Publications by authors named "Matthias G Pauthner"

13 Publications

  • Page 1 of 1

A Fc engineering approach to define functional humoral correlates of immunity against Ebola virus.

Immunity 2021 Apr;54(4):815-828.e5

Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA. Electronic address:

Protective Ebola virus (EBOV) antibodies have neutralizing activity and induction of antibody constant domain (Fc)-mediated innate immune effector functions. Efforts to enhance Fc effector functionality often focus on maximizing antibody-dependent cellular cytotoxicity, yet distinct combinations of functions could be critical for antibody-mediated protection. As neutralizing antibodies have been cloned from EBOV disease survivors, we sought to identify survivor Fc effector profiles to help guide Fc optimization strategies. Survivors developed a range of functional antibody responses, and we therefore applied a rapid, high-throughput Fc engineering platform to define the most protective profiles. We generated a library of Fc variants with identical antigen-binding fragments (Fabs) from an EBOV neutralizing antibody. Fc variants with antibody-mediated complement deposition and moderate natural killer (NK) cell activity demonstrated complete protective activity in a stringent in vivo mouse model. Our findings highlight the importance of specific effector functions in antibody-mediated protection, and the experimental platform presents a generalizable resource for identifying correlates of immunity to guide therapeutic antibody design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2021.03.009DOI Listing
April 2021

Integration of genomic sequencing into the response to the Ebola virus outbreak in Nord Kivu, Democratic Republic of the Congo.

Nat Med 2021 Apr 12;27(4):710-716. Epub 2021 Apr 12.

Institut National de Recherche Biomédicale, Kinshasa, Democratic Republic of the Congo.

On 1 August 2018, the Democratic Republic of the Congo (DRC) declared its tenth Ebola virus disease (EVD) outbreak. To aid the epidemiologic response, the Institut National de Recherche Biomédicale (INRB) implemented an end-to-end genomic surveillance system, including sequencing, bioinformatic analysis and dissemination of genomic epidemiologic results to frontline public health workers. We report 744 new genomes sampled between 27 July 2018 and 27 April 2020 generated by this surveillance effort. Together with previously available sequence data (n = 48 genomes), these data represent almost 24% of all laboratory-confirmed Ebola virus (EBOV) infections in DRC in the period analyzed. We inferred spatiotemporal transmission dynamics from the genomic data as new sequences were generated, and disseminated the results to support epidemiologic response efforts. Here we provide an overview of how this genomic surveillance system functioned, present a full phylodynamic analysis of 792 Ebola genomes from the Nord Kivu outbreak and discuss how the genomic surveillance data informed response efforts and public health decision making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-021-01302-zDOI Listing
April 2021

Ebola Virus Transmission Initiated by Relapse of Systemic Ebola Virus Disease.

N Engl J Med 2021 04;384(13):1240-1247

From the Institut National de Recherche Biomédicale (P.M.-K., A.N.-N., E.K.-L., A.A., D.M., N.B., D.K., B.N., M.A., O.T., S.M, S.A.-M., J.-J.M.T.), the University of Kinshasa (P.M.-K., A.N.-N., F.M., F.E., M.M., J.B.B., S.A.-M., J.-J.M.T.), and Ministère de la Santé (F.B., V.E., E.S.-P., Y.T.T.N.) - all in Kinshasa, Democratic Republic of Congo; the University of Nebraska Medical Center, Omaha (C.P., B.W., M.R.W.); International Medical Corps (M.M.-R.) and the University of California, Los Angeles (A.W.R., M.A.S.), Los Angeles, and the Scripps Research Institute, La Jolla (M.G.P., K.G., E.S., A.T., K.G.A.) - all in California; the Fred Hutchinson Cancer Research Center, Seattle (A.B., J.H., T.B.); the Institut Pasteur de Dakar, Dakar, Senegal (M.F., M.M.D., O.F., A.S.); the Vaccine Research Center, National Institutes of Health, Bethesda (J.M., A.P., N.J.S.), and the Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research (I.C.), and the Integrated Research Facility at Fort Detrick, National Institutes of Health (L.H.), Frederick - all in Maryland; the World Health Organization, Geneva (B.D., M.K., M.R.D.B., I.S.F., A.Y.); and the University of Edinburgh, Edinburgh, United Kingdom (A.R.).

During the 2018-2020 Ebola virus disease (EVD) outbreak in North Kivu province in the Democratic Republic of Congo, EVD was diagnosed in a patient who had received the recombinant vesicular stomatitis virus-based vaccine expressing a ZEBOV glycoprotein (rVSV-ZEBOV) (Merck). His treatment included an Ebola virus (EBOV)-specific monoclonal antibody (mAb114), and he recovered within 14 days. However, 6 months later, he presented again with severe EVD-like illness and EBOV viremia, and he died. We initiated epidemiologic and genomic investigations that showed that the patient had had a relapse of acute EVD that led to a transmission chain resulting in 91 cases across six health zones over 4 months. (Funded by the Bill and Melinda Gates Foundation and others.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2024670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888312PMC
April 2021

Rectal Acquisition of Simian Immunodeficiency Virus (SIV) SIVmac239 Infection despite Vaccine-Induced Immune Responses against the Entire SIV Proteome.

J Virol 2020 11 23;94(24). Epub 2020 Nov 23.

Department of Pathology, University of Miami, Miami, Florida, USA.

Given the complex biology of human immunodeficiency virus (HIV) and its remarkable capacity to evade host immune responses, HIV vaccine efficacy may benefit from the induction of both humoral and cellular immune responses of maximal breadth, potency, and longevity. Guided by this rationale, we set out to develop an immunization protocol aimed at maximizing the induction of anti-Envelope (anti-Env) antibodies and CD8 T cells targeting non-Env epitopes in rhesus macaques (RMs). Our approach was to deliver the entire simian immunodeficiency virus (SIV) proteome by serial vaccinations. To that end, 12 RMs were vaccinated over 81 weeks with DNA, modified vaccinia Ankara (MVA), vesicular stomatitis virus (VSV), adenovirus type 5 (Ad5), rhesus monkey rhadinovirus (RRV), and DNA again. Both the RRV and the final DNA boosters delivered a near-full-length SIVmac239 genome capable of assembling noninfectious SIV particles and inducing T-cell responses against all nine SIV proteins. Compared to previous SIV vaccine trials, the present DNA-MVA-VSV-Ad5-RRV-DNA regimen resulted in comparable levels of Env-binding antibodies and SIV-specific CD8 T-cells. Interestingly, one vaccinee developed low titers of neutralizing antibodies (NAbs) against SIVmac239, a tier 3 virus. Following repeated intrarectal marginal-dose challenges with SIVmac239, vaccinees were not protected from SIV acquisition but manifested partial control of viremia. Strikingly, the animal with the low-titer vaccine-induced anti-SIVmac239 NAb response acquired infection after the first SIVmac239 exposure. Collectively, these results highlight the difficulties in eliciting protective immunity against immunodeficiency virus infection. Our results are relevant to HIV vaccine development efforts because they suggest that increasing the number of booster immunizations or delivering additional viral antigens may not necessarily improve vaccine efficacy against immunodeficiency virus infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.00979-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925177PMC
November 2020

Broadly Neutralizing Antibodies to Highly Antigenically Variable Viruses as Templates for Vaccine Design.

Curr Top Microbiol Immunol 2020 ;428:31-87

The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.

Development of vaccines to highly variable viruses such as Human Immunodeficiency Virus and influenza A viruses faces multiple challenges. In this article, these challenges are described and reverse vaccinology approaches to generate universal vaccines against both pathogens are laid out and compared.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/82_2020_221DOI Listing
September 2020

Harnessing Activin A Adjuvanticity to Promote Antibody Responses to BG505 HIV Envelope Trimers.

Front Immunol 2020 16;11:1213. Epub 2020 Jun 16.

Scripps Center for HIV/AIDS Vaccine Immunogen Development (CHAVD), The Scripps Research Institute, La Jolla, CA, United States.

T follicular helper (T) cells are powerful regulators of affinity matured long-lived plasma cells. Eliciting protective, long-lasting antibody responses to achieve persistent immunity is the goal of most successful vaccines. Thus, there is potential in manipulating T cell responses. Herein, we describe an HIV vaccine development approach exploiting the cytokine activin A to improve antibody responses against recombinant HIV Envelope (Env) trimers in non-human primates. Administration of activin A improved the magnitude of Env-specific antibodies over time and promoted a significant increase in Env-specific plasma cells in the bone marrow. The boost in antibody responses was associated with reduced frequencies of T follicular regulatory (T) cells and increased germinal center T follicular helper (GC-T) to T cell ratios. Overall, these findings suggest that adjuvants inducing activin A production could potentially be incorporated in future rational design vaccine strategies aimed at improving germinal centers, long-lived plasma cells, and sustained antibody responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.01213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308430PMC
April 2021

Lassa Virus Genetics.

Curr Top Microbiol Immunol 2020 May 17. Epub 2020 May 17.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

In a pattern repeated across a range of ecological niches, arenaviruses have evolved a compact four-gene genome to orchestrate a complex life cycle in a narrow range of susceptible hosts. A number of mammalian arenaviruses cross-infect humans, often causing a life-threatening viral hemorrhagic fever. Among this group of geographically bound zoonoses, Lassa virus has evolved a unique niche that leads to significant and sustained human morbidity and mortality. As a biosafety level 4 pathogen, direct study of the pathogenesis of Lassa virus is limited by the sparse availability, high operating costs, and technical restrictions of the high-level biocontainment laboratories required for safe experimentation. In this chapter, we introduce the relationship between genome structure and the life cycle of Lassa virus and outline reverse genetic approaches used to probe and describe functional elements of the Lassa virus genome. We then review the tools used to obtain viral genomic sequences used for phylogeny and molecular diagnostics, before shifting to a population perspective to assess the contributions of phylogenetic analysis in understanding the evolution and ecology of Lassa virus in West Africa. We finally consider the future outlook and clinical applications for genetic study of Lassa virus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/82_2020_212DOI Listing
May 2020

Induction of Transient Virus Replication Facilitates Antigen-Independent Isolation of SIV-Specific Monoclonal Antibodies.

Mol Ther Methods Clin Dev 2020 Mar 13;16:225-237. Epub 2020 Feb 13.

Department of Pathology, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.

Structural characterization of the HIV-1 Envelope (Env) glycoprotein has facilitated the development of Env probes to isolate HIV-specific monoclonal antibodies (mAbs). However, preclinical studies have largely evaluated these virus-specific mAbs against chimeric viruses, which do not naturally infect non-human primates, in contrast to the unconstrained simian immunodeficiency virus (SIV)mac239 clone. Given the paucity of native-like reagents for the isolation of SIV-specific B cells, we examined a method to isolate SIVmac239-specific mAbs without using Env probes. We first activated virus-specific B cells by inducing viral replication after the infusion of a CD8β-depleting mAb or withdrawal of antiretroviral therapy in SIVmac239-infected rhesus macaques. Following the rise in viremia, we observed 2- to 4-fold increases in the number of SIVmac239 Env-reactive plasmablasts in circulation. We then sorted these activated B cells and obtained 206 paired Ab sequences. After expressing 122 mAbs, we identified 14 Env-specific mAbs. While these Env-specific mAbs bound to both the SIVmac239 SOSIP.664 trimer and to infected primary rhesus CD4 T cells, five also neutralized SIVmac316. Unfortunately, none of these mAbs neutralized SIVmac239. Our data show that this method can be used to isolate virus-specific mAbs without antigenic probes by inducing bursts of contemporary replicating viruses .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.omtm.2020.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021589PMC
March 2020

A Meta-analysis of Passive Immunization Studies Shows that Serum-Neutralizing Antibody Titer Associates with Protection against SHIV Challenge.

Cell Host Microbe 2019 Sep;26(3):336-346.e3

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA 98109, USA; Department of Biostatistics, University of Washington, Seattle, WA 98195, USA. Electronic address:

Passively administered broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope glycoprotein (Env) have been shown to protect non-human primates (NHPs) against chimeric simian-human immunodeficiency virus (SHIV) infection. With data from multiple non-human primate SHIV challenge studies that used single bNAbs, we conducted a meta-analysis to examine the relationship between predicted serum 50% neutralization titer (ID50) against the challenge virus and infection outcome. In a logistic model that adjusts for bNAb epitopes and challenge viruses, serum ID50 had a highly significant effect on infection risk (p < 0.001). The estimated ID50 to achieve 50%, 75%, and 95% protection was 91 (95% confidence interval [CI]: 55, 153), 219 (117, 410), and 685 (319, 1471), respectively. This analysis indicates that serum neutralizing titer against the relevant virus is a key parameter of protection and that protection from acquisition by a single bNAb might require substantial levels of neutralization at the time of exposure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chom.2019.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755677PMC
September 2019

Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance.

Cell 2019 05 9;177(5):1153-1171.e28. Epub 2019 May 9.

Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (Scripps CHAVI-ID), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA. Electronic address:

Conventional immunization strategies will likely be insufficient for the development of a broadly neutralizing antibody (bnAb) vaccine for HIV or other difficult pathogens because of the immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. We found that two independent methods of slow delivery immunization of rhesus monkeys (RMs) resulted in more robust T follicular helper (T) cell responses and GC B cells with improved Env-binding, tracked by longitudinal fine needle aspirates. Improved GCs correlated with the development of >20-fold higher titers of autologous nAbs. Using a new RM genomic immunoglobulin locus reference, we identified differential IgV gene use between immunization modalities. Ab mapping demonstrated targeting of immunodominant non-neutralizing epitopes by conventional bolus-immunized animals, whereas slow delivery-immunized animals targeted a more diverse set of epitopes. Thus, alternative immunization strategies can enhance nAb development by altering GCs and modulating the immunodominance of non-neutralizing epitopes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2019.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619430PMC
May 2019

Vaccine-Induced Protection from Homologous Tier 2 SHIV Challenge in Nonhuman Primates Depends on Serum-Neutralizing Antibody Titers.

Immunity 2019 01 11;50(1):241-252.e6. Epub 2018 Dec 11.

Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139, USA. Electronic address:

Passive administration of HIV neutralizing antibodies (nAbs) can protect macaques from hard-to-neutralize (tier 2) chimeric simian-human immunodeficiency virus (SHIV) challenge. However, conditions for nAb-mediated protection after vaccination have not been established. Here, we selected groups of 6 rhesus macaques with either high or low serum nAb titers from a total of 78 animals immunized with recombinant native-like (SOSIP) Env trimers. Repeat intrarectal challenge with homologous tier 2 SHIV led to rapid infection in unimmunized and low-titer animals. High-titer animals, however, demonstrated protection that was gradually lost as nAb titers waned over time. An autologous serum ID nAb titer of ∼1:500 afforded more than 90% protection from medium-dose SHIV infection. In contrast, antibody-dependent cellular cytotoxicity and T cell activity did not correlate with protection. Therefore, Env protein-based vaccination strategies can protect against hard-to-neutralize SHIV challenge in rhesus macaques by inducing tier 2 nAbs, provided appropriate neutralizing titers can be reached and maintained.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2018.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335502PMC
January 2019

Rhesus Macaques Vaccinated with , , and Manifest Early Control of SIVmac239 Replication.

J Virol 2018 08 31;92(16). Epub 2018 Jul 31.

Department of Pathology, University of Miami, Miami, Florida, USA.

Certain major histocompatibility complex class I (MHC-I) alleles are associated with spontaneous control of viral replication in human immunodeficiency virus (HIV)-infected people and simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs). These cases of "elite" control of HIV/SIV replication are often immune-mediated, thereby providing a framework for studying anti-lentiviral immunity. In this study, we examined how vaccination impacts SIV replication in RMs expressing the MHC-I allele Approximately 21% of and 50% of RMs control chronic-phase viremia after SIVmac239 infection. Because CD8 T cells targeting Mamu-B*08-restricted SIV epitopes have been implicated in virologic suppression in RMs, we investigated whether this might also be true for RMs. Two groups of RMs were vaccinated with genes encoding Mamu-B*17-restricted epitopes in Vif and Nef. These genes were delivered by themselves (group 1) or together with (group 2). Group 3 included MHC-I-matched RMs and served as the control group. Surprisingly, the group 1 vaccine regimen had little effect on viral replication compared to group 3, suggesting that unlike RMs, preexisting SIV-specific CD8 T cells alone do not facilitate long-term virologic suppression in RMs. Remarkably, however, 5/8 group 2 vaccinees controlled viremia to <15 viral RNA copies/ml soon after infection. No serological neutralizing activity against SIVmac239 was detected in group 2, although vaccine-elicited gp140-binding antibodies correlated inversely with nadir viral loads. Collectively, these data shed new light on the unique mechanism of elite control in RMs and implicate vaccine-induced, nonneutralizing anti-Env antibodies in the containment of immunodeficiency virus infection. A better understanding of the immune correlates of protection against HIV might facilitate the development of a prophylactic vaccine. Therefore, we investigated simian immunodeficiency virus (SIV) infection outcomes in rhesus macaques expressing the major histocompatibility complex class I allele Approximately 21% of macaques spontaneously controlled chronic phase viremia after SIV infection, an effect that may involve CD8 T cells targeting Mamu-B*17-restricted SIV epitopes. We vaccinated macaques with genes encoding immunodominant epitopes in Vif and Nef alone (group 1) or together with (group 2). Although neither vaccine regimen prevented SIV infection, 5/8 group 2 vaccinees controlled viremia to below detection limits shortly after infection. This outcome, which was not observed in group 1, was associated with vaccine-induced, nonneutralizing Env-binding antibodies. Together, these findings suggest a limited contribution of Vif- and Nef-specific CD8 T cells for virologic control in macaques and implicate anti-Env antibodies in containment of SIV infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.00690-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069176PMC
August 2018