Seroepidemiological study of factors affecting anti-spike IgG antibody titers after a two-dose mRNA COVID-19 vaccination in 3744 healthy Japanese volunteers.

Several factors related to anti-spike(S) IgG antibody titers after mRNA COVID-19 vaccination have been elucidated, but the magnitude of the effects of each factor has not been fully understood. This cross-sectional study assessed anti-S and anti-nucleocapsid (N) antibody titers on 3744 healthy volunteers (median age, 36 years; IQR, 24-49 years; females, 59.0%) who received two doses of mRNA-1273 or BNT162b2 vaccine and completed a survey questionnaire. Multiple regression was conducted to identify factors associated with antibody titers. All but one participant tested positive for anti-S antibodies (99.97%). The following factors were independently and significantly associated with high antibody titer: < 3 months from vaccination (ratio of means 4.41); mRNA-1273 vaccine (1.90, vs BNT162b2); anti-N antibody positivity (1.62); age (10's: 1.50, 20's: 1.37, 30's: 1.26, 40's: 1.16, 50's: 1.15, vs ≧60's); female (1.07); immunosuppressive therapy (0.54); current smoking (0.85); and current drinking (0.96). The largest impact on anti-S IgG antibody titers was found in elapsed time after vaccination, followed by vaccine brand, immunosuppressants, previous SARS-CoV-2 infection (anti-N antibody positive), and age. Although the influence of adverse reactions after the vaccine, gender, smoking, and drinking was relatively small, they were independently related factors.

Early human B cell signatures of the primary antibody response to mRNA vaccination.

Messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective at inducing protective immunity. However, weak antibody responses are seen in some individuals, and cellular correlates of immunity remain poorly defined, especially for B cells. Here we used unbiased approaches to longitudinally dissect primary antibody, plasmablast, and memory B cell (MBC) responses to the two-dose mRNA-1273 vaccine in SARS-CoV-2-naive adults. Coordinated immunoglobulin A (IgA) and IgG antibody responses were preceded by bursts of spike-specific plasmablasts after both doses but earlier and more intensely after dose 2. While antibody and B cell cellular responses were generally robust, they also varied within the cohort and decreased over time after a dose-2 peak. Both antigen-nonspecific postvaccination plasmablast frequency after dose 1 and their spike-specific counterparts early after dose 2 correlated with subsequent antibody levels. This correlation between early plasmablasts and antibodies remained for titers measured at 6 months after vaccination. Several distinct antigen-specific MBC populations emerged postvaccination with varying kinetics, including two MBC populations that correlated with 2- and 6-month antibody titers. Both were IgG-expressing MBCs: one less mature, appearing as a correlate after the first dose, while the other MBC correlate showed a more mature and resting phenotype, emerging as a correlate later after dose 2. This latter MBC was also a major contributor to the sustained spike-specific MBC response observed at month 6. Thus, these plasmablasts and MBCs that emerged after both the first and second doses with distinct kinetics are potential determinants of the magnitude and durability of antibodies in response to mRNA-based vaccination.

Risk Factors Associated With SARS-CoV-2 Breakthrough Infections in Fully mRNA-Vaccinated Individuals: Retrospective Analysis.

BACKGROUND: COVID-19 messenger RNA (mRNA) vaccines have demonstrated efficacy and effectiveness in preventing symptomatic COVID-19, while being relatively safe in trial studies. However, vaccine breakthrough infections have been reported. OBJECTIVE: This study aims to identify risk factors associated with COVID-19 breakthrough infections among fully mRNA-vaccinated individuals. METHODS: We conducted a series of observational retrospective analyses using the electronic health records (EHRs) of the Columbia University Irving Medical Center/New York Presbyterian (CUIMC/NYP) up to September 21, 2021. New York City (NYC) adult residences with at least 1 polymerase chain reaction (PCR) record were included in this analysis. Poisson regression was performed to assess the association between the breakthrough infection rate in vaccinated individuals and multiple risk factors-including vaccine brand, demographics, and underlying conditions-while adjusting for calendar month, prior number of visits, and observational days in the EHR. RESULTS: The overall estimated breakthrough infection rate was 0.16 (95% CI 0.14-0.18). Individuals who were vaccinated with Pfizer/BNT162b2 (incidence rate ratio [IRR] against Moderna/mRNA-1273=1.66, 95% CI 1.17-2.35) were male (IRR against female=1.47, 95% CI 1.11-1.94) and had compromised immune systems (IRR=1.48, 95% CI 1.09-2.00) were at the highest risk for breakthrough infections. Among all underlying conditions, those with primary immunodeficiency, a history of organ transplant, an active tumor, use of immunosuppressant medications, or Alzheimer disease were at the highest risk. CONCLUSIONS: Although we found both mRNA vaccines were effective, Moderna/mRNA-1273 had a lower incidence rate of breakthrough infections. Immunocompromised and male individuals were among the highest risk groups experiencing breakthrough infections. Given the rapidly changing nature of the SARS-CoV-2 pandemic, continued monitoring and a generalizable analysis pipeline are warranted to inform quick updates on vaccine effectiveness in real time.

Determinants of early antibody responses to COVID-19 mRNA vaccines in a cohort of exposed and naïve healthcare workers.

BACKGROUND: Two doses of mRNA vaccination have shown >94% efficacy at preventing COVID-19 mostly in naïve adults, but it is not clear if the second dose is needed to maximize effectiveness in those previously exposed to SARS-CoV-2 and what other factors affect responsiveness. METHODS: We measured IgA, IgG and IgM levels against SARS-CoV-2 spike (S) and nucleocapsid (N) antigens from the wild-type and S from the Alpha, Beta and Gamma variants of concern, after BNT162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna) vaccination in a cohort of health care workers (N=578). Neutralizing capacity and antibody avidity were evaluated. Data were analyzed in relation to COVID-19 history, comorbidities, vaccine doses, brand and adverse events. FINDINGS: Vaccination induced robust IgA and IgG levels against all S antigens. Neutralization capacity and S IgA and IgG levels were higher in mRNA-1273 vaccinees, previously SARS-CoV-2 exposed, particularly if symptomatic, and in those experiencing systemic adverse effects (p<0·05). A second dose in pre-exposed did not increase antibody levels. Smoking and comorbidities were associated with 43% (95% CI, 19-59) and 45% (95% CI, 63-18) lower neutralization, respectively, and 35% (95% CI, 3-57%) and 55% (95% CI, 33-70%) lower antibody levels, respectively. Among fully vaccinated, 6·3% breakthroughs were detected up to 189 days post-vaccination. Among pre-exposed non-vaccinated, 90% were IgG seropositive more than 300 days post-infection. INTERPRETATION: Our data support administering a single-dose in pre-exposed healthy individuals as primary vaccination. However, heterogeneity of responses suggests that personalized recommendations may be necessary depending on COVID-19 history and life-style. Higher mRNA-1273 immunogenicity would be beneficial for those expected to respond worse to vaccination and in face of variants that escape immunity such as Omicron. Persistence of antibody levels in pre-exposed unvaccinated indicates maintenance of immunity up to one year. FUNDING: This work was supported by Institut de Salut Global de Barcelona (ISGlobal) internal funds, in-kind contributions from Hospital Clínic de Barcelona, the Fundació Privada Daniel Bravo Andreu, and European Institute of Innovation and Technology (EIT) Health (grant number 20877), supported by the European Institute of Innovation and Technology, a body of the European Union receiving support from the H2020 Research and Innovation Programme. We acknowledge support from the Spanish Ministry of Science and Innovation and State Research Agency through the "Centro de Excelencia Severo Ochoa 2019-2023" Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. L. I. work was supported by PID2019-110810RB-I00 grant from the Spanish Ministry of Science & Innovation. Development of SARS-CoV-2 reagents was partially supported by the National Institute of Allergy and Infectious Diseases Centers of Excellence for Influenza Research and Surveillance (contract number HHSN272201400008C). The funders had no role in study design, data collection and analysis, the decision to publish, or the preparation of the manuscript.

Indeterminate mycobacterium tuberculosis QuantiFERON post Moderna mRNA Covid-19 vaccination.

We report an interesting case of an indeterminate MTB QuantiFERON for a 26-year-old healthy soldier planned for a routine field exercise to Brunei. Further medical history revealed that the patient had a Moderna mRNA Covid-19 vaccine the day before his MTB QuantiFERON test. The patient was subsequently asked to repeat a T-spot test which was non-reactive, there were no longer any issues with the positive control for the T-spot test. Current Covid-19 research suggests that infection causes a dysregulation of the immune system, perhaps this might also be extrapolated where a Covid-19 vaccine might provoke an immune response which might interfere with some immunological assays. In summary there should be more research invested into the immunological interactions that the newly developed Covid-19 vaccinations have with our existing immunological tests such as QuantiFERON tests which forms a key cornerstone in our fight against tuberculosis.

Reactogenicity among health care workers following a BNT162b2 or mRNA-1273 second dose after priming with a ChAdOx1 nCOV-19 vaccine.

OBJECTIVES: In March 2021, French authorities recommended a heterologous second dose of the mRNA vaccine for persons aged <55 years, with administration 9 to 12 weeks after the first dose of ChAdOx1 nCoV-19. This recommendation was despite a lack of data on the reactogenicity and safety of the regimen. Since then, several studies have shown an acceptable short-term safety profile of ChAdOx1 nCoV-19 and BNT162b2 heterologous vaccination, although some transient increased reactogenicity has been described. METHODS: We performed a single-centre prospective observational cohort study among health care workers (HCWs) at a tertiary care hospital to assess the reactogenicity of the BNT162b2 and mRNA-1273 vaccines administered as a second dose in participants primed with ChAdOx1 nCoV-19. RESULTS: Among 1184 HCWs, 356 (30%) agreed to participate. Of the participants, 32.3% were male, and the mean age was 35 years (standard deviation: 10.1 years). Of the participants, 229 received BNT162b2 and 127 received mRNA-1273. A systemic reaction was observed in 130 of 229 (56.8%) and 100 of 127 (78.7%) HCWs, respectively. Injection site reactions were generally limited (grade 1 or 2 in 163 of 229 (97.6%) and 90 of 127 (85.7 %) HCWs, respectively). After adjustment for age, sex, and HCW role, receiving the mRNA-1273 vaccine was associated with higher reactogenicity with more grade 3 side effects (adjusted OR (aOR): 3.34; 95% CI, 1.91-5.85), more systemic symptoms (aOR: 2.82; 95% CI, 1.69-4.7), and not being able to work (aOR: 8.35; 95% CI, 3.78-18.44) compared with receiving the BNT162b2 vaccine. DISCUSSION: Among patients receiving the mRNA1273 vaccine as a second dose, our study confirms good tolerance of the heterologous schedule with a higher risk of short-term side effects in comparison with patients receiving the BNT162b2 vaccine.

Effectiveness of mRNA vaccines and waning of protection against SARS-CoV-2 infection and severe covid-19 during predominant circulation of the delta variant in Italy: retrospective cohort study.

OBJECTIVES: To estimate the effectiveness of mRNA vaccines against SARS-CoV-2 infection and severe covid-19 at different time after vaccination. DESIGN: Retrospective cohort study. SETTING: Italy, 27 December 2020 to 7 November 2021. PARTICIPANTS: 33 250 344 people aged ≥16 years who received a first dose of BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine and did not have a previous diagnosis of SARS-CoV-2 infection. MAIN OUTCOME MEASURES: SARS-CoV-2 infection and severe covid-19 (admission to hospital or death). Data were divided by weekly time intervals after vaccination. Incidence rate ratios at different time intervals were estimated by multilevel negative binomial models with robust variance estimator. Sex, age group, brand of vaccine, priority risk category, and regional weekly incidence in the general population were included as covariates. Geographic region was included as a random effect. Adjusted vaccine effectiveness was calculated as (1-IRR)×100, where IRR=incidence rate ratio, with the time interval 0-14 days after the first dose of vaccine as the reference. RESULTS: During the epidemic phase when the delta variant was the predominant strain of the SARS-CoV-2 virus, vaccine effectiveness against SARS-CoV-2 infection significantly decreased (P<0.001) from 82% (95% confidence interval 80% to 84%) at 3-4 weeks after the second dose of vaccine to 33% (27% to 39%) at 27-30 weeks after the second dose. In the same time intervals, vaccine effectiveness against severe covid-19 also decreased (P<0.001), although to a lesser extent, from 96% (95% to 97%) to 80% (76% to 83%). High risk people (vaccine effectiveness -6%, -28% to 12%), those aged ≥80 years (11%, -15% to 31%), and those aged 60-79 years (2%, -11% to 14%) did not seem to be protected against infection at 27-30 weeks after the second dose of vaccine. CONCLUSIONS: The results support the vaccination campaigns targeting high risk people, those aged ≥60 years, and healthcare workers to receive a booster dose of vaccine six months after the primary vaccination cycle. The results also suggest that timing the booster dose earlier than six months after the primary vaccination cycle and extending the offer of the booster dose to the wider eligible population might be warranted.

The Advisory Committee on Immunization Practices' Recommendation for Use of Moderna COVID-19 Vaccine in Adults Aged ≥18 Years and Considerations for Extended Intervals for Administration of Primary Series Doses of mRNA COVID-19 Vaccines - United States, February 2022.

The mRNA-1273 (Moderna) COVID-19 vaccine is a lipid nanoparticle-encapsulated, nucleoside-modified mRNA vaccine encoding the stabilized prefusion spike glycoprotein of SARS-CoV-2, the virus that causes COVID-19. During December 2020, the vaccine was granted Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA), and the Advisory Committee on Immunization Practices (ACIP) issued an interim recommendation for use among persons aged ≥18 years (1), which was adopted by CDC. During December 19, 2020-January 30, 2022, approximately 204 million doses of Moderna COVID-19 vaccine were administered in the United States (2) as a primary series of 2 intramuscular doses (100 µg [0.5 mL] each) 4 weeks apart. On January 31, 2022, FDA approved a Biologics License Application (BLA) for use of the Moderna COVID-19 vaccine (Spikevax, ModernaTX, Inc.) in persons aged ≥18 years (3). On February 4, 2022, the ACIP COVID-19 Vaccines Work Group conclusions regarding recommendations for the use of the Moderna COVID-19 vaccine were presented to ACIP at a public meeting. The Work Group's deliberations were based on the Evidence to Recommendation (EtR) Framework,* which incorporates the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach† to rank evidence quality. In addition to initial clinical trial data, ACIP considered new information gathered in the 12 months since issuance of the interim recommendations, including additional follow-up time in the clinical trial, real-world vaccine effectiveness studies, and postauthorization vaccine safety monitoring. ACIP also considered comparisons of mRNA vaccine effectiveness and safety in real-world settings when first doses were administered 8 weeks apart instead of the original intervals used in clinical trials (3 weeks for BNT162b2 [Pfizer-BioNTech] COVID-19 vaccine and 4 weeks for Moderna COVID-19 vaccine). Based on this evidence, CDC has provided guidance that an 8-week interval might be optimal for some adolescents and adults. The additional information gathered since the issuance of the interim recommendations increased certainty that the benefits of preventing symptomatic and asymptomatic SARS-CoV-2 infection, hospitalization, and death outweigh vaccine-associated risks of the Moderna COVID-19 vaccine. On February 4, 2022, ACIP modified its interim recommendation to a standard recommendation§ for use of the fully licensed Moderna COVID-19 vaccine in persons aged ≥18 years.

Association Between 3 Doses of mRNA COVID-19 Vaccine and Symptomatic Infection Caused by the SARS-CoV-2 Omicron and Delta Variants.

Importance: Assessing COVID-19 vaccine performance against the rapidly spreading SARS-CoV-2 Omicron variant is critical to inform public health guidance. Objective: To estimate the association between receipt of 3 doses of Pfizer-BioNTech BNT162b2 or Moderna mRNA-1273 vaccine and symptomatic SARS-CoV-2 infection, stratified by variant (Omicron and Delta). Design, Setting, and Participants: A test-negative case-control analysis among adults 18 years or older with COVID-like illness tested December 10, 2021, through January 1, 2022, by a national pharmacy-based testing program (4666 COVID-19 testing sites across 49 US states). Exposures: Three doses of mRNA COVID-19 vaccine (third dose ≥14 days before test and ≥6 months after second dose) vs unvaccinated and vs 2 doses 6 months or more before test (ie, eligible for a booster dose). Main Outcomes and Measures: Association between symptomatic SARS-CoV-2 infection (stratified by Omicron or Delta variants defined using S-gene target failure) and vaccination (3 doses vs unvaccinated and 3 doses vs 2 doses). Associations were measured with multivariable multinomial regression. Among cases, a secondary outcome was median cycle threshold values (inversely proportional to the amount of target nucleic acid present) for 3 viral genes, stratified by variant and vaccination status. Results: Overall, 23 391 cases (13 098 Omicron; 10 293 Delta) and 46 764 controls were included (mean age, 40.3 [SD, 15.6] years; 42 050 [60.1%] women). Prior receipt of 3 mRNA vaccine doses was reported for 18.6% (n = 2441) of Omicron cases, 6.6% (n = 679) of Delta cases, and 39.7% (n = 18 587) of controls; prior receipt of 2 mRNA vaccine doses was reported for 55.3% (n = 7245), 44.4% (n = 4570), and 41.6% (n = 19 456), respectively; and being unvaccinated was reported for 26.0% (n = 3412), 49.0% (n = 5044), and 18.6% (n = 8721), respectively. The adjusted odds ratio for 3 doses vs unvaccinated was 0.33 (95% CI, 0.31-0.35) for Omicron and 0.065 (95% CI, 0.059-0.071) for Delta; for 3 vaccine doses vs 2 doses the adjusted odds ratio was 0.34 (95% CI, 0.32-0.36) for Omicron and 0.16 (95% CI, 0.14-0.17) for Delta. Median cycle threshold values were significantly higher in cases with 3 doses vs 2 doses for both Omicron and Delta (Omicron N gene: 19.35 vs 18.52; Omicron ORF1ab gene: 19.25 vs 18.40; Delta N gene: 19.07 vs 17.52; Delta ORF1ab gene: 18.70 vs 17.28; Delta S gene: 23.62 vs 20.24). Conclusions and Relevance: Among individuals seeking testing for COVID-like illness in the US in December 2021, receipt of 3 doses of mRNA COVID-19 vaccine (compared with unvaccinated and with receipt of 2 doses) was less likely among cases with symptomatic SARS-CoV-2 infection compared with test-negative controls. These findings suggest that receipt of 3 doses of mRNA vaccine, relative to being unvaccinated and to receipt of 2 doses, was associated with protection against both the Omicron and Delta variants, although the higher odds ratios for Omicron suggest less protection for Omicron than for Delta.

Antibody Response to SARS-CoV-2 Infection and Vaccination in COVID-19-naïve and Experienced Individuals.

Understanding the magnitude of responses to vaccination during the ongoing SARS-CoV-2 pandemic is essential for ultimate mitigation of the disease. Here, we describe a cohort of 102 subjects (70 COVID-19-naïve, 32 COVID-19-experienced) who received two doses of one of the mRNA vaccines (BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)). We document that a single exposure to antigen via infection or vaccination induces a variable antibody response which is affected by age, gender, race, and co-morbidities. In response to a second antigen dose, both COVID-19-naïve and experienced subjects exhibited elevated levels of anti-spike and SARS-CoV-2 neutralizing activity; however, COVID-19-experienced individuals achieved higher antibody levels and neutralization activity as a group. The COVID-19-experienced subjects exhibited no significant increase in antibody or neutralization titer in response to the second vaccine dose (i.e., third antigen exposure). Finally, we found that COVID-19-naïve individuals who received the Moderna vaccine exhibited a more robust boost response to the second vaccine dose (p = 0.004) as compared to the response to Pfizer-BioNTech. Ongoing studies with this cohort will continue to contribute to our understanding of the range and durability of responses to SARS-CoV-2 mRNA vaccines.

Moyamoya disease with Sjogren disease and autoimmune thyroiditis presenting with left intracranial hemorrhage after messenger RNA-1273 vaccination: A case report.

RATIONALE: The new vaccines are emergently authorized and currently approved for use to protect against the coronavirus disease 2019 (COVID-19) pandemic and serious adverse events are uncommon. Moyamoya disease (MMD) with autoimmune disease is a rare entity and usually presents with intracranial hemorrhage in adults. PATIENT CONCERNS: We reported a 40-year-old female patient with Sjogren disease and autoimmune thyroiditis, who had received the second dose of Moderna (mRNA-1273) vaccination. Three days later, she presented with left intraventricular and intracerebral hemorrhage as a complication. DIAGNOSIS: After a series of diagnostic workups, left intracranial hemorrhage was associated with MMD. INTERVENTIONS: Emergent external ventricular drainage and subsequent stereotactic evacuation of hematoma with insertion of intracranial pressure monitoring were performed. OUTCOMES: Under the care of the neurocritical care team, her physical condition improved gradually. The neurological sequelae was noted by defects of cognitive function, apraxia, agnosia, and impaired executive function. She was discharged after eight weeks with a follow-up in the vascular neurology clinic planning for performing revascularization. LESSONS: To the best of our knowledge, no similar case has been reported before, and this is the first case of MMD complicated with intracerebral and intraventricular hemorrhage after mRNA-1273 vaccination. It is noticeable to assess the vaccine safety surveillance and raise the alertness about moyamoya in patients with autoimmune diseases during the COVID-19 pandemic. Further studies for risk evaluation of COVID-19 vaccines in patients with autoimmune diseases might be required in the future.

Seroresponse to SARS-CoV-2 Vaccines among Maintenance Dialysis Patients over 6 Months.

BACKGROUND AND OBJECTIVES: Although most patients receiving maintenance dialysis exhibit initial seroresponse to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, concerns exist regarding the durability of this antibody response. This study evaluated seroresponse over time. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective cohort study included patients on maintenance dialysis, from a midsize national dialysis provider, who received a complete SARS-CoV-2 vaccine series and had at least one antibody titer checked after full vaccination. IgG spike antibodies (anti-spike IgG) titers were assessed monthly with routine laboratory tests after vaccination; the semiquantitative assay reported a range between zero and ≥20 Index. Descriptive analyses compared trends over time by history of coronavirus disease 2019 (COVID-19) and vaccine type. Time-to-event analyses examined the outcome of loss of seroresponse (anti-spike IgG <1 Index or development of COVID-19). Cox regression adjusted for additional clinical characteristics. RESULTS: Among 1870 patients receiving maintenance dialysis, 1569 had no prior COVID-19. Patients without prior COVID-19 had declining titers over time. Among 443 recipients of BNT162b2 (Pfizer), median (interquartile range) anti-spike IgG titer declined from ≥20 (5.89 to ≥20) in month 1 after full vaccination to 1.96 (0.60-5.88) by month 6. Among 778 recipients of mRNA-1273 (Moderna), anti-spike IgG titer declined from ≥20 (interquartile range, ≥20 to ≥20) in month 1 to 7.99 (2.61 to ≥20) by month 6. The 348 recipients of Ad26.COV2.S (Janssen) had a lower titer response than recipients of an mRNA vaccine over all time periods. In time-to-event analyses, recipients of Ad26.COV2.S and mRNA-1273 had the shortest and longest time to loss of seroresponse, respectively. The maximum titer reached in the first 2 months after full vaccination was associated with durability of the anti-spike IgG seroresponse; patients with anti-spike IgG titer 1-19.99 had a shorter time to loss of seroresponse compared with patients with anti-spike IgG titer ≥20 (hazard ratio, 15.5; 95% confidence interval, 11.7 to 20.7). CONCLUSIONS: Among patients receiving maintenance dialysis, vaccine-induced seroresponse wanes over time across vaccine types. Early titers after full vaccination are associated with the durability of seroresponse.

Broad anti-SARS-CoV-2 antibody immunity induced by heterologous ChAdOx1/mRNA-1273 vaccination.

Heterologous prime-boost immunization strategies have the potential to augment COVID-19 vaccine efficacy. We longitudinally profiled severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)-specific serological and memory B cell (MBC) responses in individuals who received either homologous (ChAdOx1:ChAdOx1) or heterologous (ChAdOx1:mRNA-1273) prime-boost vaccination. Heterologous messenger RNA (mRNA) booster immunization induced higher serum neutralizing antibody and MBC responses against SARS-CoV-2 variants of concern (VOCs) compared with that of homologous ChAdOx1 boosting. Specificity mapping of circulating B cells revealed that mRNA-1273 boost immunofocused ChAdOx1-primed responses onto epitopes expressed on prefusion-stabilized S. Monoclonal antibodies isolated from mRNA-1273-boosted participants displayed overall higher binding affinities and increased breadth of reactivity against VOCs relative to those isolated from ChAdOx1-boosted individuals. Overall, the results provide molecular insight into the enhanced quality of the B cell response induced after heterologous mRNA booster vaccination.

Effectiveness of COVID-19 vaccines against symptomatic SARS-CoV-2 infection and severe outcomes with variants of concern in Ontario.

SARS-CoV-2 variants of concern (VOC) are more transmissible and may have the potential for increased disease severity and decreased vaccine effectiveness. We estimated the effectiveness of BNT162b2 (Pfizer-BioNTech Comirnaty), mRNA-1273 (Moderna Spikevax) and ChAdOx1 (AstraZeneca Vaxzevria) vaccines against symptomatic SARS-CoV-2 infection and COVID-19 hospitalization or death caused by the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1) and Delta (B.1.617.2) VOC in Ontario, Canada, using a test-negative design study. We identified 682,071 symptomatic community-dwelling individuals who were tested for SARS-CoV-2, and 15,269 individuals with a COVID-19 hospitalization or death. Effectiveness against symptomatic infection ≥7 d after two doses was 89-92% against Alpha, 87% against Beta, 88% against Gamma, 82-89% against Beta/Gamma and 87-95% against Delta across vaccine products. The corresponding estimates ≥14 d after one dose were lower. Effectiveness estimates against hospitalization or death were similar to or higher than against symptomatic infection. Effectiveness against symptomatic infection was generally lower for older adults (≥60 years) than for younger adults (<60 years) for most of the VOC-vaccine combinations. Our findings suggest that jurisdictions facing vaccine supply constraints may benefit from delaying the second dose in younger individuals to more rapidly achieve greater overall population protection; however, older adults would likely benefit most from minimizing the delay in receiving the second dose to achieve adequate protection against VOC.

Risk of infection, hospitalisation, and death up to 9 months after a second dose of COVID-19 vaccine: a retrospective, total population cohort study in Sweden.

BACKGROUND: Vaccine effectiveness against COVID-19 beyond 6 months remains incompletely understood. We aimed to investigate the effectiveness of COVID-19 vaccination against the risk of infection, hospitalisation, and death during the first 9 months after vaccination for the total population of Sweden. METHODS: This retrospective, total population cohort study was done using data from Swedish nationwide registers. The cohort comprised all individuals vaccinated with two doses of ChAdOx1 nCoV-19, mRNA-1273, or BNT162b2, and matched unvaccinated individuals, with data on vaccinations and infections updated until Oct 4, 2021. Two outcomes were evaluated. The first was SARS-CoV-2 infection of any severity from Jan 12 to Oct 4, 2021. The second was severe COVID-19, defined as hospitalisation for COVID-19 or all-cause 30-day mortality after confirmed infection, from March 15 to Sept 28, 2021. FINDINGS: Between Dec 28, 2020, and Oct 4, 2021, 842 974 individuals were fully vaccinated (two doses), and were matched (1:1) to an equal number of unvaccinated individuals (total study cohort n=1 685 948). For the outcome SARS-CoV-2 infection of any severity, the vaccine effectiveness of BNT162b2 waned progressively over time, from 92% (95% CI 92 to 93; p<0·001) at 15-30 days, to 47% (39 to 55; p<0·001) at 121-180 days, and to 23% (-2 to 41; p=0·07) from day 211 onwards. Waning was slightly slower for mRNA-1273, with a vaccine effectiveness of 96% (94 to 97; p<0·001) at 15-30 days and 59% (18 to 79; p=0·012) from day 181 onwards. Waning was also slightly slower for heterologous ChAdOx1 nCoV-19 plus an mRNA vaccine, for which vaccine effectiveness was 89% (79 to 94; p<0·001) at 15-30 days and 66% (41 to 80; p<0·001) from day 121 onwards. By contrast, vaccine effectiveness for homologous ChAdOx1 nCoV-19 vaccine was 68% (52 to 79; p<0·001) at 15-30 days, with no detectable effectiveness from day 121 onwards (-19% [-98 to 28]; p=0·49). For the outcome of severe COVID-19, vaccine effectiveness waned from 89% (82 to 93; p<0·001) at 15-30 days to 64% (44 to 77; p<0·001) from day 121 onwards. Overall, there was some evidence for lower vaccine effectiveness in men than in women and in older individuals than in younger individuals. INTERPRETATION: We found progressively waning vaccine effectiveness against SARS-CoV-2 infection of any severity across all subgroups, but the rate of waning differed according to vaccine type. With respect to severe COVID-19, vaccine effectiveness seemed to be better maintained, although some waning became evident after 4 months. The results strengthen the evidence-based rationale for administration of a third vaccine dose as a booster. FUNDING: None.

Antibody Responses after SARS-CoV-2 Vaccination in Patients with Liver Diseases.

The novel mRNA-based vaccines against SARS-CoV-2 display encouraging safety and efficacy profiles. However, there is a paucity of data regarding their immunogenicity and safety in patients with liver diseases (PWLD), especially in those with cirrhosis. We prospectively assessed anti-SARS-CoV-2 S-spike IgG antibodies and neutralizing activity in fully vaccinated PWLD (n = 87) and controls (n = 40). Seroconversion rates were 97.4% (37/38) in cirrhotic PWLD, 87.8% (43/49) in non-cirrhotic PWLD and 100% (40/40) in controls. Adequate neutralizing activity was detected in 92.1% (35/38), 87.8% (43/49) and 100% (40/40) of cirrhotics, non-cirrhotics and controls, respectively. On multivariable analysis, immunosuppressive treatment was negatively correlated with anti-SARS-CoV-2 antibody titers (coefficient (SE): -2.716 (0.634), p < 0.001) and neutralizing activity (coefficient (SE): -24.379 (4.582), p < 0.001), while age was negatively correlated only with neutralizing activity (coefficient (SE): -0.31(0.14), p = 0.028). A total of 52 responder PWLD were reassessed approximately 3 months post-vaccination and no differences were detected in humoral responses between cirrhotic and non-cirrhotic PWLD. No significant side effects were noted post vaccination, while no symptomatic breakthrough infections were reported during a 6-month follow up. Overall, our study shows that m-RNA-based SARS-CoV-2 vaccines are safe and efficacious in PWLD. However, PWLD under immunosuppressive treatment and those of advanced age should probably be more closely monitored after vaccination.