Changes in pneumococcal carriage prevalence and factors associated with carriage in Norwegian children, four years after introduction of PCV13.

BACKGROUND: Streptococcus pneumoniae carriage is often asymptomatic but can cause invasive pneumococcal disease. Pneumococcal carriage is a prerequisite for disease, with children as main reservoir and transmitters. Childhood carriage can therefore be used to determine which serotypes circulate in the population and which may cause disease in the non-vaccinated population. In 2006, a pneumococcal conjugate vaccine (PCV7) was introduced into the Norwegian Childhood Immunisation Programme, which was replaced by the more valent PCV13 in 2011. We investigated changes in pneumococcal carriage prevalence 4 years after switching to PCV13 compared to three previous surveys, and analysed factors associated with carriage in children. METHODS: We conducted a cross-sectional study in Norway, autumn 2015, among children attending day-care centres. We collected questionnaire data and nasopharyngeal swabs to identify pneumococcal serotypes. We compared the carriage prevalence in 2015 with surveys conducted in the same setting performed before widespread vaccination (2006; n = 610), 2 years after PCV7 introduction (2008; n = 600), and 2 years after switching to PCV13 (2013; n = 874). Using multilevel logistic regression we determined the association between pneumococcal carriage and previously associated factors. RESULTS: In 2015, 896 children participated, with age ranging from 8 to 80 months. The overall carriage prevalence was 48/100 children [95%CI 44-53] in 2015, 38% [29-46] lower than in 2006 pre-PCV7, and 23% [12-32] lower than in 2013, 2 years after switching to PCV13. The PCV13 carriage prevalence was 2.8/100 children [1.9-4.2] in 2015. Increasing age (p < 0.001), recent antimicrobial use (odds ratio = 0.42 [0.21-0.57]) and being vaccinated (odds ratio = 0.37 [0.29-0.47]) were negatively associated with carriage. CONCLUSIONS: Our study showed a continued decrease in overall pneumococcal carriage, mainly fuelled by the decline in vaccine serotypes after vaccine introduction. Childhood vaccination with PCV13 should be continued to keep low PCV13 carriage, transmission and disease. Furthermore, the low prevalence of PCV13-type carriage in children endorse the choice of not recommending PCV13 in addition to the 23-valent pneumococcal polysaccharide vaccine to most medical risk groups in Norway, as little disease caused by these serotypes can be expected.

A review of the evidence to inform pneumococcal vaccine recommendations for risk groups aged 2 years and older.

For decades, vaccination with the 23-valent polysaccharide pneumococcal vaccine (PPV23) has been available for risk groups aged ⩾2 years to prevent invasive pneumococcal disease (IPD). Recently, a 13-valent pneumococcal conjugated vaccine (PCV13) has been licensed for use in all age groups. PCV13 may induce better protection than PPV23 because of different immunogenic properties. This called for a revision of vaccine recommendations for risk groups. We therefore reviewed literature on risk groups for IPD, and effectiveness and safety of pneumococcal vaccines and supplemented that with information from public health institutes, expert consultations and data on IPD epidemiology. We included 187 articles. We discuss the implications of the heterogenic vulnerability for IPD within and between risk groups, large indirect effects of childhood immunization, and limited knowledge on additional clinical benefits of PCV13 in combination with PPV23 for the Norwegian recommendations. These are now step-wise and consider the need for vaccination, choice of pneumococcal vaccines, and re-vaccination interval by risk group.

Pectic polysaccharides isolated from Malian medicinal plants protect against Streptococcus pneumoniae in a mouse pneumococcal infection model.

The aim of this study was to investigate whether the pectic polysaccharides BP-II, Oc50A1.I.A and CC1P1 isolated from the Malian medicinal plants Biophytum petersianum, Opilia celtidifolia and Cola cordifolia, respectively, were able to protect against Streptococcus pneumoniae infection in mice. The pectin preparations were administered intraperitoneally 3 h before challenge with S. pneumoniae serotype 6B. Blood samples were obtained from all animals before and at 3 h, 24 h and 72 h after challenge with the pneumococci. The number of bacteria in blood was recorded and the blood concentration of a range of cytokines measured. The pretreatment with BP-II, Oc50A1.I.A and CC1P1 demonstrated a protective activity against S. pneumoniae serotype 6B infection, albeit at different range of concentrations. The pectins showed no direct antibacterial effects towards S. pneumonia; however, they induced the production of a range of cytokines and chemokines. We have previously shown that BP-II, Oc50A1.I.A and CC1P1 exhibit complement fixation activity and also that BP-II and Oc50A1.I.A stimulate macrophages to produce NO. The observed clinical effect might therefore be linked to the ability of the pectic polysaccharides to stimulate the innate immune system.

Seroepidemiological study after a long-distance industrial outbreak of legionnaires' disease.

Following a long-distance outbreak of Legionnaires' disease from an industrial air scrubber in Norway in 2005, a seroepidemiological study measuring levels of immunoglobulin G (IgG) and IgM antibodies to Legionella pneumophila was performed with a polyvalent enzyme-linked immunosorbent assay. One year after the outbreak, IgG levels in employees (n = 213) at the industrial plant harboring the scrubber and in blood donors (n = 398) from the outbreak county were low but significantly higher (P < or = 0.002) than those in blood donors (n = 406) from a nonexposed county. No differences in IgM levels among the three groups were found after adjustment for gender and age. Home addresses of the seroresponders in the exposed county clustered to the city of the outbreak, in contrast to the scattering of addresses of the seroresponding donors in the nonexposed county. Factory employees who operated at an open biological treatment plant had significantly higher IgG and IgM levels (P < or = 0.034) than those working >200 m away. Most of the healthy seroresponders among the factory employees worked near this exposure source. Immunoblotting showed that IgG and IgM antibodies in 82.1% of all seroresponders were directed to the lipopolysaccharide of the L. pneumophila serogroup 1 outbreak strain. In conclusion, 1 year after the long-distance industrial outbreak a small increase in IgG levels of the exposed population was observed. The open biological treatment plant within the industrial premises, however, constituted a short-distance exposure source of L. pneumophila for factory employees working nearby.

Detection of measles- and mumps-specific IgG antibodies in paired serum and oral fluid samples from Norwegian conscripts.

The aim of this study was to measure the seroprevalence to mumps in Norwegian conscripts belonging to the first children vaccination cohorts that had been offered two doses of MMR vaccine. The seroprevalence to mumps was 76% with the Microimmune assay and 85% with the Enzygnost assay. We also compared the performance of the Microimmune assay for detection of mumps- and measles-specific IgG antibodies in 340 paired serum and oral fluid samples from the conscripts and evaluated the effect of revaccination. Mumps-specific IgG antibodies were detected in only 61% of the oral fluids. In contrast, high levels of measles-specific IgG antibodies were detected in both the serum and oral fluid samples. Based on these results, we are only able to recommend the use of oral fluid for surveillance of measles in Norway. Our results may also indicate that the seroprevalence necessary to interrupt transmission of mumps has not been reached in vaccinated young adult Norwegians. Seroconversion was observed in all initially measles seronegative conscripts after revaccination, whereas 23 of 27 initially mumps seronegative conscripts failed to seroconvert.

Carriage of Streptococcus pneumoniae in healthy Norwegian children attending day-care centres.

An observational study to examine Streptococcus pneumoniae carriage in Norwegian children was initiated after two cases of pneumococcal meningitis, caused by the England(14)-9 clone, occurred in one day-care centre in Oslo. All children recruited from the day-care centre where the cases occurred were vaccinated with a seven-valent pneumococcal conjugate vaccine; the other participants who attended three other day-care centres nearby were not. The children were followed for 9 months, and three samplings took place. At the first visit, 45.7% of the children were colonised by pneumococci in the nasopharynx. The children harboured a variety of serotypes, with serotypes 6A, 23F, 6B and 19F being the most frequent. The numbers of children carrying vaccine serotypes decreased in both the vaccinated and the non-vaccinated groups. Thus, no significant effect of vaccine on carriage was detected in this relatively small study.

Pneumococcal conjugate vaccine followed by pneumococcal polysaccharide vaccine; immunogenicity in patients with ataxia-telangiectasia.

The immunodeficiency in Ataxia-telangiectasia (A-T) is characterised by low T and B cell counts, low levels of IgE, IgA and/or IgG2, and especially low levels of pneumococcal antibodies. The 23-valent pneumococcal polysaccharide vaccine (PPV23) has previously been shown not to be effective in A-T, but these patients are capable of making protective antibodies to other vaccines such as diphtheria and tetanus toxin, promising effect of the seven-valent pneumococcal conjugated vaccine (PCV7). Nine A-T patients and 25 age and sex matched controls were vaccinated with both PCV7 and PPV23, and three A-T patients were vaccinated with PCV7 only. In the A-T patients, no significant increase in pneumococcal antibody levels were observed after the single PCV7, while the subsequent PPV23 vaccination resulted in a significant increase in antibody levels to the PPV23 mix, as well as to serotype 4, 14, 19F and to the geometric mean of serotype 4, 6B, 14, 18C, 19F, 23F which increased from median 0.2 (range 0.1-0.5) microg/mL to 0.6 (0.2-1.5) microg/mL (P= 0.014). Compared to the patients' baseline levels, the vaccinations induced a 1.5- to 7-fold increase in antibodies to the six different serotypes tested. The increases in pneumococcal antibody titres were lower than those observed in the controls (9- to 34-fold increase). The results are valuable in planning the care of A-T patients, using PCV7 to trigger and PPV23 to booster the immune response and possibly prevent severe pneumococcal disease.

The impact of an early truncating founder ATM mutation on immunoglobulins, specific antibodies and lymphocyte populations in ataxia-telangiectasia patients and their parents.

Eleven Norwegian patients (aged 2-33 years, seven males and four females) with Ataxia-telangiectasia (A-T) and their parents were investigated. Five of the patients were homozygous for the same ATM mutation, 3245delATCinsTGAT, a Norwegian founder mutation. They had the lowest IgG2 levels; mean (95% confidence interval) 0.23 (0.05-0.41) g/l versus 0.91 (0.58-1.26) g/l in the other patients (P = 0.002). Among the 11 A-T patients, six had IgG2 deficiency, six had IgA deficiency (three in combination with IgG2 deficiency) and seven had low/undetectable IgE values. All patients had very low levels of antibodies to Streptococcus pneumoniae 0.9 (0.4-1.4) U/ml, while normal levels were found in their parents 11.1 (8.7-13.4) U/ml (P < 0.001). A positive linear relationship between pneumococcal antibodies and IgG2 (r = 0.85, P = 0.001) was found in the patients. Six of 11 had diphtheria antibodies and 7 of 11 tetanus antibodies after childhood vaccinations, while 4 of 7 Hemophilus influenzae type b (Hib) vaccinated patients had protective antibodies. Ten patients had low B cell (CD19+) counts, while six had low T cell (CD3+) counts. Of the T cell subpopulations, 11 had low CD4+ cell counts, six had reduced CD8+ cell counts, and four had an increased portion of double negative (CD3+/CD4-/CD8-) gamma delta T cells. Of the 22 parents (aged 23-64 years) 12 were heterozygous for the ATM founder mutation. Abnormalities in immunoglobulin levels and/or lymphocyte subpopulations were also observed in these carriers, with no correlation to a special ATM genotype.

The immune response to pneumococcal polysaccharide vaccine in zinc-depleted mice.

Zinc depletion affects several facets of the immune system and the resistance to infections. We assessed the effect of zinc deprivation on the immune response to the pneumococcal polysaccharide antigens in the commercially available Pneumovax pneumococcal vaccine. Young female BALB/c mice were fed diets with 2.7, 5.8 or 25 micro g of elemental zinc per mg diet. After six weeks of pair feeding, there were significant differences in the mean body weights between the feeding groups and we demonstrated a dose response of the zinc level in the diet on growth. The induced zinc deficiency had no discernible effect on the antipneumococcal polysaccharide immunoglobulin M (IgM) response following immunization with the pneumococcal vaccine. Although zinc depletion has a detrimental effect on the immune system, the murine T-cell-independent response to antigens such as those in the pneumococcal polysaccharide capsule does not seem to be affected.

Serum bactericidal activity correlates with the vaccine efficacy of outer membrane vesicle vaccines against Neisseria meningitidis serogroup B disease.

For evaluation of serum bactericidal activity (SBA) as surrogate for the efficacy of outer membrane vesicle (OMV) vaccines against Neisseria meningitidis serogroup B disease, we have reanalyzed data from a randomized double blind placebo-controlled efficacy trial involving 172000 secondary school students (aged 13-14 years) in Norway (1988-1991). A cohort of the efficacy trial consisting of 880 individuals was selected for immunogenicity studies. An efficacy of 87% was calculated for a 10-month observation period. However, after an observation period of 29 months, the estimated efficacy against group B disease induced by vaccination was 57%. The immunogenicity study showed that the SBA geometric mean titer (GMT) for the vaccinees was 2.4 before vaccination and 19.0 six weeks after the second vaccine dose. One year after vaccination the GMT was reduced to 2.8. A separate three-dose study with 304 adolescents showed that with a third dose at 10 months after the second dose (i.e. when cases of disease started to appear) a strong booster response was induced. Ten months after the second dose the SBA was reduced to near pre-immunization level. Following the third dose the SBA geometric mean titer of 2.7 increased to 62.3. One year after the third dose, the GMT was markedly higher than 6 weeks after the second dose (12.6 versus 8.8). Thus, protection after vaccination corresponds with the level of SBA. In order to reach lasting protective levels of SBA in a population, three vaccine doses are probably required. Measurements of SBA are likely to be useful for evaluating various upcoming formulations and improvements of immunization regimens for OMV vaccines.

Predictive value of immunologic parameters and HIV RNA in relation to humoral pneumococcal polysaccharide vaccine responses in patients with HIV infection.

In the study presented here immunologic markers and HIV RNA were related to specific antibody responses in 50 HIV-infected patients who had moderate immunodeficiency (median CD4+, 295) and were vaccinated with a pneumococcal polysaccharide vaccine. Low responses were associated with low IgG2 or high IgM levels ( P=0.01) and good responses with high IgG4 ( P=0.05) or IgG2 ( P=0.07) or low beta(2) microglobulin ( P=0.04) levels. A combination of IgG2 levels >1.0 g/l and IgM <1.6 g/l at baseline significantly predicted a twofold or better response in logistic regression analysis ( P=0.025). Neither CD4+ lymphocyte counts nor HIV RNA levels were predictive, but it should be noted that good antibody responses were not restricted to patients with high CD4+ cell counts or low HIV RNA levels.

Humoral immunity to viral and bacterial antigens in lymphoma patients 4-10 years after high-dose therapy with ABMT. Serological responses to revaccinations according to EBMT guidelines.

The aim of this study was to investigate the late effects of ABMT on the immune system with regard to protective humoral immunity against common antigens and responses to recall antigens (vaccines). The vaccines were given according to EBMT guidelines from 1995. The protocol included 35 patients with malignant lymphoma in CR 4-10 years after ABMT, and 35 controls. The results show that prior to ABMT the proportion of patients with protective immunity against poliomyelitis, tetanus and diphtheria was similar to that of controls. At study entry 4-10 years after ABMT, the proportion of patients with protective immunity against poliomyelitis and diphtheria was reduced, while all patients maintained protection against tetanus. A significant decrease in geometric mean antibody concentrations or titres was observed against all three antigens during this period. Serum levels of antibodies against different pneumococcal serotypes were lower in the patients than in the controls prior to vaccination. The responses to pneumococcal vaccination, which is considered to be a T cell-independent vaccine, were studied. Unlike controls, a minority of patients achieved protective levels of antibodies after a single vaccination. Despite persistent levels of protective antibodies in many patients post ABMT, secondary booster responses after one vaccination with T cell-dependent vaccines (tetanus, diphtheria and polio) were absent. In conclusion, this study shows that post ABMT, a full re-vaccination program was necessary to mount responses comparable to those observed after a single vaccination in controls.

Meningococcal outer membrane vesicle vaccine given intranasally can induce immunological memory and booster responses without evidence of tolerance.

We have studied the ability of outer membrane vesicle (OMV) vaccines from Neisseria meningitidis serogroup B to induce vaccine-specific antibody and spleen cell proliferative responses in mice after being administered intranasally (i.n.) and/or subcutaneously (s.c.). A series of four weekly i.n. doses (25 microg) without adjuvant or a single s.c. dose (2.5 microg) with aluminum hydroxide was followed 2 months later by secondary i.n. or s.c. immunizations. After i.n. priming, both immunoglobulin G (IgG) antibody responses in serum, measured by enzyme-linked immunosorbent assay, and IgA antibodies in saliva and extracts of feces were significantly boosted by later i.n. immunizations. The IgG antibody responses in serum were also significantly augmented by secondary s.c. immunization after i.n. as well as s.c. priming. Sera from mice immunized i.n. reached the same level of bactericidal activity as after s.c. immunizations. The s.c. immunizations alone, however, had no effect on mucosal IgA antibody responses, but could prime for booster antibody responses in secretions to later i.n. immunizations. The i.n. immunizations also led to marked OMV-specific spleen cell proliferation in vitro. Both serum antibody responses and spleen cell proliferation were higher after i.n. priming and later s.c. immunizations than after s.c. immunizations alone. There was thus no evidence that i.n. priming had induced immunological tolerance within the B- or T-cell system. Our results indicate that a nonproliferating meningococcal OMV vaccine given i.n. can induce immunological memory and that it may be favorably combined with similar vaccines for injections.

Radioimmunotherapy with iodine-131 tositumomab in patients with low-grade non-Hodgkin's B-cell lymphoma does not induce loss of acquired humoral immunity against common antigens.

Thirty-one previously untreated patients with follicular low-grade B-cell non-Hodgkin's lymphoma expressing the CD20 antigen were treated with iodine-131 tositumomab therapy between 1996 and 1998. The therapy led to a temporary depletion of peripheral blood B-lymphocytes. Recovery of B-cells occurred in most cases by 3 to 6 months and in all patients by 12 months posttherapy. A temporary decline in T-cell subpopulations, but no reduction in serum immunoglobulin levels, could be observed. ELISA techniques were used to detect specific antibodies against rubella, mumps, varicella zoster, measles, and tetanus. Almost all patients remained seropositive against the different antigens during the 1- to 2-year follow-up. No significant reduction in antibody concentrations to tetanus or measles could be detected. The data show that acquired humoral immunity against common antigens appears to be preserved despite a temporary loss of B-lymphocytes.

Protective effect of Plantago major L. Pectin polysaccharide against systemic Streptococcus pneumoniae infection in mice.

The antibacterial effect of a soluble pectin polysaccharide, PMII, isolated from the leaves of Plantago major, was examined in inbred NIH/OlaHsd and Fox Chase SCID mice experimentally infected with Streptococcus pneumoniae serotype 6B. Serotype 6B is known to give a more protracted infection when injected intraperitoneally into susceptible mice than more virulent serotypes like type 4. PMII was administered i.p. either once 3 days before challenge or once to thrice from 3 to 48 h after challenge. The number of bacteria in blood and the mouse survival rate were recorded. Pre-challenge administration of PMII and also lipopolysaccharide (LPS), included as a control, gave a dose-dependent protective effect against S. pneumoniae type 6B infection. However, injection of PMII after establishment of the infection in NIH/OlaHsd mice had no effect. The data demonstrate that, firstly, the polysaccharide fraction PMII from P. major protects against pneumococcal infection in mice when administered systemically prechallenge, and secondly that the protective effect is owing to stimulation of the innate and not the adaptive immune system.

Protective effect of beta-glucan against systemic Streptococcus pneumoniae infection in mice.

The antimicrobial effect of soluble beta-1,3-D-glucan from Sclerotinia sclerotiorum (SSG) was examined in mice experimentally infected intraperitoneally (i.p.) with Streptococcus pneumoniae serotypes 4 and 6B. SSG was administered i.p. either 3 days before challenge or 3-48 h after challenge. The number of bacteria in blood samples and the mouse survival rates were recorded. Pre-challenge SSG administration protected dose-dependently against both S. pneumoniae type 4 and 6B infections. SSG injected 24 h post-challenge had a curative effect against type 6B but not type 4 pneumococcal infection. The data demonstrate that SSG administered systemically protects against pneumococcal infection in mice.

Intranasal immunization with heat-inactivated Streptococcus pneumoniae protects mice against systemic pneumococcal infection.

In order to study the mucosal and serum antibody response to polysaccharide-encapsulated bacteria in mice, a preparation of heat-inactivated Streptococcus pneumoniae type 4 was administered, with and without cholera toxin, at various mucosal sites. It appeared that intranasal immunization of nonanesthesized animals was superior to either oral, gastric, or colonic-rectal antigen delivery with regard to the induction of serum immunoglobulin G (IgG) and IgA, as well as saliva IgA antibodies specific for pneumococci. The marked IgA antibody response in feces after intranasal, but not after oral or gastric, immunization is suggestive of a cellular link between the nasal induction site and the distant mucosal effector sites. Intranasal immunization also induced antibodies in serum and in mucosal secretions against type-specific capsular polysaccharide. IgA and IgG antibody levels in pulmonary lavage fluids correlated well with saliva IgA and serum IgG antibodies, respectively. Antibody determinations in pulmonary secretions may therefore be redundant in some cases, and the number of experimental animals may be reduced accordingly. After intraperitoneal challenge with type 4 pneumococci, mice immunized intranasally were protected against both systemic infection and death, even without the use of cholera toxin as a mucosal adjuvant. Thus, an efficient intranasal vaccine against invasive pneumococcal disease may be based on a very simple formulation with whole killed pneumococci.

Human opsonins induced during meningococcal disease recognize outer membrane proteins PorA and PorB.

Human opsonins directed against specific meningococcal outer membrane structures in sera obtained during meningococcal disease were quantified with a recently developed antigen-specific, opsonin-dependent phagocytosis and oxidative burst assay. Outer membrane vesicles (OMVs) and PorA (class 1) and PorB (class 3) proteins purified from mutants of the same strain (44/76; B:15:P1.7. 16) were adsorbed to fluorescent beads, opsonized with acute- and convalescent-phase sera from 40 patients with meningococcal disease, and exposed to human leukocytes. Flow cytometric quantitation of the resulting leukocyte phagocytosis products (PPs) demonstrated that disease-induced serum opsonins recognized meningococcal OMV components and both porins. The PPPorA and PPPorB values induced by convalescent-phase sera correlated positively with the PPOMV values. However, the PPPorB values were higher than the PPPorA values in convalescent-phase sera (medians [ranges] of 754 [17 to 1,057] and 107 [4 to 458], respectively) (P < 0.0001) and correlated positively with higher levels of immunoglobulin G against PorB than against PorA as evaluated by enzyme-linked immunosorbent assay. Extensive individual variations in the anti-OMV and antiporin serum opsonic activities between patients infected by serotypes and serosubtypes homologous and heterologous to the target antigens were observed. Simultaneously measured oxidative burst activity correlated with the opsonophagocytosis, an indication that both of these important steps in the in vitro phagocytic elimination of meningococci are initiated by opsonins directed against OMV components, including PorA and PorB. In conclusion, human patient opsonins against meningococcal OMV components and in particular PorB epitopes were identified by this new method, which might facilitate selection of opsonin-inducing meningococcal antigens for inclusion in future vaccines.

Interleukin-13 and human immunoglobulin E production in severe combined immunodeficiency mice transplanted with human peripheral blood lymphocytes.

As normal mice do not respond to interleukin-13 (IL-13), we have used mice with severe combined immunodeficiency transplanted with human peripheral blood lymphocytes (hu-PBL-SCID mice) as an in vivo model for studying human IL-13. PBL from three donors (two allergic and one non-allergic) were prestimulated with IL-13 in vitro and thereafter transplanted into SCID mice. As evidenced by flow cytometry, IL-13 in the in vitro cell cultures was physiologically active and suppressed CD14 expression, while it enhanced the expression of CD23 on human monocytes. In the in vivo experiments, SCID mice transplanted with cells from both allergic donors produced twice as high maximum levels of IgE when the cells were preincubated with IL-13 in vitro before transplantation, as compared with mice receiving cells that had not been preincubated with IL-13. Two succeeding intraperitoneal (i.p.) injections of IL-13 resulted in a further increase of maximum IgE levels. Using cells from the non-allergic donor, no enhancing effect of IL-13 was observed. Transplanted human cells from one allergic donor examined were shown to migrate to the spleen and lungs of the recipient mice, while cells from the non-allergic donor were found only in the peritoneal cavity. Altogether, our results indicate that IL-13 enhances human IgE production in vivo and suggest that lymphocytes in allergic individuals are hyper-reactive to this cytokine. Furthermore, the allergic status of the cell donor may affect migration and engraftment of cells transplanted into SCID mice.

Pneumococcal vaccine in the elderly: the Norwegian experience.

Pneumococcal infections have increased during the last 10 to 15 years in Norway. Their incidence is now about 20 per 100,000 population for all age groups, but is 2 to 3 times higher among the elderly. In 1996, the Advisory Board of Infectious Disease Control, National Institute of Public Health, Norway, recommended that pneumococcal polysaccharide vaccine should be administered to all individuals aged > or = 65 years. This recommendation has led to an increased use of pneumococcal vaccine, with a marked peak during the influenza vaccination season.