Immunogenicity of mRNA-1273 and BNT162b2 in Immunocompromised Patients: Systematic Review and Meta-analysis Using GRADE.

INTRODUCTION: Immunocompromised (IC) patients mount poor immune responses to vaccination. Higher-dose coronavirus disease 2019 (COVID-19) vaccines may offer increased immunogenicity. METHODS: A pairwise meta-analysis of 98 studies reporting comparisons of mRNA-1273 (50 or 100 mcg/dose) and BNT162b2 (30 mcg/dose) in IC adults was performed. Outcomes were seroconversion, total and neutralizing antibody titers, and cellular immune responses. RESULTS: mRNA-1273 was associated with a significantly higher seroconversion likelihood [relative risk, 1.11 (95% CI, 1.08, 1.14); P < 0.0001; I2 = 66.8%] and higher total antibody titers [relative increase, 50.45% (95% CI, 34.63%, 66.28%); P < 0.0001; I2 = 89.5%] versus BNT162b2. mRNA-1273 elicited higher but statistically nonsignificant relative increases in neutralizing antibody titers and cellular immune responses versus BNT162b2. CONCLUSION: Higher-dose mRNA-1273 had increased immunogenicity versus BNT162b2 in IC patients.

Comparative Effectiveness of mRNA-1273 and BNT162b2 COVID-19 Vaccines Among Older Adults: Systematic Literature Review and Meta-Analysis Using the GRADE Framework.

INTRODUCTION: The mRNA vaccines mRNA-1273 and BNT162b2 demonstrated high efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in phase 3 clinical trials, including among older adults. To inform coronavirus disease 2019 (COVID-19) vaccine selection, this systematic literature review (SLR) and meta-analysis assessed the comparative effectiveness of mRNA-1273 versus BNT162b2 in older adults. METHODS: We systematically searched for relevant studies reporting COVID-19 outcomes with mRNA vaccines in older adults aged ≥ 50 years by first cross-checking relevant published SLRs. Based on the cutoff date from a previous similar SLR, we then searched the WHO COVID-19 Research Database for relevant articles published between April 9, 2022, and June 2, 2023. Outcomes of interest were SARS-CoV-2 infection, symptomatic SARS-CoV-2 infection, severe SARS-CoV-2 infection, COVID-19-related hospitalization, and COVID-19-related death following ≥ 2 vaccine doses. Random effects meta-analysis models were used to pool risk ratios (RRs) across studies. Heterogeneity was evaluated using chi-square testing. Evidence certainty was assessed per GRADE framework. RESULTS: Twenty-four non-randomized real-world studies reporting clinical outcomes with mRNA vaccines in individuals aged ≥ 50 years were included in the meta-analysis. Vaccination with mRNA-1273 was associated with significantly lower risk of SARS-CoV-2 infection (RR 0.72 [95% confidence interval (CI) 0.64‒0.80]), symptomatic SARS-CoV-2 infection (RR 0.72 [95% CI 0.62‒0.83]), severe SARS-CoV-2 infection (RR 0.67 [95% CI 0.57‒0.78]), and COVID-19-related hospitalization (RR 0.65 [95% CI 0.53‒0.79]) but not COVID-19-related death (RR 0.80 [95% CI 0.64‒1.00]) compared with BNT162b2. There was considerable heterogeneity between studies for all outcomes (I2 > 75%) except death (I2 = 0%). Multiple subgroup and sensitivity analyses excluding specific studies generally demonstrated consistent results. Certainty of evidence across outcomes was rated as low (type 3) or very low (type 4), reflecting the lack of randomized controlled trial data. CONCLUSION: Meta-analysis of 24 observational studies demonstrated significantly lower risk of asymptomatic, symptomatic, and severe infections and hospitalizations with the mRNA-1273 versus BNT162b2 vaccine in older adults aged ≥ 50 years.

Comparative effectiveness of mRNA-1273 and BNT162b2 COVID-19 vaccines in immunocompromised individuals: a systematic review and meta-analysis using the GRADE framework.

Introduction: Despite representing only 3% of the US population, immunocompromised (IC) individuals account for nearly half of the COVID-19 breakthrough hospitalizations. IC individuals generate a lower immune response after vaccination in general, and the US CDC recommended a third dose of either mRNA-1273 or BNT162b2 COVID-19 vaccines as part of their primary series. Influenza vaccine trials have shown that increasing dosage could improve effectiveness in IC populations. The objective of this systematic literature review and pairwise meta-analysis was to evaluate the clinical effectiveness of mRNA-1273 (50 or 100 mcg/dose) vs BNT162b2 (30 mcg/dose) in IC populations using the GRADE framework. Methods: The systematic literature search was conducted in the World Health Organization COVID-19 Research Database. Studies were included in the pairwise meta-analysis if they reported comparisons of mRNA-1273 and BNT162b2 in IC individuals ≥18 years of age; outcomes of interest were symptomatic, laboratory-confirmed SARS-CoV-2 infection, SARS-CoV-2 infection, severe SARS-CoV-2 infection, hospitalization due to COVID-19, and mortality due to COVID-19. Risk ratios (RR) were pooled across studies using random-effects meta-analysis models. Outcomes were also analyzed in subgroups of patients with cancer, autoimmune disease, and solid organ transplant. Risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies. Evidence was evaluated using the GRADE framework. Results: Overall, 17 studies were included in the pairwise meta-analysis. Compared with BNT162b2, mRNA-1273 was associated with significantly reduced risk of SARS-CoV-2 infection (RR, 0.85 [95% CI, 0.75-0.97]; P=0.0151; I2 = 67.7%), severe SARS-CoV-2 infection (RR, 0.85 [95% CI, 0.77-0.93]; P=0.0009; I2 = 0%), COVID-19-associated hospitalization (RR, 0.88 [95% CI, 0.79-0.97]; P<0.0001; I2 = 0%), and COVID-19-associated mortality (RR, 0.63 [95% CI, 0.44-0.90]; P=0.0119; I2 = 0%) in IC populations. Results were consistent across subgroups. Because of sample size limitations, relative effectiveness of COVID-19 mRNA vaccines in IC populations cannot be studied in randomized trials. Based on nonrandomized studies, evidence certainty among comparisons was type 3 (low) and 4 (very low), reflecting potential biases in observational studies. Conclusion: This GRADE meta-analysis based on a large number of consistent observational studies showed that the mRNA-1273 COVID-19 vaccine is associated with improved clinical effectiveness in IC populations compared with BNT162b2.

COVID-19 Vaccination Among Patients Receiving Maintenance Renal Replacement Therapy: Immune Response, Real-World Effectiveness, and Implications for the Future.

Chronic kidney disease affects more than 800 million people worldwide and often progresses to end-stage renal disease, which requires maintenance dialysis. Patients receiving dialysis are at higher risk for severe respiratory infections, including SARS-CoV-2 (the causative agent of COVID-19). In addition, many patients who receive dialysis also receive immunosuppressive treatments for conditions such as systemic vasculitis, systemic lupus erythematosus, or malignancies. Many studies have shown that while mRNA COVID-19 vaccines induce some level of immune response in patients receiving dialysis, the magnitude of response is often lower than that of healthy individuals, and responses rapidly wane. Importantly, the risk of COVID-19-related hospitalization and mortality for patients receiving dialysis is 4- to 8-fold higher compared with the general population. In this article, we summarize recent immunogenicity and real-world outcomes of COVID-19 mRNA vaccination among patients receiving dialysis, with a focus on the 3-dose extended primary series and additional (fourth) doses.

The Burden of COVID-19 in the Immunocompromised Patient: Implications for Vaccination and Needs for the Future.

Approximately 3% of US adults are immunocompromised and less capable of fighting infections such as SARS-CoV-2 (the causative agent of COVID-19). Individuals may be immunocompromised for reasons related to an underlying medical condition or to immunomodulatory therapies that alter the immune response. In general, vaccination with mRNA-based vaccines is effective at reducing COVID-19-associated hospitalization and death among immunocompromised populations, particularly after 3 or more doses. However, the immunocompromised population is heterogeneous, with COVID-19 vaccine-elicited immune responses and risk for severe COVID-19 existing on a continuum. Therefore, understanding the impact of vaccination and the complexity of immune responses across heterogeneous immunocompromised individuals is essential for guiding effective vaccination regimens including additional (booster) doses. In this article, we provide an overview of the immunocompromised population and the burden of disease attributable to COVID-19, while discussing key opportunities and challenges of vaccinating immunocompromised individuals.

Rituximab and antimetabolite treatment of granulomatous and lymphocytic interstitial lung disease in common variable immunodeficiency.

BACKGROUND: Granulomatous and lymphocytic interstitial lung disease (GLILD) is a life-threatening complication in patients with common variable immunodeficiency (CVID), but the optimal treatment is unknown. OBJECTIVE: Our aim was to determine whether rituximab with azathioprine or mycophenolate mofetil improves the high-resolution computed tomography (HRCT) chest scans and/or pulmonary function test results in patients with CVID and GLILD. METHODS: A retrospective chart review of clinical and laboratory data on 39 patients with CVID and GLILD who completed immunosuppressive therapy was performed. Chest HRCT scans, performed before therapy and after the conclusion of therapy, were blinded, randomized, and scored independently by 2 radiologists. Differences between pretreatment and posttreatment HRCT scan scores, pulmonary function test results, and lymphocyte subsets were analyzed. Whole exome sequencing was performed on all patients. RESULTS: Immunosuppressive therapy improved patients' HRCT scan scores (P < .0001), forced vital capacity (P = .0017), FEV1 (P = .037), and total lung capacity (P = .013) but not their lung carbon monoxide diffusion capacity (P = .12). Nine patients relapsed and 6 completed retreatment, with 5 of 6 of these patients (83%) having improved HRCT scan scores (P = .063). Relapse was associated with an increased number of B cells (P = .016) and activated CD4 T cells (P = .016). Four patients (10%) had pneumonia while undergoing active treatment, and 2 patients (5%) died after completion of therapy. Eight patients (21%) had a damaging mutation in a gene known to predispose (TNFRSF13B [n = 3]) or cause a CVID-like primary immunodeficiency (CTLA4 [n = 2], KMT2D [n = 2], or BIRC4 [n = 1]). Immunosuppression improved the HRCT scan scores in patients with (P = .0078) and without (P < .0001) a damaging mutation. CONCLUSIONS: Immunosuppressive therapy improved the radiographic abnormalities and pulmonary function of patients with GLILD. A majority of patients had sustained remissions.

The Use of Salmonella Typhim Vaccine to Diagnose Antibody Deficiency.

PURPOSE: The specific antibody response to the unconjugated 23-valent pneumococcal polysaccharide vaccine is one of the most common tests used to assess for possible humoral immunodeficiency. The results can be difficult to interpret because most people have been immunized with one or more of the pneumococcal vaccines and there is controversy regarding what constitutes a normal response. To circumvent this problem, we developed an ELISA to measure IgG-specific antibodies to the Salmonella Vi Typhim (S. Typhim) vaccine, a pure polysaccharide vaccine, which is a neoantigen for the vast majority of people in the USA. METHODS: We compared the pre- and post-vaccination serum titers to the Vi Typhim vaccine in healthy controls (n = 22), patients previously diagnosed with a primary immunodeficiency (n = 30), and patients referred for possible humoral immune deficiency (n = 29). We also determined if the S. Typhim vaccine could be used to assess specific antibody responses in people on antibody replacement therapy. RESULTS: Following immunization with the S. Typhim vaccine, we found that a 2-fold increase in titers is 100% sensitive and specific in detecting known humoral immune deficiencies as determined by ROC curve analysis. This cut-off value was successfully applied to possible immune deficiency patients (n = 29), resulting in the diagnosis of seven subjects with humoral immunodeficiency. The use of immunoglobulin replacement therapy did not affect the median response ratios compared to subjects not receiving gammaglobulin. CONCLUSION: This study suggests that measurement of the specific antibody response to the S. Typhim vaccine may have advantages over pneumococcal vaccination in the evaluation of the humoral immune response.