Invasive pneumococcal disease among the elderly in the later era of paediatric pneumococcal conjugate vaccination-A longitudinal study over 10 years based on public surveillance data in the Nordics.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) have proven effective in preventing both non-invasive and invasive pneumococcal disease (IPD) in small children and in older age groups. However, long-term observations and country comparisons of IPD incidence in the elderly following introduction of PCVs in paediatric national immunisation programmes (NIPs) are scarce. We aimed to estimate and compare incidence of IPD in the elderly in Denmark, Finland, Norway, and Sweden over a 10-year time span. During the study period Denmark and Norway used PCV13 in their paediatric NIP, Sweden both PCV10 and PCV13 and Finland used PCV10. Uptake of pneumococcal vaccines for the elderly was low. METHOD: We collected longitudinal data on confirmed IPD cases and their serotypes among elderly people (aged ≥65 years) 2010-2019 in the four countries of interest. Annual IPD incidence rates were calculated per country, by vaccine-associated serotypes (PCV10, PCV13, PCV15, PCV20 and PPV23) and for non-vaccine serotypes. A regression model was used to estimate average annual change in incidence in each country. RESULTS: Incidence rates of IPD in the elderly in 2019 ranged from 31.4 to 41.8 per 100,000 people across the countries. Denmark and Norway showed an annual average decline in IPD incidence (-3.3; 95% CI: -5.6 to -1.1; p<0.01) and (-3.3; 95% CI: -5.5 to -1.0; p<0.01) respectively from 2010 to 2019, whereas no change was seen for Sweden (-0.5; 95% CI: -1.9 to 0.8; p = 0.39) or Finland (0.9; 95% CI: -1.0 to 2.7; p = 0.32). IPD incidence due to emerging serotypes, e.g., serotypes 8 and 12F, has increased. Serotype 19A remained a major cause of IPD in countries with PCV10 in paediatric NIPs. CONCLUSION: Despite paediatric PCV programmes, a considerable vaccine preventable IPD burden remains in the elderly. Further, choice of PCV in paediatric programs was associated with differences in serotype distribution and incidence amongst the elderly. Direct vaccination of the elderly with recently approved broad coverage PCVs holds promise for meaningful impact on disease burden with PCV20 covering a majority of IPD amongst the elderly in the four studied countries. Effectiveness of new vaccines in real-life clinical practice should be followed.

Estimated Number of Symptomatic Lyme Borreliosis Cases in Adults in Finland in 2021 Using Seroprevalence Data to Adjust the Number of Surveillance-Reported Cases: A General Framework for Accounting for Underascertainment by Public Health Surveillance.

Background: Finland conducts public health surveillance for Lyme borreliosis (LB) based on clinically diagnosed and laboratory-confirmed cases. We used data from seroprevalence studies to determine the extent to which LB cases were underascertained by public health surveillance. Methods: The numbers of incident symptomatic LB cases in 2011 in six regions in Finland were estimated using (1) data from Borrelia burgdorferi sensu lato seroprevalence studies, (2) estimates of the proportion of LB infections that are asymptomatic, and (3) estimates of the duration of LB antibody detection. The numbers of estimated incident symptomatic LB cases were compared with the numbers of surveillance-reported LB cases to estimate regional underascertainment multipliers. Underascertainment multipliers were applied to the numbers of surveillance-reported LB cases in each region in 2021 and summed to estimate the number of symptomatic LB cases in Finland among adults in 2021. A sensitivity analysis evaluated the impact of different durations of antibody detection. Results: Using an asymptomatic proportion of 50% and a 10-year duration of antibody detection, the estimated regional underascertainment multipliers in Finland ranged from 1.0 to 12.2. Applying the regional underascertainment multipliers to surveillance-reported LB cases in each region and summing nationally, there were 19,653 symptomatic LB cases in Finland among adults in 2021 (526/100,000 per year). With 7,346 surveillance-reported LB cases in Finland among adults in 2021, the estimated number of symptomatic LB cases indicate that there were 2.7 symptomatic LB cases for every surveillance-reported LB case among adults. With a 5- or 20-year duration of antibody detection, there were an estimated 36,824 or 11,609 symptomatic LB cases among adults in 2021, respectively. Discussion: Finland has robust public health surveillance for LB, but cases are underascertained. This framework for estimating LB underascertainment can be used in other countries that conduct LB surveillance and have conducted representative LB seroprevalence studies.

Estimating the Impact of Switching from a Lower to Higher Valent Pneumococcal Conjugate Vaccine in Colombia, Finland, and The Netherlands: A Cost-Effectiveness Analysis.

INTRODUCTION: Widespread use of ten-valent (Synflorix™, GSK) or 13-valent (Prevenar 13™; Pfizer) conjugate vaccination programs has effectively reduced invasive pneumococcal disease (IPD) globally. However, IPD caused by serotypes not contained within the respective vaccines continues to increase, notably serotypes 3, 6A, and 19A in countries using lower-valent vaccines. Our objective was to estimate the clinical and economic benefit of replacing PCV10 with PCV13 in Colombia, Finland, and The Netherlands. METHODS: Country-specific databases, supplemented with published and unpublished data, informed the historical incidence of pneumococcal disease as well as direct and indirect medical costs. A decision-analytic forecasting model was applied, and both costs and outcomes were discounted. The observed invasive pneumococcal disease (IPD) trends from each country were used to forecast the future number of IPD cases given a PCV13 or PCV10 program. RESULTS: Over a 5-year time horizon, a switch to a PCV13 program was estimated to reduce overall IPD among 0-2 year olds by an incremental - 37.6% in Colombia, - 32.9% in Finland, and - 26% in The Netherlands, respectively, over PCV10. Adults > 65 years experienced a comparable incremental decrease in overall IPD in Colombia (- 32.2%), Finland (- 15%), and The Netherlands (- 3.7%). Serotypes 3, 6A, and 19A drove the incremental decrease in disease for PCV13 over PCV10 in both age groups. A PCV13 program was dominant in Colombia and Finland and cost-effective in The Netherlands at 1 × GDP per capita (€34,054/QALY). CONCLUSION: In Colombia, Finland, and The Netherlands, countries with diverse epidemiologic and population distributions, switching from a PCV10 to PCV13 program would significantly reduce the burden of IPD in all three countries in as few as 5 years.

Exploring the costs of a 13-valent pneumococcal conjugate vaccination program for home care patients.

OBJECTIVE: The city of Joensuu in Finland vaccinated 409 elderly home care patients with the 13-valent pneumococcal conjugate vaccine (PCV13) in autumn 2012. All home care patients were also eligible for a seasonal influenza vaccine. The objective of this retrospective real-world data cohort study was to evaluate whether the immunization intervention with PCV13 for home care patients was cost saving from the payer's (municipality's) perspective in terms of a return on investment (ROI). METHODS: This was a retrospective observational registry study. We used registry data from the regional Mediatri patient information system covering all North Karelian municipalities, including individual-level data for all health and social care service utilization, diagnoses and procedures. Home care patients and their use of services were followed for 2 years. Cost comparisons were based on two specifications: (1) pneumonia-related health care costs; and (2) total health care costs. We compared patients who had received both influenza and PCV13 vaccinations to patients only vaccinated against influenza. RESULT: The pneumonia-related costs in the PCV13-vaccinated group were 434 EUR lower and the total health care costs 3800 EUR lower per person, compared to the non-PCV13-vaccinated group (bootstrapped 95% CIs -1682-527 EUR and -8233-621 EUR, respectively). PCV13 vaccination was associated with a return on investment of 7 EUR per 1 EUR spent during the 2 year follow-up period when pneumonia-related costs were used as baseline. Probability of the positive return on investment was .715. CONCLUSION: The results suggest that vaccinating home care patients could potentially be cost saving from the health care and service producer's perspectives. The uncertainty from the decision-making perspective was due to the large variation in individual costs.

Economic impact of 13-valent pneumococcal conjugate vaccine in Finnish adults ≥50 years with underlying chronic medical conditions.

RATIONALE, AIMS AND OBJECTIVES: Invasive pneumococcal diseases (IPD) are associated with substantial burden in adults (≥50 years). Moreover, adults with vascular, metabolic or respiratory diseases have been shown to have a 3-6 times higher risk of IPD when compared with their healthy controls. These persons at higher risk are likely to benefit most from pneumococcal vaccinations. The 13-valent pneumococcal conjugate vaccine (PCV13) was recently introduced to prevent the 13 most prevalent serotypes causing invasive pneumococcal disease in adults. The objective of this study was to estimate the expected 5-year economic impact of targeted PCV13 vaccination compared with no vaccination in Finnish adults (≥50 years) at moderate or high risk for IPD. METHODS: A budget impact model was developed to predict the impact of PCV13 vaccination in terms of the costs and IPD events avoided for years 2012-2016. RESULTS: Approximately 35% of the 2.2 million Finns over 50 years of age can be considered to be at moderate or high risk for IPD because of underlying chronic medical conditions. Vaccination of these people with PCV13 could provide an estimated net budget savings of about €218 million compared with the current no-vaccination situation over the next 5 years. Among the risk groups considered, the largest absolute net savings (€66.2 million) could be expected to be obtained by vaccinating people with heart disease, due to its high prevalence in the target population. CONCLUSION: In Finland, the immunization with PCV13 vaccine, of adults (≥50 years) at moderate and high risk of IPD, is estimated to lead to substantial cost savings in the 5 years after vaccination.

Concentration and high avidity of pneumococcal antibodies persist at least 4 years after immunization with pneumococcal conjugate vaccine in infancy.

To provide more extensive evidence of long-term effects of vaccination on immunity against Streptococcus pneumoniae, a follow-up study of the Finnish Otitis Media (FinOM) Vaccine Trial was conducted. One of the objectives was to assess the persistence and avidity of pneumococcal antibodies 4 years after pneumococcal vaccination given in infancy. Children with complete follow-up in the FinOM trial up to 24 months of age were invited to a single visit in their fifth year of life. A blood sample was taken from all children for determination of anticapsular antibody concentrations to vaccine serotypes and avidity of antibodies to three serotypes. Children had been vaccinated at 2, 4, 6, and 12 months of age with 7-valent pneumococcal capsular polysaccharide, CRM197 conjugate vaccine (PCV7), or a control vaccine. Serum IgG antibody concentrations to vaccine serotypes remained significantly higher in children who had received PCV7 than in control children for 4 years after the fourth PCV7 dose. Concentrations of antibodies to frequently carried serotypes (6B and 19F) declined less than those of antibodies to a rarely carried serotype (4), suggesting that natural boosting contributed to antibody persistence. Furthermore, antibody avidity was significantly higher in PCV7 than control vaccine recipients. Four doses of PCV7 given in infancy elicit long-lasting antibody responses with high avidity. (This study has been registered at ClinicalTrials.gov under registration no. NCT00378417.).

Immunogenicity and tolerability of a heptavalent pneumococcal conjugate vaccine administered at 3, 5 and 12 months of age.

BACKGROUND: The recommended vaccination schedule for the pneumococcal conjugate vaccine (PCV) includes 4 immunizations, according to the national programs in the United States and some European countries. Other countries use a national schedule for routine vaccinations in early childhood that includes only 3 doses. AIMS: The goals were to assess the immunogenicity and tolerability of PCV with a vaccination schedule that included 3 doses during the first 1 year of life (a 2+1 dose schedule) and to determine the immune responses to concomitantly administered Haemophilus influenzae type b (Hib) vaccine. METHODS: A total of 101 healthy Swedish infants were enrolled in an open, nonrandomized, multicenter study. PCV was administered concomitantly with (at separate sites) a diphtheria-tetanus toxoids-acellular pertussis vaccine, inactivated polio vaccine and Hib conjugate vaccine combination at 3, 5 and 12 months of age. IgG antibody concentrations for the 7 serotypes included in the PCV and the Hib capsular polysaccharide in serum samples taken at 3, 6, 12 and 13 months were determined with enzyme immunoassays. Local and systemic reactions were monitored for 3 days after each immunization, and serious adverse reactions were monitored for the whole study period. RESULTS: Two doses of PCV induced satisfactory antibody responses, with the exception of serotypes 6B and 23F. The third dose evoked strong responses for all serotypes, which suggests good immunologic priming with the primary series of 2 doses. The mean anti-Hib antibody concentrations were similar to those noted in earlier studies among Swedish children. The PCV was well tolerated. CONCLUSION: The pneumococcal antibody concentrations at 13 months were comparable with those noted previously with the 4-dose schedule. The results suggest that the implementation of a 2+1 dose schedule for PCV should be considered.

Kinetics and avidity of antibodies evoked by heptavalent pneumococcal conjugate vaccines PncCRM and PncOMPC in the Finnish Otitis Media Vaccine Trial.

The licensure of new pneumococcal conjugate vaccines (PCVs) relies on immunogenicity data. When defining correlates of protection, vaccine efficacy data must be included. In the FinOM Vaccine Efficacy Trial, the PncOMPC vaccine showed an efficacy profile similar to that of the licensed PncCRM vaccine despite different antibody responses after primary and booster vaccinations. We determined antibody kinetics and avidities in a subgroup of infants participating in the FinOM trial. A total of 166 infants in three vaccine groups were immunized at 2, 4, 6, and 12 months of age with 7-valent PCV, PncCRM or PncOMPC, or hepatitis B vaccine. Concentrations of serum immunoglobulin G (IgG) against pneumococcal capsular polysaccharides were determined at 2, 4, 6, 7, 12, 13, and 24 months of age, and the avidity index (AI) to serotypes 6B, 19F, and 23F were determined at 7, 12, 13, and 24 months of age by enzyme immunoassay. Both PCVs were highly immunogenic, but they demonstrated different kinetics of antibody response; the concentration of IgG against serotypes 6B, 19F, and 23F declined faster after the third and fourth doses of vaccine in the PncCRM group than in the PncOMPC group. For both PCVs, the mean AI of anti-6B and -23F, but not of anti-19F, increased during the follow-up, which is in line with serotype-specific protection in the FinOM trial. Our data suggest that the kinetics and avidities of antibodies should be considered, in addition to antibody responses, when defining correlates of protection.

Concentration of antipneumococcal antibodies as a serological correlate of protection: an application to acute otitis media.

BACKGROUND: For the licensing of new pneumococcal vaccines, it is vital to be able to predict their protective efficacy on the basis of immunogenicity. However, the serological correlates of protection have not been established for pneumococcal diseases. METHODS: A total of 1666 children were immunized with the pneumococcal conjugate vaccine. Acute otitis media (AOM) events were identified, and middle-ear fluid was cultured for pneumococci. The association between the concentration of antibodies against serotypes 6B, 19F, and 23F and the risk of AOM caused by the homologous serotypes or by the cross-reactive serotype 6A was assessed. An association model was used to predict efficacy at different geometric mean concentrations (GMCs). RESULTS: An association between antibody concentration and risk of AOM was found, but with large differences between serotypes. On the basis of the association, the predicted efficacy for 19F was negligible up to the highest GMC tested. In contrast, 6B was found to be highly efficacious (>65%) at a GMC of 0.5 microg/mL. CONCLUSIONS: The results challenge the view that a new vaccine candidate should always induce antibody concentrations that are not inferior to those produced by the licensed vaccine. Furthermore, the differences between serotypes caution against defining a common correlate of protection that is applicable to all serotypes.

Protective efficacy of a second pneumococcal conjugate vaccine against pneumococcal acute otitis media in infants and children: randomized, controlled trial of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine in 1666 children.

To assess the efficacy of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine (PncOMPC) against acute otitis media (AOM), 1666 infants were randomly assigned to receive either PncOMPC or control vaccine (hepatitis B vaccine) at 2, 4, 6, and 12 months of age. Of the 835 children assigned to receive PncOMPC, 187 received a 23-valent pneumococcal polysaccharide vaccine (PncPS) at 12 months of age instead. Whenever AOM was diagnosed, middle ear fluid was aspirated for bacterial culture. In the PncOMPC and control groups, there were 110 and 250 AOM episodes, respectively, in children between 6.5 and 24 months of age that could be attributed to vaccine serotypes, which indicates a vaccine efficacy of 56% (95% confidence interval, 44%-66%). The serotype-specific efficacy ranged from 37% for 19F to 82% for 9V. The 2 boosters seemed to provide equal protection against AOM, but PncPS induced markedly higher antibody concentrations. The efficacy of PncOMPC was comparable to that of the recently licensed pneumococcal conjugate vaccine.

Antigenically diverse reference strains and autologous strains of Actinobacillus actinomycetemcomitans are equally efficient antigens in enzyme-linked immunosorbent assay analysis.

Actinobacillus actinomycetemcomitans is a major pathogen in periodontitis. Data on the clinical relevance of serum immunoglobulin G (IgG) antibody levels against this species are controversial. The aim of the present study was to elucidate how different strains used as antigens in enzyme-linked immunosorbent assay (ELISA) influence the detection of individuals with elevated serum IgG levels against A. actinomycetemcomitans. We hypothesized that the highest antibody levels are targeted to the autologous strains. A total of 19 strains-six antigenically diverse reference strains (serotypes a through e and a nonserotypeable strain) and 13 serotyped autologous strains-were used as whole-cell antigens in ELISA. Serum samples were from 26 untreated adult patients with periodontitis, whose subgingival bacterial samples were either culture positive (n = 13) or culture negative (n = 13) for A. actinomycetemcomitans, and from 10 culture-negative nonperiodontitis subjects. The highest individual (P < 0.05) IgG levels against the reference strains were most commonly against serotypes a and b in patients and against serotype c in nonperiodontitis subjects. The culture-positive patients had the highest (P < 0.05) IgG antibody levels against their autologous strains and against the reference strains of the same serotype. On the contrary, for these patients the levels of antibody against the reference strains of other serotypes were comparable to those of the nonperiodontitis subjects. The results indicated that the serum IgG antibody levels against A. actinomycetemcomitans strongly depend on the strains used as antigens in the ELISA. Elevated serum IgG levels against A. actinomycetemcomitans can be detected equally well using either the autologous strains or a variety of antigenically diverse reference strains as antigens.