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Biomedical subjects

E D Kilbourne

Publications and source records attributed to E D Kilbourne.

At least 37 records · Page 2Linked to original sources
PubMed1991

Programmed antigenic stimulation: kinetics of the immune response to challenge infections of mice primed with influenza inactivated whole virus or neuraminidase vaccine.

Mice were immunized with either inactivated whole virus influenza A (H3N2) virus (WV) vaccine or with purified N2 neuraminidase (NA) vaccine then challenged with mouse-adapted homologous infective virus at intervals of 1-141 days later in order to ascertain the optimal vaccine-infection interval for induction of resistance to subsequent infection. Measured by serological or infection suppressing response, this interval was 15 days for both vaccines. Maximal reduction in pulmonary virus replication during initial (postvaccination) infection was achieved with WV vaccine, but in second infection by NA vaccine. This study provides further support for the concept of infection-permissive immunization with NA vaccines and suggests the promise of programmed antigenic stimulation by coupling of non-replicating and replicating antigens in the induction of solid immunity.

Animals↗
PubMed1991

New viruses and new disease: mutation, evolution and ecology.

Given the extraordinarily high mutation rate of viruses, particularly those with RNA genomes, it is not surprising that new viruses are continually evolving. However, the symptomatology of old viral diseases has remained stable for centuries. The combination of genetic and ecological factors that constrain as well as facilitate the emergence of new viruses is analyzed.

Genes, Viral↗
PubMed1990

New viral diseases. A real and potential problem without boundaries.

Viruses are the most mutable and rapidly evolving human parasites. Therefore, it is not surprising that new virus diseases, such as the acquired immunodeficiency syndrome, are emerging. However, these new viruses are relatively few in number, which reflects the constraints placed on viral evolution by the requirement for maintenance of virus structure and function and virus adaptation to restricted ecologic sites. Most "new" viral diseases, such as the hemorrhagic fevers, result from environmental disruptions that increase human contact with animals or insect vectors of old viruses. However, truly novel viruses with lethal potential or capacity for global spread have emerged in animals as a consequence of single-point mutations or genetic recombination between viruses. Given the mutability of viruses and the inevitability of environmental change, we must be prepared for the evolution of new virus diseases.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Independent and disparate evolution in nature of influenza A virus hemagglutinin and neuraminidase glycoproteins.

The hemagglutinin (HA) and neuraminidase (NA) external glycoprotein antigens of H1N1 and H3N2 subtypes of epidemiologically important influenza A viruses prevalent during recent decades were subjected to intensive antigenic analysis by four different methods. Prior to serological analysis with polyclonal rabbit antisera, HA and NA antigens of four viruses of each subtype were segregated by genetic reassortment to forestall nonspecific steric hindrance during antigen-antibody combination. This analysis has demonstrated that with respect to antigenic phenotype, HA and NA proteins have evolved at different rates. With H1N1 viruses, an arrest of significant evolution of the NA discordant with the continuing antigenic drift of HA was found in the 1980-1983 period. It is probable that the different and independent rates of evolution of HA and NA reflect the greater selective pressure of HA antibodies, which forces the more rapid emergence of HA escape mutants. The slower antigenic change found for NA further supports the potential for NA-specific infection-permissive immunization as a useful stratagem against influenza.

Biological Evolution↗
PubMed1990

Comparative long-term effects in a mouse model system of influenza whole virus and purified neuraminidase vaccines followed by sequential infections.

A comparison of inactivated whole influenza virus vaccine and purified influenza neuraminidase (NA) in BALB/c mice repeatedly challenged by homologous or heterologous H3N2 variant infections demonstrated an initial superiority of whole virus vaccine but the ultimate superiority of NA vaccine in immunization after one or two boosting infections. Parenteral administration of either vaccine followed by infection was much more effective than infection alone in the induction of either homologous or heterologous immunity. On the basis of this model simulation of human experience and other earlier studies, it seems that purified NA vaccine may offer an important new strategy as an initial step in immunization against influenza in humans.

Animals↗
PubMed1989

Identification of PR8 M1 protein in influenza virus high-yield reassortants by M1-specific monoclonal antibodies.

A panel of monoclonal antibodies to the M1 protein of A/PR8/34 (H1N1) (PR8) influenza A virus was found to distinguish in ELISA high-yielding reassortant viruses derived from reassortment of PR8 and X-31 (H3N2) viruses with recently prevalent field strains of H1N1 or H3N2 subtype. These findings are concordant with results of genotyping that demonstrated the presence of PR8 RNA 7 or M1 protein in high-yield reassortants by RNA or protein PAGE. All high-yield vaccine candidate reassortants Application of the M1 monoclonal antibody panel facilitates the isolation of high-yield vaccine candidate reassortants bearing the PR8 M1 gene, and should aid in epidemiologic strain tracking as well.

Antibodies, Monoclonal↗
PubMed1989

Complementation of recombinant baculoviruses by coinfection with wild-type virus facilitates production in insect larvae of antigenic proteins of hepatitis B virus and influenza virus.

We describe the coinfection of insects with wild-type and recombinant baculoviruses in which the polyhedrin gene promoter is used to express hepatitis B virus envelope protein (hepatitis B virus surface antigen; HBsAg) or influenza A virus neuraminidase (NA). Viruses were administered per os to larvae of the cabbage looper, Trichoplusia ni, causing an infection that within 5 days resulted in the production of approximately 0.15 mg of HBsAg per insect, representing 1.5% of the total extracted protein, or approximately 2.8 mg of NA per insect, representing 28% of the total extractable protein. The HBsAg and NA produced by infected larvae were purified from insect lysates. These proteins were antigenic as determined by conformation-dependent immunoassays. The NA was enzymatically active with conventional substrates. The method of infection described allows genetic complementation by wild-type virus of recombinant viruses lacking the polyhedrin gene essential for infection per os and has implications for the high-yield production in insect larvae of other recombinant proteins of baculoviruses.

Animals↗
PubMed1989

Purified influenza virus hemagglutinin and neuraminidase are equivalent in stimulation of antibody response but induce contrasting types of immunity to infection.

BALB/c mice immunized with graded doses of chromatographically purified hemagglutinin (HA) and neuraminidase (NA) antigens derived from A/Hong Kong/1/68 (H3N2) influenza virus demonstrated equivalent responses when HA-specific and NA-specific serum antibodies were measured by enzyme-linked immunosorbent assays (ELISAs). Antibody responses measured by hemagglutination inhibition or neuraminidase inhibition titrations showed similar kinetic patterns, except for more rapid decline in hemagglutination inhibition antibody. Injection of mice with either purified HA or NA resulted in immunity manifested by reduction in pulmonary virus following challenge with virus containing homologous antigens. However, the nature of the immunity induced by the two antigens differed markedly. While HA immunization with all but the lowest doses of antigen prevented manifest infection, immunization with NA was infection-permissive at all antigen doses, although reduction in pulmonary virus was proportional to the amount of antigen administered. The immunizing but infection-permissive effect of NA immunization over a wide range of doses is in accord with results of earlier studies with mice in which single doses of NA and antigenically hybrid viruses were used. The demonstrable immunogenicity of highly purified NA as a single glycoprotein without adjuvant offers a novel infection-permissive approach with potentially low toxicity for human immunization against influenza virus.

Animals↗
PubMed1988

Hemagglutinin polymorphism as the basis for low- and high-yield phenotypes of swine influenza virus.

Single amino acid substitutions at the rim of the receptor binding site of the hemagglutinin molecule of swine influenza virus markedly influence the replicative capacity of the virus in chicken embryos, Madin-Darby canine kidney cells (MDCK), and swine as well as its antigenic phenotype. Mutants of low-yield (L) phenotype replicate poorly in chicken embryos and produce small plaques in MDCK cells but are highly infective for swine. Such mutants have lysine at position 153 and glycine at position 155 of the hemagglutinin (residues 156 and 158 in the H3 model). High-yield (H) mutants have the converse replicative characteristics and can be antigenically distinguished from L mutants (and from each other) based on their differential reactivity with two monoclonal antibodies, 9C8 and Sa-13. H mutants differ from L mutants in that the H mutants express glutamic acid at either position 153 or 155. L and H mutants act in an allelic fashion in effecting predictable one-step adaptation to different hosts. Selection for replication (e.g., high-yielding) phenotype results in concordant pleiotropic change in antigenic phenotype and in genotype. Conversely, immunoselection leads to change in replicative phenotype. Although the mechanism by which these mutations affect viral replication has not yet been defined, they may reflect differences in the affinity of each mutant for different host receptors.

Animals↗
PubMed1988

Evolution to predominance of swine influenza virus hemagglutinin mutants of predictable phenotype during single infections of the natural host.

L and H2 mutants of the A/NJ/11/76 H1N1 strain of swine influenza virus differ by having either a lysine or a glutamic acid at position 153 of the hemagglutinin glycoprotein of the virus. In two separate experiments, experimental infection of swine with various doses of the H2 mutant resulted in the emergence in 11 of 20 animals of virus with the L phenotype. All evidence indicates that the H2----L mutation, selection, and evolution to predominance occurred within the 7-day span of individual infections. L and H2 mutations appear to act as alleles in the adaptation of virus, respectively, to natural and laboratory hosts. Although the gradual evolution of mutants during sequential infections is commonplace, the present recognition of rapid and predictable evolution of mutants of increased replication efficiency and specific phenotype in the natural host, to our knowledge, is unprecedented.

Animals↗
PubMed1987

Immunologic response to influenza virus neuraminidase is influenced by prior experience with the associated viral hemagglutinin. III. Reduced generation of neuraminidase-specific helper T cells in hemagglutinin-primed mice.

In BALB/c mice primed by influenza virus infection to H3 hemagglutinin and N2 neuraminidase, presentation of N2 in association with a heterosubtypic (H7) hemagglutinin results in production of a greater amount of N2 antibody than is found with homologous (H3N2) reimmunization. Titration of primed helper T cell (Th) activity by adoptive transfer of purified T cells to athymic mice given H6N2 vaccine demonstrates a lesser number of N2-specific Th cells in mice subjected to homologous reimmunization. We conclude that Th cells participate in the mediation of intermolecular (intravirionic) antigenic competition between influenza virus hemagglutinin and neuraminidase.

Animals↗
PubMed1987

Immunologic response to influenza virus neuraminidase is influenced by prior experience with the associated viral hemagglutinin. II. Sequential infection of mice simulates human experience.

In man, vaccination with neuraminidase (NA) in H7N2 virus hybrids elicits greater anti-NA response than does N2 NA in H3N2 conventional vaccine, presumably because humans are H3 hemagglutinin (HA) primed and anti-H3 anamnestic response depresses concomitant N2 responses by antigenic competition. In a laboratory model, BALB/c mice were primed by different schedules of infection with H3N1, H3N2, and H3N7 viruses and given H3N2 and H7N2 vaccines equivalent in NA immunogenicity. In schedules using sequential infections, but not after a single infection with any virus, anti-N2 booster response was fourfold greater with H7N2 vaccine and was reciprocal to the magnitude of anti-H3 response. Thus, HA-influenced suppression of immunologic response to viral NA requires adequate HA priming but is not unique to man and can be studied in the murine model. An incidental finding of this study was the sharing of cross-reactive determinants by N1, N2, and N7 NA.

Animals↗
PubMed1987

Immunologic response to the influenza virus neuraminidase is influenced by prior experience with the associated viral hemagglutinin. I. Studies in human vaccinees.

Analysis of an earlier study of H3N2 and H7N2 inactivated influenza vaccines in schoolchildren demonstrated a greater viral neuraminidase (NA) immunogenicity of the vaccine containing the H7 hemagglutinin (HA) antigen to which they had not been primed, despite the lesser NA antigen content of that vaccine. Thus, prior experience with the influenza viral HA appeared to have a negative influence on immune response to NA, the associated external glycoprotein, presumably on the basis of intermolecular antigenic competition. In a second study, sequential immunologic response to influenza viral NA was compared in college students who were immunized with either conventional commercial vaccine or an antigenic reassortant H7N1 vaccine, and who subsequently experienced natural infection with an H1N1 influenza virus. Although both vaccines were only marginally immunogenic in inducing NA antibody response in seronegative subjects, in vaccinees initially seropositive for HA antibody significant NA antibody titer increases occurred with H7N1 vaccine. Subsequent natural infection boosted NA antibody less effectively in the population previously primed by natural infection than in initially seronegative subjects primed by H7N1 vaccination. It is suggested that primary immunization monospecific for influenza viral NA may alter the subsequent pattern of immune response to one more favorable to the induction of NA antibody when virus is encountered.

Adult↗
PubMed1987

Antigen-presenting B cells and helper T cells cooperatively mediate intravirionic antigenic competition between influenza A virus surface glycoproteins.

Parenteral vaccination of BALB/c mice primed by infection with H3N2 variants of influenza A virus results in a reduced production of N2 antibody in response to homologous (H3N2) vaccine compared with the response to an H7N2 vaccine equal in N2 immunologenicity. We now have studied the interaction in vitro of purified splenic B and T lymphocytes from variably immunized mice to ascertain the cellular basis of the hemagglutinin (HA)-influenced antibody response to neuraminidase (NA). Assay of the proliferative response of T cells in B/T-cell mixtures stimulated by H3N1 (HA-specific) and H6N2 (NA-specific) reassortant (recombinant) viruses in vitro has enabled us to differentiate cellular responses to HA and NA antigens. Using a factorial design in analysis of B/T-cell mixtures, we have shown that: (i) intravirionic HA is dominant over NA in both B- and T-cell priming; (ii) an increase in H3-specific B cells occurs in mice administered boosters of H3N2 vaccine, and an increase in N2-specific B cells occurs in those given a booster of H7N2 vaccine; and (iii) memory B cells function as antigen-presenting cells and interact with memory helper T cells in the mediation of intravirionic HA-NA antigenic competition in favor of HA. The damping of response to the NA antigen in favor of HA with reinfection prohibits balanced immunologic response to the two antigens. The present studies define further the complex immunology of influenza virus infection.

Animals↗
PubMed1984

Isolation of immunogenic neuraminidases of human influenza viruses by a combination of genetic and biochemical procedures.

Neuraminidases were purified from reassortant viruses (H6N1 and H6N2) containing the two antigenic subtypes (N1 and N2) found in human influenza viruses. Surface glycoproteins were solubilized with octylglucoside, and the neuraminidase was isolated by chromatography on DEAE-Sephadex. Neuraminidase isolated by this technique coeluted with viral lipids and spontaneously formed liposomes on dialysis. The purified neuraminidase was immunogenic in rabbits, producing a significant antibody response at dose levels as low as 1 microgram.

Animals↗