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Methods for enhancing immune responses to influenza were explored in 2 double-blind, placebo-controlled trials. Intranasal (inl) immunization with monovalent, live attenuated, cold-adapted recombinant (CR) or inactivated influenza virus (MIV) vaccine and intramuscular (im) immunization with MIV were evaluated in various combinations. Healthy susceptible adults were assigned randomly to receive 10(7.1) TCID(50) of CR (A/H1N1 or A/H3N2), homologous MIV (15 microg), or placebo inl and placebo or homologous MIV im (6 groups in each study). Serum antibody responses were greatest in groups given im vaccine (with or without inl vaccine). A 2-fold increase in nasal wash antibody response frequencies was seen in groups given combined inl (CR or MIV) and im vaccine, compared with subjects given a single im (MIV) or inl (CR or MIV) vaccine. Combined inl and im immunization is a promising approach for enhancing both local and systemic immune responses against influenza.

In a blinded, placebo-controlled study, the reactogenicity, immunogenicity, and clinical efficacy of single doses of US inactivated split-virus and Russian live attenuated, cold-adapted influenza vaccines were compared in 555 schoolchildren in Vologda, Russia. Serial serum samples were collected and school absenteeism was assessed. Systemic reactions were rare, but local reactions (primarily erythema at the injection site) were observed in 27% of the inactivated vaccine group, and coryza (12%) and sore throat (8%) were observed in the attenuated vaccine group. At 4 weeks after vaccination a > or = 4-fold rise in titer of hemagglutination inhibition antibody to A (H1N1), A (H3N2), and B was noted, respectively, among 78%, 88%, and 53% of children who received inactivated vaccine and among 55%, 79%, and 30% of children who received attenuated vaccine. The vaccine efficacy for preventing school absenteeism due to respiratory illness during the period of peak influenza activity was 56% for inactivated vaccine and 47% for attenuated vaccine.

The immunogenicity and toxicity of a purified influenza virus (N2) neuraminidase vaccine (NAV) were investigated in 88 human subjects aged 18-40, and compared to response to a conventional trivalent influenza vaccine, Fluogen (Parke-Davis). NAV doses ranged from 2.6 to 69.9 micrograms and were given intramuscularly. Serologic neuraminidase-inhibiting (NI) and neuraminidase-specific ELISA responses in this N2-primed population were roughly proportional to the dose administered. Maximal response was seen in 14-21 days and NI antibody titers persisted unabated for the 6-month post-vaccination follow-up period. All doses were well tolerated with respect to local and systemic reactions. NI tests performed with the putative (1975) priming N2 antigen demonstrated anamnestic response but did not reveal responses not already shown with the homologous (1992) antigen. Response to this purified, non-adjuvanted preparation encourages continuing investigation of the induction of infection-permissive immunity with influenza virus neuraminidase.

A trivalent cold-adapted recombinant (CR) influenza virus vaccine containing types A and B viruses was compared with monovalent vaccines of each virus in a double-blind, placebo-controlled trial. Adults with a wide range of preexisting antibody titers received one 0.5-mL dose intranasally of trivalent vaccine; monovalent A/H1N1, A/H3N2, or B vaccine; or placebo. All vaccines were well tolerated. Serum antibody response frequencies and postvaccination geometric mean antibody titers were similar for recipients of trivalent or the corresponding monovalent vaccine for each of the vaccine components. Stepwise logistic regression analysis of the antibody responses of trivalent vaccine recipients demonstrated that response to one vaccine virus did not adversely affect the likelihood of response to the other viruses. This study failed to find serologic evidence of interference between vaccine viruses, suggesting that trivalent CR influenza virus vaccine may be useful for preventing influenza in adult populations.

Trivalent cold-adapted recombinant (CR) influenza virus vaccines containing types A (H1N1 and H3N2) and B viruses were evaluated in two double-blind, placebo-controlled trials. Susceptible adults were randomly assigned to receive the following vaccines by intranasal drops 1 month apart: two doses of trivalent vaccine, bivalent CR influenza A (Bi A) vaccine followed by monovalent B (Mono B) vaccine or vice versa, or two doses of placebo. All vaccines were well tolerated. Shedding of each of the three vaccine viruses was reduced after the first dose of trivalent vaccine compared with primary vaccination with Bi A or Mono B. Shedding was also reduced after second vaccinations, whether homologous (trivalent-trivalent) or heterologous (Bi A/Mono B or Mono B/Bi A). Reduced viral shedding was associated with reduced serum antibody responses. Thus, both simultaneous and sequential inoculations of susceptible adults with CR influenza vaccine viruses result in reduced viral shedding and serum antibody responses.

The safety of licensed influenza virus vaccine (IVV) combined with a novel adjuvant containing muramyl tripeptide (MTP) conjugated to phosphatidylethanolamine (PE) was evaluated in a randomized pilot study. Ten healthy 23-30-year-old men were given a single intramuscular dose of IVV combined with saline (n = 5) or with 100 micrograms of MTP-PE in the MF59 adjuvant emulsion (MF59-100) (n = 5). Evaluations were performed on days 0, 1, 2, 4, 7 and 28 after inoculation. IVV alone was well tolerated. All volunteers immunized with IVV/MF59-100 experienced moderate to severe local and systemic reactions which interfered with usual activities. Discomfort at the injection site was first noted at 2-6 h; induration (5/5), erythema (3/5), and regional adenopathy (3/5) persisted for up to 4 days. Systemic symptoms including chills (5/5), fever (3/5), nausea (3/5) and/or dizziness (2/5) developed within 12 h of inoculation and resolved by 48 h. Elevated white blood cell count (days 1 and 2), erythrocyte sedimentation rate and serum fibrinogen were transiently observed. Although peak serum neutralizing antibody titres versus influenza A/H3N2 and influenza B antigens were higher in the group given IVV with MF59-100, these unexpected reactions indicate that this dose of adjuvant is unsuitable for use in combination with this IVV.

Since influenza A/H1N1 viruses reappeared during the 1977-1978 season, this subtype has contributed 27% of 6,609 documented influenza infections of persons with acute respiratory disease presenting to clinics serving as surveillance sites of the Influenza Research Center in Houston for the 12-year period ending June 1989. Wide differences in the distribution of H1N1 viruses occurred by age group: more than 50% of H1N1 infections were detected among persons aged 10-34 years, compared with 28% for influenza A/H3N2 and 35% for influenza B. Over age 35 years, the contribution of H1N1 viruses dropped to only 4%, compared with 20% and 16% for influenza A/H3N2 and influenza B, respectively. When birth dates of persons with positive cultures were examined, it was found that most of the H1N1-positive persons were born after 1950. Concurrently, longitudinal studies of families and other adults under intensive surveillance for infection, including cultures of all respiratory illnesses and tests for serum antibody rise over the respiratory disease season, revealed appreciable infection rates for adults born before 1950. Furthermore, the annual peak of hospitalization of older persons with pneumonia and other acute respiratory illnesses was significantly correlated with the peak of H1N1 virus activity in 1978-1979, a year when H1N1 viruses were the only influenza viruses prevalent. These observations indicate that many persons infected with influenza A/H1N1 viruses that circulated from 1946 through 1953 have immunity which has persisted for more than 25 years but this immunity is not complete. Reinfection that may result in serious illness in older vulnerable adults does occur but with lower frequency than with influenza A/H3N2 infection. Currently prevalent H1N1 variants are antigenically different from those that circulated in the 1950s; however, older adults readily acquire immunity to these new variants--perhaps as a result of immunologic priming that occurred in childhood.

Influenza type A nucleoprotein (NP) derived from the full length cloned gene expressed in E. coli was evaluated in a solid phase enzyme immunoassay (EIA) for detection of human antibody to influenza. Monoclonal antibody to human IgG was used for detection. Direct and indirect assays were developed and sera were tested in serial and single dilution formats. Preliminary results indicated that recombinant-and virion-derived NP antigens were comparable in binding ability to plastic and binding human antibody. Eighty-seven paired sera from influenza patients were tested. The most sensitive assay (indirect-serial dilution) detected 56 (64%) rises and the simplest assay (direct-single dilution) detected 43 (49%) rises, compared to 36 (41%) for complement fixation. Paired sera from 18 control patients showed no evidence of antibody rises by any of the assays. Forty-nine paired sera from influenza B infected patients were negative for antibody rises except for one borderline rise by the indirect-serial dilution assay. These results indicate that the use of recombinant DNA derived nucleoprotein for immunoassay is feasible. The sensitivity of immunoassays using NP adsorbed to the solid phase and monoclonal antibody specific for human IgG to detect bound antibody exceeded that of conventional complement fixation testing for establishing serologic evidence of influenza type A infection.