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Background/Objectives: The emergence of the Omicron variant has complicated COVID-19 control and prompted vaccine updates. Recent studies have shown that a fourth dose significantly protects against infection and severe disease, though long-term immunity data remain limited. This study aimed to assess Anti-S-RBD antibodies and interferon-γ levels in healthcare workers 12 months after receiving bivalent Original/Omicron BA.4-5 fourth SARS-CoV-2 vaccine. Methods: In this prospective cohort study, 549 healthcare workers were categorized by the initial vaccination schedule, with 229 individuals having received the fourth SARS-CoV-2 vaccine dose. Blood samples were collected from all participants 12 months post-vaccination. Results: Significant differences in Anti-S-RBD antibody levels were observed between those receiving a fourth dose and those who did not, while no differences were seen in interferon-γ levels. After 12 months, there were no significant differences in humoral and cellular immunity response between volunteers primoinfected or reinfected across different periods by the Omicron variant. A multivariable analysis revealed an association between high antibody levels (>6000 U/mL) and interferon-γ levels (OR: 3.13; 95% CI: 1.3–7.7; p < 0.05). Regarding primary vaccine schedules, participants vaccinated with ChAdOx1 (a single or double dose) had notably lower antibody levels compared to those who received mRNA-based vaccines. Additionally, the study shows a higher frequency of multiple infections among those with a single-dose ChAdOx1 primary schedule (OR: 6.24; 95% CI: 1.25–31.15; p < 0.01). Conclusions: Overall, mRNA-based vaccines exhibited stronger long-term immunogenicity. Repeated exposure to the Omicron variant seems to mitigate immune imprinting from the wild-type SARS-CoV-2. An association was observed between high antibody levels and a strong cellular response, although the correlation was not linear. [ABSTRACT FROM AUTHOR]

Objective The effectiveness of COVID-19 vaccinations wanes due to immune evasion by the B.1.1.529 (Omicron) variant and diminished antibody titres over time. We aimed to evaluate the benefit of a fourth vaccination dose in patients with autoimmune rheumatic diseases (ARDs). Methods This retrospective analysis included ARD patients aged 18 years or older and members of Clalit Health Services in Israel (which at the time of the study insured 52% of the entire population), and covered the period from 16 January 2022 to 31 March 2022, when the predominant SARS-CoV-2 variant was Omicron. We compared patients without previous COVID-19 infection who had received three doses of the BNT162b2 vaccine (the control group) with those who had received the fourth dose. The primary outcome was COVID-19 infection, which was analysed using multivariate Cox regression in the entire cohort and within ARD subgroups. Secondary outcomes were COVID-19–related hospitalizations and COVID-19–related death. Results We included 43 748 ARD patients, of whom 27 766 and 15 982 were in the control and fourth vaccination groups, respectively. COVID-19 infection occurred in 6942 (25.0%) of the control group and 1754 (11.0%) of the fourth dose group (P  < 0.001). Patients vaccinated with the fourth dose had a lower risk of COVID-19 infection than the entire cohort [Hazard Ratio (HR) 0.54, 95% CI 0.52, 0.58] and throughout every subgroup regardless of the baseline characteristic or medical treatment, except for rituximab. A similar association was observed for risk of COVID-19–related hospitalization (HR 0.36, 95% CI 0.22, 0.61) and of COVID-19–related death (HR 0.41, 95% CI 0.24, 0.71). Conclusion A fourth BNT162b2 vaccination of ARD patients was associated with favourable outcomes compared with three doses among patients with no history of COVID-19 infection. [ABSTRACT FROM AUTHOR]

Introduction: China experienced a record surge of coronavirus disease 2019 cases in December 2022, during the pandemic. Methods: We conducted a randomized, parallel-controlled prospective cohort study to evaluate efficacy and antibody duration after a fourth-dose booster with Ad5-nCoV or inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Results: A total of 191 participants aged =18 years who had completed a threedose regimen of the inactivated SARS-CoV-2 vaccine 6 months earlier were recruited to receive the intramuscular Ad5-nCoV booster or the inactivated SARS-CoV-2 vaccine. The Ad5-nCoV group had significantly higher antibody levels compared with the inactivated vaccine group at 6 months after the fourth vaccination dose. After the pandemic, the breakthrough infection rate for the Ad5-nCoV and the inactivated vaccine groups was 77.89% and 78.13%, respectively. Survival curve analysis (p = 0.872) and multivariable logistic regression analysis (p = 0.956) showed no statistically significant differences in breakthrough infection between the two groups. Discussion: Compared with a homologous fourth dose, a heterologous fourth dose of Ad5-nCoV elicited a higher immunogenic response in healthy adults who had been immunized with three doses of inactivated vaccine. Nevertheless, the efficacy of the two vaccine types was equivalent after the pandemic. [ABSTRACT FROM AUTHOR]

Patients with heart transplantation (HT) have an increased risk of COVID-19 disease and the efficacy of vaccines on antibody induction is lower, even after three or four doses. The aim of our study was to assess the efficacy of four doses on infections and their interplay with immunosuppression. We included in this retrospective study all adult HT patients (12/21–11/22) without prior infection receiving a third or fourth dose of mRNA vaccine. The endpoints were infections and the combined incidence of ICU hospitalizations/death after the last dose (6-month survival rate). Among 268 patients, 62 had an infection, and 27.3% received four doses. Following multivariate analysis, three vs. four doses, mycophenolate (MMF) therapy, and HT < 5 years were associated with an increased risk of infection. MMF ≥ 2000 mg/day independently predicted infection, together with the other variables, and was associated with ICU hospitalization/death. Patients on MMF had lower levels of anti-RBD antibodies, and a positive antibody response after the third dose was associated with a lower probability of infection. In HT patients, a fourth dose of vaccine against SARS-CoV-2 reduces the risk of infection at six months. Mycophenolate, particularly at high doses, reduces the clinical effectiveness of the fourth dose and the antibody response to the vaccine. [ABSTRACT FROM AUTHOR]

Background Waning immunity and an increased incidence of coronavirus disease 2019 (COVID-19) during the Omicron outbreak led the Israeli Ministry of Health to recommend a fourth vaccine dose for high-risk individuals. In this study, we assessed its effect for hospitalized patients with severe breakthrough COVID-19. Methods In this multicenter cohort study of hospitalized adults with severe COVID-19 in Israel, from 15 to 31 January 2022, cases were divided according to the number of vaccinations received. Poor outcome was defined as mechanical ventilation or in-hospital death and was compared between 3- and 4-dose vaccinees using logistic regression. Results Included were 1049 patients, median age 80 years. Among them, 394 were unvaccinated, 386 and 88 had received 3 or 4 doses, respectively. The 3-dose group was older, included more males, and immunosuppressed patients but with similar outcomes, 49% vs 51% compared with unvaccinated patients (P =.72). Patients who received 4 doses were similarly older and immunosuppressed but had better outcomes compared with unvaccinated patients, 34% vs 51% (P <.01). We examined independent predictors for poor outcome in patients who received either 3 or 4 doses a median of 161 days or 14 days before diagnosis, respectively. Receipt of the fourth dose was associated with protection (odds ratio, 0.51; 95% confidence interval,.3–.87), as was remdesivir. Male sex, chronic renal failure, and dementia were associated with poor outcomes. Conclusions Among hospitalized patients with severe breakthrough COVID-19, a recent fourth dose was associated with significant protection against mechanical ventilation or death compared with 3 doses. [ABSTRACT FROM AUTHOR]

A fourth dose of a COVID-19 vaccine has been recommended by a number of authorities due to waning immunity over time and the emergence of immune-escaping variants. Here, we evaluated the safety and immunogenicity of the bivalent BV-01-B5 or V-01D-351 or the prototype V-01 for heterologous boosting in three-dose inactivated COVID-19 vaccine (ICV) recipients, in comparison with ICV homologous boosting. One pilot study (NCT05583357) included 20 participants randomized at 1:1, either receiving V-01D-351 or CoronaVac. The other one (NCT05585567) recruited 36 participants randomized at 2:1, either receiving BV-01-B5 or V-01, respectively. BV-01-B5, V-01D-351, and V-01 were safe and well-tolerated as heterologous booster shots after three doses of ICV, with adverse reactions predominantly being mild and moderate in severity, similar to the safety profile of ICV boosters. The bivalent V-01D-351 and BV-01-B5 and prototype V-01 booster demonstrated remarkable cross-reactive immunogenicity against the prototype and multiple emerging variants of concern (VOCs), with the geometric mean ratio (versus CoronaVac) in particular being 31.3 (500 vs. 16), 12.0 (192 vs. 16) and 8.5 (136 vs.16) against BA.4/5 14 days after the booster, respectively. Taken together, the modified bivalent-formulation V-01 boosters induced robust neutralizing responses against multiple Omicron sublineages, better than V-01 and remarkably superior to ICV booster, without compromising the safety and tolerability. [ABSTRACT FROM AUTHOR]

The immune response of liver transplant (LT) recipients to a third dose of the BNT162b2 mRNA vaccine significantly waned after four months. We aimed to evaluate the immune response and breakthrough infection rates of a fourth dose against the Omicron variants among LT recipients. LT recipients who had no past or active SARS-CoV-2 infection and received three doses of the BNT162b2mRNA vaccine were included. Of the 73 LT recipients, 50 (68.5%) received a fourth dose. The fourth dose was associated with a significantly higher positive immune response than the third dose. Receptor-binding domain (RBD) IgG and Omicron BA.1 and BA.2 neutralizing antibodies were determined at a median of 132 and 29 days after the third and fourth vaccines. They were 345 binding antibody units per milliliter (BAU/mL) vs. 2118 BAU/mL (p < 0.0001), 10 vs. 87 (p < 0.0001), and 15 vs. 149 (p = 0.001), respectively. Breakthrough infections were documented among nine (18%) LT recipients after the fourth dose and among seven (30.4%) patients following the third dose (p = 0.2); 93.5% of breakthrough infections were mild. The infection rate after the fourth dose was higher among diabetic vs. nondiabetic recipients (33.3% vs. 6.9%, respectively; p = 0.02). Further studies are needed to evaluate additional factors influencing the breakthrough infection rate among LT recipients. [ABSTRACT FROM AUTHOR]

Background: People Living With HIV (PLWH), with advanced disease, lower CD4+ T cell counts or an unsuppressed HIV viral load can have a suboptimal vaccine response. For this reason, in the current COVID-19 pandemic, they represent a prioritized population for the SARS-CoV-2 fourth (or second booster) vaccine dose. This work aims to investigate the effects of a second booster on the reactivation of the spike-specific humoral and cell-mediated immune responses in PLWH. Methods: A total of eight PLWH, who received a fourth dose of the original mRNA vaccines were enrolled. They were evaluated before and then 7 days, 1 month and 2 months after the injection. The humoral response was assessed via a chemiluminescent immunoassay. Immunophenotyping and the functional evaluation of the SARS-CoV-2-specific cellular immune responses were performed via flow cytometry. Results: Anti-spike IgG levels were above the cut-off value for all subjects at all timepoints. The spike-specific CD4+ T cell response was reactivated one week after the fourth vaccine dose, and on average declined at two months post-vaccination. A similar trend was observed for the spike-specific B cells. A low percentage of spike-specific CD4+ T cells was activated by the B.1.1.529 BA.1 Omicron-spike mutated peptides, and the majority of these cells were reactive to the conserved portions of the spike protein. Similarly, the majority of the spike-specific memory B cells were able to bind both Wuhan and Omicron-spike entire protein. Conclusions: Spike-specific adaptive immune responses are transiently reactivated in PLWH following the fourth mRNA vaccine dose. The breadth of the immune responses to the mutated spike protein provides insight on the possible cross-reactivity for the SARS-CoV-2 variants of concern (VOCs). [ABSTRACT FROM AUTHOR]

배경: It is unknown if immunity developed by any coronavirus disease 2019 (COVID-19) vaccines before infection should be considered when deciding the optimal timing of vaccination after recovery from omicron-variant infection, or if a fourth vaccine after recovery from omicron infection confers additional immunity. 방법: The study population included patients aged ≥60 years and healthcare workers (HCWs) with omicron (BA.1) infection (February 16-March 16, 2022). Serum samples were collected (May 17-June 9, 2022) to assess the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surrogate virus neutralization test (sVNT) for antibody detection. 결과: Overall, 86 patients aged ≥60 years with different vaccination histories and 39 HCWs vaccinated three times prior to omicron infection were enrolled. Among patients aged ≥60 years, the sVNT50 titer was significantly lower in patients with incomplete vaccination prior to SARS-CoV-2 infection in the S clade (P<0.001), delta variant (P<0.001), and omicron variant (P=0.003) than in those vaccinated three times. The sVNT results against the omicron variant were not significantly different depending on the receipt of a fourth dose 2 months after COVID-19 in both patients aged ≥60 years (P=0.49) and HCWs (P=0.17). 결론: Incomplete COVID-19 vaccination prior to omicron infection in individuals aged ≥60 years confers limited protection against homologous and heterologous virus strains, while efficient cross-variant humoral immunity might be maintained for 3 months when vaccinated twice or thrice prior to omicron infection. However, a fourth dose (a second booster) 2 months after omicron infection did not enhance immunity against the homologous virus strain. [ABSTRACT FROM AUTHOR]

In this study, we aimed to determine the effect of COVID-19 vaccination on 3-month immune response and durability after natural infection by the Omicron variant and to assess the immune response to a fourth dose of COVID-19 vaccination in patients with prior natural infection with the Omicron variant. Overall, 86 patients aged ≥60 years with different vaccination histories and 39 health care workers (HCWs) vaccinated thrice before Omicron infection were enrolled. The sVNT50 titer was significantly lower in patients with incomplete vaccination before SARS-CoV-2 infection with the S clade (p < 0.001), Delta variant (p < 0.001), or Omicron variant (p = 0.003) than in those vaccinated thrice. The sVNT results against the Omicron variant did not differ significantly in patients aged ≥60 years (p = 0.49) and HCWs (p = 0.17), regardless of the recipient receiving the fourth dose 2 months after COVID-19. Incomplete COVID-19 vaccination before Omicron infection for individuals aged ≥60 years conferred limited protection against homologous and heterologous virus strains, whereas two or three doses of the vaccine provided cross-variant humoral immunity against Omicron infection for at least 3 months. However, a fourth dose 2 months after Omicron infection did not enhance immunity against the homologous strain. A future strategy using the bivalent Omicron-containing booster vaccine with appropriate timing will be crucial. [ABSTRACT FROM AUTHOR]

Background: In the ongoing COVID-19 pandemic, advanced age is a risk factor for a severe clinical course of SARS-CoV-2 infection. Thus, older people may benefit in particular from booster doses with potent vaccines and research should focus on optimal vaccination schedules. In addition to each individual's medical history, immunosenescence warrants further research in this population. This study investigates vaccine-induced immune response over 1 year.Methods/design: EU-COVAT-1-AGED is a randomised controlled, adaptive, multicentre phase II protocol evaluating different booster strategies in individuals aged ≥75 years (n=600) already vaccinated against SARS-CoV-2. The initial protocol foresaw a 3rd vaccination (1st booster) as study intervention. The present modified Part B of this trial foresees testing of mRNA-1273 (Spikevax®) vs. BNT162b2 (Comirnaty®) as 4th vaccination dose (2nd booster) for comparative assessment of their immunogenicity and safety against SARS-CoV-2 wild-type and variants. The primary endpoint of the trial is to assess the rate of 2-fold antibody titre increase 14 days after vaccination measured by quantitative enzyme-linked immunosorbent assay (Anti-RBD-ELISA) against wild-type virus. Secondary endpoints include the changes in neutralising antibody titres (Virus Neutralisation Assay) against wild-type as well as against Variants of Concern (VOC) at 14 days and up to 12 months. T cell response measured by qPCR will be performed in subgroups at 14 days as exploratory endpoint. Biobanking samples are being collected for neutralising antibody titres against potential future VOC. Furthermore, potential correlates between humoral immune response, T cell response and neutralising capacity will be assessed. The primary endpoint analysis will be triggered as soon as for all patients the primary endpoint (14 days after the 4th vaccination dose) has been observed.Discussion: The EU-COVAT-1-AGED trial Part B compares immunogenicity and safety of mRNA-1273 (Spikevax®) and BNT162b2 (Comirnaty®) as 4th SARS-CoV-2 vaccine dose in adults ≥75 years of age. The findings of this trial have the potential to optimise the COVID-19 vaccination strategy for this at-risk population.Trial Registration: ClinicalTrials.gov NCT05160766 . Registered on 16 December 2021.Protocol Version: V06_0: 27 July 2022. [ABSTRACT FROM AUTHOR]

Solid organ transplant recipients (SOTRs) show higher rates of COVID-19 breakthrough infection than the general population, and nowadays, vaccination is the key preventative strategy. Nonetheless, SOTRs show lower vaccine efficacy for the prevention of severe COVID-19. Moreover, the emergence of new SARS-CoV-2 variants of concern has highlighted the need to improve vaccine-induced immune responses by the administration of repeated booster doses. In this study, we analyzed the humoral and cellular responses in a cohort of 25 SOTRs, including 15 never-infected SOTRs who received the fourth dose of the mRNA vaccine and 10 SOTRs who contracted SARS-CoV-2 infection after the third dose. We analyzed the serum IgG and IgA levels through CLIA or ELISA, respectively, and the Spike-specific T cells by ELISpot assay. We report a significant increase in anti-Spike IgG and no differences in IgA secretion in both groups of patients before and after the booster dose or the natural infection. Still, we show higher IgA levels in recovered SOTRs compared to the fourth dose recipients. Conversely, we show the maintenance of a positive Spike-specific T-cell response in SOTRs who received the fourth dose, which, instead, was significantly increased in SOTRs who contracted the infection. Our results suggest that the booster, either through the fourth dose or natural infection, in vulnerable poor responder SOTRs, improves both humoral and cellular-specific immune responses against SARS-CoV-2. [ABSTRACT FROM AUTHOR]

There is scarce information on seroconversion and adverse events after immunization (AEFI) with the fourth dose of BNT162b2. Our aim was to correlate the magnitude of the antibody response to this vaccination regimen in terms of clinical conditions and AEFI. This was an observational pilot study in which SARS-CoV-2 S1–S2 IgG antibodies titers were measured 21–28 days after the first and second dose, three months after the second dose, 1–7 and 21–28 days after the third dose, before the fourth dose, and 21–28 days after the fourth dose. We recruited 112 subjects in a hospital in Mexico, 74% women, with an average age of 43 (SD 9) years. After the first dose, subjects had a median IgG AU/mL (IQR) of 122 (1904) that increased to 1875 (2095), 3020 (2330), and 4230 (3393) 21–28 days after the second, third, and fourth doses, respectively (p < 0.01). The number (%) who experienced any AEFI between the first and fourth doses was 90 (80.4), 89 (79), 65 (58), and 69 (61.5), respectively (p < 0.001). After the fourth dose, the most frequent of AEFI was pain at the injection site (87%). There was a correlation between AEFI and gender after the fourth dose, as well as with antibody levels (p < 0.05). During the Omicron outbreak, six (5.3%) had mild COVID-19 for 8–28 days after the fourth dose. The median increase in S1/S2 IgG was 30.8-fold after the fourth BNT162b2 dose when compared with the first dose and caused mild AEFI. [ABSTRACT FROM AUTHOR]

To date, many population pharmacokinetic models of antibiotics have been developed using blood sampling data after the fourth or fifth dose, which represents steady-state levels. However, if a model developed using blood sampled after the first dose is equivalent to that using blood sampled after the fourth dose, it would be advantageous to utilize the former. The aim of this study was to investigate the effect of blood sampling after the first and/or fourth drug administration on the accuracy and precision of parameter estimates. A previously reported robust, two-compartment model of vancomycin was used for simulation to evaluate the performances of the parameter estimates. The parameter estimation performances were assessed using relative bias and relative root mean square error. Performance was investigated in 72 scenarios consisting of a combination of two blood sampling periods (the first and fourth dose), two total clearances, three infusion times, and four sample sizes. The population pharmacokinetic models from data collected at the first dose and those collected at the fourth dose produced parameter estimates that were similar in accuracy and precision. This study will contribute to increasing the efficiency and simplicity of antibiotic pharmacokinetic studies. [ABSTRACT FROM AUTHOR]