Howard R. Six

Epidemiologic characteristics of cytomegalovirus infection in mothers and their infants

In this longitudinal study of cytomegalovirus in 4578 pregnant women of middle/upper socioeconomic status in Houston, 52% had cytomegalovirus antibody when enrolled, and 48% were serologically susceptible. Studies were completed on 3899 mothers and their infants; 2.2% of these women experienced primary cytomegalovirus during pregnancy and 24% of those with primary infection transmitted cytomegalovirus to their infants. Of 22 cytomegalovirus-infected infants, 2 had disease at birth and 20 were asymptomatic. One symptomatic infant (primary maternal infection) has developmental delay. The other (immunocompromised mother with cytomegalovirus antibody before pregnancy) had hepatitis but has no symptoms at 1 year of age. On follow-up, 4 of 16 infants asymptomatic at birth have sequelae (hearing loss in 3, developmental delay in 1). All four were born to mothers with primary cytomegalovirus infection. Infant outcome was not related to trimester of maternal infection.

Small particle aerosols of enviroxime-containing liposomes

Enviroxime inhibits the replication of all rhinoviruses tested in vitro at very low concentrations (10-100 ng/ml), but evaluations in humans have not consistently shown efficacy. Lack of an appropriate method for administering this water-insoluble drug may have contributed to the latter result. The present report describes the characteristics and utilization of small particle aerosols to continuously deliver enviroxime-containing liposomes (LE) throughout the respiratory tract. The enviroxime content of liposomes and biological fluids of exposed individuals was quantified by high performance liquid chromatography using C18 resin, a mobile phase of 60:40 acetonitrile:water, and monitoring at 215 nm. Small particle aerosols of LE generated by Puritan-Bennett nebulizers had mass median diameters ranging from 2.4 to 3.1 microns. The concentration of enviroxime in aerosol particles was proportional to the reservoir concentration; during the first hour of operation, the mean concentration was 20 micrograms of enviroxime/l of aerosol. Liposome particles in the reservoir, although initially heterogeneous in size (less than 0.1 to greater than 1 micron), were processed by passage through the nebulizer to smaller, more homogeneous particles; the majority were less than 0.2 micron. In a preliminary study to evaluate short term tolerance and toxicity, five volunteers were exposed to small particle aerosol of LE for 1 h. At 1 h post-treatment, large amounts of enviroxime were still present in the nasal wash as determined both by HPLC and biological assay. Enviroxime was not detected in any urine sample and was detected in only 1 of 5 serum samples. No side effects were noted. This data suggest that liposome aerosols offer a method for the delivery of hydrophobic compounds for the treatment of respiratory diseases.

Posttransfusion cytomegalovirus infection in neonates: Role of saline-washed red blood cells

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Immunoglobulin G subclass antibody responses of mice to influenza virus antigens given in different forms

Total IgG and IgG subclass antibody responses in mice were studied after infection with virulent and non-virulent influenza viruses, and after vaccination with inactivated whole virus or purified surface glycoproteins (HANA-flu). Infection induced high IgG2a, low IgG1 and IgG2b, and very low IgG3 levels of antibody in serum. Whole virus vaccine induced high IgG2a, moderate IgG2b, and very low IgG1 and IgG3 levels of antibody. In marked contrast, HANA-flu preparations induced high IgG1, low IgG2a, and very low IgG2b and IgG3 levels of antibody. Booster doses of whole virus and HANA-flu significantly elevated serum antibody levels, but the relative distribution of anti-influenzal antibody among the IgG subclasses was unchanged. Mice primed with HANA-flu prior to infection with mouse-adapted virus, produced high IgG2a, moderate IgG1, and low IgG2b and IgG3 levels of serum antibody. These data indicate that the physical form in which viral protein antigens are presented to the immune system can influence the subclass distribution of antibodies produced during primary immune responses and that once priming has occurred, responses to antigen presented in a different form are altered.

Immunogenicity and efficacy of orally administered inactivated influenza virus vaccine in mice

The immunogenicity and protective efficacy of formalin-inactivated whole influenza A/Bangkok/79 virus vaccine given to unprimed Swiss mice orally in capsules, in their drinking water, or by direct injection into the duodenum were studied. Virus-specific IgG and IgA antibody responses to all these methods were dose-dependent and varied according to immunization conditions. Following intranasal challenge with live A/Bangkok influenza virus, mice given greater than or equal to 66 micrograms haemagglutinin (HA) of vaccine in drinking water or capsules, and mice injected into the duodenum with greater than or equal to 0.66 microgram HA, had significantly lower virus titres in their noses and lungs than control mice comparably inoculated.

Immunization against Influenza: Comparison of Various Topical and Parenteral Regimens Containing Inactivated and/or Live Attenuated Vaccines in Healthy Adults

Methods for enhancing immune responses to influenza were explored in 2 double-blind, placebo-controlled trials. Intranasal (inl) immunization with monovalent, live attenuated, cold-adapted recombinant (CR) or inactivated influenza virus (MIV) vaccine and intramuscular (im) immunization with MIV were evaluated in various combinations. Healthy susceptible adults were assigned randomly to receive 10(7.1) TCID(50) of CR (A/H1N1 or A/H3N2), homologous MIV (15 microg), or placebo inl and placebo or homologous MIV im (6 groups in each study). Serum antibody responses were greatest in groups given im vaccine (with or without inl vaccine). A 2-fold increase in nasal wash antibody response frequencies was seen in groups given combined inl (CR or MIV) and im vaccine, compared with subjects given a single im (MIV) or inl (CR or MIV) vaccine. Combined inl and im immunization is a promising approach for enhancing both local and systemic immune responses against influenza.

Postimmunization clearance of liposome entrapped adenovirus type 5 hexon.

Abstract Clearance rates of 125I-hexon administered in three different forms from injection sites were assessed in animals. Aqueous and liposome-entrapped hexons following parental administration were cleared in linear fashion with half-lives that ranged from 1.5 to 4 and 30 to 45 hr, respectively. In contrast, hexons emulsified in complete Freunds adjuvant were cleared in a biphasic manner and tended to remain localized with 23 to 55% persisting after 16 days. No significant antigen accumulation in blood or any internal organs was detected following the three modes of immunization. These data suggest that formation of a transient antigen “depot” at injection sites may contribute to the adjuvant effect of liposomes but the complete resolution of this “depot” may avoid significant local reactogenicity.

THE BASIS FOR IMMUNITY TO INFLUENZA IN MAN

I. ABSTRACT Infection or vaccination with an influenza virus induces a variety of humoral and cellular immune responses. Among these, the subtype specificity and duration of antibody responses most closely match related characteristics of infection-induced immunity in man. Furthermore, in vitro and in vivo animal studies suggest that the most probable mediator of resistance to influenza is antibody to the hemagglutinin (HA), either in serum or respiratory secretions. A role for anti-HA antibody in secretions was sought in human studies utilizing immunization followed by virus challenge and sensitive radio-immunoprecipitation assays for detection of antibody. Serum IgG antibody was more consistently and more strongly related to resistance to challenge than was antibody in secretions. Moreover, passive immunization of infants has been recently shown to be associated with immunity to influenza. Thus, we believe currently available evidence favors the concept that serum IgG antibody to the influenza virus hemagglutinin is not only the best correlate but is probably the primary mediator of immunity to influenza.

Antigenicity of licensed whole virion and subvirion influenza vaccines in " high risk " persons.

Summary The frequency and magnitude of serum antibody response to type A and B influenza viruses induced by whole virion and subvirion vaccines were essentially comparable . Immunization was followed in vaccinated individuals by an antihemagglutinin antibody response to the common antigenic determinant shared by the type A H3N2 viruses. Relatively few individuals developed antibody to the type-specific determinant.

Serum IgG subclass antibody responses in children vaccinated with influenza virus antigens by live attenuated or inactivated vaccines

To ascertain whether live attenuated or inactivated vaccines can be considered equivalent, we examined the primary antibody response of children following vaccination with influenza virus antigens in three different formulations. Nine children received cold recombinant vaccine (CRV) containing A/Korea/82 (H3N2) and A/Dunedin/83 (H1N1) variants. Eight of these children responded to HA of the H3N2 subtype and the major portion of the elicited antibody was in the IgG1 subclass. Antibody of low titer in the IgG2 and IgG3 subclasses was detected in two and six serum specimens, respectively. Six of the nine children administered with CRV responded to the H1 antigen and only IgG1 antibody was detected. Serum specimens from eight children less than one year of age (5 less than 6 months of age) who had developed an antibody response to trivalent inactivated vaccine (TIV) vaccination were examined. High levels of IgG1 antibody to purified H3 were detected in all eight children. Low titers of antibody in IgG2 and IgG3 subclasses were detected in two and five children, respectively. Antibody responses to purified H1 showed a similar subclass distribution. In order to examine secondary response, eight children primed by immunization with TIV vaccine were subsequently given a single booster dose of purified hemagglutinin (HA) conjugated to diphtheria toxoid (HA-D). In 6/8 specimens antibody rises were detected to purified H3 and H1 antigens. Prior to the HA-D immunization, low levels of HA specific IgG1 antibody were detected in all serum specimens and vaccine induced responses were primarily of the IgG1 subclass.(ABSTRACT TRUNCATED AT 250 WORDS)