Influenza, pneumonia, tetanus: how effective is vaccination?

The rationale for immunizing older adults with influenza, pneumococcal, and tetanus-diphtheria vaccines is derived largely from epidemiological data indicating a heightened susceptibility to these illnesses within this population. The authors provide supportive information relevant to the routine use of these vaccines in adults aged 65 or older.

In vitro susceptibility of Trichomonas vaginalis to 50 antimicrobial agents.

We determined the susceptibilities of five strains of Trichomonas vaginalis, one of which was metronidazole resistant, to 50 antimicrobial agents. For the metronidazole-susceptible strains, the most active agents were metronidazole, tinidazole, mebendazole, furazolidone, and anisomycin. Against the resistant strain mebendazole, furazolidone, and anisomycin were the most active. Antifungal agents, beta-lactams, macrolides, aminoglycosides, and folic acid antagonists were ineffective against all strains.

Protective efficacy of low-dose amantadine in adults challenged with wild-type influenza A virus.

The prophylactic efficacy of a low dose (100 mg) of amantadine hydrochloride against experimental challenge with influenza A/Texas/1/85 (H1N1) wild-type virus was determined in healthy adult volunteers in a placebo-controlled, double-blind, randomized trial. No side effects of the 100-mg dose were observed in the amantadine-treated volunteers. Compared with placebo, 100 mg of amantadine significantly reduced the frequency of illness (9 of 22 versus 2 of 22 volunteers, P less than 0.04) and provided 78% protection against influenza illness. The two ill volunteers in the amantadine group had rhinitis only, whereas most of the ill placebo controls developed both systemic and upper-respiratory-tract illness. Wild-type virus was recovered from 50% of the amantadine-treated volunteers, compared with 82% of the placebo controls. Of note, the infected amantadine recipients shed 100 times less virus and shed virus for half as many days as did the infected placebo recipients. Although amantadine restricted viral replication, it did not interfere with the development of an antibody response to influenza virus. These results indicate that in adults experimentally challenged with influenza wild-type virus, 100 mg of amantadine is effective both in the prevention of influenza illness and in the restriction of virus replication.

Latamoxef in combination with aminoglycosides against Pseudomonas aeruginosa: similarity with ticarcillin.

The in vitro effect of latamoxef against 50 clinical strains of Pseudomonas aeruginosa was compared to that of ticarcillin, both alone and in combination with the aminoglycosides gentamicin, tobramycin and amikacin. Alone, the MIC90 of latamoxef was consistently one-half the MIC90 of ticarcillin. The two antibiotics appeared similar in regard to inoculum effect and bacterial killing. Adding of one-quarter the minimum inhibitory concentration of the aminoglycoside antibiotic to the beta lactam caused reduction in MIC90 of the latter (either ticarcillin or latamoxef) by one-half and decreased the MIC50 by almost one-quarter the concentration required by the beta lactams singly. Therefore, latamoxef singly or in combination with aminoglycosides behaved similarly but was more active than ticarcillin. Using combinations of antibiotics likely to be achieved in the serum of patients, a beneficial in vitro effect (either additive, partially synergistic or synergistic) generally occurred for the beta lactam-aminoglycoside combination if the strain was relatively sensitive to the aminoglycoside used in this combination. It occurred much less frequently for the highly aminoglycoside-resistant isolates.

Sensitivity of Moore sewer swabs for isolating Salmonella typhi.

Moore swabs (sewer swabs) have been used successfully to culture pathogenic organisms from wastewater. Sensitivity seems to depend on the size of the waterway sampled as well as the number of organisms present. In Santiago, Chile, we placed 24 swabs into the sewers draining the homes of 10 known chronic carriers of typhoid. Swabs were positive for Salmonella typhi in 5 of the 10 households (50%) and 6 of the 24 swabs placed (25%).

Delayed hypersensitivity skin testing and anergy in a population of gay men.

Anergy is almost universal among patients with the acquired immunodeficiency syndrome (AIDS). To determine the prevalence and correlates of anergy in a population at risk for AIDS, we performed skin tests in 1120 gay men who were enrolled in a prospective study of the natural history of human immunodeficiency virus (HIV) infection. Anergy, defined as no induration to any of four intradermal antigens, was present in 12%. Individually, no induration was detected in response to tetanus toxoid (41%), mumps (28%), candida (47%), and trichophyton (72%). Anergy was strongly associated with the presence of antibody to HIV and with a reduced number of T helper lymphocytes, but not independently with generalized lymphadenopathy, the number of reported male sexual partners in the previous 2 years, the number of T suppressor lymphocytes, or with high titers of antibodies to cytomegalovirus. Nine percent of HIV antibody-negative subjects and 20% of antibody-positive subjects were anergic; anergy is not specific for serologically documented HIV infection in this population. Skin testing with only tetanus toxoid, candida, and mumps antigens may be sufficient to detect anergy. In the presence of HIV antibody, the ability of anergy to predict progressive immunodeficiency remains to be determined.

Systemic and local antibody responses in elderly subjects given live or inactivated influenza A virus vaccines.

Intranasal live attenuated cold-adapted (ca) influenza A/Kawasaki/9/86 (H1N1) reassortant virus and parenteral inactivated influenza A/Taiwan/1/86 (H1N1) virus were given alone or in combination to 80 ambulatory elderly subjects. An enzyme-linked immunosorbent assay was used to measure hemagglutinin-specific (HA) antibodies in serum and nasal wash specimens collected before vaccination and 1 and 3 months later. Serum immunoglobulin G (IgG) and nasal wash IgA HA responses were elicited in 56 and 20%, respectively, of 25 inactivated-virus vaccinees and in 67 and 48%, respectively, of 27 recipients of both vaccines but in only 36 and 25%, respectively, of 28 vaccinees given live virus alone. Inactivated virus, administered alone or with live virus vaccine, induced higher titers of serum antibody than did the live virus alone. In contrast, nasal IgA HA antibody was elicited more often and in greater quantity by the vaccine combination than by either vaccine alone. Despite these differences, the peak titers of local antibody mounted by each group of vaccinees were similar. By 3 months postvaccination, serum IgG and nasal IgA HA antibody titers remained elevated above prevaccination levels in 50 and 17%, respectively, of the inactivated-virus vaccinees and in 46 and 23%, respectively, of recipients of both vaccines but in only 19 and 7%, respectively, of the live-virus and systemic antibodies, if vaccinees. The finding that live ca influenza A virus induced short-lived local and systemic antibodies, if confirmed, suggests that live virus vaccination may not be a suitable alternative or adjunct to inactivated virus vaccination for the elderly.

Comparison of the virologic and immunologic responses of volunteers to live avian-human influenza A H3N2 reassortant virus vaccines derived from two different avian influenza virus donors.

We compared the abilities of the six internal RNA segments of two avian influenza viruses, A/Mallard/Alberta/88/76 (H3N8) and A/Mallard/NY/6750/78 (H2N2), to confer attenuation on wild-type human influenza A/Bethesda/1/85 (H3N2) virus in seronegative adult volunteers. Live avian-human influenza A reassortant virus vaccines derived from either avian virus parent were comparable in the following properties: safety, infectivity, immunogenicity, and genetic stability. Since the avian influenza A/Mallard/Alberta/76 virus offered no clear advantage as a donor virus, we will conduct our future evaluations on live influenza A virus reassortants derived from the more extensively characterized avian influenza A/Mallard/NY/78 virus.

Enterococcal bacteremia: to treat or not to treat, a reappraisal.

The treatment of enterococcal bacteremia not associated with endocarditis has been controversial. We retrospectively reviewed 81 episodes of enterococcal bacteremia and categorized them as to their clinical significance, using a strict case definition. Of the 81 episodes, 41 met our criteria for clinical significance. Mortality was 51% among the 41 patients with clinically significant bacteremia and 50% among the 40 patients with bacteremia of uncertain clinical significance. Despite these equivalent overall mortality figures, antibiotic therapy specific for Enterococcus species was associated with reduced in-hospital mortality among patients with clinically significant infections (relative risk [RR] = 0.46, 95% confidence interval [CI] = 0.27-0.77); mortality was also reduced in the first 7 days after the detection of bacteremia, when death was relatively likely to be directly due to the bacteremic episode (RR = 0.17, CI = 0.04-0.74). The association between appropriate antibiotic therapy and reduced mortality remained statistically significant when adjustments were made for a number of other factors related to mortality, including age, underlying conditions, prior use of antibiotics, nosocomial acquisition, polymicrobial etiology, prior surgery, and source of infection. Thus enterococcal isolates from the blood, even when of doubtful clinical significance, are poor prognostic markers associated with high mortality. However, when the clinical significance of bacteremia is defined by strict criteria, specific therapy against Enterococcus species is associated with improved outcome.

Evaluation of the human immune response to outer membrane proteins of Vibrio cholerae.

The immune response of 114 volunteers with diarrhea after experimental challenge with four strains of Vibrio cholerae O1 was characterized in a microtiter enzyme-linked immunosorbent assay antibody detection system by using a partially purified outer membrane preparation (OMP) from these strains as an antigen. Analysis of paired sera from 29 persons with noncholera diarrhea (negative control population), demonstrated that a rise in net optical density greater than 0.10 was significant. A total of 50% of the 79 cholera volunteers challenged with El Tor biotype and 54% of the 35 volunteers challenged with classical biotype had significant rises in immunoglobulin G anti-OMP. Paired sera that showed significant rises when tested against homologous OMP all manifested significant rises when also tested against a serotype-heterologous OMP. Immunoblotting techniques showed that the antigens to which antibodies were reacting were mainly protein in nature, not lipopolysaccharide. Furthermore, absorption with lipopolysaccharide decreased the optical density by a mean of only 12% (0 to 30%), corroborating that antibody was mainly directed against OMP and not lipopolysaccharide. This study indicates that there is a human immunoglobulin G response to OMP during clinical cholera infection and that this response is constant among bio- and serotypes.

Comparison of live, attenuated H1N1 and H3N2 cold-adapted and avian-human influenza A reassortant viruses and inactivated virus vaccine in adults.

The infectivity, immunogenicity, and efficacy of live, attenuated influenza A/Texas/1/85 (H1N1) and A/Bethesda/1/85 (H3N2) avian-human (ah) and cold-adapted (ca) reassortant vaccines were compared in 252 seronegative adult volunteers. The immunogenicity and efficacy of the H1N1 reassortant vaccine were also compared with those of the trivalent inactivated virus vaccine. Each reassortant vaccine was satisfactorily attenuated. The 50% human infectious dose was 10(4.9) for ca H1N1, 10(5.4) for ah H1N1, 10(6.4) for ca H3N2, and 10(6.5) TCID50 for ah H3N2 reassortant virus. Within a subtype, the immunogenicities of ah and ca vaccines were comparable. Five to seven weeks after vaccination, volunteers were challenged with homologous wild-type influenza A virus. The magnitude of shedding of virus after challenge was greater than 100-fold less in H1N1 vaccinees and greater than 10-fold less in H3N2 vaccinees compared with unimmunized controls. The vaccines were equally efficacious, as indicated by an 86%-100% reduction in illness. Thus, the ah A/Mallard/New York/6750/78 and the ca A/Ann Arbor/6/60 reassortant viruses are comparable.

Evaluation of the infectivity, immunogenicity, and efficacy of live cold-adapted influenza B/Ann Arbor/1/86 reassortant virus vaccine in adult volunteers.

A cold-adapted (ca) influenza B reassortant that derived two genes encoding the hemagglutinin and neuraminidase from influenza B/Ann Arbor/1/86 wild-type virus and six internal RNA segments from ca influenza B/Ann Arbor/1/66 virus was evaluated in 66 adult volunteers having a serum hemagglutination inhibition antibody titer less than or equal to 1:8. The ca reassortant was attenuated and elicited the production of systemic and local antibodies; the 50% human infectious dose was 10(6.4) TCID50. Six weeks after vaccination, 12 unvaccinated volunteers and 13 recipients of ca virus (10(7.5) TCID50) were challenged experimentally with homologous wild-type influenza B virus. The ca vaccine completely protected against illness, and the magnitude of shedding was 50-fold less in vaccinees than in unimmunized controls, five of whom became ill. These findings indicate that the six internal RNA segments of the ca influenza B/Ann Arbor/66 donor virus confer desirable properties of a live virus vaccine to a reassortant derived from a virulent virus. Such reassortants may be suitable vaccines for healthy adults.

Is Clostridium difficile endemic in chronic-care facilities?

An apparent outbreak of Clostridium difficile diarrhoea on the chronic hospital ward of a long-term care facility prompted an investigation lasting seven months. Approximately a third of patients had stools that were positive for C difficile by either toxin or culture. Attempts to eradicate the infection by simultaneously treating all toxin-positive patients with metronidazole, limiting antibiotic use, and implementing enteric isolation were unsuccessful. New cases were both nosocomially acquired and imported into the facility. Of the C difficile toxin-positive patients, 34% had diarrhoea and 19/49 (38%) died during the study period. C difficile is not routinely sought by most clinical microbiology laboratories and may therefore be endemic in many long-term care facilities for the elderly.

Safety and prophylactic efficacy of low-dose rimantadine in adults during an influenza A epidemic.

A placebo-controlled, double-blind study to evaluate the safety and prophylactic efficacy of a low dose (100 mg) of rimantadine hydrochloride against naturally occurring influenza in adults was conducted at two sites. After the onset of the influenza season, volunteers (ages, 18 to 55 years) were assigned randomly to receive rimantadine or placebo daily. Subjects were monitored for adverse effects and evidence of influenza virus infection weekly for six weeks. Only 10 (8.7%) of 114 rimantadine recipients and 5 (4.4%) of 114 placebo control recipients reported one or more mild to moderate adverse symptoms, most of which were related to the gastrointestinal or central nervous system. Compared with placebo, low-dose rimantadine was highly effective in the prevention of influenza A virus infection (20 of 110 versus 7 of 112 participants; P less than 0.01) and influenza illness (7 of 110 versus 1 of 112 participants; P = 0.04). Influenza A/Leningrad/87-like (H3N2) virus was recovered from the nasopharynxes of only five placebo recipients. These findings indicate that low-dose rimantadine is well tolerated and highly effective for the prevention of influenza A illness in healthy adults.

Prospects for development of a rotavirus vaccine against rotavirus diarrhea in infants and young children.

Major advances have been made in elucidating the etiologic agents of severe infantile diarrhea, and it is clear that rotaviruses are the single most important etiologic agents. Progress in the development of rotavirus vaccine candidates has also moved swiftly with the "Jennerian" approach, in which a related live, attenuated rotavirus strain from a nonhuman host is used as the immunizing antigen. If this strategy is not effective against all rotavirus serotypes, reassortant rotaviruses hold great promise for the development of a multivalent vaccine. Field trials with the "Jennerian" approach vaccines are under way, and phase 1 trials with the reassortants have been initiated.

PIP: In 1972, the 27-nm Norwalk virus associated with epidemic viral gastroenteritis in older children and adults was discovered, and in 1973, the detection of the 70-nm human rotavirus associated with acute gastroenteritis in infants and young children followed. They are responsible for 35-50% of severe diarrhea in children under 2. In a Bangladesh study, rotaviruses were the most frequent pathogens in children under 2 with diarrheal illnesses. 4 epidemiologically important human rotavirus serotypes have been identified. After inoculation in utero with bovine rotavirus (NCDV), calves were protected against disease following challenge at birth with human rotavirus type 1. The human rotavirus vaccine, RIT 4237, is derived from the cold-adapted bovine rotavirus NCDV (Lincoln) strain. A single oral dose of the vaccine provided a protection rate of 88% against rotavirus diarrhea in 178 Finnish infants 8-11 months of age. An 82% protection rate was observed in 331 Finnish infants 6-12 months of age following 2 oral doses. The rhesus rotavirus strain MMU 18006 as a candidate rotavirus vaccine was safe and antigenic after oral administration in adult volunteers, children, and infants. The rhesus rotavirus vaccine induced significant febrile reactions in 64% and watery stools in 20% of 608 month old Finnish infants; and it was more antigenic than the RIT 4237 vaccine. Neither adult volunteers became ill during recent phase 1 trials in Baltimore with 2 rotaviruses: the D (human rotavirus serotype 1) x RRV (rhesus rotavirus) reassortant. Similar studies were carried out with a DS-1 x RRV reassortant in 2 volunteers with high levels of prechallenge plaque-reduction neutralization (PRN) antibody to this reassortant. Neither volunteer became ill. Later 14 volunteers with little prechallenge PRN serum antibody to this reassortant were given the reassortant; none developed diarrheal illness. Each of the 4 rotavirus serotypes has been isolated from newborns with asymptomatic infections 1 strain recovered from asymptomatic neonates within the first 14 days of life induced significant protection against serious rotavirus disease for up to 3 years. Attenuation of virulent human rotavirus strain might also be achieved by cold adaptation.

The use of Moore swabs for isolation of Salmonella typhi from irrigation water in Santiago, Chile.

In Chile, a country with an exceedingly high incidence of typhoid, untreated sewage is applied directly to fields where salad vegetables are cultivated. Water used for irrigation was examined for the presence of Salmonella typhi, by making use of the sewer-swab technique. S typhi was isolated in 8 (11%) of 76 irrigation samples examined from nonindustrial, polluted water. This supports the hypothesis that crops grown with water contaminated with feces are important vehicles in the transmission of S typhi in this endemic area. Since sewage treatment plants will not be available in Santiago in the near future, emphasis is being placed on devising alternative methods of irrigation and on growing vegetables that are cooked before being eaten.

Human-rhesus reassortant rotavirus vaccines: safety and immunogenicity in adults, infants, and children.

Human-rhesus reassortant rotavirus vaccines derived from rhesus rotavirus and human rotavirus serotypes 1, 2, or 4 were administered to adults, children, and infants after they had been given sodium bicarbonate buffer. Over 70% of infants and children developed antibody responses to or shed the candidate vaccine viruses. Individuals with prevaccination serum neutralization antibody titers less than or equal to 1:160 had significantly (P less than .0001) higher response rates than did individuals with prevaccination titers greater than or equal to 1:320. Similarly, shedding of vaccine viruses occurred significantly (P = .03) more often in children than adults and was inversely correlated with prevaccination antibody titers. No illnesses were observed in adults, and the vaccines were well tolerated in children. An increased rate of low-grade, transient fever (38.0-38.8 C) was noted only in children given serotype 2 vaccine, compared with controls (P = .006). No significant differences in the average number of unformed stools passed during the seven days after vaccination were noted in vaccinees versus controls. These vaccine strains are currently undergoing further evaluation in expanded clinical trials.

Four viral genes independently contribute to attenuation of live influenza A/Ann Arbor/6/60 (H2N2) cold-adapted reassortant virus vaccines.

Clinical studies previously demonstrated that live influenza A virus vaccines derived by genetic reassortment from the mating of influenza A/Ann Arbor/6/60 (H2N2) cold-adapted (ca) donor virus with epidemic wild-type influenza A viruses are reproducibly safe, infectious, immunogenic, and efficacious in the prevention of illness caused by challenge with virulent wild-type virus. These influenza A reassortant virus vaccines also express the ca and temperature sensitivity (ts) phenotypes in vitro, but the genes of the ca virus parent which specify the ca, ts, and attenuation (att) phenotypes have not adequately been defined. To identify the genes associated with each of these phenotypes, we isolated six single-gene substitution reassortant viruses, each of which inherited only one RNA segment from the ca parent virus and the remaining seven RNA segments from the A/Korea/1/82 (H3N2) wild-type virus parent. These were evaluated in vitro for their ca and ts phenotypes and in ferrets, hamsters, and seronegative adult volunteers for the att phenotype. We found that the polymerase PA gene of the ca parent specifies the ca phenotype and that the PB2 and PB1 genes independently specify the ts phenotype. The PA, M, PB2, and PB1 genes of the ca donor virus each contribute to the att phenotype. The finding that four genes of the ca donor virus contribute to the att phenotype provides a partial explanation for the observed phenotypic stability of ca reassortant viruses following replication in humans.