Impaired SARS-CoV-2 Variant Neutralization and CD8+ T-cell Responses Following 3 Doses of mRNA Vaccines in Myeloma: Correlation with Breakthrough Infections.

Patients with multiple myeloma (MM) mount suboptimal neutralizing antibodies (nAb) following 2 doses of SARS-CoV-2 mRNA vaccines. Currently, circulating SARS-CoV-2 variants of concern (VOC) carry the risk of breakthrough infections. We evaluated immune recognition of current VOC including BA.1, BA.2, and BA.5 in 331 racially representative patients with MM following 2 or 3 doses of mRNA vaccines. The third dose increased nAbs against WA1 in 82%, but against BA variants in only 33% to 44% of patients. Vaccine-induced nAbs correlated with receptor-binding domain (RBD)-specific class-switched memory B cells. Vaccine-induced spike-specific T cells were detected in patients without seroconversion and cross-recognized variant-specific peptides but were predominantly CD4+ T cells. Detailed clinical/immunophenotypic analysis identified features correlating with nAb/B/T-cell responses. Patients who developed breakthrough infections following 3 vaccine doses had lower live-virus nAbs, including against VOC. Patients with MM remain susceptible to SARS-CoV-2 variants following 3 vaccine doses and should be prioritized for emerging approaches to elicit variant-nAb and CD8+ T cells. SIGNIFICANCE: Three doses of SARS-CoV-2 mRNA vaccines fail to yield detectable VOC nAbs in nearly 60% and spike-specific CD8+ T cells in >80% of myeloma patients. Patients who develop breakthrough infections following vaccination have low levels of live-virus nAb. This article is highlighted in the In This Issue feature, p. 101.

Durability of immune responses to mRNA booster vaccination against COVID-19.

BackgroundMaintaining durable immunity following vaccination represents a major challenge, but whether mRNA booster vaccination improves durability is unknown.MethodsWe measured antibody responses in 55 healthy adults, who received a booster dose of the Pfizer-BioNTech or Moderna vaccine against SARS-CoV-2 and calculated the half-life of the antibody titers. We also measured memory B and T cell responses in a subset of 28 participants. In 13 volunteers who received a second booster vaccine, we measured serum antibody titers and memory B and T cell responses.ResultsThe booster (third immunization) dose at 6 to 10 months increased the half-life of the serum-neutralizing antibody (nAb) titers to 76 days from 56 to 66 days after the primary 2-dose vaccination. A second booster dose (fourth immunization) a year after the primary vaccination further increased the half-life to 88 days. However, despite this modestly improved durability in nAb responses against the ancestral (WA.1) strain, there was a loss of neutralization capacity against the Omicron subvariants BA.2.75.2, BQ.1.1, and XBB.1.5 (48-, 71-, and 66-fold drop in titers, respectively, relative to the WA.1 strain). Although only 45% to 65% of participants demonstrated a detectable nAb titer against the newer variants after the booster (third dose), the response declined to below the detection limit in almost all individuals by 6 months. In contrast, booster vaccination induced antigen-specific memory B and T cells that persisted for at least 6 months.ConclusionThe durability of serum antibody responses improves only marginally following booster immunizations with the Pfizer-BioNTech or Moderna mRNA vaccines.

Osteopontin as a biomarker for COVID-19 severity and multisystem inflammatory syndrome in children: A pilot study.

This study sought to evaluate the candidacy of plasma osteopontin (OPN) as a biomarker of COVID-19 severity and multisystem inflammatory condition in children (MIS-C) in children. A retrospective analysis of 26 children (0-21 years of age) admitted to Children's Healthcare of Atlanta with a diagnosis of COVID-19 between March 17 and May 26, 2020 was undertaken. The patients were classified into three categories based on COVID-19 severity levels: asymptomatic or minimally symptomatic (control population, admitted for other non-COVID-19 conditions), mild/moderate, and severe COVID-19. A fourth category of children met the Centers for Disease Control and Prevention's case definition for MIS-C. Residual blood samples were analyzed for OPN, a marker of inflammation using commercial ELISA kits (R&D), and results were correlated with clinical data. This study demonstrates that OPN levels are significantly elevated in children hospitalized with moderate and severe COVID-19 and MIS-C compared to OPN levels in mild/asymptomatic children. Further, OPN differentiated among clinical levels of severity in COVID-19, while other inflammatory markers including maximum erythrocyte sedimentation rate, C-reactive protein and ferritin, minimum lymphocyte and platelet counts, soluble interleukin-2R, and interleukin-6 did not. We conclude OPN is a potential biomarker of COVID-19 severity and MIS-C in children that may have future clinical utility. The specificity and positive predictive value of this marker for COVID-19 and MIS-C are areas for future larger prospective research studies.