Incidence of sinus thrombosis with thrombocytopenia-A nation-wide register study.

Safe vaccination is essential for mitigation of the COVID-19 pandemic. Two adenoviral vector vaccines, ChAdOx1 nCov-19 (AstraZeneca) and Ad26.COV2.S (Johnson&Johnson/Janssen) have shown to be effective and they are distributed globally, but reports on serious cerebral venous sinus thrombosis (CVST) associated with thrombocytopenia, have emerged. Our objective was to evaluate the background incidence of CVST with thrombocytopenia and to compare it to incidences following COVID-19 vaccines. We conducted a register-based nation-wide cohort study in Finland, including all 5.5 million individuals alive in Finland, 1 Jan 2020. COVID-19 vaccinations registered in the National Vaccination Register served as the exposure. We detected CVST admissions or hospital visits recorded in the hospital discharge register from Jan 1, 2020 through April 2, 2021. We confirmed the diagnosis of CVST and thrombocytopenia (platelet count <150,000 per cubic millimeter) using radiology reports and laboratory data. By Poisson regression, we compared the baseline incidences to the risks within four weeks after COVID-19 vaccinations. Out of the 167 CVST episodes identified in the registers, 117 were confirmed as CVST, 18 of which coincided with thrombocytopenia (baseline incidence 0.18 per 28 days per million persons). We found 2 episodes of CVST with thrombocytopenia within 28 days of the first ChAdOx1 nCov-19 vaccination (among 200,397 vaccinated, aged 16 or above). No cases were found following the first mRNA vaccine dose among 782,604 vaccinated. The background incidence of CVST combined with thrombocytopenia was minuscule compared to the incidence during the weeks following the ChAdOx1 nCov-19 vaccination. Accurate estimation of the baseline incidence is essential in the critical appraisal of the benefit-risk of any vaccination program.

Lower incidence of hospital-treated infections in infants under 3 months of age vaccinated with BCG.

BACKGROUND: Live vaccines potentially have non-specific effects that protect against other infections than those the vaccines are targeted against. The national vaccination program (NVP) in Finland was changed on September 1st, 2006: before BCG vaccine was given to all newborn babies and afterwards to babies in risk groups only. We used this natural experiment to study the non-specific effects of BCG in the frame of NVP using before-after design. METHODS: We compared the incidence of several outcomes obtained from Finnish health registers between children born between July 1st, 2004, and June 30th, 2006 (BCG-eligible) and an age- and season-matched reference cohort born between July 1st, 2007, and June 30th, 2009 (BCG-non-eligible) using Poisson regression. These cohorts were restricted to full-term children whose parents were born in Finland. Follow-up began at birth and lasted 3 months, which is the scheduled age for DTaP-IPV-Hib vaccination, and from 4 months until first birthday. The outcomes included all infections, pneumonia and injuries as a negative control outcome. RESULTS: The incidence rate ratio (IRR) of the BCG-eligible cohort (N = 93,658) compared to BCG-non-eligible cohort (N = 94,712) for hospital-diagnosed infections was 0.89 (95 %Cl 0.86-0.93) for the 3-month follow-up. The decrease was mainly caused by respiratory infections. In 4-12 months follow-up the BCG-eligible had slightly more infections than BCG-non-eligible children (IRR 1.03, 1.01-1.06). CONCLUSIONS: BCG vaccination was associated with a lower incidence of all hospital-diagnosed infections during the first three months of life. The difference cannot be attributed to lung tuberculosis, since only few paediatric cases occurred in Finland during 2000s. The disappearance of non-specific effect after administration of an inactivated vaccine is compatible with previous studies.

Evaluation of the indirect impact of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine in a cluster-randomised trial.

BACKGROUND: In the nation-wide double-blind cluster-randomised Finnish Invasive Pneumococcal disease trial (FinIP, ClinicalTrials.gov NCT00861380, NCT00839254), we assessed the indirect impact of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against five pneumococcal disease syndromes. METHODS: Children 6 weeks to 18 months received PHiD-CV10 in 48 clusters or hepatitis B/A-vaccine as control in 24 clusters according to infant 3+1/2+1 or catch-up schedules in years 2009-2011. Outcome data were collected from national health registers and included laboratory-confirmed and clinically suspected invasive pneumococcal disease (IPD), hospital-diagnosed pneumonia, tympanostomy tube placements (TTP) and outpatient antimicrobial prescriptions. Incidence rates in the unvaccinated population in years 2010-2015 were compared between PHiD-CV10 and control clusters in age groups <5 and ≥5 years (5-7 years for TTP and outpatient antimicrobial prescriptions), and in infants <3 months. PHiD-CV10 was introduced into the Finnish National Vaccination Programme (PCV-NVP) for 3-month-old infants without catch-up in 9/2010. RESULTS: From 2/2009 to 10/2010, 45398 children were enrolled. Vaccination coverage varied from 29 to 61% in PHiD-CV10 clusters. We detected no clear differences in the incidence rates between the unvaccinated cohorts of the treatment arms, except in single years. For example, the rates of vaccine-type IPD, non-laboratory-confirmed IPD and empyema were lower in PHiD-CV10 clusters compared to control clusters in 2012, 2015 and 2011, respectively, in the age-group ≥5 years. CONCLUSIONS: This is the first report from a clinical trial evaluating the indirect impact of a PCV against clinical outcomes in an unvaccinated population. We did not observe consistent indirect effects in the PHiD-CV10 clusters compared to the control clusters. We consider that the sub-optimal trial vaccination coverage did not allow the development of detectable indirect effects and that the supervening PCV-NVP significantly diminished the differences in PHiD-CV10 vaccination coverage between the treatment arms.

The association of adverse events with bivalent human papilloma virus vaccination: A nationwide register-based cohort study in Finland.

BACKGROUND: A bivalent HPV vaccine (Cervarix®; HPV2, GlaxoSmithKline) was introduced into the Finnish national vaccination programme (NVP) in November 2013 for girls aged 11-13 years with a catch-up for 14-15 year-olds. We evaluated the association between HPV2 and selected autoimmune diseases and clinical syndromes by conducting a nation-wide retrospective register-based cohort study. METHODS: First life-time occurrences of the relevant ICD-10 codes in girls aged 11-15 years between Nov-2013 and Dec-2016 were obtained from the national hospital discharge register. Population denominators were obtained from the Population Information System and vaccination records from the National Vaccination Register. Registers were linked using unique personal identity codes. Association between HPV2 and 38 selected outcomes were studied using Cox regression, with age as the main time-scale and the first vaccination dose as the time-dependent exposure. The hazard ratios (HR) with 95%CI were assessed according to the time since exposure (entire follow-up, 0-180/181-365/>365 days). RESULTS: Of 240 605 girls eligible for HPV2 vaccination, 134 615 (56%) were vaccinated. After adjustment for geographical area (6 hospital districts), country of origin (Finnish-born/not) and number of hospital contacts from 9 through 10 years of age, HRs ranged from 0.34 (95%CI 0.11-1.05) to 8.37 (95%CI 0.85-82.54) and HPV2 vaccination was not statistically significantly associated with a higher risk of any outcome during the entire follow-up. CONCLUSIONS: This study found no significantly increased risk for the selected outcomes after the HPV vaccination in girls 11-15 years of age. These results provide valid evidence to counterbalance public scepticism, fears of adverse events and possible opposition to HPV vaccination and consequently can contribute to increase HPV vaccination coverage in Finland as well as elsewhere.

Vaccine-preventable disease incidence of pneumococcal conjugate vaccine in the Finnish invasive pneumococcal disease vaccine trial.

Estimation of the full disease burden caused by Streptococcus pneumoniae is challenging due to the difficulties in assigning the aetiology especially in lower and upper respiratory infections. We estimated the pneumococcal disease burden by using the vaccine-preventable disease incidence (VPDI) of PHiD-CV10 vaccine (GSK) in our clinical trial setting. Finnish Invasive Pneumococcal disease (FinIP) trial was a cluster-randomized, double-blind trial in children <19 months who received PHiD-CV10 in 52 clusters or hepatitis B/A vaccine as control in 26 clusters according to 3+1 or 2+1 schedules (infants < 7 months) or catch-up schedules (children 7-18 months). Outcome data were collected using Finnish routine health-care registers, consisting of THL National Infectious Diseases Register, THL Care register, and Benefits Register of Social Insurance Institution of Finland. Blinded follow-up lasted from the date of first vaccination (trial enrolment Feb-2009 through Aug-2010) to January 31, 2012 for Invasive Pneumococcal Disease (IPD) and to end of December 2011 for four other outcomes: non-laboratory-confirmed IPD, hospital-diagnosed pneumonia, tympanostomy tube placements, and antimicrobial purchases. VPDI was estimated as difference in disease incidences between PHiD-CV10 clusters and control clusters. Altogether >47,000 children were enrolled. In 30,527 vaccinated infants <7 months at first dose, the VPDIs per 100,000 person-years were 75 for laboratory-confirmed IPD, 210 for non-laboratory-confirmed IPD, 271 for hospital-diagnosed pneumonia, 1143 for any tympanostomy tube placements and 11,381 for antimicrobial outpatient prescription, mainly due to otitis media. In a European developed-country setting, over 95% of the disease episode reductions in vaccinated children were seen in mild upper respiratory infections. The VPDIs of severe diseases are underestimated, because the majority of invasive disease goes undetected with routine blood-culture-based definitions. Evaluation of the absolute reduction achievable with vaccinations using sensitive case detection is essential for understanding the full disease burden, for valid cost-effectiveness analyses and for appropriate vaccination policy decisions. Registration: ClinicalTrials.gov, NCT00861380 and NCT00839254.

Population-level impact of infant 10-valent pneumococcal conjugate vaccination on adult pneumonia hospitalisations in Finland.

INTRODUCTION: Limited data are available on population-level herd effects of infant 10-valent pneumococcal conjugate vaccine (PCV10) programmes on pneumonia. We assessed national trends in pneumococcal and all-cause pneumonia hospitalisations in adults aged ≥18 years, before and after infant PCV10 introduction in 2010. METHODS: Monthly hospitalisation rates of International Statistical Classification of Diseases, 10th revision (ICD-10)-coded primary discharge diagnoses compatible with pneumonia from 2004-2005 to 2014-2015 were calculated with population denominators from the population register. Trends in pneumonia before and after PCV10 introduction were assessed with interrupted time-series analysis. Rates during the PCV10 period were estimated from adjusted negative binomial regression model and compared with those projected as continuation of the pre-PCV10 trend. All-cause hospitalisations were assessed for control purposes. RESULTS: Before PCV10, the all-cause pneumonia rate in adults aged ≥18 years increased annually by 2.4%, followed by a 4.7% annual decline during the PCV10 period. In 2014-2015, the overall all-cause pneumonia hospitalisation rate was 109.3/100 000 (95% CI 96.5 to 121.9) or 15.4% lower than the expected rate. A significant 6.7% decline was seen in persons aged ≥65 years (131.5/100 000), which translates to 1456 fewer pneumonia hospitalisations annually. In comparison, hospitalisations other than pneumonia decreased by 3.5% annually throughout the entire study period. CONCLUSION: These national data suggest that herd protection from infant PCV10 programme has reversed the increasing trend and substantially decreased all-cause pneumonia hospitalisations in adults, particularly the elderly.

Similar Antibody Levels in 3-Year-Old Children Vaccinated Against Measles, Mumps, and Rubella at the Age of 12 Months or 18 Months.

BACKGROUND: Measles-mumps-rubella (MMR) vaccinations have been offered to Finnish children at 14-18 months and 6 years of age. In May 2011, the recommended age for the first vaccine dose was lowered to 12 months because of the European measles epidemic. METHODS: Fingertip capillary blood samples were collected from 3-year-old Finnish children vaccinated once with MMR vaccine at 11-19 months of age. The immunoglobulin G (IgG) antibodies to all 3 MMR antigens were measured with enzyme-linked immunosorbent assay. Neutralizing antibodies and the avidity of antibodies were measured for measles virus. RESULTS: From April through October 2013, 187 children were enrolled. Equally high proportions of the samples were seropositive for measles virus, mumps virus, or rubella virus antibodies, and there were no significant differences in the IgG antibody concentrations in children vaccinated at 11-13 months of age, compared with those vaccinated at 17-19 months of age. However, among children vaccinated at 11-13 months of age, boys had lower antibody concentrations than girls. Neutralizing measles virus antibody titers were above the threshold for protective immunity in all 78 samples analyzed. The measles virus antibody avidity indexes were high for all children. CONCLUSIONS: MMR induces similar antibody responses in 12-month-old children as compared to 18-month-old children, but in boys increasing age appears to improve the antibody responses.

Effectiveness of the Ten-valent Pneumococcal Conjugate Vaccine Against Tympanostomy Tube Placements in a Cluster-randomized Trial.

BACKGROUND: We evaluated the impact of the new pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10, GSK Vaccines) on tympanostomy tube placements (TTPs). METHODS: Finnish Invasive Pneumococcal disease vaccine trial was a nationwide phase III/IV cluster-randomized, double-blind trial. Children younger than 19 months received PHiD-CV10 in two thirds of clusters (N = 52) or hepatitis B or A vaccine as control in 26 clusters according to 3 + 1 or 2 + 1 schedules (infants younger than 7 months) or catch-up schedules. A secondary objective of the trial was to assess vaccine effectiveness (VE) against TTPs in children who received at least one vaccine dose before or after 7 months of age. Blinded follow-up lasted from the date of first vaccination (from February 2009 through October 2010) to December 31, 2011. Outcome data were collected through the National Care register and Social Insurance Institution reimbursement register. RESULTS: More than 47,000 children were enrolled. In 30,527 infants younger than 7 months of age at enrolment, 4369 TTPs were reported in 3594 subjects. The incidence was 7.9 per 100 person-years in the infant control cohort. The VE estimate was 13% [95% confidence interval (CI): -2% to 26%] for combined PHiD-CV10 3 + 1 and 2 + 1 infant schedules. The VE estimates for the 3 + 1 and 2 + 1 infant schedules when estimated separately were similar. For the catch-up schedules, the VE was 11% (95% CI: -7% to 26%) for children enrolled at 7-11 months of age and -1% (95% CI: -21% to 16%) for children enrolled at 12-18 months of age. CONCLUSIONS: Our study results suggest that PHiD-CV10 immunization according to a 3 + 1 or 2 + 1 schedule initiated before 12 months of age may reduce the frequency of TTPs, although the primary analysis did not reach statistical significance.

Effect of pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) on outpatient antimicrobial purchases: a double-blind, cluster randomised phase 3-4 trial.

BACKGROUND: Antimicrobial drugs are frequently prescribed to children for respiratory tract infections such as otitis, tonsillitis, sinusitis, and pneumonia. We assessed the effect of the ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10; GlaxoSmithKline) on antimicrobial purchases. METHODS: In this nationwide phase 3-4 cluster-randomised, double-blind trial, children younger than 19 months were randomly assigned to receive PHiD-CV10 in 52 of 78 clusters or hepatitis B or A vaccine as control in 26 clusters according to three plus one or two plus one schedules (infants younger than 7 months) or catch-up schedules (children aged 7-18 months). The main objective for the antimicrobial treatment outcome was to assess vaccine effectiveness against outpatient prescriptions of antimicrobial drugs recommended by national treatment guidelines for acute otitis media in Finland in children who received at least one dose of study vaccine before 7 months of age. Masked follow-up lasted from the date of first vaccination (from Feb 18, 2009, through Oct 5, 2010) to Dec 31, 2011. We obtained data on all purchased antimicrobial prescriptions through the benefits register of the Social Insurance Institution of Finland. This and the nested acute otitis media trial are registered at ClinicalTrials.gov, numbers NCT00861380 and NCT00839254. FINDINGS: More than 47,000 children were enrolled. In 30,527 infants younger than 7 months at enrollment, 98,436 outpatient antimicrobial purchases were reported with incidence of 1.69 per person-year in the control clusters. Analysis of the main objective included 91% of all antimicrobial purchases: 31,982 in the control and 57,964 in the PHiD-CV10 clusters. Vaccine effectiveness was 8% (95% CI 1-14) and the incidence rate difference 0.12 per person-year corresponding to the number needed to vaccinate of five (95% CI 3-67) to prevent one purchase during the 2 year follow-up for combined PHiD-CV10 three plus one and two plus one infant schedules. The vaccine effectiveness was identical for the two infant schedules. In the catch-up schedules, the vaccine effectiveness was 3% (95% CI -4 to 10). INTERPRETATION: Despite low relative rate reductions the absolute rate reductions were substantial because of the high incidence of the outcome. This reduction would lead to over 12,000 fewer antimicrobial purchases per year in children younger than 24 months in Finland (birth cohort of 60,000 children).

Effectiveness of the ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against invasive pneumococcal disease: a cluster randomised trial.

BACKGROUND: The Finnish Invasive Pneumococcal disease (FinIP) vaccine trial was designed to assess the effectiveness of a pneumococcal vaccine containing ten serotype-specific polysaccharides conjugated to Haemophilus influenzae protein D, tetanus toxoid, and diphtheria toxoid as the carrier proteins (PHiD-CV10) against invasive pneumococcal disease. METHODS: In this cluster-randomised, double-blind trial, children aged younger than 19 months received PHiD-CV10 in 52 clusters or hepatitis vaccines as control in 26 clusters. Infants aged younger than 7 months at the first vaccination received either a 3+1 or a 2+1 vaccination schedule, children aged 7-11 months received a 2+1 schedule, and those 12-18 months of age received a two-dose schedule. The primary and secondary objectives were to assess vaccine effectiveness against culture-confirmed invasive pneumococcal disease due to any of the ten vaccine serotypes for the 3+1 and 2+1 schedules, respectively, in children who received at least one PHiD-CV10 dose before 7 months of age. Masked follow-up of pneumococcal disease lasted from the first vaccination (from February, 2009, to October, 2010) to January 31, 2012. Invasive disease data were retrieved from data accumulated in the national infectious diseases register. This trial and the nested acute otitis media trial are registered with ClinicalTrials.gov, numbers NCT00861380 and NCT00839254, respectively. FINDINGS: 47,369 children were enrolled from February, 2009, to October, 2010. 30,528 participants were assessed for the primary objective. 13 culture-confirmed vaccine-type cases of invasive pneumococcal disease were detected: none in the PHiD-CV10 3+1 group, one in the PHiD-CV10 2+1 group, and 12 in the control groups. The estimates for vaccine effectiveness were 100% (95% CI 83-100) for PHiD-CV10 3+1 and 92% (58-100) for PHiD-CV10 2+1 groups. Two cases of any culture-confirmed invasive disease irrespective of serotype were detected in combined PHiD-CV10 infant cohorts compared with 14 in the corresponding control cohorts (vaccine effectiveness 93%, 75-99). In catch-up cohorts, seven cases of invasive disease were reported, all in the control group: two cases in the children enrolled at 7-11 months of age; and five cases in children enrolled at 12-18 months of age (vaccine effectiveness 100%, 79-100). Non-fatal serious adverse events suspected to be vaccine-related were reported via routine post-immunisation safety surveillance in 18 children. INTERPRETATION: This nationwide trial showed high PHiD-CV10 effectiveness against invasive pneumococcal disease when given in different schedules. For the first time, effectiveness of a 2+1 schedule in infants was confirmed in a clinical trial. FUNDING: GlaxoSmithKline Biologicals SA and National Institute for Health and Welfare, Finland.

Survival of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis frozen in skim milk- tryptone-glucose-glycerol medium.

In STGG (skim milk, tryptone, glucose, glycerol) medium at -80 degrees C, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis isolates survived for at least 3 years, and the same species have survived in nasopharyngeal swabs for at least 1.5 years. At -20 degrees C, S. pneumoniae and M. catarrhalis survived for 1.5 years, but H. influenzae survived for only 2 months.