Chitosan as an adjuvant for poliovaccine.

The use of inactivated poliomyelitis vaccine is very important for eradicating poliomyelitis. However, this vaccine is not available readily in underdeveloped countries due to the high cost. Adjuvants can improve the immunogenicity of a vaccine and reduce the antigen dose required for vaccination, thus lowering the cost of the vaccine. Chitosan glutamate solution and a chitosan sulfate micro/nanoparticle suspension were tested as adjuvants for Imovax-inactivated poliovaccine and for inactivated monovalent poliovirus type 1, 2, and 3 vaccines obtained by inactivation of the attenuated Sabin poliovirus strains. Inactivated vaccines admixed with either chitosan glutamate or chitosan sulfate micro/nanoparticles and administered to mice showed significantly enhanced immunogenicity to poliovirus type 1, 2, and 3 strains compared to the respective vaccines administered without chitosan. Chitosan preparations increased the immunogenicity of 1:2 and 1:4 diluted inactivated Sabin strain preparations in mice 8- to 16-fold, so that the neutralizing antibody titers after vaccination with adjuvanted diluted vaccine were equal to those obtained after vaccination with undiluted vaccine administered without chitosan. Neutralizing antibodies could be detected in sera of rats vaccinated with undiluted, 1:10, and 1:100 diluted Imovax vaccine admixed with chitosan sulfate micro/nanoparticles, although in the control group, vaccination only with the undiluted vaccine resulted in antibody production. These results show that the chitosan glutamate solution and chitosan sulfate micro/nanoparticle suspension can significantly improve the immunogenicity of various poliovaccines, and reduce the effective antigen dose.

Chitosan as an adjuvant for parenterally administered inactivated influenza vaccines.

The addition of 0.5% of a chitosan derivative to inactivated influenza vaccines injected parenterally resulted in a four or six to tenfold increase in antibody titres after a single-dose or two-dose intramuscular immunization of mice, respectively, in comparison with antibody titres after immunization without chitosan. Chitosan-adjuvanted vaccines enhanced antibody titers against drift variants of A- and B-type human influenza viruses four to six times compared with the vaccines without chitosan. Inactivated avian influenza virus A/H5N2 admixed with chitosan, when administered to mice challenged afterwards with the same virus, showed higher immunogenicity and protective efficacy compared with the antigen without chitosan.

Molecular mechanisms of reversion to the ts+ (non-temperature-sensitive) phenotype of influenza A cold-adapted (ca) virus strains.

A ts+ ca- (non-temperature-sensitive, non-cold-adapted) revertant of the A/Leningrad/134/47/57 ca strain influenza virus [A/Leningrad/134/47/ts+18/1957(H2N2)], obtained in our previous study, lost phenotypic manifestation of ts mutations by the PB2, NP and NS genes, although, according to sequencing data, it acquired only two true reversions of a mutation in the PB2 and PB1 genes. Direct sequencing showed the appearance of 27 additional mutations (13 coding) in the genes encoding the PB2, PB1, PA, NP, M and NS proteins of the revertant, along with the above-mentioned two true reversions. We conjecture that some of these mutations suppressed phenotypic manifestation of ts mutations in the NS and NP genes.

The effect of mass influenza immunization in children on the morbidity of the unvaccinated elderly.

The objectives of these studies were to analyse the effect of mass influenza immunization in children on the morbidity of unvaccinated non-institutionalized elderly during an influenza epidemic. A mass vaccination campaign with vaccine was conducted in children aged 3-6 years attending kindergartens (57.4% of 6374) and aged 7-17 years attending schools (72% of 34237) in two communities of the Moscow region. The clinical effectiveness of vaccination was 60.9% for kindergartens and 68.8% for schools. There were 3.4 times fewer episodes of influenza-like illnesses and 1.7-2.6 fewer episodes in all seven diseases which are possible complications of influenza out of the 10 evaluated diseases in 158451 unvaccinated non-institutionalized elderly people during the influenza epidemic compared with the control communities. The differences were found to be statistically significant. Mass vaccination of children attending child institutions brought about a significant reduction of both influenza-like illnesses in children and influenza-associated illnesses in unvaccinated non-institutionalized elderly persons living in the home setting.

Development of cell culture (MDCK) live cold-adapted (CA) attenuated influenza vaccine.

Optimal conditions are determined for growing cold-adapted reassortant strains of a live influenza vaccine in MDCK cell line cultivated in a fermenter with a serum-free medium and microcarriers. The studied MDCK cell line meet all national and WHO requirements for the finite cell lines used for the production of biological preparations. CA reassortant vaccine strains grown in such conditions which fully preserve its mutations and the mutations lead to amino acid substitution in all genome segments of the studied CA reassortants. Under optimal cultivation conditions, the output of a monovalent live CA influenza vaccine in a 10-l fermenter may reach 100,000 doses.

Introduction to pandemic influenza through history.

For the past 400 years, epidemics resembling influenza have been recorded in many countries. Epidemics from as early as the 16th Century in England and the 18th Century in the USA are recognizable as influenza, even in the absences of precise knowledge of their causative agents.

Influenza vaccines: a main problem in control of pandemics.

The optimal strategy for control of pandemic influenza is early vaccination with influenza vaccine produced from influenza pandemic strains. However, for pandemic control, vaccine improvements are essential and should include quicker ways of manufacturing and testing of vaccine as well as flexibility on the part of licensing bodies. The production of mass doses of monovalent vaccine in a short time can be more realistic if egg independent production technology can be adopted. In this respect production of an influenza vaccine on a stable cell line can solve many of the problems in increased production of influenza vaccine. But the difficulty with influenza vaccines is that the yield of human influenza viruses on tissue culture is much lower than in embryonated eggs. A new high-yield donor is needed for construction of recombinants with a new pandemic strain, which can replicate in a stable cell line with high titre. The live influenza vaccine may be the most appropriate for prophylaxis of influenza pandemic, as the implementation of this vaccine for mass vaccination is simpler than of inactivated influenza vaccine, and this vaccine, after one immunization of unprime persons, induces local mucocosa immunity which plays an important role in the protection against influenza.

Interrupting the transmission of wild polioviruses with vaccines: immunological considerations.

In 1988 the World Health Assembly set the goal of global poliomyelitis eradication by the year 2000. Substantial progress has been made, and 143 countries reported no poliomyelitis cases associated with the wild virus in 1993. This article reviews the immunological considerations relevant to interrupting the transmission of wild polioviruses with vaccines. Although serum immunity prevents poliomyelitis in the individual, it is local immunity that is important in preventing the transmission of polioviruses in the community. Natural infection and vaccination with oral polioviruses vaccine (OPV) produce local immunity in the intestine and the nasopharynx in about 70-80% of individuals. In contrast, inactivated poliovirus vaccine (IPV) produces local intestinal immunity in only 20-30% of the individuals. With either vaccine, however, a substantial proportion of the immunized population can transmit the wild virus. Moreover, although serum immunity is long-lasting, limited data suggest that local immunity may not be as persistent. To interrupt the transmission of wild polioviruses efforts should be made to achieve and sustain high levels of poliovirus vaccine coverage. Recent outbreaks show that wild poliovirus poses a risk for unimmunized individuals, even when overall coverage levels are high. Delivery of poliovirus vaccine to hard-to-reach populations will be of increasing importance as countries progress toward the final stages of poliomyelitis eradication. The immunization status of persons from poliomyelitis-free countries should be updated prior to travel to poliomyelitis-endemic areas.

WHO recommendation on potential use of new poliomyelitis vaccines.

Due to the intensive use of Sabin attenuated oral poliomyelitis vaccine, the incidence of poliomyelitis is continuing to decline, particularly in the Americas and Western Europe. In some developing countries, the use of trivalent attenuated vaccine may, however, sometimes produce sub-optimal antibody responses. Moreover, rare cases of vaccine-associated paralytical poliomyelitis could become increasingly prevalent, especially in countries that achieve control of the wild-type polioviruses. Recent progress in understanding the molecular biology and mechanisms of attenuation of polioviruses has suggested several possible approaches to solving some of these problems with improved attenuated poliovirus strains. During WHO meetings discussions took place on the broad scientific and ethical criteria that would justify submitting new attenuated oral poliomyelitis vaccine candidates to different levels of testing in laboratories and in humans.

Influenza--its impact and control.

Influenza is an underestimated public health problem. Epidemics spread rapidly from country to country and may affect as many as 500 million people across the world in a moderate influenza year. The disease, particularly influenza A, kills and the new influenza viruses which appeared in 1957 (Asian influenza) and 1968 (Hong Kong) are estimated to have caused at least 100,000 deaths in the United States of America. Deaths from influenza also occur in years when there is no new virus; at least 10,000 excess deaths have been documented in the United States during each of 18 different epidemics recorded from 1957 to 1985. Although most deaths are among the elderly, influenza occurs in all age groups with repercussions in schools and work places, and on hospital resources, at a high cost to society. As many as 79-80% of influenza cases can be prevented when the virus inducing the outbreak and the virus used in the influenza vaccine are closely related. Preventing 80% of cases would correspond in the United States to a saving of US $2.5 billion. People at the greatest risk of influenza-related complications are adults and children with chronic disorders of the pulmonary or cardiovascular systems, residents of nursing homes and of facilities for patients with chronic medical conditions. Other priority groups for vaccination are those at moderate risk of influenza-related complications such as healthy elderly persons, people with chronic metabolic diseases, children and teenagers on long-term aspirin therapy. Groups potentially capable of transmitting influenza to high-risk persons should also be vaccinated.(ABSTRACT TRUNCATED AT 250 WORDS)

Influenza surveillance.

The main objectives of influenza surveillance are: collection of influenza virus isolates and analysis of their antigenic characteristics so that the most appropriate virus variants can be recommended as constituents of influenza vaccines for use during the next epidemiological season; collection and analysis of information on influenza morbidity and mortality; and earliest possible detection of influenza epidemics. Exact estimates of the specific morbidity and mortality due to influenza are now being carried out in only certain countries. Simple notification of clinical cases and deaths without laboratory confirmation is unsatisfactory and leads to errors in interpretation. The methods used to predict baseline mortality may be inaccurate, resulting in underestimation of mortality associated with influenza virus infection. Comparison of the impact of influenza in different countries is also difficult owing to a variety of methods used for the estimation of mortality and morbidity. Although the laboratory aspects of influenza epidemiology are more uniformly covered worldwide than the statistical aspects, it is still necessary to increase laboratory coverage of some parts of the world and to improve the techniques for the isolation and characterization of not only influenza viruses but also other acute respiratory viruses. The systems and methods for influenza surveillance should be improved and standardized.

Vaccine preventable viral diseases in developing countries.

There are several viral infectious diseases with a high impact on developing countries which can be prevented by immunization with existing vaccines. The most important are poliomyelitis, measles, hepatitis B and yellow fever. Vaccines against poliomyelitis and measles used within the framework of the WHO/Expanded Programme on Immunization prevent about 1.4 million deaths from measles and 360,000 cases of paralytic polio per year in developing countries, but about 1.5 million measles' deaths and 200,000 cases of paralytic polio still occur. Hepatitis B infection and its sequelae are responsible for over 50 million infections and one million deaths annually. Highly effective hepatitis B vaccines are now available and the price of these vaccines for the developing world has fallen dramatically. Despite the availability of a safe and efficacious yellow fever vaccine since 1937, 5400 cases of this disease with 3200 deaths were reported in Africa and South America from 1986 to 1988. Because of the efficacy of existing vaccines and the lack of animal reservoirs or vectors, systematic vaccination programmes within the framework of the Expanded Programme on Immunization (EPI) could theoretically eliminate and even eradicate poliomyelltis, measles and hepatitis B. Many different obstacles need to be overcome before these goals are realized.

Genome and antigenic analysis of influenza A (H3N2) viruses isolated from an epidemic in a closed community of Carmelite nuns.

Eighteen influenza A (H3N2) viruses were isolated during a single outbreak in a closed community of Carmelite nuns. Serological analysis of the virus haemagglutinin (HAs), using a panel of monoclonal antibodies, demonstrated antigenic microheterogeneity. In contrast, no significant biochemical differences were detected in viral genes by RNA:RNA hybridisation or in structural or nonstructural polypeptides analysed by high-resolution polyacrylamide gel electrophoresis (PAGE) or by limited proteolysis followed by PAGE. Influenza A (H3N2) viruses isolated in the vicinity of the convent were distinguishable from each other and from the epidemic viruses isolated in the convent both antigenically and biochemically.

The immune response to influenza vaccines.

Specific immunity to influenza is associated with a systemic immune response (serum haemagglutination inhibition antibody), local respiratory immune response (virus-specific local IgA and IgG antibodies in nasal wash), and with the cell-mediated immune response. Both inactivated and live influenza vaccines induce virus-specific serum antibody which can protect against infection with influenza virus possessing the same antigenic specificity. In the absence of serum antibodies, local antibodies in nasal wash are a major determinant of resistance to infection with influenza virus. In comparative studies in humans it was shown that nasal secretory IgA develops chiefly after immunization with live cold-adapted (CA) vaccine, but persistent nasal secretory IgG was detected in both CA live and inactivated vaccines. The origin of nasal wash haemagglutination inhibition (HI) antibodies is not completely known. Recently it was found that cytotoxic T-cells (CTL) play an important role in immunity against influenza and in clearance of influenza virus from the body. In primed humans, inactivated influenza vaccine stimulates a cross-reactive T-cell response, whereas the ability of inactivated vaccine to stimulate such immunity in unprimed humans has not been determined. Data on the T-cell response to live vaccine in humans are limited to the development of secondary T-cell responses in primed individuals vaccinated with a host-range (HR) attenuated vaccine. The data obtained have shown that immunity induced by inactivated influenza vaccines is presumably dependent on the stimulation of serum antibody. Live CA vaccines not only stimulate a durable serum antibody response, but also induce long-lasting local respiratory tract IgA antibody that plays an important role in host protection.

WHO strategy for the global elimination of new cases of hepatitis B.

Hepatitis B infection and its sequelae remain major public health problems internationally despite the existence of sensitive tests to screen blood and blood products for hepatitis B surface antigen (HBsAg) and immunogenic vaccines. Since the human hepatitis B virus has no known animal reservoir, a systematic vaccination programme against hepatitis B, including vaccination of all newborns and young children within the framework of the WHO Expanded Programme on Immunization, as well as protection of high-risk individuals, together with the testing of all blood and blood products for HBsAg, could eliminate hepatitis B virus infection and its sequelae. However, for the successful realization of this programme, many important and difficult problems need to be solved, especially those related to vaccination strategy, determination of the duration of immunity, investigation of the mechanisms of perinatal and horizontal virus transmission, and improvement of the immunogenicity of hepatitis B vaccine. The problem of the hepatitis B carrier is also paramount as the eradication of hepatitis B can be achieved only after the 300 million carriers of the disease in the world today are either cured or dead.