Biomedical subjects

Peter F Wright

Publications and source records attributed to Peter F Wright.

At least 37 records · Page 2Linked to original sources

PubMed2004

Role of IgA versus IgG in the control of influenza viral infection in the murine respiratory tract.

The roles of IgG and secretory IgA in the protection of the respiratory tract (RT) against influenza infection remain unclear. Passive immunization with Ab doses resulting in serum IgG anti-influenza virus Ab titers far in excess of those observed in immune mice has compounded the problem. We compared the effects of i.v. anti-influenza virus IgG and i.v. anti-influenza virus polymeric IgA (pIgA) mAb administered in amounts designed to replicate murine convalescent serum or nasal Ab titers, respectively. A serum anti-influenza virus IgG titer 2.5 times the normal convalescent serum anti-influenza virus IgG titer was required for detectible Ab transudation into nasal secretions, and a serum IgG titer 7 times normal was needed to lower nasal viral shedding by 98%. Anti-influenza virus pIgA at a nasal Ab titer comparable to that seen in convalescent mice eliminated nasal viral shedding. The RT of influenza-infected pIgA- or IgG-protected mice were studied by scanning electron microscopy. Only pIgA was found to prevent virally induced pathology in the upper RT, suggesting that IgG did not prevent viral infection of the nose, but neutralized newly replicated virus after infection had been initiated. In contrast, IgG, but not pIgA, was found to prevent viral pathology in the murine lung. Our results help to resolve the controversy of IgA- vs IgG-mediated protection of the RT; both Abs are important, with plasma IgG Ab serving as the back-up for secretory IgA-mediated protection in the nasal compartment, and IgG being the dominant Ab in protection of the lung.

Animals↗

PubMed2004

Challenges to conducting HIV preventative vaccine trials with adolescents.

It is estimated that 10.3 million people aged 15-24 are living with HIV infection/AIDS worldwide, with 7000 new infections occurring each day. Many of these infections occur during the adolescent years. These rates of infection make adolescents an important target for research in primary prevention. Currently, preparations are under way by the National Institutes of Health-supported HIV networks--the Adolescent Trials Network, the Pediatric AIDS Clinical Trials Group, and the HIV Vaccines Trials Network--for phase 1/2 HIV vaccine trials involving adolescents in the United States. Identifying the challenges to conducting HIV vaccine trials with this population is a crucial component of these preparations. Challenges to HIV vaccine trials with adolescents were identified by reviewing previous vaccine research for adolescents and HIV infection in adolescents and speaking with experts in HIV/AIDS and adolescent medicine. Adolescents (typically those younger than 18 years of age) are minors and fall under ethical and regulatory safeguards for their participation in clinical research including parental permission. Adolescents may not appropriately perceive personal risk, posing challenges for informed consent as well as prevention counseling during a trial. Safety and immunogenicity studies of adolescents are likely to be required by the US Food and Drug Administration before vaccine approval for this population. Early identification and subsequent follow-up of high-risk adolescents are problematic. Vaccine-induced seropositivity may present potential barriers to military service, employment, marriage, and acquiring health insurance. The age at optimal immunization, particularly for girls in some countries, may be during preadolescence. The successful completion of HIV vaccine trials with adolescents must address these challenges both in the United States and internationally. This report addresses relevant background information, identifies the issues surrounding HIV vaccine trials with adolescents, discusses what progress has been made, and addresses plans and implications for the implementation of these trials.

AIDS Vaccines↗

PubMed2004

Comparison of systemic and mucosal delivery of 2 canarypox virus vaccines expressing either HIV-1 genes or the gene for rabies virus G protein.

BACKGROUND: Since the primary routes of human immunodeficiency type 1 (HIV-1) infection are across mucosal barriers, a randomized trial of canarypox virus-based vectors was conducted in 84 individuals, with delivery of vaccine by mucosal routes, and was accompanied by a detailed analysis of humoral, cellular, and mucosal immune responses. METHODS: Over the course of 6 months, HIV-1-specific (vCP 205) and rabies (vCP 65) canarypox virus vectors were delivered systemically and/or mucosally into the nose, mouth, vagina, or rectum in a 4-dose schedule, followed by 2 doses of HIV-1 MN recombinant glycoprotein (rgp) 120 or subunit rabies vaccine administered by the intramuscular route. RESULTS: Administration of vaccine and collection of samples were well tolerated. Serum IgG HIV-1-specific antibodies to rgp120 were rarely seen after either systemic or mucosal delivery of canarypox virus vaccine. In contrast, serum IgG rabies and canarypox antibodies were detected in all individuals after systemic, but rarely after mucosal, delivery of vaccine. Suggestions of mucosal recognition of HIV-1 antigen included a cytotoxic T lymphocyte response in 4 of 8 individuals after administration of vaccine by the intrarectal route and a limited immunoglobulin A response at the same site. CONCLUSIONS: Each of the routes of vaccine administration was feasible in the context of a phase 1 study with motivated individuals. However, with the doses and routes of administration used, canarypox virus was not an effective mucosal immunogen.

AIDS Vaccines↗

PubMed2004

Circulating vaccine-derived polioviruses: current state of knowledge.

Within the past 4 years, poliomyelitis outbreaks associated with circulating vaccine-derived polioviruses (cVDPVs) have occurred in Hispaniola (2000-01), the Philippines (2001), and Madagascar (2001-02). Retrospective studies have also detected the circulation of endemic cVDPV in Egypt (1988-93) and the likely localized spread of oral poliovirus vaccine (OPV)-derived virus in Belarus (1965-66). Gaps in OPV coverage and the previous eradication of the corresponding serotype of indigenous wild poliovirus were the critical risk factors for all cVDPV outbreaks. The cVDPV outbreaks were stopped by mass immunization campaigns using OPV. To increase sensitivity for detecting vaccine-derived polioviruses (VDPVs), in 2001 the Global Polio Laboratory Network implemented additional testing requirements for all poliovirus isolates under investigation. This approach quickly led to the recognition of the Philippines and Madagascar cVDPV outbreaks, but of no other current outbreaks. The potential risk of cVDPV emergence has increased dramatically in recent years as wild poliovirus circulation has ceased in most of the world. The risk appears highest for the type 2 OPV strain because of its greater tendency to spread to contacts. The emergence of cVDPVs underscores the critical importance of eliminating the last pockets of wild poliovirus circulation, maintaining universally high levels of polio vaccine coverage, stopping OPV use as soon as it is safely possible to do so, and continuing sensitive poliovirus surveillance into the foreseeable future. Particular attention must be given to areas where the risks for wild poliovirus circulation have been highest, and where the highest rates of polio vaccine coverage must be maintained to suppress cVDPV emergence.

Child↗

PubMed2004

Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children.

BACKGROUND: We sought to determine the role of human metapneumovirus in lower respiratory tract illness in previously healthy infants and children. METHODS: We tested nasal-wash specimens, obtained over a 25-year period from otherwise healthy children presenting with acute respiratory tract illness, for human metapneumovirus. RESULTS: A viral cause other than human metapneumovirus was determined for 279 of 687 visits for acute lower respiratory tract illness (41 percent) by 463 children in a population of 2009 infants and children prospectively seen from 1976 to 2001. There were 408 visits for lower respiratory tract illness by 321 children for which no cause was identified. Of these 321 children, specimens from 248 were available. Forty-nine of these 248 specimens (20 percent) contained human metapneumovirus RNA or viable virus. Thus, 20 percent of all previously virus-negative lower respiratory tract illnesses were attributable to human metapneumovirus, which means that 12 percent of all lower respiratory tract illnesses in this cohort were most likely due to this virus. The mean age of human metapneumovirus-infected children was 11.6 months, the male:female ratio was 1.8:1, 78 percent of illnesses occurred between December and April, and the hospitalization rate was 2 percent. The virus was associated with bronchiolitis in 59 percent of cases, pneumonia in 8 percent, croup in 18 percent, and an exacerbation of asthma in 14 percent. We also detected human metapneumovirus in 15 percent of samples from 261 patients with upper respiratory tract infection but in only 1 of 86 samples from asymptomatic children. CONCLUSIONS: Human metapneumovirus infection is a leading cause of respiratory tract infection in the first years of life, with a spectrum of disease similar to that of respiratory syncytial virus.

Adolescent↗

PubMed2004

Phase 2 evaluation of parainfluenza type 3 cold passage mutant 45 live attenuated vaccine in healthy children 6-18 months old.

A phase 2 evaluation of live attenuated parainfluenza type 3 (PIV3)-cold passage mutant 45 (cp45) vaccine was conducted in 380 children 6-18 months old; 226 children (59%) were seronegative for PIV3. Of the 226 seronegative children, 114 received PIV3-cp45 vaccine, and 112 received placebo. No significant difference in the occurrence of adverse events (i.e., runny nose, cough, or temperature > or =38 degrees C) was noted during the 14 days after vaccination. There was no difference between groups in the occurrence of acute otitis media or serous otitis media. Paired serum samples were available for 109 of the seronegative vaccine recipients and for 110 of the seronegative placebo recipients; 84% of seronegative vaccine recipients developed a > or =4-fold increase in antibody titers. The geometric mean antibody titer after vaccination was 1 : 25 in the vaccine group and <1 : 4 in the placebo group. PIV3-cp45 vaccine was safe and immunogenic in seronegative children and should be evaluated for efficacy in a phase 3 field trial.

Acute Disease↗

PubMed2004

Do childhood vaccines have non-specific effects on mortality?

A recent article by Kristensen et al. suggested that measles vaccine and bacille Calmette-Gu rin (BCG) vaccine might reduce mortality beyond what is expected simply from protection against measles and tuberculosis. Previous reviews of the potential effects of childhood vaccines on mortality have not considered methodological features of reviewed studies. Methodological considerations play an especially important role in observational assessments, in which selection factors for vaccination may be difficult to ascertain. We reviewed 782 English language articles on vaccines and childhood mortality and found only a few whose design met the criteria for methodological rigor. The data reviewed suggest that measles vaccine delivers its promised reduction in mortality, but there is insufficient evidence to suggest a mortality benefit above that caused by its effect on measles disease and its sequelae. Our review of the available data in the literature reinforces how difficult answering these considerations has been and how important study design will be in determining the effect of specific vaccines on all-cause mortality.

Cause of Death↗

PubMed2004

Role of complement in neutralization of respiratory syncytial virus.

Serum neutralizing antibody titers to respiratory syncytial virus (RSV) are higher when assayed with guinea pig complement. A number of different mechanisms have been suggested for enhancement of neutralization by complement. The most straightforward is that complement-antibody complexes present a greater steric hindrance to viral entry than with antibody alone. To define the implications of measuring serum neutralizing antibody with and without complement, sera from adults, young children, infants, and cord bloods were run in plaque neutralization assays with representative viruses of the RSV A and B subgroups. Although titers of neutralizing antibody were higher in the presence of complement, the addition of complement did not increase the ability to detect antibody rises after natural infection. Some of the complement effect may be attributable to an inhibition of RSV replication by complement alone. While these observations do not address the role for complement in the pathogenesis of RSV infection, they suggest that neutralization assays performed without complement may be most reflective of physiologic conditions in the respiratory tract.

Adult↗

PubMed2004

Surveillance of childhood influenza virus infection: what is the best diagnostic method to use for archival samples?

Despite the clinical importance of influenza virus in pediatric respiratory infections, the optimal set of diagnostic tests to use when conducting studies using archival samples is not clear. In this study, we compared diagnostic tests for influenza virus in 75 children younger than 5 years of age who presented with symptomatic respiratory infection during one of four influenza seasons, had negative viral cultures for other respiratory pathogens, and had both an archival nasal aspirate obtained at the time of illness and serology spanning that influenza season. For all eligible children, we compared the results of viral culture performed at the time of collection with serology and PCR of archival nasal aspirates. Using real-time viral culture as the "gold standard," the test characteristics of PCR of archival nasal aspirates (sensitivity, 82%; specificity, 100%) and serology (sensitivity, 82%; specificity, 87%) were similar. The relatively low sensitivity of PCR of archival nasal samples in this study compared to that of PCR of fresh samples in a previous study suggests that RNA degradation occurred despite storage of the specimens at -70 degrees C. RNA degradation would also explain why only 11 (52%) of 21 archival nasal samples that had positive influenza virus cultures at the time of collection had positive repeat cultures in the summer of 2000. Thus, in archival specimens stored at -70 degrees C, PCR was more sensitive than viral culture. However, testing of fresh specimens had the highest yield in this study. Studies of optimal methods for specimen storage are needed.

Child, Preschool↗

PubMed2004

Signaling through the prostaglandin I2 receptor IP protects against respiratory syncytial virus-induced illness.

The role of prostanoids in modulating respiratory syncytial virus (RSV) infection is unknown. We found that RSV infection in mice increases production of prostaglandin I(2) (PGI(2)). Mice that overexpress PGI(2) synthase selectively in bronchial epithelium are protected against RSV-induced weight loss and have decreased peak viral replication and gamma interferon levels in the lung compared to nontransgenic littermates. In contrast, mice deficient in the PGI(2) receptor IP have exacerbated RSV-induced weight loss with delayed viral clearance and increased levels of gamma interferon in the lung compared to wild-type mice. These results suggest that signaling through IP has antiviral effects while protecting against RSV-induced illness and that PGI(2) is a potential therapeutic target in the treatment of RSV.

6-Ketoprostaglandin F1 alpha↗

PubMed2003

Oral epithelial cells are susceptible to cell-free and cell-associated HIV-1 infection in vitro.

Epithelial cells lining the oral cavity are exposed to HIV-1 through breast-feeding and oral-genital contact. Genital secretions and breast milk of HIV-1-infected subjects contain both cell-free and cell-associated virus. To determine if oral epithelial cells can be infected with HIV-1 we exposed gingival keratinocytes and adenoid epithelial cells to cell-free virus and HIV-1-infected peripheral blood mononuclear cells and monocytes. Using primary isolates we determined that gingival keratinocytes are susceptible to HIV-1 infection via cell-free CD4-independent infection only. R5 but not X4 viral strains were capable of infecting the keratinocytes. Further, infected cells were able to release infectious virus. In addition, primary epithelial cells isolated from adenoids were also susceptible to infection; both cell-free and cell-associated virus infected these cells. These data have potential implications in the transmission of HIV-1 in the oral cavity.

Adenoids↗

PubMed2003

A live human parainfluenza type 3 virus vaccine is attenuated and immunogenic in young infants.

BACKGROUND: Parainfluenza type 3 virus (PIV-3) infections cause lower respiratory tract illness in children throughout the world. A licensed PIV-3 vaccine is not yet available. METHODS: A live attenuated cold-adapted (ca) and temperature-sensitive (ts) PIV-3 vaccine, designated cp-45, was evaluated sequentially in open label studies in 20 adults and in placebo-controlled, double blind studies in 24 PIV-3-seropositive children, 52 PIV-3-seronegative infants and children and 49 infants 1 to 2 months old. A single dose of this intranasal vaccine was evaluated in adults [106 plaque-forming units (pfu)] and seropositive children, and 104 and 105 pfu were evaluated in seronegative children. In the infant study, two 104 pfu doses of vaccine were administered at 1- or 3-month intervals. Safety, infectivity, immunogenicity and phenotypic stability of the vaccine were evaluated in all cohorts. RESULTS: The cp-45 vaccine was well-tolerated in all age groups and infected 94% of vaccinated seronegative children and 94% of vaccinated infants. Although immunization with the first dose of cp-45 diminished the replication of a second dose in all infants, those immunized after 3 months shed vaccine virus more frequently than those immunized after 1 month (62% vs. 24%, respectively). Antibody responses to PIV-3 were readily detected in seronegative children with a variety of assays; however, the IgA response to the viral hemagglutinin-neuraminidase was the best measure of immunogenicity in young infants. Of 109 vaccine virus specimens recovered from nasal washes, 98 were ts and 11 were temperature-sensitive intermediate (tsi) viruses, with pinpoint plaques visible at 40 degrees C. tsi viruses appeared transiently at the time of peak viral replication, represented a very small proportion of the total virus shed and were not associated with changes in clinical status. ca revertants were not detected. CONCLUSIONS: The cp-45 vaccine is appropriately attenuated and immunogenic in infants as young as 1 month of age. Further development of this vaccine is warranted.

Age Factors↗

PubMed2003

Measurement of human cytomegalovirus loads by quantitative real-time PCR for monitoring clinical intervention in transplant recipients.

Quantitative monitoring of human cytomegalovirus (HCMV) infection is helpful in determining appropriate antiviral management of transplant recipients. Quantitative PCR technologies have demonstrated accuracy in measuring systemic HCMV loads. A total of 298 consecutive whole-blood specimens submitted to the Clinical Virology Laboratory at Vanderbilt University Medical Center from 15 February to 31 October 1999 were included in the study. In addition to a qualitative colorimetric microtiter plate PCR assay (MTP-PCR) and a semiquantitative pp65 antigenemia assay, each specimen was measured for HCMV loads by a quantitative PCR assay performed on an ABI PRISM 7700 Sequence Detection System (TaqMan). Compared to results of the MTP-PCR, the sensitivity, specificity, positive predictive value, and negative predictive value were 70.5, 97.5, 87.8, and 92.8% for the antigenemia assay and were 96.7, 92.0, 75.6, and 99.1% for the TaqMan assay, respectively. There was a high correlation between antigenemia values and HCMV loads as determined by the TaqMan (r = 0.989; P < 0.001). Antigenemia values of 0, 1 to 10, 11 to 100, 101 to 1,000, and over 1,000 positive cells per 2 x 10(5) leukocytes corresponded to median HCMV loads measured by TaqMan of 125, 1,593, 5,713, 16,825, and 5,425,000 copies/ml, respectively. Corresponding to antigenemia values of 1 to 2, 10, and 50 positive cells per 2 x 10(5) leukocytes, HCMV viral loads of 1,000, 4,000, and 10,000 copies/ml are proposed as cutoff points for initiating antiviral therapy in patient groups with high, intermediate, and low risk of CMV diseases.

Cytomegalovirus↗

PubMed2002

Detection of mucosal antibodies in HIV type 1-infected individuals.

HIV-1-specific mucosal IgA antibodies may correlate with protection in highly exposed but uninfected individuals, but have been detected at highly variable levels in HIV-1-infected individuals. To determine the best assays for detection of IgA antibodies in mucosal samples, rectal washes from 16 HIV-1-infected and 14 uninfected individuals were distributed to six laboratories experienced in detection of mucosal antibodies. Assays for HIV-1-specific IgA and IgG were performed in a blinded fashion by each of the laboratories using modifications of ELISA and chemiluminescence-enhanced Western blotting. Rectal washes contained easily detectable total IgA levels that did not differ between HIV-1-infected and uninfected groups. Irrespective of the assay used, HIV-1-specific IgA antibodies were absent in most samples; only one laboratory identified a higher frequency of positive samples from HIV-1-infected than uninfected individuals. In spite of 10-fold lower levels of total IgG than IgA, all but one laboratory identified HIV-1-specific IgG in most rectal washes of HIV-1-infected individuals. Comparable and readily detectable levels of influenza-specific IgA antibodies were present in nasal, salivary, and rectal secretions from both HIV-1-infected and uninfected individuals. These observations suggest a selective alteration in the production of HIV-1-specific IgA antibodies in HIV-1-infected individuals.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Winter viruses: influenza- and respiratory syncytial virus-related morbidity in chronic lung disease.

BACKGROUND: Chronic lung disease predisposes to serious consequences of respiratory viruses. While increasing influenza immunization rates in older adults signals an awareness of the impact of influenza, children with asthma are infrequently immunized. While respiratory syncytial virus (RSV) is recognized as an important target of vaccine development for infants, its impact on adults is underappreciated. METHODS: We performed a retrospective cohort study to estimate rates of hospitalizations, deaths, outpatient visits, and antibiotic courses due to influenza and RSV in persons with chronic lung disease in the Tennessee Medicaid program from 1995 to 1999. Differences between study event rates when influenza was cocirculating with RSV and event rates when RSV was circulating alone were used to calculate influenza-attributable morbidity. Differences in rates when RSV was circulating alone and during summer months were calculated to assess the effect of RSV. RESULTS: Influenza- and RSV-associated hospitalizations were highest at the extremes of age. There were an estimated 8 and 23 hospitalizations per 1000 children younger than 5 years annually due to influenza and RSV, respectively. There were 23 and 18 hospitalizations, as well as 2 and 5 deaths per 1000 persons 65 years or older annually due to influenza and RSV, respectively. Both viruses were associated with an excess of outpatient visits in children, and antibiotic prescriptions in all age groups. CONCLUSION: Among persons with chronic lung disease, influenza virus and RSV accounted for 15% to 33% of acute respiratory hospitalizations in children, 7% to 9% of such hospitalizations in adults, and 9% of deaths in those 65 years or older.

Adolescent↗

PubMed2002

Illness severity, viral shedding, and antibody responses in infants hospitalized with bronchiolitis caused by respiratory syncytial virus.

The relationships between host factors, viral shedding, illness severity, and antibody response in respiratory syncytial virus (RSV)-induced bronchiolitis are poorly defined. These relationships were prospectively evaluated in 77 infants hospitalized with RSV bronchiolitis in multicenter, double-blind, placebo-controlled trials of RSV immunoglobulin therapy. Severity of illness was influenced by age and host risk factors but was not influenced by RSV neutralizing antibody titer or by the amount of virus in nasal secretions at enrollment. Virus recovery in nasal secretions was variable but was highest at enrollment. Viral shedding was not influenced by primary diagnosis, antibody titer, age, or duration of acute respiratory illness before enrollment. In intubated patients, the amounts of virus recovered in nasal secretions and endotracheal aspirates were highly correlated. A serum neutralizing antibody response was seen in 64% of subjects who received placebo. The response was not influenced by age, primary diagnosis, amount of virus recovered, or severity of illness but was suppressed by preexisting antibody.

Adolescent↗

PubMed2002

Thermostabilization of egg grown influenza viruses.

The observation that the addition of deuterium oxide to tissue culture cell harvests stabilized trivalent oral poliovirus vaccine prompted us to examine the effect of deuterium oxide on stabilization of other licensed and experimental live viral vaccines. The most striking effect afforded by deuterium oxide was on stabilization of live, attenuated influenza A and B vaccine candidates grown in the allantoic cavity of embryonated eggs. Thermostabilization with deuterium oxide is much greater than seen with standard stabilization of these live influenza vaccines with sucrose-phosphate-glutamate. Subsequently, we have shown that a similar, stabilization is provided by diluting egg allantoic fluid in water or minimal essential medium. The mechanism of action has been explored but remains uncertain. The implications of being able to stabilize influenza after harvesting from eggs have practical application for utilization of live influenza vaccines and provides a possible way to increase and standardize the potency of inactivated vaccines that may partially degrade in the inimical environment of allantoic fluid during growth and before final vaccine purification and stabilization.

Allantois↗

PubMed2002

Cold-adapted influenza vaccines.

Because of the health impact of complicated disease from influenza in children, the role played by children in spreading influenza, and the limitations of inactivated influenza vaccine in this population, there has been ongoing effort to identify a more effective and acceptable vaccine. This review will focus on the development, limitations, and potential of a leading candidate vaccine studied in children. This is a live, attenuated, intranasally administered cold-adapted influenza vaccine.

Administration, Intranasal↗