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Two doses of a live, attentuated influenza A/England/42/72 (H3N2) vaccine virus (inhibitor-insensitive Alice strain) were administered intranasally to 130 university students, and placebo was given to 134 students. Fourfold or greater rises in titer of hemagglutination-inhibiting antibody occurred in 68% of all vaccine recipients and in 88% of those with initial titers of less than 1:8; the geometric mean titer of hemagglutination-inhibiting antibody increased from 1:15 to 1:77. A 3.2-fold rise in titer of neuraminidase-inhibiting antibody occurred in 24% of the students. Side effects produced by administration of the vaccine include mild rhinitis and sore throat, which were found only during the first four days after administration of the first dose. Inhibitor-insensitive virus was shed only by three of 31 intensively studied vaccine recipients; these three subjects all had initial serum titers of hemagglutination-inhibiting antibody of less than 1:8. No transmission of vaccine virus to spouses was detected. During a 12-month interval after vaccination, the geometric mean titer of hemagglutination-inhibiting antibody in serum and the prevalence of antibody decreased minimally among the 47 vaccine recipients still available for study.

This report summarizes the clinical trials of the A/USSR/77 (H1N1) influenza vaccines performed in 1978. A total of 2,091 subjects participated in these trials. The results of these clinical trials indicated that two doses of H1N1 viral antigen were necessary to produce serum titers of hemagglutinin-inhibiting (HAI) antibody of greater than 1:40 in 80% or more of the test subjects younger than 25 years of age, who were unlikely to have experienced natural infection during the earlier period of prevalence of H1N1 virus (1947-1957). Only one dose of the A/Texas/77 (H3N2) or B/Hong Kong/72 antigen was necessary to stimulate equivalent titers of HAI antibody in serum. Thus, previous natural exposure to H1N1 viruses primed individuals 26 years of age or older to respond to H1N1 antigens. No major differences in antigenicity were noted between whole-virus and split-virus vaccines. No differences in reaction indexes measuring systemic reactions were noted when vaccine types were compared. Only one vaccine was associated with a reaction index appreciably higher than that of placebo. The relatively uniform antibody responses observed were attributed to the newer methods of vaccine standardization introduced after the clinical trials in 1976. No cases of vaccine-related neurological problems, including Guillain-Barré syndrome, were found during these trials. Vaccines containing 7-21 micrograms of each viral antigen were antigenic and were well tolerated.

Heterologous hemagglutination-inhibiting (HAI) antibody responses to influenza A/New Jersey/76 (Hsw1N1) virus vaccine were examined in individuals receiving doses of 200, 400, or 800 chick cell-agglutinating units of whole-virus or split-virus products during the 1976 National Influenza Vaccine Test Program. Vaccination with influenza A/New Jersey/76 virus produced a high rate of heterologous antibody response to influenza A/PR/8/34 (H0N1) and A/FM/1/47 (H1N1) viruses in persons whose original antigenic experience according to their age was with H0N1 or H1N1 strains, respectively. Vaccination with A/New Jersey/76 virus produced only low levels of HAI antibody to influenza A/Japan/305/57 (H2N2) and A/Victoria/3/75 (H3N2) viruses, and these responses were less clearly related to primary infections. Thus the greatest heterologous HAI antibody responses occurred when there were shared antigenic determinants between the hemagglutinins of the vaccine virus and the viruses that had caused the initial priming infection. However, when vaccinations or infections with H3N2 and Hsw1N1 strains may both be occurring in the population, even infrequent formation of heterologous antibody may make it difficult to interpret serologic data precisely.

In collaborative clinical trials, two-dose regimens of four monovalent A/New Jersey (NJ)/76 influenza virus vaccines were evaluated in 89 children aged six to 35 months. Clinical reactions to vaccination consisted primarily of low-grade fever. Rectal temperatures of between 100 F and 102 F occurred less frequently after inoculation with split-product vaccines (seven [23%] of 31 children) than whole-virus vaccines (19 [33%] of 58). After administration of single doses of vaccines, titers of hemagglutination-inhibiting (HAI) antibody reached greater than or equal to 1:20 in three (13%) of the 23 recipients of split-product vaccines and in 23 (51%) of the 45 recipients of whole-virus vaccines. After administration of two doses, 89%-94% of recipients of Parke, Davis and Company (PD, Detroit, Mich.), Merrell-National Laboratories (Cincinnati, Ohio), and Merck Sharp and Dohme (West Point, Pa.) vaccines, but only 50% of the recipients of Wyeth Laboratories (Philadelphia, Pa.) vaccine, had titers of HAI antibody of greater than or equal to 1:20. Single doses of more reactogenic whole-virus vaccines may be justifiable for rapid immunization of young children during epidemics of influenza. Given in a two-dose regimen, however, PD split-product vaccine was immunogenic and was the most well-tolerated vaccine tested in this age group.

In recent years, it has been recommended that "high-risk" patients receive influenza immunizations annually. During the 1976 National Influenza Immunization Program, a higher priority was given to these patients than to the general population. The present study was undertaken to compare the antibody response of high-risk patients with that of a group of individuals with no underlying disease after immunization with 0.5 ml of bivalent, split-virus vaccine containing 200 CCA units each of influenza A/New Jersey/76 and A/Victoria/75. Sera were obtained before and after immunization from 41 "healthy" volunteers and from 57 cariology, 31 hematology, 13 hemodialysis, and 16 renal transplant patients. The control, cardiology, and hemodialysis groups responded equally well to A/Victoria/75 antigen, but the hematology and renal transplant groups did not respond as well (P less than .05). Only the hematology patients responded at a significantly lower level (P less than .05) than the control group to A/New Jersey/76. The control and renal transplant groups had a significantly greater response to A/New Jersey/76 antigen than to A/Victoria/75 antigen (P less than .002). Although the same pattern was demonstrated by the other patient groups, the differences were not significant. Because hematology and renal transplant patients responded relatively poorly to influenza immunization, prophylactic administration of amantadine during influenza outbreaks should be considered in patients with renal function adequate to excrete this drug.

Titers of hemagglutination-inhibiting (HAI) antibody were determined for all sera obtained from participants in the 1976 Influenza Vaccine Test Program. At least eight control sera were included in each test during the vaccine trial period for the purpose of monitoring HAI test reproducibility. Estimates of day-to-day reproducibility were defined as the percentages of duplicate aliquots of the same sera, tested on two separate days, having HAI antibody titers that did not differ by more than one twofold dilution. These reproducibility estimates ranged from 89% to 97% with influenza A/New Jersey/76 and A/Mayo Clinic/74 antigens. In contrast, within-day reproducibility estimates obtained from all sets of control sera ranged from 96% to 98%. Estimates of day-to-day test reproducibility obtained with selected sera taken after vaccination that were titrated on two differen days ranged from 90% to 98%. Geometric mean titers of these sera tested weeks or months apart differed on some occasions during the test period.

A double-blind, placebo-controlled study was conducted to evaluate the safety and efficacy of inactivated influenza virus vaccines in patients with multiple sclerosis. The vaccine used contained 200 chick cell-agglutinating (CCA) units of influenza A/New Jersey/76 and 200 CCA units of influenza A/Victoria/75 whole viruses (Merrell-National Laboratories, Cincinnati, Ohio). The frequency of clinical relapses of multiple sclerosis was the same in the vaccine-treated (four of 33 patients) and placebo-treated (four of 33) groups. An untreated control group had a slightly higher rate of relapses (four of 22). Toxic reactions to the vaccine were not a significant problem. The efficacy of the vaccination as measured by titers of hemagglutination-inhibiting antibody was comparable to that reported for the general population. However, patients with preexisting antibody were less responsive to the vaccine than normal controls studied previously. The patients who did not respond to the vaccine tended to be older and more disabled. There were no changes in titers of antibody to rubeola or rubella virus after vaccination or in relation to change in clinical course. It is concluded that the vaccine is safe and effective in patients with multiple sclerosis.

The character of the immune response to inactivated monovalent influenza A/New Jersey/76 (A/NJ/76) and bivalent influenza A/New Jersey/76-A/Victoria/75 (A/NJ/76-A/Vic/75) vaccines was studied in children 6 months to 18 years of age. Hemagglutination-inhibiting antibody levels were measured in post-vaccination serums before and after 2-mercaptoethanol treatment. IgG antibody predominated in responses to the influenza A/Vic/75 component of bivalent vaccines. In contrast, specific IgM antibody against influenza A/NJ/76 developed after both monovalent and bivalent vaccines, and appears to characterize the immune response to this antigenic "shift" strain in children. Prevalences of IgM antibody against influenza A/NJ/76 did not differ significantly by age, implying that type rather than extent of previous influenza experience determines the IgM antibody response to an antigenic "shift". Slit-product vaccines produced significantly fewer IgM antibody responses to influenza A/NJ/76 than did whole-virus vaccines, a phenomenon which may correlate with their diminished reactogenicity and immunogenicity in children.

Vaccines prepared with influenza A/swine/1976/37-like virus contained neuraminidase activity comparable to that of H3N2 vaccines, whereas little neuraminidase activity could be detected in influenza A/New Jersey/76 vaccines. In single-dose vaccine studies, A/swine/1976/37-like split-virus vaccine induced antibody to neuraminidase (NAAb) in about 20% of children younger than 18 years and this NAAb response was better than or equal to the antibody response to the vaccine's hemagglutinin (HAAb). In immunologically primed adults, the NAAb response to a single dose of Hsw1N1 or H3N2 vaccine was 38%-54%, but this value was about 1.7-fold lower than that for HAAb response. Children six to 17 years old given two doses of A/swine/1976/37-like vaccine had an overall 70% NAAb response, whereas children of similar age had an overall 30%-48% NAAb response to two doses of A/Victoria/3/75 (H3N2) virus. The findings support a hypothesis that the NAAb response to influenza vaccines can be suppressed if subjects receiving the vaccine are immunologically primed to its hemagglutinin component. NAAb responses in the absence of HAAb responses occur in only about 5% of vaccinated persons who are immunologically primed to both the hemagllutinin and neuraminidase of the vaccine.

Thirty-one unprimed children and young adults received an influenza A/USSR/77 vaccine containing 43 microgram of hemagglutinin. Their HAI antibody response was compared to that in 92 age-matched individuals from the 1978 national influenza immunization trial who received 10 and 4 microgram HA vaccines. A dose-related antibody response was observed after the first vaccine doses in the 7- to 12- and 13- to 25-year-old groups. An HAI titer greater than or equal to 40 was present in 81% and 93% of 43 microgram HA recipients, in 38% and 43% of 10 microgram HA recipients, and in 24% and 12% of 4 micrograms HA recipients respectively. The antibody response to the 43 microgram HA dose was significantly higher than was the response to the 10 and 4 microgram HA doses. The local and systemic side effects were not significantly different among the three vaccine groups and the placebo group. Thus, a high dose of influenza A/USSR/77 split-product vaccine given to unprimed children and young adults stimulated presumably protective levels of antibody and was free of a significant incidence of side effects.

Serum HI and neuraminidase-inhibiting (NI) antibody measurements were made at 3, 32 and 50 weeks after inactivated influenza Hsw1N1 vaccination of 438 adults in 1976. Although the highest postvaccination geometric mean HI titers were observed in persons greater than or equal to 52 years of age, the rate of antibody decline was similar in adults of all ages. In 14 children who had a seroconversion following two doses of whole virus or split virus vaccine, the geometric mean HI antibody titer was lower after the second vaccine dose than the peak titer observed in adults, and the decrease in titer was also more rapid by 4 to 7 months. One year after influenza Hsw1N1 vaccination of adults, the prevalence of homologous HI antibody greater than or equal to 40 was 71% to 97%, whereas only two of the 14 children maintained similar titers at 5 to 7 months. Neuraminidase-inhibiting antibody titer formation occurred more frequently in those without prevaccination NI antibody, but the rate of decline was also greatest in this initially seronegative group. The rate of antibody decline at one year in the population with preexisting antibody was similar to that observed for HI antibody decline in a primed population. Heterologous influenza A/Victoria/3/75 (H3N2) HI antibody formation occurred in 22% of adults aged 25 to 51 after Hsw1N1 vaccination and in 12% of those over the age of 51, but the rate of heterologous antibody decline was more rapid than that observed for homologous antibody.