Fourth Dose Research Articles

Final clinical results and first translational correlates of a phase 2 trial of adaptively dosed nivolumab and ipilimumab based on early radiographic assessment in advanced melanoma (ADAPT-IT).

9517 Background: Initial results from ADAPT-IT (NCT03122522) demonstrated that adaptive dosing of nivolumab (nivo) and ipilimumab (ipi) based on early radiographic assessment was associated with comparable response rates and toxicity compared to historical data for conventional nivo + ipi. Here, we report the final clinical analysis, including median progression-free survival (PFS), and present the first correlative analyses of blood-based biomarkers of response. Methods: ADAPT-IT was a multicenter, phase 2 clinical trial with a planned sample size of 60 patients with unresectable melanoma. Patients received two doses of nivo (1 mg/kg) + ipi (3 mg/kg) followed by a computed tomography scan at week 6. Patients with early favorable antitumor effect (FATE; defined as the absence of new lesions and ≤ 4% index lesion tumor growth), discontinued ipi and continued nivo alone. Patients without FATE at week 6 received third and fourth doses of nivo + ipi followed by nivo alone. The primary endpoint was investigator-assessed overall response rate (ORR; defined as the percent of patients with complete or partial responses by RECIST v1.1) at week 12. A Simon two-stage design was employed where a 43% 12-week ORR was considered not promising, a 60% 12-week ORR was considered promising, and the probabilities of type I and type II error were each set at 0.10. Pre- and on-treatment peripheral blood samples were assayed for 1) ten cytokines using a multiplex immunoassay (Meso Scale Diagnostics) and 2) circulating tumor DNA (ctDNA) using the MSK-ACCESS sequencing platform. The Wilcoxon rank sum test and Cox regression modeling were used to evaluate associations between biomarker levels with radiographic response and PFS, respectively. Results: 60 patients were enrolled. Week 12 and best ORR were 48% (95% CI, 35-61%) and 58% (95% CI, 45-71%), respectively. Median follow-up was 34 months (interquartile range: 21-36) in survivors, median PFS was 21 months (95% CI: 11-not reached) and the median overall survival was not reached. There were no new Grade 3-5 treatment-related adverse events since the initial report. Higher baseline IL-6 was observed in non-responders compared to responders (p = 0.03; n = 26) and was associated with shorter PFS (HR for progression or death 1.24; 95% CI: 1.01-1.52; p = 0.04). Among 20 patients with detectable ctDNA at baseline (of 25 patients with available samples), an increase in mean adjusted variant allele fraction from baseline to week 6 was associated with shorter PFS (HR 1.14; 95% CI: 1.02-1.27; p = 0.02). Conclusions: In this updated analysis, now with long-term follow-up, the efficacy of adaptively dosed nivo + ipi resembles that of historical data for standard dose nivo + ipi. Baseline IL-6 and on-treatment changes in ctDNA warrant further prospective study as biomarkers of response to ipi + nivo. Clinical trial information: NCT03122522 .

Altered Pharmacokinetics Parameters of Vancomycin in Patients with Hematological Malignancy with Febrile Neutropenia, a Bayesian Software Estimation.

The pharmacokinetics of vancomycin vary significantly between specific groups of patients, such as critically ill patients and patients with hematological malignancy (HM) with febrile neutropenia (FN). Recent evidence suggests that the use of the usual standard dose of antibiotics in patients with FN may not offer adequate exposure due to pharmacokinetic variability (PK). Therefore, the purpose of this study is to assess the effect of FN on AUC0-24 as a key parameter for vancomycin monitoring, as well as to determine which vancomycin PK parameters are affected by the presence of FN using Bayesian software PrecisePK in HM with FN. This study was carried out in King Abdulaziz Medical City. All adult patients who were admitted to the Princess Norah Oncology Center PNOC between 1 January and 2017 and 31 December 2020, hospitalized and received vancomycin with a steady-state trough concentration measured before the fourth dose, were included. During the trial period, 297 patients received vancomycin during their stay at the oncology center, 217 of them meeting the inclusion criteria. Pharmacokinetic parameters were estimated for the neutropenic and non-FN patients using the precise PK Bayesian platform. The result showed that there was a significant difference (p < 0.05) in vancomycin clearance Clvan, the volume of distribution at a steady-state Vdss, the volume of distribution for peripheral compartment Vdp, half-life for the elimination phase t½β, and the first-order rate constant for the elimination process β in FN compared to non-FN patients. Furthermore, AUC0-24 was lower for FN patients compared to non-FN patients, p < 0.05. FN has a significant effect on the PK parameters of vancomycin and AUC0-24, which may require specific consideration during the treatment initiation.

A Recent SARS-CoV-2 Infection Enhances Antibody-Dependent Cellular Cytotoxicity against Several Omicron Subvariants following a Fourth mRNA Vaccine Dose.

Since the beginning of the SARS-CoV-2 pandemic, several variants of concern (VOCs), such as the Alpha, Beta, Gamma, Delta and Omicron variants, have arisen and spread worldwide. Today, the predominant circulating subvariants are sublineages of the Omicron variant, which have more than 30 mutations in their Spike glycoprotein compared to the ancestral strain. The Omicron subvariants were significantly less recognized and neutralized by antibodies from vaccinated individuals. This resulted in a surge in the number of infections, and booster shots were recommended to improve responses against these variants. While most studies mainly measured the neutralizing activity against variants, we and others previously reported that Fc-effector functions, including antibody-dependent cellular cytotoxicity (ADCC), play an important role in humoral responses against SARS-CoV-2. In this study, we analyzed Spike recognition and ADCC activity against several Omicron subvariants by generating cell lines expressing different Omicron subvariant Spikes. We tested these responses in a cohort of donors, who were recently infected or not, before and after a fourth dose of mRNA vaccine. We showed that ADCC activity is less affected than neutralization by the antigenic shift of the tested Omicron subvariant Spikes. Moreover, we found that individuals with a history of recent infection have higher antibody binding and ADCC activity against all Omicron subvariants than people who were not recently infected. With an increase in the number of reinfections, this study helps better understand Fc-effector responses in the context of hybrid immunity.

Modified Foam Stability Test (Fs-50) as Predictor of Fetal Lung Maturity in Preterm Premature Rupture of Membrane Patients Given Dexamethasone Therapy

This study aims to determine the ability of the Modified Foam Stability (FS-50) test to predict fetal lung maturity in preterm premature rupture of membranes treated with Dexamethasone. The study sample included pregnant women with PROM at a gestational age of 24 to less than 34 weeks in the ER and Obstetrics Ward of Sanglah Central General Hospital, Denpasar. The patient underwent a vaginal speculum examination to collect fluid pooled in the vagina or from the outer cervical opening. Fluids are checked with the Modified Foam Stability (FS-50) test and graded from 0 to +4 to estimate fetal lung maturity. The first test was performed before Dexamethasone, followed by serial examinations at 12-hour intervals for 48 hours. Before dexamethasone injection, all patients got 0 scores as a baseline. There were statistically significant differences in FS-50 values before and after injection of the first, second, third, and fourth doses of Dexamethasone in PPROM patients. Fetal lung maturity was reached after the third dose of dexamethasone injection (36 hours after the first injection), characterized by an FS-50 value of &gt; +3 and no asphyxia in the newborn. Spearman's rank analysis showed a significant correlation (p=0.005) between infants' maximum FS-50 value and asphyxia status. The FS-50 value &gt; +3 is associated with the absence of asphyxia in infants born to PPROM patients who were given Dexamethasone for lung maturation. FS-50 can predict fetal lung maturity in preterm premature rupture of membranes given dexamethasone therapy.

Antibody Responses Against Emerging SARS-CoV-2 Omicron Lineages After the Fourth Dose of mRNA Vaccine in Kidney Transplant Recipients.

Antibody Responses Against Emerging SARS-CoV-2 Omicron Lineages After the Fourth Dose of mRNA Vaccine in Kidney Transplant Recipients.

Safety, immunogenicity, and efficacy of the mRNA vaccine CS-2034 as a heterologous booster versus homologous booster with BBIBP-CorV in adults aged ≥18 years: a randomised, double-blind, phase 2b trial

Heterologous boosting is suggested to be of use in populations who have received inactivated COVID-19 vaccines. We aimed to assess the safety and immunogenicity of a heterologous vaccination with the mRNA vaccine CS-2034 versus the inactivated BBIBP-CorV as a fourth dose, as well as the efficacy against the SARS-CoV-2 omicron (BA.5) variant. This trial contains a randomised, double-blind, parallel-controlled study in healthy participants aged 18 years or older (group A) and an open-label cohort in participants 60 years and older (group B), who had received three doses of inactivated whole-virion vaccines at least 6 months before enrolment. Pregnant women and people with major chronic illnesses or a history of allergies were excluded. Eligible participants in group A were stratified by age (18-59 years and ≥60 years) and then randomised by SAS 9.4 in a ratio of 3:1 to receive a dose of the mRNA vaccine (CS-2034, CanSino, Shanghai, China) or inactivated vaccine (BBIBP-CorV, Sinopharm, Beijing, China). Safety and immunogenicity against omicron variants of the fourth dose were evaluated in group A. Participants 60 years and older were involved in group B for safety observations. The primary outcome was geometric mean titres (GMTs) of the neutralising antibodies against omicron and seroconversion rates against BA.5 variant 28 days after the boosting, and incidence of adverse reactions within 28 days. The intention-to-treat group was involved in the safety analysis, while all patients in group A who had blood samples taken before and after the booster were involved in the immunogenicity analysis. This trial was registered at the Chinese Clinical Trial Registry Centre (ChiCTR2200064575). Between Oct 13, and Nov 22, 2022, 320 participants were enrolled in group A (240 in the CS-2034 group and 80 in the BBIBP-CorV group) and 113 in group B. Adverse reactions after vaccination were more frequent in CS-2034 recipients (158 [44·8%]) than BBIBP-CorV recipients (17 [21·3%], p<0·0001). However, most adverse reactions were mild or moderate, with grade 3 adverse reactions only reported by eight (2%) of 353 participants receiving CS-2034. Heterologous boosting with CS-2034 elicited 14·4-fold (GMT 229·3, 95% CI 202·7-259·4 vs 15·9, 13·1-19·4) higher concentration of neutralising antibodies to SARS-CoV-2 omicron variant BA.5 than did homologous boosting with BBIBP-CorV. The seroconversion rates of SARS-CoV-2-specific neutralising antibody responses were much higher in the mRNA heterologous booster regimen compared with BBIBP-CorV homologous booster regimen (original strain 47 [100%] of 47 vs three [18·8%] of 16; BA.1 45 [95·8%] of 48 vs two [12·5%] 16; and BA.5 233 [98·3%] of 240 vs 15 [18·8%] of 80 by day 28). Both the administration of mRNA vaccine CS-2034 and inactivated vaccine BBIBP-CorV as a fourth dose were well tolerated. Heterologous boosting with mRNA vaccine CS-2034 induced higher immune responses and protection against symptomatic SARS-CoV-2 omicron infections compared with homologous boosting, which could support the emergency use authorisation of CS-2034 in adults. Science and Technology Commission of Shanghai, National Natural Science Foundation of China, Jiangsu Provincial Science Fund for Distinguished Young Scholars, and Jiangsu Provincial Key Project of Science and Technology Plan. For the Chinese translation of the abstract see Supplementary Materials section.

Humoral Response After Five Successive Doses of SARS-CoV-2 mRNA Vaccine in Kidney Transplant Patients.

The poor humoral response after vaccination against SARS-CoV-2 in kidney transplant (KT) patients led to the approval of successive booster doses.1 In recent weeks, the administration of a fifth dose of bivalent vaccines to KT, including components of the original virus strain and of the Omicron variant, was approved in Spain.2 The information about the effect of this new dose of messenger RNA (mRNA) vaccine on KT humoral response is limited and inaccurate.3,4 In our center, the humoral response to mRNA vaccine was prospectively studied in 16 stable KT recipients who received 5 successive doses between March 2021 and December 2022 (Table 1). They had not received monoclonal antibodies against the virus previously. No prior SARS-CoV-2 infection was confirmed by negative IgG antibodies against the nucleocapsid in all of them. The level of SARS-CoV-2 IgG anti-S antibodies at baseline and 1 mo after 2, 3, 4, and 5 doses was quantified by SARS-CoV-2 IgG chemiluminescent microparticle immunoassay (Abbott). Seroconversion was considered with an anti-S antibody titer greater than 260 BAU/mL. The seroconversion rate was 12.5% after 2 doses, 56.2% after the third, 81.2% after the fourth, and 93.8% after the fifth one. Only 1 KT did not develop antibodies after the fifth dose, who is the oldest in this series (73 y). Patients who seroconverted after 2 doses (n = 2) doubled the antibody titer after the third one; in those who seroconverted after 3 doses (n = 7), it increased by 380% after the fourth, and by 60% after the fifth one in those who seroconverted after 4 doses (n = 4). No patients presented acute rejection or serious adverse effects. TABLE 1. - Clinical and analytical characteristics of the patients N = 16 mRNA vaccine type, n (mRNA-1273/BNT162b2) 15/1 Male gender, n (%) 12 (75) Age, median [IQR] 61.5 [52.2–68] Diabetes, n (%) 9 (56.2) Time from KT to SARS-CoV-2 vaccine (mo), median [IQR] 50 [19.8–207] Serum creatinine at first dose, median [IQR] 1.3 [1–1.47] Induction immunosuppressive therapy, n (%) 9 (56.3) Tacrolimus, n (%) 15 (93.8) MPA, n (%) 11 (68.8) mTOR inhibitors, n (%) 3 (18.7) Prednisone, n (%) 16 (100) Thymoglobulin in the 2 y before SARS-CoV-2 vaccine, n (%) 5 (31.3) Rituximab in the year before SARS-CoV-2 vaccine, n (%) 0 Belatacept, n (%) 0 Non-heart-beating donor, n (%) 4 (25) Anti-S antibody titer after the second dose (BAU/mL), median 1070 Anti-S antibody titer after the third dose (BAU/mL), median [IQR] 1218 [689–2474] Anti-S antibody titer after the fourth dose (BAU/mL), median [IQR] 2029 [1021–5250] Anti-S antibody titer after the fifth dose (BAU/mL), median [IQR] 3105 [1466–5680] Time between KT and first dose (mo), median [IQR] 50 [19.7–207] Time between second and third doses (d), median [IQR] 127 [124.2–128.7] Time between third and fourth doses (d), median [IQR] 199 [196–204.7] Time between fourth and fifth doses (d), median [IQR] 202.5 [199.2–210] IQR, interquartile range; KT, kidney transplant; MPA, mycophenolic acid; mRNA, messenger RNA. An early experience in 8 KTs was reported with encouraging results, although not all received mRNA vaccines.3 Osmanodja et al retrospectively analyzed the serological response to the fifth dose in a cohort of KT patients.4 However, these patients had previously received different types of vaccines, not only mRNA, and mycophenolic acid dose adjustments was performed before the fourth dose, hindering the interpretation of their results. Our experience includes stable patients followed up prospectively without changes in their immunosuppressive therapy, which allows to analyze the effect of successive vaccine doses with fewer confounding factors. Our results support that successive doses progressively increase the seroconversion rate, allowing the majority of KT patients to maintain an adequate serological response. The limitations of our study include the small number of patients and the lack of information on cellular immunity. However, we present for the first time the evolution of the humoral response after 5 doses of mRNA vaccine in KT. In our opinion, it seems necessary to continue with the vaccination booster given the high seroconversion rate achieved. We must also identify those nonresponders who could benefit from passive immunization. However, the continuous mutations of the virus decrease the efficacy of monoclonal antibody-based prevention,5 so if the infection becomes endemic, it may be beneficial to continue with periodic vaccination boosters in KT patients, similar to the influenza vaccination strategies.

Protection from Omicron Infection in Residents of Nursing and Retirement Homes in Ontario, Canada.

To identify factors that contribute to protection from infection with the Omicron variant of SARS-CoV-2 in older adults in nursing and retirement homes. Longitudinal cohort study with retrospective analysis of infection risk. 997 residents of nursing and retirement homes from Ontario, Canada, in the COVID in LTC study. Residents with 3 messenger RNA (mRNA) dose vaccinations were included in the study. SARS-CoV-2 infection was determined by positive nasopharyngeal polymerase chain reaction test and/or circulating antinucleocapsid IgG antibodies. Cumulative probability of Omicron infection after recent COVID-19 was assessed by log-rank test of Kaplan-Meier curves. Cox regression was used to assess risk of Omicron infection by age, sex, mRNA vaccine combination, whether individuals received a fourth dose, as well as recent COVID-19. In total, 171 residents (17.2%) had a presumed Omicron variant SARS-CoV-2 infection between December 15, 2021 (local start of the first Omicron wave) and May 3, 2022. Risk of Omicron infection was not different by age [hazard ratio (95% confidence interval) 1.01 (0.99‒1.02)], or in women compared with men [0.97 (0.70‒1.34)], but infection risk decreased 47% with 3 vaccine doses of mRNA-1273 (Moderna) compared with BNT162b2 (Pfizer) [0.53 (0.31-0.90)], 81% with any fourth mRNA vaccine dose [0.19 (0.12‒0.30)], and 48% with SARS-CoV-2 infection in the 3months prior to beginning of the Omicron wave [0.52, (0.27‒0.99)]. Vaccine type (ie, mRNA-1273/Spikevax vs BNT162b2/Cominarty), any fourth vaccine dose, and hybrid immunity from recent COVID-19, were protective against infection with the Omicron variant. These data emphasize the importance of vaccine type, and number of vaccine doses, in maintenance of protective immunity and reduction of risk of Omicron variant breakthrough infection. These findings promote continued public health efforts to support vaccination programs and monitor vaccine immunogenicity in older adults.

COVID-19 Nedeni ile Yatarak Tedavi Görenlerde Aşıların ve Hatırlatma Dozlarının Hastalık Sürecine ve Mortaliteye Etkisi

Objective: As of the first months of 2020, vaccination is the most effective method to combat the COVID-19 pandemic, which has become a part of our lives. This study aims to describe the vaccination status of inpatients, the effectiveness of booster vaccine protocols, and the risk factors for intensive care unit (ICU) and mortality of COVID-19 patients.&#x0D; Materials and Methods: Our study included 247 patients hospitalized in a tertiary care hospital due to COVID-19. Patients hospitalized for non-COVID-19 reasons were excluded from the study even if the PCR test was positive. Socio-demographic data, clinical and laboratory findings of the participants were recorded using the hospital database and a questionnaire. Patients were divided into groups as mild-moderate-severe disease in terms of disease severity, ward and ICU in terms of hospitalization clinic. According to vaccination status, they were categorized as unvaccinated, Sinovac-based protocols, BioNTech-based protocols and others. &#x0D; Results: Of the 247 patients in the study, 55.1% were male and the mean age was 60 ± 17.26 years. 38.5% of the patients were admitted to the ICU and 9.3% died. It was observed that 38.8% of those admitted to the ICU and 56.5% of those who died were not vaccinated. Being over 65 years of age (p=0.008), being hospitalized for more than 7 days (p=0.003), having a severe illness (p=0.002), having a nervous system disease (p=0.005) and having other comorbidities (p=0.000), were significant for ICU admission, whereas disease severity (p=0.000) and comorbidities such as hypertension (p=0.000), diabetes mellitus (p=0.020) and cardiovascular diseases (p=0.000) were found to be risk factors for mortality.&#x0D; Conclusion: The addition of reminder doses, especially the fourth dose, to vaccination protocols may be more beneficial in preventing the need for ICU follow-up, which increases mortality in COVID-19.

Effect of adjunct Vitamin D treatment in vitamin D deficient pulmonary tuberculosis patients: A randomized, double blind, active controlled clinical trial

BackgroundSince, Vitamin D [1α,25(OH)2D)] enhances antimicrobial activity of Innate immunity and modulate Adaptive immune responses, simultaneously, so it play a potential role for balanced immune activity against Mycobacterium tuberculosis and restricting tissue injuries within the TB patients.(Chun et al., 2011) 9 We aimed to determine the role of adjunct Vitamin D treatment on the outcome of pulmonary tuberculosis patients and evaluated the effect of Vitamin D administration on Differential Leucocyte Count, Erythrocyte Sedimentation Rate, serum Adenosine deaminase, serum C- reactive protein, Oxygen saturation (SpO2) and Body Weight in Vitamin D deficient pulmonary tuberculosis patients. MethodsWe conducted a prospective, interventional, randomized, double blind, parallel group, active controlled clinical trial. Newly diagnosed Vitamin D deficient pulmonary tuberculosis patients were randomly assigned to intervention group (received standard anti-tubercular treatment with adjunct Vitamin D3) and control group (received standard anti-tubercular treatment without adjunct Vitamin D3). Total four doses [each dose of 2.5 mg (100000 IU)] of Vitamin D3 were given, orally. First dose was given within 7 days of starting anti-tubercular treatment and second, third, fourth dose were given at 2, 4 and 6 weeks respectively. At the time of enrollment, we measured all baseline characteristics. During follow-up, we measured the study variables and monitored adverse events at 2, 4, 6, 8 and 12 weeks. Our safety parameter was serum corrected calcium level to assess the risk of hypercalcemia. ResultsTotal 130 pulmonary TB patients, 65 patients in each group, were analyzed. Our study results showed that decrease in Neutrophil count was statistically significant with small effect sizes at every time point of measurement and increase in Lymphocyte count was statistically significant with small and moderate effect sizes at 4, 6 and 8 week for intervention group than for control group. Decrease in erythrocyte sedimentation rate was statistically significant with small effect sizes at 6 and 8 week, decrease in serum adenosine deaminase and serum C- reactive protein was statistically significant with moderate effect sizes at 4, 6 and 8 week for intervention group than for control group. Increase in Oxygen saturation was statistically significant at 4 week with small effect size and increase in body weight was statistically significant with small effect sizes for intervention group than for control group. No case of hypercalcemia was reported. ConclusionOur findings suggest a potential role of adjunctive Vitamin D3 to accelerate resolution of inflammatory responses and improvement in clinical outcomes of pulmonary TB patients. Trial registrationThis trial is registered with Clinical Trials Registry - INDIA (http://ctri.nic.in) with CTRI Number - CTRI/2021/11/037914. Place of studyRoom Number 27, first floor out-patients department (OPD) and inpatient Wards, fourth floor, Department of Respiratory Medicine, Uttar Pradesh University of Medical Sciences, Saifai, Etawah (U.P.), INDIA.

Expected usefulness of fourth dose of COVID-19 vaccine for immunizing breast cancer patients.

Expected usefulness of fourth dose of COVID-19 vaccine for immunizing breast cancer patients.

Humoral Response after a Fourth Dose with mRNA-1273 in Healthcare Workers with and without a History of SARS-CoV-2 Infection and Previously Vaccinated with Two Doses of BBIBP-CorV Plus BNT162b2 Vaccine.

There is limited information on the kinetics of the humoral response elicited by a fourth dose with a heterologous mRNA1273 booster in patients who previously received a third dose with BNT162b2 and two doses of BBIBP-CorV as the primary regimen. We conducted a prospective cohort study to assess the humoral response using Elecsys® anti-SARS-CoV-2 S (anti-S-RBD) of 452 healthcare workers (HCWs) in a private laboratory in Lima, Peru at 21, 120, 210, and 300 days after a third dose with a BNT162b2 heterologous booster in HCW previously immunized with two doses of BBIBP-CorV, depending on whether or not they received a fourth dose with the mRNA1273 heterologous vaccine and on the history of previous SARS infection -CoV-2. Of the 452 HCWs, 204 (45.13%) were previously infected (PI) with SARS-CoV-2, and 215 (47.57%) received a fourth dose with a heterologous mRNA-1273 booster. A total of 100% of HCWs presented positive anti-S-RBD 300 days after the third dose. In HCWs receiving a fourth dose, GMTs 2.3 and 1.6 times higher than controls were observed 30 and 120 days after the fourth dose. No statistically significant differences in anti-S-RBD titers were observed in those HCWs PI and NPI during the follow-up period. We observed that HCWs who received a fourth dose with the mRNA1273 and those previously infected after the third dose with BNT162b2 (during the Omicron wave) presented higher anti-S-RBD titers (5734 and 3428 U/mL, respectively). Further studies are required to determine whether patients infected after the third dose need a fourth dose.

Trends in Antibody Titers after SARS-CoV-2 Vaccination—Insights from Self-Paid Tests at a General Internal Medicine Clinic

Background: The rise in antibody titers against the novel coronavirus (SARS-CoV-2) and its duration are considered an important indicator for confirming the effect of a COVID-19 vaccine, and self-paid tests of antibody titer are conducted in many facilities nationwide. Methods: The relationship between the number of days after the second and third dose of vaccines, age, and antibody titer was determined from the medical records of general internal medicine clinics that conducted self-paid testing of the SARS-CoV-2 antibody titer using Elecsys Anti-SARS-CoV-2 S (Roche Diagnostics); the relationship between the number of days after two or more doses of vaccines and antibody titer was also determined. We also examined the antibody titers in cases of spontaneous infection with SARS-CoV-2 after two or more doses of the vaccine. Results: Log-transformed SARS-CoV-2 antibody titers measured within 1 month from the second or third dose of vaccine showed a negative correlation with age (p < 0.05). In addition, the log-transformed antibody titers also showed a negative correlation trend with the number of days after the second dose of vaccine (p = 0.055); however, there were no significant correlations between the log-transformed antibody titers and the number of days after the third dose of vaccine. The median antibody titer after the third vaccination was 18,300 U/mL, more than 10 times the median antibody titer after the second dose of vaccine, of 1185 U/mL. There were also some cases of infection after the third or fourth dose of vaccine, with antibody titers in the tens of thousands of U/ml after infection, but the patients still received further booster vaccinations after the infection. Conclusions: The antibody titers after the third vaccination did not attenuate after a short follow-up period of one month, while they tended to attenuate after the second vaccination. It is considered that many people in Japan received further booster vaccinations after spontaneous infection, even though they already had antibody titers in the tens of thousands of U/mL due to "hybrid immunity" after spontaneous infection following two or more doses of vaccine. The clinical significance of the booster vaccination in this population still needs to be thoroughly investigated and should be prioritized for those with low SARS-CoV-2 antibody titers.

Antibody titer after administration of mRNA-based vaccine against severe acute respiratory syndrome coronavirus 2 in liver transplant recipients.

The mRNA-based vaccine was released as a COVID-19 prophylactic; however, its efficacy in organ transplant recipients is unknown. This study aimed to clarify this in liver transplant recipients. Herein, liver transplant recipients from two hospitals who received vaccines were included. Immunoglobulin-G antibodies against the spike and nucleocapsid proteins were measured chronologically after the second, third, and fourth vaccine doses. Antibody levels in 125 liver transplant recipients and 20 healthy volunteers were analyzed. The median age at transplant was 35 (interquartile range 1, 53) years, and the period between transplant and the first dose was 15.2 ± 7.7 years. After the second and third doses, 89.1% and 100% of recipients displayed a positive humoral response, respectively. Anti-spike antibodies after the second dose were significantly reduced at 3 and 6 months, compared to that at 1 month (26.0 [5.4, 59.5], 14.7 [6.5, 31.4] vs. 59.7 [18.3, 164.0] AU/mL, respectively, p < 0.0001). However, a booster vaccine significantly elevated anti-spike antibodies in LT recipients (p < 0.0001) as well as in healthy controls (p < 0.0001). Additionally, the decay rate was comparable between the transplant recipients and controls (2.1 [0.8, 4.5] vs. 2.7 [1.1, 4.1] AU/mL/day, p = 0.9359). Only 4.0% of vaccinated transplant recipients were positive for anti-nucleocapsid antibodies. Liver transplant recipients can acquire immunity similar to that of healthy people through vaccination against SARS-CoV-2. The antibody decay rate is the same, and booster vaccinations should be administered similarly to that in healthy individuals.

Effectiveness of Booster Doses of Monovalent mRNA COVID-19 Vaccine Against Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Children, Adolescents, and Adults During Omicron Subvariant BA.2/BA.2.12.1 and BA.4/BA.5 Predominant Periods.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) BA.2/BA.2.12.1 and BA.4/BA.5 subvariants have mutations associated with increased capacity to evade immunity when compared with prior variants. We evaluated mRNA monovalent booster dose effectiveness among persons ≥5 years old during BA.2/BA.2.12.1 and BA.4/BA.5 predominance. A test-negative, case-control analysis included data from 12 148 pharmacy SARS-CoV-2 testing sites nationwide for persons aged ≥5 years with ≥1 coronavirus disease-2019 (COVID-19)-like symptoms and a SARS-CoV-2 nucleic acid amplification test from April 2 to August 31, 2022. Relative vaccine effectiveness (rVE) was estimated comparing 3 doses of COVID-19 mRNA monovalent vaccine to 2 doses; for tests among persons ≥50 years, rVE estimates also compared 4 doses to 3 doses (≥4 months since third dose). A total of 760 986 test-positive cases and 817 876 test-negative controls were included. Among individuals ≥12 years, rVE of 3 versus 2 doses ranged by age group from 45% to 74% at 1-month post vaccination and waned to 0% by 5-7 months post vaccination during the BA.4/BA.5 period.Adults aged ≥50 years (fourth dose eligible) who received 4 doses were less likely to have symptomatic SARS-CoV-2 infection compared with those with 3 doses; this rVE remained >0% through at least 3 months since last dose. For those aged ≥65 years, rVE of 4 versus 3 doses 1-month post vaccination was higher during BA.2/BA.2.12.1 (rVE = 49%; 95% confidence interval [CI], 43%-53%) than BA.4/BA.5 (rVE = 40%; 95% CI, 36%-44%). In 50- to 64-year-olds, rVE estimates were similar. Monovalent mRNA booster doses provided additional protection against symptomatic SARS-CoV-2 infection during BA.2/BA.2.12.1 and BA.4/BA.5 subvariant circulation, but protection waned over time.

Posterior scleritis following COVID-19 vaccination in an elderly patient

We report a case of posterior scleritis masquerading as choroidal melanoma following COVID-19 vaccination. An 86-year-old Caucasian male presented to a retina specialist with a 2-month history of blurred vision and pain right eye (OD). He received his fourth dose of the Pfizer-BioNTech COVID-19 vaccine before developing ocular symptoms. An intraocular mass was found OD and he was referred to our Ocular Oncology Service for potential choroidal melanoma with exudative retinal detachment. On examination, there was a 360-degree episcleral injection and no evidence of choroidal mass OD. Multimodal imaging confirmed no abnormality. Previous ultrasonography demonstrated an echolucent choroidal mass, likely representing choroidal effusion and minimal episcleral Tenon’s edema, suggesting posterior scleritis with spontaneous resolution over 1 week. Posterior scleritis following COVID-19 vaccination can masquerade as choroidal melanoma. In our case, the scleritis resolved spontaneously with no treatment and minimal consequences.

Levels and durability of neutralizing antibodies against SARS-CoV-2 Omicron and other variants after ChAdOx-1 or BNT162b2 booster in CoronaVac-primed elderly individuals

The outbreak of the SARS-CoV-2 Omicron variant raised the need for vaccine boosting. We evaluated the efficiency of the third booster vaccine, ChAdOx-1 or BNT162b2, in causing a neutralizing antibody (NAb) response and its durability against the Omicron and other variants in elderly individuals previously vaccinated with 2-dose CoronaVac inactivated vaccine. After receiving 2-dose CoronaVac, only 2.2% of subjects had NAbs against the Omicron variant above the cut-off value. Four weeks after boosting, the number of subjects who had NAb levels above the cut-off values in the ChAdOx-1 and BNT162b2 vaccine boosting groups increased to 41.7% and 54.5%, respectively. However, after 12 and 24 weeks of boosting with any vaccines, NAb levels against the Omicron variant dramatically waned. Twenty-four weeks after boosting, only 2% had high levels of NAbs against the Omicron variant. Compared to other variants, the Omicron variant was less responsive to boosting vaccines. The waning rate of NAb levels for the Omicron variant was much faster than that observed in the Alpha, Beta and Delta variants. To combat the Omicron variant, the fourth booster dose is, therefore, recommended for elderly individuals.

Omicron BA.4/5 Neutralization and T-Cell Responses in Organ Transplant Recipients After Booster Messenger RNA Vaccine: A Multicenter Cohort Study.

In solid organ transplant (SOT) recipients, the primary vaccination series against Coronavirus Disease 2019 is 3 doses followed by boosters. We determined whether a fourth dose booster induced Omicron BA.4/5 neutralizing antibodies (nAbs) and T cells in a large multicenter cohort study. Serum was collected 4-6 weeks post-third and post-fourth doses of messenger RNA vaccine in 222 SOT recipients. nAbs were measured using a pseudovirus neutralization assay that targeted the Omicron BA.4/5 spike protein. A subset underwent T-cell testing. The median age of the cohort was 63 years (interquartile range [IQR], 50-68) with 61.7% men. BA.4/5 nAb detection increased from 26.6% (59 of 222) post-third dose to 53.6% (119 of 222) post-fourth dose (P < .0001). In patients with breakthrough infection prior to the fourth dose (n = 27), nAbs were detected in 77.8% and median nAb titers were significantly higher compared with those with 4 vaccine doses alone (P < .0001). Factors associated with a low BA.4/5 neutralization response after the fourth dose were older age (odds ratio [OR], 0.96; 95% confidence interval [CI], .94-.99), mycophenolate use (OR, 0.39; 95% CI, .20-.77) and prednisone use (OR, 0.34; 95% CI, .18-.63), and vaccine type (OR, 0.72; 95% CI, .51-.99), while breakthrough infection prior to the fourth dose (OR, 3.6; 95% CI, 1.3-9.9) was associated with a greater nAb response. Polyfunctional BA.4/5-specific CD4+ T cells significantly increased after 4 doses and were identified in 76.9% of patients at a median frequency of 213/106 cells (IQR, 98-650). In summary, a booster significantly increases BA.4/5-specific neutralization and polyfunctional CD4+ T-cell responses, suggesting protection from severe disease even with new Omicron variants. However, SOT recipients who are older and on mycophenolate and prednisone need additional preventative strategies.

Blunted humoral immune response to the fourth dose of BNT162b2 COVID-19 vaccine in patients undergoing hemodialysis.

We aimed to investigate the impact of a fourth dose of BNT162b2 vaccine (Comirnaty®, Pfizer-BioNTech) on anti-SARS-CoV-2 (anti-S IgG) antibody titers in patients receiving hemodialysis (HD) and healthcare workers (HCWs). A multi-institutional retrospective study at five dialysis clinics in Japan was conducted using 238 HD patients and 58 HCW controls who received four doses of the BNT162b2 mRNA vaccine. Anti-S IgG titers were measured at 1, 3, and 6months after the second dose, at 1 and 5/6months after the third dose, and at 1month after the fourth dose of vaccine. The log anti-S IgG titers of the HD patients after the second vaccination were significantly lower than those of the control group, but equalized 1month after the third vaccination: 9.94 (95% CI 9.82-10.10) vs. 9.81 (95% CI 9.66-9.96), (P = 0.32). In both groups, the fold-increase in anti-S IgG titers was significantly lower after the fourth dose than after the third dose of vaccine. In addition, there was a strong negative correlation between antibody titers 1month after the fourth vaccination and antibody titers immediately before the vaccination. In both groups, the waning rate of anti-S IgG titers from the post-vaccination peak level after the third vaccine dose was significantly slower than that after the second dose. These findings suggest that the humoral immune response was blunted after the fourth dose of the conventional BNT162b2 vaccine. However, multiple vaccinations could extend the window of humoral immune protection.

A Seroprevalence Study on Residents in a Senior Care Facility with Breakthrough SARS-CoV-2 Omicron Infection.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began spreading rapidly in the community in November 2021, becoming the dominant variant in the Republic of Korea in 2022. Although its pathogenesis in healthy individuals was low, the severity and hospitalization rate was higher in the elderly and immunocompromised patients. We aimed to investigate the immunogenicity in acute and convalescent phases of breakthrough infection by Omicron in elderly individuals. Serological data were assessed by electrochemiluminescence immunoassay, enzyme-linked immunosorbent assay, and plaque-reduction neutralization tests. SARS-CoV-2-specific antibody and immunoglobulin G levels in the acute phase were higher in third dose-vaccinated elderly than in first and second dose-vaccinated patients. The neutralization antibody titer was detected only in third dose-vaccinated patients, and the titer was higher for the Delta than the Omicron variant. In the convalescent phase of Omicron infection, the neutralization antibody titer of vaccinated patients was higher for the Delta than the Omicron variant except in unvaccinated individuals. We demonstrated that the cause of the vulnerability to Omicron variant infection in third dose-vaccinated elderly was due to the low neutralization antibody level against Omicron. A fourth dose of vaccination is required in the elderly to reduce hospitalization and mortality caused by the Omicron variant.