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Background: In 2009, a new influenza A H1N1 virus emerged causing a global pandemic. A range of monovalent influenza A H1N1pdm09 vaccines with or without adjuvants were developed. After the mass vaccination campaigns safety concerns related to H1N1pdm09 vaccines were reported. More than a decade later, reported AEFIs are still under scrutiny. We performed a systematic review aiming to synthesize the evidence on the safety of the H1N1pdm09 vaccines on reported outcomes from existing systematic reviews., Methods: Four electronic databases, PubMed, EMBASE, Epistimonikos and the Cochrane Database of Systematic Reviews were searched for articles on H1N1pdm09 vaccination published from 2009 to January 2021. Systematic reviews assessing short- or long-term adverse events after H1N1pdm09 vaccination were considered for inclusion. Data was extracted from all selected reviews. Outcomes were grouped and results from each included review were presented narratively and in tables., Results: 16 systematic reviews met the inclusion criteria. Reported outcomes were short-term events (3 reviews), fetal/pregnancy outcomes (8 reviews), Guillain-Barré syndrome (GBS) (4 reviews), narcolepsy (2 reviews) demyelinating diseases (1 review based on one study only) and inflammatory bowel disease (IBD) (1 review). Short-term serious adverse events were rare, 3 cases amongst 16725 subjects in 18 randomized controlled trials (0.018%). No deaths were reported. The risks of local events were generally higher for adjuvanted vaccines as compared to unadjuvanted vaccines. Maternal H1N1pdm09 vaccination in any trimester was not associated with an increase in preterm birth, small for gestational age, congenital malformations or fetal death. For GBS, results were conflicting. The main systematic review on narcolepsy found a 5-14-fold increased risk in children, and a 2-7- fold increased risk in adults after vaccination with Pandemrix. The attributable risk of narcolepsy one year after vaccination was 1 case per 18 400 vaccine doses in children/adolescents, and 1 case per 181 000 vaccine doses in adults., Conclusion: Adjuvanted vaccines had more local but not serious adverse events compared to unadjuvanted vaccines. Vaccination with Pandemrix was strongly associated with narcolepsy, particularly in children. No increased risks of pregnancy outcomes were seen after pandemic vaccination. The findings on GBS were inconclusive., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Juvet, Robertson, Laake, Mjaaland and Trogstad.)

Background: Reliable exposure information is crucial for assessing health outcomes of influenza infection and vaccination. Current serological methods are unable to distinguish between anti-hemagglutinin (HA) antibodies induced by infection or vaccination., Objectives: We aimed to explore an alternative method for differentiating influenza infection and vaccination., Methods: Sera from animals inoculated with influenza viruses or purified H1N1pdm09 HA were obtained. Human samples were selected from a pregnancy cohort established during the 2009 H1N1 pandemic. Unvaccinated, laboratory-confirmed cases (N = 18), vaccinated cases without influenza-like-illness (N = 18) and uninfected, unvaccinated controls (N = 18) were identified based on exposure data from questionnaires, national registries and maternal hemagglutination inhibition (HI) titres at delivery. Animal and human samples were tested for antibodies against the non-structural protein 1 (NS1) and HA from H1N1pdm09, using a Luciferase Immunoprecipitation System (LIPS)., Results: Anti-NS1 H1N1pdm09 antibodies were detected in sera from experimentally infected, but not from vaccinated, animals. Anti-HA H1N1pdm09 antibodies were detectable after either of these exposures. In human samples, 28% of individuals with laboratory-confirmed influenza were seropositive for H1N1pdm09 NS1, whereas vaccinated cases and controls were seronegative. There was a trend for H1N1pdm09 NS1 seropositive cases reporting more severe and longer duration of symptomatic illness than seronegative cases. Anti-HA H1N1pdm09 antibodies were detected in all cases and in 61% of controls., Conclusions: The LIPS method could differentiate between sera from experimentally infected and vaccinated animals. However, in human samples obtained more than 6 months after the pandemic, LIPS was specific, but not sufficiently sensitive for ascertaining cases by exposure., (© 2019 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Patients with multiple sclerosis (MS) are at increased risk of infections and related worsening of neurological function. Influenza infection has been associated with increased risk of various neurological complications. We conducted a population-based registry study to investigate the risk of acute hospitalization of MS patients in relation to influenza infection or pandemic vaccination in Norway. The entire Norwegian population in the years 2008-2014 was defined as our study population (N = 5,219,296). Information on MS diagnosis, influenza infection and vaccination were provided by Norwegian national registries. The self-controlled case series method was used to estimate incidence rate ratios (IRRs) with 95% confidence intervals (95% CI) in defined risk periods. 6755 MS patients were identified during the study period. Average age at first registration of an MS diagnosis was 51.8 years among men and 49.9 years among females (66.9%). The IRR for emergency hospitalization among MS patients the first week after an influenza diagnosis was 3.4 (95% CI 2.4-4.8). The IRR was 5.6 (95% CI 2.7-11.3) after pandemic influenza, and 4.8 (95% CI 3.1-7.4) after seasonal influenza. Pandemic vaccination did not influence risk of hospitalization [IRR within the first week: 0.7 (95% CI 0.5-1.0)]. Among MS patients, influenza infection was associated with increased risk for acute hospitalization while no increased risk was observed after pandemic vaccination. Influenza vaccination could prevent worsening of MS-related symptoms as well as risk of hospitalization.

Previous studies of fetal death with maternal influenza have been inconsistent. We explored the effect of maternal influenza-like illness (ILI) in pregnancy on the risk of fetal death, distinguishing between diagnoses during regular influenza seasons and the 2009/2010 pandemic and between trimesters of ILI. We used birth records from the Medical Birth Registry of Norway to identify fetal deaths after the first trimester in singleton pregnancies (2006-2013). The Norwegian Directorate of Health provided dates of clinical influenza diagnoses by primary-health-care providers, whereas dates of laboratory-confirmed influenza A (H1N1) diagnoses were provided by the Norwegian Surveillance System for Communicable Diseases. We obtained dates and types of influenza vaccinations from the Norwegian Immunisation Registry. Cox proportional-hazards regression models were fitted to estimate hazard ratios (HRs) of fetal death, with associated 95% confidence intervals (CIs), comparing women with and without an ILI diagnosis in pregnancy. There were 2510 fetal deaths among 417,406 eligible pregnancies. ILI during regular seasons was not associated with increased risk of fetal death: adjusted HR = 0.90 (95% CI 0.64-1.27). In contrast, ILI during the pandemic was associated with substantially increased risk of fetal death, with an adjusted HR of 1.75 (95% CI 1.21-2.54). The risk was highest following first-trimester ILI (adjusted HR = 2.28 [95% CI 1.45-3.59]). ILI during the pandemic-but not during regular seasons-was associated with increased risk of fetal death in the second and third trimester. The estimated effect was strongest with ILI in first trimester.

Background: A population-based pregnancy cohort was established in Norway to study potential effects of exposure to the 2009 influenza pandemic or pandemic vaccination during pregnancy., Objectives: We studied maternal A(H1N1)pdm09-specific hemagglutination inhibition (HI)-titer levels and waning in women with influenza-like illness (ILI) in pregnancy compared to vaccinated women. Moreover, we studied the association between HI-titers and self-reported severity and duration of ILI., Methods: HI-titers against the pandemic virus were measured in maternal blood samples obtained at birth, 3-9 months after exposure, and linked with information about pregnancy, influenza and vaccination from national registries and a cohort questionnaire., Results: Among 1821 pregnant women included, 43.7% were unvaccinated and 19.3% of these had ILI. HI-titers were low (geometric mean titer (GMT) 11.3) in the unvaccinated women with ILI. Higher HI-titers (GMT 37.8) were measured in the vaccinated women. Estimated HI-titer waning was similar for vaccinated women and women with ILI. Most ILI episodes were moderate and lasted 3-5 days. Women with ILI reporting specific influenza symptoms such as fever or cough had higher HI-titers than women without these symptoms. Women who reported being "very ill" or illness duration of >5 days had higher HI-titers than women reporting less severe illness or illness of shorter duration, respectively., Conclusions: Antibody waning was similar in vaccinated women and women with ILI. More severe ILI or longer duration of illness was associated with higher HI-titers. Most unvaccinated pregnant women with ILI had low HI-titers, probably due to moderate illness and HI-titer waning between exposure and sampling., (© 2018 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Background: The effects of maternal influenza infection on the fetus remain unclear. We studied mild influenza and influenza antibodies in relation to birth weight and risks of pre-eclampsia, preterm birth (PTB), and small for gestational age (SGA) birth among the unvaccinated participants in the Norwegian Influenza Pregnancy Cohort., Methods: Pregnant women attending a routine ultrasound were recruited from four hospitals in Norway shortly after the 2009 A(H1N1) pandemic. The present study was restricted to unvaccinated participants who were pregnant during the pandemic. Information on the participants was obtained through questionnaires and linkage with national registries. Maternal blood samples were collected at delivery. Women with laboratory-confirmed A(H1N1)pdm09 influenza, a clinical diagnosis of influenza, or self-reported influenza during the pandemic were classified as having had influenza. A(H1N1)pdm09-specific antibodies in serum were detected with the hemagglutination-inhibition assay. Detection of antibodies was considered an indicator of infection during the pandemic in the unvaccinated participants. Odds ratios were estimated with logistic regression. Quantile regression was used to estimate differences in the distribution of birth weight., Results: Among the 1258 women included in this study, there were 37 cases of pre-eclampsia, 41 births were PTB, and 103 births were SGA. 226 women (18.0%) had influenza during the pandemic. The majority of cases did not receive medical care, and only a small proportion (1.3%) of the cases were hospitalized. Thus, the cases consisted primarily of women with mild illness. No significant associations between influenza and risk of pre-eclampsia, PTB, or SGA birth were observed. Detection of A(H1N1)pdm09-specific antibodies was associated with a lower 10th percentile of birth weight, β = - 159 g (95% CI - 309, - 9)., Conclusions: Mild influenza illness during pregnancy was not associated with increased risk of pre-eclampsia, PTB or SGA birth. However, influenza infection during pregnancy may reduce the birth weight of the smallest children.

Objectives: To determine if pandemic influenza vaccination was associated with an increased risk of epilepsy in children., Methods: Information from Norwegian registries from 2006 through 2014 on all children <18 years living in Norway on October 1, 2009 was used in Cox regression models to estimate hazard ratios for incident epilepsy after vaccination. A self-controlled case series analysis was used to estimate incidence rate ratios in defined risk periods after pandemic vaccination., Results: In Norway, the main period of the influenza A subtype H1N1 pandemic was from October 2009 to December 2009. On October 1, 2009, 1 154 113 children <18 years of age were registered as residents in Norway. Of these, 572 875 (50.7%) were vaccinated against pandemic influenza. From October 2009 through 2014 there were 3628 new cases of epilepsy (incidence rate 6.09 per 10 000 person-years). The risk of epilepsy was not increased after vaccination: hazard ratio: 1.07; 95% confidence interval: 0.94-1.23. Results from the self-controlled case series analysis supported the finding of no association between vaccination and subsequent epilepsy., Conclusions: Pandemic influenza vaccination was not associated with increased risk of epilepsy. Concerns about pandemic vaccination causing epilepsy in children seem to be unwarranted., (Copyright © 2018 by the American Academy of Pediatrics.)

Maternal influenza infection during pregnancy is associated with increased risk of morbidity and mortality. However, the link between the anti-influenza immune responses and health-related risks during infection is not well understood. We have analyzed memory T and NK cell mediated immunity (CMI) responses in pandemic influenza A(H1N1)pdm09 (pdm09) virus infected non-vaccinated pregnant women participating in the Norwegian Influenza Pregnancy Cohort (NorFlu). The cohort includes information on immunization, self-reported health and disease status, and biological samples (plasma and PBMC). Infected cases (N = 75) were defined by having a serum hemagglutination inhibition (HI) titer > = 20 to influenza pdm09 virus at the time of delivery, while controls (N = 75) were randomly selected among non-infected pregnant women (HI titer <10). In ELISpot assays cases had higher frequencies of IFNγ+ CD8+ T cells responding to pdm09 virus or conserved CD8 T cell-restricted influenza A virus epitopes, compared to controls. Within this T cell population, frequencies of CD95+ late effector (CD45RA+CCR7-) and naive (CD45RA+CCR7+) CD8+ memory T cells correlated inversely with self-reported influenza illness (ILI) symptoms. ILI symptoms in infected women were also associated with lower numbers of poly-functional (IFNγ+TNFα+, IL2+IFNγ+, IL2+IFNγ+TNFα+) CD4+ T cells and increased frequencies of IFNγ+CD3-CD7+ NK cells compared to asymptomatic cases, or controls, after stimulation with the pdm09 virus. Taken together, virus specific and functionally distinct T and NK cell populations may serve as cellular immune correlates of clinical outcomes of pandemic influenza disease in pregnant women. Our results may provide information important for future universal influenza vaccine design.

Background: Associations between influenza infection and sleep disorders are poorly studied. We investigated if pandemic influenza infection or vaccination with Pandemrix in 2009/2010 was associated with narcolepsy or hypersomnia in children and young adults., Methods: We followed the Norwegian population under age 30 from January 2008 through December 2012 by linking national health registry data. Narcolepsy diagnoses were validated using hospital records. Risks of narcolepsy or hypersomnia were estimated as adjusted hazard ratios (HRs) in Cox regression models with influenza infection and vaccination as time-dependent exposures., Results: Among the 1,638,526 persons under age 30 in Norway in 2009, 3.6% received a physician diagnosis of influenza during the pandemic, while 41.9% were vaccinated against pandemic influenza. Between October 1st 2009 and December 31st 2012, 72 persons had onset of narcolepsy and 305 were diagnosed with hypersomnia. The risk of a sleep disorder was associated with infection during the first six months, adjusted HR 3.31 with 95% confidence interval [CI], 1.01-10.79 for narcolepsy and adjusted HR 3.13 (95% CI, 1.12-8.76) for hypersomnia. The risk of narcolepsy was strongly associated with vaccination during the first six months adjusted HR 17.21 (95% CI, 6.28-47.14), while the adjusted HR for hypersomnia was 1.54 (95% CI, 0.81-2.93)., Conclusions: The study confirms an increased HR of narcolepsy following pandemic vaccination. Slightly increased HRs of narcolepsy and hypersomnia are also seen after influenza infection. However, the role of infection should be viewed with caution due to underreporting of influenza., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Vaccinations and infections are possible triggers of Guillain-Barré syndrome (GBS). However, studies on GBS after vaccinations during the influenza A(H1N1)pmd09 pandemic in 2009, show inconsistent results. Only few studies have addressed the role of influenza infection. We used information from national health data-bases with information on the total Norwegian population (N = 4,832,211). Cox regression analyses with time-varying covariates and self-controlled case series was applied. The risk of being hospitalized with GBS during the pandemic period, within 42 days after an influenza diagnosis or pandemic vaccination was estimated. There were 490 GBS cases during 2009-2012 of which 410 cases occurred after October 1, 2009 of which 46 new cases occurred during the peak period of the influenza pandemic. An influenza diagnosis was registered for 2.47% of the population and the vaccination coverage was 39.25%. The incidence rate ratio of GBS during the pandemic peak relative to other periods was 1.46 [95% confidence interval (CI) 1.08-1.98]. The adjusted hazard ratio (HR) of GBS within 42 days after a diagnosis of pandemic influenza was 4.89 (95% CI 1.17-20.36). After pandemic vaccination the adjusted HR was 1.11 (95% CI 0.51-2.43). Our results indicated that there was a significantly increased risk of GBS during the pandemic season and after pandemic influenza infection. However, vaccination did not increase the risk of GBS. The small number of GBS cases in this study warrants caution in the interpretation of the findings.

Background: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated to infections and it has been suggested that vaccination can trigger the disease. However, little is known about the specific association between clinically manifest influenza/influenza vaccine and CFS/ME. As part of a registry surveillance of adverse effects after mass vaccination in Norway during the 2009 influenza A (H1N1) pandemic, we had the opportunity to estimate and contrast the risk of CFS/ME after infection and vaccination., Methods: Using the unique personal identification number assigned to everybody who is registered as resident in Norway, we followed the complete Norwegian population as of October 1, 2009, through national registries of vaccination, communicable diseases, primary health, and specialist health care until December 31, 2012. Hazard ratios (HRs) of CFS/ME, as diagnosed in the specialist health care services (diagnostic code G93.3 in the International Classification of Diseases, Version 10), after influenza infection and/or vaccination were estimated using Cox proportional-hazards regression., Results: The incidence rate of CFS/ME was 2.08 per 100,000 person-months at risk. The adjusted HR of CFS/ME after pandemic vaccination was 0.97 (95% confidence interval [CI]: 0.91-1.04), while it was 2.04 (95% CI: 1.78-2.33) after being diagnosed with influenza infection during the peak pandemic period., Conclusions: Pandemic influenza A (H1N1) infection was associated with a more than two-fold increased risk of CFS/ME. We found no indication of increased risk of CFS/ME after vaccination. Our findings are consistent with a model whereby symptomatic infection, rather than antigenic stimulation may trigger CFS/ME., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: During the 2009 influenza A (H1N1) pandemic, a monovalent pandemic strain vaccine containing the oil-in-water adjuvant AS03 (Pandemrix®) was offered to the Norwegian population. The coverage among children reached 54%. Our aim was to estimate the risk of febrile seizure in children after exposure to pandemic influenza vaccination or infection., Methods: The study population comprised 226,889 children born 2006-2009 resident in Norway per October 1st, 2009. Febrile seizure episodes were defined by emergency hospital admissions / emergency outpatient hospital care with International Classification of Diseases, Version 10, codes R56.0 or R56.8. The self-controlled case series method was applied to estimate incidence rate ratios (IRRs) in pre-defined risk periods compared to the background period. The total observation window was ± 180 days from exposure day. Among 113,068 vaccinated children, 656 (0.6%) had at least one febrile seizure episode., Results: The IRR of febrile seizures 1-3 days after vaccination was 2.00 (95% confidence interval [CI]: 1.15-3.51). In the period 4-7 days after vaccination, no increased risk was observed. Among the 8172 children diagnosed with pandemic influenza, 84 (1.0%) had at least one febrile seizure episode. The IRR of febrile seizures on the same day as a diagnosis of influenza was 116.70 (95% CI: 62.81-216.90). In the period 1-3 days after a diagnosis of influenza, a tenfold increased risk was observed (IRR 10.12, 95% CI: 3.82 - 26.82)., Conclusions: In this large population-based study with precise timing of exposures and outcomes, we found a twofold increased risk of febrile seizures 1-3 days after pandemic influenza vaccination. However, we found that pandemic influenza infection was associated with a much stronger increase in risk of febrile seizures.

Background: During the 2009 influenza A (H1N1) pandemic, pregnant women were at risk for severe influenza illness. This concern was complicated by questions about vaccine safety in pregnant women that were raised by anecdotal reports of fetal deaths after vaccination., Methods: We explored the safety of influenza vaccination of pregnant women by linking Norwegian national registries and medical consultation data to determine influenza diagnosis, vaccination status, birth outcomes, and background information for pregnant women before, during, and after the pandemic. We used Cox regression models to estimate hazard ratios for fetal death, with the gestational day as the time metric and vaccination and pandemic exposure as time-dependent exposure variables., Results: There were 117,347 eligible pregnancies in Norway from 2009 through 2010. Fetal mortality was 4.9 deaths per 1000 births. During the pandemic, 54% of pregnant women in their second or third trimester were vaccinated. Vaccination during pregnancy substantially reduced the risk of an influenza diagnosis (adjusted hazard ratio, 0.30; 95% confidence interval [CI], 0.25 to 0.34). Among pregnant women with a clinical diagnosis of influenza, the risk of fetal death was increased (adjusted hazard ratio, 1.91; 95% CI, 1.07 to 3.41). The risk of fetal death was reduced with vaccination during pregnancy, although this reduction was not significant (adjusted hazard ratio, 0.88; 95% CI, 0.66 to 1.17)., Conclusions: Pandemic influenza virus infection in pregnancy was associated with an increased risk of fetal death. Vaccination during pregnancy reduced the risk of an influenza diagnosis. Vaccination itself was not associated with increased fetal mortality and may have reduced the risk of influenza-related fetal death during the pandemic. (Funded by the Norwegian Institute of Public Health.).