Hanne Andersen

Induction of Broadly Neutralizing H1N1 Influenza Antibodies by Vaccination

Toward a General Flu Vaccination Current seasonal influenza virus vaccines are targeted against specific viral strains and do not provide broad, durable protection. Seasonal influenza vaccines induce protective antibody responses against regions of viral hemagglutinin (HA) that rapidly mutate so that very soon, the virus becomes resistant to vaccination. Conserved regions of HA also exist, and a major goal of influenza vaccine development is to design a vaccine that elicits antibodies against the conserved regions so that protection against a wide range of viral strains is achieved. Wei et al. (p. 1060, published online 15 July; see the Perspective by Doms) show that a combined HA DNA prime, followed by boosting with a seasonal vaccine, elicits broadly cross-reactive neutralizing antibody responses in mice, ferrets, and nonhuman primates, which were protective in mice and ferrets against heterologous influenza challenge. The neutralizing antibodies were directed against the conserved HA stem region, which indicates the possibility that a more broadly protective vaccine against influenza could be developed. An influenza virus vaccine elicits a broadly neutralizing, cross-protective antibody response in mice, ferrets, and nonhuman primates. The rapid dissemination of the 2009 pandemic influenza virus underscores the need for universal influenza vaccines that elicit protective immunity to diverse viral strains. Here, we show that vaccination with plasmid DNA encoding H1N1 influenza hemagglutinin (HA) and boosting with seasonal vaccine or replication-defective adenovirus 5 vector encoding HA stimulated the production of broadly neutralizing influenza antibodies. This prime/boost combination increased the neutralization of diverse H1N1 strains dating from 1934 to 2007 as compared to either component alone and conferred protection against divergent H1N1 viruses in mice and ferrets. These antibodies were directed to the conserved stem region of HA and were also elicited in nonhuman primates. Cross-neutralization of H1N1 subtypes elicited by this approach provides a basis for the development of a universal influenza vaccine for humans.

Rapid development of a DNA vaccine for Zika virus

A DNA vaccine candidate for Zika The ongoing Zika epidemic in the Americas and the Caribbean urgently needs a protective vaccine. Two DNA vaccines composed of the genes that encode the structural premembrane and envelope proteins of Zika virus have been tested in monkeys. Dowd et al. show that two doses of vaccine given intramuscularly completely protected 17 of 18 animals against Zika virus challenge. A single low dose of vaccine was not protective but did reduce viral loads. Protection correlated with serum antibody neutralizing activity. Phase I clinical trials testing these vaccines are already ongoing. Science, this issue p. 237 DNA-vaccine–induced neutralizing antibodies largely protect monkeys after experimental challenge by virus infection. Zika virus (ZIKV) was identified as a cause of congenital disease during the explosive outbreak in the Americas and Caribbean that began in 2015. Because of the ongoing fetal risk from endemic disease and travel-related exposures, a vaccine to prevent viremia in women of childbearing age and their partners is imperative. We found that vaccination with DNA expressing the premembrane and envelope proteins of ZIKV was immunogenic in mice and nonhuman primates, and protection against viremia after ZIKV challenge correlated with serum neutralizing activity. These data not only indicate that DNA vaccination could be a successful approach to protect against ZIKV infection, but also suggest a protective threshold of vaccine-induced neutralizing activity that prevents viremia after acute infection.

Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination

Zika virus (ZIKV) has recently emerged as a pandemic associated with severe neuropathology in newborns and adults. There are no ZIKV-specific treatments or preventatives. Therefore, the development of a safe and effective vaccine is a high priority. Messenger RNA (mRNA) has emerged as a versatile and highly effective platform to deliver vaccine antigens and therapeutic proteins. Here we demonstrate that a single low-dose intradermal immunization with lipid-nanoparticle-encapsulated nucleoside-modified mRNA (mRNA–LNP) encoding the pre-membrane and envelope glycoproteins of a strain from the ZIKV outbreak in 2013 elicited potent and durable neutralizing antibody responses in mice and non-human primates. Immunization with 30 μg of nucleoside-modified ZIKV mRNA–LNP protected mice against ZIKV challenges at 2 weeks or 5 months after vaccination, and a single dose of 50 μg was sufficient to protect non-human primates against a challenge at 5 weeks after vaccination. These data demonstrate that nucleoside-modified mRNA–LNP elicits rapid and durable protective immunity and therefore represents a new and promising vaccine candidate for the global fight against ZIKV.

Comparative efficacy of hemagglutinin, nucleoprotein, and matrix 2 protein gene-based vaccination against H5N1 influenza in mouse and ferret.

Efforts to develop a broadly protective vaccine against the highly pathogenic avian influenza A (HPAI) H5N1 virus have focused on highly conserved influenza gene products. The viral nucleoprotein (NP) and ion channel matrix protein (M2) are highly conserved among different strains and various influenza A subtypes. Here, we investigate the relative efficacy of NP and M2 compared to HA in protecting against HPAI H5N1 virus. In mice, previous studies have shown that vaccination with NP and M2 in recombinant DNA and/or adenovirus vectors or with adjuvants confers protection against lethal challenge in the absence of HA. However, we find that the protective efficacy of NP and M2 diminishes as the virulence and dose of the challenge virus are increased. To explore this question in a model relevant to human disease, ferrets were immunized with DNA/rAd5 vaccines encoding NP, M2, HA, NP+M2 or HA+NP+M2. Only HA or HA+NP+M2 vaccination conferred protection against a stringent virus challenge. Therefore, while gene-based vaccination with NP and M2 may provide moderate levels of protection against low challenge doses, it is insufficient to confer protective immunity against high challenge doses of H5N1 in ferrets. These immunogens may require combinatorial vaccination with HA, which confers protection even against very high doses of lethal viral challenge.

Kuhn's mature philosophy of science and cognitive psychology

Abstract Drawing on the results of modem psychology and cognitive science we suggest that the traditional theory of concepts is no longer tenable, and that the alternative account proposed by Kuhn may now be seen to have independent empirical support quite apart from its success as part of an account of scientific change. We suggest that these mechanisms can also be understood as special cases of general cognitive structures revealed by cognitive science. Against this background, incommensurability is not an insurmountable obstacle to accepting Kuhns position, as many philosophers of science still believe. Rather it becomes a natural consequence of cognitive structures that appear in all human beings.

Epistemic dependence in interdisciplinary groups

In interdisciplinary research scientists have to share and integrate knowledge between people and across disciplinary boundaries. An important issue for philosophy of science is to understand how scientists who work in these kinds of environments exchange knowledge and develop new concepts and theories across diverging fields. There is a substantial literature within social epistemology that discusses the social aspects of scientific knowledge, but so far few attempts have been made to apply these resources to the analysis of interdisciplinary science. Further, much of the existing work either ignores the issue of differences in background knowledge, or it focuses explicitly on conflicting background knowledge. In this paper we provide an analysis of the interplay between epistemic dependence between individual experts with different areas of expertise. We analyze the cooperative activity they engage in when participating in interdisciplinary research in a group, and we compare our findings with those of other studies in interdisciplinary research.

A philosophical analysis of the Hill criteria

The epidemiological literature contains an ongoing and diversified discussion of the Hill criteria. This article offers a philosophical analysis of the criteria, showing that the criteria are related to two different views of causality. The authors argue that the criteria of strength, specificity, consistency, experiment, and biological gradient are related to a probabilistic regularity view of causality, whereas the criteria of coherence, plausibility, and analogy are related to a generative view of causality. The criterion of temporality is not related to either view, but may in contrast be central in inferring direction from cause to effect. The authors illuminate the aim and limitations of the various criteria that need to be included when discussing them.

Kuhn's theory of scientific revolutions and cognitive psychology

Abstract In a previous article we have shown that Kuhns theory of concepts is independently supported by recent research in cognitive psychology. In this paper we propose a cognitive re‐reading of Kuhns cyclical model of scientific revolutions: all of the important features of the model may now be seen as consequences of a more fundamental account of the nature of concepts and their dynamics. We begin by examining incommensurability, the central theme of Kuhns theory of scientific revolutions, according to two different cognitive models of concept representation. We provide new support for Kuhn ‘s mature views that incommensurability can be caused by changes in only a few concepts, that even incommensurable conceptual systems can be rationally compared, and that scientific change of the most radical sort—the type labeled revolutionary in earlier studies—does not have to occur holistically and abruptly, but can be achieved by a historically more plausible accumulation of smaller changes. We go on to sug...

Prior Exposure to Zika Virus Significantly Enhances Peak Dengue-2 Viremia in Rhesus Macaques

Structural and functional homologies between the Zika and Dengue viruses’ envelope proteins raise the possibility that cross-reactive antibodies induced following Zika virus infection might enhance subsequent Dengue infection. Using the rhesus macaque model we show that prior infection with Zika virus leads to a significant enhancement of Dengue-2 viremia that is accompanied by neutropenia, lympocytosis, hyperglycemia, and higher reticulocyte counts, along with the activation of pro-inflammatory monocyte subsets and release of inflammatory mediators. Zika virus infection induced detectable Dengue cross-reactive serum IgG responses that significantly amplified after Dengue-2 virus infection. Serum from Zika virus immune animals collected prior to Dengue-2 infection showed significant capacity for in vitro antibody dependent enhancement of Dengue-1, 2, 3 and 4 serotypes suggesting that pre-existing immunity to Zika virus could potentially enhance infection by heterologous Dengue serotypes. Our results provide first in vivo evidence that prior exposure to Zika virus infection can enhance Dengue infection, which has implications for understanding pathogenesis and the development of vaccines.

Kuhn's Account Of Family Resemblance: A Solution To The Problem Of Wide-Open Texture

It is a commonly raised argument against thefamily resemblance account of concepts that, on thisaccount, there is no limit to a concepts extension.An account of family resemblance which attempts toprovide a solution to this problem by including bothsimilarity among instances and dissimilarity tonon-instances has been developed by the philosopher ofscience Thomas Kuhn. Similar solutions have beenhinted at in the literature on family resemblanceconcepts, but the solution has never received adetailed investigation. I shall provide areconstruction of Kuhns theory and argue that hissolution necessitates a developmental perspective withbuilds on both the transmission of taxonomies betweengenerations and a progressive development throughhistory.