Primary diphtheria immunisation of adolescents and adults with low-dose vaccine, a survey of historic evidence from the literature.

The Public Health Agency of Sweden carried out a literature review on diphtheria vaccinations for seronegative people above 6 years of age with an uncertain vaccine history. The aim was to harmonise national Swedish recommendations with the current World Health Organization recommendations. There was no firm conclusion about dosage. Some low-dose vaccines used in the past had suboptimal potency, while others evoked adequate levels of antitoxin after three primary doses. We concluded that low-dose diphtheria vaccines that have been approved by a national medical products agency can be used for primary vaccination against diphtheria for individuals above 6 years of age.

National guidelines recommend rotavirus vaccination to inpatient preterm infants.

AIM: The aim was to perform a literature search of the latest evidence of administration of dose 1 of rotavirus vaccine to children admitted in neonatal intensive care or special care unit settings. METHODS: The literature search focused on the outcome of serious adverse events of rotavirus vaccination in vaccinated children and on possible symptomatic infection in controls and in unvaccinated children via transmission of the vaccine virus in the same ward. Results and guidelines were discussed with a working group selected from the national advisory group of child health. Also, a survey to neonatal care units in Sweden was sent out due to the subject. RESULTS: Administration of rotavirus vaccine is safe for age-eligible preterm children and unvaccinated children in the same ward. A satisfactory immune response has been shown, and basic hygiene routines are enough. Also, hospitalised age-eligible children with paediatric surgical conditions should be considered the rotavirus vaccine. CONCLUSION: The Swedish Public Health Agency recommends that preterm infants as well as children who are admitted for other reasons in the neonatal ward be vaccinated with dose 1 against rotavirus infection when hospitalised and when age eligible.

Vaccination and allergy: EAACI position paper, practical aspects.

Immunization is highly effective in preventing infectious diseases and therefore an indispensable public health measure. Allergic patients deserve access to the same publicly recommended immunizations as non-allergic patients unless risks associated with vaccination outweigh the gains. Whereas the number of reported possible allergic reactions to vaccines is high, confirmed vaccine-triggered allergic reactions are rare. Anaphylaxis following vaccination is rare, affecting <1/100 000, but can occur in any patient. Some patient groups, notably those with a previous allergic reaction to a vaccine or its components, are at heightened risk of allergic reaction and require special precautions. Allergic reactions, however, may occur in patients without known risk factors and cannot be predicted by currently available tools. Unwarranted fear and uncertainty can result in incomplete vaccination coverage for children and adults with or without allergy. In addition to concerns about an allergic reaction to the vaccine itself, there is fear that routine childhood immunization may promote the development of allergic sensitization and disease. Thus, although there is no evidence that routine childhood immunization increases the risk of allergy development, such risks need to be discussed.

Monitoring of timely and delayed vaccinations: a nation-wide registry-based study of Norwegian children aged < 2 years.

BACKGROUND: Delayed vaccinations increase the risk for vaccine preventable diseases (VPDs). Monitoring of delayed vaccinations by using a national immunisation registry has not been studied in countries recommending a two-dose (3 and 5 months of age) primary series of e.g., pertussis vaccine. Surveillance/monitoring of all vaccinations may improve vaccination programmes functioning. METHODS: We obtained information from the Norwegian immunisation registry (SYSVAK) on all programme vaccinations received at age up to 730 days in children born in 2010 (n = 63,382). Timely vaccinations were received up to 7 days after the recommended age. Vaccinations were considered delayed if they were received more than one month after the recommended age in the schedule. RESULTS: In vaccinated children, timely administration of the subsequent three doses of pertussis and one dose of measles occurred in 73.8, 47.6, 53.6 and 43.5 % respectively. Delay for one or more programme vaccinations (diphtheria, tetanus, pertussis, polio, Haemophilus influenza type B, invasive pneumococcal disease, measles, mumps or rubella) was present in 28,336 (44.7 %) children. Among those who were delayed the mean duration was 139 days. The proportion of children that had vaccinations delayed differed among counties (range 37.4 %-57.8 %). Immigrant children were more frequently delayed 52.3 % vs. 43.1 %, RR 1.21 (95 % CI 1.19, 1.24). Children scheduled for vaccines in the summer holiday month (July) were more frequently delayed than others (1(st) dose pertussis vaccine 6.5 % vs. 3.9 % RR 1.65 (95 % CI 1.48, 1.85). Priming against pertussis (2(nd) dose), pneumococcal (2(nd) dose) and measles (1(st) dose) was delayed in 16.8, 18.6 and 29.3 % respectively. CONCLUSION: Vaccinations were frequently delayed. Delayed vaccinations differed among counties and occurred more frequently during the summer vacation (July) and in the immigrant population. Monitoring improves programme surveillance and may be used on an annual basis.

Burden of severe rotavirus disease leading to hospitalization assessed in a prospective cohort study in Sweden.

BACKGROUND: The aim of this prospective cohort study was to estimate the burden of severe disease caused by rotavirus-induced gastroenteritis in Swedish children aged < 5 y. METHODS: Rotavirus-positive children admitted to hospitals serving 3 geographical regions with 155,838 children aged < 5 y, were offered inclusion in this 1-year study. Rotavirus strains identified were genotyped using multiplex PCR. Disease progression was documented through interviews and chart reviews. RESULTS: In total, 604 children with rotavirus-induced gastroenteritis were included in the study. Forty-nine of 604 (8.1%) fulfilled the criteria for nosocomial infection. The minimum incidence was 388 per 100,000, with significant variability between study regions, ranging from 280 to 542 per 100,000. In all regions, the peak season occurred in February-April, but the season start varied, with first cases observed in October in the eastern region and December in the northern region. Genotypes identified differed between the regions: G1[P8] was most prevalent in all regions (77%), while the most varied pattern was observed in the western region, with G1[P8] observed in 61%, G4[P8] in 13%, G9[P8] in 10%, G2[P4] in 8%, and G3[P8] in 8% of the children. The median age of hospitalized children was 14 months and the median total duration of diarrhoea was 6.9 days. Sixty-eight percent reported a temperature > 38.5°C upon admission. Complications occurred in > 10% of the children, with hypertonic dehydration (32/604) and seizures (10/604) occurring most frequently. CONCLUSIONS: Rotaviruses may cause severe febrile acute gastroenteritis leading to dehydration requiring acute rehydration in hospital. In addition, further complications occurred in > 10% of hospitalized children.

Waning infant pertussis during COVID-19 pandemic.

Measures to reduce the spread of COVID-19 have been associated with reduction in other respiratory infections. Results of a national Swedish cohort study of infant pertussis during April 2020-September 2021 were compared with those during January 2014-March 2020. The number of pertussis cases decreased significantly during the COVID-19 pandemic, from an average of 21 infant cases per quarter of a year before the pandemic to an average of 1 case per quarter during the pandemic. Swedish strategies to mitigate the spread of COVID-19 seem to have had an impact on pertussis incidence in infants.

Vaccine allergy: evidence to consider for COVID-19 vaccines.

PURPOSE OF REVIEW: Whereas the COVID-19 pandemic has changed our lives worldwide, we hope that vaccination can combat the disease. We propose how to evaluate suspected severe allergic reactions to the vaccines so that as many as possible may be safely vaccinated. RECENT FINDINGS: Rare cases of severe allergic reactions after COVID-19 vaccination have been observed, seemingly at a higher frequency than for other vaccines. Few excipients are likely to have caused these reactions. IgE-mediated reactions to polyethylene glycol (PEG) and its derivatives are the most suspected, albeit hitherto unproven, causes. We suggest to make a diagnosis based on skin tests with PEG and PEG derivatives and that these be considered in relation to the decisions required before the first and the second vaccine dose. A vaccine without these excipients is available, but published data about its side effects are limited. SUMMARY: The underlying immunological mechanisms of the rare severe allergic reactions to the COVID-19 vaccines are poorly understood and need to be clarified. Identifying those who have an undiagnosed allergy to PEG and PEG derivatives is crucial before vaccination, and these substances are found in laxatives, cosmetics and in 30% of all our medications today.

Cost-effectiveness of pneumococcal vaccination for elderly in Sweden.

INTRODUCTION: The aim was to assess cost-effectiveness of including pneumococcal vaccination for elderly in a national vaccination programme in Sweden, comparing health-effects and costs of pneumococcal related diseases with a vaccination programme versus no vaccination. METHOD: We used a single-cohort deterministic decision-tree model to simulate the current burden of pneumococcal disease in Sweden. The model accounted for invasive pneumococcal disease (IPD) and pneumonia caused by pneumococci. Costs included in the analysis were those incurred when treating pneumococcal disease, and acquisition and administration of the vaccine. Health effects were measured as quality-adjusted life years (QALY). The time-horizon was set to five years, both effects and costs were discounted by 3% annually. Health-effects and costs were accumulated over the time-horizon and used to create an incremental cost-effectiveness ratio. The 23-valent polysaccharide vaccine (PPV23) was used in the base-case analysis. The 13-valent pneumococcal conjugate vaccine PCV13 was included in sensitivity analyses. RESULTS: A vaccination programme using PPV23 would reduce the burden of pneumococcal related disease significantly, both when vaccinating a 65-year-old cohort and a 75-year-old cohort. IPD would decrease by 30% in the 65-year-old cohort, and by 29% in the 75-year-old cohort. The corresponding figures for CAP (communicable acquired pneumonia) are 19% and 15%. The cost per gained QALY was estimated to EUR 94,000 for vaccinating 65-year-olds and EUR 29,500 for 75-year-olds. With one dose PCV13 given instead of PPV23, the cost per gained QALY would increase by around 400% for both cohorts. The results were robust in sensitivity analyses. CONCLUSION: Introducing a vaccination programme against pneumococcal disease for 65-year-olds in Sweden is unlikely to be cost-effective, whereas it for 75 year-olds and using PPV23 can be considered good value for money. Our model indicates that vaccine price needs to be reduced by 55% for vaccination of 65-year-olds to be cost-effective, given a threshold of EUR 50,000.

Safety and immunogenicity of the live attenuated intranasal pertussis vaccine BPZE1: a phase 1b, double-blind, randomised, placebo-controlled dose-escalation study.

BACKGROUND: Long-term protection and herd immunity induced by existing pertussis vaccines are imperfect, and a need therefore exists to develop new pertussis vaccines. This study aimed to investigate the safety, colonisation, and immunogenicity of the new, live attenuated pertussis vaccine, BPZE1, when given intranasally. METHODS: This phase 1b, double-blind, randomised, placebo-controlled, dose-escalation study was done at the phase 1 unit, Karolinska Trial Alliance, Karolinska University Hospital, Stockholm, Sweden. Healthy adults (18-32 years) were screened and included sequentially into three groups of increasing BPZE1 dose strength (107 colony-forming units [CFU], 108 CFU, and 109 CFU), and were randomly assigned (3:1 within each group) to receive vaccine or placebo. Vaccine and placebo were administered in phosphate-buffered saline contained 5% saccharose as 0·4 mL in each nostril. The primary outcome was solicited and unsolicited adverse events between day 0 and day 28. The analysis included all randomised participants who received a vaccine dose. Colonisation with BPZE1 was determined by repeatedly culturing nasopharyngeal aspirates at day 4, day 7, day 11, day 14, day 21, and day 28 after vaccination. Immunogenicity, as serum IgG and IgA responses were assessed at day 0, day 7, day 14, day 21, day 28, 6 months, and 12 months after vaccination. This trial is registered at Clinicaltrials.gov, NCT02453048. FINDINGS: Between Sept 1, 2015, and Feb 3, 2016, 120 participants were assessed for eligibility, 48 of whom were enrolled and randomly assigned (3:1) to receive vaccine or placebo, with 12 participants each in a low-dose, medium-dose, and high-dose vaccine group. Adverse events between day 0 and day 28 were reported by one (8%, 95% CI 0-39) of 12 participants in both the placebo and low-dose groups, and two (17%; 2-48) of 12 participants in both the medium-dose and high-dose groups, including cough of grade 2 or more, oropharyngeal pain, and rhinorrhoea and nasal congestion. During this time, none of the participants experienced any spasmodic cough, difficulties in breathing, or adverse events following immunisation concerning vital signs. The tested doses of BPZE1 or placebo were well tolerated, with no apparent difference in solicited or unsolicited adverse events following immunisation between groups. Colonisation at least once after vaccination was observed in 29 (81%; 68-93) of 36 vaccinated participants. The tested vaccine doses were immunogenic, with increases in serum IgG and IgA titres against the four B pertussis antigens from baseline to 12 months. INTERPRETATION: The tested vaccine was safe, induced a high colonisation rate in an adult population, and was immunogenic at all doses. These findings justify further clinical development of BPZE1 to ultimately be used as a priming vaccine for neonates or a booster vaccine for adolescents and adults, or both. FUNDING: ILiAD Biotechnologies.

Immunogenicity and reactogenicity of two diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b vaccines administered at 3, 5 and 11-12 months of age.

The use of combination vaccines in the routine childhood program reduces distress to the recipients and is likely to improve uptake rates and timeliness of vaccination but requires careful evaluation and surveillance. The aim of this study was to evaluate the immunogenicity and reactogenicity of two commercial diphtheria-tetanus- acellular pertussis-hepatitis b-inactivated polio virus-Haemophilus influenzae type b (DTaP-HBV-IPV/Hib) combination vaccines when administered to infants at 3, 5 and 11-12 months of age. A total of 494 infants were randomized to receive three doses of either Infanrix hexa (GlaxoSmithKline Biologicals; N = 246) or Hexavac (Sanofi Pasteur MSD; N = 248) in 10 centers in Italy, Finland and Sweden. After the third dose, antibodies to diphtheria, tetanus, polio and Hib were at the protective level in nearly all infants in both groups whereas the proportion of subjects who had achieved the protective concentration of >or=10 mIU/ml to hepatitis B surface antigen was 99.1% (95% CI 96.7-99.9) in the Infanrix hexa group as compared to 94.4% (95% CI 90.4.97.1) in the Hexavac group. Antibody titers to all three polio antigens were highest in Italy and lowest in Finland. Clinically relevant general reactions (such as fever of >39.5 degrees C) were mostly reported in less than 5% of the vaccinees. Three doses of DTaP-HBV-IPV/Hib combination vaccines produced sufficient immune responses in nearly all vaccinees.

Impact on affected families and society of severe rotavirus infections in Swedish children assessed in a prospective cohort study.

BACKGROUND: Few prospective cohort studies have estimated the overall impact of severe rotavirus gastroenteritis (RVGE) leading to hospitalization on families and society. We assessed human and economic resources needed to care for an affected average child aged <5 years in Sweden. METHODS: The study was conducted in Astrid Lindgren Children's Hospital which serves approximately 14% of all Swedish children <5 years of age. All children admitted with acute gastroenteritis in the study period were tested for rotavirus. Health care consumption was collected prospectively and publically available unit costs used to calculate direct costs. Non-medical and indirect costs were collected in interviews with families using a standardized questionnaire during the hospital stay and approximately 14 days post-discharge. RESULTS: 144/206 children (70%) with laboratory-confirmed RVGE were included. The median age was 14 months. The average total cost per hospitalized child was €3894, of which €2169 (56%) was due to direct healthcare-related costs (including Emergency Department visits and in-patient care), €104 (2%) to non-medical direct costs and €1621 (42%) to indirect costs due to productivity loss. Carers of children with severe RVGE were absent from work on average five days per study child: four days during hospitalization of affected child and one day due to gastroenteritis in the carer. CONCLUSIONS: Costs for RVGE are dominated by direct costs which are similar to some other countries in Europe, but indirect costs due to productivity loss are also important, and should be considered in decisions to introduce rotavirus vaccines into national vaccination programmes.

Preterm Children Have Higher Risk Than Full-term Children of Invasive Pneumococcal Disease During the First 2 Years of Life.

BACKGROUND: A few previous studies have reported an increased risk of invasive pneumococcal disease (IPD) in children born preterm, but this has not been investigated in a cohort study. The impact of 7-valent pneumococcal conjugate vaccine (PCV7) on IPD incidence rates in preterm children is unknown. METHODS: Data from the Medical Birth Registry of Norway (2002-2010) were linked to other national registries. In total, 628,138 children were included in our study and followed until 2 years of age. Incidence rate ratios (IRRs) and confidence intervals (CIs) were estimated with Poisson regression. RESULTS: We identified 411 cases of IPD. We observed higher rates of IPD in preterm than in full-term children for the intervals 0-23, 0-5 and 6-23 months of age, IRRs = 1.83 (95 % CI: 1.36-2.47), 2.95 (95% CI: 1.44-6.06) and 1.69 (95% CI: 1.22-2.34), respectively. The risk for IPD was reduced in the PCV7-period (2007-2010) compared with that of the pre PCV7-period (2002-2005) for children 6-23 months of age, IRRs = 0.20 (95% CI: 0.08-0.53) for preterm children and 0.28 (95% CI: 0.21-0.38) for full-term children, but not for those 0-5 months of age, IRRs = 1.94 (95% CI: 0.48-7.80) and 0.71 (95% CI: 0.38-1.33). CONCLUSIONS: Preterm children had an increased risk of IPD. After introduction of PCV7, the rate of IPD was reduced among preterm and full-term children from 6 months of age.

Risk of Pertussis in Relation to Degree of Prematurity in Children Less Than 2 Years of Age.

BACKGROUND: A few previous studies reported increased risk of pertussis in children with birth weight less than 2500 g. The risk of pertussis by degree of prematurity has not been determined in a cohort study. The vaccine effectiveness (VE) against reported pertussis in preterm infants is unknown. METHODS: Data were obtained from the Medical Birth Registry of Norway (1998-2010) and linked to other national registries. In total, 713,166 children were included in our study and followed until 2 years of age. Incidence rate ratios (IRRs) and confidence intervals (CIs) were estimated with Poisson regression. RESULTS: We identified 999 reported cases of pertussis. We observed a higher rate of reported pertussis in preterm than in full-term infants, IRR = 1.65 (95% CI: 1.32-2.07). Compared to full-term infants, the risk of reported pertussis in infants born at gestational age (GA) 35-36, 32-34 and 23-27 weeks were higher [IRRs = 1.49 (95% CI: 1.11-2.01), 1.63 (95% CI: 1.06-2.51) and 4.49 (95% CI: 2.33-8.67), respectively]. Moreover, preterm infants had a higher rate of pertussis-related hospitalization than full-term infants [IRR = 1.99 (95% CI: 1.47-2.71)]. The VE against reported pertussis for the third dose was 88.8% (95% CI: 84.3-92.0) in full-term infants and 93.0% (95% CI: 85.8-96.5) in preterm infants. CONCLUSIONS: In this cohort study, preterm infants including those born at GA 35 and 36 weeks had increased risk of reported pertussis. The VE was similar in preterm and full-term infants.

Changes in seroprevalence to four herpesviruses over 30 years in Swedish children aged 9-12 years.

BACKGROUND: Changing social conditions and life-styles in Sweden may have affected the spread of varicella-zoster virus (VZV), herpes simplex virus (HSV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). OBJECTIVES: To study possible changes over 30 years in prevalence of antibodies against VZV, HSV, CMV, and EBV in Swedish children, using modern serological methods. STUDY DESIGN: Serum samples from 819 Swedish children who were 9-12 years old in 1967-1968, in 1977-1978 (two cohorts), and in 1997, respectively, were examined. IgG antibodies against VZV, HSV, and CMV were measured by well validated enzyme-linked immunosorbent assays and against EBV by indirect immunoflourescense. RESULTS: The seropositivity for VZV for 9-12 years old children was 50% in 1967-1968, 74-82% in 1977-1978, and 98% in 1997. The corresponding figures were 31%, 53%, 50%, and 58% for CMV, 35%, 35%, 32%, and 38% for HSV, and 64% in 1967-1968 and in 1977-1978 (both cohorts), and 62% in 1997 for EBV. CONCLUSIONS: The seroprevalence for VZV increased significantly from 1967-1968 to 1997, and there was also a significant but smaller increase in the CMV seroprevalence, while seroprevalence to HSV and EBV remained relatively stable.

Is there a need for a new generation of vaccines against pertussis?

Current vaccines against pertussis have proved their safety and efficacy in large-scale clinical trials. Despite high vaccination coverage, pertussis is still prevalent and increasing, probably as a result of waning immunity. Addition of new antigens, such as adenylate cyclase, to current vaccines might improve some aspects of the immune response to vaccination, but are unlikely to significantly increase the duration of protection. Intranasal, oral and DNA pertussis vaccines are some way from clinical development, although one live attenuated, intranasal pertussis vaccine may soon enter Phase I trials. In the meantime, the potential of currently available safe and efficacious pertussis vaccines should be maximised. Rationalisation of pertussis boosters in childhood and introduction of widespread repeat booster vaccination in adolescents and adults would already lessen disease prevalence and morbidity among susceptible infants.

Guillain-Barré syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccines: a multinational self-controlled case series in Europe.

BACKGROUND: The risk of Guillain-Barré syndrome (GBS) following the United States' 1976 swine flu vaccination campaign in the USA led to enhanced active surveillance during the pandemic influenza (A(H1N1)pdm09) immunization campaign. This study aimed to estimate the risk of GBS following influenza A(H1N1)pdm09 vaccination. METHODS: A self-controlled case series (SCCS) analysis was performed in Denmark, Finland, France, Netherlands, Norway, Sweden, and the United Kingdom. Information was collected according to a common protocol and standardised procedures. Cases classified at levels 1-4a of the Brighton Collaboration case definition were included. The risk window was 42 days starting the day after vaccination. Conditional Poisson regression and pooled random effects models estimated adjusted relative incidences (RI). Pseudo likelihood and vaccinated-only methods addressed the potential contraindication for vaccination following GBS. RESULTS: Three hundred and three (303) GBS and Miller Fisher syndrome cases were included. Ninety-nine (99) were exposed to A(H1N1)pdm09 vaccination, which was most frequently adjuvanted (Pandemrix and Focetria). The unadjusted pooled RI for A(H1N1)pdm09 vaccination and GBS was 3.5 (95% Confidence Interval (CI): 2.2-5.5), based on all countries. This lowered to 2.0 (95% CI: 1.2-3.1) after adjustment for calendartime and to 1.9 (95% CI: 1.1-3.2) when we accounted for contra-indications. In a subset (Netherlands, Norway, and United Kingdom) we further adjusted for other confounders and there the RI decreased from 1.7 (adjusted for calendar month) to 1.4 (95% CI: 0.7-2.8), which is the main finding. CONCLUSION: This study illustrates the potential of conducting European collaborative vaccine safety studies. The main, fully adjusted analysis, showed that the RI of GBS was not significantly elevated after influenza A(H1N1)pdm09 vaccination (RI = 1.4 (95% CI: 0.7-2.8). Based on the upper limits of the pooled estimate we can rule out with 95% certainty that the number of excess GBS cases after influenza A(H1N1)pdm09 vaccination would be more than 3 per million vaccinated.