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Now showing items 1 - 16 of 1192

  • Design of a broadly reactive Lyme disease vaccine

    Kamp, Heather D.   Swanson, Kurt A.   Wei, Ronnie R.   Dhal, Pradeep K.   Dharanipragada, Ram   Kern, Aurelie   Sharma, Bijaya   Sima, Radek   Hajdusek, Ondrej   Hu, Linden T.   Wei, Chih-Jen   Nabel, Gary J.  

    A growing global health concern, Lyme disease has become the most common tick-borne disease in the United States and Europe. Caused by the bacterial spirochete Borrelia burgdorferi sensu lato (sl), this disease can be debilitating if not treated promptly. Because diagnosis is challenging, prevention remains a priority; however, a previously licensed vaccine is no longer available to the public. Here, we designed a six component vaccine that elicits antibody (Ab) responses against all Borrelia strains that commonly cause Lyme disease in humans. The outer surface protein A (OspA) of Borrelia was fused to a bacterial ferritin to generate self-assembling nanoparticles. OspA-ferritin nanoparticles elicited durable high titer Ab responses to the seven major serotypes in mice and non-human primates at titers higher than a previously licensed vaccine. This response was durable in rhesus macaques for more than 6 months. Vaccination with adjuvanted OspA-ferritin nanoparticles stimulated protective immunity from both B. burgdorferi and B. afzelii infection in a tick-fed murine challenge model. This multivalent Lyme vaccine offers the potential to limit the spread of Lyme disease.
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  • Next-generation influenza vaccines: opportunities and challenges

    Wei, Chih-Jen   Crank, Michelle C.   Shiver, John   Graham, Barney S.   Mascola, John R.   Nabel, Gary J.  

    Seasonal influenza vaccines lack efficacy against drifted or pandemic influenza strains. Developing improved vaccines that elicit broader immunity remains a public health priority. Immune responses to current vaccines focus on the haemagglutinin head domain, whereas next-generation vaccines target less variable virus structures, including the haemagglutinin stem. Strategies employed to improve vaccine efficacy involve using structure-based design and nanoparticle display to optimize the antigenicity and immunogenicity of target antigens; increasing the antigen dose; using novel adjuvants; stimulating cellular immunity; and targeting other viral proteins, including neuraminidase, matrix protein 2 or nucleoprotein. Improved understanding of influenza antigen structure and immunobiology is advancing novel vaccine candidates into human trials. Current seasonal influenza vaccines lack efficacy against drifted or pandemic virus strains, and the development of novel vaccines that elicit broader immunity represents a public health priority. Here, Nabel and colleagues discuss approaches to improve vaccine efficacy which harness new insights from influenza antigen structure and human immunity, highlighting major targets, vaccines in development and ongoing challenges.
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  • Development of a Pan-H1 Influenza Vaccine

    Darricarrere, Nicole   Pougatcheva, Svetlana   Duan, Xiaochu   Rudicell, Rebecca S.   Chou, Te-Hui   DiNapoli, Joshua   Ross, Ted M.   Alefantis, Tim   Vogel, Thorsten U.   Kleanthous, Harry   Wei, Chih-Jen   Nabel, Gary J.  

    The efficacy of current seasonal influenza vaccines varies greatly, depending on the match to circulating viruses. Although most vaccines elicit strain-specific responses, some present cross-reactive epitopes that elicit antibodies against diverse viruses and remain unchanged and effective for several years. To determine whether combinations of specific H1 hemagglutinin (HA) antigens stimulate immune responses that protect against diverse H1 influenza viruses, we evaluated the antibody responses elicited by HA-ferritin nanoparticles derived from six evolutionarily divergent H1 sequences and two computationally optimized broadly reactive antigen (COBRA) HA antigens. Humoral responses were assessed against a panel of 16 representative influenza virus strains from the past 80 years. HAs from the strains A/NewCaledonia/20/1999 (NC99), A/California/04/2009 (CA09), A/HongKong/117/1977 (HK77), COBRA X6, or P1 elicited neutralization against diverse strains, and a combination of three wild-type HA or two COBRA HA nanoparticles conferred significant additional breadth beyond that observed with any individual strain. Therefore, combinations of H1 HAs may constitute a pan-H1 influenza vaccine. IMPORTANCE Seasonal influenza vaccines elicit strain-specific immune responses designed to protect against circulating viruses. Because these vaccines often show limited efficacy, the search for a broadly protective seasonal vaccine remains a priority. Among different influenza virus subtypes, H1N1 has long been circulating in humans and has caused pandemic outbreaks. In order to assess the potential of a multivalent HA combination vaccine to improve the breadth of protection against divergent H1N1 viruses, HA-ferritin nanoparticles were made and evaluated in mice against a panel of historical and contemporary influenza virus strains. Trivalent combinations of H1 nanoparticles improved the breadth of immunity against divergent H1 influenza viruses.
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  • All for one and one for all to fight flu

    Nabel, Gary J.   Shiver, John W.  

    Antibodies have been engineered to recognize diverse strains of influenza, including both the A and B types of virus that cause human epidemics. Are we moving closer to achieving 'universal' protection against all flu strains?
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  • All for one and one for all to fight flu

    Nabel, Gary J.   Shiver, John W.  

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  • HIV integration and T cell death: additional commentary

    Cooper, Arik   Garcia, Mayra   Petrovas, Constantinos   Yamamoto, Takuya   Koup, Richard A.   Nabel, Gary J.  

    Estaquier et al. provide commentary on our paper that elucidated the mechanism by which HIV-1 causes cell death in activated CD4 T lymphocytes. We showed that proviral DNA integration triggers DNA-PK dependent death signaling, leading to p53 phosphorylation and cell demise (Cooper A et al. Nature 498:376-379, 2013). They have raised several hypothetical points that we further clarify here.
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  • Designing Tomorrow's Vaccines

    Nabel, Gary J.  

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  • Getting to the Heart of Influenza

    Yewdell, Jonathan W.   Spiro, David J.   Golding, Hana   Quill, Helen   Mittelman, Abraham   Nabel, Gary J.  

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  • Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection

    Yassine, Hadi M.   Boyington, Jeffrey C.   McTamney, Patrick M.   Wei, Chih-Jen   Kanekiyo, Masaru   Kong, Wing-Pui   Gallagher, John R.   Wang, Lingshu   Zhang, Yi   Joyce, M. Gordon   Lingwood, Daniel   Moin, Syed M.   Andersen, Hanne   Okuno, Yoshinobu   Rao, Srinivas S.   Harris, Audray K.   Kwong, Peter D.   Mascola, John R.   Nabel, Gary J.   Graham, Barney S.  

    The antibody response to influenza is primarily focused on the head region of the hemagglutinin (HA) glycoprotein, which in turn undergoes antigenic drift, thus necessitating annual updates of influenza vaccines. In contrast, the immunogenically subdominant stem region of HA is highly conserved and recognized by antibodies capable of binding multiple HA subtypes(1-6). Here we report the structure-based development of an H1 HA stem-only immunogen that confers heterosubtypic protection in mice and ferrets. Six iterative cycles of structure-based design (Gen1-Gen6) yielded successive H1 HA stabilized-stem (HA-SS) immunogens that lack the immunodominant head domain. Antigenic characterization, determination of two HA-SS crystal structures in complex with stem-specific monoclonal antibodies and cryo-electron microscopy analysis of HA-SS on ferritin nanoparticles (H1-SS-np) confirmed the preservation of key structural elements. Vaccination of mice and ferrets with H1-SS-np elicited broadly cross-reactive antibodies that completely protected mice and partially protected ferrets against lethal heterosubtypic H5N1 influenza virus challenge despite the absence of detectable H5N1 neutralizing activity in vitro. Passive transfer of immunoglobulin from H1-SS-np-immunized mice to naive mice conferred protection against H5N1 challenge, indicating that vaccine-elicited HA stem-specific antibodies can protect against diverse group 1 influenza strains.
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  • The changing face of HIV vaccine research

    Kwong, Peter D.   Mascola, John R.   Nabel, Gary J.  

    While there has been remarkable progress in understanding the biology of HIV-1 and its recognition by the human immune system, we have not yet developed an efficacious HIV-1 vaccine. Vaccine challenges include the genetic diversity and mutability of HIV-1 which create a plethora of constantly changing antigens, the structural features of the viral envelope glycoprotein that disguise conserved receptor-binding sites from the immune system, and the presence of carbohydrate moieties that shield potential epitopes from antibodies. Despite these challenges, there has been significant scientific progress in recent years. In 2009, a large-scale clinical trial known as RV144 demonstrated that a HIV-1 vaccine could modestly reduce the incidence of HIV-1 infection. Further, the identification of broadly neutralizing monoclonal antibodies (such as VRC01, a human monoclonal antibody capable of neutralizing over 90% of natural HIV-1 isolates, as well as PG and PGT antibodies that recognize conserved glycopeptide epitopes) has revealed new opportunities for vaccine design. Our ability to understand HIV-1 structure and antibody epitopes at the atomic level, the rapid advance of computational and bioinformatics approaches to immunogen design, and our newly acquired knowledge that it is possible for a vaccine to reduce the risk of HIV-1 infection, have all opened up new and promising pathways towards the development of an urgently needed effective HIV-1 vaccine. This article summarizes challenges to the development of an HIV-1 vaccine, lessons learned from scientific investigation and completed vaccine trials, and promising developments in HIV-1 vaccine design.
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  • The Development of CD4 Binding Site Antibodies during HIV-1 Infection

    Lynch, Rebecca M.   Tran, Lillian   Louder, Mark K.   Schmidt, Stephen D.   Cohen, Myron   DerSimonian, Rebecca   Euler, Zelda   Gray, Elin S.   Karim, Salim Abdool   Kirchherr, Jennifer   Montefiori, David C.   Sibeko, Sengeziwe   Soderberg, Kelly   Tomaras, Georgia   Yang, Zhi-Yong   Nabel, Gary J.   Schuitemaker, Hanneke   Morris, Lynn   Haynes, Barton F.   Mascola, John R.  

    Broadly neutralizing antibodies to the CD4 binding site (CD4bs) of gp120 are generated by some HIV-1-infected individuals, but little is known about the prevalence and evolution of this antibody response during the course of HIV-1 infection. We analyzed the sera of 113 HIV-1 seroconverters from three cohorts for binding to a panel of gp120 core proteins and their corresponding CD4bs knockout mutants. Among sera collected between 99 and 258 weeks post-HIV-1 infection, 88% contained antibodies to the CD4bs and 47% contained antibodies to resurfaced stabilized core (RSC) probes that react preferentially with broadly neutralizing CD4bs antibodies (BNCD4), such as monoclonal antibodies (MAbs) VRC01 and VRC-CH31. Analysis of longitudinal serum samples from a subset of 18 subjects revealed that CD4bs antibodies to gp120 arose within the first 4 to 16 weeks of infection, while the development of RSC-reactive antibodies was more varied, occurring between 10 and 152 weeks post-HIV-1 infection. Despite the presence of these antibodies, serum neutralization mediated by RSC-reactive antibodies was detected in sera from only a few donors infected for more than 3 years. Thus, CD4bs antibodies that bind a VRC01-like epitope are often induced during HIV-1 infection, but the level and potency required to mediate serum neutralization may take years to develop. An improved understanding of the immunological factors associated with the development and maturation of neutralizing CD4bs antibodies during HIV-1 infection may provide insights into the requirements for eliciting this response by vaccination.
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    This invention provides vaccines for inducing an immune response and protection against filovirus infection for use as a preventative vaccine in humans. In particular, the invention provides chimpanzee adenoviral vectors expressing filovirus proteins from different strains of Ebolavirus (EBOV) or Marburg virus (MARV).
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    The present invention provides recombinant adenovirus vectors (serotype 26 and serotype 35) encoding filovirus antigens. The adenovirus vectors can be used to induce protective immune responses against filovirus infection.
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  • Accelerating Next-Generation Vaccine Development for Global Disease Prevention

    Koff, Wayne C.   Burton, Dennis R.   Johnson, Philip R.   Walker, Bruce D.   King, Charles R.   Nabel, Gary J.   Ahmed, Rafi   Bhan, Maharaj K.   Plotkin, Stanley A.  

    Vaccines are among the greatest successes in the history of public health. However, past strategies for vaccine development are unlikely to succeed in the future against major global diseases such as AIDS, tuberculosis, and malaria. For such diseases, the correlates of protection are poorly defined and the pathogens evade immune detection and/or exhibit extensive genetic variability. Recent advances have heralded in a new era of vaccine discovery. However, translation of these advances into vaccines remains impeded by lack of understanding of key vaccinology principles in humans. We review these advances toward vaccine discovery and suggest that for accelerating successful vaccine development, new human immunology based clinical research initiatives be implemented with the goal of elucidating and more effectively generating vaccine-induced protective immune responses.
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  • HIV-1 Vaccines and Adaptive Trial Designs

    Corey, Lawrence   Nabel, Gary J.   Dieffenbach, Carl   Gilbert, Peter   Haynes, Barton F.   Johnston, Margaret   Kublin, James   Lane, H. Clifford   Pantaleo, Giuseppe   Picker, Louis J.   Fauci, Anthony S.  

    Developing a vaccine against the human immunodeciency virus (HIV) poses an exceptional challenge. There are no documented cases of immune-mediated clearance of HIV from an infected individual, and no known correlates of immune protection. Although nonhuman primate models of lentivirus infection have provided valuable data about HIV pathogenesis, such models do not predict HIV vaccine efficacy in humans. The combined lack of a predictive animal model and undefined biomarkers of immune protection against HIV necessitate that vaccines to this pathogen be tested directly in clinical trials. Adaptive clinical trial designs can accelerate vaccine development by rapidly screening out poor vaccines while extending the evaluation of efficacious ones, improving the characterization of promising vaccine candidates and the identification of correlates of immune protection.
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  • Vaccinate for the next H2N2 pandemic now

    Nabel, Gary J.   Wei, Chih-Jen   Ledgerwood, Julie E.  

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