. This study showed that humoral immune response following COVID-19 infection may persist up to 12 months after infection despite the potential risk for reinfection that is mainly explained by the emergence of new variants.

Initial COVID-19 severity influenced by SARS-CoV-2-specific T cells imprints T-cell memory and inversely affects reinfection.

The immunoprotective components control COVID-19 disease severity, as well as long-term adaptive immunity maintenance and subsequent reinfection risk discrepancies across initial COVID-19 severity, remain unclarified. Here, we longitudinally analyzed SARS-CoV-2-specific immune effectors during the acute infection and convalescent phases of 165 patients with COVID-19 categorized by severity. We found that early and robust SARS-CoV-2-specific CD4+ and CD8+ T cell responses ameliorate disease progression and shortened hospital stay, while delayed and attenuated virus-specific CD8+ T cell responses are prominent severe COVID-19 features. Delayed antiviral antibody generation rather than titer level associates with severe outcomes. Conversely, initial COVID-19 severity imprints the long-term maintenance of SARS-CoV-2-specific adaptive immunity, demonstrating that severe convalescents exhibited more sustained virus-specific antibodies and memory T cell responses compared to mild/moderate counterparts. Moreover, initial COVID-19 severity inversely correlates with SARS-CoV-2 reinfection risk. Overall, our study unravels the complicated interaction between temporal characteristics of virus-specific T cell responses and COVID-19 severity to guide future SARS-CoV-2 wave management.

Heterogeneous SARS-CoV-2 kinetics due to variable timing and intensity of immune responses.

The viral kinetics of documented SARS-CoV-2 infections exhibit a high degree of interindividual variability. We identified 6 distinct viral shedding patterns, which differed according to peak viral load, duration, expansion rate, and clearance rate, by clustering data from 768 infections in the National Basketball Association cohort. Omicron variant infections in previously vaccinated individuals generally led to lower cumulative shedding levels of SARS-CoV-2 than other scenarios. We then developed a mechanistic mathematical model that recapitulated 1,510 observed viral trajectories, including viral rebound and cases of reinfection. Lower peak viral loads were explained by a more rapid and sustained transition of susceptible cells to a refractory state during infection as well as by an earlier and more potent late, cytolytic immune response. Our results suggest that viral elimination occurs more rapidly during Omicron infection, following vaccination, and following reinfection due to enhanced innate and acquired immune responses. Because viral load has been linked with COVID-19 severity and transmission risk, our model provides a framework for understanding the wide range of observed SARS-CoV-2 infection outcomes.

Long-term monitoring of SARS-CoV-2 seroprevalence and variants in Ethiopia provides prediction for immunity and cross-immunity.

Under-reporting of COVID-19 and the limited information about circulating SARS-CoV-2 variants remain major challenges for many African countries. We analyzed SARS-CoV-2 infection dynamics in Addis Ababa and Jimma, Ethiopia, focusing on reinfection, immunity, and vaccination effects. We conducted an antibody serology study spanning August 2020 to July 2022 with five rounds of data collection across a population of 4723, sequenced PCR-test positive samples, used available test positivity rates, and constructed two mathematical models integrating this data. A multivariant model explores variant dynamics identifying wildtype, alpha, delta, and omicron BA.4/5 as key variants in the study population, and cross-immunity between variants, revealing risk reductions between 24% and 69%. An antibody-level model predicts slow decay leading to sustained high antibody levels. Retrospectively, increased early vaccination might have substantially reduced infections during the delta and omicron waves in the considered group of individuals, though further vaccination now seems less impactful.

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

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

Patient and Immunological Factors Associated With Delayed Clearance of Mucosal Severe Acute Respiratory Syndrome Coronavirus 2 RNA and Symptom Persistence.

Serial blood and mucosal samples were characterized for 102 participants enrolled a median of 7.0 days after coronavirus disease 2019 diagnosis. Mucosal RNA was detectable for a median of 31.5 (95% confidence interval [CI], 20.5-63.5) days, with persistence ≥1 month associated with obesity (body mass index [BMI] ≥30 kg/m2; odds ratio [OR], 3.9 [95% CI, 1.2-13.8]) but not age, sex, or chronic conditions. Fifteen participants had likely reinfection; lower serum anti-spike IgG levels were associated with reinfection risk. Nearly half of participants (47%) reported symptoms lasting ≥2-3 months; persistence ≥3 months was associated with BMI ≥30 kg/m2 (OR, 4.2 [95% CI, 1.1-12.8]) and peak anti-spike and anti-nucleocapsid antibody levels.

Risk of herpes zoster according to past history in the general population: The Japanese Shozu herpes zoster study.

Immunity is known to persist after vaccination for varicella zoster virus, but the duration of immunity in patients who develop herpes zoster (HZ) remains unknown. To investigate the association between a past history of HZ and its occurrence in the general population. The Shozu HZ (SHEZ) cohort study included data for 12 299 individuals aged ≥50 years with information on their HZ history. Cross-sectional and 3-year follow-up studies were carried out to analyze the associations between a history of HZ (yes <10 years, yes ≥10 years, no) and the proportion of positive varicella zoster virus skin test results (erythema diameter ≥5 mm) and the risk of HZ after adjusting for potential confounding factors including age, sex, body mass index, smoking status, sleep duration, and mental stress. The incidences of positive skin test results were 87.7% (470/536) for individuals with a history of HZ <10 years ago, 82.2% (396/482) for those with a history of HZ ≥10 years, and 80.2% (3614/4509) for those with no history of HZ. The multivariable odds ratios (95% confidence intervals) of erythema diameter ≥5 mm were 2.07 (1.57-2.73) and 1. 39 (1.08-1.80) for individuals with a history <10 years and ≥10 years ago, respectively, compared with no history. The corresponding multivariable hazard ratios of HZ were 0.54 (0.34-0.85) and 1.16 (0.83-1.61), respectively. A past history of HZ <10 years ago may reduce the occurrence of HZ.

Asymptomatic COVID-19 Reinfection in a Pediatric Patient with Heterotaxy Syndrome.

We report an asymptomatic child with heterotaxy syndrome who had recurrent positive SARS-CoV-2 polymerase chain reaction testing. An aberrant lymphocyte population expressing CD19, CD16, and CD56 was identified; its phenotyping revealing atypical NK cells. This subset's role in protection from severe disease or in reinfection cannot be ascertained.