ABSTRACTHIV broadly neutralizing antibodies (bNAbs) are capable of both blocking viral entry and ... more ABSTRACTHIV broadly neutralizing antibodies (bNAbs) are capable of both blocking viral entry and recruiting innate immunity to HIV-infected cells through their fragment crystallizable (Fc) region. Vaccination or productive infection results in a polyclonal mixture of class-switched IgG antibodies comprised of four subclasses, each encoding distinct Fc regions that differentially engage innate immune functions. Despite evidence that innate immunity contributes to protection, the relative contribution of individual IgG subclasses is unknown. Here we use vectored immunoprophylaxis (VIP) in humanized mice to interrogate the efficacy of individual IgG subclasses during prevention of vaginal HIV transmission by VRC07, a potent CD4-binding site directed bNAb. We find that VRC07-IgG2, which lacks Fc-mediated functionality, exhibits significantly reduced protection in vivo relative to other subclasses. However, even low concentrations of highly functional VRC07-IgG1 yields substantial protec...
Monoclonal antibodies are the fastest growing therapeutic class in medicine today. They hold grea... more Monoclonal antibodies are the fastest growing therapeutic class in medicine today. They hold great promise for a myriad of indications, including cancer, allergy, autoimmune and infectious diseases. However, the wide accessibility of these therapeutics is hindered by manufacturing and purification challenges that result in high costs and long lead times. Efforts are being made to find alternative ways to produce and deliver antibodies in more expedient and cost-effective platforms. The field of mRNA has made significant progress in the last ten years and has emerged as a highly attractive means of encoding and producing any protein of interest in vivo. Through the natural role of mRNA as a transient carrier of genetic information for translation into proteins, in vivo expression of mRNA-encoded antibodies offer many advantages over recombinantly produced antibodies. In this review, we examine both preclinical and clinical studies that demonstrate the feasibility of mRNA-encoded anti...
Plasmodium sporozoites can be neutralized in vitro by monoclonal antibodies (MAb) against the cir... more Plasmodium sporozoites can be neutralized in vitro by monoclonal antibodies (MAb) against the circumsporozoite protein (CSP) and can block liver invasion in vivo by sporozoites of a transgenic rodent parasite that expresses P. falciparum CSP (Pb-Pf), preventing infection in mice. Despite this, attempts at targeting CSP for a vaccine have fallen short of expectations, in part due to inability to induce durable high-titer antibodies. A single un-neutralized sporozoite can initiate infection, necessitating sustained high-titer neutralizing antibodies for lasting protection. Recently, David Baltimore’s laboratory developed an adeno-associated virus type 8 (AAV8) platform that efficiently delivers pre-formed MAb genes in vivo and directs sustained, high-level MAb production. With the Baltimore lab, we have adopted that technology to express humanized MAbs against the central repeat region of the CSP protein of P. falciparum in mice. Mice developed high titer human IgG antibodies as early...
To discuss recent progress in the use of vectors to produce antibodies in vivo as an alternative ... more To discuss recent progress in the use of vectors to produce antibodies in vivo as an alternative form of HIV prophylaxis or therapy. Instead of passive transfer of monoclonal antibody proteins, a transgene encoding an antibody is delivered to cells by the vector, resulting in expression and secretion by the host cell. This review will emphasize adeno-associated virus (AAV)-based strategies and summarize the evidence in support of this strategy as an alternative to traditional vaccines. We will highlight the major findings in the field and discuss the impact that this approach could have on the prevention, treatment and possibly eradication of HIV in patients. In this emerging field, the emphasis has been on the use of vectors delivering antibodies as an alternative to the development of an HIV vaccine. However, recent findings suggest that AAV-delivered broadly neutralizing antibodies can suppress HIV replication. As such, a single injection of AAV could mediate long-term antibody e...
Proceedings of the National Academy of Sciences of the United States of America, Jan 26, 2014
Malaria caused by Plasmodium falciparum kills nearly one million children each year and imposes c... more Malaria caused by Plasmodium falciparum kills nearly one million children each year and imposes crippling economic burdens on families and nations worldwide. No licensed vaccine exists, but infection can be prevented by antibodies against the circumsporozoite protein (CSP), the major surface protein of sporozoites, the form of the parasite injected by mosquitoes. We have used vectored immunoprophylaxis (VIP), an adeno-associated virus-based technology, to introduce preformed antibody genes encoding anti-P. falciparum CSP mAb into mice. VIP vector-transduced mice exhibited long-lived mAb expression at up to 1,200 µg/mL in serum, and up to 70% were protected from both i.v. and mosquito bite challenge with transgenic Plasmodium berghei rodent sporozoites that incorporate the P. falciparum target of the mAb in their CSP. Serum antibody levels and protection from mosquito bite challenge were dependent on the dose of the VIP vector. All individual mice expressing CSP-specific mAb 2A10 at ...
Decades of success with live adenovirus vaccines suggest that replication-competent recombinant a... more Decades of success with live adenovirus vaccines suggest that replication-competent recombinant adenoviruses (rAds) could serve as effective vectors for immunization against other pathogens. To explore the potential of a live rAd vaccine against malaria, we prepared a viable adenovirus 5 (Ad5) recombinant that displays a B-cell epitope from the circumsporozoite protein (CSP) of Plasmodium falciparum on the virion surface. The recombinant induced P. falciparum sporozoite-neutralizing antibodies in mice. Human adenoviruses do not replicate in mice. Therefore, to examine immunogenicity in a system in which, as in humans, the recombinant replicates, we constructed a similar recombinant in an adenovirus mutant that replicates in monkey cells and immunized four Aotus nancymaae monkeys. The recombinant replicated in the monkeys after intratracheal instillation, the first demonstration of replication of human adenoviruses in New World monkeys. Immunization elicited antibodies both to the Pl...
Monoclonal antibody (mAb) therapy is a promising infectious disease intervention strategy but is ... more Monoclonal antibody (mAb) therapy is a promising infectious disease intervention strategy but is limited to IgG1 isotypes that have restricted access to mucosal sites. IgA is well-established as the predominant antibody isotype in mucosal secretions but is clinically underutilized. To enable development of IgA-based mAbs, we exploited mRNA platform technology and demonstrated expression of functional, antigen-specific IgA (IgAmRNA) that can limit bacterial invasion in the intestine and prevent colonization in the lung. Moreover,in vivoIgAmRNAhad enhanced serum half-life and a greater degree of sialylation than a recombinantly produced IgA. The results underscore the potential of mRNA-based platforms to deliver protective human mAbs to mucosal surfaces and open new avenues to combat infectious diseases in the face of pervasive antibiotic resistance.One Sentence SummarymRNA-encoded human monoclonal IgA traffics to mucosal tissues and provides protection against bacterial challenge
ABSTRACTHIV broadly neutralizing antibodies (bNAbs) are capable of both blocking viral entry and ... more ABSTRACTHIV broadly neutralizing antibodies (bNAbs) are capable of both blocking viral entry and recruiting innate immunity to HIV-infected cells through their fragment crystallizable (Fc) region. Vaccination or productive infection results in a polyclonal mixture of class-switched IgG antibodies comprised of four subclasses, each encoding distinct Fc regions that differentially engage innate immune functions. Despite evidence that innate immunity contributes to protection, the relative contribution of individual IgG subclasses is unknown. Here we use vectored immunoprophylaxis (VIP) in humanized mice to interrogate the efficacy of individual IgG subclasses during prevention of vaginal HIV transmission by VRC07, a potent CD4-binding site directed bNAb. We find that VRC07-IgG2, which lacks Fc-mediated functionality, exhibits significantly reduced protection in vivo relative to other subclasses. However, even low concentrations of highly functional VRC07-IgG1 yields substantial protec...
Monoclonal antibodies are the fastest growing therapeutic class in medicine today. They hold grea... more Monoclonal antibodies are the fastest growing therapeutic class in medicine today. They hold great promise for a myriad of indications, including cancer, allergy, autoimmune and infectious diseases. However, the wide accessibility of these therapeutics is hindered by manufacturing and purification challenges that result in high costs and long lead times. Efforts are being made to find alternative ways to produce and deliver antibodies in more expedient and cost-effective platforms. The field of mRNA has made significant progress in the last ten years and has emerged as a highly attractive means of encoding and producing any protein of interest in vivo. Through the natural role of mRNA as a transient carrier of genetic information for translation into proteins, in vivo expression of mRNA-encoded antibodies offer many advantages over recombinantly produced antibodies. In this review, we examine both preclinical and clinical studies that demonstrate the feasibility of mRNA-encoded anti...
Plasmodium sporozoites can be neutralized in vitro by monoclonal antibodies (MAb) against the cir... more Plasmodium sporozoites can be neutralized in vitro by monoclonal antibodies (MAb) against the circumsporozoite protein (CSP) and can block liver invasion in vivo by sporozoites of a transgenic rodent parasite that expresses P. falciparum CSP (Pb-Pf), preventing infection in mice. Despite this, attempts at targeting CSP for a vaccine have fallen short of expectations, in part due to inability to induce durable high-titer antibodies. A single un-neutralized sporozoite can initiate infection, necessitating sustained high-titer neutralizing antibodies for lasting protection. Recently, David Baltimore’s laboratory developed an adeno-associated virus type 8 (AAV8) platform that efficiently delivers pre-formed MAb genes in vivo and directs sustained, high-level MAb production. With the Baltimore lab, we have adopted that technology to express humanized MAbs against the central repeat region of the CSP protein of P. falciparum in mice. Mice developed high titer human IgG antibodies as early...
To discuss recent progress in the use of vectors to produce antibodies in vivo as an alternative ... more To discuss recent progress in the use of vectors to produce antibodies in vivo as an alternative form of HIV prophylaxis or therapy. Instead of passive transfer of monoclonal antibody proteins, a transgene encoding an antibody is delivered to cells by the vector, resulting in expression and secretion by the host cell. This review will emphasize adeno-associated virus (AAV)-based strategies and summarize the evidence in support of this strategy as an alternative to traditional vaccines. We will highlight the major findings in the field and discuss the impact that this approach could have on the prevention, treatment and possibly eradication of HIV in patients. In this emerging field, the emphasis has been on the use of vectors delivering antibodies as an alternative to the development of an HIV vaccine. However, recent findings suggest that AAV-delivered broadly neutralizing antibodies can suppress HIV replication. As such, a single injection of AAV could mediate long-term antibody e...
Proceedings of the National Academy of Sciences of the United States of America, Jan 26, 2014
Malaria caused by Plasmodium falciparum kills nearly one million children each year and imposes c... more Malaria caused by Plasmodium falciparum kills nearly one million children each year and imposes crippling economic burdens on families and nations worldwide. No licensed vaccine exists, but infection can be prevented by antibodies against the circumsporozoite protein (CSP), the major surface protein of sporozoites, the form of the parasite injected by mosquitoes. We have used vectored immunoprophylaxis (VIP), an adeno-associated virus-based technology, to introduce preformed antibody genes encoding anti-P. falciparum CSP mAb into mice. VIP vector-transduced mice exhibited long-lived mAb expression at up to 1,200 µg/mL in serum, and up to 70% were protected from both i.v. and mosquito bite challenge with transgenic Plasmodium berghei rodent sporozoites that incorporate the P. falciparum target of the mAb in their CSP. Serum antibody levels and protection from mosquito bite challenge were dependent on the dose of the VIP vector. All individual mice expressing CSP-specific mAb 2A10 at ...
Decades of success with live adenovirus vaccines suggest that replication-competent recombinant a... more Decades of success with live adenovirus vaccines suggest that replication-competent recombinant adenoviruses (rAds) could serve as effective vectors for immunization against other pathogens. To explore the potential of a live rAd vaccine against malaria, we prepared a viable adenovirus 5 (Ad5) recombinant that displays a B-cell epitope from the circumsporozoite protein (CSP) of Plasmodium falciparum on the virion surface. The recombinant induced P. falciparum sporozoite-neutralizing antibodies in mice. Human adenoviruses do not replicate in mice. Therefore, to examine immunogenicity in a system in which, as in humans, the recombinant replicates, we constructed a similar recombinant in an adenovirus mutant that replicates in monkey cells and immunized four Aotus nancymaae monkeys. The recombinant replicated in the monkeys after intratracheal instillation, the first demonstration of replication of human adenoviruses in New World monkeys. Immunization elicited antibodies both to the Pl...
Monoclonal antibody (mAb) therapy is a promising infectious disease intervention strategy but is ... more Monoclonal antibody (mAb) therapy is a promising infectious disease intervention strategy but is limited to IgG1 isotypes that have restricted access to mucosal sites. IgA is well-established as the predominant antibody isotype in mucosal secretions but is clinically underutilized. To enable development of IgA-based mAbs, we exploited mRNA platform technology and demonstrated expression of functional, antigen-specific IgA (IgAmRNA) that can limit bacterial invasion in the intestine and prevent colonization in the lung. Moreover,in vivoIgAmRNAhad enhanced serum half-life and a greater degree of sialylation than a recombinantly produced IgA. The results underscore the potential of mRNA-based platforms to deliver protective human mAbs to mucosal surfaces and open new avenues to combat infectious diseases in the face of pervasive antibiotic resistance.One Sentence SummarymRNA-encoded human monoclonal IgA traffics to mucosal tissues and provides protection against bacterial challenge
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Papers by Cailin Deal