Pedro A. Piedra

The Efficacy of Live Attenuated, Cold-Adapted, Trivalent, Intranasal Influenzavirus Vaccine in Children

BACKGROUND Influenzavirus vaccine is used infrequently in healthy children, even though the rates of influenza in this group are high. We conducted a multicenter, double-blind, placebo-controlled trial of a live attenuated, cold-adapted, trivalent influenzavirus vaccine in children 15 to 71 months old. METHODS Two hundred eighty-eight children were assigned to receive one dose of vaccine or placebo given by intranasal spray, and 1314 were assigned to receive two doses approximately 60 days apart. The strains included in the vaccine were antigenically equivalent to those in the inactivated influenzavirus vaccine in use at the time. The subjects were monitored with viral cultures for influenza during the subsequent influenza season. A case of influenza was defined as an illness associated with the isolation of wild-type influenzavirus from respiratory secretions. RESULTS The intranasal vaccine was accepted and well tolerated. Among children who were initially seronegative, antibody titers increased by a factor of four in 61 to 96 percent, depending on the influenza strain. Culture-positive influenza was significantly less common in the vaccine group (14 cases among 1070 subjects) than the placebo group (95 cases among 532 subjects). The vaccine efficacy was 93 percent (95 percent confidence interval, 88 to 96 percent) against culture-confirmed influenza. Both the one-dose regimen (89 percent efficacy) and the two-dose regimen (94 percent efficacy) were efficacious, and the vaccine was efficacious against both strains of influenza circulating in 1996-1997, A(H3N2) and B. The vaccinated children had significantly fewer febrile illnesses, including 30 percent fewer episodes of febrile otitis media (95 percent confidence interval, 18 to 45 percent; P<0.001). CONCLUSIONS A live attenuated, cold-adapted influenzavirus vaccine was safe, immunogenic, and effective against influenza A(H3N2) and B in healthy children.

Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine

OBJECTIVE To determine the safety, immunogenicity, and efficacy of revaccination of children with live attenuated influenza vaccine. STUDY DESIGN A 2-year multicenter, double-blind, placebo-controlled, efficacy field trial of live attenuated, cold-adapted trivalent influenza vaccine administered by nasal spray to children. This report summarizes year 2 results, a year in which the epidemic strain of influenza A/Sydney was not well matched to the vaccine strains. Each year, vaccine strains were antigenically equivalent to the contemporary inactivated influenza vaccine. In year 2, a single intranasal revaccination was administered. Active surveillance for influenza was conducted during the influenza season by means of viral cultures. Influenza cases were defined as illnesses with wild-type influenza virus isolated from respiratory secretions. RESULTS In year 2, 1358 (85%) children, 26 to 85 months of age, returned for revaccination. The intranasal vaccine was easily accepted, well tolerated, and immunogenic. Revaccination resulted in 82% to 100% of the vaccinated children in a subset studied for immunogenicity being seropositive as compared with 26% to 65% of placebo recipients, depending on the influenza strain tested. No serious adverse events were associated with the vaccine. In addition to the strains in the vaccine, antibody was induced to the variant strain A/Sydney/H3N2. In year 2, influenza A/Sydney/H3N2, a variant not contained in the vaccine, caused 66 of 70 cases of influenza A; nonetheless, intranasal vaccine was 86% efficacious in preventing A/Sydney influenza. Eight cases of lower respiratory tract disease were associated with A/Sydney influenza; all cases were in the placebo group. CONCLUSIONS This live attenuated, cold-adapted influenza vaccine was safe, immunogenic, and efficacious against influenza A/H3N2 (including a variant, A/Sydney, not contained in the vaccine) and influenza B. The characteristics of this vaccine make it suitable for routine use in children to prevent influenza.

Correlates of Immune Protection Induced by Live, Attenuated, Cold-Adapted, Trivalent, Intranasal Influenza Virus Vaccine

The authors conducted a 2-year, multicenter, double-blind, placebo-controlled efficacy field trial of live, attenuated, cold-adapted, trivalent influenza vaccine administered by nasal spray to children 15-71 months old. Overall, vaccine was 92% efficacious at preventing culture-confirmed infection by influenza A/H3N2 and influenza B. Because influenza A/H1N1 did not cause disease during the years in which this study was conducted, the authors sought to determine vaccine efficacy and correlates of immune protection against experimental challenge with 107 TCID50 of attenuated H1N1 (vaccine strain) by intranasal spray. Prechallenge assessments included serum hemaglutination-inhibiting (HAI) antibody and nasal wash IgA antibody to H1N1. Vaccine was 83% efficacious (95% confidence interval, 60%-93%) at preventing shedding of H1N1 virus after challenge. Any serum HAI antibody or any nasal wash IgA antibody was correlated with significant protection from H1N1 infection as indicated by vaccine-virus shedding, and high efficacy against H1N1 challenge was demonstrated.

Influenza virus infections in infants

BACKGROUND Universal immunization of children with live attenuated cold recombinant vaccine has been proposed. The renewed recommendation for maternal immunization with influenza vaccine should increase the amount of antibody transmitted to the infant and postpone the need for active immunization. This study examines the risk of influenza during the first year of life to provide information about the time to initiate active immunization. METHODS Infants followed from birth to 1 year of age in the Houston Family Study were monitored weekly for influenza virus infection. Serum specimens were tested for evidence of infection at 4-month intervals. RESULTS One-third of 209 infants were infected during the first year; most of the infections occurred during the second 6 months of life. Only 26 of 69 infections were detected before 6 months of age compared with 43 afterward. More striking was the concentration of serious illnesses in the latter half of the first year; 8 of 9 otitis media episodes and 9 of 11 lower respiratory tract illnesses occurred in the older infants. CONCLUSIONS The combination of increased maternal antibody titers that should result from influenza immunization and the lesser risk of influenza in the first 6 months of life allows initiation of active immunization of children after 6 months of age.

Lifetime correction of genetic deficiency in mice with a single injection of helper-dependent adenoviral vector

Ideally, somatic gene therapy should result in lifetime reversal of genetic deficiencies. However, to date, phenotypic correction of monogenic hyperlipidemia in mouse models by in vivo gene therapy has been short-lived and associated with substantial toxicity. We have developed a helper-dependent adenoviral vector (HD-Ad) containing the apolipoprotein (apo) E gene. A single i.v. injection of this vector completely and stably corrected the hypercholesterolemia in apoE-deficient mice, an effect that lasted the natural lifespan of the mice. At 2.5 years, control aorta was covered 100% by atherosclerotic lesion, whereas aorta of treated mice was essentially lesion-free. There was negligible toxicity associated with the treatment. We also developed a method for repeated HD-Ad vector administration that could be applied to organisms, e.g., humans, with life spans longer than 2–3 years. These studies indicate that HD-Ad is a promising system for liver-directed gene therapy of metabolic diseases.

Safety and immunogenicity of respiratory syncytial virus purified fusion protein-2 vaccine in pregnant women.

A randomized, double-blind, placebo controlled study was carried out to determine the safety and immunogenicity of RSV PFP-2 vaccine (Wyeth-Lederle Vaccines, NY) in 35 healthy women in the third trimester of pregnancy and their offspring. Infants were followed during their first RSV season for occurrence and severity of respiratory illnesses. RSV-PFP-2 vaccine was safe and well tolerated by pregnant women. Mild pain at the site of injection occurred in 65% of PFP-2 and 13% of placebo recipients (P=0.005). There were no systemic reactions, fever, or serious adverse events associated with vaccine administration in mothers. All 35 infants were born healthy, and there were no differences among the groups in perinatal or neonatal outcomes, growth and development in the first year of life. During the RSV season, there was no increase in the frequency or morbidity associated with respiratory tract illnesses in infants of vaccine recipients. 15/20 (75%) vaccine recipients had a response to PFP-2 by Western blot vs. 0/15 placebo recipients (P<0.01). 19/20 (95%) vaccine recipients had a > or =4 fold rise in IgG ELISA Ab after immunization with PFP-2 vs. 0/15 placebo recipients (P<0.01). Geometric mean concentrations of IgG ELISA Ab were 4 fold higher in infants of vaccine recipients at birth, 2 and 6 months after delivery than in infants of placebo recipients (P<0.01). A modest (0.5log2) increase in neutralization Ab was observed in vaccine recipients and their infants. The half-life of maternal antibodies in infants was > or =3 weeks. There was no evidence of enhanced T-cell or cytokine activity in infants of vaccine recipients vs. infants of placebo recipients. Vaccine specific anti-F IgA and IgG concentrations in breast milk were higher in mothers who received RSV-PFP-2.

Disseminated Adenovirus Disease in Immunocompromised and Immunocompetent Children

A retrospective review of adenovirus infections at Texas Childrens Hospital during 1990-1996 was performed to evaluate the epidemiology, clinical course, management, and outcome of disseminated adenovirus disease (DAD) in children. DAD with multiorgan involvement occurred in 11 (2.5%) of 440 adenovirus-infected patients. Six (54%) of the 11 were immunocompromised and 5 (45%) were immunocompetent. Mortality was 83% among the immunodeficient, 60% in the immunocompetent, and 73% overall. Two (28%) of the 7 patients receiving immunoglobulins with or without antivirals and 3 (75%) of the 4 not treated died of DAD. DAD was caused by particular serotypes (3, 5, and 7) and occurred at a younger age in immunocompetent children. Viremia and prolonged viral excretion were more common in the immunocompromised. Clinical features and outcome were similar in both groups. Prospective studies addressing the use of new antiviral agents, combination antiviral therapy, and preventive strategies are necessary to determine the optimal therapeutic approach for patients with DAD.

Lethal Toxicity, Severe Endothelial Injury, and a Threshold Effect with High Doses of an Adenoviral Vector in Baboons

The effects of intravenous administration of a first-generation adenoviral vector expressing beta-galactosidase were compared in two baboons receiving a high dose or lower dose of vector, 1.2 x 10(13) or 1.2 x 10(12) particles/kg, respectively. The high-dose baboon developed acute symptoms, decreased platelet counts, and increased liver enzymes, and became moribund at 48 hr after injection, while the lower-dose baboon developed no symptoms. Expression of the beta-galactosidase transgene was prominent in liver, spleen, and endothelium of the arterial vasculature in the high-dose baboon, but was much more limited and spared the endothelium in the lower-dose baboon. Injury to the vascular endothelium was the most prominent abnormality in the high-dose baboon. Extensive histological studies provide a detailed picture of the pathology associated with a lethal dose of first-generation adenoviral vector in a primate.

Comparison of the inhibition of human metapneumovirus and respiratory syncytial virus by ribavirin and immune serum globulin in vitro

Human metapneumovirus (hMPV) is a newly recognized pathogen that like its better-known relative, human respiratory syncytial virus (hRSV), appears to be ubiquitous and an important cause of respiratory disease in diverse subpopulations. No antivirals or vaccines are currently approved for the treatment or prevention of hMPV infections. However, ribavirin is licensed to treat serious hRSV-induced infections in children and immune globulin designed for intravenous administration (i.v.IG) and palivizumab (Synagis), a humanized monoclonal antibody preparation, have been utilized as alternatives to vaccines for preventing or reducing the severity of infections caused by this virus. Because both ribavirin and i.v.IG have broad viral specificities, studies were performed to compare the ability of these two agents to inhibit the replication of hRSV and hMPV in tissue culture-based assays. Two experimental chemotherapeutic agents (i.e. VP14637 and JNJ2408068) and different antibody preparations were included in this testing for comparison. Ribavirin and the i.v.IG utilized were found to have equivalent antiviral activity against hMPV and hRSV. In contrast, except for antisera specifically raised against hMPV, all of the other materials tested had marked activity only against hRSV.

Lower Respiratory Tract Infections due to Adenovirus in Hospitalized Korean Children: Epidemiology, Clinical Features, and Prognosis

On occasion, outbreaks of infection with adenovirus types 3, 7, and 21 cause severe lower respiratory tract infections (LRTIs) in children. From 1990 to 1998, all cases of LRTI due to adenovirus at the Seoul National University Childrens Hospital, Seoul, Korea, were reviewed. Adenoviruses were recovered from nasal aspirate specimens of 87 (5.9%) of 1472 children with LRTI. The principal adenovirus serotypes were type 2 (13 [15%] of 87 strains), type 3 (13 [15%]), and type 7 (36 [41%]). Of the 87 infections, 62 (71%) occurred in children <2 years of age, and 81 (94%) occurred in children <5 years of age. Infections due to types 3 and 7 occurred during epidemics, whereas infections due to type 2 occurred sporadically. For patients who were infected with types 3 and 7, extrapulmonary abnormalities were more common and homogeneous consolidation and pleural effusion were frequently identified on radiographs. The mortality rate was 12% overall and 19% among patients who were infected with type 7. Residual sequelae were identified in 6 (50%) of 12 patients who were infected with type 3 and in 9 (25%) of 36 who were infected with type 7. The data confirm that adenovirus types 3 and 7 can cause epidemics of severe LRTI in young children. Epidemics of LRTIs caused by adenovirus types 3 and 7 in Korea have not been described in reports published elsewhere.