Carl D. Brandt

Cell-mediated Immunity to Respiratory Syncytial Virus Induced by Inactivated Vaccine or by Infection

Extract: Transformation and increased mitotic activity in donor lymphocytes exposed to specific antigens is considered by many to be a manifestation of cell-mediated immunity. In attempts to understand the apparent “sensitization” of individuals to respiratory syncytial virus (RSV) as a result of receiving inactivated RSV vaccine, in vitro lymphocyte transformation studies were carried out on infants who had received inactivated RSV vaccine and on infants who had received a similarly prepared inactivated African green monkey kidney (AGMK) cell-grown parainfluenza type 1 virus vaccine or a trivalent parainfluenza vaccine prepared in hens eggs. Each group included some infants who had, and others who had not, undergone natural RSV infection under our observation before the lymphocyte studies.Lymphocytes were studied from 21 infants and young children who had received the inactivated RSV vaccine, 14 who received a similarly prepared inactivated parainfluenza 1 vaccine, and 5 who received a trivalent parainfluenza vaccine. Twelve of the RSV vaccinees and 14 of the parainfluenza vaccinees had been naturally infected with RSV as indicated by virus recovery and/or antibody rise between the time of vaccination and the lymphocyte studies. In comparing the arithmetic mean for RSV-specific transformation and mitotic activity there was a significant difference between RSV vaccinees and parainfluenza vaccinees whether one compared those who had undergone natural RSV infection or those who had not undergone natural infection. The difference between RSV vaccinees who had not undergone natural RSV infection and RSV-infected parainfluenza vaccinees also was significant. There was a greater level of transformation and mitotic activity in those who had experienced natural infection than those who had not among both RSV vaccinees and parainfluenza vaccinees, but these differences were not significant statistically.Speculation: We take these findings to mean that natural RSV infection probably stimulates a systemic cell-mediated immunity response and that such a response is definitely induced after administration of killed RSV antigen. These findings are consistent with the hypothesis that cell-mediated sensitization may in some way contribute to the altered response to natural infection which occurred after use of inactivated RSV vaccine. Our findings do not support the hypothesis that systemic cell-mediated immunity per se is important in protecting against RSV infection. The findings also suggest the possibility that transplacentally conferred RSV lymphocyte sensitization might play a part in the pathogenesis of nonvaccine related RSV bronchiolitis which characteristically occurs during early infancy, frequently in the presence of measurable serum antibody.

Clinical features of acute gastroenteritis associated with human reovirus-like agent in infants and young children

Between January, 1974, and June, 1975, infection with a human reovirus-like agent was detected in 47% of 152 infants and children hospitalized with acute gastroenteritis. Certain epidemiologic, clinical, and laboratory findings appear to be helpful in distinguishing gastroenteritis due to HRVLA from other causes in those children sick enough to require hospitalization. Age: 76% of infants and children seven through 12 months of age and 76% of those 13 through 24 months of age had infection with the HRVLA, whereas such infection was found in only 21% of infants under six months of age and 23% of children 25 through 60 months of age. Time of Year: 61% of patients studied during the cooler months had HRVLA infection and such infection was not found from June to October. Frequency of vomiting and dehydration: Twice as many patients infected with HRVLA as those who were not had vomiting (92%) and significant dehydration (83%).

Longitudinal study of rotavirus infection and gastroenteritis in families served by a pediatric medical practice: clinical and epidemiologic observations.

During 29 months of prospective longitudinal study of diarrhea in the home, human rotaviruses (HRVs) infected one or more members in 51% of 65 families, 35 of 126 children (28%) and 16 of 124 adults (13%). Within the 33 affected families, 57% of 62 children and 25% of 65 adults were infected. HRV gastroenteritis peaked at 40/100 person years at ages 12 to 23 months and decreased to 5 episodes/100 person years in adults. Among 25 children 0 through 36 months of age who had HRV infection, 88% were symptomatic. Of the 22 children with symptomatic HRV infection, 1 required hospitalization and 8 were seen by their physician for supportive care. HRVs were found in 12% of 216 stools obtained during gastrointestinal illness, but in only 0.2% of 1238 non-illness stools tested. HRV infections were noted as early as October and as late as April. Of 33 families who were studied for 2 seasons, at least 1 individual in each of 3 families experienced HRV infections in both years, but only one, an adult, shed virus and had symptoms in both seasons.

Aerosolized ribavirin in the treatment of patients with respiratory syncytial virus disease

Thirty children 1 to 33 months of age were enrolled in a study of aerosolized ribavirin therapy for respiratory syncytial virus lower respiratory tract illness. Twenty patients received ribavirin and 10 received placebo. There were no significant differences between the groups in chronologic or gestational age or in days of illness prior to admission. Among patients with pneumonia 17% of 6 placebo patients vs. 64% of 11 ribavirin patients had radiographic evidence that multiple lung lobes were affected (P = 0.06). Placebo patients received 42.5 to 94.7 hours (mean, 58.6) of aerosol therapy, whereas ribavirin patients received 36.3 to 95.6 hours (mean, 55.7). Seventy-seven percent of all study patients were discharged within 5 days of starting treatment. Severity of illness was evaluated daily using a scale of 0 (normal) to 4+ (most severe). Ribavirin patients initially had a mean severity score 0.5 higher than placebo patients. By Day 2, their rate of improvement was significantly greater than that of placebo patients (P = 0.001). By Day 5, 36% of ribavirin patients with rales showed improvement, whereas rales persisted in 100% of placebo patients. The rate of improvement of oxygen saturation from first to last day of treatment was statistically significant only for ribavirin patients (P = 0.02). On Day 3, 65% of ribavirin patients (13) vs. 50% (5) placebo patients shed 10-0.5 50% tissue culture infective dose virus per 0.2 ml of nasal wash. No side effects or toxicity were associated with aerosol therapy. A short course of ribavirin treatment (approximately 3 days) proved safe and beneficial.

Respiratory syncytial virus neutralizing activity in nasal secretions following natural infection.

Summary The development of RS virus neutralizing activity in nasal secretions was documented in 7 of 17 infants and children who were hospitalized for RS virus lower respiratory tract disease. Most of the patients in whom a rise in secretory neutralizing activity did not occur possessed moderately high levels of such activity in secretions collected at the time of admission to the hospital. At present we favor the view that this acute phase neutralizing activity represents antibody which developed early in the course of infection (possibly earlier than serum antibody) rather than the alternate possibility of nonspecific inhibitors in secretions.

Temperature-sensitive mutants of influenza A virus: response of children to the influenza A/Hong Kong/68-ts-1(E) (H3N2) and influenza A/Udorn/72-ts-1(E) (H3N2) candidate vaccine viruses and significance of immunity to neuraminidase antigen.

Extract: The influenza A/Hong Kong/1968-ts-1[E] (H3N2) candidate live virus vaccine strain, which had previously been shown to be safe and protective in seronegative adult volunteers, was administered intranasally to 21 children at a dose of 105 TCID50. One group contained 15 children (5–11 years of age) who lacked serum anti-body to the hemagglutinin (≤ 1:8), but possessed serum antibody to the neuraminidase antigen. The second group included six children (2 4/12–3 10/12 years of age) who lacked serum antibody to both hemagglutinin and neuraminidase surface antigens of the influenza A virus. Twelve of the 15 children in the first group were infected, but only one child developed mild rhinitis; 6 of the 12 infected vaccinees shed virus for a short interval, while 11 of the group developed an immunologic response. In contrast, each of the six vaccinees who lacked serum antibody for both surface of the virus shed a relatively larger quanity of virus over a longer interval than those in the first group, and each child developed an immunologic response. Four of the doubly seronegative vaccinees developed a febrile response during their infection and three had rhinitis. Two additional children who lacked serum antibody to both surface antigens of influenza virus were given the influenza A/Udorn/1972-ts-1[E] recombinat virus which had the same genetic temperature-sensitive (ts) lesions as the Hong Kong virus but possessed a more contemporary hemagglutinin. this recombinant virus infected both of the children and induced transient fever in one. None of the total of 23 vaccinees developed signs or symptoms of lower respiratory tract involvement. Although the Hong Kong and Udorn ts-1[E] recombinants possessed two discrete ts lesions, evidence of genetic instability was detected during infection of two of the eight young children who lacked immunity to both surface antigens of the virus. It seems likely that a complete assessement of the virulence of vaccine candidate influenza a viruses can only made in individuals who lack immunity to both surface antigens of the influenza A virus.Speculation: These findings suggest the following.1. Antineuraminidase antibody (ANAB) to previously experienced influenza strains can modify clinical response to infection with attenuated influenza virus as well as natural infection.2. The full expression of virulence of ts recombinants or any live influenza vaccine may be mainfest only in individuals lacking both hemagglutination-inhibition (HI) antibody and ANAB.3. Evaluation of the immune and clinical response to viruses such as the ts-1[E] recombinant in young infants and children who lack both HI antibody and ANAB has value both because of their potential as vacciness and also as a model for an attenuated vaccine against the next pandemic influenza variant.4. Standards for future ts or other live influenza vacciness must include genetic stability in individuals lacking HI antibody and ANAB and failure to induce a febrile response in such individuals.

Fecal adenoviruses from a longitudinal study of families in metropolitan Washington, D.C.: Laboratory, clinical, and epidemiologic observations

During a 29-month period, we studied enteric infection in 70 families from a pediatric practice in suburban Washington, D.C. Fecal adenoviruses were detected in stools of 18 patients by tissue culture and electron microscopic procedures. From 6 through 11 months of age, the incidence of fecal adenoviruses associated with enteritis was seven per 100, and of confirmed enteric adenoviruses (EAds), three per 100 individuals per year. All EAds belonged to subgenus G (type 41). All three patients with EAds had diarrhea; two had vomiting and one had fever, but none required hospitalization. Ten of the 15 patients with non-EAds were younger than 2 years, and 60% had diarrhea, 40% had vomiting, and 20% had fever. Combined gastrointestinal and respiratory symptoms occurred more often in those who shed non-EAds (three of 11) than in matched controls (two of 48, P = 0.04). An adenovirus was detected in approximately 6% of gastroenteritis episodes, and confirmed EAds were present in approximately 2% of episodes of gastroenteritis in children younger than 2 years of age. None of the contacts of patients with non-EAds shed such virus in their stools. None of nine family contacts of those with EAd appeared to shed adenovirus in stool. In contrast, rotavirus spread readily to exposed adults (25% of 65) and children (56% of 62) when a child in similar families had rotavirus infection.

Respiratory syncytial virus infections and intravenous gamma-globulins.

The respiratory syncytial virus (RSV) is a common cause of bronchiolitis and pneumonia in infants and young children. Throughout the world annual RSV epidemics result in numerous hospitalizations, substantial morbidity and some mortality. Until the recent introduction of ribavirin only supportive therapy has been available for treating these infections. The development of animal models of RSV infection and the observation that some lots of immunoglobulin prepared for intravenous administration contained substantial RSV-neutralization antibody titers, prompted a series of studies examining the safety and efficacy of immunoglobulin prepared for intravenous administration in the prophylaxis and treatment of RSV infections. This discussion will review our published, or soon to be published, studies on the use of Sandoglobulin® for both immunoprophylaxis and immunotherapy of RSV infections in cotton rats. It will summarize studies utilizing both parenteral and topical (tracheal) Sandoglobulin® therapy for RSV infections in owl monkeys. Finally the results of a small double blind trial of parenteral albumin or Sandoglobulin® in the therapy of RSV bronchiolitis and/or pneumonia in hospitalized children will be reviewed. The data show that immunoprophylaxis and immunotherapy of RSV infections in laboratory animals was well-tolerated, was safe and induced highly significant reductions in RSV shedding from the lower respiratory tract. Further, immunotherapy of RSV infections in children was also well-tolerated, induced no short or long term evidence of toxicity or injury and caused significant improvements in oxygenation and reductions in RSV shed from the respiratory tract. We believe that further studies are indicated to explore efficacy and safety of immunoglobulin prepared for intravenous administration in RSV as well as other viral lower respiratory tract infections in children.

Serum complement in acute bronchiolitis.

Summary The levels of total complement and β1C/1A-globulin were tested in 20 infants with acute bronchiolitis and in 7 infants without respiratory tract disease. The level of total complement or complement component β1C was not depressed in the acute phase of acute bronchiolitis whether RS virus-associated or not. This does not negate the possibility of an immunological pathogenesis of RS virus disease.

Epstein-Barr virus DNA in the blood of infants, young children, and adults by age and HIV status.

Polymerase chain reaction (PCR) methodology was used to detect Epstein-Barr virus (EBV) DNA in peripheral blood mononuclear cells (PBMCs) from children and adults whose HIV status (i.e., infected or uninfected) is known. Initial EBV infections especially occurred in children between the ages of 7 and 24 months. EBV-positive children with vertically acquired HIV infection tended to have a detectable blood level of EBV DNA for a period of years, and their EBV DNA blood levels often exceeded 10,000 copies/0.1 ml of blood--hundreds of times higher than levels typically found in EBV-positive, HIV-uninfected children of the same age. EBV DNA was found in PBMCs in 26% of 49 HIV-infected mothers who were sampled during their pregnancy, but the median EBV DNA level in their EBV-positive samples was low--only 50 copies/0.1 ml blood. In limited tests with specimens from children infected with both HIV and EBV, high blood levels of EBV DNA unexpectedly appeared to be associated with decreased blood levels of HIV DNA (p = .063).