Explore the vast range of titles available.

Multiple studies have shown loss of severe acute respiratory syndrome coronavirus 2-specific (SARS-CoV-2-specific) antibodies over time after infection, raising concern that humoral immunity against the virus is not durable. If immunity wanes quickly, millions of people may be at risk for reinfection after recovery from coronavirus disease 2019 (COVID-19). However, memory B cells (MBCs) could provide durable humoral immunity even if serum neutralizing antibody titers decline. We performed multidimensional flow cytometric analysis of S protein receptor binding domain-specific (S-RBD-specific) MBCs in cohorts of ambulatory patients with COVID-19 with mild disease (n = 7), and hospitalized patients with moderate to severe disease (n = 7), at a median of 54 days (range, 39-104 days) after symptom onset. We detected S-RBD-specific class-switched MBCs in 13 of 14 participants, failing only in the individual with the lowest plasma levels of anti-S-RBD IgG and neutralizing antibodies. Resting MBCs (rMBCs) made up the largest proportion of S-RBD-specific MBCs in both cohorts. FCRL5, a marker of functional memory on rMBCs, was more dramatically upregulated on S-RBD-specific rMBCs after mild infection than after severe infection. These data indicate that most SARS-CoV-2-infected individuals develop S-RBD-specific, class-switched rMBCs that resemble germinal center-derived B cells induced by effective vaccination against other pathogens, providing evidence for durable B cell-mediated immunity against SARS-CoV-2 after mild or severe disease.

Group A Streptococcus (Strep A) causes both uncomplicated and severe invasive infections, as well as the post-infection complications acute rheumatic fever and rheumatic heart disease. Despite the high global burden of disease resulting from Strep A infections, there is not a licensed vaccine. A 30-valent M protein-based vaccine has previously been shown to be immunogenic in animal models and in a Phase I clinical trial (NCT02564237). Here, we assessed the immunogenicity of a 30-valent messenger (m)RNA vaccine designed to express the same M peptide targets as the 30-valent protein vaccine and compared it with the protein vaccine. Female New Zealand white rabbits were immunized with one of four vaccine formulations (3 doses of each formulation at days 1, 28, and 56): soluble mRNA (100 μg/animal), C-terminal transmembrane mRNA (100 μg/animal), protein vaccine (400 μg/animal), or a non-translatable RNA control (100 μg/animal). Serum was collected one day prior to the first dose and on days 42 and 70. Rabbit serum samples were assayed for antibody levels against synthetic M peptides by ELISA. HL-60 opsonophagocytic killing (OPK) assays were performed to assess functional antibody levels. Serum IgG levels were similar for the mRNA and protein vaccines. The CtTM version of the mRNA vaccine elicited slightly higher antibody levels than the mRNA designed to express soluble proteins. OPK activity was similar for the mRNA and protein vaccines, regardless of M type. The total antibody responses and functional antibody levels elicited by the 30-valent mRNA Strep A vaccines were similar to those observed following immunization with the analogous protein vaccine. The mRNA vaccine platform provides potential advantages to protein-based vaccines including inherent adjuvant activity, increased production efficiency, lower cost, and the potential to rapidly change epitopes/peptides, all of which are important considerations related to multivalent Strep A vaccine development.

Antibodies targeting the hepatitis C virus (HCV) envelope glycoprotein E2 are associated with delayed disease progression, and these antibodies can also facilitate spontaneous clearance of infection in some individuals. However, many infected people demonstrate low titer and delayed anti-E2 antibody responses. Since a goal of HCV vaccine development is induction of high titers of anti-E2 antibodies, it is important to define the mechanisms underlying these suboptimal antibody responses. By staining lymphocytes with a cocktail of soluble E2 (sE2) glycoproteins, we detected HCV E2-specific (sE2+) B cells directly ex vivo at multiple acute infection timepoints in 29 HCV-infected subjects with a wide range of anti-E2 IgG titers, including 17 persistently infected subjects and 12 subjects with spontaneous clearance of infection. We performed multi-dimensional flow cytometric analysis of sE2+ and E2-nonspecific (sE2-) class-switched B cells (csBC). In sE2+ csBC from both persistence and clearance subjects, frequencies of resting memory B cells (rMBC) were reduced, frequencies of activated MBC (actMBC) and tissue-like MBC (tlMBC) were increased, and expression of FCRL5, an IgG receptor, was significantly upregulated. Across all subjects, plasma anti-E2 IgG levels were positively correlated with frequencies of sE2+ rMBC and sE2+ actMBC, while anti-E2 IgG levels were negatively correlated with levels of FCRL5 expression on sE2+ rMBC and PD-1 expression on sE2+ actMBC. Upregulation of FCRL5 on sE2+ rMBC and upregulation of PD-1 on sE2+ actMBC may limit anti-E2 antibody production in vivo . Strategies that limit upregulation of these molecules could potentially generate higher titers of protective antibodies against HCV or other pathogens.

Early development of broadly neutralizing antibodies (bNAbs) targeting the hepatitis C virus (HCV) envelope glycoprotein E2 is associated with spontaneous clearance of infection, so induction of bNAbs is a major goal of HCV vaccine development. However, the molecular antibody features important for broad neutralization are not known. To identify B cell repertoire features associated with broad neutralization, we performed RNA sequencing of the B cell receptors (BCRs) of HCV E2-reactive B cells of HCV-infected individuals with either high or low plasma neutralizing breadth. We then produced a monoclonal antibody (mAb) expressed by pairing the most abundant heavy and light chains from public clonotypes identified among clearance, high neutralization subjects. We found distinctive BCR features associated with broad neutralization of HCV, including long heavy chain complementarity determining region 3 (CDRH3) regions, specific VH gene usage, increased frequencies of somatic hypermutation, and particular VH gene mutations. Most intriguing, we identified many E2-reactive public BCR clonotypes (heavy and light chain clones with the same V and J-genes and identical CDR3 sequences) present only in subjects who produced highly neutralizing plasma. The majority of these public clonotypes were shared by two subjects who cleared infection. A mAb expressing the most abundant public heavy and light chains from these clearance, high neutralization subjects had features enriched in high neutralization clonotypes, such as increased somatic hypermutation frequency and usage of , and was cross-neutralizing. Together, these results demonstrate distinct BCR repertoires associated with high plasma neutralizing capacity. Further characterization of the molecular features and function of these antibodies can inform HCV vaccine development.

[This corrects the article DOI: 10.3389/fimmu.2023.1135841.].

Acellular multivalent vaccines for pertussis (DTaP and Tdap) prevent symptomatic disease and infant mortality, but immunity to Bordetella pertussis infection wanes significantly over time resulting in cyclic epidemics of pertussis. The messenger RNA (mRNA) vaccine platform provides an opportunity to address complex bacterial infections with an adaptable approach providing Th1-biased responses. In this study, immunogenicity and challenge models were used to evaluate the mRNA platform with multivalent vaccine formulations targeting both B. pertussis antigens and diphtheria and tetanus toxoids. Immunization with mRNA formulations were immunogenetic, induced antigen specific antibodies, as well as Th1 T cell responses. Upon challenge with either historical or contemporary B. pertussis strains, 6 and 10 valent mRNA DTP vaccine provided protection equal to that of 1/20th human doses of either DTaP or whole cell pertussis vaccines. mRNA DTP immunized mice were also protected from pertussis toxin challenge as measured by prevention of lymphocytosis and leukocytosis. Collectively these pre-clinical mouse studies illustrate the potential of the mRNA platform for multivalent bacterial pathogen vaccines.

The continued evolution of the SARS-CoV-2 Omicron JN.1 lineage has led to the emergence of antigenically distinct subvariants including KP.2, KP.3, XEC, and LP.8.1, which became the dominant strains in the Americas and Europe by mid-2025. LP.8.1 was designated a Variant Under Monitoring by the WHO in January 2025 due to its potential to displace prior circulating variants. Informed by early growth modeling and antigenic analysis, we selected LP.8.1 as a candidate strain for the 2025-2026 vaccine season. Here, we describe the development of updated LP.8.1-matched mRNA vaccine compositions encoding either the full-length spike protein for mRNA-1273 (monovalent) or the membrane-anchored receptor-binding and N-terminal domains for the mRNA-1283 vaccine. Initial in vitro characterization, including structural analysis, demonstrated robust antigen expression and intact antigenic features. Immunogenicity of both vaccines were evaluated in murine models following immunization as either a primary series in naïve animals or as a booster dose. LP.8.1-matched vaccines elicited strong neutralizing antibody responses against the homologous LP.8.1 strain and more recently emerging JN.1-lineage subvariants, including XFG and NB.1.8.1. Notably, the mRNA-1283 vaccine expressing LP.8.1 induced higher mean neutralization titers than the mRNA-1273 version across multiple variants. These data demonstrate the immunogenicity and breadth of both LP.8.1-based mRNA-1273 and mRNA-1283 vaccines in the context of ongoing JN.1 lineage evolution and support the selection of LP.8.1 as the updated vaccine antigen for the 2025-2026 season.

Monkeypox virus (MPXV) caused a global outbreak in 2022, fueled by behaviorally-altered and enhanced human-to-human transmission. While smallpox vaccines were rapidly deployed to curb spread and disease among those at highest risk, breakthrough disease was noted after complete immunization. Given the imminent threat of additional zoonotic events as well as the viruses evolving ability to drive human-to-human transmission, there is an urgent need for the development of a MPXV-specific vaccine that is able to also confer broad protection against evolving strains and related orthopoxviruses. Here, we demonstrate that an mRNA-lipid nanoparticle vaccine encoding a set of four highly conserved MPXV surface proteins involved in virus attachment, entry and transmission can induce MPXV-specific immunity and heterologous protection against a lethal vaccinia virus (VACV) challenge. Compared to Modified Vaccinia Virus Ankara (MVA), which forms the basis for the current MPXV vaccine, mRNA-vaccination generated superior neutralizing and cellular spread-inhibitory activities against MPXV and VACV as well as greater Fc-effector Th1-biased humoral immunity to the four MPXV antigens and the four VACV homologs. Single MPXV antigen mRNA vaccines provided partial protection against VACV challenge, while combinations of two, three or four MPXV antigen expressing mRNAs protected against disease-related weight loss and death. Remarkably, the cross-protection by multivalent MPXV mRNAs was superior to the homologous protection by MVA, associated with a combination of neutralizing and non-neutralizing antibody functions. These data reveal robust protection against VACV using an mRNA-based vaccine targeting four highly conserved viral surface antigens, linked to the induction of highly functional antibodies able to rapidly control viral infection.Competing Interest StatementAWF, CA, GYC, Hn, TRF, gaa, CO, AN, HB, jj, MAD, GSJ, TC, AC, and GA are all employees of Moderna.