Biomedical subjects
Publications and source records attributed to J P Fox.
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We have completed production in rabbits of potent antisera to the 90 classified rhinovirus serotypes by using methods previously described (M. K. Cooney and G. E. Kenny, Proc. Soc. Exp. Biol. Med. 133:645-650, 1970). Systematic testing by neutralization tests has revealed significant numbers of cross-relationships among rhinovirus types, some of which have already been reported. Herein, our observations are compared with cross-reactions reported in National Institutes of Health reference guinea pig antisera. Also, original rhinovirus isolates, representing serotypes known to be antigenically related to other rhinoviruses, were tested against rabbit antisera to the related serotypes. These tests revealed extensive antigenic variation among isolates identified as rhinovirus 12:78 or 36:58, which are reciprocally related pairs, 41, reciprocally related to 13, and 67, which is related to both 9 and 32. If the rhinovirus serotypes were grouped according to antigenic relationships, 50 types could be included in 16 groups.
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Young adults vaccinated in late spring of 1978 with one dose of vaccine containing either 7 microgram or 20 microgram of A/USSR (H1N1) hemagglutinin, followed by a dose of trivalent (A/USSR, A/Texas, B/Hong Kong) vaccine, were observed through an epidemic of A/Brazil influenza in the winter of 1978-1979, and of influenza B in 1979-1980. Influenza infection was diagnosed by virus isolation or serological titer rises between the spring seasons of 1978, 1979, and 1980. During the A/Brazil epidemic, rates of reported influenza-like illness and serologically confirmed H1N1 influenza infections were similar for all vaccine groups and two control groups. Naturally acquired antibody, but not vaccine-induced hemagglutination-inhibiting antibodies (HAI), appeared protective. During the influenza B epidemic, a lower rate of serologically confirmed infections was observed in the 1978 vaccine cohort than in one control group.
A double-blind trial of influenza virus vaccines was initiated in the fall of 1976. One dose of 500 chick cell-agglutinating units of subvirion influenza B vaccine gave negligible adverse reactions in schoolchildren and young adults, whereas whole-virus vaccine caused systemic reactions. Subvirion vaccines induced a complement-fixing antibody response, particularly in children, that returned to near original levels over a two-year period. Levels of hemagglutination-inhibiting (HAI) antibodies induced by the vaccine remained elevated for at least 2.5 years in the absence of natural challenge. When a major epidemic of influenza B occurred in the winter of 1979-1980, the youngest children (originally six to nine years of age) had the highest infection rate (53%); in this group protection was estimated at 44% +/- 17% by serologic evidence of infection. Little vaccine efficacy was demonstrated in older age groups at three years after vaccination, despite the persistence of HAI antibodies induced by the vaccine.
A double-blind placebo-controlled trial of ribavirin was conducted in 97 young adult males naturally infected with influenza virus similar to A/Brazil/11/78 (H1N1). Ribavirin was given orally at a dose of 1,000 mg/day for five days beginning within 24 or 48 hr after onset of clinical influenza. The clinical signs and symptoms of influenza and quantitative viral shedding were the same in ribavirin- and placebo-treated groups. Ribavirin treatment was associated with significantly fewer fourfold or greater rises in antibody to influenza A viral antigen by the complement-fixation test, while rises in hemagglutination-inhibiting antibody titers occurred with equal frequency in both groups. The ribavirin-treated group experienced significant increases in bilirubin and in reticulocyte counts after onset of therapy.
Antibody levels before and after vaccination were studied among schoolchildren and young adults given commercial A/New Jersey/76 (HswN1), A/Victoria/75 (H3N2), and B/Hong Kong/72 vaccines in the fall of 1976. Children responded better to a single dose of the A/New Jersey subvirion vaccine than had previously been observed, particularly to a new subvirion vaccine. Hemagglutination-inhibiting antibody titers decreased during the first six months after vaccination but appeared stable thereafter. Persistence seemed to depend on the antigenic mass in the first dose, since persons given one or two doses of the most potent whole-virus vaccine had by far the highest levels of antibody to A/New Jersey virus after 2 1/2 years, higher than for those given two doses of any of the other vaccines. Natural infection with A/USSR (H1N1) influenza virus boostered the titers of antibody to A/New Jersey virus, particularly in children. Persons given a bivalent subvirion vaccine had the best response to A/Victoria antigen. Subvirion vaccines induced complement-fixing antibodies in half of the children.
Surveillance for influenza virus infections began in mid-1976, continued through three small influenza A outbreaks (mixed A/Victoria and A/Texas outbreaks in Spring, 1977, and Winter, 1977-1978 and an A/USSR outbreak peaking in March, 1978). Nasopharyngeal specimens were collected for virus isolation from febrile respiratory disease patients coming from four sources: 1) the Sunday walk-in clinic of the Group Health Cooperative of Puget Sound; 2) 200 families under continuous surveillance for respiratory viral infections; 3) patients referred by interested community physicians or self-referred persons in vaccine evaluation studies; and 4) students presenting at the University of Washington health center. Influenza virus isolation rates were as high in children as adults and peaked earlier in adults than in children in all three epidemics. Although referred patients and university students yielded the highest isolation rate, nearly 30%, all four community sources were important in detecting an impending epidemic.
One hundred forty-two allergic children aged three to 18 years were studied for evaluation of the usefulness of skin testing with influenza vaccine as a means of identifying those children who could be immunized safely despite their allergies to chickens, eggs, or feathers. One hundred twenty-eight children were fully immunized with bivalent influenza A/New Jersey/76-A/Victoria/75 vaccine. Twelve children had positive skin tests and were not immunized, and two developed positive skin tests after their first injection. One child had urticaria 8 hr later, one had a nonspecific reaction, and one had a self-limited erythema multiforme reaction eight days after the second injection. All others tolerated the procedure well. History of sensitivity to eggs was not as reliable an indication of vaccine sensitivity as skin testing with vaccine. A negative result of an intradermal skin test with a 1:100 dilution of the vaccine in saline appeared to be a reliable indicator of allergic subjects who could be immunized against influenza without fear of life-threatening acute allergic reactions.
The following findings were made from observations of adenovirus (AV) infections in Seattle VW families, 1965-1969, which extended the 1961-1965 New York VW studies: That infections are predominantly enteric, may be abortive or invasive and followed by persistent intermittent excretion was confirmed. That such excretion is most characteristic of types 1, 2, 3 and 5 viruses may explain why these types were usually endemic. However, since observed duration of excretion was not increased despite a longer average observation period, persistent excretion appears not to continue indefinitely and generation-to-generation transmission now seems improbable. Unilike New York, alternate cycling of types 1 and 2 viruses was not seen. Among homotypic susceptibles, infection rates for the endemic types were highest in infants (greater than 90% for types 1 and 2), decreased with age in older children but increased in parents, perhaps because of closer contact with infants. Development of serum neutralizing antibody was most frequent (about 90%) after types 1 and 2 infection; in all cases, titers decayed over time. While delayed virus spread related to persistent intermittent excretion did occur, spread closely following new or renewed (after larger than or equal to 3 months) excretion was more important. Sibling introducers were more effective spreaders than infants, and duration of excretion was more important than mode. These data indicate that homotypic immunity is 85% protective against infection. A protective effect of heterotypic immunity could not be shown. Illness (chiefly respiratory and often febrile) was associated with 49% of infections in susceptibles and with 65% when respiratory shedding occurred. The contribution of AV to all infectious illness, based on virus-positive infections only, was 5% in infants and 3% in the 2-4-year age group; for febrile illness, the corresponding contributions were about 10% and 5%. Inclusion of infections discovered only be serology (49% of all infections) would greatly increase the contribution of AV to illness.
Nearly two thousand nonimmune, postpubertal females given rubella vaccine in western Washington state in 1970 to 1974 were followed up for acute reactions, inadvertent pregnancy onset, and (776 women) seroresponse. Low-level prevaccination immunity appears to explain most of the apparent vaccine failure (11.6%). The 27 vaccine-complicated pregnancies identified resulted in 17 apparently normal infants (nine from nonimmune mothers). The remaining ten were terminated by abortion (four in nonimmune women), but no abortus yielded rubella virus. Frequency of post-vaccination complaints (largely joint-related) varied with age (higher in those over 25 years), with vaccine (higher after HPV-77-DE-5 than after Cendehill strain virus), with stage of menstrual cycle when vaccine was given, and with method of contraception.
A stochastic simulation epidemic model based on discrete time intervals and appropriate for any infectious agent spread by person-to-person contacts is presented. The population is highly structured, allowing for five age groups and for subgrouping mixing in families, neighborhoods, schools, and preschool playgroups as well as total community mixing. With proper choice of relative susceptibility by age, length of latency and infectivity periods, pathogenicity and withdrawal patterns, and the relative infectiousness of silent infections, the model becomes highly agent-specific. The model includes flexible immunization routines and variable vaccine response patterns. The model is applied to the 1957 Asian and 1968 Hong Kong pandemic strains of influenza A. The results of several schedules of immunization of school children are presented and compared for the two strains.
Renewal of support for efforts to develop a rhinovirus vaccine seems justified in the light of newer epidemiologic and immunologic studies. The major contribution of RV to acute upper respiratory disease in all age groups but especially in young children emphasizes the public health importance of an effective vaccine. Epidemiologic surveillance of RV infections in widely separated areas has identified two relevant phenomena. First, in each area, certain serotypes were more frequently encountered and tended to persist. Such "common" serotypes accounted for a disproportionate share of the infections recognized and, hence, constitute special targets for immunization. Second, a clear increase over time in the proportion of RV isolates representing higher numbered (types 56-89) serotypes or untypable strains (potentially new serotypes) suggests that new serotypes continue to emerge as the result of progressive antigenic shift. The common origin of the multitudinous RV serotypes so suggested is consistent with the extensive antigenic cross-relations which are becoming evident. Systematic cross-testing with monospecific antisera, especially when high titer sera are employed, has revealed an appreciable number of one-way and reciprocal relations. Largely fortuitous observations of naturally or experimentally infected humans have revealed many additional cross-relations manifested by concurrent response to heterologous RV and presumably attributable to sensitizations resulting from prior RV infections. A model for this has been provided by rabbits immunized sequentially with different potent RV immunogens. Available information as displayed in figure 2 indicates that extensive cross-relations do exist and that sizeable groups of closely related serotypes may be identified. More intensive search for heterotypic response to infection of man coupled with selective use of the rabbit model should define the full extent and strength of cross-relations and identify completely the more closely related groups of serotypes as the basis for formulation of a broadly effective RV vaccine containing a limited number of serotypes. The cross-relations described are based entirely on development of serum neutralizing antibody, the presence of which in man is clearly correlated with relative protection against infection and disease. While this protection may well prove to be mediated largely by concomitant nasal secretory antibody, it is not unreasonable to expect that the antigenic cross-relations also would be manifested in secretory antibody response. These important questions concerning secretory antibody can be best explored in a limited series of volunteer trials with selected cross-related RV serotypes in which homotypic and heterotypic protection could be correlated with serum and nasal secretory antibody. The state of current knowledge, as I view it, is sufficient to justify initiation of such trials at any time.
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Rhinovirus (RV) infections in Seattle Virus Watch (VW) families (1965-1969) were monitored by screening respiratory specimens in WI-38 cell cultures and by homotypic neutralization tests on sera related to family episodes revealed by RV isolation. Temporally related illness in members not proven infected was also taken to indicate infection. RV isolates (including those from the New York VW, 1961-1965) were typed within the official 90-serotype frame. Typed isolates from New York (165 with 39 serotypes) and Seattle (456 with 59 serotypes) were compared with the Tecumseh Study to test the hypothesis that some serotypes are "common," persisting because of greater infectivity. Of 32 serotypes qualifying as "common" in at least 1 study, 4 were "common" in all 3 studies and 8 in 2 studies. The 23 "common" Seattle serotypes differed from the remaining 36 serotypes in being more infective and in their more frequent association with prolonged shedding. The New York and Seattle isolates together revealed an increase over time in the proportion not typable or of of higher numbered types, consistent with progressive shift in RV antigenic character. WI-38 isolates indicated spring peaks of RV all 4 years but a fall peak only in 1967. An even larger fall peak was seen when all specimens from September-November 1968 were re-examined in fetal tonsil diploid cells. Thus, both spring and fall peaks appear to describe RV seasonality. RV infections explained 16% of all reported respiratory illness (20% of upper respiratory), but RV-associated illness in young children, especially under 2 years, was more severe and almost twice as frequent as in adults. The age of introducers and the direct relation of family size to frequency of episodes indicate that community spread depends largely on preschool children, including infants. Within families, the secondary attack rate (SAR) was highest following paternal introduction and, for all introducers, the SAR varied inversely with age (mother excepted). RV shedding was observed most often (85% of specimens) from the day before to 6 days after illness onset but prolonged shedding was common (to 21 days in 20% and 28 days in 1.4% of infections). RV infectivity, reflected by SAR among nonimmunes, was highest for infants (78%) and, for all ages, was greater with ill than with well introducers (71% versus 27%). Immunogenicity of RV was poor (Seroresponse: 48% of shedders, 32% of nonshedding contacts) but varied greatly with serotype. Illness frequencies among non-immunes were 59% for all proven infections and 35% when infection was not shown..
Seattle Virus Watch families were observed, 1965-1969, for infections with paramyxoviruses and M. pneumoniae by agent isolation and antibody assay of serial sera. Infection rates, based on serology, exceeded those in Tecumseh where families contained fewer young children. Rates per 100 person-years were 44.4 for parainfluenzavirus, 21.6 for respiratory syncytial (RS) virus and 12.3 for M. pneumoniae. Preschool children experienced the highest rates for RS and parainfluenza-viruses but, for the latter, rates were also high among older children and adults. Within invaded families infection rates generally varied inversely with age, although for M. pneumoniae the rates for adults and 6-9 year old children nearly equalled the infant rate. The introducers' identity and/or the age-specific infection rates in invaded families support the role of young schoolchildren in community spread of M. pneumoniae and, together with older children and adults, of RS virus. Young schoolchildren were less important than infants, preschoolers, and adults in spreading parainfluenza-viruses and less important than preschoolers and infants for mumps. The frequent infection of exposed older children and adults suggests that reinfection with all the agents studied is common. All agents spread significantly within families and secondary attack rates for the mostly non-immune infants indicated high infectivity of parainfluenza and mumps viruses. The basic high pathogenicity of these agents and of RS virus is indicated by the high frequency of illness among virus shedders (80-90%) and among seroconverting infants (greater than or equal 68%). The less frequent illness of older persons with serologically proven infection is consistent with diminished clinical response to reinfection. Parainfluenza-associated illnesses were relatively severe and contributed up to 9.3% to total respiratory illnesses. RS virus-related illnesses also were severe but contributed less (4-5%) to total respiratory disease. Mumps-associated illness was largely respiratory, 65% overall, 77% in infected infants and 75% above age 9. Thus, mumps virus emerges as another respiratory pathogen which is spread largely by 2-5-year old children rather than by schoolchildren with "typical" parotitis.
The rhinoviruses are a large group of at least 89 serotypes and extensive cross-relationships have been demonstrated among these serotypes using both rabbit and human antisera. The extent of these cross-relationships was further investigated by sequential intravenous immunization of rabbits with different virus serotypes, known to be both related and unrelated. In all cases in which a relationship had previously been demonstrated with monovalent antiserum, after heterotypic stimulation with the related virus, the antibody titer to the virus used as primary immunogen showed an anamnestic response, whereas the antibody response to the secondary immunogen was good, but resembled a primary response. In some instances when immunized rabbits were injected with an unrelated antigen, previously unsuspected relationships were revealed. A number of clusters of related rhinoviruses were demonstrated: 5, 17, 42; 3, 4, 6, 14; 9, 32, 67; and 13, 14, 41. Heterotypic immunization proved to be a powerful biologic probe for detecting relationships among the rhinoviruses, and together with newly available epidemiologic data it offers a possible approach for design of a vaccine for the common cold.
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