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Background and objectiveThe 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.MethodsPublished 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.ResultsA 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%.ConclusionThe 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.

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.

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.

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).

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.

Booster doses for the ongoing COVID-19 pandemic are under consideration in many countries. We report a three-month follow-up of 700 participants in a fourth vaccine dose study, comparing BNT162b2 and mRNA1273, administered four months after a third BNT162b2 dose. Waning of the immune response was evident during follow-up, with an 11% (ß=0.89, 95% CI, 0.88–0.9) and 21% (ß=0.79, 95% CI, 0.76–0.82) multiplicative decay per week of IgG and neutralizing antibodies, respectively, in the mRNA1273 group, and of 14% (ß=0.86, 95% CI, 0.86–0.87) and 26% (ß=0.74, 95% CI, 0.72–0.76), respectively, in the BNT162b2 group. Direct neutralization of Omicron variants was low relative to ancestral strains. Cumulatively over the study period, both vaccines showed little efficacy against infection but were highly efficacious against substantial disease [89% [(IRR 0.11, 95% CI, 0.02–0.37) and 71% (IRR 0.29, 95% CI, 0.13–0.57) for mRNA1273 and BNT162b2, respectively]. These results are informative for further boosting policy-making.

In immunocompetent subjects, the effectiveness of SARS-CoV-2 vaccines against the delta variant appears three- to five-fold lower than that observed against the alpha variant. Additionally, three doses of SARS-CoV-2 mRNA-based vaccines might be unable to elicit a sufficient immune response against any variant in immunocompromised kidney transplant recipients. This study describes the kinetics of the neutralizing antibody (NAbs) response against the delta strain before and after a fourth dose of a mRNA vaccine in 67 kidney transplant recipients who had experienced a weak antibody response after three doses. While only 16% of patients harbored NAbs against the delta strain prior to the fourth injection – this percentage raised to 66% afterwards. We also found that, after the fourth dose, the NAbs titer increased significantly (p=0.0001) from

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 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.

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

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.

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.