Influenza surveillance in England and Wales: October 1995 to June 1996

This report summarises information collected for the surveillance of influenza virus infection in England and Wales from October 1995 to June 1996 (weeks 40/95 to 25/96). Total respiratory disease' activity, as reported by the Birmingham Research Unit of the Royal College of General Practitioners, rose to peaks in weeks 48/95, 51/95, and 01/96. The first peak coincided with a peak in "influenza and flu-like illness'. The subsequent peaks were accounted for by an increase in reports of acute bronchitis, including bronchiolitis, and may have been associated with the annual rise in infections with respiratory syncytial virus. Influenza A virus was responsible for most infections, with moderate activity occurring in the early part of the winter, peaking in December (week 48/95). Influenza A subtype H3N2 predominated until week 07/96, after which subtype H1N1 accounted for most infections. Influenza activity was first seen in central and northern England, followed by the south of England, Wales, and Scotland. Circulating influenza viruses were antigenically similar to the components of the 1995/96 vaccine. International surveillance during 1995/96 has led to a different H3N2 component being included in the influenza vaccine recommended for 1996/97.     

Evolutionary characteristics of influenza B virus since its first isolation in 1940: dynamic circulation of deletion and insertion mechanism

New antigenic variants of B/Yamagata/16/88-like lineage which appeared in the season of 1997 as a minor strain tended to predominate in the following season. Also, we could observe for the first time, three peaks of activity caused by H3N2 virus and two variants of B influenza virus. Antigenic and phylogenetic analyses revealed that B/Victoria/2/87-like variants appeared again in Japan in 1997 after a nine-year absence. Influenza B viruses evolved into three major lineages, including the earliest strain (I), B/Yamagata/16/88-like variants (II), which comprised of three sublineages (II-(i), II-(ii), II-(iii)), and B/Victoria/2/87-like variants (III). Evolution of influenza B virus hemagglutinin was apparently distinguishable from that of influenza A virus, showing a systematic mechanism of nucleotide deletion and insertion. This phenomenon was observed to be closely related to evolutionary pathways of I, II-(i), II-(ii), II-(iii) and III lineages. It was noteworthy to reveal that the nucleotide deletion and insertion mechanism of influenza B virus completed one cycle over a fifty-year period, and that a three nucleotide deletion was again observed in 1997 strains belonging to lineage II-(iii). It was evident that amino acid substitutions accompanying nucleotide insertions were highly conserved.     

Influenza surveillance in England and Wales: October 1996 to June 1997

This report summarises information collected for the surveillance of influenza in England and Wales during the winter of 1996/97. Consultations for 'influenza and influenza-like illness' with sentinel general practitioners in England and Wales began to increase towards the end of November and peaked at the start of January. In England, consultations for 'aggregated respiratory disease' (ARD) began to increase a little earlier, perhaps as a result of increased respiratory syncytial virus activity, but also peaked in early January. Influenza A (H3N2) viruses were first detected in early October, but rarely until November, and activity peaked in early January, coinciding with the peak in consultations for flu-like illness. A few influenza B viruses were detected in late November and early December, and substantial activity was recorded in mid-January. Approximately equal numbers of influenza A(H3N2) and B viruses were identified over the winter as a whole, and circulating strains were antigenically similar to those included in the vaccine for 1996/97. Although influenza activity was 'moderate' in terms of consultations and laboratory confirmed infections, a large peak in death registrations occurred at the same time as influenza A(H3N2) virus activity peaked. The number of deaths during the winter was similar to that seen in 1989/90, when the last severe influenza epidemic occurred in England and Wales.     

UK takes steps to improve handling of patients'' complaints about MDs

Annually the influenza centre receives more than 1000 virus isolates from around the world to monitor the changing pattern of viruses causing influenza throughout the year. These are characterized antigenically using both polyclonal and monoclonal antibodies and selected viruses are subjected to closer scrutiny by nucleotide sequence analyses of their HA genes. This information is used in making the annual recommendation of vaccine composition. As in the last 15 years, influenza A viruses of both H3N2 and H1N1 subtypes and influenza B viruses have been isolated during the recent influenza season. Outbreaks in the northern hemisphere were largely caused by influenza B viruses which are similar to the B/Panama/45/90 reference strain. The proportion of influenza A increased later in the season and was predominantly of the H3N2 subtype, viruses similar to the recent A/Beijing/32/92 variant being most prevalent. The observed changes taking place will be discussed in the context of recent trends.     

Recurrent intracranial neurenteric cysts

To determine the efficacy of a single influenza vaccine administration in the elderly receiving annual influenza vaccination, antibody response to influenza vaccine was compared between once and twice injections in a geriatric cohort. Influenza vaccination had been done for 69 inpatients in the year prior to the study, and was administered twice for 34 of them and once for the other 35 during the study period. Influenza vaccine was injected twice to 77 inpatients who had not received influenza vaccine in the year prior to the study. Hemoagglutination inhibition (HI) antibody titer for influenza A/H1N1, A/H3N2, and B was measured before vaccination, after the first vaccination, after the second vaccination, and after the epidemic period, September 1995 to April 1996. HI antibody titer prior to vaccination was significantly higher in the patients who had received influenza vaccination the previous year. The influenza vaccine induced an increase in HI titer in almost all subjects, and the geometric mean of the HI titer after vaccination in the patients who received vaccine once was comparable to that of the patients injected vaccine twice. The number of patients with HI titers of over 128x increased, and the frequency ranged from 60.0% to 97.1% for the influenza viruses of the three subtypes. The frequency of HI titers over 128x was not significantly different among the three groups. The second vaccination did not increase the number of patients with HI titers over 128x when compared with the number after the first injection in the patients who had received influenza vaccine the previous year. These results suggest that prior vaccination does not diminish the antibody response to influenza vaccine in the elderly. The efficacy of a single influenza vaccination is comparable to that achieved by twice injections in the elderly receiving annual influenza vaccination.     

Immunogenicity and efficacy of DNA vaccines encoding influenza A proteins in aged mice

Influenza is a leading cause of morbidity and mortality in older persons. The current influenza vaccine is only modestly successful, in part because of an age-related decline in immunogenicity and also because it induces only type-specified immunity. To overcome this, we evaluated DNA vaccines encoding A/PR8/34 haemagglutinin (HA) and nucleoprotein (NP) in young and aged BALB/c mice. Control mice were given formalin-inactivated A/PR8/34, control DNA, or a non-lethal dose of PR8. Aged mice given HA DNA developed slightly lower anti-HA serum antibodies than young mice; however, both young and aged mice were protected from a homotypic PR8 challenge. Following vaccination with NP DNA, both young and aged mice developed anti-NP bulk cytotoxic T-lymphocyte (CTL) activity and pCTL frequency similar to control animals. When challenged with a low dose of A/HK/68 (H3N2) influenza virus, both young mice and aged mice showed significant protection as measured by inhibition of weight loss. When challenged with a relatively high dose of A/HR/68 (H3N2) influenza virus, however, the anti-NP vaccine only partially protected young mice and failed to protect aged mice. These data demonstrate that DNA-based vaccines are immunogenic in aged animals, but suggest that factors other than the age-related decline in CTL activity also contribute to the increased morbidity and mortality of influenza in the elderly.     

Supplementation of conventional influenza A vaccine with purified viral neuraminidase results in a balanced and broadened immune response

Influenza virus neuraminidase was chromatographically extracted from A/Johannesburg/33/94 (H3N2) and used to supplement conventional monovalent H3JHN2JH inactivated influenza vaccine. Immunization of mice with this preparation resulted in high titers of antibodies to both hemagglutinin (HA) and neuraminidase (NA) equivalent for each antigen to titers in animals immunized with either antigen alone. Homotypic infection was suppressed and greater reduction in viral replication was observed following heterotypic infectious challenge than was observed following the non-supplemented vaccine. There was no evidence of suppression of the immune response to the HA despite the presence of high amounts of NA in the vaccine. Supplementation of conventional inactivated influenza vaccine with NA takes advantage of the equivalent immunogenicity of dissociated HA and NA, to produce a more balanced immune response to both surface antigens, without the antigenic competition tht occurs after immunization with conventional vaccine or infection. These studies in a mouse model system suggest that supplementation of current inactivated influenza vaccines offers the prospect of improved immunization of humans against influenza.     

Efficacy of an influenza hemagglutinin-diphtheria toxoid conjugate vaccine in elderly nursing home subjects during an influenza outbreak

OBJECTIVE: To compare the efficacy of an influenza hemagglutinin-diphtheria toxoid conjugate vaccine with the commercially available influenza hemagglutinin-subunit vaccine in preventing influenza in older adults living in a nursing home. DESIGN: A prospective, randomized, double-blind vaccine trial with 5 months of follow-up after vaccination. SETTING: Fourteen Wisconsin nursing homes. PARTICIPANTS: Nursing home residents at least 65 years old who were able to give informed consent and were free of malignancy and not receiving immunosuppressive therapy. INTERVENTIONS: Participants received, by intramuscular injection, 0.5 mL of a trivalent influenza vaccine containing 15 micrograms each of A/Leningrad/360/86 (H3N2), A/Taiwan/1/86 (H1N1), and B/Ann Arbor/1/86 (HA) or 0.5 mL of an influenza vaccine containing the same antigens conjugated to diphtheria toxoid (HA-D). MEASUREMENTS: Blood was obtained pre- and 1 month post-vaccination to assess for any vaccine-induced antibody titer change. Clinical surveillance for respiratory illness was performed twice weekly for 5 months. A record was kept of all signs and symptoms of new respiratory illness, and a viral culture and acute and convalescent sera were obtained. RESULTS: 204 participants received HA and 204 received HA-D. Both groups had similar baseline antibody levels to all influenza antigens. HA-D recipients seroconverted more frequently based on serum neutralizing activity (P < 0.05), had a greater increase in geometric mean titer (GMT), and sustained the increase in antibody titer longer than HA recipients. Vaccine hemagglutinin recall was greater in a subset of HA-D recipients as measured by lymphocyte proliferative assays (P < 0.05). During an outbreak of influenza A (H3N2 A/Shanghai/11/87-like and A/Victoria/7/87-like), fewer HA-D (29/195) than HA (43/204) recipients had laboratory-confirmed infection (P = 0.053), and, of these, fewer HA-D-treated subjects had lower respiratory tract involvement (5/29 HA-D and 17/43 HA) (P = 0.022). CONCLUSIONS: HA-D was more immunogenic in institutionalized elderly recipients and produced greater protection from influenza infection. Superior protection may be due to HA-D's ability to stimulate and recruit antigen-presenting cells, thus enabling the recipient to achieve and maintain functional antibody titers.     

Epidemic of influenza in Kyushu-Okinawa District (April 1994-March 1995)

The prevalence of influenza in Kyushu-Okinawa District in April 1994- March 1995 was studied as the prevalence of influenza virus, to determine the sero-type of influenza viruses isolated in Kyushu- Okinawa District prefectures and cities. As a result, three sero-types of influenza viruses, i.e. type A/H1N1, type H3N2 and type B, were isolated in Kyushu-Okinawa District in this season, but most of the isolates were type A/H3N2 and type B. Weekly changes of reported influenza patients and period of virus isolation at local public health institutes revealed that influenza epidemics of the earlier part in this season was caused by type A/H3N2 and the latter part due to type B. Type A/H3N2 spread all over Kyushu-Okinawa District in a shorter period (about 2 weeks) through the westside of Kyushu and down south, and type B stayed about one month in northern Kyushu and took about 7 weeks to spread all over Kyushu-Okinawa District. Based on these results, the spread of influenza virus in Kyushu-Okinawa District was visualized on the isopleth maps.     

Human immune responses to influenza virus vaccines administered by systemic or mucosal routes

Healthy adult volunteers were immunized by parenteral or oral routes with trivalent inactivated influenza vaccine (A/Chile/1/83 (H1N1), A/Mississippi/1/85 (H3N2), and B/Ann Arbor/1/86), or intranasally with live attenuated, cold-adapted influenza type A/Texas/1/85 (H1N1) reassortant virus. In all volunteers, cells spontaneously secreting IgA, IgG or IgM antibodies specific to influenza virus were detected in peripheral blood on days 6-13 after immunization, and specific IgA, IgG and IgM antibodies to influenza vaccine were measured in sera and external secretions (saliva and nasal lavage). Following systemic immunization, a raise in specific antibodies of all isotypes was observed in sera beginning on day 13. Although small variations in IgA and IgM antibodies in saliva and nasal lavages were detected, antigen-specific IgG significantly increased between days 13 and 27. Intranasal administration of attenuated virus induced IgA and IgG antibodies in serum as well as in secretions. Serum antibodies were not substantially influenced by oral immunization, only a small increase in all isotypes was observed in volunteers' sera 21 days after ingestion of vaccine. However, in secretions, antigen-specific IgA and IgG responses were detected one week after immunization and reached a peak response on day 20. These studies show that different routes of immunization can be effective for the induction of specific antibodies, and support the concept of the common mucosal immune system in humans by demonstrating that the oral or intranasal administration of antigen-induced specific antibodies of IgA isotype in external secretions, preceded by the transient appearance in peripheral blood of specific antibody-producing cells.     

Susceptibilities to rimantadine of influenza A/H1N1 and A/H3N2 viruses isolated during the epidemics of 1988 to 1989 and 1989 to 1990

Clinical isolates of influenza A viruses identified during outbreaks in two winters were tested for their rimantadine susceptibilities by an enzyme-linked immunosorbent assay modified from that described previously by Belshe et al. (R. B. Belshe, B. Burk, F. Newman, R. L. Cerruti, and I. S. Sim, J. Virol. 62:1508-1512, 1988). The infectivity titer and the 50% inhibitory concentration of rimantadine were calculated for each virus. Of 105 influenza virus A isolates tested, 28 influenza A/H1N1 isolates from the 1988 and 1989 outbreak and 77 influenza A/H3N2 isolates from the outbreak in following year, were susceptible to the antiviral action of rimantadine.     

Effect of prednisone on response to influenza virus vaccine in asthmatic children

OBJECTIVE: To evaluate the immunogenicity of the influenza virus vaccine in children receiving short-course (a burst) prednisone therapy for acute asthmatic exacerbations. DESIGN: Prospective cohort study. SETTING: Outpatient pediatric clinic of a military medical center. PATIENTS: Children aged 6 months to 18 years requiring the 1996 influenza virus vaccine were eligible for the study. A total of 58 children were enrolled initially. The control group included 37 asthmatic children requiring less than 900 microg/d of inhaled prednisone and their siblings. The prednisone group included 21 children vaccinated at the beginning of a course of prednisone prescribed to treat an asthma exacerbation. Thirty-one control subjects (84%) and 19 patients in the prednisone group (90%) completed the study. Dropout was due to failure to come in for the postvaccination serum sampling. INTERVENTIONS: All study patients underwent immunization with the 1996-1997 trivalent subvirion influenza virus vaccine (FluShield; Wyeth Laboratories Inc, Marietta, Pa) containing 15-microg hemagglutinin antigens each of A/Texas/36/91 (H1N1) (A/H1), A/Wuhan/359/95 (H3N2)(A/H3), and B/Beijing/184/93 (B). The prednisone cohort received a burst of oral prednisone therapy (2 mg/kg per day for 5 days). MAIN OUTCOME MEASURES: To assess the immunogenicity of the vaccine between both groups, at least a 4-fold rise in titer and end titers of at least 1:40 to each of the 3 antigens were compared. Mean changes in geometric titers to the 3 antigens were also compared. RESULTS: Proportion of patients in each group with at least a 4-fold rise in titer to each of the influenza antigens was as follows: for A/H3N3 antigen, 15 patients (79%) in the prednisone group vs 22 controls (71%) (P = .74); for A/ H1N1 antigen, 16 patients in the prednisone group (84%) vs 20 controls (64%) (P = .20); and for B antigen, 7 patients in the prednisone group (37%) vs 8 controls (26%) (P = .53). Proportion of patients in each group with an end titer of at least 1:40 to each of the antigens was as follows: for A/ H3N2 antigen, 18 patients in the prednisone group (95%) vs 28 controls (90%) (P = .69); for A/H1N1 antigen, 17 patients in the prednisone group (89%) vs 26 controls (84%) (P = .99); and for B antigen, 7 patients in the prednisone group (37%) vs 13 controls (42%) (P = .99). There were also no significant differences between groups in the mean changes in geometric titers to any of the 3 antigens. CONCLUSIONS: Prednisone bursts did not diminish the response of asthmatic children to the 1996 influenza virus vaccine, compared with controls. Children can be effectively vaccinated against influenza virus while they are receiving prednisone therapy bursts for asthmatic exacerbations.     

Clinical and serological responses to an inactivated influenza vaccine in adults with HIV infection, diabetes, obstructive airways disease, elderly adults and healthy volunteers

To investigate the clinical and serological responses to an inactivated influenza vaccine (split-virion A/Singapore/6/86-like strains H1N1 (15 ug HA), A/Beijing/353/89-like H3N2 (15 ug HA) and B/Yamagata/16/88-like strain (15 ug HA): MFV-JECT, Merieux, UK) in persons with HIV infection, diabetes, obstructive lung diseases, elderly adults and healthy volunteers. Forty-nine HIV-infected persons received 2 doses of the vaccine at one-month intervals; 34 healthy volunteers, 30 elderly persons, 29 with insulin and non-insulin diabetes and 14 with obstructive airways diseases were vaccinated with one single dose between October 1992 to January 1993. Serological testing of antibody responses was done using haemagglutination assay. Beta2-microglobulin in HIV-infected persons was measured using radioimmunodiffusion between 1st and 2nd dose. Fructosamine levels in diabetic persons were assessed for diabetic control and peak expiratory flow rate (PEFR) was self monitored in persons with lung diseases. All groups apart from the elderly filled in a symptom score chart for the first 5 days following vaccination. A 4-fold rise in titre equal to or more than 1:64 to all the 3 antigens occurred in 20 (58.8%) of healthy volunteers compared with 13 (44.8%) diabetics, 5 (35.7%) with lung diseases, 10 (33.3%) elderly and 13 (26.5%) with HIV infection. A significant correlation of serological response to number of CD4 count in persons with HIV infection was noted (H1N1 P=0.0013, H3N2 P=0.025, BYAM P=0.0018). Mean beta2-microglobulin levels did not change significantly post 1st and 2nd vaccination. Mean fructosamine level did not change significantly. There was no significant change in PEFR. The vaccine was well tolerated. Persons with HIV infection and low CD4 count do not serologically respond well to influenza vaccine even with 2 doses compared to the other 4 groups. The other 4 groups had adequate protective serologic responses. The vaccine was well tolerated in all groups.     

Serologic study for determining the circulation of respiratory viruses in Havana City

During 1991, 2,400 serum samples from subjects under 15 years, and 2,400 serum samples from subjects with the same age or over 15 years were assessed against antigens of 7 respiratory viruses by the complement fixation test or by the haemagglutination inhibition technique. The results from these investigations allowed to determine the little circulation of the respiratory syncytial virus which may result in an increase of a susceptible population and the occurrence of outbreaks. The endemic state of Adenoviruses was determined and the subtype H1N1 of influenza viruses was found to have a little circulation with a raise in the population under 1 year old age during November. The subtype H3N2 of influenza A was the most important agent within the population studied, followed by Influenza B virus during September and November. All viral agents were found to have circulated in the different age groups of the population assessed.     

Safety of influenza vaccine in heart transplant recipients

BACKGROUND: Influenza vaccine is recommended for heart transplant recipients, but its administration is often deferred because of anecdotal reports of rejection associated with the vaccine. We evaluated the safety of influenza vaccine in a group of stable heart transplant recipients over a 2-year period. METHODS: During the 1993 to 1994 influenza season, stable heart transplant recipients who had undergone transplantation a minimum of 1 year before study entry were randomized to vaccination with a single dose of influenza vaccine versus no vaccination. Routine endomyocardial biopsies and postvaccination influenza serologic studies were performed between 2 and 6 weeks after enrollment/immunization. During the 1994 to 1995 season, patients were given 2 doses of influenza vaccine, separated by 3 weeks; endomyocardial biopsies and serologic studies were performed between 2 and 6 weeks after the second immunization or enrollment (if control subject). Biopsy results were evaluated with respect to vaccine response, immunosuppressive regimens, and patient demographics. RESULTS: Eighteen patients were enrolled in the single vaccine trial and 10 in the booster vaccine trial. Four of 14 vaccine recipients had biopsy specimens consistent with International Society for Heart and Lung Transplantation grades 2 to 3A as compared with 1 of 14 control subjects (grade 2) (p = .326). All episodes of rejection in the vaccine recipients were asymptomatic and responded to a single course of treatment. Rejection was unrelated to the time from transplantation, doses of immunosuppression, age, or number of doses of or response to vaccine. CONCLUSIONS: Influenza vaccine can be safely administered to most heart transplant recipients but may be associated with low-level histologic rejection.     

Disability among the population of the Russian Federation

Previously we demonstrated that in the course of intracellular reproduction of WSN influenza virus strain, part of monomeric nucleoprotein (NP) undergo polymerization into dimers and trimers, which dissociate into monomers after boiling. Further studies showed that different strains of influenza virus are characterized by different degree of NP-oligomerization. Specifically, Duck/ Ukraine/63 (H3N8) and Seal Massacuhsets 1/80 (H7N7) NP monomers are completely transformed into oligomers. As a result of 40-min chase and of prolonged label exposure only NP-oligomers but not monomers can be detected in unboiled samples of infected cells or in virions. NP monomers of A/Duck/Ukraine strain are detectable in unboiled samples only after a short period of labeling. Influenza virus NP oligomers are more hydrophobic than NP monomers. Oligomers are hypothesized to be the native functionally important form of influenza virus NP.     

Involvement of both donor cytotoxic T lymphocytes and host NK1.1+ T cells in the thymic atrophy of mice suffering from acute graft-versus-host disease

The control and eventual eradication of H5N2 influenza virus from domestic poultry in Mexico is dependent on the use of avian influenza (AI) vaccine strategies. This study was performed to determine the amount of hemagglutinin (HA) antigen required to control the signs of disease from a highly pathogenic H5N2 influenza virus (A/Chicken/ Queretaro/19/95) and the amount of antigen required to prevent shedding of virus from vaccinated birds. Six commercial inactivated water in oil H5N2 vaccines available in Mexico were compared with standardized vaccines to assess their efficacy. The amount of HA required to prevent the signs of disease from A/Chicken/Queretaro/19/95 influenza virus was approximately 0.4 microgram per dose. Each of the six commercially available vaccines prevented disease signs, and half of the vaccines significantly reduced viral shedding from vaccinated birds. There is a need for standardization of AI virus vaccine, and the antigen content should be increased in some of the commercially available AI vaccines in Mexico.     

Continued circulation of reassortant H1N2 influenza viruses in pigs in Japan

In 1991 and 1992, H1N2 influenza A viruses were isolated from the lungs of pigs with overt signs of respiratory disease at farms in the Chiba and Kanagawa prefectures of Japan. To determine the genetic origin of these isolates, we phylogenetically analyzed partial nucleotide sequences of their genes. The results indicate that influenza viruses possessing the N2 of human influenza virus and seven other gene segments of classical H1N1 swine influenza virus, which were first isolated in 1980, have become established in Japanese pigs.     

The role of sodium bisulfite in the 1996-1997 USA influenza vaccine recall

During the 1996-1997 influenza season, all the lots of influenza vaccine manufactured by Parke-Davis were recalled. This voluntary recall by the manufacturer was prompted by the finding of decreasing potency of the A/Nanchang/933/95 (H3N2) component of the vaccine. The primary cause of this lowered potency has been identified as primarily due to the presence of sodium bisulfite which was used to neutralize residual formaldehyde which in turn is used to inactivate the live influenza vaccine strains. This paper reviews these events and what we have learned.