Influenza vaccination in 22 developed countries: an update to 1995.

This study expands and updates through 1995 our earlier report on influenza vaccine use in 18 developed countries. Five of the six countries with high levels of vaccine use in 1992 (> or = 130 doses/1000 population) showed little change or slight declines over the subsequent 3 years. The exception was the United States, where a new federal program for vaccination reimbursement for the elderly helped to increase vaccine distribution from 144 to 239 doses/1000 population. The six countries with medium levels of vaccine use in 1992 (76-96 doses/1000 population) increased to > or = 100 doses/1000 population by 1995. Among the six low-use countries in 1992 (< or = 65 doses/1000 population), only Finland showed substantial improvement (96 doses/1000 population) in 1995. Four new countries were added to the study. In Germany, vaccine use increased to 80 doses/1000 population in 1995, but in Ireland it remained at a low level (48 doses/1000 population). In Korea, vaccine use increased from 17 to 95 doses/ 1000 population during the period 1987-1995. In Japan, very high levels of vaccine use (approximately 280 doses/1000 population) in the early 1980s were associated with vaccination programs for school children. However, vaccine use fell precipitously when these programs were discontinued, and only 2 and 8 doses/1000 population were used in 1994 and 1995, respectively. In all 22 countries, higher levels of vaccine use were associated with vaccination reimbursement programs under national or social health insurance and were not correlated with different levels of economic development. Excluding Japan, in 1995 there was still a greater than fourfold difference between the highest and lowest levels of vaccine use among the other 21 countries in the study. Given its well established clinical effectiveness and cost-effectiveness, none of these countries has yet achieved the full benefits of its programs for influenza vaccination.

Influenza vaccination in 18 developed countries, 1980-1992.

Influenza continues to be an important cause of preventable morbidity and mortality. Although influenza vaccine is widely recommended for older high-risk individuals, no studies have compared its use in different countries. We gathered information on influenza vaccine distribution in 18 developed countries for the period 1980-1992. During the 1980s there was a > or = 10-fold difference in annual per capita vaccine distribution among these countries, and in 1992 the difference was still more than 7-fold. Several countries demonstrated large increases in vaccine use over the study period, some showing substantial increases in specific years. Thirteen of the 18 countries recommend influenza vaccination for all elderly persons and 11 countries provide reimbursement for vaccination through national or social health insurance. These countries tend to have higher levels of vaccine use. Historical, economic and political factors also affect vaccination practices and policies, but their relationships to differences in vaccine use between countries are not known. A better understanding of why the use of influenza vaccine varies among countries will be important if its protective benefits are to be fully realized.

[Influenza. Consequences for health and prevention]. / Influenza. Sundhedsmaessige k9nsekvenser og forebyggelse.

Investigations from abroad and from Denmark show that epidemics of influenza are not only accompanied by considerable morbidity but also by considerable excess mortality and a sizable increase in the number of admissions to hospital. The increases in the number of deaths comprise 170-320 per million of the population per epidemic. The excess mortality occurs primarily among individuals with chronic pulmonary and circulatory disease and may be very great in nursing homes and similar institutions. Influenza vaccination will, in general, provide protection of approximately 70% and does not cause noteworthy side effects. Amantadine and rimantadine chemoprophylaxis, which is employed in some countries, provides protection of 80-90% from Influenza A. Recommendations are established for influenza vaccination and a series of situations are quoted where it would be advisable to supplement or replace vaccination with chemoprophylaxis. It is important to attempt to improve the vaccination rates, eg. by means of informative activity, improved planning of the vaccination programmes and public support to vaccination of high-risk groups.

Mechanisms of lymphocytic choriomeningitis virus-induced hemopoietic dysfunction.

Results of this study showed that lymphocytic choriomeningitis virus infection causes a marked activation of natural killer (NK) cells not only in the spleen but also in the bone marrow. This activity reached its peak at about day 3 of infection and declined after days 6 to 7. Enhanced NK cell activity was found to correlate with decreased receptivity for syngeneic stem cells in bone marrow and spleen, with the notable exception that decreased receptivity persisted longer in bone marrow. Treatment of infected recipients with anti-asialo GM1 (ganglio-N-tetraosylceramide) significantly increased the receptivity for syngeneic hemopoietic cells. These findings are consistent with the hypothesis that NK cell activation causes rejection of syngeneic stem cells, thus resulting in hemopoietic depression. To understand the mechanisms behind the prolonged decrease in bone marrow receptivity (and bone marrow function in the intact mouse) mentioned above, we followed the changes in the number of pluripotential stem cells (CFU-S) circulating in the peripheral blood and in endogenous spleen colonies in irradiated mice, the limbs of which were partially shielded. It was found that following a marked early decline, both parameters increased to normal or supranormal levels at about day 9 after infection. Because the bone marrow pool of CFU-S is only about 20% of normal at this time after infection, a marked tendency for CFU-S at this stage in the infection to migrate from the bone marrow to the spleen is suggested. It seems, therefore, that as NK cell activity declines, the spleen regains the ability to support growth of hemopoietic cells and the bone marrow resumes an elevated export of stem cells to the spleen. This diversion of hemopoiesis could explain both the long-standing deficiencies of the bone marrow compartment and the prolonged decrease in the receptivity of this organ.

Virus elimination in acute lymphocytic choriomeningitis virus infection. Correlation with virus-specific delayed-type hypersensitivity rather than cytotoxicity.

The immunological effector mechanism responsible for the elimination of virus in murine acute non-fatal extracranial lymphocytic choriomeningitis virus infection was studied. In this infection virus clearance is generally regarded as the result of a direct action of virus-specific cytotoxic T cells (Tc cells) on virus-producing target cells in the infected mouse. However, by manipulating the antiviral immune response by pretreatment with various doses of cyclophosphamide, we found lack of correlation between Tc-cell activity and the clearance of virus. In contrast, we observed a conspicuous correlation between the host's ability to mount a virus-specific delayed-type hypersensitivity (DTH) response and its capacity to combat virus. Moreover, pretreatment with silica and carrageenan prolonged viraemia without impairment of the peak Tc-cell response. These findings indicate that Tc cells have little or no capacity to eliminate virus, at least in the absence of an inflammatory response, and our findings suggest that virus clearance reflects a DTH-like process.

Fatal meningitis following lymphocytic choriomeningitis virus infection reflects delayed-type hypersensitivity rather than cytotoxicity.

Fatal meningitis following intracerebral inoculation of lymphocytic choriomeningitis virus (LCMV) reflects an immunopathological lesion believed to be mediated by cytotoxic T cells. The results presented here demonstrate that pretreatment with cyclophosphamide (Cy; 150 mg/kg body weight) 2 days before intracerebral infection significantly reduced the lethality of the infection. However, this treatment did not impair the antiviral cytotoxic response as measured in the spleen. On the other hand, virus-specific delayed-type hypersensitivity (DTH) was significantly reduced. This reduction seems to be the result of a Cy-induced lack of non-committed ancillary cells since: (1) virus-primed spleen cells from Cy-pretreated donors conferred normal LCMV-specific DTH to naive recipients; (2) transfer of virus-primed spleen cells from untreated donors did not increase the suppressed DTH response of the Cy-pretreated mice; and (3) inoculation of irrelevant antigen and antigen-primed spleen cells into the footpads of Cy-pretreated, infected mice resulted in a significantly reduced footpad swelling as compared with untreated, infected controls. Taken together, these results indicate that LCMV-induced meningitis does not solely represent T-cell-mediated cytotoxicity in vivo but that a fatal outcome of the infection critically involves not only effector T cells but also ancillary cells.

Lymphocytic choriomeningitis virus-induced immunosuppression: evidence for viral interference with T-cell maturation.

Acute lymphocytic choriomeningitis virus (LCMV) infection is associated with general immunosuppression which develops during the second week of the infection and persists for several weeks. In the present study, the ability of LCMV-infected mice to mount a cytotoxic T-lymphocyte response was investigated in a transplantation assay, using LCMV-immunized mice as recipients. By this means it was possible to evaluate the T-cell responsiveness of the acutely infected mice separately. Our results revealed a marked depression of the T-cell function temporally related to immunosuppression in the intact mouse. Furthermore, this hyporesponsiveness could not be explained as an effect of suppressor cells. Occurring shortly before these changes were a drastic decrease in cortical thymocytes and a reduction in T-cell progenitors in the bone marrow and spleen. Our findings are consistent with the assumption that a numerical deficiency of immunocompetent T-cells due to viral interference with T-cell maturation plays an important role in LCMV-induced immunosuppression.

Changes in hemopoiesis during the course of acute LCM virus infection in mice.

Although severe hematologic and immunologic disorders occur in several viral infections, insight into the mechanisms by which viruses may affect hemopoietic tissues is poor. The previous demonstration of distinct immunohemopoietic lesions in mice with acute lymphocytic choriomeningitis (LCM) virus infection has led us to investigate the function of hemopoietic precursor cells in the course of this experimental infection. During the first week of infection, there was profound suppression of pluripotential stem cell (CFU) and in vitro colony-forming cell (CFU) compartments, and of 59Fe uptake into hemopoietic tissues. During the same period, we found enhanced activity of colony-stimulating factor, lack of responsiveness to erythropoietin, and appreciable titers of interferon in blood and spleen. After day 10 post infection, there was a striking increase in CFU and 59Fe uptake confined to spleen and blood. Restoration of bone marrow, however, was markedly delayed. With reference to recent studies on interferon, and the findings in mice with persistent LCM virus infection, we suggest that interferon may be the comprehensive suppressor of the hemopoietic precursor cells in the first stage of acute LCM virus infection, and that these cells in the recovery period are directed preferentially into erythropoiesis.

The activity of T and B lymphocytes in immunity and tolerance to the lymphocytic choriomeningitis virus in mice.

Treatment with anti-theta serum and the Wigzell column technique for cell separation was employed to study the separate functions of the B and T lymphocytes in the late states of immunity to the LCM virus in mice. The cell preparations examined were mixtures of spleen and lymph node cells from immune mice. The results revealed that the anti-viral effect of such cells after transfer to virus carriers was unimpaired in T cell-enriched and B cell-deprived cell preparations. The anti-viral effect was also retained in cell preparations deprived so much of B cells that no antibody was produced in the virus carrier mice receiving transplants of these cells. The results strongly indicate that the anti-viral effect of late immune cells is not only T cell-dependent but that it is also mediated solely by T cells and, moreover, that antibodies have no or very little influence on the virus elimination. The observation that antibody production could be caused neither by column-passed cells nor by anti-theta serum-treated cells, but was obtained by mixtures of these cells, demonstrates that co-operation between T and B cells is crucial for the LCM antibody response. Accordingly, the convincing demonstration of the absence in the persistent virus carriers of cells which, in respect of antibody production, are able to co-operate either with column-passed or with anti-theta serum-treated immune cells, implies that such animals are extremely deficient as regards immune function of both B and T LCM-primed lymphocytes.

T lymphocyte function as the principal target of lymphocytic choriomeningitis virus-induced immunosuppression.

Plaque-forming cell responses against sheep erythrocytes, Escherichia coli lipopolysaccharide, pneumococcal polysaccharide, and polyvinylpyrrolidone were examined in mice infected with lymphocytic choriomeningitis virus. A 92 to 96 percent reduction of the thymus-dependent anti-sheep erythrocyte responses was observed 2 to 4 weeks after infection. However, the thymus-independent responses against the three other antigens were close to normal at all stages of the infetion. Studies on allograft immunity of infected C3H mice against DBA/2 mastocytoma cells revealed a severe suppression of the T cell-mediated cytotoxic response which was temporally related to the impaired humoral responsiveness against sheep erythrocytes. The capacity of spleen cells from infected mice to restore immune responsiveness of lethally irradiated recipients against sheep erythrocytes was significantly reduced. The adoptive responses, however, were clearly improved when normal thymus cells were added to the inferior spleen cells. Moreover, it appeared that the spleen cells from immunosuppressed donor mice could not confer suppression to normal lymphoid cells. The presented findings are consistent with the assumption that a numeric deficiency of T cells, or cells belonging to some T cell subpopulation, is the primary cause of lymphocytic choriomeningitis virus-induced immunosuppression.

Persistent LCM virus infection in the mouse. Immunity and tolerance.

The initiation of persistent infections with the Traub strain of the LCM virus is dependent not only on the number of immunocompetent cells present in the infected animals but probably also on the fact that the virus depresses the development of the bone marrow cells and causes a pronounced immunosuppression at the T cell level. By analysing the events leading to the termination of the virus carrier state by adoptive immunization, it was clearly demonstrated that the cellular immunity provoked was solely responsible for the virus elimination. Furthermore, helper T cells were shown to be necessary for the production of antibodies, which also occurs in adoptively immunized mice. In view of this finding, further experiments were performed, which strongly indicated that neither LCM-primed B cells nor LCM-primed helper T cells are present in mice that are persistent virus carriers. Similarly, neither cellular immunity to the LCM virus nor the presence of enhancing factors or suppressor cells could be detected. It is concluded that C(3)H mice that are persistent virus carriers have developed a humoral as well as a cellular immunological tolerance to the LCM virus.

Transient impaired cell-mediated tumor immunity after acute infection with lymphocytic choriomeningitis virus.

Intraperitoneal injection of nononcogenic lymphocytic choriomeningitis (LCM) virus in adult C3H mice causes a symptomless infection but stimulates specific cell-mediated and humoral immune responses. However, median survival time of virus-infected mice inoculated with syngeneic tumor cells was significantly shortened, and growth of semiallogeneic tumors was significantly enhanced. Cell-mediated cytotoxicity measured as chromium-51 release from labeled tumor cells was significantly suppressed but was recovered within 55 days after infection. The suppressed immune responsiveness could be conferreo on a normal spleen cell population when activated in virus-infected recipients. Chronically LCM virus-infected mice showed an unimpaired cell-mediated immune response to tumor allografts.

Twp populations of T lymphocytes immune to the lymphocytic choriomeningitis virus.

In this report seven different parameters were employed to investigate the spleen and lymph node cells from mice at the early and the late state of immunity to the lymphocytic choriomeningitis (LCM) virus. Distinct differences were observed. Morphological studies revealed a different size distribution of the cells in the preparations from the early and the late state of immunity. The cell mixtures of early immune cells contained many more large and blast-like lymphoid cells than the other. Where the cell function was concerned, the cytotoxic activity against LCM virus-infected target cells was almost entirely a function of the early immune cells, and our data strongly indicate that enhancement does not play any role for the disappearance by time of this cell activity. The antiviral effect after transfer to acutely infected animals was also predominantly a function of the early immune cells and the same was the case concerning the ability to protect against a lethal acute infection. However, the early immune cells were almost inactive after transfer to chronically infected virus carriers, whereas transplants of late immune cells to such mice had a very strong antiviral effect. The resistance to X irradiation also varied. Even high X-ray doses could not destroy the function of early immune cells, whereas the function of the late immune cells was readily impaired by X-ray treatment. The early and the late immune cells have one thing in common-both are susceptible to treatment with anti-theta serum. Because of the differences observed between the early and the late immune cells, it is concluded that they belong to different cell populations. However, because of the common susceptibility to anti-theta serum, probably both populations are T-cell lymphocytes. The implications of the results and the role of the different cells in the combat of the viral infection are discussed.

Defects in the immune system of mice infected with lymphocytic choriomeningitis virus.

Acute lymphocytic choriomeningitis virus infection of adult mice is associated with general immunosuppression, which develops during the 2nd week of the infection and persists for a period of 2 to 3 months. Studies of some cellular events in the immune system of infected mice brought to light a number of findings which seemed relevant to this immunosuppressive effect. Colony-forming stem cells, which may act as the precursors of the lymphoid cells, were temporarily inhibited during the first period of the infection. Presumably this inhibition also affected the thymus cells, which decreased dramatically at the same time. At a later stage of infection, defects developed within the population of immunocompetent cells, and this was most probably a consequence of the preceding suppression of the precursor cells. The defects in the immunocompetent cells were temporally related to the immunosuppression and seemed to be the ultimate cause of this phenomenon. At all events, antibody-forming cells were not damaged by the virus. In studies of neonatally infected baby mice, it was found that the development of immunological responsiveness was completely abolished for the first 2 weeks of life. It is therefore probable that the generation of immunocompetent cells was also affected in the babies. Evidence was obtained supporting the hypothesis that this effect played an important role for the induction of tolerance to the virus in the neonatally infected mice.