This study examined the durability of humoral and cell-mediated immune responses to COVID-19 mRNA vaccines over six months, focusing on age-related changes.

SARS-CoV-2 uninfected Japanese subjects aged 20-99 who received two doses of mRNA COVID-19 vaccine were recruited. SARS-CoV-2 Spike IgG antibody (IgG) level in the serum and the levels of interferon (IFN)-γ in blood stimulated with SARS-CoV-2 specific antigens by QuantiFERON (QFN) SARS-CoV-2 assay were measured.

The IgG levels of 138 subjects declined significantly with age and time post-vaccination (p < 0.001). For participants aged 70 and above (n = 80), the IFN-γ levels, an indicator of cell-mediated immunity, also significantly declined over time (p < 0.05). However, in those under 70 (n = 58), the IFN-γ levels were maintained at three- and six months post-vaccination. There was no significant difference in IFN-γ levels between three- and six months post-vaccination for all 138 subjects, including CD4+ and CD8+ T cell counts. No correlation was observed between IgG antibody levels and secreted IFN-γ values. Multivariate regression analysis revealed a significant correlation between IgG levels and age. In contrast, IFN-γ levels were associated with CD4+ T cell counts, CD8+ T cell counts, and Performance Status Scores but not with age.

The findings suggest that while humoral immunity (IgG levels) decreases with age and time, cell-mediated immunity (IFN-γ levels) is relatively preserved in individuals under 70 up to six months post-vaccination. However, this immune response is significantly attenuated in older adults aged 70 and above, indicating age-related immunosenescence in long-term immunity following COVID-19 vaccination.

To evaluate the immune persistence and cross-immune response of elderly individuals after Omicron BA.5 infections.

The neutralizing antibodies against WT, BA.5, XBB.1 and EG.5 strains were analyzed. The T/B-cell subsets' responses were tested through intracellular cytokine staining and flow cytometry.

The neutralizing antibodies titers against WT and BA.5 strain, remaining high level for at least 6 months, were higher than that of both XBB.1 and EG.5 variants. The neutralizing antibodies of WT, BA.5, XBB.1, and EG.5 strains in the elderly were slightly lower than those in middle-age. The memory B cells decreased rapidly in the elderly, and Tfh, Th17 cells of the elderly continued to increase for only 3 months, while Tfh and Th17 cells increased in the middle-aged for over 6 months. For the elderly, after peptide stimulation, unswitched/switched memory B cells decreased, while double negative B cells displayed higher proliferation. The proportions of both naïve and Temra cells in CD4+ and CD8+ T cells declined, whereas those of Tcm and Tem cells elevated. In the meantime, both CD69+ and CD38+ T cells decreased, but the frequencies of PD-1+ and CTLA-4+ of CD4+ and CD8+ T cells showed an increasing trend. The proportions of PD-1+ and CTLA-4+ cells also increased in older people with long COVID symptoms at 3m post-infection.

Omicron BA.5 infection induced lower neutralizing antibodies against XBB.1 and EG.5 variant. The decrease of memory B cells, CD69+ and CD38+T cells, as well as the increase of PD-1+, CTLA-4+ of CD4+/CD8+T cells and double negative B cells, indicate that sustained immune responses against BA.5 infection may wane more rapidly in elderly populations.

Inducing T cell responses by vaccines among elderly has been a long-standing challenge. There is a need for effective COVID-19 vaccines to boost waning immunity against emerging SARS-CoV-2 variants, especially for the elderly. This study investigated the safety and immunogenicity of a PD-1-enhanced COVID-19 DNA vaccine (ICCOV™), as a booster vaccine in healthy adults (aged 18-59 years) and elderly (aged 60-75 years).

This open-label, non-randomised Phase 2 study enrolled healthy participants aged 18-75 years who had previously been vaccinated with Sinovac CoronaVac, Pfizer-bioNTech Comirnaty vaccines, or both. Participants were stratified into four cohorts according to age, primary vaccination, and COVID-19 infection history, namely Adult-CoronaVac, Adult-Comirnaty, Adult-Mixed, and Elderly-Mixed cohorts. Participants were administered with a single dose of 2 mg ICCOV intramuscularly followed by electroporation using the proprietary TERESA-EPT-I device. Participants were followed up for 60 days. The primary endpoint was T cell immunogenicity within 28 days post-ICCOV vaccination. The secondary endpoints were safety, T cell and antibody responses within 60 days post-vaccination (ClinicalTrials.govNCT05904054).

The study was conducted at Gleneagles Hospital Hong Kong between 30 June and 30 November 2023. In total, 31 participants were enrolled across the Adult-Comirnaty (n = 4), Adult-Mixed (n = 15), and Elderly-Mixed (n = 12) cohorts. All enrolled participants completed the study and were included in safety and immunogenicity analyses. Among these participants, 2 from the Adult-Comirnaty cohort, 9 from the Adult-Mixed cohort, and 4 from the Elderly-Mixed cohort reported a total of 31 adverse events, all in grade 1-2. Pain at the administration site was the most frequently reported (38·7%). The proportion of participants demonstrating an increase of SARS-CoV-2-specific ELISpot T cell responses within 28 days post ICCOV vaccination was 100% (4/4), 80% (12/15), and 75% (9/12) in Adult-Comirnaty, Adult-Mixed, and Elderly-Mixed cohorts, respectively. Single ICCOV vaccination elicited SARS-CoV-2-specific, polyfunctional CD8+ and CD4+ T cells against both ancestral and Omicron strains in all cohorts. The magnitude of responses was not inferior in the elderly, compared to adults. No elevation of antibody responses was detected.

Single PD-1-enhanced ICCOV booster DNA vaccination did not show major safety concerns. The ICCOV booster elicited cross-reactive T cell responses to multiple SARS-CoV-2 strains, including in the elderly. This report demonstrates the T-cell boosting immunogenicity of ICCOV in the susceptible elderly population.

Clinical Translational Catalyst, Hong Kong Science & Technology Parks Corporation.

Susceptibility to life-threatening influenza increases with age, partly due to declining immunity. Frequency, phenotype and T-cell receptor (TCR) composition of influenza-specific CD8+ T-cells directed at the prominent A2/M158 influenza epitope change across the human lifespan.

We investigated longevity and mechanisms underlying age-related changes in influenza-specific TCR repertoires by performing longitudinal analyses in young and older adults across 7-12 years within A2/M158+CD8+ T-cells using peptide-HLA tetramers directly ex vivo. Paired TCRαβ-chains were used to track clonotypes over time within individuals.

Expanded public and private TCR clonotypes were long-lived but gradually declined over time. Loss of public clonotypes was initially compensated by expansions of clonotypes expressing public-associated features. Once these public-associated TCR clonotypes were abated in older adults, the void was filled by expansions of less similar private TCR clonotypes. Expanded older private TCR clonotypes also declined over time and were gradually replaced by other private TCR clonotypes with low similarity to public TCR clonotypes detected in adults.

Despite our relatively small cohort, we provided conclusive evidence that CD8+ T-cells to a single HLA-A2-restricted influenza-epitope are long-lived. However, dynamic changes occur at the clonotypic level, which eventually result in loss of public clonotypes, indicating that T-cell-based influenza vaccines are likely more effective in adults than older adults.

This research was supported by the National Health and Medical Research Council (#1173871, #1159272), the Australian Research Council (#190102704), European Union's Horizon 2020 (#792532), the University of Melbourne. Funders had no role in design, analysis or reporting of the study.

Aging-associated vulnerability to coronavirus disease 2019 (COVID-19) remains poorly understood. Here, we show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected aged mice lacking SIRT2, a cytosolic NAD+-dependent deacetylase, develop more severe disease and show increased mortality, while treatment with an NAD+ booster, 78c, protects aged mice from lethal infection. Mechanistically, we demonstrate that SIRT2 modulates the acetylation of cyclic GMP-AMP synthase (cGAS), an immune sensor for cytosolic DNA, and suppresses aging-associated cGAS activation and inflammation. Furthermore, we show that SARS-CoV-2 infection-induced inflammation is mediated at least in part by ORF3a, which triggers mtDNA release and cGAS activation. Collectively, our study reveals a molecular basis for aging-associated susceptibility to COVID-19 and suggests therapeutic approaches to protect aged populations from severe SARS-CoV-2 infection.

Despite the efficacy of SARS-CoV-2 vaccines in reducing mortality and severe cases of COVID-19, a proportion of survivors experience long-term symptoms, known as post-acute sequelae of SARS-CoV-2 infection (PASC). This study investigates the long-term immunological and neurodegenerative effects associated with extracellular vesicles (EVs) in COVID-19 survivors, 15 months after SARS-CoV-2 infection.

13 Controls and 20 COVID-19 survivors, 15 months after SARS-CoV-2 infection, were recruited. Pro-inflammatory cytokines were analyzed in both plasma and EVs. A deep-immunophenotyping of monocytes, T-cells and dendritic cells (DCs) was performed, along with immunostainings of SARS-CoV-2 in the colon.

Higher concentrations of pro-inflammatory cytokines and neurofilaments were found in EVs but not in plasma from COVID-19 survivors. Additionally, COVID-19 participants exhibited altered monocyte activation markers and elevated cytokine production upon lipopolysaccharide stimulation. Increased activation markers in CD4+ T-cells and decreased indoleamine 2,3-dioxygenase expression in DCs were observed in COVID-19 participants. Furthermore, the amount of plasmacytoid DCs expressing β7-integrin were higher in COVID-19, potentially associated with the viral persistence observed in the colon.

COVID-19 survivors exhibit long-term immune dysregulation and neurodegeneration, emphasizing the need for ongoing monitoring of PASC. The cargo of EVs can be a promising tool for early detection of virus-induced neurological disorders.

Ageing-associated remodeling of the murine B cell system is accompanied with a reduction of CD19+ B cells such as follicular B cells (FOB) and an accumulation of age-associated B cells (ABC) or activated B cell subsets. This remodeling is thought to confer an attenuated antibody response, such as to SARS-CoV-2 spike (S) vaccines in both aged mice and humans. To gain insight into the de novo development and function of an old B cell system, we reconstituted young and old immune systems by transferring hematopoietic stem cells (HSCs) from immune-competent young (2-3 months) CD45.1+ donors (DY-HSC) or old (20-24 months) donors (DO-HSC) into T and B cell-deficient young recipient CD45.2+ RAG1-/- mice, followed by protein-based vaccination.

In the same environment of young RAG1-/- mice, transplanted DO-HSCs compared to DY-HSCs reconstituted lower numbers of CD19+ B cells and CD45.1+ cells, though the engraftment of donor-derived HSCs in the young bone marrow (BM) was very similar. Furthermore, indicative for youthful and unchallenged B cell systems, and in contrast to aged mice, very low levels of antigen-experienced memory B cells or age-associated B cells (ABC) developed in both DY-HSC and DO-HSC hosts. The commercially available recombinant SARS-CoV-2 S vaccine (NVX-CoV2373) induced lower IgG+ S-antibody titers and pseudovirus neutralization activity in old compared to young mice. In contrast, very similar high IgG+ S-antibody titers were induced in DO-HSC and DY-HSC hosts, and pseudovirus neutralization activity was even enhanced in DO-HSC compared with DY-HSC hosts.

Both DO-HSCs and DY-HSCs established in the young recipient BM to a similar extend, suggesting that the concomitant reduction in the de novo reconstitution of CD19+ B cells in DO-HSC vs. DY-HSC transplanted animals is specifically related to old HSCs. DO-HSCs and DY-HSCs reconstitute very similar unchallenged B cell systems that efficiently elicit antigen-specific IgG antibodies by protein-based vaccination. Old HSCs thus retain competence to reconstitute a youthful and functional B cell system, at least in the young environment of transplanted RAG1-/- mice. This suggests that it is primarily age-related factors, and not HSCs per se, that influence the composition and functionality of the old B cell system.

Elderly adults are at higher risk for severe COVID-19 infection. This multicenter, prospective cohort study assessed immunogenicity after COVID-19 vaccinations in elderly residents compared with staff in geriatric intermediate care facilities. Predictors of lower antibody titers were also examined.

Fifty-four residents and 117 staff who had received three doses of the COVID-19 mRNA vaccine between March 2021 and September 2022 were included. Anti-receptor binding domain antibody titers were measured 3-4 weeks and 6 months after the vaccinations. Adjusted geometric mean titers (GMT) were calculated using multivariable linear mixed effects models.

After the first dose, residents had a significantly lower adjusted GMT than did staff (115 vs. 267 AU/mL, P < 0.01), whereas the adjusted GMT of residents was comparable to that of staff after the third dose (14 178 vs. 12 159 AU/mL, P = 0.63). However, 6 months later, the adjusted GMT of residents was less than half that of staff (1645 vs. 4302 AU/mL, P < 0.01). In residents, steroid users had a significantly lower adjusted GMT than did steroid nonusers.

The third dose of mRNA vaccine boosted the immune response of elderly residents. However, their antibody titers, particularly in steroid users, were highly attenuated 6 months after the last vaccination. For this population, attention should be focused on additional vaccinations. Geriatr Gerontol Int 2025; 25: 588-597.

The immune system, critical for human health and implicated in many diseases, defends against pathogens, monitors physiological stress, and maintains tissue and organismal homeostasis. It exhibits substantial variability both within and across individuals and populations. Recent technological and conceptual progress in systems human immunology has provided predictive insights that link personal immune states to intervention responses and disease susceptibilities. Artificial intelligence (AI), particularly machine learning (ML), has emerged as a powerful tool for analyzing complex immune data sets, revealing hidden patterns across biological scales, and enabling predictive models for individualistic immune responses and potentially personalized interventions. This review highlights recent advances in deciphering human immune variation and predicting outcomes, particularly through the concepts of immune setpoint, immune health, and use of the immune system as a window for measuring health. We also provide a brief history of AI; review ML modeling approaches, including their applications in systems human immunology; and explore the potential of AI to develop predictive models and personal immune state embeddings to detect early signs of disease, forecast responses to interventions, and guide personalized health strategies.

Vaccination against COVID-19 has been pivotal in reducing the global burden of the disease. However, Phase III trial results and observational studies underscore differences in efficacy across vaccine technologies and dosing regimens. Notably, mRNA vaccines have exhibited superior effectiveness compared to Adenovirus (AdV) vaccines, especially with extended dosing intervals.

Using in-host mechanistic modelling, this study elucidates these variations and unravels the biological mechanisms shaping the immune responses at the cellular level. We used data on the change in memory B cells, plasmablasts, and antibody titres after the second dose of a COVID-19 vaccine for Australian healthcare workers. Alongside this dataset, we constructed a kinetic model of humoral immunity which jointly captured the dynamics of multiple immune markers, and integrated hierarchical effects into this kinetics model, including age, dosing schedule, and vaccine type.

Our analysis estimated that mRNA vaccines induced 2.1 times higher memory B cell proliferation than AdV vaccines after adjusting for age, interval between doses and priming dose. Additionally, extending the duration between the second vaccine dose and priming dose beyond 28 days boosted neutralising antibody production per plasmablast concentration by 30%. We also found that antibody responses after the second dose were more persistent when mRNA vaccines were used over AdV vaccines and for longer dosing regimens.

Reconstructing in-host kinetics in response to vaccination could help optimise vaccine dosing regimens, improve vaccine efficacy in different population groups, and inform the design of future vaccines for enhanced protection against emerging pathogens.

Vaccines against COVID-19 have high efficacy and low rates of adverse events. However, none of the available vaccines provide sterilizing immunity, and reinfections remain possible. This review aims to summarize the immunological responses elicited by different immunization strategies, examining the roles of homologous and heterologous vaccination and hybrid immunity. Homologous vaccination regimens exhibit considerable variation in immune responses depending on the vaccine platform, particularly concerning antibody titers, B cell activation, and T cell responses. mRNA vaccines, such as mRNA-1273 and BNT162b2, consistently generate higher and more durable levels of neutralizing antibodies and memory B cells compared to adenovirus-based vaccines like Ad26.COV2.S and ChAdOx1. The combination of two distinct vaccine platforms, each targeting different immune pathways, seems to be more effective in promoting long-lasting B cell responses and potent T cell responses. The high heterogeneity of the available studies, the different dosing schemes, the succession of new variants, and the subjects' immunological background do not allow for a definitive conclusion. Overall, heterologous vaccination strategies, combining sequentially viral vector and mRNA may deliver a more balanced and robust humoral and cellular immune response compared to homologous regimens. Hybrid immunity, which arises from SARS-CoV-2 infection preceded or followed by vaccination produces markedly stronger immune responses than either vaccination or infection alone. The immune response to SARS-CoV-2 variants of concern varies depending on both the vaccine platform and prior infection status. Hybrid immunity leads to a broader antibody repertoire, providing enhanced neutralization of variants of concern. Heterologous vaccination and hybrid immunity may provide further opportunities to enhance immune responses, offering broader protection and greater durability of immunity. However, from all-cause mortality, symptomatic or severe COVID, and serious adverse events at present it is not possible to infer different effects between homologous and heterologous schemes. Next-generation vaccines could involve tweaks to these designs or changes to delivery mechanisms that might improve performance.

During the COVID-19 pandemic, incidence of brain abscesses is difficult to assess. Numerous studies reported benign and severe post SARS-CoV-2 vaccine side effects, including rare cases of brain abscesses associated with COVID-19 or Anti-SARS-CoV-2 vaccines. Here in, we report what we believe to be, up to date, the fourth known case in the medical literature of a streptococcus salivarius brain abscess, the first intra parenchymatous or supra-tentorial streptococcus salivarius brain abscess and also the first that occurs following an anti-SARS-CoV-2 vaccine.

We describe the case of a north african 63-year-old man with an unremarkable medical history except for recent anti-SARS-CoV-2 vaccinations. Following the administration of a third anti-SARS-CoV-2 booster vaccine, the patient developed neurological symptoms, including left hemiparesis, facial palsy, vertigo, and balance issues. Imaging studies revealed a right temporo-parietal lesion consistent with intracranial suppuration. Stereotaxic cerebral biopsy confirmed the presence of purulent content, indicating a brain abscess caused by multi-sensitive streptococcus salivarius.

Sepsis-induced immunodepression appears to be a consequence of severe inflammatory state, as it dysregulates leukocytes population and results in serious infections. A plausible hypothesis is that a previous stress such as anti-SARS-CoV-2 vaccination could lead to the development of a streptococcus salivarius septicemia. In light of the available evidence and research findings, no definitive conclusion can be drawn regarding any potential link between anti-SARS-CoV-2 vaccines and the physiopathology of sepsis-induced immunodepression.

Vaccine immunogenicity is influenced by the vaccinee's genetic background. Here, we perform a genome-wide association study of vaccine-induced SARS-CoV-2-specific immunoglobulin G (IgG) antibody titers and T cell immune responses in 1,559 mRNA-1273 and 537 BNT162b2 vaccinees of Japanese ancestry. SARS-CoV-2-specific antibody titers are associated with the immunoglobulin heavy chain (IGH) and major histocompatibility complex (MHC) locus, and T cell responses are associated with MHC. The lead variants at IGH contain a population-specific missense variant (rs1043109-C; p.Leu192Val) in the immunoglobulin heavy constant gamma 1 gene (IGHG1), with a strong decreasing effect (β = -0.54). Antibody-titer-associated variants modulate circulating immune regulatory proteins (e.g., LILRB4 and FCRL6). Age-related hematopoietic expanded mosaic chromosomal alterations (mCAs) affecting MHC and IGH also impair antibody production. MHC-/IGH-affecting mCAs confer infectious and immune disease risk, including sepsis and Graves' disease. Impacts of expanded mosaic loss of chromosomes X/Y on these phenotypes were examined. Altogether, both germline and somatic mutations contribute to adaptive immunity functions.

The purpose of this study was to measure and examine the levels of IgG, IgM, and Spike antibody induced by inactivated vaccines, including CoronaVac and BBIBP-CorV.

Two groups of healthy adults over 18 years old (50 participants per group), who had previously received 1 dose of either BBIBP-CorV or CoronaVac and receiving either a homologous booster of BBIBP-CorV or a heterologous booster of CoronaVac. Serum IgG, IgM, and Spike antibody levels against SARS-COV-2 were measured using magnetic particle chemiluminescence immunoassay and the ELISA method.

The results showed that both spike antibody and IgG/IgM antibodies elicited by a CoronaVac booster following 1 dose of BBIBP-CorV were significantly higher than those elicited by either a homologous BBIBP-CorV booster or a heterologous BBIBP-CorV booster. The Spike antibody against SARS-COV-2 induced by the heterologous CoronaVac booster reached 200.3, which is substantially greater than that induced by the homologous BBIBP-CorV booster (127.5 pg/mL). Conversely, the Spike antibody against SARS-COV-2 induced by the heterologous BBIBP-CorV booster reached 53.93 pg/mL, which is substantially greater than that induced by the homologous CoronaVac booster (9.60 pg/mL).

In summary, CoronaVac is immunogenic as a booster dose following 1 dose of BBIBP-CorV and is immunogenically superior to both the homologous booster and the heterologous BBIBP-CorV booster.

Objectives: The SARS-CoV-2 JN.1 lineage emerged in late 2023 and quickly replaced the XBB lineages, becoming the predominant Omicron variant worldwide in 2024. We estimate the epidemiologic impact of this SARS-CoV-2 lineage replacement in Brazil and we further assessed the cross-reactive neutralizing antibody (NAb) responses in a cohort of convalescent Brazilian patients infected during 2023.

We analyzed the evolution of SARS-CoV-2 lineages and severe acute respiratory infection (SARI) cases in Brazil between July 2023 and March 2024. We evaluated the cross-reactive NAb responses to the JN.1 variant in a cohort of convalescent Brazilian patients before and after infection with XBB.1* lineages.

JN.1 replaced XBB with similar temporal dynamics across all country regions, although its epidemiologic impact varied between locations. The southeastern, southern, and central-western regions experienced a brief XBB wave around October 2023, shortly before the introduction of JN.1, without any immediate upsurge of SARI cases during viral lineage replacement. By contrast, the northeastern and northern regions did not experience an XBB wave in the latter half of 2023 and displayed a rapid surge in SARI cases driven by the emergence of the JN.1. We found that recent XBB infections in the Brazilian population significantly boosted cross-reactive NAb levels against JN.1.

The XBB wave observed in the second half of 2023 in some Brazilian states likely acted as a booster for population immunity, providing short-term protection against JN.1 infections and delaying the rise of SARI cases in certain regions of the country.

The emergence of XBB- and JN.1-lineages with remarkable immune evasion characteristics have led to rises in breakthrough infections within populations. In addition, the unfavorable impacts of immune imprinting, stemming from continuous exposure to antigens from circulated viruses, have been observed to incline immune response against earlier lineages, thereby declining the neutralization to newly emerged Omicron subvariants. In response to this, the advancement of next-generation vaccines against COVID-19 targeting components from new subvariants such as XBB-lineage is imperative. In the current study, a self-assembled trimeric recombinant protein (RBDXBB.1.5-HR) was generated by concatenating the sequences of the receptor binding domain (RBD) derived from XBB.1.5 with heptad-repeat 1 (HR1) and HR2 sequences from the spike S2 subunit. Adjuvanted-RBDXBB.1.5-HR induced robust humoral and cellular immune responses, characterized by elevated neutralization against JN.1-inculuded subvariants and a substantial population of antigen-specific T memory cells. Protective immunity conferred by RBDXBB.1.5-HR vaccine was preserved post-immunization, as evidenced by germinal center B (GC B) and T follicular helper (Tfh) responses, sustained neutralization potency, and an increase in memory B cells (MBCs) and long-lived plasma cells (LLPCs). The RBDXBB.1.5-HR vaccine showed a favorable boosting effect when administered heterologously after three doses of inactivated virus (IV) and mRNA vaccines. Significantly, it provided protection against live Omicron EG.5.1 viruses in vivo. The monovalent RBDXBB.1.5-HR vaccine showed favorable safety and immunogenicity, boosting neutralizing antibodies against JN.1- and XBB-lineage subvariants in individuals with prior COVID-19 vaccinations. These findings highlight its clinical potential in safeguarding against circulating Omicron subvariants.

The COVID-19 pandemic has significantly impacted people with cancer. Initial vaccine studies excluded patients with malignancy. Immunocompromised individuals remain vulnerable to SARS-CoV-2, necessitating detailed understanding of vaccine response. The epidemiology of COVID-19 in Australia offered unique opportunities to study cancer populations with minimal community exposure to SARS-CoV-2.

SerOzNET prospectively examined previously unvaccinated patients with solid and haematological malignancies receiving up to five COVID-19 vaccine doses. Antibody response was measured by live virus neutralisation assay (neutralising antibody (NAb); positive titre ≥1:20; study primary endpoint) and commercial assay. T cell response was measured by cytometric bead array; positive defined as interferon gamma (IFN-γ) ≥10 pg/mL in response to Spike antigen. Patient and physician-reported adverse events were secondary endpoints.

395 adults were enrolled prior to receiving mRNA vaccine (BNT162b2 = 347; mRNA-1273 = 1) or viral vector vaccine (ChadOx1-S = 43) for initial two-dose course, plus up to three additional doses. Median age was 58 years (range: 20-85); 60 % were female; 35 % had haematological malignancy, 2/395 (0.5 %) had baseline positive nucleocapsid antibody indicating prior SARS-CoV-2 exposure. NAb response post dose three was demonstrated in 84 % overall; 96 % of patients with solid cancers and 64 % with haematological cancer (p < 0·001). Risk factors for non-response were haematological cancer and anti B-cell therapies. Some patients with haematological cancer seroconverted for the first time after the fourth or fifth dose. IFN-γ response was seen in many patients with haematological cancer who lacked NAb response. Serious adverse events were rare. COVID-19 infection occurred in 29 % with no deaths.

COVID-19 vaccination elicits B and T cell responses in patients with solid and haematological cancers, with an acceptable safety profile. A significant proportion of haematological cancer patients require >3 doses to elicit NAb, with many demonstrating T cell response, which may be an alternative pathway of immune protection.

The SARS-CoV-2 Omicron BA.2.86 variant and its descendant lineages, including JN.1, are rapidly spreading and becoming dominant globally. Vaccination is an essential primary preventative measure. While mRNA vaccines have been widely used worldwide, it is essential that we continue to prepare alternative vaccine modalities. Consistent with WHO recommendations, we developed an inactivated Omicron XBB.1.5 vaccine and assessed its efficacy against XBB.1.5 and JN.1 strains. Immunization with the inactivated XBB.1.5 vaccine induced antigen-specific antibodies leading to protection from XBB.1.5 and antigenically distinct JN.1 strains in a hamster model. In addition, we found that immunization reduced viral replication in hamster respiratory organs, suggesting protection against XBB.1.5 and JN.1 variants. Our findings highlight the potential of inactivated vaccines against evolving SARS-CoV-2 variants.

COVID-19 vaccine programmes must account for variable immune responses and waning protection. Existing descriptions of antibody responses to COVID-19 vaccination convey limited information about the mechanisms of antibody production and maintenance. We describe antibody dynamics after COVID-19 vaccination with two biologically motivated mathematical models. We fit the models using Markov chain Monte Carlo to seroprevalence data from 14 602 uninfected individuals in England between May 2020 and September 2022. We analyse the effect of age, vaccine type, number of doses and the interval between doses on antibody production and longevity. We find evidence that individuals over 35 years old twice vaccinated with ChAdOx1-S generate a persistent antibody response suggestive of long-lived plasma cell induction. We also find that plasmablast productive capacity is greater in: younger people than older people (≤4.5-fold change in point estimates); people vaccinated with two doses than one dose (≤12-fold change); and people vaccinated with BNT162b2 than ChAdOx1-S (≤440-fold change). We find the half-life of an antibody to be 23-106 days. Routinely collected seroprevalence data are invaluable for characterizing within-host mechanisms of antibody production and persistence. Extended sampling and linking seroprevalence data to outcomes would enable conclusions about how humoral kinetics protect against disease.

Memory T and B cells in tissues are essential for protective immunity. Here, we performed a comprehensive analysis of the tissue distribution, phenotype, durability, and transcriptional profile of COVID-19 mRNA vaccine-induced immune memory across blood, lymphoid organs, and lungs obtained from 63 vaccinated organ donors aged 23-86, some of whom experienced SARS-CoV-2 infection. Spike (S)-reactive memory T cells were detected in lymphoid organs and lungs and variably expressed tissue-resident markers based on infection history, and S-reactive B cells comprised class-switched memory cells resident in lymphoid organs. Compared with blood, S-reactive tissue memory T cells persisted for longer times post-vaccination and were more prevalent with age. S-reactive T cells displayed site-specific subset compositions and functions: regulatory cell profiles were enriched in tissues, while effector and cytolytic profiles were more abundant in circulation. Our findings reveal functional compartmentalization of vaccine-induced T cell memory where surveilling effectors and in situ regulatory responses confer protection with minimal tissue damage.

Age-associated differences in the effect of repetitive vaccination, particularly on memory T-cell and B-cell responses, remain unclear. While older adults (aged ≥65 years) exhibited enhanced IgG responses following COVID-19 mRNA booster vaccination, they produced fewer spike-specific circulating follicular helper T cells-1 than younger adults. Similarly, the cytotoxic CD8+ T-cell response remained diminished with reduced PD-1 expression even after booster vaccination compared with that in younger adults, suggesting impaired memory T-cell activation in older adults. In contrast, although B-cell responses in older adults were weaker than those in younger adults in the primary response, the responses were significantly enhanced upon booster vaccination, reaching levels comparable with that observed in younger adults. Therefore, while booster vaccination ameliorates impaired humoral immunity in older adults by efficiently stimulating memory B-cell responses, it may less effectively enhance T-cell-mediated cellular immunity. Our study provides insights for the development of effective therapeutic and vaccine strategies for the most vulnerable older population.

The mRNA vaccines have proven to be very effective in preventing severe disease and death from SARS-CoV-2 in the general population. However, in patients with chronic kidney disease (CKD) in dialysis or with kidney transplants (KT) the vaccine responses vary, with severe breakthrough infections as a consequence. In this intervention study we investigated the magnitude and quality of the responses to mRNA vaccination administered prior to kidney replacement therapy (KRT). Twenty patients with CKD G4/5 and nine healthy controls were followed for 12 months after receiving two doses of BNT162b2 four weeks apart and a booster dose after 3-6 months. Induction of anti-Spike and anti-RBD IgG in plasma followed the same kinetics in CKD patients and controls, with a trend towards higher titers in controls. In accordance, there was no differences in the establishment of Spike-specific memory B-cells between groups. In contrast, the CKD patients showed lower levels of anti-Spike IgG in saliva and Spike-specific CD8+ T-cells in blood, possibly influencing the capacity of viral clearance which can contribute to an elevated risk of severe breakthrough infections. In conclusion, we found that CKD patients, despite having a reduced mucosal and cytotoxic immunity to BNT162b2, demonstrated a serological response in plasma similar to healthy controls. This suggests that immunization prior to RRT is efficient and motivated. (EudraCT-nr 2021-000988-68).

It is important to be able to retrospectively determine severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections with high accuracy, both for post-coronavirus disease 2019 (COVID-19) epidemiological studies, and to distinguish between Long COVID and other multi-syndromic diseases that have overlapping symptoms. Although serum antibody levels can be measured to retrospectively diagnose SARS-CoV-2 infections, peptide stimulation of memory T cell responses is a more sensitive approach. This is because robust memory T cells are generated after SARS-CoV-2 infection and persist even after antibodies wane below detectability thresholds. In this study, we compare T cell responses using FluoroSpot-based methods and overnight stimulation of whole blood with SARS-CoV-2 peptides followed by an ELISA. Both approaches have comparable sensitivity and specificity but require different equipment and samples to be used. Furthermore, the elimination of peptides that cross-react with other coronaviruses increases the assay specificity but trades off some sensitivity. Finally, this approach can be used on archival, cryopreserved PBMCs. This work shows comparative advantages for several methods to measure SARS-CoV-2 T cell responses that could be utilized by any laboratory studying the effects of the coronavirus disease 2019 pandemic.

Mutations occurring in the spike (S) protein of SARS-CoV-2 enables the virus to evade COVID-19 vaccine- and infection-induced immunity.

Here we provide a comprehensive analysis of humoral and cell-mediated immunity in 111 healthcare workers who received three or four vaccine doses and were followed up to 12 and 6 months, respectively, after the last vaccine dose. Omicron breakthrough infection occurred in 71% of the vaccinees, enabling evaluation of vaccine- and vaccine/infection-induced hybrid immunity.

Neutralizing antibodies were the highest against the ancestral D614G and were sequentially reduced against the Omicron variants BA.2, BA.5 and XBB.1.5. S1-specific IgG and neutralizing antibody levels were significantly higher in infected than in uninfected vaccinees, and the fourth vaccine dose in combination with a breakthrough infection resulted in high neutralizing antibody levels against all variants. T cell-mediated immunity, instead, was well retained already after two vaccine doses, and was not significantly strengthened by additional booster vaccine doses or Omicron breakthrough infections.

While humoral immunity is sensitive to mutations in the S protein and thus declined rapidly, the cell-mediated immunity is durable to antigenic variation, which may explain the good efficacy of COVID-19 vaccines against a severe disease.