Modulation of innate immune response to mRNA vaccination after SARS-CoV-2 infection or sequential vaccination in humans.

mRNA vaccines are likely to become widely used for the prevention of infectious diseases in the future. Nevertheless, a notable gap exists in mechanistic data, particularly concerning the potential effects of sequential mRNA immunization or preexisting immunity on the early innate immune response triggered by vaccination. In this study, healthy adults, with or without documented prior SARS-CoV-2 infection, were vaccinated with the BNT162b2/Comirnaty mRNA vaccine. Prior infection conferred significantly stronger induction of proinflammatory and type I IFN-related gene signatures, serum cytokines, and monocyte expansion after the prime vaccination. The response to the second vaccination further increased the magnitude of the early innate response in both study groups. The third vaccination did not further increase vaccine-induced inflammation. In vitro stimulation of PBMCs with TLR ligands showed no difference in cytokine responses between groups, or before or after prime vaccination, indicating absence of a trained immunity effect. We observed that levels of preexisting antigen-specific CD4 T cells, antibody, and memory B cells correlated with elements of the early innate response to the first vaccination. Our data thereby indicate that preexisting memory formed by infection may augment the innate immune activation induced by mRNA vaccines.

Early acquisition of S-specific Tfh clonotypes after SARS-CoV-2 vaccination is associated with the longevity of anti-S antibodies.

SARS-CoV-2 vaccines have been used worldwide to combat COVID-19 pandemic. To elucidate the factors that determine the longevity of spike (S)-specific antibodies, we traced the characteristics of S-specific T cell clonotypes together with their epitopes and anti-S antibody titers before and after BNT162b2 vaccination over time. T cell receptor (TCR) αß sequences and mRNA expression of the S-responded T cells were investigated using single-cell TCR- and RNA-sequencing. Highly expanded 199 TCR clonotypes upon stimulation with S peptide pools were reconstituted into a reporter T cell line for the determination of epitopes and restricting HLAs. Among them, we could determine 78 S epitopes, most of which were conserved in variants of concern (VOCs). After the 2nd vaccination, T cell clonotypes highly responsive to recall S stimulation were polarized to follicular helper T (Tfh)-like cells in donors exhibiting sustained anti-S antibody titers (designated as 'sustainers'), but not in 'decliners'. Even before vaccination, S-reactive CD4+ T cell clonotypes did exist, most of which cross-reacted with environmental or symbiotic microbes. However, these clonotypes contracted after vaccination. Conversely, S-reactive clonotypes dominated after vaccination were undetectable in pre-vaccinated T cell pool, suggesting that highly responding S-reactive T cells were established by vaccination from rare clonotypes. These results suggest that de novo acquisition of memory Tfh-like cells upon vaccination may contribute to the longevity of anti-S antibody titers.

PMMA dialyzers modulate both humoral and cell-mediate immune response to anti-COVID-19 vaccine (BNT162b2) in a cohort of chronic hemodialyzed patients.

Patients on hemodialysis (HD) have a high risk of death from COVID-19. We evaluated the humoral and cell-mediated immune response to BNT162b2 (Pfizer-BioNTech) vaccine in HD patients, comparing HD with Poly-methyl-methacrylate (PMMA) and HD with Polysulphone (PS). Samples were collected before vaccination (T0) and 14-days after the 2ndvaccine (T2) in a TG (TG, n = 16-Foggia) and in a VG (CG, n = 36-Novara). Anti-SARS-CoV-2-Ig were titrated in the cohort 2-weeks after the 2nddose of vaccine. In the Testing-Group, serum neutralizing antibodies (NAb) were assayed and PBMCs isolated from patients were thawed, counted and stimulated with SARS-CoV-2 IGRA stimulation tube set. All patients had a positive ab-response, except in a case. PMMA-patients had higher levels of anti-SARS-CoV-2 IgG (p = 0.031); VG data confirmed these findings (p < 0.05). NAb evaluation: PMMA patients passed the positive cut-off value, while in PS group only only 1/8 patient did not respond. PMMA patients showed higher percentages of anti-SARS-CoV-2 S1/RBD-Ig after a complete vaccine schedule (p = 0.028). Interferon-gamma release: PMMA patients showed significantly higher release of IFNγ (p = 0.014). The full vaccination course provided sufficient protection against SARS-CoV-2 across the entire cohort, regardless of dialyzer type. After vaccination, PMMA patients show a better immune response, both humoral and cellular, at the end of the vaccination course than PS patients.

Effectiveness of different booster vaccine combinations against SARS-CoV-2 during a six-month follow-up in Mexico and Argentina.

Introduction: Given the limited number of patients in Latin America who have received a booster dose against the COVID-19, it remains crucial to comprehend the effectiveness of different vaccine combinations as boosters in real-world scenarios. This study aimed to assess the real-life efficacy of seven different vaccine schemes against COVID-19, including BNT162b2, ChAdOx1-S, Gam-COVID-Vac, and CoronaVac as primary schemes with either BNT162b2 or ChAdOx1-S as booster vaccines. Methods: In this multicentric longitudinal observational study, participants from Mexico and Argentina were followed for infection and SARS-CoV-2 Spike 1-2 IgG antibodies during their primary vaccination course and for 185 days after the booster dose. Results: A total of 491 patients were included, and the booster dose led to an overall increase in the humoral response for all groups. Patients who received BNT162b2 exhibited the highest antibody levels after the third dose, while those with primary Gam-COVID-Vac maintained a higher level of antibodies after six months. Infection both before vaccination and after the booster dose, and Gam-COVIDVac + BNT162b2 combination correlated with higher antibody titers. Discussion: The sole predictor of infection in the six-month follow-up was a prior COVID-19 infection before the vaccination scheme, which decreased the risk of infection, and all booster vaccine combinations conveyed the same amount of protection.

Distinct T cell responsiveness to different COVID-19 vaccines and cross-reactivity to SARS-CoV-2 variants with age and CMV status.

Introduction: Accumulating evidence indicates the importance of T cell immunity in vaccination-induced protection against severe COVID-19 disease, especially against SARS-CoV-2 Variants-of-Concern (VOCs) that more readily escape from recognition by neutralizing antibodies. However, there is limited knowledge on the T cell responses across different age groups and the impact of CMV status after primary and booster vaccination with different vaccine combinations. Moreover, it remains unclear whether age has an effect on the ability of T cells to cross-react against VOCs. Methods: Therefore, we interrogated the Spike-specific T cell responses in healthy adults of the Dutch population across different ages, whom received different vaccine types for the primary series and/or booster vaccination, using IFNÉ£ ELISpot. Cells were stimulated with overlapping peptide pools of the ancestral Spike protein and different VOCs. Results: Robust Spike-specific T cell responses were detected in the vast majority of participants upon the primary vaccination series, regardless of the vaccine type (i.e. BNT162b2, mRNA-1273, ChAdOx1 nCoV-19, or Ad26.COV2.S). Clearly, in the 70+ age group, responses were overall lower and showed more variation compared to younger age groups. Only in CMV-seropositive older adults (>70y) there was a significant inverse relation of age with T cell responses. Although T cell responses increased in all age groups after booster vaccination, Spike-specific T cell frequencies remained lower in the 70+ age group. Regardless of age or CMV status, primary mRNA-1273 vaccination followed by BNT162b2 booster vaccination showed limited booster effect compared to the BNT162b2/BNT162b2 or BNT162b2/mRNA-1273 primary-booster regimen. A modest reduction in cross-reactivity to the Alpha, Delta and Omicron BA.1, but not the Beta or Gamma variant, was observed after primary vaccination. Discussion: Together, this study shows that age, CMV status, but also the primary-booster vaccination regimen influence the height of the vaccination-induced Spike-specific T cell response, but did not impact the VOC cross-reactivity.

18-month longitudinal SARS COV-2 neutralizing antibody dynamics in haemodialysis patients receiving heterologous 3-dose vaccination (AZD-1222- AZD-1222- BNT162b2) in a lower middle income setting.

BACKGROUND: Patients with chronic kidney disease on haemodialysis (HD) were given priority COVID-19 vaccination due to increased disease risk. The immune response to COVID-19 vaccination in patients on HD was diminished compared to healthy individuals in 2-dose studies. This study aimed to evaluate seroconversion rate, neutralizing antibody (nAB) levels and longitudinal antibody dynamics to 3-dose heterologous vaccination against COVID-19 in a cohort of HD patients compared to healthy controls and assess patient factors associated with antibody levels. METHODS: This study was a case-control longitudinal evaluation of nAB dynamics in 74 HD patients compared to 37 healthy controls in a low/middle income setting. Corresponding samples were obtained from the two cohorts at time-points (TP) 1-1-month post 2nd dose of AZD1222 vaccine, TP2- 4 months post 2nd dose, TP4- 2 weeks post 3rd dose with BNT162b2 vaccine, TP5-5 months post 3rd dose and TP6-12 months post 3rd dose. Additional data is available at TP0- pre 2nd dose and TP3- 6 months post 2nd dose in HC and HD cohorts respectively. Anti-SARS-CoV-2 nAB were detected using Genscript cPassTM pseudoviral neutralization kit. Demographic and clinical details were obtained using an interviewer administered questionnaire. RESULTS: Cohorts were gender matched while mean age of the HD cohort was 54.1yrs (vs HCs mean age, 42.6yrs, p < 0.05). Percentage seroconverted and mean/median antibody level (MAB) in the HD cohort vs HCs at each sampling point were, TP1-83.7% vs 100% (p < 0.05), MAB-450 IU/ml vs 1940 IU/ml (p < 0.0001); TP2-71.4% vs 100%, (p < 0.001), MAB- 235 IU/ml vs 453 IU/ml, (p < 0.05); TP4-95.2% vs 100% (p > 0.05), MAB-1029 IU/ml vs 1538 IU/ml (p < 0.0001); TP5-100% vs 100%, MAB-1542 IU/ml vs 1741IU/ml (p > 0.05); TP6-100% vs 100%, MAB-1961 IU/ml vs 2911 IU/ml (p > 0.05). At TP2, patients aged < 60 years (p < 0.001) were associated with maintaining seropositivity compared to patients > 60 years. CONCLUSION: Two dose vaccination of haemodialysis patients provided poor nAB levels which improved markedly following 3rd dose vaccination, the effect of which was long- lasting with high nAB levels in both patients and controls detectable at 1 year follow-up.

Immunogenicity of third dose COVID-19 vaccine strategies in patients who are immunocompromised with suboptimal immunity following two doses (OCTAVE-DUO): an open-label, multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: The humoral and T-cell responses to booster COVID-19 vaccine types in multidisease immunocompromised individuals who do not generate adequate antibody responses to two COVID-19 vaccine doses, is not fully understood. The OCTAVE DUO trial aimed to determine the value of third vaccinations in a wide range of patients with primary and secondary immunodeficiencies. METHODS: OCTAVE-DUO was a prospective, open-label, multicentre, randomised, controlled, phase 3 trial investigating humoral and T-cell responses in patients who are immunocompromised following a third vaccine dose with BNT162b2 or mRNA-1273, and of NVX-CoV2373 for those with lymphoid malignancies. We recruited patients who were immunocompromised from 11 UK hospitals, aged at least 18 years, with previous sub-optimal responses to two doses of SARS-CoV-2 vaccine. Participants were randomly assigned 1:1 (1:1:1 for those with lymphoid malignancies), stratified by disease, previous vaccination type, and anti-spike antibody response following two doses. Individuals with lived experience of immune susceptibility were involved in the study design and implementation. The primary outcome was vaccine-specific immunity defined by anti-SARS-CoV-2 spike antibodies (Roche Diagnostics UK and Ireland, Burgess Hill, UK) and T-cell responses (Oxford Immunotec, Abingdon, UK) before and 21 days after the third vaccine dose analysed by a modified intention-to-treat analysis. The trial is registered with the ISRCTN registry, ISRCTN 15354495, and the EU Clinical Trials Register, EudraCT 2021-003632-87, and is complete. FINDINGS: Between Aug 4, 2021 and Mar 31, 2022, 804 participants across nine disease cohorts were randomly assigned to receive BNT162b2 (n=377), mRNA-1273 (n=374), or NVX-CoV2373 (n=53). 356 (45%) of 789 participants were women, 433 (55%) were men, and 659 (85%) of 775 were White. Anti-SARS-CoV-2 spike antibodies measured 21 days after the third vaccine dose were significantly higher than baseline pre-third dose titres in the modified intention-to-treat analysis (median 1384 arbitrary units [AU]/mL [IQR 4·3-7990·0] compared with median 11·5 AU/mL [0·4-63·1]; p<0·001). Of participants who were baseline low responders, 380 (90%) of 423 increased their antibody concentrations to more than 400 AU/mL. Conversely, 166 (54%) of 308 baseline non-responders had no response after the third dose. Detectable T-cell responses following the third vaccine dose were seen in 494 (80%) of 616 participants. There were 24 serious adverse events (BNT612b2 eight [33%] of 24, mRNA-1273 12 [50%], NVX-CoV2373 four [17%]), two (8%) of which were categorised as vaccine-related. There were seven deaths (1%) during the trial, none of which were vaccine-related. INTERPRETATION: A third vaccine dose improved the serological and T-cell response in the majority of patients who are immunocompromised. Individuals with chronic renal disease, lymphoid malignancy, on B-cell targeted therapies, or with no serological response after two vaccine doses are at higher risk of poor response to a third vaccine dose. FUNDING: Medical Research Council, Blood Cancer UK.

Investigation of SARS-CoV-2 antibody levels after COVID-19 vaccine in chronic hepatitis B patients.

AIM: The aim was to compare SARS-CoV-2 IgG antibody levels in chronic hepatitis B patients and healthcare personnel selected as the control group and to determine factors such as age, gender, vaccine type, and number of vaccines that may affect the antibody levels. MATERIALS AND METHODS: 87 chronic hepatitis B (CHB) patients followed in Ankara Training and Research Hospital Infectious Diseases Clinic and Mamak State Hospital Infectious Diseases outpatient clinic and 89 healthcare personnel selected as the control group were included in the study.SARS-CoV-2 IgG antibody levels in the serum samples of patients and healthcare personnel who received the COVID-19 vaccine were studied with the ELISA method in the Microbiology Laboratory of Ankara Training and Research Hospital, using a commercial ELISA kit (Abbott, USA) in line with the recommendations of the manufacturer. In the study, SARS-CoV-2 IgG levels were compared in CHB patients and healthcare personnel. In addition, the relationship between SARS-CoV-2 antibody level, gender, average age, natural history of the disease, number of vaccinations, vaccine type (Coronavac TM vaccine alone, BNT162b2 vaccine alone or Coronavac TM and BNT162b2 vaccine (heterologous vaccination)), treatment duration of CHB was investigated. Statistical analyses were made in the SPSS program. A value of p≤ 0.05 was considered statistically significant. FINDINGS: A total of 167 people, including 87 CKD patients and 80 healthcare personnel as the control group, were included in the study. SARS-CoV-2 IgG antibody levels were detected above the cut-off level in the entire study group, regardless of the vaccine type. No difference was detected in SARS-CoV-2 IgG titers after COVID-19 vaccination between CHB patients and healthcare personnel. There was a statistically significant difference in SARS-CoV-2 IgG antibody levels among individuals participating in the study according to vaccine types. Compared to those who received Coronavac TM vaccine alone, the average SARS-CoV-2 IgG level was found to be statistically significantly higher in those who received BNT162b2 vaccine alone or heterologous vaccination with Coronavac TM + BNT162b2 vaccine. There was no difference between the groups in terms of age, gender, number of vaccinations, natural transmission of the disease, and duration of antiviral therapy in the CHD patient group. CONCLUSION: As a result, SARS-CoV-2 IgG antibody levels above the cut-off value were achieved with Coronavac TM and BNT162b2 vaccines in both CHD patients and healthy control groups. however, both CHD patients and healthcare personnel had higher antibody levels than those who received BNT162b2 alone or those who received heterologous vaccination had higher antibody levels than those with Coronavac TM alone. Therefore, if there are no contraindications, BNT162b2 vaccine may be preferred in CHB and health personnel (Tab. 2, Ref. 14).

Evaluation of SARS-CoV-2 interferon gamma release assay in BNT162b2 vaccinated healthcare workers.

To predict protective immunity to SARS-CoV-2, cellular immunity seems to be more sensitive than humoral immunity. Through an Interferon-Gamma (IFN-γ) Release Assay (IGRA), we show that, despite a marked decrease in total antibodies, 94.3% of 123 healthcare workers have a positive cellular response 6 months after inoculation with the 2nd dose of BNT162b2 vaccine. Despite the qualitative relationship found, we did not observe a quantitative correlation between IFN-γ and IgG levels against SARS-CoV-2. Using stimulated whole blood from a subset of participants, we confirmed the specific T-cell response to SARS-CoV-2 by dosing elevated levels of the IL-6, IL-10 and TNF-α. Through a 20-month follow-up, we found that none of the infected participants had severe COVID-19 and that the first positive cases were only 12 months after the 2nd dose inoculation. Future studies are needed to understand if IGRA-SARS-CoV-2 can be a powerful diagnostic tool to predict future COVID-19 severe disease, guiding vaccination policies.

Homologous and Heterologous Covid-19 Booster Vaccinations Against SARS-CoV-2 Infection in the Elderly.

A third booster doses for the 2019 coronavirus disease (COVID-19) is widely used all over the world, especially in risky individuals, with the recommendation of WHO. The purpose of this study was to evaluate the effectiveness of mRNA (BNT162b2), and CoronaVac (Sinovac Biotech) vaccines as a reminder dose following two doses of CoronaVac against COVID-19 infection, serious illness, and mortality in the geriatric population aged 75 and older during the delta variant dominant period. Our study comprised 2730 individuals the age of 75 and older in total, of which 1082 (39.6%) were male and 1648 (60.4%) were female. The vaccine effectiveness (VE) of 2 doses of CoronaVac + 1 dose of BNT162b2 vaccine combination against COVID-19 was determined as 89.2% (95% Confidence interval (CI) 80.7-93.9%), while the VE of 3 doses of CoronaVac vaccine was determined as 80.4% (95% CI 60.5-90.2%). Geriatric patients who received three doses of CoronaVac vaccine did not need intensive care. No deaths were observed in the vaccinated groups. While the VE of vaccination with 2 doses of CoronaVac + 1 dose of BNT162b2 was 41.8% (95% CI 0-74.1%) against hospitalization, 64.4% (95% CI 0-94.7%) against intensive care unit admission, the VE of vaccination with three doses of the CoronaVac was 78.2% (95% CI 0-96.5%) against hospitalization. In conclusion, our research showed that, even with the emergence of viral variants, a third dose of the CoronaVac and BNT162b2 vaccines is highly effective against symptomatic SARS-CoV-2 infection. Third-dose vaccination regimens, including heterologous and homologous vaccines, can be an effective tool in controlling the COVID-19 pandemic and the emergence of new variants.

Evaluation of SARS-CoV-2 anti-Spike antibody levels and breakthrough infection risk among vaccinated adults in North Lebanon.

Since March 2020, the COVID-19 pandemic has swiftly propagated, triggering a competitive race among medical firms to forge vaccines that thwart the infection. Lebanon initiated its vaccination campaign on February 14, 2021. Despite numerous studies conducted to elucidate the characteristics of immune responses elicited by vaccination, the topic remains unclear. Here, we aimed to track the progression of anti-spike SARS-CoV-2 antibody titers at two-time points (T1: shortly after the second vaccination dose, T2: six months later) within a cohort of 201 adults who received Pfizer-BioNTech (BNT162b2), AstraZeneca, or Sputnik V vaccines in North Lebanon. Blood specimens were obtained from participants, and antibody titers against SARS-CoV-2 were quantified through the Elecsys-Anti-SARS-CoV-2 S assay (Roche Diagnostics, Switzerland). We used univariate analysis and multivariable logistic regression models to predict determinants influencing the decline in immune response and the occurrence of breakthrough infections among vaccinated patients. Among the 201 participants, 141 exhibited unchanging levels of antibody titers between the two sample collections, 55 displayed waning antibody titers, and only five participants demonstrated heightened antibody levels. Notably, age emerged as the sole variable significantly linked to the waning immune response. Moreover, the BNT162b2 vaccine exhibited significantly higher efficacy concerning the occurrence of breakthrough infections when compared with the AstraZeneca vaccine. Overall, our study reflected the immune status of a sample of vaccinated adults in North Lebanon. Further studies on a larger scale are needed at the national level to follow the immune response after vaccination, especially after the addition of the third vaccination dose.

Follow-Up and Comparative Assessment of SARS-CoV-2 IgA, IgG, Neutralizing, and Total Antibody Responses After BNT162b2 or mRNA-1273 Heterologous Booster Vaccination.

BACKGROUND: Priming with ChAdOx1 followed by heterologous boosting is considered in several countries. Nevertheless, analyses comparing the immunogenicity of heterologous booster to homologous primary vaccination regimens and natural infection are lacking. In this study, we aimed to conduct a comparative assessment of the immunogenicity between homologous primary vaccination regimens and heterologous prime-boost vaccination using BNT162b2 or mRNA-1273. METHODS: We matched vaccinated naïve (VN) individuals (n = 673) with partial vaccination (n = 64), primary vaccination (n = 590), and primary series plus mRNA vaccine heterologous booster (n = 19) with unvaccinated naturally infected (NI) individuals with a documented primary SARS-CoV-2 infection (n = 206). We measured the levels of neutralizing total antibodies (NTAbs), total antibodies (TAbs), anti-S-RBD IgG, and anti-S1 IgA titers. RESULTS: Homologous primary vaccination with ChAdOx1 not only showed less potent NTAb, TAb, anti-S-RBD IgG, and anti-S1 IgA immune responses compared to primary BNT162b2 or mRNA-1273 vaccination regimens (p < 0.05) but also showed ~3-fold less anti-S1 IgA response compared to infection-induced immunity (p < 0.001). Nevertheless, a heterologous booster led to an increase of ~12 times in the immune response when compared to two consecutive homologous ChAdOx1 immunizations. Furthermore, correlation analyses revealed that both anti-S-RBD IgG and anti-S1 IgA significantly contributed to virus neutralization among NI individuals, particularly in symptomatic and pauci-symptomatic individuals, whereas among VN individuals, anti-S-RBD IgG was the main contributor to virus neutralization. CONCLUSION: The results emphasize the potential benefit of using heterologous mRNA boosters to increase antibody levels and neutralizing capacity particularly in patients who received primary vaccination with ChAdOx1.

Effectiveness of two and three doses of COVID-19 mRNA vaccines against infection, symptoms, and severity in the pre-omicron era: A time-dependent gradient.

BACKGROUND: Vaccines were developed and deployed to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to characterize patterns in the protection provided by the BNT162b2 and mRNA-1273 mRNA vaccines against a spectrum of SARS-CoV-2 infection symptoms and severities. METHODS: A national, matched, test-negative, case-control study was conducted in Qatar between January 1 and December 18, 2021, utilizing a sample of 238,896 PCR-positive tests and 6,533,739 PCR-negative tests. Vaccine effectiveness was estimated against asymptomatic, symptomatic, severe coronavirus disease 2019 (COVID-19), critical COVID-19, and fatal COVID-19 infections. Data sources included Qatar's national databases for COVID-19 laboratory testing, vaccination, hospitalization, and death. RESULTS: Effectiveness of two-dose BNT162b2 vaccination was 75.6% (95% CI: 73.6-77.5) against asymptomatic infection and 76.5% (95% CI: 75.1-77.9) against symptomatic infection. Effectiveness against each of severe, critical, and fatal COVID-19 infections surpassed 90%. Immediately after the second dose, all categories-namely, asymptomatic, symptomatic, severe, critical, and fatal COVID-19-exhibited similarly high effectiveness. However, from 181 to 270 days post-second dose, effectiveness against asymptomatic and symptomatic infections declined to below 40%, while effectiveness against each of severe, critical, and fatal COVID-19 infections remained consistently high. However, estimates against fatal COVID-19 often had wide 95% confidence intervals. Analogous patterns were observed in three-dose BNT162b2 vaccination and two- and three-dose mRNA-1273 vaccination. Sensitivity analyses confirmed the results. CONCLUSION: A gradient in vaccine effectiveness exists and is linked to the symptoms and severity of infection, providing higher protection against more symptomatic and severe cases. This gradient intensifies over time as vaccine immunity wanes after the last vaccine dose. These patterns appear consistent irrespective of the vaccine type or whether the vaccination involves the primary series or a booster.

Altered transcriptomic immune responses of maintenance hemodialysis patients to the COVID-19 mRNA vaccine.

Background: End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines. Methods: The immune response to the COVID-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and 7 d after the second dose (V2D7) using anti-spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified 6 mo after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response. Results: Transcriptomic analyses demonstrated differing time courses of immune responses, with prolonged myeloid cell activity in HD at 1 wk after the first vaccination dose. HD also demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p<0.05). Anti-spike IgG remained elevated above baseline at 6 mo in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development. Conclusions: Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance HD subjects comparable to healthy controls and identify transcriptomic and clinical predictors of anti-spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of ESRD. Funding: F30HD102093, F30HL151182, T32HL144909, R01HL138628. This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.

Assessment of the neutralizing antibody response in Omicron breakthrough cases in healthcare workers who received the homologous booster of Moderna mRNA-1273.

Vaccines against SARS-CoV-2 were developed during the pandemic including the BNT162b2 and the mRNA-1273. We evaluated the levels of binding antibodies against the receptor binding domain and the levels of NAbs in individuals who developed a breakthrough infection after having received three doses of mRNA-1273. A total of 51 participants were included. The breakthrough group was compared to a 1:1 matched-control group. Among the 51 individuals, 18 (35%) developed a breakthrough infection. The GMT of NAbs against the BA.1 in the BK population was 278.1 (95%CI: 168.1-324.1). This titer was significantly lower compared to the matched-control group when considering all data (GMT = 477.4; 95%CI: 316.2-541.0; p = 0.0057). Results were similar for the BA.5 (GMT = 152.0 (95%CI: 76.9-172.9) for breakthrough and 262.0 (95%CI: 171.3-301.8) for control (p = 0.0043)). Our study found that individuals receiving the mRNA-1273 booster and who developed a breakthrough infection presented lower levels of binding antibodies and NAbs before the infection as compared to a matched-control group.

Immunogenicity of COVID-19 adsorbed inactivated vaccine (CoronaVac) and additional doses of mRNA BNT162b2 vaccine in immunocompromised adults compared with immunocompetent persons.

Inactivated COVID-19 vaccines data in immunocompromised individuals are scarce. This trial assessed the immunogenicity of two CoronaVac doses and additional BNT162b2 mRNA vaccine doses in immunocompromised (IC) and immunocompetent (H) individuals. Adults with solid organ transplant (SOT), hematopoietic stem cell transplant, cancer, inborn immunity errors or rheumatic diseases were included in the IC group. Immunocompetent adults were used as control group for comparison. Participants received two CoronaVac doses within a 28-day interval. IC received two additional BNT162b2 doses and H received a third BNT162b2 dose (booster). Blood samples were collected at baseline, 28 days after each dose, pre-booster and at the trial end. We used three serological tests to detect antibodies to SARS-CoV-2 nucleocapsid (N), trimeric spike (S), and receptor binding domain (RBD). Outcomes included seroconversion rates (SCR), geometric mean titers (GMT) and GMT ratio (GMTR). A total of 241 IC and 100 H adults participated in the study. After two CoronaVac doses, IC had lower SCR than H: anti-N, 33.3% vs 79%; anti-S, 33.8% vs 86%, and anti-RBD, 48.5% vs 85%, respectively. IC also showed lower GMT than H: anti-N, 2.3 vs 15.1; anti-S, 58.8 vs 213.2 BAU/mL; and anti-RBD, 22.4 vs 168.0 U/mL, respectively. After the 3rd and 4th BNT162b2 doses, IC had significant anti-S and anti-RBD seroconversion, but still lower than H after the 3rd dose. After boosting, GMT increased in IC, but remained lower than in the H group. CoronaVac two-dose schedule immunogenicity was lower in IC than in H. BNT162b2 heterologous booster enhanced immune response in both groups.

Specific and off-target immune responses following COVID-19 vaccination with ChAdOx1-S and BNT162b2 vaccines-an exploratory sub-study of the BRACE trial.

BACKGROUND: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. METHODS: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. FINDINGS: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. INTERPRETATION: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. FUNDING: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children's. BRACE trial funding is detailed in acknowledgements.

Correlates of protection against symptomatic SARS-CoV-2 in vaccinated children.

The paucity of information on longevity of vaccine-induced immune responses and uncertainty of the correlates of protection hinder the development of evidence-based COVID-19 vaccination policies for new birth cohorts. Here, to address these knowledge gaps, we conducted a cohort study of healthy 5-12-year-olds vaccinated with BNT162b2. We serially measured binding and neutralizing antibody titers (nAbs), spike-specific memory B cell (MBC) and spike-reactive T cell responses over 1 year. We found that children mounted antibody, MBC and T cell responses after two doses of BNT162b2, with higher antibody and T cell responses than adults 6 months after vaccination. A booster (third) dose only improved antibody titers without impacting MBC and T cell responses. Among children with hybrid immunity, nAbs and T cell responses were highest in those infected after two vaccine doses. Binding IgG titers, MBC and T cell responses were predictive, with T cells being the most important predictor of protection against symptomatic infection before hybrid immunity; nAbs only correlated with protection after hybrid immunity. The stable MBC and T cell responses over time suggest sustained protection against symptomatic SARS-CoV-2 infection, even when nAbs wane. Booster vaccinations do not confer additional immunological protection to healthy children.

Immunogenicity of Two Doses of BNT162b2 mRNA COVID-19 Vaccine with a ChAdOx1-S Booster Dose among Navy Personnel in Mexico.

Booster doses of the SARS-CoV-2 vaccine have been recommended to improve and prolong immunity, address waning immunity over time, and contribute to the control of the COVID-19 pandemic. A heterologous booster vaccine strategy may offer advantages over a homologous approach. To compare the immunogenicity of two doses of BNT162b2 mRNA COVID-19 vaccine with a ChAdOx1-S booster dose, immunoglobulin G (IgG) anti-spike (anti-S) and anti-nucleocapsid (anti-N) antibody titers (Ab) were compared over 1 year and post-booster vaccination. Results showed that, at 3- to 9-month assessments in vaccinated subjects, an-ti-N Ab were undetectable in participants with no history of COVID-19. In contrast, anti-S Ab measurements were lower than those with COVID-19, and a decrease was observed during the 9 months of observation. After booster vaccination, no differences were found in anti-S between participants who reported a history of COVID-19 and those who did not. Anti-S levels were higher after booster vaccination measurement vs. at 9 months in participants with COVID-19 and without COVID-19, i.e., independent of an infection history. Vaccine administration elicited a response of higher anti-S IgG levels in those infected before vaccination, although levels decreased during the first nine months. IgG anti-N titers were higher in participants with a history of declared infection and who were asymptomatic. The ChAdOx1-S booster increased anti-S Ab levels in participants regardless of whether they had been infected or not to a significantly higher value than with the first two vaccines. These findings underscore the importance of booster vaccination in eliciting a robust and sustained immune response against COVID-19, regardless of the prior infection status.