Science Translational Medicine

Unlike mRNA vaccines based only on the Spike protein, inactivated SARS-CoV-2 vaccines should induce a diversified T cell response recognizing distinct structural proteins. Here we performed a comparative analysis of SARS-CoV-2 specific T cells in healthy individuals following vaccination with inactivated SARS-CoV-2 or mRNA vaccines. Relative to Spike mRNA vaccination, inactivated vaccines elicited a lower magnitude of Spike-specific T cells, but the combined Membrane, Nucleoprotein and Spike-spe...

Mucosal vaccines may reduce both infection and transmission by engaging local immunity, yet the immunological pathways they activate in humans remain poorly defined. Here, we present a comprehensive systems vaccinology analysis of a Modified Vaccinia virus Ankara (MVA)-based SARS-CoV-2 vaccine candidate tested in two distinct phase 1 clinical trials as a booster vaccination with either inhaled or intramuscular delivery, and benchmarked findings against published mRNA vaccine data. Longitudinal m...

The human nasopharynx is colonized by commensal bacteria and pathobionts, which comprise a complex microbial ecosystem capable of generating primary and secondary immune responses. Experimental intranasal infection of human adults with the commensal Neisseria lactamica results in safe, sustained colonization. Herein is described a novel technology to chromosomally transform N. lactamica with heterologous antigen, for the purpose of safe delivery to the mucosal surface and the generation of an an...

Anti-bacterial monoclonal antibody (mAb) therapies either rely on toxin neutralization or opsonophagocytic killing (OPK). Toxin neutralization protects the host from toxin-induced damage, while leaving the organism intact. OPK inducing antibodies clear the bacteria but leave the released toxins unencountered. Infection site targeted anti-toxin antibodies (ISTAbs) that we report here addresses this binary paradigm by combining both functionalities into a single molecule. ISTAbs consist of cell wa...

Detailed characterization of the antibody profile induced by SARS-CoV-2 mRNA vaccines has shown that repeat dosing boosts all IgG subclasses, with a notable emergence of antigen-specific IgG4 antibodies. While the IgG4 subclass is traditionally associated with limited Fc-effector functions, its role in SARS-CoV-2 mRNA vaccine-induced immunity remains unclear. This study tracked IgG subclass dynamics, IgG Fc-mediated functions and neutralization following immunization with two or three doses of m...

Repeated mRNA SARS-CoV-2 vaccination has been associated with increases in the proportion of IgG4 in spike-specific antibody responses and concurrent reductions in Fc{gamma}-mediated effector functions that may limit control of viral infection. Here, we assessed anti-Spike total IgG, IgG1, IgG2, IgG3 and IgG4, and surrogate markers for antibody-dependent cellular phagocytosis (ADCP, Fc{gamma}RIIa binding), antibody-dependent cellular cytotoxicity (ADCC, Fc{gamma}RIIIa binding), and antibody-depe...

Several vaccines have been found effective against COVID-19, usually administered in homologous regimens, with the same vaccine used for the prime and boost doses. However, recent studies have demonstrated improved protection via heterologous mix-and-match COVID-19 vaccine combinations, and a direct comparison among these regimens is needed to identify the best employment strategies. Here, we show a single-cohort comparison of changes to the humoral and cellular immune compartments following fiv...

In a cohort of infants, we found that lack of the Lewis histo-blood group antigen was associated with increased susceptibility to shigellosis. Broadly inhibiting fucosylation in epithelial cells in vitro decreased invasion by Shigella flexneri. These results support a role for fucosylated glycans in susceptibility to shigellosis.

Human cytomegalovirus (HCMV) is the most common vertically transmitted infection worldwide, yet there are no licensed vaccines or therapeutics to prevent congenital HCMV (cCMV) infection. Emerging evidence from studies of natural infection and HCMV vaccine trials indicates that antibody Fc effector functions may defend against HCMV infection. We previously reported that antibody-dependent cellular phagocytosis (ADCP) and IgG activation of Fc{gamma}RI/Fc{gamma}RII were associated with reduced ris...

Understanding humoral immune responses to SARS-CoV-2 infection will play a critical role in the development of vaccines and antibody-based interventions. We report systemic and mucosal antibody responses in convalescent individuals who experienced varying disease severity. Robust antibody responses to diverse SARS-CoV-2 antigens and evidence of elevated responses to endemic CoV were observed among convalescent donors. SARS-CoV-2-specific IgA and IgG responses were often negatively correlated, pa...

Influenza virus infections affect millions of people annually. Current available vaccines provide varying rates of protection. There is a knowledge gap on how the nasal microbiota, particularly established pneumococcal colonization, shapes the response to influenza vaccination. In this study, we inoculated healthy adults with live S. pneumoniae and vaccinated them three days later with either TIV or LAIV. Vaccine-induced immune responses were assessed in nose, blood and lung. Nasal pneumococcal ...

BackgroundMucosal antibodies can prevent virus entry and replication in mucosal epithelial cells and hence virus shedding. Preclinical and clinical studies have shown that a parenteral booster injection of a vaccine against a mucosal pathogen promotes stronger mucosal immune responses following prior infection compared to two injections of a parenteral vaccine. We investigated whether this was also the case for a COVID-19 mRNA vaccine. MethodsTwenty-three COVID-19 convalescent patients and 20 S...

The durability of vaccine-induced immune memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for preventing infection, especially severe disease. This follow-up report from a phase 1/2 study of S-268019-b (a recombinant spike protein vaccine) after homologous booster vaccination confirms its long-term safety, tolerability, and immunogenicity. Booster vaccination with S-268019-b resulted in an enhancement of serum neutralizing antibody (NAb) titers and a broad range ...

Human cytomegalovirus (HCMV) is the most common infectious cause of congenital disease and post-transplant complications worldwide, yet vaccine development remains hampered by a limited understanding of protective immune responses. We investigated humoral immune correlates of protection against HCMV acquisition elicited by the most efficacious HCMV vaccine tested to-date, soluble glycoprotein B (gB) with MF59 adjuvant (gB/MF59), which achieved [~]50% efficacy in two phase II clinical trials. Pro...

Currently available mRNA vaccines are extremely safe and effective to prevent severe SARS-CoV-2 infections. However, the emergence of novel variants of concerns has highlighted the importance of high population-based vaccine rates to effectively suppress viral transmission and breakthrough infections. While initially left out from vaccine efforts, children have become one of the most affected age groups and are key targets to stop community and household spread. Antibodies are central for vaccin...

BackgroundParenteral COVID-19 vaccines induce strong systemic immunity, but they do not typically trigger pronounced respiratory immunity. In this context, mucosally applied vaccines might help to induce local immune responses for early viral clearance and reduced viral transmission. MethodsIn this investigator-initiated, open-label single-dose phase I trial, we analyzed the immunogenicity and safety of the vaccine candidate MVA-SARS-2-ST administered as an inhalation boost in COVID-19-immunize...

BackgroundLong term outcomes of allograft recipients are compromised by the development of chronic lung allograft dysfunction (CLAD) promoting bronchiolitis obliterans syndrome (BOS). We established baseline transcriptomic profiles of both the large and small airway epithelial cells (referred as LAEC and SAEC, respectively) to identify regional differences irrespective of initiating disease. MethodsWe obtained matched primary LAEC and SAEC from lung allograft recipients (n=4, 42.5 {+/-} 4.2 yea...

While evidence for pre-existing SARS-CoV-2-cross-reactive CD4+ T cells in unexposed individuals is increasing, their functional significance remains unclear. Here, we comprehensively determined SARS-CoV-2-cross-reactivity and human coronavirus-reactivity in unexposed individuals. SARS-CoV-2-cross-reactive CD4+ T cells were ubiquitous, but their presence decreased with age. Within the spike glycoprotein fusion domain, we identified a universal immunodominant coronavirus-specific peptide epitope (...

The durability of infection-induced SARS-CoV-2 immunity has major implications for public health mitigation and vaccine development. Animal studies1,2 and the scarcity of confirmed re-infection3 suggests immune protection is likely, although the durability of this protection is debated. Lasting immunity following acute viral infection requires maintenance of both serum antibody and antigen-specific memory B and T lymphocytes and is notoriously pathogen specific, ranging from life-long for smallp...

Immunological memory mediates rapid protection following infection or vaccination including heterologous exposure. However, cross-reactive memory responses in humans remain poorly characterized. We explored the longevity and specificity of cross-protective responses to orthopoxviruses through smallpox vaccination and Mpox virus (MPXV) infection. Smallpox vaccination using Vaccinia virus (VACV)-based vaccines provides a unique opportunity to study long-term cross-protective immunity without antig...