HIV vaccine design: insights from live attenuated SIV vaccines

The International AIDS Vaccine Initiative has established a consortium to elucidate mechanisms of protection conferred by live attenuated simian immunodeficiency virus vaccines in monkeys. Here, the strategies defining key components of the protective immune response elicited by these vaccines are discussed.     

Macaques vaccinated with live-attenuated SIV control replication of heterologous virus

An effective AIDS vaccine will need to protect against globally diverse isolates of HIV. To address this issue in macaques, we administered a live-attenuated simian immunodeficiency virus (SIV) vaccine and challenged with a highly pathogenic heterologous isolate. Vaccinees reduced viral replication by approximately 2 logs between weeks 2-32 (P < or = 0.049) postchallenge. Remarkably, vaccinees expressing MHC-I (MHC class I) alleles previously associated with viral control completely suppressed acute phase replication of the challenge virus, implicating CD8(+) T cells in this control. Furthermore, transient depletion of peripheral CD8(+) lymphocytes in four vaccinees during the chronic phase resulted in an increase in virus replication. In two of these animals, the recrudescent virus population contained only the vaccine strain and not the challenge virus. Alarmingly, however, we found evidence of recombinant viruses emerging in some of the vaccinated animals. This finding argues strongly against an attenuated virus vaccine as a solution to the AIDS epidemic. On a more positive note, our results suggest that MHC-I-restricted CD8(+) T cells contribute to the protection induced by the live-attenuated SIV vaccine and demonstrate that vaccine-induced CD8(+) T cell responses can control replication of heterologous challenge viruses.     

Effects of neuromedin-β on caloric compensation, eating behaviours and habitual food intake

We have previously shown that a missense mutation (p.P73T) located in the neuromedin-β gene, a satiety peptide, was associated with higher levels of disinhibition, susceptibility to hunger, and body weight gain over time. In this study we compare caloric compensation, eating behaviour traits, food intake and adiposity between premenopausal women with (T73T) and without (P73P) mutation. Subjects (N = 153) were screened to find homozygous women (T73T) that were matched for age, BMI and use of oral contraceptives with 7 women (P73P) not carrying the mutation. Eating behaviour traits were assessed with the Three-Factors Eating Questionnaire and habitual dietary intakes with a 3-day dietary record. A randomized single-blind cross-over design was used to test the effect of p.P73T on caloric compensation. We measured appetite sensations and ad libitum dietary intake following two different energy preloads. We found no difference in eating behaviour traits, adiposity, appetite sensations, ad libitum dietary intake and caloric compensation. However, T73T women had lower habitual energy and carbohydrate intakes than P73P. Differences in carbohydrate intakes disappeared when expressed in percentage of energy. These results suggest that the neuromedin-β p.P73T mutation modulates energy intake without effects on macronutrient. A lack of power resulting from our difficulty to recruit enough T73T women precludes any definitive conclusion regarding the impact of this mutation on caloric compensation.     

Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study

BACKGROUND: Repeated subcutaneous injections of a monoclonal antibody against the p40 subunit of interleukins 12 and 23, ustekinumab, were used to treat patients with relapsing-remitting multiple sclerosis (RRMS) to assess the drug's safety, efficacy, and pharmacokinetics. METHODS: In this phase II, multicentre, randomised, double-blind, placebo-controlled study, 249 patients with RRMS, aged 18-65 years, were eligible to be assigned equally (by a central randomisation procedure based on study site and presence or absence of gadolinium-enhancing T1-weighted lesions at baseline) to one of five groups that received placebo or four different ustekinumab dosages at weeks 0, 1, 2, 3, 7, 11, 15, and 19. Ustekinumab doses were 27 mg, 90 mg q8w, 90 mg, or 180 mg; the 90 mg q8w dosage group received placebo substitute at weeks 7 and 15. The primary endpoint was the cumulative number of new gadolinium-enhancing T1-weighted lesions on serial cranial MRI through week 23. Patients were followed up through week 37. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00207727. FINDINGS: From August, 2004, to December, 2006, 249 patients underwent randomisation (49 for placebo; 50 for each ustekinumab group). Ustekinumab treatment did not show a significant reduction in the primary endpoint for any dosage groups versus placebo. At week 37, adverse events occurred in 38 (78%) placebo-treated patients and 170 (85%) ustekinumab-treated patients, with infections most commonly reported. Serious adverse events occurred in one (2%) placebo-treated patient and six (3%) ustekinumab-treated patients. Malignant diseases were reported in two patients shortly after the initiation of ustekinumab treatment; both patients were withdrawn from the trial and given appropriate treatment, which resulted in complete remission. No serious infections, cardiovascular events, or exacerbation of demyelinating events occurred. A dose-dependent increase in serum concentrations of ustekinumab was recorded. INTERPRETATION: Ustekinumab is generally well tolerated but does not show efficacy in reducing the cumulative number of gadolinium-enhancing T1-weighted lesions in multiple sclerosis.     

The research assessment exercise in nursing: learning from the past, looking to the future

Aims and objectives. The aim of the study was to enable those planning to make submissions to the 2008 Research Assessment Exercise to make informed decisions regarding their research strategies. The objective of the study was to identify the factors that distinguish those units of assessment (Universities and Higher Education Institutions) that were highly rated from those that received a low rating for nursing in the Research Assessment Exercise of 2001. Background. Nursing research differs in kind from other types of biomedical research. There is a tendency for research in nursing to be characterized by an inward‐looking focus and dominated by a concern with the profession itself. Design. The examination of the research output of nursing. Methods. Data from the abstracts of journal articles submitted to the 2001 Research Assessment Exercise for nursing were extracted, classified, collated and analysed. Results. The publications submitted by those in the higher‐rated units showed a greater tendency than those submitted by those in the lower‐rated units to report on a study involving the collection of primary data; to be multi‐authored; to use either qualitative methodology or randomized‐controlled trials; and to focus upon clinical issues and have patients as the subjects of the research. Conclusion. Nursing research is in a process of change and growth and is still of variable quality. The development of research towards patient care and clinical issues, and away from issues relating to the profession itself, is most evident among those units of assessment rated highly in the 2001 Research Assessment Exercise. Relevance to clinical practice. The study indicates that the best of current nursing research is focused upon clinical issues and patient care.     

The Course of Geriatric Syndromes in Acutely Hospitalized Older Adults: The Hospital-ADL Study

Objectives

To establish the prevalence and course of geriatric syndromes from hospital admission up to 3 months postdischarge and to determine the probability to retain geriatric syndromes over the period from discharge until 3 months postdischarge, once they are present at admission.

A sequential cohort study evaluating single-agent KappaMab and KappaMab combined with lenalidomide and low-dose dexamethasone in relapsed and/or refractory kappa light chain-restricted multiple myeloma (AMaRC 01-16)

KappaMab (KM; formerly MDX-1097) is a monoclonal antibody specific for the kappa myeloma antigen (KMA), a cell-surface antigen expressed on malignant plasma cells in kappa-restricted multiple myeloma (κMM), some lymphomas, occasional tonsillar B cells and in vitro activated B cells, but not on normal B cells in bone marrow. Phase I/IIa studies of single-agent KM confirmed a favourable toxicity profile and evidence of anti-myeloma activity. Ex-vivo studies demonstrating upregulation of KMA by lenalidomide, and enhanced effector-cell cytotoxicity provided the rationale for this phase IIb study where KM or KM in combination with lenalidomide and dexamethasone (KM-Rd) was administered in relapsed, refractory κMM patients. In addition, outcomes for a real-world matched case–control cohort from the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR) who received Rd were compared to the KM-Rd cohort. KM-Rd demonstrated an overall response rate of 82.5% which compared favourably to the Rd-MRDR cohort of 45.1%. Both single-agent KM and KM-Rd regimens were well tolerated, with the KM-Rd safety profile similar to patients given only Rd in other clinical settings. Based on the excellent safety profile and significant efficacy, further clinical trials escalating the KM dose and pairing KM with other standard-of-care treatments are planned.