Humoral response after a fourth dose of SARS-CoV-2 vaccine in immunocompromised patients. Results of a systematic review.

Background and objective: The fourth dose the COVID-19 vaccine was first proposed to immunocompromised patients. The aim of the article is to systematically review the literature and report the humoral response and outcomes after the fourth dose administration in people with impaired immune system. Methods: Published studies on the humoral response, efficacy and safety of the fourth dose of the COVID-19 vaccine were analyzed in various settings of immunocompromised patients. We conducted systematic searches of PubMed, Cochrane Library and WHO COVID-19 Research Database for series published through January 31, 2023, using the search terms "fourth dose" or "second booster" or "4th dose" and "Coronavirus" or "COVID-19" or "SARS-CoV-2." All articles were selected according to the PRISMA guidelines. Results: A total of 24 articles including 2,838 patients were comprised in the systematic review. All the studies involved immunocompromised patients, including solid organ transplant recipients, patients with autoimmune rheumatic disease, patients with human immunodeficiency virus (HIV) and patients with blood cancers or diseases. Almost all patients received BNT162b2 or mRNA-1273 as fourth dose. All the studies demonstrated the increase of antibody titers after the fourth dose, both in patients who had a serological strong response and in those who had a weak response after the third dose. No serious adverse events after the 4th dose have been reported by 13 studies. COVID-19 infection after the fourth dose ranged from 0 to 21%. Conclusion: The present review highlights the importance of the fourth dose of covid-19 vaccines for immunocompromised patients. Across the included studies, a fourth dose was associated with improved seroconversion and antibody titer levels. In particular, a fourth dose was associated with increasing immunogenicity in organ transplant recipients and patients with hematological cancers, with a very low rate of serious side effects.

Assessing acceptability of the fourth dose against COVID-19 among Chinese adults: A population-based survey.

Coronavirus disease 2019 (COVID-19) has wreaked havoc across the globe for approximately three years. Vaccination is a key factor to ending this pandemic, but its protective effect diminishes over time. A second booster dose at the right time is needed. To explore the willingness to receive the fourth dose of the COVID-19 vaccine and its influencing factors, we commenced a national, cross-sectional and anonymous survey in mainland China among people aged 18 and above from October 24 to November 7, 2022. A total of 3,224 respondents were eventually included. The acceptance rate of the fourth dose was 81.1% (95% CI: 79.8-82.5%), while it was 72.6% (95% CI: 71.1-74.2%) for a heterologous booster. Confidence in current domestic situation and the effectiveness of previous vaccinations, and uncertainty about extra protection were the main reasons for vaccine hesitancy. Perceived benefit (aOR = 1.29, 95% CI: 1.159-1.40) and cues to action (aOR = 1.73, 95% CI: 1.60-1.88) were positively associated with the vaccine acceptance, whereas perceived barriers (aOR = 0.78, 95% CI: 0.72-0.84) and self-efficacy (aOR = 0.79, 95% CI: 0.71-0.89) were both negatively associated with it. Additionally, sex, age, COVID-19 vaccination history, time for social media, and satisfaction with the government's response to COVID-19 were also factors affecting vaccination intention. Factors influencing the intention of heterologous booster were similar to the above results. It is of profound theoretical and practical significance to clarify the population's willingness to vaccinate in advance and explore the relevant influencing factors for the subsequent development and promotion of the fourth-dose vaccination strategies.

Effect of a Fourth Dose of mRNA Vaccine and of Immunosuppression in Preventing SARS-CoV-2 Breakthrough Infections in Heart Transplant Patients.

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.

The Bivalent COVID-19 Booster Immunization after Three Doses of Inactivated Vaccine Augments the Neutralizing Antibody Response against Circulating Omicron Sublineages.

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.

Fourth Dose of BNT162b2 Vaccine for Patients with Autoimmune Rheumatic Diseases in a Nationwide Setting.

OBJECTIVE: The effectiveness of COVID-19 vaccinations wanes due to immune evasion of the B.1.1.529 (Omicron) variant and diminished antibody titers over time. We aim to evaluate the benefit of a fourth vaccination dose in patients with autoimmune rheumatic diseases (ARD). METHODS: A retrospective analysis included ARD patients 18 years or older in the Clalit health management organization in Israel, insured 52% of the entire population, from January 16, 2022, to March 31, 2022, when the predominant SARS-CoV-2 variant was Omicron. We compared patients without previous COVID-19 infection who received three doses of the BNT162b2 vaccine (control) to those who received the fourth dose. The primary outcome was COVID-19 infection, which was analyzed using multivariate Cox regression in the entire cohort and within ARD subgroups. Secondary outcomes were COVID-19-related hospitalizations and 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 6,942 (25.0%) of the control group and 1,754 (11.0%) of the fourth dose group (p < 0.001). Patients vaccinated with the fourth dose had a lower risk for COVID-19 infection in the entire cohort (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 in COVID-19-related hospitalization (HR 0.36, 95% C.I 0.22-0.61) and COVID-19-related death (HR 0.41, 95% C.I 0.24-0.71). CONCLUSION: Fourth BNT162b2 vaccination of ARD patients was associated with favourable outcomes compared to three doses among patients with no history of COVID-19 infection.

Hospitalized patients with severe COVID-19 during the Omicron wave in Israel - benefits of a fourth vaccine dose.

BACKGROUND: Waning vaccine-immunity and an increased incidence of COVID-19 during the Omicron outbreak led the Israeli Ministry of Health to recommend a fourth dose of BNT162b2 for high-risk individuals. This study assessed the effect of that dose for hospitalized patients with severe/critical, breakthrough COVID-19. METHODS: In this multi-center retrospective cohort study of hospitalized adults with severe/critical COVID-19 in Israel, from 01/15/2022-01/31/2022, 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 1,049 patients, median age 80 years (IQR 69-87), 51% males. Among them, 394 were unvaccinated, 386 had received 3 doses and 88 4 doses. The 3-dose group was older, had more males and immunosuppression, but with similar outcomes, 49% vs. 51% compared to unvaccinated patients (p = 0.72). Patients after 4 doses were similarly older and immunosuppressed, but had better outcomes compared to unvaccinated patients, 34% vs. 51% (p < 0.01). We examined independent predictors for poor outcome in patients with either 3 or 4 doses, received a median of 161 (IQR 147-168) or 14 (IQR 10-18) days before diagnosis, respectively. Receipt of the fourth dose was associated with protection: OR 0.51 (95%CI 0.3-0.87), as was Remdesivir OR 0.65 (95%CI 0.44-0.96). Male sex, chronic renal failure and dementia were associated with poor outcomes. CONCLUSIONS: Among hospitalized patients with severe/critical breakthrough COVID-19, a recent fourth dose was associated with significant protection against mechanical ventilation or death, compared to three doses.

Cellular and humoral immune response to the fourth Pfizer-BioNTech COVID-19 vaccine dose in individuals aged 60 years and older.

With the emergence of the severe acute respiratory syndrome 2 (SARS-CoV-2) B.1.1.529/BA.1 (Omicron) variant in early 2022, Israel began vaccinating individuals 6o years of age or older with a fourth BNT162b2 vaccine. While the decision was based on little experimental data, longer follow-up showed clinical effectiveness of the fourth dose with reduction in the number of severely affected individuals. However, the immune response to fourth vaccine dose in this age group was not yet characterized, and little is known about the immunogenicity of repeated vaccine dosing in this age group. We therefore aimed to evaluate the humoral and cellular immune response pre- and 3-week post- the fourth vaccine dose in patients age 60 years or older. For this purpose, blood samples were collected from donors age 60 years or older, all received their 3rd vaccine dose 5 months prior. Serum samples were evaluated for the presence of anti-Spike protein (anti-S) antibodies (N = 133), and peripheral blood mononuclear cells (PBMCs) were evaluated by flow cytometry for their ability to respond to the SARS-CoV-2 wild type Spike-glycoprotein peptide mix, Membrane-glycoprotein (M) peptide mix and to the mutated Spike-regions of the Omicron variant (N = 34). Three weeks after the fourth vaccine dose, 24 out of 34 donors (70.5%) showed significant increase in the number of cells responding to the wild type S-peptide mix. Of note, out of 34 donors, 11 donors (32.3%) had pre-boost anti-M T-cell response, none of which had history of confirmed COVID-19, suggesting possible asymptomatic exposure. Interestingly, in M non-responding individuals, no statistically significant increase in the cellular response was observed following stimulation with omicron S-mutated regions. While there are limited data regarding the longevity of the observed response, our results are in accordance with the described clinical efficacy, provide mechanistic evidence to support it and argue against vaccine-induced or age-related immunosenescence.

High Immune Response Rate to the Fourth Boost of the BNT162b2 Vaccine against the Omicron Variants of Concern among Liver Transplant Recipients.

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.

Fourth Dose of mRNA COVID-19 Vaccine Transiently Reactivates Spike-Specific Immunological Memory in People Living with HIV (PLWH).

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).

Effect of Previous COVID-19 Vaccination on Humoral Immunity 3 Months after SARS-CoV-2 Omicron Infection and Booster Effect of a Fourth COVID-19 Vaccination 2 Months after SARS-CoV-2 Omicron Infection.

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.

Immune Response after the Fourth Dose of SARS-CoV-2 mRNA Vaccine Compared to Natural Infection in Three Doses' Vaccinated Solid Organ Transplant Recipients.

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.

A multinational, phase 2, randomised, adaptive protocol to evaluate immunogenicity and reactogenicity of different COVID-19 vaccines in adults ≥75 already vaccinated against SARS-CoV-2 (EU-COVAT-1-AGED): a trial conducted within the VACCELERATE network.

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.

SARS-CoV-2 anti-spike antibodies after a fourth dose of COVID-19 vaccine in adult solid-organ transplant recipients.

BACKGROUND: A fourth dose of SARS-CoV-2 vaccine is recommended in solid-organ transplant (SOT) recipients, but the immunogenicity is poorly known. METHODS: We conducted a retrospective, observational, monocentric study between the 1st January 2021 and 31st March 2022 of the anti-Spike antibody titers after one to four doses of vaccine in SOT. RESULTS: 825 SOT were included. Median age at first vaccine injection was 61.2 (IQR 50.9-69.3) years; 66.7 % were male; 63.4 % had received four vaccine doses. The proportion of participants with a strong humoral response (>260 BAU/mL) increased with the number of vaccine doses: 10.6 % after the 1st dose (D1), 35.1 % after the 2nd (D2), 48.5 % after the 3rd (D3), and 65.1 % after the 4th (D4) (p < 0.001). Among the tested patients, the proportion with a detectable humoral response was significantly higher after D4 than after D3 (47 % vs 22 %, p = 0.01). Liver transplant recipients had more frequently a strong humoral response after D2, D3 and D4 (OR = 5.3, 3.7 and 6.6 respectively when compared with other organ transplant recipients, p < 0.001). In kidney transplant recipients, belatacept-containing regimen was associated with a lower rate of detectable humoral (9 % vs 40 %, p = 0.025) after D3, but there was no statistical difference after D4. CONCLUSION: A fourth dose should be proposed to SOT recipients who did not developed an immune response after 3 doses. Kidney transplant recipients receiving belatacept have a poorer, although frequently detectable response.

Analysis of Immunization, Adverse Events, and Efficacy of a Fourth Dose of BNT162b2 Vaccine in Health Workers in Mexico, a Pilot Study.

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.

Immune response and reactogenicity after immunization with two-doses of an experimental COVID-19 vaccine (CVnCOV) followed by a third-fourth shot with a standard mRNA vaccine (BNT162b2): RescueVacs multicenter cohort study.

Background: There is no evidence to date on immunogenic response among individuals who participated in clinical trials of COVID-19 experimental vaccines redirected to standard national vaccination regimens. Methods: This multicentre, prospective controlled cohort study included subjects who received a COVID-19 experimental vaccine (CVnCoV)(test group, TG) - and unvaccinated subjects (control group, CG), selected among individuals to be vaccinated according to the Spanish vaccination program. All study subjects received BNT162b2 as a standard national vaccination schedule, except 8 (from CG) who received mRNA-1273 and were excluded from immunogenicity analyses. Anti-RBD antibodies level and neutralising titres (NT50) against G614, Beta, Mu, Delta and Omicron variants were analysed. Reactogenicity was also assessed. Findings: 130 participants (TG:92; CG:38) completed standard vaccination. In TG, median (IQR) of anti-RBD antibodies after first BNT162b2 dose were 10740·0 BAU/mL (4466·0-12500) compared to 29·8 BAU/mL (14·5-47·8) in CG (p <0·0001). Median NT50 (IQR) of G614 was 2674·0 (1865·0-3997·0) in TG and 63·0 (16·0-123·1) in CG (p <0·0001). After second BNT162b2 dose, anti-RBD levels increased to ≥12500 BAU/mL (11625·0-12500) in TG compared to 1859·0 BAU/mL (915·4-3820·0) in CG (p <0·0001). NT50 was 2626·5 (1756·0-5472·0) and 850·4 (525·1-1608·0), respectively (p <0·0001). Variant-specific (Beta, Mu, Omicron) response was also assessed. Most frequent adverse reactions were headache, myalgia, and local pain. No severe AEs were reported. Interpretation: Heterologous BNT162b2 as third and fourth doses in previously suboptimal immunized individuals elicit stronger immune response than that obtained with two doses of BNT162b2. This apparent benefit was also observed in variant-specific response. No safety concerns arose. Funding: Partly funded by the Institute of Health Carlos-III and COVID-19 Fund, co-financed by the European Regional Development Fund (FEDER) "A way to make Europe".

Fourth BNT162b2 vaccination neutralization of omicron infection after heart transplantation.

We investigated changes in receptor-binding domain IgG and neutralizing antibodies against the omicron and delta variants, vs the wild-type virus, in response to a fourth BNT162b2 dose in 90 heart transplant (HT) recipients. The fourth dose induced anti-RBD IgG antibodies and a higher neutralization efficiency against the wild-type virus and the variants; however, neutralization efficiency against the omicron variant was lower than that against the delta variant (the latter demonstrating efficacy similar to that against the wild-type virus). Notably, while IgG anti-RBD antibodies were detectable in >80% of the HT recipients, only about half demonstrated neutralization efficiency against the omicron variant. A SARS-CoV-2-specific-T-cell response following the fourth dose was evident in the majority of transplant recipients. Boosting vulnerable groups improves antibody responses (including neutralizing responses) and cellular immunity, but the incomplete immunological response, particularly for omicron, suggests continued preventive measures and optimization of vaccination strategies that elicit strong, and long-lasting immune responses, in this high-risk population, should remain a priority.