Phase I/II trial of immunogenicity of a human papillomavirus (HPV) type 16 E7 protein–based vaccine in women with oncogenic HPV-positive cervical intraepithelial neoplasia

Purpose: Infection with oncogenic human papillomavirus (HPV) and HPV-16 in particular is a leading cause of anogenital neoplasia. High-grade intraepithelial lesions require treatment because of their potential to progress to invasive cancer. Numerous preclinical studies have demonstrated the therapeutic potential of E7-directed vaccination strategies in mice tumour models. In the present study, we tested the immunogenicity of a fusion protein (PD-E7) comprising a mutated HPV-16 E7 linked to the first 108 amino acids of Haemophilus influenzae protein D, formulated in the GlaxoSmithKline Biologicals adjuvant AS02B, in patients bearing oncogenic HPV-positive cervical intraepithelial neoplasia (CIN). Methods: Seven patients, five with a CIN3 and two with a CIN1, received three intramuscular injections of adjuvanted PD-E7 at 2-week intervals. Three additional CIN1 patients received a placebo. CIN3 patients underwent conization 8 weeks postvaccination. Cytokine flow cytometry and ELISA were used to monitor antigen-specific cellular and antibody responses from blood taken before and after vaccine or placebo injection. Results: Some patients had preexisting systemic IFN- CD4⁺ (1/10) and CD8⁺ (5/10) responses to PD-E7. Vaccination, not placebo injection, elicited systemic specific immune responses in the majority of the patients. Five vaccinated patients (71%) showed significantly increased IFN- CD8⁺ cell responses upon PD-E7 stimulation. Two responding patients generated long-term T-cell immunity toward the vaccine antigen and E7 as well as a weak H. influenzae protein D (PD)–directed CD4⁺ response. All the vaccinated patients, but not the placebo, made significant E7- and PD-specific IgG. Conclusions: The encouraging results obtained from this study performed on a limited number of subjects justify further analysis of the efficacy of the PD-E7/AS02B vaccine in CIN patients.     

The AIDS epidemic: the spread of a deadly disease in the biotech era

In the last two decades we have witnessed the progression of a newly introduced infection in humans. It is sobering that despite a world-wide effort and the tremendous progression of technical capabilities and scientific knowledge we are still not able to control the global epidemic of HIV. In 2004 more than 40 million people were infected. Educational approaches to modify risk-taking behavior is still the most critical component of prevention and the most important measure to limit the spread of the infection. Vaccine development, which is still far from promising, is probably the only way to control the disease in the future.     

Distortion of the three-dimensional structure of the vnd/NK-2 homeodomain bound to DNA induced by an embryonically lethal A35T point mutation

The three-dimensional solution structure obtained by NMR of the A35T mutant vnd/NK-2 homeodomain bound to the vnd/NK-2 consensus 16 bp DNA sequence was determined. This mutation to threonine from alanine in position 35 in helix II of the vnd/NK-2 homeodomain is associated with early embryonic lethality in Drosophila melanogaster. Although the unbound mutant protein is not structured, in the DNA-bound state it adopts the three-helix fold characteristic of all known homeodomains, but with alterations relative to the structure of the wild-type analogue. These structural modifications occur, and are accompanied by a 50-fold reduction in the DNA binding affinity, even though most of the protein-DNA interactions originally seen for the wild-type homeodomain are found likewise in the threonine analogue. Alterations include torsional angle changes in the loop between helix I and helix II, and in the turn between helix II and helix III, as well as in a distortion of the usual antiparallel orientation of helix I with respect to helix II. The alteration of the position of leucine 40 in the A35T mutant is proposed to explain the observed 1.27 ppm upfield shift of the corresponding amide proton resonance relative to the value observed for the wild-type analogue. A detailed comparison of the structures of the mutant A35T and wild-type vnd/NK-2 homeodomains bound to the cognate DNA is presented. The consequences of the structural alteration of the DNA-bound A35T mutant vnd/NK-2 protein may constitute the basis of the observed early embryonic lethality.     

Indirect effects of lemming cycles on sandpiper dynamics: 50 years of counts from southern Sweden

The bird-lemming hypothesis postulates that breeding success of tundra-nesting geese and waders in Siberia follows the cyclic pattern of lemming populations, as a result of predators switching from lemmings to birds when the lemming population crashes. We present 50 years of data on constant-effort catches of red knot Calidris canutus and curlew sandpiper C. ferruginea at an autumn migratory stopover site (Ottenby) at the Baltic Sea, supplemented with literature data on winter censuses of dark-bellied brent goose Branta b. bernicla and white-fronted goose Anser albifrons in northwestern Europe, and waders in Germany and Southern Africa. Number and proportion of juveniles in these bird populations (both our own and literature data) were compared with an index of predation pressure (calculated from the abundance of lemmings on the Taimyr peninsula), and climate indices for the North Eurasia and the North Atlantic regions. The index of predation pressure correlated significantly with the number of juveniles of red knot and curlew sandpiper, but not with number of adults. Also, this index correlated with the reproductive performance of geese and waders reported in the literature. Fourier analysis revealed a significant deviation from random noise with the maximum spectral density at the period length of 3 years for number of juvenile red knots and curlew sandpipers captured at Ottenby, abundance of lemmings, reproduction in arctic fox Alopex lagopus, and reproductive performance in geese on the Siberian tundra. Also, the date of passage at Ottenby for adult red knot and curlew sandpiper showed a spectral density peak at a period length of 3 years, the latter species also showing a peak at a period length of 5-6 years. Passage dates for adult red knot and curlew sandpiper were earlier in years of high predation pressure compared with years of low predation pressure. The fluctuations in reproductive success of the studied Siberian goose and wader species appear to be primarily influenced by biotic factors in the breeding area, rather than by abiotic factors, such as climate oscillations. Annual variations in migratory arctic bird populations may have far reaching effects in habitats along their migration routes and in their wintering areas. We suggest a link between lemming cyclicity in the Northern Hemisphere and predation pressure on Southern Hemisphere benthos, in which the signal is carried between continents by long distance migrating waders.     

Minimal number of generations out of polymorphism in the one-locus two-allele model with unpredictable fertilities

 Fertilities varying in time in an unpredictable manner raise the question of the maintenance of polymorphism, and the subsequent question of the minimal total number of generations spent by the system in impoverished polymorphism. In the one-locus two-allele model, level surfaces of this minimal time out of a given set K of constraints defining polymorphism are delineated. The surface of null minimal time is also the largest set of genotype frequencies from which there exists at least one route remaining in K forever. The influence of the range of admissible fertilities clarifies the trade-off between homozygotes and heterozygotes. Notably, ranges of fertility forbidding a system leaving K to ever return to it are determined. Generally, keeping a chance to regain polymorphism demands a sufficiently relatively high fertility for matings involving heterozygotes. Received: 5 January 2001 / Revised version: 20 October 2001 / Published online: 17 May 2002     

Making ecosystem models viable

Viability conditions permit to characterize all processes compatible with given constraints, notably of available food, so that there exists at least one possibility for the system to perpetuate itself forever. The concept of contingent cone to a set of constraints permits to identify two classes of corrections to apply to equations of natural growth. Usual basic models convey those corrections only in certain regions of the parameter space. A general model-building stemming from the constraints is presented. Experimental populations from historical case studies highlight the mathematical concept of viability corrections.