Innate immune mechanisms of mRNA vaccines.

The lipid nanoparticle (LNP)-encapsulated, nucleoside-modified mRNA platform has been used to generate safe and effective vaccines in record time against COVID-19. Here, we review the current understanding of the manner whereby mRNA vaccines induce innate immune activation and how this contributes to protective immunity. We discuss innate immune sensing of mRNA vaccines at the cellular and intracellular levels and consider the contribution of both the mRNA and the LNP components to their immunogenicity. A key message that is emerging from recent observations is that the LNP carrier acts as a powerful adjuvant for this novel vaccine platform. In this context, we highlight important gaps in understanding and discuss how new insight into the mechanisms underlying the effectiveness of mRNA-LNP vaccines may enable tailoring mRNA and carrier molecules to develop vaccines with greater effectiveness and milder adverse events in the future.

mRNA vaccination of naive and COVID-19-recovered individuals elicits potent memory B cells that recognize SARS-CoV-2 variants.

In addition to serum immunoglobulins, memory B cell (MBC) generation against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is another layer of immune protection, but the quality of MBC responses in naive and coronavirus disease 2019 (COVID-19)-recovered individuals after vaccination remains ill defined. We studied longitudinal cohorts of naive and disease-recovered individuals for up to 2 months after SARS-CoV-2 mRNA vaccination. We assessed the quality of the memory response by analysis of antibody repertoires, affinity, and neutralization against variants of concern (VOCs) using unbiased cultures of 2,452 MBCs. Upon boosting, the MBC pool of recovered individuals expanded selectively, matured further, and harbored potent neutralizers against VOCs. Although naive individuals had weaker neutralizing serum responses, half of their RBD-specific MBCs displayed high affinity toward multiple VOCs, including delta (B.1.617.2), and one-third retained neutralizing potency against beta (B.1.351). Our data suggest that an additional challenge in naive vaccinees could recall such affinity-matured MBCs and allow them to respond efficiently to VOCs.

Antibody and T-cell response to bivalent booster SARS-CoV-2 vaccines in people with compromised immune function (COVERALL-3).

BACKGROUND: Bivalent mRNA vaccines, designed to combat emerging SARS-CoV-2 variants, incorporate ancestral strains and a new variant. Our study assessed the immune response in previously vaccinated individuals of the Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS) following bivalent mRNA vaccination. METHODS: Eligible SHCS and STCS participants received approved bivalent mRNA SARS-CoV-2 vaccines (mRNA-1273.214 or BA.1-adapted BNT162b2) within clinical routine. Blood samples were collected at baseline, 4 weeks, 8 weeks, and 6 months post vaccination. We analyzed the proportion of participants with anti-spike protein antibody response ≥1642 units/ml (indicating protection against SARS-CoV-2 infection), and in a subsample T-cell response (including mean concentrations), stratifying results by cohorts and population characteristics. RESULTS: In SHCS participants, baseline anti-spike antibody concentrations ≥1642 were observed in 87% (96/112), reaching nearly 100% at follow-ups. Among STCS participants, 58% (35/60) had baseline antibodies ≥1642, increasing to 80% at 6 months. Except for lung transplant recipients, all participants showed a five-fold increase in geometric mean antibody concentrations at 4 weeks and a reduction by half at 6 months. At baseline, T-cell responses were positive in 96% (26/27) of SHCS participants and 36% (16/45) of STCS participants (moderate increase to 53% at 6 months). Few participants reported SARS-CoV-2 infections, side-effects, or serious adverse events. CONCLUSIONS: Bivalent mRNA vaccination elicited a robust humoral response in individuals with HIV or solid organ transplants, with delayed responses in lung transplant recipients. Despite a waning effect, antibody levels remained high at 6 months and adverse events were rare.

Immune responses and reinfection of SARS-CoV-2 Omicron variant in patients with lung cancer.

A significant Omicron wave emerged in China in December 2022. To explore the duration of humoral and cellular response postinfection and the efficacy of hybrid immunity in preventing Omicron reinfection in patients with lung cancer, a total of 447 patients were included in the longitudinal study after the Omicron wave from March 2023 to August 2023. Humoral responses were measured at pre-Omicron wave, 3 months and 7 months postinfection. The detected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specific antibodies including total antibodies, anti-receptor binding domain (RBD) specific IgG, and neutralizing antibodies against SARS-CoV-2 wild type (WT) and BA.4/5 variant. T cell responses against SARS-CoV-2 WT and Omicron variant were evaluated in 101 patients by ELISpot at 3 months postinfection. The results showed that Omicron-infected symptoms were mild, while fatigue (30.2%), shortness of breath (34.0%) and persistent cough (23.6%) were long-lasting, and vaccines showed efficacy against fever in lung cancer patients. Humoral responses were higher in full or booster vaccinated patients than those unvaccinated (p < .05 for all four antibodies), and the enhanced response persisted for at least 7 months. T cell response to Omicron was higher than WT peptides (21.3 vs. 16.0 SFUs/106 PBMCs, p = .0093). Moreover, 38 (9.74%) patients were reinfected, which had lower antibody responses than non-reinfected patients (all p < .05), and those patients of unvaccinated at late stage receiving anti-cancer immunotherapy alone were at high risk of reinfection. Collectively, these data demonstrate the Omicron infection induces a high and durable immune response in vaccinated patients with lung cancer, which protects vaccinated patients from reinfection.

A design strategy to generate a SARS-CoV-2 RBD vaccine that abrogates ACE2 binding and improves neutralizing antibody responses.

The structure-based design of antigens holds promise for developing vaccines with higher efficacy and improved safety profiles. We postulate that abrogation of host receptor interaction bears potential for the improvement of vaccines by preventing antigen-induced modification of receptor function as well as the displacement or masking of the immunogen. Antigen modifications may yet destroy epitopes crucial for antibody neutralization. Here, we present a methodology that integrates deep mutational scans to identify and score SARS-CoV-2 receptor binding domain variants that maintain immunogenicity, but lack interaction with the widely expressed host receptor. Single point mutations were scored in silico, validated in vitro, and applied in vivo. Our top-scoring variant receptor binding domain-G502E prevented spike-induced cell-to-cell fusion, receptor internalization, and improved neutralizing antibody responses by 3.3-fold in rabbit immunizations. We name our strategy BIBAX for body-inert, B-cell-activating vaccines, which in the future may be applied beyond SARS-CoV-2 for the improvement of vaccines by design.

Cellular immune response to the anti-SARS-CoV-2 BNT162b2 mRNA vaccine in pediatric autoimmune inflammatory rheumatic disease patients and controls.

This paper aims to compare the cellular immune response to the SARS-CoV-2 BNT162b2 vaccine of pediatric patients with autoimmune inflammatory rheumatic disease (pAIIRD) and healthy controls. A prospective longitudinal study was conducted between April 2021 and December 2022 at the Tel Aviv Medical Center. Children <18 years, with pediatric-onset AIIRD and healthy controls, who have received at least two doses of the BNT162b2 vaccine, were included. Humoral response was evaluated by serum levels of anti-SARS-CoV-2 receptor-binding domain antibodies. Cellular response was evaluated by flow cytometry, measuring IFNγ and TNFα production by CD4+ T cells following stimulation with SARS-CoV-2 Spike peptide mix. The study included 20 pAIIRD patients and 11 controls. The mean age of participants was 12.6 ±â€…2.94 years, with 58.1% females. The cellular response to the BNT162b2 vaccine was statistically similar in both groups. However, the humoral response was statistically lower in pAIIRD compared with the healthy control group. There was no statistically significant correlation between the humoral response and cellular response. During the study period, 43.75% of AIIRD children and 72.7% of controls had a breakthrough COVID-19 infection (P = 0.48). Bivariate models examining the effect of the cellular response and presence of an AIIRD on breakthrough infections found no effect. Compared with healthy controls, pAIIRD demonstrated similar cellular responses. Patients showed reduced humoral response compared with healthy adolescents, but similar breakthrough infection rates. These findings may support the importance of the cellular response in protecting against COVID-19 infections.

SARS-CoV-2 vaccine immunogenicity for people living with HIV: A systematic review and meta-analysis.

BACKGROUND: Previous publications on the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in people living with HIV (PLWH) have reported inconsistent results. Additionally, a meta-analysis investigating the immunogenicity in PLWH after the third SARS-CoV-2 vaccine dose is lacking. In this article we aim to provide a systematic review and a meta-analysis studying the immunogenicity of SARS-CoV-2 vaccines in PLWH and to identify potential drivers for antibody response in PLWH. METHODS: We used three databases (PubMed, Embase and Web of Science) to conduct our review. Studies with information on numbers of PLWH producing immunoglobulin G (IgG) antibodies or neutralizing antibodies were included. RESULTS: The meta-analysis included 59 studies and illustrated a pooled serological response of 87.09% in the 10 343 PLWH after they received a SARS-CoV-2 vaccine. High CD4 T-cell counts and low viral load indicated that the study populations had HIV that was well treated, despite varying in location. The pooled effect increased to 91.62% for 8053 PLWH when excluding studies that used inactivated vaccines (BBIBP-CorV and CoronaVac). For the third vaccine dose, the pooled effect was 92.35% for 1974 PLWH. Additionally, weighted linear regression models demonstrated weak relationships between CD4 T-cell count, percentages of people with undetectable HIV load, and age compared with the percentages of PLWH producing a serological response. However, more research is needed to determine the effect of those factors on SARS-CoV-2 vaccine immunogenicity in PLWH. CONCLUSION: SARS-CoV-2 vaccines show a favourable effect on immunogenicity in PLWH. However, the results are not ideal. This meta-analysis suggests that a third SARS-CoV-2 vaccine dose and good HIV treatment procedures are vital to induce a good immunogenicity in PLWH.

The characteristics of BCR-CDR3 repertoire in COVID-19 patients and SARS-CoV-2 vaccinated volunteers.

The global COVID-19 pandemic has caused more than 1 billion infections, and numerous SARS-CoV-2 vaccines developed rapidly have been administered over 10 billion doses. The world is continuously concerned about the cytokine storms induced by the interaction between SARS-CoV-2 and host, long COVID, breakthrough infections postvaccination, and the impact of SARS-CoV-2 variants. BCR-CDR3 repertoire serves as a molecular target for monitoring the antiviral response "trace" of B cells, evaluating the effects, mechanisms, and memory abilities of individual responses to B cells, and has been successfully applied in analyzing the infection mechanisms, vaccine improvement, and neutralizing antibodies preparation of influenza virus, HIV, MERS, and Ebola virus. Based on research on BCR-CDR3 repertoire of COVID-19 patients and volunteers who received different SARS-CoV-2 vaccines in multiple laboratories worldwide, we focus on analyzing the characteristics and changes of BCR-CDR3 repertoire, such as diversity, clonality, V&J genes usage and pairing, SHM, CSR, shared CDR3 clones, as well as the summary on BCR sequences targeting virus-specific epitopes in the preparation and application research of SARS-CoV-2 potential therapeutic monoclonal antibodies. This review provides comparative data and new research schemes for studying the possible mechanisms of differences in B cell response between SARS-CoV-2 infection or vaccination, and supplies a foundation for improving vaccines after SARS-CoV-2 mutations and potential antibody therapy for infected individuals.

Immunologic responses to the third and fourth doses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in cell therapy recipients: a systematic review and meta-analysis.

BACKGROUND: Multiple studies have provided evidence of suboptimal or poor immune responses to SARS-CoV-2 vaccines in recipients of hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor-T (CAR-T) cell therapy compared to healthy individuals. Given the dynamic nature of SARS-CoV2, characterized by the emergence of many viral variations throughout the general population, there is ongoing discussion regarding the optimal quantity and frequency of additional doses required to sustain protection against SARS-CoV2 especially in this susceptible population. This systematic review and meta-analysis investigated the immune responses of HSCT and CAR-T cell therapy recipients to additional doses of the SARS-CoV-2 vaccines. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the study involved a comprehensive search across PubMed, Scopus, Web of Science Core Collection, Embase, and Cochrane Biorxiv and medRxiv, focusing on the serological responses to the third and fourth vaccine doses in HSCT and CAR-T cell patients. RESULTS: This study included 32 papers, with 31 qualifying for the meta-analysis. Results showed that after the third dose, the seroconversion rate in HSCT and CAR-T cell therapy recipients who didn't respond to the second dose was 46.10 and 17.26%, respectively. Following the fourth dose, HSCT patients had a seroconversion rate of 27.23%. Moreover, post-third-dose seropositivity rates were 87.14% for HSCT and 32.96% for CAR-T cell therapy recipients. Additionally, the seropositive response to the fourth dose in the HSCT group was 90.04%. CONCLUSION: While a significant portion of HSCT recipients developed antibodies after additional vaccinations, only a minority of CAR-T cell therapy patients showed a similar response. This suggests that alternative vaccination strategies are needed to protect these vulnerable groups effectively. Moreover, few studies have reported cellular responses to additional SARS-CoV-2 vaccinations in these patients. Further studies evaluating cellular responses are required to determine a more precise assessment of immunogenicity strength against SARS-CoV-2 after additional doses.

Immunogenicity and safety of BNT162b2 vaccination in adolescents with systemic lupus erythematosus.

OBJECTIVES: We evaluated the immunogenicity and safety of BNT162b2 vaccination in adolescents with systemic lupus erythematosus (adoSLE) receiving either high- or low-dose immunosuppressant (High-IS and Low-IS). METHODS: Patients aged 12-18 years diagnosed with SLE were enrolled. High-IS was defined as >7.5 mg/day prednisolone or with other immunosuppressant, while Low-IS was defined as only ≤7.5 mg/day of prednisolone and no immunosuppressant. Two doses of BNT162b2 vaccination were given 4 weeks apart, followed by a booster (third) dose at 4-6 months later. Anti-spike receptor binding domain (anti-RBD) IgG against Wuhan, neutralising antibody (NT) against Wuhan and Omicron variants, and cellular immune response by IFN-γ-ELISpot assay were evaluated following vaccination. Adverse events (AEs) and SLE flare were monitored. RESULTS: A total of 73 participants were enrolled, 40 and 33 in the High-IS and Low-IS group, respectively. At 4 weeks following the 2nd dose, overall anti-RBD IgG seropositivity was 97.3%, with no difference between the groups (p = .498). AdoSLE on High-IS had lower anti-RBD IgG (p < .001), Wuhan NT (p < .001), and IFN-γ-ELISpot (p = .022) than those on Low-IS. A 3rd dose induced significantly higher antibody responses than after the 2nd dose (p < .001) in both groups and established seroconversion against Omicron variants, with persistent lower antibody levels in High-IS group. SELENA-SLEDAI scores within 12 weeks after 2-dose vaccination was higher than before vaccination (3.1 vs 2.5; p < .036); however, the occurrence of disease flare by SELENA-SLEDAI flare index was not different after vaccination compared to before vaccination, consistent across groups. Non-severe AEs occurred similarly in both groups. CONCLUSION: AdoSLE on High-IS induced lower SARS-CoV-2 vaccine immune responses than Low-IS. Vaccination can increase disease activity and requires close monitoring for disease flare.

A single-center review of outcomes between COVID-19 vaccinated and unvaccinated liver transplant recipients.

BACKGROUND: With the availability of vaccines against SARS-COV-2, recommendations for vaccination of transplant candidates are widespread. At our institution, patients may receive liver transplant (LTx) regardless of vaccine status. The purpose of this study is to compare post-LTx outcomes between vaccinated (VAX) and unvaccinated (UNVAX) LTx recipients. METHODS: This is a retrospective, single-center study of LTx from January 1, 2021-March 30, 2022. The primary outcome is incidence of post-LTx COVID-19. Secondary outcomes include graft function, mortality, graft loss, and COVID-19 treatment. RESULTS: One hundred and seventy-seven LTx recipients were included, 57% [101/177] VAX and 43% [76/177] UNVAX. Baseline characteristics were similar between groups. Overall, 28 (36.8%) UNVAX and 34 (33.7%) VAX tested COVID-19 positive during the study period (p = .193) at a mean of 312.6 [255.4-369.8] days for UNVAX versus 254.6 [215.2-293.9] days for VAX (p = .084). COVID-19 treatment was administered in 15 (53.6%) of the UNVAX compared to 22 (64.7%) in the VAX (p = .374), although eight (28.6%) of UNVAX required hospital admission for treatment compared with two (5.9%) of VAX (p = .016). There were no statistically significant differences in death, and no COVID-19 related death or graft loss. There were no statistically significant differences in liver function tests at 3- and 12-months post LTx. CONCLUSION: In a series with a large percentage of UNVAX patients, LTx appears to be safe, with no difference in the rate of COVID-19 or transplant-related outcomes compared to VAX. While we encourage vaccination to prevent severe COVID, based on our results, vaccine status should not be reason to deny lifesaving transplant.

SARS-CoV-2 Vaccination Rates and Uptake of Tixagevimab-Cilgavimab Among a Cohort of Pediatric Solid Organ Transplant Recipients.

INTRODUCTION: There is a lack of data regarding SARS-CoV-2 vaccination rates and tixagevimab-cilgavimab (TC) uptake among pediatric solid organ transplant recipients. The purpose of our study was to assess these rates. MATERIALS AND METHODS: We reviewed vaccination records of pediatric recipients of heart, kidney, and liver transplants at Mayo Clinic, Rochester, MN, who received a transplant between January 2011 and December 2021. All SARS-CoV-2 vaccines and doses of TC received on or before September 1, 2022, the date of approval of the bivalent SARS-CoV2 vaccine, were included. We also assessed whether patients had been seen by an infectious diseases physician (ID) in the preceding 6 months. RESULTS: Our study included 110 patients: 47 kidney, 36 heart, and 27 liver transplant recipients. All vaccine doses recorded were monovalent SARS-CoV-2 vaccines. Sixty-eight (61.8%) patients received at least one vaccine. This varied by age group, with f of ≥12 years olds, 40.9% of 5-11 year olds and 14.3% of under 5 year olds (p = 0.001). Seven patients (6.4%) were up-to-date (UTD) for age. There was no difference in UTD status by organ type (p = 0.335). Patients who saw ID were significantly more likely to be UTD (13.2% versus 2.8%; p = 0.047). Among those eligible, 14 (18.2%) received TC, with rates not different based on transplanted organ type (p = 0.158) or whether they saw ID (p = 0.273). CONCLUSIONS: Despite the availability of vaccines, nearly 40% of pediatric solid organ transplant recipients remained unvaccinated against SARS-CoV-2 at time of the bivalent vaccine release. Less than a fifth of eligible patients received TC. Strategies to increase uptake of SARS-CoV-2 vaccines as well as adjunctive agents among this vulnerable group should be further explored.

Arginine vasopressin deficiency onset after COVID-19 vaccination with positive anti-rabphilin-3A antibodies: a case report and literature review.

BACKGROUND: Arginine vasopressin deficiency (AVP-D) can occur due to various conditions, so clarifying its cause is important for deciding treatment strategy. Although several cases of AVP-D following coronavirus disease 2019(COVID-19) infection or COVID-19 vaccination have been reported, the diagnosis of the underlying disease has not been reported in most cases. CASE PRESENTATION: A 75-year-old woman who presented with polydipsia and polyuria 9 weeks after contracting COVID-19 and 5 weeks after receiving the SARS-CoV-2 vaccination, leading to the final diagnosis of AVP-D 8 months after the first appearance of symptoms. Interestingly, pituitary magnetic resonance imaging (MRI) still revealed stalk enlargement frequently observed in patients with SARS-CoV-2 vaccination-induced AVP-D. Although this finding could not rule out any malignancies, we additionally measured anti-rabphilin-3A antibodies, a known marker for lymphocytic infundibulo-neurohypophysitis (LINH), and found that the results were positive, strongly suggesting LINH as the cause of this disease. Thus, we avoided pituitary biopsy. At the follow-up MRI conducted 12 months after the initial consultation, enlargement of the pituitary stalk was still observed. CONCLUSION: We experienced a case with LINH probably induced by SARS-CoV-2 vaccination. In SARS-CoV-2 vaccination-related LINH, unlike typical LINH, there is a possibility of persistent pituitary stalk enlargement on MRI images for an extended period, posing challenges in differential diagnosis from other conditions. Pituitary stalk enlargement and positive anti-rabphilin-3A antibodies may help in the diagnosis of AVP-D induced by SARS-CoV-2 vaccination.

Cellular and humoral immune responses to COVID-19 booster vaccination in Japanese dialysis patients.

BACKGROUND: Dialysis patients are susceptible to developing severe coronavirus disease 2019 (COVID-19) due to hypoimmunity. Antibody titers against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) after the primary vaccinations are lower in hemodialysis (HD) patients than in healthy individuals. This study aimed to evaluate the effect of a SARS-CoV-2 booster vaccination in HD and peritoneal dialysis (PD) patients based on antibody titers and cellular and humoral immunity. METHODS: Participants of the control, HD, and PD groups were recruited from 12 facilities. SARS-CoV-2 antigen-specific cytokine and IgG-antibody levels were measured. Regulatory T cells and memory B cells were counted using flow cytometry at 6 months after primary vaccination with BNT162b2 and 3 weeks after the booster vaccination in HD and PD patients and compared with those of a control group. RESULTS: Booster vaccination significantly enhanced the levels of antibodies, cytokines, and memory B cells in three groups. The HD group showed significantly higher levels of IgG-antibodies, IL-1ß, IL-2, IL-4, IL-17, and memory B cells than those in the control group at 3 weeks after the booster dose. The PD group tended to show similar trends to HD patients but had similar levels of IgG-antibodies, cytokines, and memory B cells to the control group. CONCLUSIONS: HD patients had significantly stronger cellular and humoral immune responses than the control 3 weeks after the booster dose. Our findings will help in developing better COVID-19 vaccination strategies for HD and PD patients.

Association between use of antipyretics and antibody titers after two doses of the BNT162b2 SARS-CoV-2 vaccine in adolescents and young adults with underlying diseases.

There are few reports on the association between antipyretic use and antibody titers in adolescents and young adults following SARS-CoV-2 vaccination. Multivariable linear regression analyses were performed to examine the association between antipyretic use and antibody titers. The use of antipyretics was not associated with antibody titers (ß coefficient [95% CI] = -0.107 [-0.438 to 0.224]).

A safe and highly efficacious measles virus-based vaccine expressing SARS-CoV-2 stabilized prefusion spike.

The current pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights an urgent need to develop a safe, efficacious, and durable vaccine. Using a measles virus (rMeV) vaccine strain as the backbone, we developed a series of recombinant attenuated vaccine candidates expressing various forms of the SARS-CoV-2 spike (S) protein and its receptor binding domain (RBD) and evaluated their efficacy in cotton rat, IFNAR-/-mice, IFNAR-/--hCD46 mice, and golden Syrian hamsters. We found that rMeV expressing stabilized prefusion S protein (rMeV-preS) was more potent in inducing SARS-CoV-2-specific neutralizing antibodies than rMeV expressing full-length S protein (rMeV-S), while the rMeVs expressing different lengths of RBD (rMeV-RBD) were the least potent. Animals immunized with rMeV-preS produced higher levels of neutralizing antibody than found in convalescent sera from COVID-19 patients and a strong Th1-biased T cell response. The rMeV-preS also provided complete protection of hamsters from challenge with SARS-CoV-2, preventing replication in lungs and nasal turbinates, body weight loss, cytokine storm, and lung pathology. These data demonstrate that rMeV-preS is a safe and highly efficacious vaccine candidate, supporting its further development as a SARS-CoV-2 vaccine.

A natural experiment during lockdown and on-going care-home COVID-19 outbreaks showed a single dose of vaccine reduced hospitalisation and deaths of care-home residents in North West England.

OBJECTIVE: To examine the effectiveness of one dose of the COVID-19 vaccine on care-home residents. STUDY DESIGN: Natural experiment. METHODS: We compared the effectiveness of single doses of Pfizer/BioNTech BNT162b2 (effective at 10 days) and AstraZeneca ChAdOx1 (effective at 14 days) vaccines in vaccinated and control (unvaccinated) homes. Using routine data, all care-homes reporting COVID-19 outbreaks between 11/12/2020 and 12/3/2021 in a sub-region of North West England were included. RESULTS: Of 126 care-homes (4042 residents), with outbreaks, 55 (44%, 1686 residents) reported onset dates before vaccination commenced; 38 (30%, 1304 residents) reported onset < 10 (BNT162b2) and < 14 days (ChAdOx1) after vaccine administration; and 33 (26%, 1052 residents) reported onset > 10 (BNT162b2) and > 14 (ChAdOx1) days after vaccination. Eighty-nine (71%) homes used ChAdOx1 vaccine. A single dose of vaccine before the outbreak onset significantly lowered the risk of symptoms (reduced by 48%), positivity (by 65%), hospitalisation (by 68%), and death (by 81%). Some vaccine effectiveness was also noted in care-homes that received one dose of vaccine within 10-14 days of outbreak onset. The number needed to vaccinate to prevent one resident from COVID-19-related hospitalisation was 34, and death was 17. CONCLUSIONS: This real-world, natural experiment adds to the evidence of COVID-19 vaccine effectiveness from different studies using varying designs. In the context of lockdown's impact on infection rates and on-going care-home outbreaks, a single dose of either ChAdOx1 or BNT162b2 vaccine had a significant impact on reducing COVID-19 related hospitalisation and death in care-home residents. Natural experiments should be used more in public health.

Enhancement of Humoral and Cellular Immunity Against Severe Acute Respiratory Syndrome Coronavirus 2 by a Third Dose of BNT162b2 Vaccine in Japanese Healthcare Workers.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised concerns regarding vaccine effectiveness. We investigated humoral and cellular immune responses against SARS-CoV-2 in healthcare workers before and after a third (booster) dose of the BNT162b2 messenger RNA vaccine. It significantly enhanced both humoral and cellular immunity in previously uninfected individuals. However, cellular immunity was not enhanced in previously infected persons, suggesting that 3 antigenic stimuli by vaccination or natural infection reached a plateau of cellular immunity. Even with reinforced immunity to SARS-CoV-2, we confirmed several postbooster breakthrough cases caused by the Omicron variant.

A Bivalent Omicron-BA.4/BA.5-Adapted BNT162b2 Booster in ≥12-Year-Olds.

BACKGROUND: Protection against contemporary SARS-CoV-2 variants requires sequence-adapted vaccines. METHODS: In this ongoing phase 2/3 trial, 12-17-year-olds (n=108), 18-55-year-olds (n=313), and >55-year-olds (n=306) who previously received 3 original BNT162b2 30-µg doses, received a fourth dose (second booster) of 30-µg bivalent original/Omicron-BA.4/BA.5-adapted BNT162b2 (BNT162b2-Omi.BA.4/BA.5). For comparisons with original BNT162b2, participants were selected from another phase 3 trial. Immunologic superiority 1-month post-vaccination, with respect to 50% neutralizing titers (GMR lower bound [LB] 2-sided 95%CI >1), and noninferiority with respect to seroresponse rates (rate-difference LB 2-sided 95%CI >-5%), for Omicron BA.4/BA.5 were assessed in >55-year-olds versus original BNT162b2 as a second booster. Noninferiority with respect to neutralizing titer level (GMR LB 2-sided 95%CI >0.67) and seroresponse rate (rate-difference LB 2-sided 95%CI >-10%) of Omicron BA.4/BA.5 immune response for BNT162b2-Omi.BA.4/BA.5 in 18‒55-year-olds versus >55-year-olds was assessed. RESULTS: One-month post-vaccination in >55-year-olds, model-adjusted GMR of Omicron BA.4/BA.5 neutralizing titers for the BNT162b2-Omi.BA.4/BA.5 versus BNT162b2 group (2.91; 95%CI 2.45-3.44) demonstrated superiority of BNT162b2-Omi.BA.4/BA.5. Adjusted difference in percentages of >55-year-olds with seroresponse (26.77%; 95%CI 19.59-33.95) showed noninferiority of BNT162b2-Omi.BA.4/BA.5 to BNT162b2. Noninferiority of BNT162b2-Omi.BA.4/BA.5 in 18‒55-year-olds to >55-year-olds was met for model-adjusted GMR and seroresponse. GMTs in 12-17-year-olds increased from baseline to 1-month post-vaccination. The BNT162b2-Omi.BA.4/BA.5 safety profile was similar to booster doses of bivalent Omicron BA.1-modified BNT162b2 and original BNT162b2 reported in previous studies. CONCLUSIONS: Based on immunogenicity and safety data up to 1-month post-vaccination in participants who previously received 3 original BNT162b2 doses, a BNT162b2-Omi.BA.4/BA.5 30 µg booster has a favorable benefit-risk profile. CLINICAL TRIAL REGISTRATION: NCT05472038.

Relative Effectiveness of Coronavirus Disease 2019 Vaccination and Booster Dose Combinations Among 18.9 Million Vaccinated Adults During the Early Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Period-United States, 1 January 2022 to 31 March 2022.

BACKGROUND: Small sample sizes have limited prior studies' ability to capture severe COVID-19 outcomes, especially among Ad26.COV2.S vaccine recipients. This study of 18.9 million adults aged ≥18 years assessed relative vaccine effectiveness (rVE) in three recipient cohorts: (1) primary Ad26.COV2.S vaccine and Ad26.COV2.S booster (2 Ad26.COV2.S), (2) primary Ad26.COV2.S vaccine and mRNA booster (Ad26.COV2.S+mRNA), (3) two doses of primary mRNA vaccine and mRNA booster (3 mRNA). METHODS: We analyzed two de-identified datasets linked using privacy-preserving record linkage (PPRL): insurance claims and retail pharmacy COVID-19 vaccination data. We assessed the presence of COVID-19 diagnosis during January 1-March 31, 2022 in: (1) any claim, (2) outpatient claim, (3) emergency department (ED) claim, (4) inpatient claim, and (5) inpatient claim with intensive care unit (ICU) admission. rVE for each outcome comparing three recipient cohorts (reference: two Ad26.COV2.S doses) was estimated from adjusted Cox proportional hazards models. RESULTS: Compared with two Ad26.COV2.S doses, Ad26.COV2.S+mRNA and three mRNA doses were more effective against all COVID-19 outcomes, including 57% (95% CI: 52-62) and 62% (95% CI: 58-65) rVE against an ED visit; 44% (95% CI: 34-52) and 54% (95% CI: 48-59) rVE against hospitalization; and 48% (95% CI: 22-66) and 66% (95% CI: 53-75) rVE against ICU admission, respectively. CONCLUSIONS: This study demonstrated that Ad26.COV2.S + mRNA doses were as good as three doses of mRNA, and better than two doses of Ad26.COV2.S. Vaccination continues to be an important preventive measure for reducing the public health impact of COVID-19.