Julita O. Arrobio

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%).

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.

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.

585 ENTERIC ADENOVIRUS 40 & 41(EAds) IN GASTROENTERITIS S8S OF INFANTS & YOUNG CHILDREN

From 9/81 thru 9/83, adenoviruses (ad) were detected by electron microscopy and/or tissue culture in the stools (st) of 3.8% (46 of 1121)children with acute diarrhea. 35 viruses (76%) were EAds; 33 of these were the sole enteric pathogen. The EAds were confirmed by neutralization in 293 cells (25); by restriction endonuclease analysis (13) [two (15%) type 40, 11 (85%) type 41]; and/or by hybridization probes (22). The latter two tests were done directly on st. (26% of the EAd infections were nosdcomial.) Mean age for 35 EAd patients (pts) was 8.3 mos (range 1-34). 77% were younger than 1 year; 43% were 6 mos or younger. 83% of EAd infections were seen from Sept thru March with a peak in December when 9.8% of 61 enteritis pts had EAd in their st. 54% with EAd had vomiting, 63% of these for >4 days. All had diarrhea (>4 days in 74%) and fever (>4 days in 38%). 26% had mild dehydration. Upper respiratory (URI) symptoms were noted in 20%, râles and wheezing in 9%. St had PMNs in 18% of 22. 11 pts with non-EAd fecal ad in st were young (mean 6.8 mos range 2-11 mos). Non-EAd cases exhibited no seasonality and had vomiting for ≥4 days in 28%. 36% of 11 non-EAd pts vs 74% of 35 EAd ⊕pts had diarrhea for >4 days (p=.034). Non-EAd pts had more URI (40%) than non-nosocomial EAd pts, 8% (p=.033). In young infants and children, EAds are associated with enteritis, resulting in hospitalization and nosocomial enteritis.

DIARRHEA-ASSOCIATED ADENOVIRUSES: RAPID PRESUMPTIVE DIAGNOSIS BY ELECTRON MICROSCOPY

There is a need for the rapid recognition of infection by the newly-described enteral or diarrhea-associated adenoviruses (adenoviruses that are of proposed neutralizing serotypes 40 and 41, or that have restriction endonuclease electrophoretic profiles of Wadell groups F or G). These viruses especially infect infants, and they tend to be fastidious in their growth in conventional cell cultures.During a 6 minute viewing per specimen, adenoviruses were visualized by direct electron microscopy (EM) or immune EM in the stools of 52 pediatric inpatients with acute gastroenteritis. Forty (77%) of these viruses proved to be enteral adenoviruses on the basis of neutralization test in 293 cells and/or electrophoretic profile. However, only 5 (36%) of 14 patients with less than 1 adenovirus particle per minute of direct EM viewing of the original diarrhea stools were found to have an enteral adenovirus, as compared to 35 (92%) of 38 patients with 1 or more such particles per minute of viewing (X2 = 18.34, P = < .01). Thus the quantity of adenoviruses found in a diarrhea stool would appear to provide a strong presumptive indication of the presence or absence of an enteral adenovirus. This determination can be made within 15 minutes of specimen collection.