Sean Callaghan
A5066837018- SARS-CoV-2 and COVID-19 Research
- Animal Virus Infections Studies
- Viral gastroenteritis research and epidemiology
- Monoclonal and Polyclonal Antibodies Research
- COVID-19 Clinical Research Studies
- HIV Research and Treatment
- Bacteriophages and microbial interactions
- SARS-CoV-2 detection and testing
- vaccines and immunoinformatics approaches
- Immune Cell Function and Interaction
- HIV/AIDS drug development and treatment
- T-cell and B-cell Immunology
- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- RNA and protein synthesis mechanisms
- Mitochondrial Function and Pathology
- interferon and immune responses
- Immunotherapy and Immune Responses
- Respiratory viral infections research
- Viral Infections and Outbreaks Research
- Cytomegalovirus and herpesvirus research
- Tryptophan and brain disorders
- Organic Food and Agriculture
- COVID-19 epidemiological studies
- Environmental Sustainability in Business
Scripps Research Institute
2020-2024
International AIDS Vaccine Initiative
2020-2023
Countermeasures to prevent and treat coronavirus disease 2019 (COVID-19) are a global health priority. We enrolled cohort of severe acute respiratory syndrome 2 (SARS-CoV-2)-recovered participants, developed neutralization assays investigate antibody responses, adapted our high-throughput generation pipeline rapidly screen more than 1800 antibodies, established an animal model test protection. isolated potent neutralizing antibodies (nAbs) two epitopes on the receptor binding domain (RBD)...
Abstract Pre-existing immunity to seasonal endemic coronaviruses could have profound consequences for antibody responses SARS-CoV-2, induced from natural infection or vaccination. A first step establish whether pre-existing can impact SARS-CoV-2 is understand the nature and extent of cross-reactivity in humans coronaviruses. Here we compare serum memory B cell coronavirus spike proteins pre-pandemic convalescent donors using binding functional assays. We show weak evidence cross-reactive...
Broadly neutralizing antibodies (bnAbs) to coronaviruses (CoVs) are valuable in their own right as prophylactic and therapeutic reagents treat diverse CoVs templates for rational pan-CoV vaccine design. We recently described a bnAb, CC40.8, from CoV disease 2019 (COVID-19) convalescent donor that exhibits broad reactivity with human β-CoVs. Here, we showed CC40.8 targets the conserved S2 stem helix region of spike fusion machinery. determined crystal structure Fab SARS-CoV-2 peptide at 1.6-Å...
Pan-betacoronavirus neutralizing antibodies may hold the key to developing broadly protective vaccines against novel pandemic coronaviruses and more effectively respond SARS-CoV-2 variants. The emergence of Omicron subvariants illustrates limitations solely targeting receptor-binding domain (RBD) spike (S) protein. Here, we isolated a large panel (bnAbs) from recovered-vaccinated donors, which targets conserved S2 region in betacoronavirus fusion machinery. Select bnAbs showed broad vivo...
Abstract Pre-existing immune responses to seasonal endemic coronaviruses could have profound consequences for antibody SARS-CoV-2, either induced in natural infection or through vaccination. Such are well established the influenza and flavivirus fields. A first step establish whether pre-existing can impact SARS-CoV-2 is understand nature extent of cross-reactivity humans coronaviruses. We compared serum memory B cell coronavirus spike (S) proteins from pre-pandemic convalescent donors using...
A central tenet in the design of vaccines is display native-like antigens elicitation protective immunity. The abundance N-linked glycans across SARS-CoV-2 spike protein a potential source heterogeneity among many different vaccine candidates under investigation. Here, we investigate glycosylation recombinant proteins from five laboratories and compare them against S infectious virus, cultured Vero cells. We find patterns that are conserved all samples, this can be associated with...
ABSTRACT The development of countermeasures to prevent and treat COVID-19 is a global health priority. In under 7 weeks, we enrolled cohort SARS-CoV-2-recovered participants, developed neutralization assays interrogate serum monoclonal antibody responses, adapted our high throughput isolation, production characterization pipeline rapidly screen over 1000 antigen-specific antibodies, established an animal model test protection. We report multiple highly potent neutralizing antibodies (nAbs)...
HIV Env trimers elicit antibodies that lead to their own destruction.
To prepare for future coronavirus (CoV) pandemics, it is desirable to generate vaccines capable of eliciting broadly neutralizing antibody responses CoVs. Here, we show that immunization macaques with SARS-CoV-2 spike (S) protein a two-shot protocol generated potent serum receptor binding domain cross-neutralizing both and SARS-CoV-1. Furthermore, were equally effective against most variants concern (VOCs) some highly Omicron. This result contrasts human infection or many vaccination...
Broadly neutralizing antibodies (bnAbs) to coronaviruses (CoVs) are valuable in their own right as prophylactic and therapeutic reagents treat diverse CoVs and, importantly, templates for rational pan-CoV vaccine design. We recently described a bnAb, CC40.8, from coronavirus disease 2019 (COVID-19)-convalescent donor that exhibits broad reactivity with human beta-coronaviruses (β-CoVs). Here, we showed CC40.8 targets the conserved S2 stem-helix region of spike fusion machinery. determined...
Pan-betacoronavirus neutralizing antibodies may hold the key to developing broadly protective vaccines against coronaviruses that cause severe disease, for anticipating novel pandemic-causing viruses, and respond more effectively SARS-CoV-2 variants. The emergence of Omicron variant has illustrated limitations solely targeting receptor binding domain (RBD) envelope Spike (S)-protein. Here, we isolated a large panel (bnAbs) from recovered-vaccinated donors target conserved S2 region in fusion...
Developing broad coronavirus vaccines requires identifying and understanding the molecular basis of broadly neutralizing antibody (bnAb) spike sites. In our previous work, we identified sarbecovirus RBD group 1 2 bnAbs. We have now shown that many these bnAbs can still neutralize highly mutated SARS-CoV-2 variants, including XBB.1.5. Structural studies revealed use recurrent germline-encoded CDRH3 features to interact with a conserved region overlaps class 4 bnAb site. Group recognize less...
Abstract Broadly neutralizing antibodies targeting the V2 apex of HIV-1 envelope trimer are among most common specificities elicited in HIV-1-infected humans and simian-human immunodeficiency virus (SHIV)-infected macaques. To gain insight into prevalent induction these antibodies, we isolated characterized 11 apex-directed antibody lineages from SHIV-infected rhesus Remarkably, all SHIV-induced were derived reading frame two DH3-15*01 gene. Cryo-EM structures trimers complex with nine...
Humoral and cellular immunity have been investigated in 15 patients with dystrophia myotonica. No abnormalities total serum levels of the five major immunoglobulin classes were found but there was a rise mean level beta(1)A complement. Altogether, 54% failed to make antibody tetanus toxoid as compared 1% controls: 13% Salmonella typhi H antigen no failure this function control subjects. There reduced uptake tritiated thymidine by whole blood lymphocyte cultures spontaneously, while presence...
Abstract A central tenet in the design of vaccines is display native-like antigens elicitation protective immunity. The abundance N-linked glycans across SARS-CoV-2 spike protein a potential source heterogeneity between many different vaccine candidates under investigation. Here, we investigate glycosylation recombinant proteins from five laboratories and compare them against infectious virus S protein. We find patterns which are conserved all samples this can be associated with...
ABSTRACT To prepare for future coronavirus (CoV) pandemics, it is desirable to generate vaccines capable of eliciting neutralizing antibody responses against multiple CoVs. Because the phylogenetic similarity humans, rhesus macaques are an animal model choice many virus-challenge and vaccine-evaluation studies, including SARS-CoV-2. Here, we show that immunization with SARS-CoV-2 spike (S) protein generates potent receptor binding domain cross- (nAb) both SARS-CoV-1, in contrast human...
Abstract SIVmac239 infection of macaques is a favored model human HIV infection. However, the envelope (Env) trimer structure, glycan occupancy, and targets ability neutralizing antibodies (nAbs) to protect against remain unknown. Here, we report isolation nAbs that recognize hole V1/V4 loop. A high-resolution structure Env trimer-nAb complex shows many similarities SIVcpz Envs, but with distinct V4 features an extended V1 Moreover, has higher shield density than may contribute poor or...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike pseudotyped virus (PSV) assays are widely used to measure neutralization titers of sera and isolated neutralizing Abs (nAbs). PSV safer than live do not require access biosafety level 3 laboratories. However, many nevertheless somewhat challenging at least d carry out. In this study, we report a rapid (<30 min), sensitive, cell-free, off-the-shelf, accurate assay for receptor binding domain nAb detection. Our proximity-based...
Abstract Rationally designed protein subunit vaccines are being developed for a variety of viruses including influenza, RSV, SARS-CoV-2 and HIV. These based on stabilized versions the primary targets neutralizing antibodies viral surface, namely fusion glycoproteins. While these immunogens display epitopes potent antibodies, they also present recognized by non or weakly (“off-target”) antibodies. Using our recently electron microscopy epitope mapping approach, we have uncovered phenomenon...
The emergence of current SARS-CoV-2 variants concern (VOCs) and potential future spillovers SARS-like coronaviruses into humans pose a major threat to human health the global economy
Numerous proteins perform their functions by transitioning between various structures. Understanding the conformational ensembles associated with these states is essential for uncovering crucial mechanistic aspects that regulate protein function. In this study, we utilized AlphaFold3 (
Lassa virus (LASV), an arenavirus endemic to West Africa, poses a significant public health threat due its high pathogenicity and expanding geographic risk zone. LASV glycoprotein complex (GPC) is the only known target of neutralizing antibodies, but inherent metastability conformational flexibility have hindered development GPC-based vaccines. We employed variant AlphaFold2 (AF2), called subsampled AF2, generate diverse structures GPC that capture array potential states using MSA...
SUMMARY Eliciting broadly neutralizing antibodies-(bnAbs) remains a major goal of HIV-1 vaccine research. Previously, we showed that soluble chimpanzee SIV Envelope-(Env) trimer, MT145K, bound several human V2-apex bnAb-precursors and stimulated an appropriate response in bnAb precursor-expressing knock-in mice. Here, tested the immunogenicity three MT145 variants (MT145, MT145K.dV5) expressed as chimeric simian-chimpanzee-immunodeficiency-viruses-(SCIVs) rhesus macaques-(RMs). All viruses...