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Annual influenza epidemics in humans affect 5-15% of the population, causing an estimated half million deaths worldwide per year [Stohr K. Influenza-WHO cares. Lancet Infectious Diseases 2002;2(9):517]. The virus can infect this proportion of people year after year because the virus has an extensive capacity to evolve and thus evade the immune response. For example, since the influenza A(H3N2) subtype entered the human population in 1968 the A(H3N2) component of the influenza vaccine has had to be updated almost 30 times to track the evolution of the viruses and remain effective. The World Health Organization Global Influenza Surveillance Network (WHO GISN) tracks and analyzes the evolution and epidemiology of influenza viruses for the primary purpose of vaccine strain selection and to improve the strain selection process through studies aimed at better understanding virus evolution and epidemiology. Here we give an overview of the strain selection process and outline recent investigations into the global migration of seasonal influenza viruses.

Antigenic and genetic analysis of the hemagglutinin of approximately 13,000 human influenza A (H3N2) viruses from six continents during 2002-2007 revealed that there was continuous circulation in east and Southeast Asia (E-SE Asia) via a region-wide network of temporally overlapping epidemics and that epidemics in the temperate regions were seeded from this network each year. Seed strains generally first reached Oceania, North America, and Europe, and later South America. This evidence suggests that once A (H3N2) viruses leave E-SE Asia, they are unlikely to contribute to long-term viral evolution. If the trends observed during this period are an accurate representation of overall patterns of spread, then the antigenic characteristics of A (H3N2) viruses outside E-SE Asia may be forecast each year based on surveillance within E-SE Asia, with consequent improvements to vaccine strain selection.

Worldwide influenza pandemics have occurred at irregular and unpredictable intervals throughout history and it is confidently expected that they will continue to occur in the future. It is now recognised that these pandemics result when avian influenza A viruses succeed in adaptation to and transmission between humans. The impact of pandemic influenza is substantial in terms of morbidity, mortality and economic cost and there is the potential for serious social disruption. Influenza vaccines remain the most effective defence against influenza but will be in short supply during a pandemic, as will the new specific anti-influenza drugs, due to the lead-time required for production and rapid spread of the virus. To minimise the impact of pandemics it is imperative to maximise the availability of both vaccines and antivirals and to ensure that they are used optimally. This requires planning at both the international and national levels. The World Health Organization has, therefore, developed a staged plan for responding to a pandemic threat which is based principally on its surveillance program. It has also prepared guidelines to assist national agencies in their planning. However, there may be further options for increasing our preparedness which should also be considered., (Copyright 2001 John Wiley & Sons, Ltd.)

Hepatitis B is hyperendemic in Taiwan; more than 15% of adults are chronic carriers of the virus and longterm sequelae (chronic active hepatitis, cirrhosis, and hepatocellular carcinoma) are common. A national immunisation programme was implemented in 1984 to tackle the problem. This entailed immunisation of newborn children, followed by susceptible school children and young adults. The programme, which has been in place for a decade, has resulted in a pronounced reduction in the prevalence of HBsAg among young children and seems to have led to a reduction in horizontal transmission among older children.

The Western Pacific and South East Asia regions are the largest and most populous of the six World Health Organisation regions and include more than 40 countries. More than 75% of the world's estimated 350 million carriers are located here. The region has therefore provided many insights into the epidemiology, natural history, and control of hepatitis B infection and has been home to the first national control programmes. Hepatitis B is hyperendemic in most countries of the region, with carrier rates ranging from 5-35% except in Australia, New Zealand, and Japan, where the mean carrier rate is less than 2%. Patterns of infection vary considerably from country to country, city to city, and even village to village, and can change with time. Most infections are acquired early in childhood or in early adult life. A variety of control measures are in place and many countries in the region have introduced widespread or universal childhood immunisation policies with significant success. While it is theoretically possible that hepatitis B infection could be eradicated by universal childhood immunisation, there are several biological and practical issues that make this extremely difficult, suggesting that, for the foreseeable future, control may be a more realisable goal.

Like other medicine, all vaccines have some side effects or complications; in general the incidence and severity of complications is lower than for pharmaceuticals. When considered on a population basis, the incidence of serious complications of vaccination is minute, when compared with the outcome of natural infection. Enlightened governments, which promote immunisation as a means of minimising the impact of infectious diseases in their communities, also accept the responsibility for any adverse events which can be demonstrated to be vaccine related, and provide compensation and care for people who are affected.

The Lombok Hepatitis B (HB) Model Immunization Project was the first mass infant HB immunization project in Indonesia. Key aspects were the procurement of low-cost HB vaccine, integration into routine infant immunization services, and delivery of the first dose in the home within 1 week of birth. The project achieved > 90% coverage with 3 doses of vaccine. The prevalence of HB surface antigen was 1.4% in infants who received 3 doses (with the first dose within 7 days of birth) and 3.0% in those who received the first dose > 7 days after birth, compared with a baseline prevalence of 6.2% (P < .001 in each case). Most vaccine failures occurred in children born to HBe antigen-positive mothers. Antibody prevalence and titers did not correlate with protection. HB vaccine can be successfully integrated into the Expanded Programme on Immunization (EPI), strengthening the EPI and significantly reducing chronic HB infection.

Strains of respiratory syncytial virus from 3 major areas of Australia and Papua New Guinea (PNG) were analyzed for variations in their antigenic and biological properties and in the molecular weights of their major structural proteins. Seventy-eight strains from infants and young children with LRI were collected from 1981-1984. The RSV season in the Australian cities lasted from April through September, with major peaks in July of each year, while the RSV season in tropical PNG was year-round, with small peaks in March and October of each year coinciding with excessive rainfall. Fifty-six strains were analyzed in detail; 40 were typed by time-resolved fluoroimmunoassay with monoclonal antibodies as group A strains and 16 were group B; both groups were concurrent. Three children of one family had sequential RSV infections 13 months apart, and the etiologic group A strain was identical both years in terms of growth and antigenic properties with strain-specific ferret antisera; the second infection was milder in all three children. On average, the group A strains replicated considerably better than group B strains in HEp2 cells, producing 53% more syncytia and 99% higher infectious virus titers in 31% less time in culture. Ten group A and B reference strains exhibited the same growth patterns as the A and B regional strains, respectively. Differences in antigenicity as measured with hyperimmune antisera to prototype Long strain were even greater. Group A strains exhibited a mean 68% greater IFA staining than B strains, a 71% greater EIA reaction, and were neutralized to 69% higher serum titers than B strains. Again, the reference A and B strains included as controls gave patterns identical to those of the regional strains. Finally, the P phosphoprotein had consistently higher molecular weight in A strains (mean 35,900) than B strains (mean 33,100). Small variations in the sizes of the F and G glycoproteins were not sufficient to suggest grouping on this basis.

Viral hepatitis, caused by one of five different viruses, is an important cause of illness in tropical countries and a significant cause of death. Vaccines against hepatitis A and B are now available and, if used widely, have the potential virtually to eliminate both these diseases (and also hepatitis D). Vaccines against hepatitis C and E are being developed.

The prevalence of infection with human T lymphotropic virus type I (HTLV-I) in 19,975 blood samples from Australia and the western Pacific was determined by measuring the presence of specific antibody (anti-HTLV-I) by enzyme-linked immunosorbent assay (ELISA) with confirmation by western blot and/or radioimmunoprecipitation techniques. In Australia no evidence of HTLV-I infection was found in injecting drug users, patients with the acquired immunodeficiency syndrome (AIDS), subjects attending a sexually transmitted diseases clinic, female prostitutes, or transfusion recipients. A low prevalence of infection was detected in people with haemophilia (0.5%) and in male homosexuals (0.5%-1%). No antibody was detected in sera from Vanuatu, Kiribati, American Samoa, the Cook Islands, New Caledonia, the Federated States of Micronesia, French Polynesia and Fiji, but a low frequency of anti-HTLV-I was detected in sera from the Solomon Islands (1.2%) and Nauru (0.6%).

Objective: To elucidate the seroepidemiology of hepatitis C in patients with clotting disorders in comparison with other blood borne infections; to examine the effects of hepatitis C on liver function; and to assess the effectiveness of current screening and inactivation procedures used in preventing the transmission of blood borne viruses by clotting factor preparations., Design: A retrospective analysis of the prevalence of antibodies to hepatitis C virus (HCV), hepatitis B virus (HBV) and human immunodeficiency virus (HIV) by means of commercially available enzyme immunoassays (for antibodies to HCV and HIV) or radioimmunoassays (for HBV antibodies and surface antigen). An analysis was made of serum transaminase levels where such information was available and this was correlated with HCV status., Patients and Setting: Panels of sera were collected from adults and children with clotting disorders attending two Melbourne haemophilia treatment centres in 1973 (n = 33), 1980 (n = 33), 1984-1985 (n = 111) and 1987-1990 (n = 217) and tested for antibodies to HCV, HBV and HIV., Results: The prevalence of antibodies to HCV in the four panels tested was 45%, 74%, 75% and 76%, and the prevalence of markers of infection with HBV was 66%, 74%, 62% and 65% respectively. No antibodies to HIV were found in sera in Panels I and II but the prevalence in Panels III and IV was 23% and 36% respectively. In subjects in whom liver function test results were available, there was a significant association between the presence of antibodies to HCV and raised transaminase levels. Since heat inactivation of clotting factors was commenced in Australia in 1984, no new cases of transmission of HIV by clotting factors has been detected, but transmission of HCV in 19 subjects and HBV in one subject could not be excluded., Conclusions: Hepatitis C infection in haemophiliacs has been a very frequent event, and the presence of antibodies to HCV is associated with an increased incidence of raised transaminase levels. Screening and heat inactivation of clotting factors has prevented further HIV transmission, but exposure to HBV and HCV has not been eliminated.

Objective: To determine the relationship between the development of hepatitis C antibody (anti-HCV) and the clinical symptoms in acute hepatitis C., Design: Retrospective analysis of sera from patients with acute non-A non-B hepatitis., Setting and Patients: Patients admitted to Fairfield Hospital with the diagnosis of acute non-A non-B hepatitis between 1979 and 1989. Inclusion criteria included a typical clinical illness, accompanied by an alanine aminotransferase level of more than 2.5 times the upper limit of normal (normal, less than or equal to 40 U/L) and negative serological test results for acute hepatitis A and B., Main Outcome Measure: Time to develop anti-HCV after the onset of symptoms in patients with acute hepatitis C., Results: Seroconversion was demonstrated in 26 of the 128 patients who fulfilled the inclusion criteria. In these patients, antibody was detected between one week and 32 weeks after the onset of dark urine; more than half the patients (54%) had seroconverted by four weeks and a third (34%) developed antibodies within two weeks. Of 20 patients who had sera collected within four weeks of the onset of dark urine, 14 (70%) had developed antibody., Conclusion: These results suggest that in patients with community-acquired hepatitis C, seroconversion occurs significantly earlier than is observed in patients who have been infected by blood transfusion. Sera taken shortly after the onset of symptomatic hepatitis C may be useful in the diagnosis of this condition.

Serological surveys in many communities show a high prevalence of antibodies to hepatitis A virus (HAV) in people over the age of 50 years. However, few of that age can recall a previous episode of hepatitis, indicating that subclinical infections are common. The outcome of infection with HAV depends on the age at which infection occurs and, perhaps, the infectious dose. Fulminant disease is well recorded, with the frequency varying from one to eight per 1000 cases. Information on the frequency of hepatitis A can be obtained by analysing hospital records and notifications to health authorities or by serological surveys. In many countries, these data are limited and seriously underestimate the true frequency of the disease. At a conservative estimate, the incidence of disease in most developed countries is probably four to five times higher than the number of notifications. HAV appears to circulate in most parts of the world and to be responsible for both epidemic and sporadic disease. Three major patterns of infection are known which reflect different epidemiological situations. These are demonstrated by different patterns of the age-specific prevalence of antibodies to HAV which reflect standards of hygiene and sanitation, the degree of crowding of the population and opportunities for the virus to survive and spread.

To determine whether active viral replication is associated with increased morbidity and mortality in chronic carriers of hepatitis B virus (HBV) undergoing renal transplantation, we reviewed 23 years of experience at our hospital. Over the period 1966-1989, 42 chronic carriers of hepatitis B surface antigen (HBsAg) received renal transplants, 32 of whom had functioning grafts for 12 months or longer. Stored sera were tested for markers of hepatitis B virus, hepatitis C virus (HCV), and hepatitis delta virus (HDV) infection, and the serologic findings were correlated with clinical and biochemical data. The presence of HBV DNA and/or hepatitis Be antigen (HBeAg) in serum samples collected prior to transplantation was associated with an increased probability of death from liver disease. Whereas 5 of 10 patients in this group died of chronic liver disease, only 1 of 15 patients who were HBV DNA and/or HBeAg negative prior to transplantation died of liver disease. This difference is highly significant (P less than 0.02). No difference in outcome was attributable to age at transplantation, gender, country of birth, or the presence of abnormal hepatic transaminase levels prior to transplantation.

The prevalence of antibodies to hepatitis C virus (anti-HCV) was measured in a number of groups known to be at increased risk of blood-borne viral infections, using an enzyme-linked immunosorbent assay (EIA) based on a nonstructural peptide generated by recombinant DNA technology. The assay was repeatably reactive in 75.6% of men with haemophilia, 61.9% of intravenous drug users, 34.1% of homosexual men who were regular attenders at a gay sauna and 30.8% of prisoners. A lower reactivity was detected in sera collected from female prostitutes (10.4%), patients undergoing maintenance haemodialysis (5.9%), or renal transplantation (6.9%) and patients attending a sexually transmitted diseases clinic (6.2%). We also measured reactivity among inmates of a large institution for the mentally handicapped in which hepatitis B is known to be endemic, and in panels of sera which had been stored for 25-35 years. The test was positive in 41.1% of mentally handicapped patients with Down's syndrome and 7% of subjects with other forms of mental retardation. Similarly some 23% and 20% of sera collected in 1954 and 1964 from patients with a variety of illnesses were found to be reactive. As most diagnostic assays suffer from some degree of non-specificity and confirmatory tests for the anti-HCV assay were not initially available in Australia, we analysed the distribution of optical density (OD) values in the different groups, in an attempt to obtain an insight into the specificity of the results being obtained. Whereas the ODs of sera collected from patients with haemophilia and IVDU had a bimodal pattern, with two well separated sets of results on either side of the cut-off.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine whether saliva is a potentially useful sample for screening for HIV infection when serum is not obtainable, saliva and serum samples from 50 HIV-infected and 50 uninfected subjects were tested for antibody to HIV-1 (anti-HIV-1) using a second-generation enzyme-linked immunosorbent assay (ELISA; Abbott) and prototype antibody-capture ELISA (Wellcome). Of saliva specimens from HIV-infected people, six gave negative results on the Abbott and one on the Wellcome assays; all specimens from uninfected people were negative by both assays. Sensitivity for the Abbott assay was therefore 88.0% [95% confidence interval (Cl) 76.2-94.4%], an unacceptable level for screening purposes. Sensitivity for the Wellcome assay was 98% (95% Cl 89.5-99.6%), a more satisfactory level for population screening. Further validation of this technique is necessary, and of methods for collection of saliva specimens in particular.

Parenterally transmitted non-A, non-B (NANB) hepatitis virus or hepatitis C virus is a common cause of both acute and chronic hepatitis. Using a recently developed enzyme-linked immunosorbent assay we looked at the prevalence of antibodies to hepatis C virus (anti-HCV) in a number of groups. People with haemophilia (75.6%) and intravenous drug users (61.9%) had the highest prevalence, while homosexual men attending a sauna (34.1%) and prisoners (30.8%) had a moderately high prevalence of anti-HCV. A lower prevalence of antibody was detected in female prostitutes (10.4%), institutionalised mentally retarded subjects (9.5%), homosexual men requesting human immunodeficiency virus (HIV) testing through their local doctor (8.8%), dialysis patients (5.9%), renal transplant patients (6.9%), and patients referred from a sexually transmitted diseases clinic (6.2%). The lowest prevalence of anti-HCV was recorded in women attending a provincial hospital for antenatal care (0.4%). The predominance of anti-HCV in groups of people exposed to blood-borne and sexually transmitted infections suggests that these routes may be primarily involved in the spread of hepatitis C virus infection.

Acyclovir (ACV)-resistant herpes simplex virus type 2 (HSV-2) was isolated from a patient with acquired immunodeficiency syndrome after long-term but intermittent ACV therapy. These thymidine kinase-defective isolates were sensitive in vitro to foscarnet. While combined therapy with ACV and interferon produced only partial clinical improvement, the in vitro effect of this combination against an ACV-resistant isolate from the patient was strongly synergistic. A short course (10-12 days) of intravenous foscarnet controlled severe ulceration, and clinical improvement lasted 6 months. After recurrence and further courses of foscarnet, however, the patient responded poorly, and subsequent HSV isolates were resistant to both ACV and foscarnet and hypersensitive to aphidicolin.

There is an urgent need for new, powerful adjuvants suitable for use with sub-unit and peptide vaccines in humans. We have measured the humoral immune response in BALB/c mice to vaccine formulations using recombinant HBsAg antigens, and gamma inulin and alum adjuvants. Using Merck, Sharpe & Dohme (MSD) HBsAg at 10 micrograms/mL, high levels of anti-HBs were generated and geometric mean S/N ratios of 88, 133 and 107 were obtained for alum absorbed vaccine, gamma inulin, and a mixture of the two adjuvants, respectively. A dilution series produced ED50 values of 0.08, 0.15 and 0.22 micrograms/mL respectively. In a second series of experiments comparing alum and algamulin (a complex of gamma inulin and alum), MSD HBsAg induced anti-HBs levels of 81 and 52, and ED50 values of 0.3 and 0.4 when used in conjunction with alum and algamulin, respectively. SKF HBsAg induced anti-HBs levels of 126 and 111 with alum and algamulin, and ED50 values of 0.11 and 0.075. The class, subclass and level of antibody produced in mice boosted with a second dose of vaccine at 21 days was also examined. Both alum and gamma inulin induced higher levels of total antibody, IgG1 and minor IgG subclasses than algamulin, or HBsAg alone. Overall, gamma inulin appears to be an equivalent adjuvant to alum, although their mechanisms of action are different. Mixtures or complexes of the two adjuvants appear to be less effective in inducing humoral immune responses in mice than either alone.

Hepatitis A is a major public health problem in many rapidly developing countries and it is still an important disease in many developed countries. Isolation of the virus in cell culture and access to reliable animal models has led to the development of several candidate vaccines. Both inactivated and attenuated vaccines have been developed which appear to be safe, antigenic and protective in laboratory animals. If studies in man support the data which have been obtained in other primates, the first commercially available vaccines are likely to be licensed within the next two years.

An enzyme immunoassay (EIA) utilizing a synthetic peptide analogue of HIV gp41 (amino acids 579-599, RILAVERYLKDQQLLGIWGCS) as antigen was compared with two commercial assays (Genetic Systems, Abbott ENVACORE) for the ability to detect antibodies in the early stages of infection. Two panels, consisting of 96 sera from 15 people and 140 sera from 44 people seroconverting to HIV, were examined. In the first group the synthetic peptide assay (gp41 EIA) detected antibodies before the Genetic Systems EIA in seven out of 15 people and concurrently in the remaining eight. With the second panel the Abbott ENVACORE assay detected antibodies before the gp41 EIA in two out of 44 people while the gp41 EIA detected antibodies first in six out of 44. In the remaining 36 people antibodies were detected simultaneously by the two tests. The gp41 EIA usually detected anti-HIV antibodies before or concurrently with the two commercial assays examined suggesting that the epitope cluster represented by this peptide is recognized early in infection.

Negative staining electron microscopy was used to identify viruses in 166 normal and 62 diarrhoeal faecal samples from 208 cats admitted to an animal shelter during a 16-month period (March 1984 to June 1985). On the basis of size and shape 7 distinct viral types were detected: 24 nm parvovirus-like particles, 30 nm astrovirus, 30 nm picornavirus-like particles, reovirus, rotavirus, coronavirus and a 75 nm "togavirus-like" particle. The incidence of these particles in the 208 cats was 11%, 7%, 6%, 0.4%, 5%, 1% and 1% respectively. Virus isolation studies using 40 of the faecal samples succeeded in isolating reovirus 1 in 2 cases. Immune electron microscope studies demonstrated the presence of antibody in a human serum to cat astrovirus, but failed to clarify the identity of the parvovirus-like particles and picornavirus-like particles, other than showing that some of the parvovirus-like particles were not related to feline panleukopenia virus. It was found that parvovirus-like particles, astrovirus, picornavirus-like particles, reovirus and rotavirus could be excreted by cats with normal faeces as well as cats with diarrhoeal faeces. Parvovirus-like particles, astrovirus, picornavirus-like particles and rotavirus could be excreted in high concentration in normal faeces. There was no simple relationship between age and diarrhoea in the population of cats studied. Age was not a critical factor in the excretion of parvovirus-like particles, astrovirus, picornavirus-like particles and rotavirus. The incidence of diarrhoea was not clearly associated with the seasons.