A Christian theological response to human gene patenting

The publication of the draft of the complete human genome is likely to prove to be one of the most significant breakthroughs for the medical sciences in this millennium because of the potential information it will yield. Patenting of human genetic material is permissible if these are can be shown to meet the four standard criteria applicable to all patents, which are that they are novel, involve an inventive step, are non-obvious and possess an industrial application. This dissertation addresses the main theological issue concerning patents, which is property as well as the ownership and use of such. It is argued that in the Bible, though a well-defined scriptural doctrine of property is absent, the right to property is tenable provided that it is in principle subordinate to the obligation to care for the weaker members of society. Property, in that regard, is to be used in fulfilment of the common good. I show that patenting human DNA can lead to injustice and therefore does not serve the common good. As this is contrary to the Christian theological understanding of the objective of property, I advocate that the correct response is to reject the practice. As a second line of argument, I also argue that because of its bi-elemental non-dual nature, human DNA is a metonymy for the human person since both possess a material and an immaterial component. These components are nonetheless inseparable without altering the overall nature of the DNA or the person. In this sense, human DNA is symbolic of the human person and on this account also should not be subjects of patents

Development of Pan-filovirus vaccine against Ebola and Marburg virus challenges

Filoviruses such as Ebola (EBOV) and Marburg (MARV) viruses cause deadly viral hemorrhagic fever in humans with high case fatality rates. To date, no licenced therapeutic or vaccine has been clinically approved to prevent infection. Several vaccine candidates are under development against the few most common filoviruses targeting the virus glycoprotein (GP). However, protective antibodies induced by such GP vaccines are usually limited to the same species. In contrast, T-cell vaccines offer an opportunity to design a single pan-filovirus vaccine protecting against all members of the Filoviridae family. In this study FILOcepX vaccines were constructed targeting the four most conserved regions among the viral proteomes with the aim to induce protective T-cell responses against different filoviruses. BALB/c mice were immunized with FILOcep 1 and 2 vaccines vectored by non-replicating engineered simian adenovirus and poxvirus MVA. Groups of 20 BALB/c mice were primed and boosted with either the FILOcep1 and FILOcep2 vaccines or control ChAdOx1- and MVA-vectored vaccines. Four animals in each group were sacrificed after 1 week of boosting to detect T-cell response for the FILOcepX antigen. High frequency T cells specific responses were detected in mice receiving the test vaccines by IFN-γ ELISPOT kits. Of the remaining 16 animals in each group, 8 were challenged with mouse-adapted EBOV and 8 were challenged with mouse adapted MARV in Containment Level 4 laboratory. All the mice in the control group either died or had to be euthanized between 4 and 6 days post challenge. On the other hand all the FILOcepX vaccinated mice maintained their normal body mass and survived till the end of the scheduled protocol on day 29 post challenge. These FILOcepX vaccines provided 100% protection against the lethal challenges with filoviruses of two different genera. Further evaluation the efficacy of this vaccine in non-human primates (NHPs) is warranted

HIV-1 Conserved Mosaics Delivered by Regimens with Integration-Deficient DC-Targeting Lentiviral Vector Induce Robust T Cells

To be effective against HIV type 1 (HIV-1), vaccine-induced T cells must selectively target epitopes, which are functionally conserved (present in the majority of currently circulating and reactivated HIV-1 strains) and, at the same time, beneficial (responses to which are associated with better clinical status and control of HIV-1 replication), and rapidly reach protective frequencies upon exposure to the virus. Heterologous prime-boost regimens using virally vectored vaccines are currently the most promising vaccine strategies; nevertheless, induction of robust long-term memory remains challenging. To this end, lentiviral vectors induce high frequencies of memory cells due to their low-inflammatory nature, while typically inducing only low anti-vector immune responses. Here, we describe construction of novel candidate vaccines ZVex.tHIVconsv1 and ZVex.tHIVconsv2, which are based on an integration-deficient lentiviral vector platform with preferential transduction of human dendritic cells and express a bivalent mosaic of conserved-region T cell immunogens with a high global HIV-1 match. Each of the two mosaic vaccines was individually immunogenic. When administered together in heterologous prime-boost regimens with chimpanzee adenovirus and/or poxvirus modified vaccinia virus Ankara (MVA) vaccines to BALB/c and outbred CD1-Swiss mice, they induced a median frequency of over 6,000 T cells/10^6splenocytes, which were plurifunctional, broadly specific, and cross-reactive. These results support further development of this vaccine concept

Novel Conserved-region T-cell Mosaic Vaccine With High Global HIV-1 Coverage Is Recognized by Protective Responses in Untreated Infection

An effective human immunodeficiency virus type 1 (HIV-1) vaccine is the best solution for halting the acquired immune deficiency syndrome epidemic. Here, we describe the design and preclinical immunogenicity of T-cell vaccine expressing novel immunogens tHIVconsvX, vectored by DNA, simian (chimpanzee) adenovirus, and poxvirus modified vaccinia virus Ankara (MVA), a combination highly immunogenic in humans. The tHIVconsvX immunogens combine the three leading strategies for elicitation of effective CD8+ T cells: use of regions of HIV-1 proteins functionally conserved across all M group viruses (to make HIV-1 escape costly on viral fitness), inclusion of bivalent complementary mosaic immunogens (to maximize global epitope matching and breadth of responses, and block common escape paths), and inclusion of epitopes known to be associated with low viral load in infected untreated people (to induce field-proven protective responses). tHIVconsvX was highly immunogenic in two strains of mice. Furthermore, the magnitude and breadth of CD8+ T-cell responses to tHIVconsvX-derived peptides in treatment-naive HIV-1+ patients significantly correlated with high CD4+ T-cell count and low viral load. Overall, the tHIVconsvX design, combining the mosaic and conserved-region approaches, provides an indisputably better coverage of global HIV-1 variants than previous T-cell vaccines. These immunogens delivered in a highly immunogenic framework of adenovirus prime and MVA boost are ready for clinical development

Una mirada retrospectiva sobre Quevedo y lo grotesco (autocrítica, autobombo y perplejidad)

Este ensayo examina retrospectivamente el problema de la relación entre Quevedo y lo grotesco. El autor reflexiona principalmente sobre el impacto ejercido por su Quevedo and the Grotesque (1978, 1982) en conexión con los muchos cambios que se han dado dentro del campo de los estudios hispánicos y de la enseñanza universitaria en general desde su aparición. Explora la compleja relación afectiva / intelectual que se desarrolla entre los estudiosos y los autores y temas que investigan, junto con la manera en que esa relación es afectada por la dinámica socioeconómica de la academia. Examina cómo el ethos de la investigación erudita ha evolucionado durante las últimas cuatro décadas, incluyendo la creciente brecha que separa los estudios hispánicos tal como se practican en los Estados Unidos y España. El autor desarrolla varias hipótesis para explicar por qué la parte de su libro que él considera su contribución más importante pasó esencialmente desapercibida por los críticos. También señala las partes del libro que considera las más débiles y sugiere maneras en que se pudieran haber mejorado. Finalmente, reflexiona sobre el modo en que los estudiosos tienden a ser definidos casi exclusivamente por sus colegas en términos de ciertos (a menudo tempranos) aportes, lo cual lleva a una tergiversación de su trayectoria profesional completa.This essay engages in a retrospective examination of the problem of Quevedo’s relationship to the grotesque. The author reflects primarily on the impact exercised by his Quevedo and the Grotesque (1978, 1982) in connection with the many changes that have occurred in the field of Hispanic studies and the teaching profession at the university level in general since its appearance. It explores the complex affective / intellectual relationship that develops between scholars and the authors and subjects they study and how that relationship is affected by the socio-economic dynamics of the academy. It examines how the ethos of scholarship has evolved in the last four decades, including the growing divide that separates Hispanic studies as practiced in the United States and Spain. The author develops hypotheses to explain why the part of his book that he considers its most original contribution went essentially unnoticed by critics. He also points to the parts of the book he considers to be its weakest and suggests ways in which they could have been improved. Finally, he reflects on the way scholars tend to be defined almost exclusively by their colleagues in terms of certain (often early) contributions, thereby leading to a misrepresentation of their full professional trajectory

Combined intranasal and intramuscular parainfluenza 5-, simian adenovirus ChAdOx1- and poxvirus MVA-vectored vaccines induce synergistically HIV-1-specific T cells in the mucosa

IntroductionThe primary goal of this work is to broaden and enhance the options for induction of protective CD8+ T cells against HIV-1 and respiratory pathogens.MethodsWe explored the advantages of the parainfluenza virus 5 (PIV5) vector for delivery of pathogen-derived transgenes alone and in combination with the in-human potent regimen of simian adenovirus ChAdOx1 prime-poxvirus MVA boost delivering bi-valent mosaic of HIV-1 conserved regions designated HIVconsvX.ResultsWe showed in BALB/c mice that the PIV5 vector expressing the HIVconsvX immunogens could be readily incorporated with the other two vaccine modalities into a single regimen and that for specific vector combinations, mucosal CD8+ T-cell induction was enhanced synergistically by a combination of the intranasal and intramuscular routes of administration.DiscussionEncouraging safety and immunogenicity data from phase 1 human trials of ChAdOx1- and MVA-vectored vaccines for HIV-1, and PIV5-vectored vaccines for SARS-CoV-2 and respiratory syncytial virus pave the way for combining these vectors for HIV-1 and other indications in humans

HIV-1 Conserved Mosaics Delivered by Regimens with Integration-Deficient DC-Targeting Lentiviral Vector Induce Robust T Cells

To be effective against HIV type 1 (HIV-1), vaccine-induced T cells must selectively target epitopes, which are functionally conserved (present in the majority of currently circulating and reactivated HIV-1 strains) and, at the same time, beneficial (responses to which are associated with better clinical status and control of HIV-1 replication), and rapidly reach protective frequencies upon exposure to the virus. Heterologous prime-boost regimens using virally vectored vaccines are currently the most promising vaccine strategies; nevertheless, induction of robust long-term memory remains challenging. To this end, lentiviral vectors induce high frequencies of memory cells due to their low-inflammatory nature, while typically inducing only low anti-vector immune responses. Here, we describe construction of novel candidate vaccines ZVex.tHIVconsv1 and ZVex.tHIVconsv2, which are based on an integration-deficient lentiviral vector platform with preferential transduction of human dendritic cells and express a bivalent mosaic of conserved-region T cell immunogens with a high global HIV-1 match. Each of the two mosaic vaccines was individually immunogenic. When administered together in heterologous prime-boost regimens with chimpanzee adenovirus and/or poxvirus modified vaccinia virus Ankara (MVA) vaccines to BALB/c and outbred CD1-Swiss mice, they induced a median frequency of over 6,000 T cells/10^6splenocytes, which were plurifunctional, broadly specific, and cross-reactive. These results support further development of this vaccine concept

Therapeutic Vaccination Refocuses T-cell Responses Towards Conserved Regions of HIV-1 in Early Treated Individuals (BCN 01 study)

Background Strong and broad antiviral T-cell responses targeting vulnerable sites of HIV-1 will likely be a critical component for any effective cure strategy. Methods BCN01 trial was a phase I, open-label, non-randomized, multicenter study in HIV-1-positive individuals diagnosed and treated during early HIV-1 infection to evaluate two vaccination regimen arms, which differed in the time (8 versus 24 week) between the ChAdV63.HIVconsv prime and MVA.HIVconsv boost vaccinations. The primary outcome was safety. Secondary endpoints included frequencies of vaccine-induced IFN-γ+ CD8+ T cells, in vitro virus-inhibitory capacity, plasma HIV-1 RNA and total CD4+ T-cells associated HIV-1 DNA. (NCT01712425). Findings No differences in safety, peak magnitude or durability of vaccine-induced responses were observed between long and short interval vaccination arms. Grade 1/2 local and systemic post-vaccination events occurred in 22/24 individuals and resolved within 3 days. Weak responses to conserved HIV-1 regions were detected in 50% of the individuals before cART initiation, representing median of less than 10% of their total HIV-1-specific T cells. All participants significantly elevated these subdominant T-cell responses, which after MVA.HIVconsv peaked at median (range) of 938 (73-6,805) IFN-γ SFU/106 PBMC, representing on average 58% of their total anti-HIV-1 T cells. The decay in the size of the HIV-1 reservoir was consistent with the first year of early cART initiation in both arms

HIVconsv Vaccines and Romidepsin in Early-Treated HIV-1-Infected Individuals: Safety, Immunogenicity and Effect on the Viral Reservoir (Study BCN02)

Kick&kill strategies combining drugs aiming to reactivate the viral reservoir with therapeutic vaccines to induce effective cytotoxic immune responses hold potential to achieve a functional cure for HIV-1 infection. Here, we report on an open-label, single-arm, phase I clinical trial, enrolling 15 early-treated HIV-1-infected individuals, testing the combination of the histone deacetylase inhibitor romidepsin as a latency-reversing agent and the MVA.HIVconsv vaccine. Romidepsin treatment resulted in increased histone acetylation, cell-associated HIV-1 RNA, and T-cell activation, which were associated with a marginally significant reduction of the viral reservoir. Vaccinations boosted robust and broad HIVconsv-specific T cells, which were strongly refocused toward conserved regions of the HIV-1 proteome. During a monitored ART interruption phase using plasma viral load over 2,000 copies/ml as a criterium for ART resumption, 23% of individuals showed sustained suppression of viremia up to 32 weeks without evidence for reseeding the viral reservoir. Results from this pilot study show that the combined kick&kill intervention was safe and suggest a role for this strategy in achieving an immune-driven durable viremic control