Status of varicella vaccine for healthy children.
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Antibodies, Viral↗
Biomedical subjects
S E Starr
Publications and source records attributed to S E Starr.
Prophylaxis of serious cytomegalovirus infection in renal transplant candidates using live human cytomegalovirus vaccine. Interim results of a randomized controlled trial.
We report the interim results of a randomized, double-blind, placebo-controlled, clinical trial of prophylactic, live, attenuated cytomegalovirus (CMV) vaccination (Towne strain of CMV) of renal transplant candidates (RTCs). One hundred seventy-two RTCs were treated and subsequently underwent transplantation and followed up for at least one year and up to five years after transplantation. Eighty-eight RTCs received vaccine, and 84 received placebo. Results were analyzed according to the prevaccination serologic status (anti-CMV antibody titer) of the recipient (R- or R+) and the donor (D- or D+). The overall incidence of CMV disease was highest in the R-D+ group and almost absent in the R-D- group. There was no difference in the incidence of CMV infection or disease between vaccinated and respective placebo control recipients in either the R-D+, R+D+, R+D-, or R-D- groups. In contrast, the severity of CMV disease was significantly decreased in R-D+ vaccinees vs R-D+ placebo-treated recipients. Moreover, in the R-D+ group, one- and five-year cadaver renal allograft actuarial survival rates were 73% and 62%, respectively, for CMV vaccinees vs 40% and 25%, respectively, for control placebo patients. We conclude that seronegative cadaver RTCs may benefit from vaccination with live, attenuated, Towne strain CMV vaccine before transplantation.
Adult↗
Natural killing of fibroblasts infected with low-passage clinical isolates of human cytomegalovirus.
Fibroblasts infected with most low-passage clinical isolates of human cytomegalovirus (CMV) were as susceptible to lysis by human natural killer (NK) cells as high passage AD-169-infected fibroblasts. NK lysis occurred despite the absence of detectable CMV-specific late membrane antigen(s) on the majority of the target cells infected with most of the low passage strains. The magnitude of NK lysis of different CMV-infected target cells did not correlate with their ability to induce IFN-alpha. NK cell-mediated lysis of cells infected with low-passage clinical isolates of CMV required both NK cells and HLA-DR+ accessory cells, as previously shown for AD-169-infected target cells.
Antigen-Presenting Cells↗
Cooperation between CD16(Leu-11b)+ NK cells and HLA-DR+ cells in natural killing of herpesvirus-infected fibroblasts.
We reported previously that natural killer (NK) cell-mediated lysis of cytomegalovirus-infected targets requires the presence of HLA-DR+ nonadherent peripheral blood mononuclear cells (NPBMC). In the present study we determined whether NK cell-mediated lysis of other herpesvirus-infected targets also requires HLA-DR+ cells. Depletion of either cluster designation (CD)16+ NK cells or HLA-DR+ cells from NPBMC significantly reduced their ability to lyse herpes simplex virus (HSV)- and varicella-zoster virus (VZV)-infected fibroblasts. When CD16- and HLA-DR- populations were mixed, lysis of both HSV- and VZV-infected targets was virtually completely restored, indicating that NK cells and HLA-DR+ cells were required for lysis to occur. Cell-free supernatants, obtained by incubating NPBMC or CD16- cells with HSV-o-VZV-infected targets, contained antiviral activity and stimulated HLA-DR-cells to mediate lysis of corresponding virus-infected targets. The addition of anti-interferon-alpha to supernatants abolished their ability to stimulate lysis. Thus, secretion of interferon-alpha by HLA-DR+ cells contributes to NK cell-mediated lysis of herpesvirus-infected targets.
Antigens, Differentiation↗
Detection of Toxoplasma gondii in the spinal fluid of a bone marrow transplant recipient.
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Adolescent↗
Effects of interferons and interleukin 2 on natural killing of cytomegalovirus-infected fibroblasts.
The ability of nonadherent peripheral blood mononuclear cells of normal individuals to lyse noninfected and cytomegalovirus (CMV)-infected human fibroblasts was enhanced by preincubation with recombinant human alpha interferon (alpha-rIFN) or beta (beta-rIFN). In contrast, recombinant human gamma IFN (gamma-rIFN) augmented natural killing (NK) against both targets relatively poorly. Recombinant or natural human interleukin 2(IL-2) also augmented NK against noninfected and CMV-infected targets. Augmentation of NK by IFN or IL-2 could be blocked by the addition of corresponding antisera. IL-2-enhanced NK against CMV-infected targets was usually independent of alpha-IFN production.
Cytomegalovirus Infections↗
Requirement for HLA-DR+ accessory cells in natural killing of cytomegalovirus-infected fibroblasts.
The role of HLA-DR+ cells in NK activity against CMV-infected FS4 foreskin fibroblasts and K562 erythroleukemia cells was examined. When nonadherent PBMC were depleted of either HLA-DR+ or Leu-11b+ cells by treatment with mAbs plus C, NK activity against CMV-FS4 target cells was markedly reduced. In contrast, depletion of HLA-DR+ cells had no effect on NK activity against K562 target cells. When HLA-DR-depleted cells were added to Leu-11b-depleted cells, NK activity against CMV-FS4 was restored. Negative selection experiments indicated that the HLA-DR+ cells contributing to NK activity against CMV-FS4 are not B or T cells, while negative and positive selection experiments excluded a role for monocytes. Experiments in which HLA-DR- and Leu-11b- cells were mixed in varying proportions indicated that NK(CMV-FS4) is mediated by Leu-11b+ cells, while HLA-DR+ cells provide an accessory function. Irradiation (50 GY) abolished the NK effector function of Leu-11b+ cells, but not the accessory function of HLA-DR+ cells. The NK activity against CMV-FS4 of HLA-DR- cells was restored by the addition of rIFN-alpha or of cell-free supernatants generated by coculturing PBMC or Leu-11b- cells with CMV-FS4. The ability of these supernatants to restore NK activity of HLA-DR- cells was completely abrogated by the addition of neutralizing amounts of antibody to IFN-alpha. In related experiments, neutralization of IFN-alpha in NK assays had little or no effect on NK activity against CMV-FS4, suggesting that the accessory function of HLA-DR+ cells might be mediated by alternative mechanisms in addition to the secretion of extracellular IFN-alpha.
Antigen-Presenting Cells↗
Varicella vaccine studies in healthy children and adults.
Immunization of normal children and adults with Oka strain live varicella vaccine from several manufacturers has been studied in our laboratory and elsewhere. This paper summarizes clinical trials designed to obtain information on minimum dose immunogenicity pre- and postexposure prophylaxis, immunization of various age groups, and booster immunizations for seropositive individuals. These studies documented a 94% to 100% seroconversion rate with 95% to 100% persistence of antibodies at 3 to 4 years. Protective efficacy was more than 90%, and the vaccine was successful in preventing varicella when a high dose was given postexposure. Clinical reactions were limited to temperature elevations and minor papulovesicular rashes that occurred in 5% to 10% of vaccinees. Herpes zoster has been absent in vaccinated healthy individuals.
Adult↗
The combination measles, mumps, rubella and varicella vaccine in healthy children.
A clinical trial was conducted to compare the combination measles, mumps, rubella, varicella vaccine (MMRV) and the standard measles, mumps, rubella vaccine and subsequent varicella vaccine (MMR + V) in 15 to 17 month old healthy children. Both the MMRV and MMR + V schedules stimulated virtually 100% seroconversion for all component viruses. Mean antibody titers were similar for each virus component in the two vaccine groups. Clinical reactivity post immunization was also similar with 25-29% morbilliform rashes, 12-25% mild papulovesicular (varicella) rashes, and 12.5-18% temperature elevations above 101 degrees F. Antibodies to measles, mumps, and rubella viruses were persistent in 8/10 originally seronegative MMRV vaccinees and 5/5 MMR + V recipients tested. On MMRV recipient had a household exposure to chickenpox during the year postvaccination that resulted in a subclinical boost in varicella antibody titer. Two children in the MMR + V group had close varicella exposures: one developed mild varicella (20 lesions). There were no known exposures to natural measles, mumps, or rubella. Three of four MMRV vaccinees with low titer antibody to varicella prior to immunization had greater than four-fold rises in antibodies. The combination measles, mumps, rubella, varicella vaccine is an immunogenic, safe and cost effective approach to varicella immunization of healthy children.
Antibodies, Viral↗
Interleukin 2 enhances natural killing of varicella-zoster virus-infected targets.
Preincubation of peripheral blood non-adherent mononuclear cells with purified or recombinant interleukin 2 (IL-2) significantly enhanced natural killer (NK) activity against uninfected and varicella-zoster virus (VZV)-infected targets, while antibody-dependent cellular cytotoxicity (ADCC) against VZV-infected targets was not increased. Preincubation of effector cells with IL-2 had no effect on conjugate formation, but lysis of both targets was increased in single cell assays. IL-2-enhanced NK against VZV-infected targets was independent of gamma-interferon (gamma-IFN) production.
Adult↗
Combination measles, mumps, rubella and varicella vaccine.
A comparative clinical trial was conducted in 15- to 17-month-old healthy children to compare an investigational combination measles, mumps, rubella, varicella (MMRV) vaccine v standard measles, mumps, rubella vaccine followed 6 weeks later with the varicella (MMR + V) vaccine. Both the MMRV and MMR + V vaccine schedules stimulated virtually 100% seroconversion for all component viruses. Mean antibody titers were similar for each virus component in the two vaccine groups. Clinical reactivity postimmunization was also similar with 25% to 29% morbilliform rashes, 12% to 25% mild papulovesicular (varicella) rashes, and 12.5% to 18% temperature elevations above 38.3 degrees C (101 degrees F). Antibodies to measles, mumps, and rubella viruses were persistent at 1 year of follow-up in both groups. Varicella antibody was persistent in 8/10 originally seronegative MMRV vaccinees and 5/5 MMR + V vaccine recipients tested. One MMRV vaccine recipient had a household exposure to chickenpox during the year postvaccination that resulted in a subclinical boost in varicella antibody titer. Two children in the MMR + V vaccine group had close varicella exposures; mild varicella (20 lesions) developed in one. There were no known exposures to natural measles, mumps, or rubella. Three of four MMRV vaccinees with low titer antibody to varicella prior to immunization had greater than fourfold increases in antibodies after vaccination. The combination MMRV vaccine is an immunogenic, safe, and cost-effective approach to varicella immunization of healthy children. Continued work is needed to select the appropriate dose of varicella component, to assure higher persistence rate of varicella antibody.
Antibodies, Viral↗
Human lymphocyte, monocyte and polymorphonuclear leucocyte mediated antibody-dependent cellular cytotoxicity against varicella-zoster virus-infected targets.
The ability of lymphocytes, monocytes and polymorphonuclear leucocytes (PMN) to mediate antibody-dependent cellular cytotoxicity (ADCC) against varicella-zoster virus (VZV) infected fibroblasts was tested in 51Cr release and single-cell assays. Lymphocytes had the greatest lytic activity, monocytes were intermediate in activity and PMN were the least active. Lymphocyte-mediated ADCC was complete by as early as 4 h, while maximal monocyte and PMN-mediated ADCC required 18 h. In single-cell assays, monocytes formed conjugates with both uninfected and VZV-infected targets, but did not cause lysis. PMN failed to bind or lyse either target. Few lymphocytes formed conjugates with uninfected targets, while a higher percentage bound to VZV-infected targets and caused lysis. In the presence of human antibodies to VZV conjugate formation and lysis of VZV-infected targets was significantly increased with each of the effector-cell populations. Lymphocytes had the highest lytic activity in single-cell assays as well as in 51Cr release assays, and were responsible for most of the ADCC detected in adult peripheral blood against VZV-infected targets.
Antibodies, Monoclonal↗
Antimicrobial therapy of bacterial sepsis in the newborn infant.
Septicemia continues to be an important cause of neonatal morbidity and mortality. The bacteria most commonly responsible are group B beta-hemolytic streptococci and Escherichia coli, but regional differences exist. Recently sepsis caused by Staphylococcus epidermidis has occurred with increasing frequency in several neonatal intensive care units. Other organisms are less commonly responsible. The choice of antibiotics for suspected sepsis is based on the possible organisms involved and their antibiotic susceptibility patterns, which vary from hospital to hospital and at different times in the same hospital. Currently recommended initial therapy consists of a penicillin and an aminoglycoside, usually ampicillin and gentamicin. The addition of vancomycin is indicated when staphylococcal septicemia is suspected. During outbreaks of neonatal sepsis caused by aminoglycoside-resistant gram-negative bacteria, the use of third-generation cephalosporins or acylaminopenicillins may be appropriate, depending on the results of susceptibility tests. Continuing efforts to develop antibiotics for the treatment of neonatal sepsis are warranted.
Aminoglycosides↗
Resistance of seropositive volunteers to subcutaneous challenge with low-passage human cytomegalovirus.
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Antibodies, Viral↗
The role of pretransplant immunity in protection from cytomegalovirus disease following renal transplantation.
To determine the extent to which pretransplant immunity resulting from natural infection protects against cytomegalovirus (CMV) disease, we analyzed CMV serology on 153 kidney donor and recipient pairs and followed transplant patients to determine incidence and severity of CMV disease. The overall incidence of CMV disease was 22%. Significant differences occurred in CMV disease incidence and severity, depending on the immune status of the kidney donor and recipient. Among recipients of kidneys from seropositive donors, immunity offered significant protection from CMV disease, reducing its incidence from 61% in nonimmune to 24% in immune patients (P less than 0.01). Pretransplant immune patients also had fever CMV-related complications. Among recipients of kidneys from seronegative donors, pretransplant immunity conferred a significant risk of CMV disease; immune patients had a 20% incidence of CMV disease compared with 2% in nonimmune patients (P less than 0.02). Disease was generally mild in all patients receiving kidneys from CMV infection had a 3-fold higher incidence of CMV disease than patients with reactivation infection (P less than 0.01). The incidence of CMV disease was similar in immune patients, whether they received a kidney from a seropositive or a seronegative donor. However, an important observation was that disease was significantly more severe in immune patients receiving a kidney from a seropositive donor (P less than 0.05). This indicates that if kidneys from seropositive donors are selected for use only in seropositive recipients, this places the immune patient at a higher risk for severe CMV disease. We conclude that pretransplant immunity offers a significant advantage to patients receiving kidneys from seropositive donors.
Adolescent↗
The future of varicella vaccine.
Based on conservative figures, an estimated 60 million varicella-zoster cases occur annually worldwide, highlighting the global significance of this disease. The development of a viable varicella vaccine, therefore, raises important questions as to the indications for its use in normal children, normal seropositive and seronegative adults, and immunocompromised patients. A review of the available data addresses the potential future role of the varicella vaccine in these groups.
Chickenpox↗
Towne-vaccine-induced prevention of cytomegalovirus disease after renal transplants.
91 renal transplant candidates were randomised to receive Towne strain cytomegalovirus (CMV) vaccine or placebo at least 8 weeks before transplantation. The vaccine was well tolerated and there was no vaccine virus excretion. Serological and cellular immune responses developed in most vaccines but were lower in the transplant patients than in healthy volunteers and some of the seronegative patients failed to mount responses. CMV infection occurred in most of the seronegative vaccine-treated or placebo-treated patients who received kidneys from seropositive donors, but the illnesses were less severe in the vaccines than those in similarly exposed placebo-treated patients. Vaccine-treated patients who received kidneys from seronegative donors did not excrete virus, and therefore the vaccine virus was not reactivated from a putative latent state despite immunosuppression at the time of transplantation.
Antibodies, Viral↗
Varicella vaccine trials in healthy children. A summary of comparative and follow-up studies.
Beginning in 1979, OKA and KMcC strains of varicella zoster virus (VZV) vaccine were administered to 369 healthy seronegative children in a sequence of ten comparative clinical trials. Postimmunization clinical reactivity was minimal with the OKA vaccines but was unacceptably high (32%) with the KMcC passage-40 vaccine. Ninety-three percent to 100% immunogenicity was noted by fluorescent antibody assay and in vitro lymphocyte proliferation to VZV antigens. Follow-up studies demonstrated persistence of antibody and in vitro lymphocyte proliferation responses and protection or modification of infection nine to 48 months after immunization. Only five episodes of mild varicella occurred in children in whom seroconversion had occurred. These episodes were noted after at least 281 known varicella exposures. Vaccine virus reactivation as zoster had not occurred in any child.
Adolescent↗