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Biomedical subjects

Robert C Brunham

Publications and source records attributed to Robert C Brunham.

At least 19 recordsLinked to original sources
PubMed2007

Protective measures and human antibody response during an avian influenza H7N3 outbreak in poultry in British Columbia, Canada.

BACKGROUND: In 2004 an outbreak of avian influenza of the H7N3 subtype occurred among poultry in British Columbia, Canada. We report compliance with recommended protective measures and associated human infections during this outbreak. METHODS: We sought voluntary participation by anyone (cullers, farmers and their families) involved in efforts to control the poultry outbreak. Recruitment was by advertisements at the worker deployment site, in local media and through newsletters sent directly to farmers. Sera were tested for antibody to H7N3 by microneutralization assay. A subset of 16 sera (including convalescent sera from 2 unprotected workers with conjunctivitis from whom virus had been isolated) was further tested by Western blot and routine and modified hemagglutination inhibition assays. RESULTS: A total of 167 people (20% to 25% of all workers) participated between May 7 and July 26, 2004. Of these, 19 had experienced influenza-like illness and 21 had experienced red or watery eyes. There was no significant association between illness reports and exposure to infected birds. Among 65 people who entered barns with infected birds, 55 (85%) had received influenza vaccine, 48 (74%) had received oseltamivir, and 55 (85%), 54 (83%) and 36 (55%) reported always wearing gloves, mask or goggles, respectively. Antibody to the H7 subtype was not detected in any sera. INTERPRETATION: During the BC outbreak, compliance with recommended protective measures, especially goggles, was incomplete. Multiple back-up precautions, including oseltamivir prophylaxis, may prevent human infections and should be readily accessible and consistently used by those involved in the control of future outbreaks of avian influenza in poultry. Localized human avian influenza infections may not result in serologic response despite confirmed viral detection and culture.

Adolescent↗
PubMed2006

Genetic profiling of dendritic cells exposed to live- or ultraviolet-irradiated Chlamydia muridarum reveals marked differences in CXC chemokine profiles.

Chlamydia trachomatis is a major cause of sexually transmitted disease worldwide for which an effective vaccine is being actively pursued. Current vaccine efforts will be aided by elucidating the interaction between Chlamydia and dendritic cells (DCs). Protective immunity appears to develop slowly following natural infection in humans, and early vaccine trials using inactivated C. trachomatis resulted in partial, short-lived protection with possible enhanced inflammatory pathology during re-infection. Thus, immunity following natural infection with live chlamydia may differ fundamentally from immune responses induced by immunization with inactivated chlamydia. We explored this conjecture by studying the response of DCs exposed to either viable or inactivated [ultraviolet (UV) -irradiated] chlamydia elementary bodies (EBs; designated as Live-EB and UV-EB, respectively) using Affymetrix GeneChip microarrays. Thirty-one immunologically characterized genes were differentially expressed by DCs following exposure to Live-EB or UV-EB, including two glutamic acid-leucine-arginine cysteine-X-cysteine (ELR CXC) neutrophil chemoattractant chemokines, Cxcl1 (KC), and Cxcl2 (MIP-2). Up-regulation of these genes by Live-EB as compared to UV-EB was verified by quantitative reverse transcription-polymerase chain reaction and increased chemokine secretion was confirmed by enzyme-linked immunosorbent assay both in vitro and in vivo. Immunofluorescence and fluorescence-activated cell sorter analysis of chlamydia-infected lung tissue confirmed that Live-EB but not UV-EB induced significant DC and neutrophil infiltration during infection. These observations demonstrate that the development of an antichlamydial immune response is dramatically influenced by chlamydial viability. This has implications as to why early inactivated chlamydial vaccines were ineffective and suggests that new vaccine design efforts may benefit from in vitro DC screening for ELR chemokine expression profiles.

Animals↗
PubMed2006

Immunogenicity of a receptor-binding domain of SARS coronavirus spike protein in mice: implications for a subunit vaccine.

We studied the immunogenicity of an anti-SARS subunit vaccine comprised of the fragment of the SARS coronavirus (SARS-CoV) spike protein amino acids 318-510 (S318-510) containing the receptor-binding domain. The S protein fragment was purified from the culture supernatant of stably transformed HEK293T cells secreting a tagged version of the protein. The vaccine was given subcutaneously to 129S6/SvEv mice in saline, with alum adjuvant or with alum plus CpG oligodeoxynucleotides (ODN). Mice immunized with the adjuvanted antigen elicited strong antibody and cellular immune responses; furthermore, adding the CpG ODN to the alum resulted in increased IgG2a antibody titers and a higher number of INF-gamma-secreting murine splenocytes. Mice vaccinated with S318-510 deglycosylated by PNGase F (dgS318-510) showed a lower neutralizing antibody response but had similar numbers of INF-gamma-producing cells in the spleen. This finding suggests that carbohydrate is important for the immunogenicity of the S318-510 protein fragment and provide useful information for designing an effective and safe SARS subunit vaccine.

Alum Compounds↗
PubMed2006

Potential cost-effectiveness of annual influenza immunization for infants and toddlers: experience from Canada.

BACKGROUND: In 2004, expert groups in North America recommended annual influenza immunization for healthy infants and toddlers aged 6-23 months with a goal of reducing high hospitalization rates (HR). We assess cost-effectiveness of this program in Canada. METHODS: Analysis was from third-party payer and societal perspectives in preventing hospitalization and other outcomes among 500,000 vaccinated or non-vaccinated infants/toddlers. Base-case assumptions include: 25% attack rate (AR), 1% case hospitalization rate (HR), 0.002% case fatality, vaccine effectiveness (VE) of 66%, CDN dollar 15 per dose for vaccine and administration, half of mothers requiring 2h from work per dose to immunize and two doses required by 100% (first year) or 33% (subsequent years) of infants/toddlers immunized. RESULTS: After the first year, infant/toddler influenza immunization costs the third-party approximately CDN dollar 9 per day of illness averted, CDN dollar 120 per physician visit averted, CDN dollar 7000 per hospitalization averted, CDN dollar 3 million per death averted and CDN dollar 450,000 per life year gained. Corresponding costs from societal perspective are approximately CDN dollar 3, CDN dollar 45, CDN dollar 2500, CDN dollar 1 million and CDN dollar 170,000. The program becomes cost-saving from the third-party perspective at AR>55%, HR>4%, or cost per dose (for vaccine and its administration) 74%. CONCLUSIONS: In the base case, infant/toddler influenza immunization is not cost-saving but could become more cost-effective in settings of higher attack rate and lower immunization cost. In this context, immunization of children in daycare or other group settings should be preferentially considered. Economic analyses should routinely inform expansions to influenza immunization programs.

Canada↗
PubMed2006

Comparative evaluation of two severe acute respiratory syndrome (SARS) vaccine candidates in mice challenged with SARS coronavirus.

Two different severe acute respiratory syndrome (SARS) vaccine strategies were evaluated for their ability to protect against live SARS coronavirus (CoV) challenge in a murine model of infection. A whole killed (inactivated by beta-propiolactone) SARS-CoV vaccine and a combination of two adenovirus-based vectors, one expressing the nucleocapsid (N) and the other expressing the spike (S) protein (collectively designated Ad S/N), were evaluated for the induction of serum neutralizing antibodies and cellular immune responses and their ability to protect against pulmonary SARS-CoV replication. The whole killed virus (WKV) vaccine given subcutaneously to 129S6/SvEv mice was more effective than the Ad S/N vaccine administered either intranasally or intramuscularly in inhibiting SARS-CoV replication in the murine respiratory tract. This protective ability of the WKV vaccine correlated with the induction of high serum neutralizing-antibody titres, but not with cellular immune responses as measured by gamma interferon secretion by mouse splenocytes. Titres of serum neutralizing antibodies induced by the Ad S/N vaccine administered intranasally or intramuscularly were significantly lower than those induced by the WKV vaccine. However, Ad S/N administered intranasally, but not intramuscularly, significantly limited SARS-CoV replication in the lungs. Among the vaccine groups, SARS-CoV-specific IgA was found only in the sera of mice immunized intranasally with Ad S/N, suggesting that mucosal immunity may play a role in protection for the intranasal Ad S/N delivery system. Finally, the sera of vaccinated mice contained antibodies to S, further suggesting a role for this protein in conferring protective immunity against SARS-CoV infection.

Administration, Intranasal↗
PubMed2006

Longitudinal analysis of genotype distribution of influenza A virus from 2003 to 2005.

Influenza A viruses cause yearly epidemics, in part, due to their ability to overcome immunity from previous infections through acquisition of mutations. Amino acid sequences encoded by genes 4 (HA), 6 (NA), 7 (M), and 8 (NS) from 77 H3N2 influenza A isolates, collected between November 2003 and March 2005, were analyzed to determine the extent to which the viruses mutated within epidemic periods and between the epidemics. Nucleotide and amino acid sequences were stable throughout the epidemics but experienced substantial changes between epidemics. Major changes occurred in the HA gene in 5 to 7 amino acids and the NA gene in 11 to 13 amino acids and changes of 5 amino acids occurred in the M and NS genes. In the HA gene, changes occurred in sites known to be epitopes that determine the hemagglutination inhibition reactivity, and these were shown to be associated with a change of strain from A/Fujian/411/2002-like to A/California/7/2004-like viruses. Our findings indicate that genotype determination promises to be a rapid approach for detecting new strains of influenza A viruses in a population.

Amino Acid Sequence↗
PubMed2006

Coordinated response to SARS, Vancouver, Canada.

Two Canadian urban areas received travelers with severe acute respiratory syndrome (SARS) before the World Health Organization issued its alert. By July 2003, Vancouver had identified 5 cases (4 imported); Toronto reported 247 cases (3 imported) and 43 deaths. Baseline preparedness for pandemic threats may account for the absence of sustained transmission and fewer cases of SARS in Vancouver.

Adult↗
PubMed2005

The unexpected impact of a Chlamydia trachomatis infection control program on susceptibility to reinfection.

BACKGROUND: After the introduction of a program to control Chlamydia trachomatis infection in British Columbia, Canada, case rates fell from 216 cases/100,000 population in 1991 to 104 cases/100,000 population in 1997. Since 1998, rates have increased, and case counts now exceed those recorded before the intervention. METHODS: We used Cox proportional-hazards survival analysis and developed a compartmental mathematical model to investigate the cause of resurgence in chlamydia cases. RESULTS: Cox proportional-hazards survival analysis showed that the relative risk of C. trachomatis reinfection has increased 4.6% per year since 1989, with the increased risk greatest among the young and greater among women than men. A compartmental mathematical model of C. trachomatis transmission showed that a control strategy based on shortening the average duration of infection results in an early reduction in prevalence followed by a rebound in prevalence, reproducing the observed trends. CONCLUSIONS: We speculate that a C. trachomatis infection control program based on early case identification and treatment interferes with the effects of immunity on population susceptibility to infection and that, in the absence of strategies to alter sexual networks, a vaccine will be needed to halt the spread of infection at the population level.

Adolescent↗
PubMed2005

Sexually transmitted disease thresholds in Manitoba, Canada.

PURPOSE: Persistence of sexually transmitted infections (STI) in a population is due to the activities of a small proportion of the population with STI, who transmit infection on average to one or more susceptible sex partners during an infectious period. Within these groups, the average number of transmissions by infectious people to susceptible people in a closed group is measured by the reproductive number; a threshold, above which endemic infection is likely occur and below which, in the rest of the population, it is unlikely to occur. We hypothesized that people with repeated bacterial STI's and their sex partners include the theoretical core group and that they differ from singly infected noncore individuals. METHODS: Data on infected individuals and nominated sex partners for the years 1990-1992 were extracted from the notifiable disease and health insurance registries in Manitoba, Canada. Individuals with repeated gonorrhea, chlamydia and coinfected infections were compared using logistic regression, and reproductive numbers were calculated using sex partner data. RESULTS: Of the three groups, the coinfected were youngest, and they were largely of aboriginal descent and had the lowest incomes. Repeaters were older; they had higher incomes, and there were fewer aboriginal people in this group. Chlamydia repeaters had even higher incomes, and this group comprised the least number of aboriginal people. The reproductive numbers showed the same gradient; (1.09, 1.01, and 2.41, respectively.) CONCLUSIONS: These data show that these groups do not contribute equally to STI endemicity and indicate that sexual network structure affects epidemic thresholds.

Adult↗
PubMed2005

Immunoepidemiologic profile of Chlamydia trachomatis infection: importance of heat-shock protein 60 and interferon- gamma.

Epidemiological, animal, and in vitro investigations suggest that Chlamydia trachomatis infection engenders acquired immunity, the basis for which is incompletely defined, especially in humans. In a prospective cohort study of women at high risk for C. trachomatis infection, we found that, at baseline and after adjustment for age and other potential confounding variables, production of interferon- gamma by peripheral-blood mononuclear cells (PBMCs) stimulated with chlamydia heat-shock protein 60 strongly correlated with protection against incident C. trachomatis infection. This investigation supports a direct role for C. trachomatis-specific immune responses in altering the risk of infection and suggests immune correlates of protection that are potentially useful in vaccine development.

Adolescent↗
PubMed2005

Effect of immune response on transmission dynamics for sexually transmitted infections.

Transmission dynamics for sexually transmitted infections (STIs) exhibit a large degree of heterogeneity, much of which has been attributed to behavioral variability. However, because STI transmission concentrates among individuals who frequently change sex partners, immune responses also are likely to contribute to the heterogeneity in STI transmission dynamics. We review both theoretical and experimental data on the effects of immunity on STI transmission dynamics. We conclude that research should be directed more intensively toward the characterization of sexual network structures, together with qualitative and quantitative analyses of the immune responses of individuals who are identifiable within the network structure itself. Elucidation of the immunobiological and behavioral factors that shape STI transmission should inform better STI prevention and control programs.

Contact Tracing↗
PubMed2005

Network theory and SARS: predicting outbreak diversity.

Many infectious diseases spread through populations via the networks formed by physical contacts among individuals. The patterns of these contacts tend to be highly heterogeneous. Traditional "compartmental" modeling in epidemiology, however, assumes that population groups are fully mixed, that is, every individual has an equal chance of spreading the disease to every other. Applications of compartmental models to Severe Acute Respiratory Syndrome (SARS) resulted in estimates of the fundamental quantity called the basic reproductive number R0--the number of new cases of SARS resulting from a single initial case--above one, implying that, without public health intervention, most outbreaks should spark large-scale epidemics. Here we compare these predictions to the early epidemiology of SARS. We apply the methods of contact network epidemiology to illustrate that for a single value of R0, any two outbreaks, even in the same setting, may have very different epidemiological outcomes. We offer quantitative insight into the heterogeneity of SARS outbreaks worldwide, and illustrate the utility of this approach for assessing public health strategies.

Adult↗
PubMed2005

Immunology of Chlamydia infection: implications for a Chlamydia trachomatis vaccine.

Sexually transmitted Chlamydia trachomatis infections are a serious public-health problem. With more than 90 million new cases occurring annually, C. trachomatis is the most common cause of bacterial sexually transmitted disease worldwide. Recent progress in elucidating the immunobiology of Chlamydia muridarum infection of mice has helped to guide the interpretation of immunological findings in studies of human C. trachomatis infection and has led to the development of a common model of immunity. In this review, we describe our current understanding of the immune response to infection with Chlamydia spp. and how this information is improving the prospects for development of a vaccine against infection with C. trachomatis.

Animals↗
PubMed2005

A live and inactivated Chlamydia trachomatis mouse pneumonitis strain induces the maturation of dendritic cells that are phenotypically and immunologically distinct.

The intracellular bacterial pathogen Chlamydia trachomatis is a major cause of sexually transmitted disease worldwide. While protective immunity does appear to develop following natural chlamydial infection in humans, early vaccine trials using heat-killed C. trachomatis resulted in limited and transient protection with possible enhanced disease during follow-up. Thus, immunity following natural infection with live chlamydia may differ from immune responses induced by immunization with inactivated chlamydia. To study this differing immunology, we used murine bone marrow-derived dendritic cells (DC) to examine DC maturation and immune effector function induced by live and UV-irradiated C. trachomatis elementary bodies (live EBs and UV-EB, respectively). DC exposed to live EBs acquired a mature DC morphology; expressed high levels of major histocompatibility complex (MHC) class II, CD80, CD86, CD40, and ICAM-1; produced elevated amounts of interleukin-12 and tumor necrosis factor alpha; and were efficiently recognized by Chlamydia-specific CD4+ T cells. In contrast, UV-EB-pulsed DC expressed low levels of CD40 and CD86 but displayed high levels of MHC class II, ICAM-1, and CD80; secreted low levels of proinflammatory cytokines; and exhibited reduced recognition by Chlamydia-specific CD4+ T cells. Adoptive transfer of live EB-pulsed DC was more effective than that of UV-EB-pulsed DC at protecting mice against challenge with live C. trachomatis. The expression of DC maturation markers and immune protection induced by UV-EB could be significantly enhanced by costimulation of DC ex vivo with UV-EB and oligodeoxynucleotides containing cytosine phosphate guanosine; however, the level of protection was significantly less than that achieved by using DC pulsed ex vivo with viable EBs. Thus, exposure of DC to live EBs results in a mature DC phenotype which is able to promote protective immunity, while exposure to UV-EB generates a semimature DC phenotype with less protective potential. This result may explain in part the differences in protective immunity induced by natural infection and immunization with whole inactivated organisms and is relevant to rational chlamydia vaccine design strategies.

Adoptive Transfer↗
PubMed2005

Severe acute respiratory syndrome (SARS): a year in review.

Severe acute respiratory syndrome (SARS) emerged from China as an untreatable and rapidly spreading respiratory illness of unknown etiology. Following point source exposure in February 2003, more than a dozen guests infected at a Hong Kong hotel seeded multi-country outbreaks that persisted through the spring of 2003. The World Health Organization responded by invoking traditional public health measures and advanced technologies to control the illness and contain the cause. A novel coronavirus was implicated and its entire genome was sequenced by mid-April 2003. The urgency of responding to this threat focused scientific endeavor and stimulated global collaboration. Through real-time application of accumulating knowledge, the world proved capable of arresting the first pandemic threat of the twenty-first century, despite early respiratory-borne spread and global susceptibility. This review synthesizes lessons learned from this remarkable achievement. These lessons can be applied to re-emergence of SARS or to the next pandemic threat to arise.

Anti-Inflammatory Agents↗
PubMed2005

Modeling control strategies of respiratory pathogens.

Effectively controlling infectious diseases requires quantitative comparisons of quarantine, infection control precautions, case identification and isolation, and immunization interventions. We used contact network epidemiology to predict the effect of various control policies for a mildly contagious disease, such as severe acute respiratory syndrome, and a moderately contagious disease, such as smallpox. The success of an intervention depends on the transmissibility of the disease and the contact pattern between persons within a community. The model predicts that use of face masks and general vaccination will only moderately affect the spread of mildly contagious diseases. In contrast, quarantine and ring vaccination can prevent the spread of a wide spectrum of diseases. Contact network epidemiology can provide valuable quantitative input to public health decisionmaking, even before a pathogen is well characterized.

British Columbia↗
PubMed2004

Structural characterization of genomes by large scale sequence-structure threading: application of reliability analysis in structural genomics.

BACKGROUND: We establish that the occurrence of protein folds among genomes can be accurately described with a Weibull function. Systems which exhibit Weibull character can be interpreted with reliability theory commonly used in engineering analysis. For instance, Weibull distributions are widely used in reliability, maintainability and safety work to model time-to-failure of mechanical devices, mechanisms, building constructions and equipment. RESULTS: We have found that the Weibull function describes protein fold distribution within and among genomes more accurately than conventional power functions which have been used in a number of structural genomic studies reported to date. It has also been found that the Weibull reliability parameter beta for protein fold distributions varies between genomes and may reflect differences in rates of gene duplication in evolutionary history of organisms. CONCLUSIONS: The results of this work demonstrate that reliability analysis can provide useful insights and testable predictions in the fields of comparative and structural genomics.

Computational Biology↗