Hanna Nohynek

AS03 Adjuvanted AH1N1 Vaccine Associated with an Abrupt Increase in the Incidence of Childhood Narcolepsy in Finland

Background Narcolepsy is a chronic sleep disorder with strong genetic predisposition causing excessive daytime sleepiness and cataplexy. A sudden increase in childhood narcolepsy was observed in Finland soon after pandemic influenza epidemic and vaccination with ASO3-adjuvanted Pandemrix. No increase was observed in other age groups. Methods Retrospective cohort study. From January 1, 2009 to December 31, 2010 we retrospectively followed the cohort of all children living in Finland and born from January 1991 through December 2005. Vaccination data of the whole population was obtained from primary health care databases. All new cases with assigned ICD-10 code of narcolepsy were identified and the medical records reviewed by two experts to classify the diagnosis of narcolepsy according to the Brighton collaboration criteria. Onset of narcolepsy was defined as the first documented contact to health care because of excessive daytime sleepiness. The primary follow-up period was restricted to August 15, 2010, the day before media attention on post-vaccination narcolepsy started. Findings Vaccination coverage in the cohort was 75%. Of the 67 confirmed cases of narcolepsy, 46 vaccinated and 7 unvaccinated were included in the primary analysis. The incidence of narcolepsy was 9.0 in the vaccinated as compared to 0.7/100,000 person years in the unvaccinated individuals, the rate ratio being 12.7 (95% confidence interval 6.1–30.8). The vaccine-attributable risk of developing narcolepsy was 1∶16,000 vaccinated 4 to 19-year-olds (95% confidence interval 1∶13,000–1∶21,000). Conclusions Pandemrix vaccine contributed to the onset of narcolepsy among those 4 to 19 years old during the pandemic influenza in 2009–2010 in Finland. Further studies are needed to determine whether this observation exists in other populations and to elucidate potential underlying immunological mechanism. The role of the adjuvant in particular warrants further research before drawing conclusions about the use of adjuvanted pandemic vaccines in the future.

Pneumococcal vaccination in developing countries

WHO estimates that about 1·6 million people, including up to 1 million children under 5 years old, die every year of pneumococcal pneumonia, meningitis, and sepsis.1 In populations with high child-mortality rates, pneumonia is the leading infectious cause of mortality and accounts for about 20–25% of all child deaths.2 In these populations, Streptococcus pneumoniae is identified consistently as the leading cause of bacterial pneumonia, and pneumococcal bacteraemia is an important cause of child mortality. 3, 4 and 5 HIV infection increases risk for pneumococcal disease 20–40-fold, and antibiotic resistance makes treatment difficult and expensive. 6 Thus pneumococcal disease is a major global-health issue.

Efficacy of an 11-valent pneumococcal conjugate vaccine against radiologically confirmed pneumonia among children less than 2 years of age in the Philippines: a randomized, double-blind, placebo-controlled trial.

Background: Pneumococcus is a leading cause of childhood pneumonia worldwide. Pneumococcal conjugate vaccines (PCV) have demonstrated efficacy against childhood invasive pneumococcal disease (IPD) and pneumonia in the United States and Africa. No information is available from Asia on the impact of PCV on childhood pneumonia. Methods: We conducted a randomized, placebo-controlled, double-blind trial in Bohol, the Philippines (ISRCTN 62323832). Children 6 weeks to <6 months of age were randomly allocated to receive 3 doses of either an 11-valent PCV (11PCV, sanofi pasteur, Lyon, France) or a saline placebo, with a minimum interval of 4 weeks between doses to determine vaccine efficacy (VE) against the primary outcome of a child experiencing first episode of community-acquired radiologically defined pneumonia in the first 2 years of life. Secondary end points were clinical pneumonia, IPD, safety, and immunogenicity. Results: Twelve thousand one hundred ninety-one children were enrolled. By per protocol (PP) analysis, 93 of 6013 fully vaccinated 11PCV recipient children had a first episode of radiologic pneumonia compared with 120 of 6018 placebo recipients. VE against radiologically defined pneumonia for the PP cohort of children 3 to 23 months old was 22.9% (95% CI: −1.1, 41.2; P = 0.06), for the prespecified subgroups of children 3 to 11 months of age, 34.0% (95% CI: 4.8, 54.3; P = 0.02), and of those 12 to 23 months old, 2.7% (95% CI: −43.5, 34.0; P = 0.88). By intent-to-treat (ITT) analysis, 119 of 6097 11PCV recipient children had an episode of radiologic pneumonia compared with 141 of 6094 placebo recipients. VE against radiologic pneumonia for the ITT cohort of children <2 years old was 16.0% (95% CI −7.3, 34.2; P = 0.16), for a subgroup of children <12 months of age, 19.8% (95% CI: −8.8, 40.8; P = 0.15). VE against clinical pneumonia by PP was not significant (VE 0.1%; 95% CI −9.4, 8.7; P = 0.99). IPD was rare: only 3 cases of IPD due to vaccine serotypes were observed during the study. 11PCV was immunogenic and well tolerated. Among 11PCV recipients, a small excess of serious adverse respiratory events was observed in the first 28 days after the first and second dose of vaccine, and of nonrespiratory events after the first dose. An excess of pneumonia episodes in 11PCV recipients in the month following the second dose of vaccination was the principal reason for lower VE by ITT analysis than by PP analysis. Conclusions: In PP analysis, a 22.9% reduction of community-acquired radiologically confirmed pneumonia in children younger than 2 years of age in the 11-valent tetanus-diphtheria toxoid-conjugated PCV vaccinated group was observed; a reduction similar as observed in other PCV trials. We could not demonstrate any VE against clinical pneumonia. Our finding confirms for the first time that in a low-income, low-mortality developing country in Asia, at least one-fifth of radiologically confirmed pneumonia is caused by pneumococcus, and thus preventable by PCV. Whether PCV should be included in national program in such settings, however, depends on careful country specific disease burden measurement and cost-effectiveness calculation.

Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2.

Similarity between influenza nucleoprotein and hypocretin receptor 2 may trigger vaccine-associated narcolepsy. Immunological mistaken identity New reports of narcolepsy increased after the vaccination campaign against the 2009 A(H1N1) influenza pandemic in some countries but not others. Now Ahmed et al. examine differences between the vaccines used and find a potential mechanistic explanation for the vaccine-specific effect. They found a peptide in influenza nucleopeptide A that shared protein residues with human hypocretin receptor 2, which has been linked to narcolepsy. The vaccine used in unaffected countries contained less influenza nucleoprotein. Indeed, patients with putative vaccine-associated narcolepsy produced antibodies that cross-reacted to both the influenza and the hypocretin receptor 2 epitopes. Although these data do not demonstrate causation, they provide a possible explanation for the association of this particular influenza vaccination with increased reports of narcolepsy. The sleep disorder narcolepsy is linked to the HLA-DQB1*0602 haplotype and dysregulation of the hypocretin ligand-hypocretin receptor pathway. Narcolepsy was associated with Pandemrix vaccination (an adjuvanted, influenza pandemic vaccine) and also with infection by influenza virus during the 2009 A(H1N1) influenza pandemic. In contrast, very few cases were reported after Focetria vaccination (a differently manufactured adjuvanted influenza pandemic vaccine). We hypothesized that differences between these vaccines (which are derived from inactivated influenza viral proteins) explain the association of narcolepsy with Pandemrix-vaccinated subjects. A mimic peptide was identified from a surface-exposed region of influenza nucleoprotein A that shared protein residues in common with a fragment of the first extracellular domain of hypocretin receptor 2. A significant proportion of sera from HLA-DQB1*0602 haplotype–positive narcoleptic Finnish patients with a history of Pandemrix vaccination (vaccine-associated narcolepsy) contained antibodies to hypocretin receptor 2 compared to sera from nonnarcoleptic individuals with either 2009 A(H1N1) pandemic influenza infection or history of Focetria vaccination. Antibodies from vaccine-associated narcolepsy sera cross-reacted with both influenza nucleoprotein and hypocretin receptor 2, which was demonstrated by competitive binding using 21-mer peptide (containing the identified nucleoprotein mimic) and 55-mer recombinant peptide (first extracellular domain of hypocretin receptor 2) on cell lines expressing human hypocretin receptor 2. Mass spectrometry indicated that relative to Pandemrix, Focetria contained 72.7% less influenza nucleoprotein. In accord, no durable antibody responses to nucleoprotein were detected in sera from Focetria-vaccinated nonnarcoleptic subjects. Thus, differences in vaccine nucleoprotein content and respective immune response may explain the narcolepsy association with Pandemrix.

Erythrocyte sedimentation rate, white blood cell count and serum C-reactive protein in assessing etiologic diagnosis of acute lower respiratory infections in children

The clinical signs, symptoms and host responses (erythrocyte sedimentation rate, white blood cell count and C-reactive protein) were studied to distinguish bacterial from viral acute lower respiratory infection (ALRI) in 121 children hospitalized for ALRI. Etiologic diagnosis was based on blood culture, antibody assays and antigen detection. Children with bacterial involvement only were older than those with viral involvement alone (mean, 5.1 vs. 2.5 years), and their duration of respiratory symptoms had lasted longer (mean, 4.6 vs. 3.3 days). Children with unknown etiology had a shorter duration of fever before hospitalization than those with etiology identified with the methods used (mean, 1.6 vs. 2.9 days). The host response ranged widely within etiologic groups. The mean erythrocyte sedimentation rate did not differ significantly between the bacterial and viral ALRI (38 vs. 28 mm/hour); neither did white blood cell count (13.2 vs. 13.6 x 10(9)/liter) or C-reactive protein (68 vs. 49 mg/liter). No combination of clinical signs and host responses or any cutoff values could be shown to differentiate reliably bacterial from viral ALRI.

Safety of immunization during pregnancy: A review of the evidence of selected inactivated and live attenuated vaccines

Vaccine-preventable infectious diseases are responsible for significant maternal, neonatal, and young infant morbidity and mortality. While there is emerging scientific evidence, as well as theoretical considerations, indicating that certain vaccines are safe for pregnant women and fetuses, policy formulation is challenging because of perceived potential risks to the fetus. This report presents an overview of available evidence on pregnant women vaccination safety monitoring in pregnant women, from both published literature and ongoing surveillance programs. Safety data were reviewed for vaccines against diseases which increase morbidity in pregnant women, their fetus or infant as well as vaccines which are used in mass vaccination campaigns against diseases. They include inactivated seasonal and pandemic influenza, mono- and combined meningococcal polysaccharide and conjugated vaccines, tetanus toxoid and acellular pertussis combination vaccines, as well as monovalent or combined rubella, oral poliomyelitis virus and yellow fever vaccines. No evidence of adverse pregnancy outcomes has been identified from immunization of pregnant women with these vaccines.

Bacterial antibody assays in the diagnosis of acute lower respiratory tract infection in children

Bacterial antibodies were studied in acute, intermediate and convalescent phase sera (mean duration from first to last sample 36 days) of 121 children hospitalized for acute lower respiratory tract infection. Antibody responses were observed in 45% of all cases and in 29% of the 21 children < 1 year old. A total of 15 responses to Streptococcus pneumoniae (pneumolysin), 20 to Haemophilus influenzae, 9 to Moraxella catarrhalis, 3 to chlamydiae and 8 to Mycoplasma pneumoniae were found. In 79 patients with 4 consecutive samples available, 52% of the 31 responses were measurable within 5 days from admission. Overall the responses were not associated with upper respiratory tract bacterial findings or acute otitis media. Significantly more responses were found in the 121 children with acute lower respiratory tract infection than in healthy controls (P < 0.007). We conclude that bacterial antibody assays provide a useful tool in the study of the etiology of acute lower respiratory tract infection in young children, even if the interval between paired serum samples is short.

Nasopharyngeal colonization: a target for pneumococcal vaccination

The pneumococcal conjugate vaccine (PCV), licensed in 2000, is highly efficient in preventing serious disease caused by serotypes in the vaccine and also prevents symptomless colonization of the nasopharynx. Prevention of this first step in the infection cycle has important consequences: it reduces chances of spread of the infection and indirectly protects from disease. Through these indirect effects, the protection afforded by the vaccine extends to the whole population, including those not vaccinated (herd immunity). Already now, after 5 years of wide use of PCV for infant immunization in the USA, more cases are prevented through the indirect effects than by vaccine-induced immunity in those vaccinated. The extended protection increases the cost–effectiveness of PCV and should clearly encourage its use in poorly resourced countries. However, the accumulated experience also shows that the herd immunity, due to PCV, is partly offset by replacement of the vaccine serotypes by other, nonvaccine serotypes. Owing to the general reduced virulence of the latter, this has only had a modest effect on disease, but the possibility of more virulent nonvaccine serotypes arising cannot be ignored and should be the focus of continued surveillance.

Pneumococcal vaccination policy in Europe.

Infection due to Streptococcus pneumoniae (Pneumococcus) (Pnc) is an important cause of invasive clinical manifestations such as meningitis, septicaemia and pneumonia, particularly in young children and the elderly. A 23-valent polysaccharide Pnc vaccine (PPV) has been available for many years and a 7-valent conjugate Pnc vaccine (PCV) has been licensed since 2001 in Europe. As part of a European Union (EU) funded project on pneumococcal disease (Pnc-EURO), a questionnaire was distributed to all 15 EU member states, Switzerland, Norway and the 10 accession countries in 2003 to ascertain current pneumococcal vaccination policy. Twenty three of the 27 target countries, constituting the current European Union (plus Norway and Switzerland), completed the questionnaire. PPV was licensed in 22 of the 23 responding countries and was in the official recommendations of 21. In all the 20/21 countries for which information was available, risk groups at higher risk of infection were targeted. The number of risk groups targeted ranged from one to 12. At least 17 countries recommend that PPV be administered to all those >65 years of age (in three countries, to those over 60 years of age). Thirteen countries had developed national recommendations for PCV in 2003. No country recommended mass infant immunisation at that time, but rather targeted specific risk groups (between 1 and 11), particularly children with asplenia (n=13) and HIV infection (n=12). PCV use was restricted to children under two years of age in seven countries, and in four countries to children under five years of age. Future decisions on use of pneumococcal vaccines in Europe will be decided on the basis of several factors including: local disease burden; the predicted impact of any universal programme, particularly the importance of serotype replacement and herd immunity (indirect protection to the unvaccinated population); the effectiveness of reduced dose schedules, and vaccine cost. Indeed, at least one country, Luxembourg, has since implemented a universal infant PCV immunisation policy.

Antigenic Differences between AS03 Adjuvanted Influenza A (H1N1) Pandemic Vaccines: Implications for Pandemrix-Associated Narcolepsy Risk

Background Narcolepsy results from immune-mediated destruction of hypocretin secreting neurons in hypothalamus, however the triggers and disease mechanisms are poorly understood. Vaccine-attributable risk of narcolepsy reported so far with the AS03 adjuvanted H1N1 vaccination Pandemrix has been manifold compared to the AS03 adjuvanted Arepanrix, which contained differently produced H1N1 viral antigen preparation. Hence, antigenic differences and antibody response to these vaccines were investigated. Methods and Findings Increased circulating IgG-antibody levels to Pandemrix H1N1 antigen were found in 47 children with Pandemrix-associated narcolepsy when compared to 57 healthy children vaccinated with Pandemrix. H1N1 antigen of Arepanrix inhibited poorly these antibodies indicating antigenic difference between Arepanrix and Pandemrix. High-resolution gel electrophoresis quantitation and mass spectrometry identification analyses revealed higher amounts of structurally altered viral nucleoprotein (NP) in Pandemrix. Increased antibody levels to hemagglutinin (HA) and NP, particularly to detergent treated NP, was seen in narcolepsy. Higher levels of antibodies to NP were found in children with DQB1*06∶02 risk allele and in DQB1*06∶02 transgenic mice immunized with Pandemrix when compared to controls. Conclusions This work identified 1) higher amounts of structurally altered viral NP in Pandemrix than in Arepanrix, 2) detergent-induced antigenic changes of viral NP, that are recognized by antibodies from children with narcolepsy, and 3) increased antibody response to NP in association of DQB1*06∶02 risk allele of narcolepsy. These findings provide a link between Pandemrix and narcolepsy. Although detailed mechanisms of Pandemrix in narcolepsy remain elusive, our results move the focus from adjuvant(s) onto the H1N1 viral proteins.