Marion F. Gruber

Macrophage Colony-Stimulating Factor Antagonists Inhibit Replication of HIV-1 in Human Macrophages

Macrophages infected with HIV-1 produce high levels of M-CSF and macrophage-inflammatory protein-1α (MIP-1α). M-CSF facilitates the growth and differentiation of macrophages, while the chemotactic properties of MIP-1α attract both T lymphocytes and macrophages to the site of HIV infection. Studies described in this work indicate M-CSF may function in an autocrine/paracrine manner to sustain HIV replication, and data suggest possible therapeutic strategies for decreasing viral load following HIV infection. We show that macrophage infection with measles virus or respiratory syncytial virus, in contrast to HIV-1, results in production of MIP-1α, but not M-CSF. Thus, M-CSF appears to be specifically produced upon infection of macrophages with HIV-1. Furthermore, addition of M-CSF antagonists to HIV-1-infected macrophages, including anti-M-CSF monoclonal or polyclonal Abs or soluble M-CSF receptors, dramatically inhibited HIV-1 replication and reduced production of MIP-1α. Our results suggest that biologic antagonists for M-CSF may represent novel strategies for inhibiting the spread of HIV-1 by 1) blocking virus replication in macrophages, 2) reducing recruitment of HIV-susceptible T cells and macrophages by MIP-1α, and 3) preventing the establishment and maintenance of infected macrophages as a reservoir for HIV.

Predictive markers of safety and immunogenicity of adjuvanted vaccines.

Vaccination represents one of the greatest public health triumphs; in part due to the effect of adjuvants that have been included in vaccine preparations to boost the immune responses through different mechanisms. Although a variety of novel adjuvants have been under development, only a limited number have been approved by regulatory authorities for human vaccines. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference on the current state of the art in the adjuvant field. Held at the U.S. Pharmacopeial Convention (USP) in Rockville, Maryland, USA, from 18 to 19 April 2013 and organized by the International Association for Biologicals (IABS), the conference focused particularly on the future development of effective adjuvants and adjuvanted vaccines and on overcoming major hurdles, such as safety and immunogenicity assessment, as well as regulatory scrutiny. More information on the conference output can be found on the IABS website, http://www.iabs.org/.

Production of macrophage colony-stimulating factor (M-CSF) by human monocytes is differentially regulated by GM-CSF, TNFα, and IFN-γ

Macrophage colony-stimulating factor (M-CSF) stimulates the survival, proliferation, and differentiation of mononuclear phagocytes. In this study, the qualitative and relative quantitative ability of various cytokines to induce and to synergize in M-CSF production by monocytes was studied. GM-CSF and the phorbolester PMA were strong inducers of M-CSF m-RNA expression. This was correlated closely with the secretion of M-CSF protein as measured in the murine M-NFS-60 cell line bioassay. Both TNF alpha and IFN-gamma enhanced M-CSF message levels induced by GM-CSF, but only TNF alpha synergized with GM-CSF in the induction of M-CSF protein secretion. M-CSF transcripts induced by TNF alpha and IFN-gamma were much lower compared to those induced by GM-CSF and PMA and were not accompanied by the secretion of M-CSF protein. In addition, costimulation of cells with TNF alpha and IFN-gamma did not result in M-CSF production. Although M-CSF did not induce its own message, it further enhanced M-CSF transcripts induced by GM-CSF. LPS also failed to induce M-CSF message or secretion. These results show that cytokines differ in their ability to induce or to synergize in the induction of biologically active M-CSF protein. They further demonstrate that M-CSF message expression, induced by cytokines, does not always correlate with M-CSF protein secretion.

Maternal immunization: US FDA regulatory considerations.

Vaccination of pregnant women provides important health benefits to both, mother and infant, and has been an important disease prevention strategy in these two groups. While most vaccines currently licensed in the US are not indicated for use during pregnancy, depending on the vaccine, vaccination programs do frequently include pregnant women. In addition, recent emphasis has been placed on maternal immunization strategies to protect young infants from severe infections. Currently, unless the vaccine is specifically indicated four maternal immunization, no data are collected regarding the vaccines safety in pregnant women prior to licensure. However, more females of childbearing age participate in clinical trials and a broad range of novel vaccine products are in development indicated for adolescents and adults. Thus, there is increasing concern for the unintentional exposure of an embryo/fetus before information is available regarding the potential risk versus benefit of the vaccine. Since pregnant women are usually excluded from participation in clinical trials, conclusions regarding developmental risk at the time of licensure are frequently based solely on data derived from developmental toxicity studies in animal models. This paper will review regulatory, preclinical and clinical issues as they pertain to development programs for vaccines intended for vaccination during pregnancy.

Regulatory considerations in the clinical development of vaccines indicated for use during pregnancy

Despite supportive public health policies (e.g., ACIP recommendations), the potential for providing clinical benefit through maternal immunization has yet to be fully realized. For vaccines already licensed and approved for use in adults, specific FDA approval for use during pregnancy to prevent disease in the mother and/or infant may have a significant impact on uptake and usage in pregnant women. In addition, for either a licensed vaccine or a novel vaccine, FDA approval for use during pregnancy would result in labeling that would serve as a resource for practitioners and would facilitate the safe and effective use of the vaccine during pregnancy. In the U.S., while many vaccines are approved for use in adults and most are not contraindicated for use in pregnant women, no vaccine is licensed for use specifically during pregnancy. Among the perceived obstacles hindering the clinical development of vaccines for use in pregnancy, regulatory issues are frequently cited. One aim of this article is to address the perceived regulatory obstacles. General concepts and regulatory considerations for clinical safety and effectiveness evaluations for vaccines indicated for use during pregnancy will be discussed. This discussion is not intended to establish data requirements or to articulate agency policy or guidance regarding specific vaccine products.

Influence of human T lymphocytes identified by antibodies to dipeptidyl peptidase IV on differentiation of human B lymphocytes stimulated with Staphylococcus aureus cowan I and pokeweed mitogen

The influence of human T lymphocytes expressing the enzyme dipeptidyl peptidase IV (DPP IV) was investigated with respect to human peripheral B-lymphocyte differentiation. B cells stimulated with pokeweed mitogen in the presence of DPP IV-positive T cells produced high amounts of immunoglobulin. Moderate amounts of immunoglobulin could be measured when B cells were cultured in the presence of DPP IV-negative T cells. DPP IV defines a T-cell subset partially overlapping the subsets characterized by the differentiation antigens Leu 3a (helper/inducer) and Leu 2a (suppressor/cytotoxic). DPP IV-positive T cells exert, in contrast to DPP IV-negative T cells, high interleukin-2 activity after stimulation with phytohemagglutinin and pokeweed mitogen. To further functionally characterize DPP IV-positive and DPP IV-negative T cells, the helper effects of Leu 3a-positive T-cell subsets, differing in DPP IV expression, were investigated in pokeweed mitogen- and Staphylococcus aureus-driven B-cell differentiation systems. After pokeweed mitogen stimulation, immunoglobulin production was markedly reduced when B cells were cultured in the presence of Leu 3a-positive T cells expressing DPP IV (DPP IV+/Leu 3a+). In contrast, high amounts of immunoglobulin were produced in cultures with Leu 3a-positive but DPP IV-negative T cells (DPP IV-/Leu 3a+). This difference in immunoglobulin production of B cells cultured with DPP IV+/Leu 3a+ and DPP IV-/Leu 3a+ T cells could not be observed in Staphylococcus aureus-stimulated cultures. Here, both T-cell subsets supported terminal differentiation of B cells. We conclude that in the pokeweed mitogen-driven culture systems, DPP IV+/Leu 3a+ and DPP IV-/Leu 3a+ T cells may differ in the production of growth and/or differentiation factors distinct from interleukin-2.

Influenza immunization during pregnancy: US regulatory perspective

Maternal immunization with inactivated influenza vaccines is an important public health strategy to protect mothers and young infants from the serious complications of influenza. Although not contraindicated in pregnant women, currently US-licensed influenza vaccines are not specifically labeled for use during pregnancy. Several postmarketing initiatives are ongoing to obtain maternal and infant safety and immunogenicity data on US-licensed inactivated influenza vaccines used in pregnant women. The Food and Drug Administration is revising its pregnancy labeling regulations to improve the characterization and communication of risks of drugs and biologics used during pregnancy. To obtain a specifically labeled indication for use of an influenza vaccine during pregnancy, adequate and well-controlled prelicensure studies are needed to obtain data on the products safety and effectiveness and to demonstrate protection of the mother and/or infant against influenza illness.

Immunology of protection from Ebola virus infection

Immunological data could be used to demonstrate Ebola vaccine efficacy. A December 2014 meeting reviewed Ebola virus immunology relevant to vaccine development, including Ebola prevention, immunity, assay standardization, and regulatory considerations. Vaccinated humans appear to achieve immune responses comparable in magnitude with those associated with protection in nonhuman primates, suggesting that immunological data could be used to demonstrate vaccine efficacy.

Clinical Evaluation of Pertussis Vaccines: US Food and Drug Administration Regulatory Considerations

The resurgence of pertussis in the United States has stimulated considerable public health interest in developing new vaccination strategies to improve control of pertussis. The purpose of this article is to review the US Food and Drug Administrations regulatory framework for the prelicensure clinical evaluation of preventive vaccines and the clinical approaches that have been used to demonstrate effectiveness of US-licensed vaccines containing an acellular pertussis component.

US FDA review and regulation of preventive vaccines for infectious disease indications: impact of the FDA Amendments Act 2007.

Vaccines for prevention or treatment of infectious diseases are biological products that are regulated by the Office of Vaccines Research and Review in the Center for Biologics Evaluation and Research of the US FDA. The legal framework for the regulation of vaccines derives primarily from Section 351 of the Public Health Service Act and from certain sections of the Federal Food, Drug and Cosmetic Act (FFD & C Act). The FDA Amendments Act of 2007 (FDAAA 2007) includes extensive modifications to the FFD & C Act. This article provides an overview of the review process for preventive vaccines and highlights applicable statutory provisions. In addition, this article will discuss changes in the pre-and post-licensure evaluation process for preventive and therapeutic infectious disease vaccines since implementation of the FDAAA 2007.