Thomas G. Boyce

Evaluation of a Live, Cold-Passaged, Temperature-Sensitive, Respiratory Syncytial Virus Vaccine Candidate in Infancy

A live-attenuated, intranasal respiratory syncytial virus (RSV) candidate vaccine, cpts-248/404, was tested in phase 1 trials in 114 children, including 37 1-2-month-old infants-a target age for RSV vaccines. The cpts-248/404 vaccine was infectious at 104 and 105 plaque-forming units in RSV-naive children and was broadly immunogenic in children >6 months old. Serum and nasal antibody responses in 1-2 month olds were restricted to IgA, had a dominant response to RSV G protein, and had no increase in neutralizing activity. Nevertheless, there was restricted virus shedding on challenge with a second vaccine dose and preliminary evidence for protection from symptomatic disease on natural reexposure. The cpts-248/404 vaccine candidate did not cause fever or lower respiratory tract illness. In the youngest infants, however, cpts-248/404 was unacceptable because of upper respiratory tract congestion associated with peak virus recovery. A live attenuated RSV vaccine for the youngest infant will use cpts-248/404 modified by additional attenuating mutations.

Mucosal immune response to trivalent live attenuated intranasal influenza vaccine in children.

Intranasal trivalent, cold-adapted, live attenuated influenza vaccine (CAIV-T) is a promising alternative to inactivated vaccine for protection against influenza in children. However, correlates of immunity are not well defined. To determine the mucosal immune response to CAIV-T, 19 children ages 15–55 months were randomized to receive two doses of CAIV-T or placebo. Influenza-specific IgA to the haemagglutinin of each of three contemporary strains was measured in nasal washes collected pre- and postvaccination using a kinetic enzyme-linked immunosorbent assay. After two doses of study drug, 62, 69 and 85% of CAIV-T recipients demonstrated a mucosal IgA response to influenza A/H1N1, A/H3N2, and B strains respectively; in comparison, 33, 0 and 17% of placebo recipients demonstrated an IgA response to the same strains (p=0.35, 0.01 and 0.01). Overall, seropositive vaccinees were 4.5 times more likely to develop a mucosal immune response than an HAI response (p=0.015). Two doses of CAIV-T induce a mucosal IgA response to all three influenza vaccine antigens in the majority of children. In addition, a mucosal antibody response may be the only indication of a vaccine take in a seropositive child.

Incidence and Temporal Trends of Primary Immunodeficiency: A Population-Based Cohort Study

OBJECTIVE: To determine the incidence and temporal trends of primary immunodeficiency diseases (PIDs) and examine whether an association exists between delayed diagnosis and increased morbidity. PATIENTS AND METHODS: We performed a historical cohort study to describe the epidemiology of PIDs in Olmsted County, Minnesota, during a 31-year period from January 1, 1976, through December 31, 2006, using the Rochester Epidemiology Project. Incidence and trends over time, presence of comorbid conditions, and trends in management were determined. RESULTS: During the 31-year study period, 158 new cases of PIDs were diagnosed, with an overall incidence rate of 4.6 per 100,000 person-years. The rate of PIDs from 2001 through 2006 (10.3 per 100,000 person-years) was nearly 5 times higher than that from 1976 through 1980 (2.4 per 100,000 person-years). The associations between continuous variable(s) and categorical outcome(s) were assessed by using the Wilcoxon rank sum test. Longer delay in diagnosis was significantly associated with recurrent sinusitis (P<.001), recurrent pneumonia (P=.03), and subsequent treatment with immunoglobulins (P<.001). On the basis of Kaplan-Meier survival estimates, the proportion of patients surviving at 10 years after diagnosis was 93.5% (95% confidence interval, 85.9%-97.1%). However, older age at diagnosis was significantly associated with mortality (P=.01). CONCLUSION: This is one of the first population-based studies to examine the temporal trends of PIDs. The incidence of PIDs increased markedly between 1976 and 2006. In this cohort, a delay in diagnosis was common and was associated with increased morbidity. Despite substantial morbidity, most patients with PIDs can expect a normal life span.

Safety and immunogenicity of adjuvanted and unadjuvanted subunit influenza vaccines administered intranasally to healthy adults

Antigen-specific mucosal immunity is thought to be important for protection against influenza virus infection. Currently licensed parenteral influenza vaccines stimulate the production of serum antibodies, but are poor inducers of mucosal immunity. The adjuvant MF59 has been shown to enhance the humoral immune response to parenteral influenza vaccine in humans and the mucosal immune response to intranasally-administered influenza vaccine in mice. We conducted an open-label safety study followed by an observer-blind, randomized trial comparing the immune response to intranasally-administered subunit influenza vaccine adjuvanted with MF59, unadjuvanted subunit influenza vaccine, and placebo. Adverse reactions did not occur significantly more frequently in vaccinees than placebo recipients. Of 31 subjects receiving 2 doses of MF59-adjuvanted influenza vaccine, 19 (61%), 8 (26%), and 11 (35%) developed a mucosal IgA response to influenza A/H1N1, A/H3N2, and B, respectively. The percentage of subjects with a serum antibody response was slightly lower. The immune responses to adjuvanted vaccine were not significantly different from those to unadjuvanted vaccine. Both vaccines gave more frequent responses than seen in placebo recipients, indicating the potential of intranasal inactivated vaccines to stimulate local IgA responses.

Increased risk of serious pneumococcal disease in patients with atopic conditions other than asthma

BACKGROUND We reported an increased risk of serious pneumococcal disease (SPD) among patients with asthma. It is not known whether this is true for patients with other atopic conditions. OBJECTIVE To determine the relationship between atopic conditions other than asthma and SPD. METHODS The study subjects were residents of Rochester, Minn, who developed SPD between 1964 and 1983 and their 2 sex-matched and age-matched controls. We used a population-based computer-linked medical diagnosis system to identify all individuals with potential SPD. All records were reviewed by using explicit predetermined criteria for SPD. All individuals with atopic conditions were identified by the physician diagnoses including atopic dermatitis or eczema, allergic rhinitis, and hay fever documented in medical records. The associations between these atopic conditions and SPD were assessed by using conditional logistic regression. RESULTS A total of 3941 records were reviewed, and we identified 174 SPD cases. Of these 174 cases, 50.6% were male, and 94.3% were Caucasian. Twenty-six (14.9%) of the SPD cases and 29 (8.3%) of the controls had atopy. Atopic conditions other than asthma were associated with an increased risk of SPD (odds ratio, 2.13; 95% CI, 1.04-4.35; P = .04) after adjusting for smoking status, previous high-risk conditions for SPD, educational status, and ethnicity. CONCLUSION Like asthma, other atopic conditions, particularly atopic dermatitis, are associated with an increased risk of SPD. There may be a common immunogenetic mechanism underlying increased risk of SPD among individuals with either asthma or other atopic conditions. Our study findings need to be studied further.

Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency

Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-α or anti-IFN-ω antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1S723C/S723C mice, which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations.

Flu Myths: Dispelling the Myths Associated With Live Attenuated Influenza Vaccine

Live attenuated influenza vaccine (LAIV), commercially available since 2003, has not gained widespread acceptance among prescribers. This underuse can be traced to several misperceptions and fears regarding LAIV. This review examines both the facts (safety, immunogenicity, and effectiveness) and the most pervasive myths about LAIV. Live attenuated influenza vaccine is a safe, highly immunogenic, and effective vaccine. It is well tolerated; only mild and transient upper respiratory infection symptoms occur with LAIV vs placebo, even in higher-risk patients with asthma or the early stages of human immunodeficiency virus. It is immunogenic, especially in induction of mucosal immunity. In certain populations, LAIV is as effective as, and in some cases more effective than, inactivated influenza in preventing influenza infection. It appears to be more effective in preventing influenza infection than trivalent inactivated influenza vaccine when the vaccine virus strain does not closely match that of the circulating wild-type virus. Many myths and misperceptions about the vaccine exist, foremost among them the myth of genetic reversion. Independent mutation in 4 gene segments would be required for reversion of the vaccine strain of influenza virus to a wild type, an unlikely and as yet unobserved event. Although shedding of vaccine virus is common, transmission of vaccine virus has been documented only in a single person, who remained asymptomatic. In the age groups for which it is indicated, LAIV is a safe and effective vaccine to prevent influenza infection.

Increased risk of pertussis in patients with asthma

BACKGROUND The recent pertussis outbreak in California highlights the effect of pertussis on public health. In 2004, a pertussis outbreak occurred in Olmsted County, Minnesota, despite a high vaccine uptake. This outbreak provided a natural experiment to assess the relationship between asthma and pertussis. OBJECTIVE We sought to determine whether asthmatic subjects have a higher risk of pertussis than nonasthmatic subjects. METHODS We conducted a population-based case-control study. There were 223 pertussis cases identified by means of PCR in 2004 and 2005. We identified age- and sex-matched control subjects from 5537 patients with negative test results for pertussis. We conducted a comprehensive medical record review and applied predetermined criteria to ascertain asthma status. Conditional logistic regression was fit to assess the effect of asthma status on the risk of pertussis. RESULTS Of the 223 subjects, 164 were eligible for the study, and 328 matched control subjects (1:2 matching) were enrolled. Of these 164 subjects, 50% were male, and 82% were white. The median age at the index date of pertussis was 14 years. Sixty-two (38%) of the 164 cases had asthma before the index date of pertussis compared with 85 (26%) of the 328 control subjects (odds ratio, 1.73; 95% CI, 1.12-2.67; P = 013). The population attributable risk percentage of asthma for risk of pertussis was 17%. CONCLUSIONS Given the high prevalence of asthma and the ongoing risk of pertussis throughout the United States, consideration of defining asthmatic subjects as a target group for pertussis vaccination (eg, replacing decennial tetanus-diphtheria booster with tetanus, diphtheria, and acellular pertussis vaccine for adolescents and adults) should be given.

Prevalence and clinical significance of human herpesviruses 6 and 7 active infection in pediatric liver transplant patients

Abstract:  Recent studies in adult liver transplant patients have suggested that both human herpesvirus (HHV)‐6 and HHV‐7 infection are important causes of morbidity following liver transplantation. However, the impact of HHV‐6 and ‐7 infection in pediatric liver transplant patients remains largely unknown. The aims were to determine the prevalence of HHV‐6 and ‐7 infection in pediatric liver transplant patients and to determine whether there is an association between HHV‐6 and ‐7 infection with episodes of graft rejection and cytomegalovirus (CMV) infection. A total of 46 pediatric liver transplant patients transplanted at Mayo Clinic between January 1994 and January 2000 were evaluated. Quantitative polymerase chain reaction (PCR) assays for CMV, HHV‐6 and HHV‐7 were performed on stored sera obtained prior to transplant, weekly for 8 wk and at 4 months and 1 yr post‐transplant. Pretransplant sera were tested for HHV‐6 antibodies by indirect immunofluorescence assay. A total of 215 blood samples were tested (mean 6.5 ± 3.1, range 3–18). CMV infection occurred in 11 of 33 (33.3%) patients, while CMV disease occurred in 4 of 33 (12%) patients. Infection with HHV‐6 (variant B) was detected in three of 33 (9.1%) patients. HHV‐7 infection was not detected. Case 1 and 2 were infants (10‐ and 11‐month old, respectively). Both were seronegative for HHV‐6 pretransplant. In both cases, HHV‐6 infection was associated with concurrent episodes of moderate to severe acute graft rejection. Case 3 was a 16‐yr‐old girl who was seropositive for HHV‐6 pretransplant. No clinical events were recorded and a liver biopsy performed per protocol showed no evidence of rejection. None of the three patients had concomitant CMV infection or disease. In this study, HHV‐6 infection occurred in 9% of pediatric liver transplant patients while HHV‐7 was not detected. A potential association between primary HHV‐6 infection and allograft rejection warrants further investigation.

Treatment outcomes of human bartonellosis: a systematic review and meta-analysis.

BACKGROUND Bartonella henselae, Bartonella quintana, and Bartonella bacilliformis are responsible for the majority of cases of bartonellosis in humans. These species have various unique epidemiologic characteristics, clinical manifestations, and treatment approaches. The objective of this study was to summarize the evidence on the treatment for the three most common species of Bartonella in humans. METHODS We searched electronic databases through August 2011 for randomized controlled trials and observational studies designed to evaluate the efficacy and safety of the regimens used to treat diseases produced by B. henselae, B. quintana, and B. bacilliformis. Study selection and appraisal were done in duplicate. RESULTS We found two randomized and seven non-randomized studies at high risk of bias. For cat scratch disease, antibiotics did not significantly affect the cure rate or time to achieve cure. In chronic bacteremia, gentamicin and doxycycline significantly increased the resolution rate. The recommended treatment was not better than other regimens for infectious endocarditis and bacillary angiomatosis. CONCLUSIONS Current clinical practice for the treatment of bartonellosis relies mostly on expert opinion and antimicrobial susceptibility data. Randomized controlled trials are needed in the field to compare different treatment options.