Split Virus Vaccine Research Articles

Induction, persistence and strain specificity of haemagglutinin-specific secretory antibodies in lungs of mice after intragastric administration of inactivated influenza virus vaccines.

Two split influenza virus vaccines administered intragastrically induced lower titres of haemagglutinin (HA)-specific antibodies in pulmonary secretions than whole virus vaccine or a third split virus vaccine. IgA antibody was the predominant HA-specific Ig class. HA-specific IgA titres decayed substantially within 2 weeks following booster immunization, but persisted for at least another 3.5 months. In contrast, HA-specific IgG was maintained at low titres throughout the 4 month study period. When the total vaccine antigenic mass was administered as one dose or as equally divided doses spread over several days, pulmonary antibody responses were comparable. Mice immunized intragastrically with whole virus vaccine were completely protected against intranasal challenge with a homologous virulent virus of the H3 subtype. Partial protection was obtained when the vaccine used for immunization was a distantly related, antigenically variant strain of the same subtype, but no protection was obtained with a monovalent vaccine of an influenza A subtype different to the challenge virus. These characteristics of the response to intragastric immunization against influenza are consistent with features of a useful vaccine.

The Effect of Whole Virus Influenza Vaccination on Theophylline Pharmacokinetics

The effect of whole virus influenza vaccination on theophylline pharmacokinetics was evaluated in 16 normal subjects. Because previous reports had suggested that influenza vaccine induces interferon production and may potentially depress hepatic metabolism of theophylline, serum interferon concentrations were monitored for 6 days after vaccination. Lymphocytes from 6 subjects were incubated in vitro with dilute whole virus vaccine (WVV) or dilute split virus vaccine (SVV) to assess their immunocompetence and the immunogenic potential of the 2 vaccine preparations. Additionally, influenza antibody response was monitored by prevaccination and postvaccination serum antibody titers in 11 subjects. No significant change in half-life, total body clearance, volume of distribution of maximal serum theophylline concentration compared to prevaccine values was observed at either 2 or 6 days after vaccination. No interferon production was detected in vivo up to 6 days after vaccination. In vitro lymphocyte interferon induction assay demonstrated mean interferon levels of 12,252 +/- 9,819 IU/ml for WVV and 888 +/- 1,180 IU/ml for SVV (p less than 0.05), demonstrating the immunocompetence of the subject's lymphocytes and confirming the greater immunogenic potential of WVV. Seven of 11 subjects (64%) showed a 4-fold rise in influenza antibody titer to at least one of the vaccine antigens. We conclude that whole virus influenza vaccine does not alter theophylline pharmacokinetics. In addition, it has greater immunogenic potential than split virus vaccine in vitro but does not induce significant interferon production in vivo. This study adds further evidence supporting the safety of the concomitant use of influenza vaccine in patients taking theophylline.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of disease states on theophylline elimination

Host factors play an important role in the dosing requirements of theophylline. Theophylline metabolism and clearance depend principally on liver cell function rather than on hepatic flow. The effects of acute hypoxemia require more study; however, patients with chronic obstructive pulmonary disease who have chronic hypoxemia appear to have some impairment of clearance. Clearance is variably and sometimes drastically reduced in patients with liver disease and heart failure, and is reduced by some viral infections. It is not impaired by renal failure. Current split-virus vaccine mixtures do not appear to affect clearance. Clearance is increased in patients with cystic fibrosis and hyperthyroidism. The depressed clearance seen in the severely ill patients who require intensive care improves with improvement in the patient's condition, but the individual factors involved have not been identified. An area requiring more study is the effect of pH on the apparent distribution volume for theophylline. In the presence of liver disease, heart failure, or serious illness, caution must be applied in theophylline dosing, with frequent monitoring of serum levels. Stable patients also warrant an initially conservative dose until serum levels are obtained to guide further dose adjustments.

Electroelution for purification of influenza A matrix protein for use in immunoassay

A new preparative method for isolation of matrix protein from type A influenza virus was developed. Commercially available whole virus or split virus vaccines were lysed, and the soluble proteins separated by electrophoresis on polyacrylamide gel. The matrix protein was located on the gel by precipitation with KCl, and recovered by electroelution. The method was technically simple and required little direct supervision during the two-step recovery process. Yields of A matrix were consistently high, averaging 68.1% in five trials with A/Brazil/X-71. The method was also successful with other A viruses, although not with influenza B virus. Isolated A matrix had less than 0.5% contamination by hemagglutinin or nucleoprotein, as determined by immunoblotting and ELISA, Matrix protein was immunoreactive in Western blots and was detectable in concentrations as low as l ng/ml with ELISA. The isolated matrix provided a suitable standard for detection of matrix protein in nasal washes from patients with influenza A virus infection, and could also be used to detect anti-matrix antibodies, including monoclonal antibodies in tissue culture supernatants. The advantages of electroelution for separation of matrix protein compared to other methods were its technical simplicity, applicability to formalin-fixed influenza virus in commercially available vaccines, its consistently high yield, and its very high level of purification. influenza matrix electroelution polyacrylamide gel electrophoresis

The effect of split virus influenza vaccination on theophylline pharmacokinetics.

The effects of split virus influenza vaccine on the pharmacokinetics of theophylline and the in vivo and in vitro induction of interferon were studied in 23 volunteers. No effect on the total body clearance, half-life, or mean residence time of theophylline was found as a result of influenza virus vaccine. Additionally, no interferon activity was detected in vivo for as long as 24 h after vaccination. Finally, no production of interferon occurred in tonsil or peripheral lymphocyte cultures inoculated with split virus vaccine. We conclude that split virus influenza vaccine does not affect theophylline pharmacokinetics. In addition, we find no evidence that split virus influenza vaccine functions as an interferon inducer in humans.

Depression of chemiluminescence response in mouse spleen cells by infective and inactivated influenza virus

The effect on respiratory burst of murine splenic cells after exposure to influenza viruses was studied by luminol-dependent chemiluminescence (CL). Infectious influenza A and B viruses considerably depressed the zymosan-induced CL response of the cells. Commercially available trivalent influenza virus vaccines also depressed CL activity. The whole-virus vaccine induced the greatest inhibition of the CL response, followed by the subunit and the split-virus vaccines. Virus-induced depression of CL was observed in the unseparated and in the granulocyte-enriched populations but no apparent effect was found in the lymphocyte-enriched populations. Prior sensitization of mice with representative, inactivated prototype strains of human influenza A and B viruses depressed the moderate CL induced by infectious influenza viruses. These results indicate that both infectious and inactivated influenza viruses impair the generation of the respiratory burst.

Persistence of Antibody After the Administration of Influenza Vaccine to Children with Cancer

Children with cancer who received an intramuscular injection of inactivated split or whole bivalent (A/New Jersey/76-A/Victoria/75) influenza virus vaccine during the fall of 1976 were tested up to 18 months later for the persistence of antibody. Titers of antibody greater than of equal to 10 to influenza A/New Jersey/76 virus were present in the sera of 34 children two weeks after immunization. The geometric mean titer was 40.0. Eighteen months later a titer greater than or equal to 10 was present in 13 (38%) children; the geometric mean titer was 8.5. Of 36 children with a titer of antibody greater than or equal to 10 to A/Victoria/75 virus two weeks after immunization, 34 still had a detectable titer in the later examination. The geometric mean titer declined from 65.3 to 25.6. Titers of antibody to B/Hong Kong/72 virus (not included in the vaccine) remained relatively stable. In 11 children the usual chemotherapy was discontinued during the study. The shorter persistence of antibody to A/New Jersey/76 virus, in contrast to that of the other two influenza viruses tested, was associated with a lack of prior exposure to the virus and the absence of subsequent natural infection with this virus or an antigenically related subtype. The potential effect of cancer chemotherapy on the persistence of antibody levels is unclear.

Reactogenicity and immunogenicity of three inactivated influenza virus vaccines in children

The reactogenicity and immunogenicity of an aqueous inactivated whole virus vaccine, splitvirus vaccine and a subunit vaccine was studied in young children. In volunteers aged 9–12 years inoculated with two doses of vaccine given 1 month apart, the number of reactions seen following both immunization with either whole virus or subunit virus vaccine was small; the reactions were all mild in nature; and both vaccines gave comparable results. Two doses of vaccine induced relatively high tires of serum HI antibody against A/Texas/77 virus, but poorer responses against influenza A (H1N1) virus and B/Hong Kong/73 virus; the serum HI antibody responses were similar for the two vaccines. The incidence of local reactions in volunteers aged 5–9 years given two doses of whole virus, subunit or split-virus vaccines was also low, and mild in nature: all three vaccines gave similar results; however, systemic reactions occurred more frequently in volunteers given whole virus vaccine than in those inoculated with subunit or split-virus vaccines, but the differences were not statistically significant. The serum HI antibody responses were similar for the three influenza vaccine forms: the response to the A/Texas/77 virus haemagglutinin was relatively satisfactory but poor antibody responses were found for the influenza A (H1N1) and B/Hong Kong/73 haemagglutinins. In addition, the response of volunteers aged 5–9 years to influenza virus A (H1N1) haemagglutinin was significantly less than for volunteers aged 9–12 years.

The specificity of the anti-haemagglutinin antibody response induced in man by inactivated influenza vaccines and by natural infection.

The anti-haemagglutinin antibody response in adult human volunteers to inactivated whole virus or tween ether split influenza A/Victoria/75 (H3N2) and A/Scotland/74 (H3N2) virus vaccines was investigated using antibody absorption and single-radial-haemolysis (SRH) techniques. The concentrations of haemagglutinin (HA), nucleoprotein (NP) and matrix (M) antigens measured by single radial diffusion (SRD) and rocket immunoelectrophoresis were similar for both the whole virus and split vaccines. Whole virus and split vaccines induced crossreactive (CR) antibody in 87% of vaccinees. Strain specific (SS) antibody to A/Hong Kong/1/68 of the homologous virus was induced less frequently than CR antibody. Higher anti-haemagglutinin antibody titres were detected in persons receiving the split virus vaccines than in those receiving the whole virus vaccines. No antibody to the type-specific matrix protein was detectable, but 33% of volunteers developed an antibody rise to type-specific nucleoprotein antigen. The specificity of the anti-haemagglutinin antibody response in human adults to natural infection with A/Port Chalmers/73 (H3N2) virus was similar to that induced by inactivated vaccines in that a high proportion of subjects developed CR anti-haemagglutinin antibody, which reacted with A/Hong Kong/68 virus and the homologous A/Port Chalmers/73 virus, and SS antibody for A/Hong Kong/68 virus but SS antibody for A/Port Chalmers/73 virus was infrequently stimulated by natural infection.

Response to Influenza A Vaccine Among High-Risk Patients

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.

Serologic and clinical response of children with sickle cell disease to bivalent influenza A split virus vaccine

INCREASED SUSCEPTIBILITY to severe bacterial infections is well documented in sickle cell disease? Although there is little evidence that non-bacterial infections pose similar problems, viral diseases such as influenza can predispose to infection with bacteria, particularly Streptococcuspneumoniae, which may be a major cause of death in children with SCD. 2' 3 In addition, viral infections may trigger a sickle cell crisis, necessitating hospitalization. 4 Prevention of viral diseases is therefore desirable. The availability of bivalent influenza vaccine (A/New Jersey/ 76-A/Victoria/75) during the latter half of 1976 provided an opportunity to evaluate the clinical response of young SCD patients to immunization.

The effect of ABO blood groups on the incidence of epidemic influenza and on the response to live attenuated and detergent split influenza virus vaccines.

The effect of blood group status on the incidence of epidemic influenza A (H3N2) infections and on serological response to influenza vaccination with killed subunit and live attenuated vaccines have been investigated during comparative vaccine trials in Western Australia. A significantly higher incidence of epidemic influenza was observed in subjects of blood group B compared with those of other blood groups, regardless of whether they had serological evidence of previous exposure to H3N2 antigens or not. Volunteers of different blood groups exhibited similar seroconversion frequencies to both vaccines after the administration of two doses, but a significantly higher proportion of blood group A subjects seroconverted after receiving their first dose of live attenuated vaccine compared with those of other blood groups. Although this finding was inconsistent with the increased incidence of epidemic influenza in subjects of blood group B, it is discussed in terms of the methods employed to obtain attenuation. Higher geometric mean HI antibody titres were observed in blood group O subjects after the administration of killed subunit vaccine. The results described in this report supported the contention that genetic factors linked to ABO blood groups may play a role in susceptibility to infection with influenza A virus, but that any association must be indirect.

Sequential immunization of laboratory personnel with influenza A/New Jersey/76 split- and whole-virus vaccines.

One hundred thirty-three healthy, at-risk Fort Detrick laboratory workers were inoculated with 400 chick cell-agglutinating (CCA) units of influenza A/New Jersey/76 split-virus vaccine (Wyeth Laboratories, Philadelphia, Pa.). Systemic and local reactions were infrequent, mild, and comparable to those of a sham-vaccinated group of volunteers. Only 28% of subjects 19-24 years old developed titers of hemagglutination-inhibiting (HAI) antibody of greater than or equal to 1:20, whereas titers of 91%-100% of subjects 25-62 years old reached this level. Thirty-one vaccinated subjects with no or low titers of antibody were given a booster dose (400 CCA units) of Wyeth vaccine six weeks after the first inoculation. Only 58%-67% of these vaccinees achieved HAI titers of greater than or equal to 1:20 after the booster. Fourteen persons required a second booster dose for protection; after vaccination with 400 CCA units of whole-virus vaccine from Merck Sharp and Dohme (West Point, Pa.), 89%-100% of the 14 vaccinees finally achieved HAI titers of greater than or equal to 1:20. The split-virus vaccine was safe, but it was poorly antigenic as a primary vaccine in persons 19-24 years old and as a booster in persons of all ages who have poor antibody responses in general.

Reactogenicity and Immunogenicity of Parenteral Monovalent Influenza A/Victoria/3/75 (H3N2) Virus Vaccine in Healthy Adults

Monovalent influenza A/Victoria/3/75 whole-virus vaccines prepared by Merck Sharp and Dohme (West Point, Pa.) and Merrell-National Laboratories (Cincinnati, Ohio) and split-virus vaccines prepared by Parke, Davis and Company (Detroit, Mich.) and Wyeth Laboratories (Philadelphia, Pa.) containing 200, 400, and 800 chick cell-agglutinating units per dose were compared with a placebo in double-blind trials in which 208 adults participated. Titers of hemagglutination-inhibiting antibody of greater than or equal to 1:20 were found in greater than 80% of the volunteers 21 days after vaccination. Seroconversion, defined as a fourfold or greater increase in antibody titer, occurred more frequently among seronegative volunteers than among seropositive volunteers. The geometric mean titers obtained with the whole-virus or split-virus vaccines were not significantly different. Reaction rates had no relation to seroconversion, nor did seronegative subjects have more reactions than seropositive subjects. Local reactions from all vaccines increased with increasing dose. Significantly more overall reactions, "bothersome" reactions, and febrile reactions occurred in the recipients of whole-virus vaccine. Of nine volunteers who reported temperatures of greater than 100 F, one had received split-virus vaccine, seven had received whole-virus vaccine, and one had received the placebo. Most systemic reactions were mild, and all were self-limited.

Summary of clinical trials of influenza virus vaccines in adults.

Trials in approximately 3,900 adults were conducted with influenza A/New Jersey/76, A/Victoria/75, and B/Hong Kong/72 virus vaccines. Subjects were observed following a standard protocol, and serologic testing was performed in a single laboratory. The data indicate that prior experience of the population with earlier influenza viruses ("priming") is a determinant in response to vaccination. Thus, participants older than 25 years showed good serologic response following a single inoculation of A/New Jersey/76 virus, while younger persons responded poorly. Serological responses to A/Victoria/75 and B/Hong Kong/72 viruses were, in contrast, equally good in the younger and older adults. Whole-virus vaccines were measurably more reactive than split-virus vaccines, a finding more easily discernined in unprimed populations. In the unprimed persons, a single dose of split-virus vaccine was less immunogenic than a single dose of whole-virus vaccine. The presence of preexisting antibodies appeared to reduce systemic reactivity. For adequate immunization of a totally unprimed population, a single relatively large and reactive dose of whole-virus vaccine or two, properly spaced, smaller nonreactive doses of either whole-virus vaccine or split-virus vaccine would be required.

Response of children with cardiac disease to the bivalent influenza A vaccines.

During the recent nationwide trials of influenza vaccine, 121 children with cardiac disease, aged three to 18 years, were evaluated with respect to their immune response and reaction rate after administration of a whole-virus or split-virus bivalent influenza A/New Jersey/76-A/Victoria/75 vaccine given as a single dose or two divided doses. The serologic response of the cardiac children did not differ significantly from that of the total group of high-risk children or normal children who recived the same vaccine. The major reaction to the vaccines was fever, which occurred in one-fourth to one-half of children receiving the whole-virus vaccines. The split-virus vaccines were generally well tolerated. The reaction index of the cardiac children was slightly lower than that of the normal children receiving the same vaccine during the single-dose trial but higher during the two-dose trial. The second dose was generally better tolerated than the first dose. Reactions in the children with cardiac disease could not be adequately evaluated according to specific diagnoses or functional disabilities.

Studies of Inactivated Influenza Virus Vaccines in Hospital Employees: Reactogenicity and Absenteeism

The impact of a mass influenza vaccination program on the operation of a major medical center was evaluated in adult volunteer employees who were given either ether-split or whole-virus bivalent influenza vaccine in a double-blind manner by jet-injector gun. Each volunteer completed a reaction information form, nurses monitored temperatures, and data on absenteeism of the employees of the Nursing Service and the Building Management Service were collected. The results of this study demonstrated that the mass campaign did not adversely affect absenteeism. However, the whole-virus vaccine caused significantly more local, systemic, and febrile reactions thant the split-virus vaccine. Purified inactivated influenza virus vaccines can be given in a mass campaign to hospital personnel without adversely affecting the operation of the hospital.

Safety and antigenicity of inactivated influenza virus vaccines in children: trials with monovalent and bivalent A/New Jersey/76 (HswN1) and A/Victoria/75 virus vaccines in Washington, D.C..

Safety and antigenicity of monovalent and bivalent A/New Jersey/NJ)/76 (HssN1) and A/Victoria/75 inactivated influenza virus vaccines were studied in 125 children aged three to 18 years. In recruitment, families who knew the study team, who were professionally involved, and/or who were under close continuing care were more likely to volunteer for such studies than those who were unfamiliar with the team or institution. Antibody responses and systemic reactions occurred more often after administration of inactivated whole-virus vaccine than after split-virus vaccine. Significant titers (greater than or equal to 1:40) of hemagglutination-inhibiting antibody to A/NJ/76 virus occurred in 95% of normal children three to 18 years of age who received two doses of the same vaccine (whole or split). However, insufficient numbers of children achieved a reasonable antibody titer (greater than or equal to 1:40) after one dose of vaccine.

Comparative Study of Reactogenicity and Immunogenicity of Influenza A/New Jersey/8/76 (Hsw1N1) Virus Vaccines in Normal Volunteers

Local and systemic reactions and antibody responses to three different doses of influenza virus vaccine (A/New Jersey/76 [Hsw1N1]) produced by four different manufacturers were studied. Local and systemic reactions that peaked between 8 and 24 hr after vaccine administration were related to the source of the vaccine more than to the dose. Antibody conversion occurred in almost 90% of subjects over the age of 25 years but in only 61% of subjects 25 years or younger. This low response rate was due almost entirely to the lack of response of volunteers who received split-product vaccine (only 49% of subjects became seropositive). In addition, individuals with symptoms of local reaction had a rate of antibody conversion and magnitude of antibody response that were significantly higher than those observed in subjects who did not have local reactions. These findings suggest that in subjects older than 25 years, all four vaccines produced a high frequency of antibody response with a minimum of side effects. In addition, split-virus vaccine is less immunogenic than whole-virus vaccine in subjects younger than 25 years. Production of a vaccine devoid of local reaction may not be advisable.

Trials of Influenza A/New Jersey/76 Virus Vaccine in Normal Children: An Overview of Age-Related Antigenicity and Reactogenicity

The total multicenter data from trials with inactivated monovalent influenza A/New Jersey/76 virus vaccine in 2,326 normal children were collected and summarized at Vanderbilt University (Nashville, Tenn.). These combined data provided the best measure of the relative antigenicity and reactogenicity of each manufacturer's vaccine. Children younger than 10 years of age were shown to have vaccine-associated reactions to doses of whole-virus vaccine containing as little as 50 chick cell-agglutinating units. Split-virus vaccines were well tolerated in doses eight times as high. No vaccine was satisfactorily antigenic in a single dose. A two-dose regimen of split-virus vaccine was antigenic, and this regimen was not associated with acute reactions.