Use of live cold-adapted influenza A H1N1 and H3N2 virus vaccines in seropositive adults.

To investigate the immunogenicity and protective efficacy of cold-adapted influenza vaccine in individuals with underlying immunity to influenza A virus, we administered cold-adapted H1N1 and H3N2 vaccines to adults with prevaccination serum hemagglutination inhibition antibody titers of 1:16 or more and challenged them 1 month afterwards with homologous wild-type influenza A virus. Both cold-adapted vaccines were immunogenic in seropositive adults. In addition, individuals receiving cold-adapted vaccines had lower rates of virus shedding and illness following challenge with wild-type influenza virus than did unvaccinated seropositive volunteers.

Attenuated influenza produced by experimental intranasal inoculation.

To assess the relative effect of natural versus experimental influenza illness on pulmonary function, we compared 43 normal adults with documented nonpneumonic influenza A infection during three outbreaks, 1974 (A/Port Chalmers/74), 1975 (A/Port Chalmers/74), and 1976 (A/Victoria/75) to 24 normal volunteers following nasal inoculation with wild-type influenza A/England/42/72, A/Scotland/74 or A/Victoria/75. In naturally acquired illness, abnormalities in small airway functiion and transiently increase airway reactivity were observed. In contrast, no such dysfunction was observed in experimentally induced illness. This group manifested milder illness and significantly shorter duration of cough.

Efficacy of live attenuated influenza A/Scotland/74 (H3N2) virus vaccine against challenge with influenza A/Victoria/3/75 (H3N2) virus.

For evaluation of heterologous protection by live attenuated influenza virus vaccine, 42 healthy volunteers with low titers of or no antibody to A/Scotland/74 (H3N2) and A/Victoria/3/75 (H3N2) influenza viruses were given live attenuated A/Scotland/74 (H3N2) virus vaccine or placebo by the intranasal route with no resultant vaccine-related illness. Seventeen of 21 vaccine recipients and none of 21 placebo recipients developed antibody conversion. Thirty-seven days after administration of vaccine or placebo, all subjects were challenged intranasally with wild-type A/Victoria/3/75 influenza virus. Five placebo recipients and no vaccine recipients developed moderately severe illness, whereas 10 vaccine recipients and three placebo recipients developed no illness (p less than 0.025). Although 16 of 21 vaccine recipients fulfilled criteria of infection with the challenge virus, shedding of virus was significantly less frequent, less prolonged, and of significantly lower magnitude than that in the placebo recipients. Thus, live attenuated influenza virus vaccine showed a significant protective effect against illness following challenge with heterologous wild-type virus. The protective effect and the negligible side effects of this vaccine merit consideration of its use in a large-scale field trial.

Influenza A/Brazil/78(H1N1) infection in the elderly.

Although influenza A/H1N1 virus has caused both sporadic illness and epidemics throughout the world, there have been few cases and no outbreaks reported in older persons. Using a surveillance program for detection of viral respiratory tract illness, we documented an outbreak of influenza (A/Brazil/78(H1N1) infection in one floor of a chronic disease hospital. We prospectively studied all 32 patients and 16 personnel on that floor. Infection was proved in 11 subjects by serology and/or virus isolation, including 9 patients (median age, 84 yr) and 2 personnel (36 and 58 yr of age), for attack rates of 28% and 12.5%, respectively. Six patients had fever, 38 degrees C to 39 degrees C, lasting for 1 to 5 days (median, 4), and/or respiratory and constitutional symptoms lasting for 2 to 17 days (median, 13). Bacterial pneumonia occurred in 1 patient 12 days after the onset of upper respiratory tract illness. Risk factors for acquisition of infection in patients included a nonvaccinated state (p = 0.03) and a preinfection antibody titer of less than or equal to 32 (p = 0.02). These findings indicate that older persons are at risk for infection with influenza A/H1N1 virus, which may also cause outbreaks of respiratory illness in the elderly institutionalized population similar to other influenza viruses.

Reduction in fever and symptoms in young adults with influenza A/Brazil/78 H1N1 infection after treatment with aspirin or amantadine.

During an outbreak of influenza A/Brazil/78 H1N1 infection, 47 volunteers with clinical and virological influenza of less than 2 days duration were treated in a randomized double-blind fashion for 5 days with 100 or 200 mg of amantadine daily or with 3.25 g of aspirin daily. The aspirin treatment group defervesced more rapidly (10.3 h versus 21.5 h and 23.6 h; P less than 0.01), but by the second daily follow-up visit, both groups of amantadine recipients exhibited greater symptomatic improvement. Bothersome side effects resulted in discontinuation of therapy by 35% of the aspirin treatment group but only 3% of the amantadine treatment group (P less than 0.05). Individuals who present to a physician during an influenza A epidemic with characteristic symptoms will experience symptomatic benefit from amantadine treatment, with negligible toxicity.

Evaluation of a topical interferon inducer in experimental influenza infection in volunteers.

The prophylactic and/or therapeutic effect of a low-molecular-weight interferon inducer, CP-20,961, was tested in a double-blind placebo controlled study of experimental influenza A/England/42/72 (H(3)N(2)) infection in normal volunteers. Ten volunteers received CP-20,961 and 10 received placebo. Interferon was detected in nasal secretions of nine of the former and three of the latter group (P < 0.05). Seven in each group became ill, and severity of illness was not different. Also, quantitative virus shedding patterns and antibody response were not different between the two groups. The negative result may have been due to the relatively low quantities of interferon induced.

Double-blind evaluation of oral ribavirin (Virazole) in experimental influenza A virus infection in volunteers.

The prophylactic effectiveness of oral administration of ribavirin (1-beta-d-ribofuranosyl-1,2,4-triazole-3-carboxamide) against experimentally induced influenza A infection was evaluated in a double-blind clinical trial in normal volunteers. Fourteen men received ribavirin capsules (1,000 mg/day in four divided doses) and 15 other men received identical-appearing placebo capsules beginning 6 h after the intranasal inoculation of 3.4 log(10) 50% tissue culture infectious doses of influenza virus A/Victoria/3/75 H3N2 and continuing for 5 days after challenge. The total number of moderate-to-severe symptom scores and the total number of temperatures >/=100 degrees F (37.8 degrees C) were significantly lower in the ribavirin group compared with the placebo group. The mean quantity of virus shed in nasal wash specimens and the total number of days that there were viral titers greater than 1.0 log(10) 50% tissue culture infectious doses per ml were significantly greater in the placebo group. There was no difference between the frequencies of virus isolated or the antibody responses in the two groups. Therefore, prophylactic ribavirin ameliorated symptoms and fever indicative of moderate-to-severe illness, but had no effect on the manifestations of mild illness in response to influenza A challenge. A transient rise in total serum bilirubin occurred in 29% of the ribavirin-treated volunteers and in none of the placebo-treated volunteers.

Pulmonary mechanics after uncomplicated influenza A infection.

Pulmonary mechanics were evaluated in 13 nonsmoking adults with acute, uncomplicated influenza A/Port Chalmers/73(H3N2) virus infection. Subjects had no evidence of lower respiratory tract involvement on physical examination. Viral and/or scrologic evidence of influenza infection was established for all subjects. Physiologic measurements included forced expiratory rates by spirometry and total pulmonary resistance (RT) measured at 3, 5, 7, and 9 cycles per sec by the oscillometric technique. Subjects were studied at time of acute illness and at 1, 3, and 5 weeks thereafter. Spirometric measurements were initially normal in all subjects and did not change significantly throughout the study. Elevated RT measured at 3 cycles per sec and an abnormal degree of frequency dependence of RT, determined by comparing RT at 3 cycles per sec to RT at 9 cycles per sec, were initially present in 10 of 13 subjects. All 7 of these subjects initially abnormal who were tested 7 days after the onset of illness had abnormal frequency dependence. At 3 weeks, 7 of the 10 subjects initially abnormal continued to have frequency dependence of RT. All but 2 subjects reverted to normal levels by 5 weeks. Frequency dependence of RT indicates that acute influenza infection produces uneven time constants in the airways. A generalized increase in peripheral airway resistance or localized compliance changes could account for these abnormalities. Because these abnormalities persisted well beyond the period of clinical illness, these data imply that asymptomatic mechanical dysfunction of the lungs is a frequent sequela to acute influenza A virus infection. RT measured by the oscillometric method was a suitable noninvasive method for detecting abnormal airway time constants in these subjects with acute upper respiratory diseases.

Evaluation of a temperature-sensitive influenza virus in elderly and chronically ill subjects.

A temperature-sensitive influenza virus, influenza A/Hong Kong/68-ts-1 (E), was administered to 18 elderly subjects and to 18 chronically ill subjects. Clinical reactions were infrequent (n = 3), mild, and afebrile. Vaccine virus was recovered from 5 subjects. Serum-neutralizing antibody responses to A/Hong Kong/68 antigen were detected in 13. Serum hemagglutination inhibiting antibodies were detected in 6 to A/Hong Kong/68 antigen and in 7 to A/England/42/72 antigen. Nasal antibodies were detected in 3. Using any criteria, a total of 17 patients developed evidence of infection, and occurrence of infection was related to concentration of serum antibody before inoculation. Transmission of vaccine virus may have occurred to one of 10 uninoculated subjects. In the presence of a naturally occurring outbreak of influenza A/England/42/72, 15 ts-1 (E) vaccines and 17 of 42 persons who had received parenteral vaccine became ill. Evidence of infection with influenza virus was obtained in 8 of the former and 10 of the latter group.

Safety and efficacy of "Alice" influenza virus vaccine in normal healthy adults.

A live influenza virus candidate vaccine, "Alice" strain, was evaluated in normal healthy adults. It proved to be safe, with minimal clinical reactions. Thirteen of 21 volunteers (61.9%) with pre-existing titers of hemagglutination-inhibiting antibody of less than or equal to 1:4 and three of nine (33.3%) with initial titers of 1:8-1:16 had four-fold increases in titers of serum antibody. A second dose of vaccine did not increase the frequency or the magnitude of the serum antibody response. Nasal neutralizing antibody responses occurred in six of 18 subjects tested (38.8%). The vaccine virus appeared to produce its effect by replication since vaccine virus was recovered from six of 17 subjects (35%), administration of a vaccine inactivated by ultraviolet irradiation did not produce a response, a 1:10 dilution of virus infected two of five subjects, and a 1:100 dilution infected none of six subjects. The virus was not transmitted to the antibody-negative controls who were confined with infected volunteers. Challenge of 20 volunteers and 26 control subjects with wild-type influenza A/Udorn/307/72 (H3N2) virus revealed a significant reduction in the frequency of infection and illness among subjects who responded to "Alice" vaccine compared with the frequency among unvaccinated controls.

Serological diagnosis of influenza A/USSR/77 H1N1 infection: value of ELISA compared to other antibody techniques.

Serologic diagnosis of influenza is an important but imperfect tool. During an outbreak of natural H1N1 A/USSR/77 infection, volunteers who received either amantadine, rimantadine, or placebo were tested to determine serologic response to infection by four different antibody techniques. Hemagglutination inhibition (HAI) and complement fixation (CF) were least sensitive, detecting only about half of the virus-positive subjects, whereas neutralization detected 81% and enzyme-linked immune peroxidase (ELISA) detected 95%. Failure to detect significant antibody response was associated with a higher titer of antibody in acute serum specimens and with a history of receipt of A/New Jersey/76 Hsw1N1 vaccine. Although antibody response measured by ELISA was of lower magnitude in vaccinees, it still was sufficient to be diagnostic. Thus, in situations where there is no access to viral isolation facilities, ELISA antibody techniques appear to be an excellent measure of assessing the rate of influenza infection.