The efficacy and safety of rotavirus vaccines in countries in Africa and Asia with high child mortality.

Rotavirus remains a leading cause of diarrhoeal morbidity and mortality in young children and rotavirus vaccines are critical for reducing global disease burden. This report addresses the performance of rotavirus vaccines in countries with high child mortality. We performed a sensitivity analysis as part of a systematic review on rotavirus vaccines to inform development of World Health Organization vaccine recommendations. The efficacy of four prequalified vaccines against severe rotavirus gastroenteritis was similar across high mortality settings in Asia and Africa. Within the first year following vaccination, vaccine efficacy for the four vaccines ranged from 48% to 57% while in the second year, efficacy ranged from 29% to 54%. The four vaccines showed no increase in intussusception risk in these settings. All four vaccines appear to prevent significant numbers of severe rotavirus gastroenteritis episodes with no measurable increase in intussusception risk in high mortality settings in Africa and Asia.

Distinct calcium signals in developing cortical interneurons persist despite disorganization of cortex by Tbr1 KO.

Cortical development involves the structuring of network features by genetically programmed molecular signaling pathways. Additionally, spontaneous ion channel activity refines neuronal connections. We examine Ca(2+) fluctuations in the first postnatal week of normal mouse neocortex and that expressing knockout of the transcription factor T-brain-1 (Tbr1): a signaling molecule in cortical patterning and differentiation of excitatory neurons. In cortex, glutamatergic neurons express Tbr1 just before the onset of population electrical activity that is accompanied by intracellular Ca(2+) increases. It is known that glutamatergic cells are disordered with Tbr1 KO such that normal laying of the cortex, with newer born cells residing in superficial layers, does not occur. However, the fate of cortical interneurons is not well studied, nor is the ability of Tbr1 deficient cortex to express normal physiological activity. Using fluorescent proteins targeted to interneurons, we find that cortical interneurons are also disordered in the Tbr1 knockout. Using Ca(2+) imaging we find that population activity in mutant cortex occurs at normal frequencies with similar sensitivity to GABAA receptor blockade as in nonmutant cortex. Finally, using multichannel fluorescence imaging of Ca(2+) indicator dye and interneurons labeled with red fluorescent protein, we identify an additional Ca(2+) signal in interneurons distinct from population activity and with different pharmacological sensitivities. Our results show the population activity described here is a robust property of the developing network that continues in the absence of an important signaling molecule, Tbr1, and that cortical interneurons generate distinct forms of activity that may serve different developmental functions. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 705-720, 2016.

Efficacy and immunogenicity of two or three dose rotavirus-vaccine regimen in South African children over two consecutive rotavirus-seasons: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Human rotavirus vaccine (HRV; i.e., Rotarix) reduced the incidence of severe rotavirus gastroenteritis (RVGE) by 77% (95% Confidence interval: 56-88%) during the first year of life in South Africa. Persistence of HRV-derived protection against RVGE during subsequent rotavirus seasons, although evident in industrialized settings, remains to be established in African settings. This study reports on the efficacy of HRV against severe RVGE over two consecutive rotavirus seasons in South African children. METHODS: A prospective, double-blind, placebo controlled multi-centered trial in South Africa and Malawi randomly assigned infants in a 1:1:1 ratio to receive either two (10 and 14 weeks; HRV_2D) or three (6, 10 and 14 weeks; HRV_3D) doses of HRV or placebo. The primary analysis involved pooling of HRV_2D and HRV_3D arms. Episodes of gastroenteritis caused by wild-type rotavirus were identified through active follow-up surveillance and graded by the Vesikari scale. RESULTS: 1339 infants (447 in the HRV_2D group, 447 in the HRV_3D group and 445 in the placebo group) were enrolled in Year 2 of the study, including 1035 (77.3%) who were followed up over two consecutive rotavirus seasons (i.e., Cohort 2 subjects). Rotarix was associated with ongoing protection against severe RVGE, preventing 2.5 episodes per 100 vaccinated children over two consecutive rotavirus seasons; vaccine efficacy: 59% (95% Confidence interval: 1-83%). An exploratory analysis indicated better immunogenicity (among Cohort 1 subjects) and a higher point-efficacy estimate over two seasons in the HRV_3D compared to HRV_2D arms of the study in Cohort 2 subjects. CONCLUSION: Rotarix is associated with significant reductions in severe gastroenteritis episodes through 2 years of life among South African children. Further research is needed to determine the optimal dosing schedule of Rotarix in providing long-term protection against rotavirus illness in African children.

Evaluation of rotavirus vaccines in Asia--are there lessons to be learnt?

Rotavirus mortality is highest in the Asia-Pacific region and rotavirus vaccines could have enormous impact here. Yet, live-attenuated orally administered rotavirus vaccines have been evaluated in a small number of immunogenicity studies in some Asian countries, where the immune responses have been documented to be moderate in low-income countries with high diarrhoeal disease burden and mortality, and high in middle-/high-income countries with little reported rotavirus deaths. This review of these rotavirus clinical trials examines the results observed and attempts to draw lessons to inform decision-making, aid design of additional clinical trials and guide vaccine development by local manufacturers.

Successful co-administration of a human rotavirus and oral poliovirus vaccines in Bangladeshi infants in a 2-dose schedule at 12 and 16 weeks of age.

Co-administration of oral live-attenuated human rotavirus vaccine RIX4414 (Rotarix) and oral polio vaccine (OPV) was assessed. Healthy infants were randomised to receive 2-doses of either: RIX4414 or placebo co-administered with OPV (12 and 16 weeks of age); or RIX4414 or placebo given 15 days after OPV. After vaccination, 56.5-66.7% of RIX4414 and 18.6% of placebo recipients had seroconverted for rotavirus IgA. No significant differences between RIX4414 groups with or without OPV co-administration were observed. No statistically significant differences were observed between groups for polio seroprotection rates. RIX4414 vaccine was immunogenic when co-administered with OPV and did not interfere with OPV seroprotection rates.

A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

Efficacy of inactivated and cold-adapted vaccines against influenza A infection, 1985 to 1990: the pediatric experience.

BACKGROUND: Influenza is a common and potentially serious infection in children. Although there is interest in broadening the use of influenza vaccine in healthy children, there are few large, randomized, controlled trials that evaluate the safety and efficacy of inactivated vaccine in the pediatric population. METHODS: From 1985 through 1990 a randomized, controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease was conducted at Vanderbilt University, and the cumulative results from this trial in patients of all ages have been previously published. We reanalyzed the data from this trial in the subset of patients who were younger than 16 years at the time of their participation. We determined vaccine safety, immunogenicity and efficacy, based on culture-positive illness and seroconversion, in this subset of patients. RESULTS: During the 5 years of the study, 791 children younger than 16 years received 1809 doses of either inactivated or cold-adapted vaccine or placebo. The vaccines were well-tolerated, and there were no serious reactions. Inactivated trivalent influenza vaccines were 91.4 and 77.3% efficacious in preventing symptomatic, culture-positive influenza A H1N1 and H3N2 illness, respectively. The efficacy of the inactivated vaccine based on hemagglutination inhibition assay seroconversion was 67.1 and 65.5%, respectively, for H1N1 and H3N2 serotypes. CONCLUSIONS: Inactivated trivalent influenza A vaccines are well-tolerated and efficacious in the prevention of influenza A disease in children 1 to 16 years old.

Influenza vaccine: issues and opportunities.

Several recent developments offer opportunities to improve the diagnosis, treatment, and prevention of influenza. Rapid diagnostic tests assist in selecting patients for antiviral therapy and avoid some antibiotic use. The neuraminidase inhibitors now offer therapeutic options with potentially fewer side effects than the traditional drugs, albeit at greater cost. Inactivated influenza vaccine is now recommended annually for all persons aged 50 and older and younger adults and children (aged 6 months and older) who have underlying risk factors for the severe complications of influenza. This includes pregnant women who are in their second or third trimesters during influenza season.

The burden of influenza illness in children with asthma and other chronic medical conditions.

OBJECTIVE: Although influenza immunization is recommended for children with high-risk medical conditions, the majority of such children do not receive influenza vaccine. This study was designed to measure the burden of influenza among children with asthma and other chronic medical conditions. STUDY DESIGN: We performed a retrospective cohort study of children younger than 15 years with medically treated asthma or other chronic medical conditions enrolled in the Tennessee Medicaid program from 1973 to 1993. We determined rates of hospitalization for acute cardiopulmonary disease, outpatient visits, and antibiotic courses throughout the year. Annual differences between event rates when influenza virus was circulating and event rates during winter months when there was no influenza in the community were used to calculate influenza-attributable morbidity. RESULTS: Influenza accounted for an average of 19, 8, and 2 excess hospitalizations for cardiopulmonary disease yearly per 1000 high-risk children aged <1 year, 1 to <3 years, and 3 to <15 years, respectively. For every 1000 children, an estimated 120 to 200 outpatient visits and 65 to 140 antibiotic courses were attributable to influenza annually. CONCLUSIONS: Children younger than 15 years with asthma and other chronic medical conditions experience substantial morbidity requiring inpatient and outpatient care during influenza season. More effective targeting of this population for annual influenza immunization is warranted.

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.

The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children.

BACKGROUND: Despite high annual rates of influenza in children, influenza vaccines are given to children infrequently. We measured the disease burden of influenza in a large cohort of healthy children in the Tennessee Medicaid program who were younger than 15 years of age. METHODS: We determined the rates of hospitalization for acute cardiopulmonary conditions, outpatient visits, and courses of antibiotics over a period of 19 consecutive years. Using the differences in the rates of these events when influenzavirus was circulating and the rates from November through April when there was no influenza in the community, we calculated morbidity attributable to influenza. There was a total of 2,035,143 person-years of observation. RESULTS: During periods when influenzavirus was circulating, the average number of hospitalizations for cardiopulmonary conditions in excess of the expected number was 104 per 10,000 children per year for children younger than 6 months of age, 50 per 10,000 per year for those 6 months to less than 12 months, 19 per 10,000 per year for those 1 year to less than 3 years, 9 per 10,000 per year for those 3 years to less than 5 years, and 4 per 10,000 per year for those 5 years to less than 15 years. For every 100 children, an annual average of 6 to 15 outpatient visits and 3 to 9 courses of antibiotics were attributable to influenza. In winter, 10 to 30 percent of the excess number of courses of antibiotics occurred during periods when influenzavirus was circulating. CONCLUSIONS: Healthy children younger than one year of age are hospitalized for illness attributable to influenza at rates similar to those for adults at high risk for influenza. The rate of hospitalization decreases markedly with age. Influenza accounts for a substantial number of outpatient visits and courses of antibiotics in children of all ages.

Influenza-associated morbidity and mortality in young and middle-aged women.

CONTEXT: Data are limited on rates of influenza-associated hospitalizations and deaths among adults younger than 65 years. OBJECTIVE: To quantify serious morbidity and mortality from influenza for women younger than 65 years with and without certain chronic medical conditions, including human immunodeficiency virus infection. DESIGN: Retrospective cohort study. SETTING AND POPULATION: Women aged 15 to 64 years enrolled in the Tennessee Medicaid program from 1974 to 1993. MAIN OUTCOME MEASURE: All hospitalizations for and deaths from pneumonia, influenza, and other selected acute cardiopulmonary conditions for women with and without selected chronic medical conditions during 19 consecutive years. Influenza-attributable risk was calculated by subtracting event rates during peri-influenza season (November through April of each year when influenza virus was not circulating) from adjusted rates during influenza season (November through April when influenza virus was circulating). RESULTS: During the 19 years of the study, we identified 53607 acute cardiopulmonary hospitalizations and deaths. Rates of such events were consistently higher during influenza seasons than peri-influenza seasons. Among high-risk women, the estimated annual excess was 23 hospitalizations and deaths per 10000 women aged 15 to 44 years and 58 such events per 10000 women aged 45 to 64 years. The estimated annual excess mortality due to influenza was 2 deaths per 10000 high-risk women for both age groups combined. Among women with no identified high-risk conditions, estimated annual excess hospitalizations and deaths were 4 and 6 per 10000 women aged 15 to 44 and 45 to 64 years, respectively. CONCLUSIONS: Women younger than 65 years with certain chronic medical conditions experience substantial morbidity and mortality from acute cardiopulmonary events during influenza season. More effective targeting of these populations for annual influenza immunization is warranted.

Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women.

This study sought to quantify influenza-related serious morbidity in pregnant women, as measured by hospitalizations for or death from selected acute cardiopulmonary conditions during predefined influenza seasons. The study population included women aged 15-44 years who were enrolled in the Tennessee Medicaid program for at least 180 days between 1974 and 1993. In a nested case-control study, 4,369 women with a first study event during influenza season were compared with 21,845 population controls. The odds ratios associated with study events increased from 1.44 (95% confidence interval (CI) 0.97-2.15) for women at 14-20 weeks' gestation to 4.67 (95% CI 3.42-6.39) for those at 37-42 weeks in comparison with postpartum women. A retrospective cohort analysis, which controlled for risk factors identified in the case-control study, identified 22,824 study events during 1,393,166 women-years of follow-up. Women in their third trimester without other identified risk factors for influenza morbidity had an event rate of 21.7 per 10,000 women-months during influenza season. Approximately half of this morbidity, 10.5 (95% CI 6.7-14.3) events per 10,000 women-months, was attributable to influenza. Influenza-attributable risks in comparable nonpregnant and postpartum women were 1.91 (95% CI 1.51-2.31) and 1.16 (95% CI -0.09 to 2.42) per 10,000 women-months, respectively. The data suggest that, out of every 10,000 women in their third trimester without other identified risk factors who experience an average influenza season of 2.5 months, 25 will be hospitalized with influenza-related morbidity.

Adjuvants influence the quantitative and qualitative immune response in BALB/c mice immunized with respiratory syncytial virus FG subunit vaccine.

The ability of monophosphoryl lipid A (MPL), QS-21 and alum to alter the immunologic response to immunization with respiratory syncytial virus a chimeric FG construct (FG) subunit vaccine was examined in BALB/c mice. FG/MPL, FG/alum, and FG/MPL/QS-21 combinations increased non-neutralizing antibody response, while FG/QS-21 did not. FG subunit vaccine with MPL, QS-21, or both had cytokine responses more closely resembling primary infection than FG/alum, with decreased interleukin-4 mRNA levels and increased IgG2a isotype antibody. The lungs of the mice immunized with FG subunit vaccines showed a heightened inflammatory response to respiratory syncytial virus challenge as compared to live virus immunization. Adjuvants can be used to alter the humoral and cellular responses to RSV subunit immunization.

Determinants and kinetics of cytokine expression patterns in lungs of vaccinated mice challenged with respiratory syncytial virus.

The development of a successful respiratory syncytial virus (RSV) vaccine will be advanced by an improved understanding of the pathogenesis of natural disease and vaccine-enhanced illness. Using a murine model, we have examined cytokine message expression and cytokine secretion in lungs of mice primed with killed or live antigens and challenged with RSV. Stable cytokine mRNA expression was achieved if the prime-challenge interval was 2 weeks. The pattern of expression of interleukin-4 (IL-4) and interferon-7 (IFN-gamma 1 mRNA was established by day 4 after challenge and was maintained at least through day 12, and was not affected by the concentration of priming immunogen or virus challenge. An enzyme-linked immunospot assay demonstrated that CD4+ T cells were responsible for the production of IL-4, while many cell types secreted IFN-gamma. These experiments begin to define the kinetics of cytokine expression and phenotypes of cytokine-producing cells following RSV infection, supporting previous findings that suggested aberrant infiltration of CD4+ T lymphocytes and excessive IL-4 secretion may play a role in the vaccine-enhanced disease associated with RSV.

Protective Role of TNF-alpha in respiratory syncytial virus infection in vitro and in vivo.

Respiratory syncytial virus (RSV) infection causes substantial morbidity in young children and immunocompromised adults, yet its pathogenesis is poorly understood. Because the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) may be important in host response to viral infection, HEp-2 cells were treated with TNF-alpha and mice were given TNF-alpha antibody before RSV infection. Pretreatment of HEp-2 cells with TNF-alpha inhibited RSV replication as determined by cytopathic effect. Respiratory syncytial virus-infected BALB/c mice treated with antibody to TNF-alpha had greater maximal weight loss and slower recovery time than control mice. These results suggest a protective role for TNF-alpha in RSV infection.

Safety and pharmacokinetics of vitamin A therapy for infants with respiratory syncytial virus infections.

Infants with respiratory syncytial virus infection have low serum vitamin A levels. We treated 21 respiratory syncytial virus-infected children with 12,500 to 25,000 IU of oral vitamin A. Vitamin A levels were normalized at 6 h, and none of the children experienced vitamin A toxicity or exacerbation of respiratory illness. Vitamin A treatment of previously healthy respiratory syncytial virus-infected infants at these doses is safe and well tolerated.