H1N1pdm09 Vaccine Research Articles

Vaccine-induced neutralizing antibody responses to seasonal influenza virus H1N1 strains are not enhanced during subsequent pandemic H1N1 infection.

The first exposure to influenza is presumed to shape the B-cell antibody repertoire, leading to preferential enhancement of the initially formed responses during subsequent exposure to viral variants. Here, we investigated whether this principle remains applicable when there are large genetic and antigenic differences between primary and secondary influenza virus antigens. Because humans usually have a complex history of influenza virus exposure, we conducted this investigation in influenza-naive cynomolgus macaques. Two groups of six macaques were immunized four times with influenza virus-like particles (VLPs) displaying either one (monovalent) or five (pentavalent) different hemagglutinin (HA) antigens derived from seasonal H1N1 (H1N1) strains. Four weeks after the final immunization, animals were challenged with pandemic H1N1 (H1N1pdm09). Although immunization resulted in robust virus-neutralizing responses to all VLP-based vaccine strains, there were no cross-neutralization responses to H1N1pdm09, and all animals became infected. No reductions in viral load in the nose or throat were detected in either vaccine group. After infection, strong virus-neutralizing responses to H1N1pdm09 were induced. However, there were no increases in virus-neutralizing titers against four of the five H1N1 vaccine strains; and only a mild increase was observed in virus-neutralizing titer against the influenza A/Texas/36/91 vaccine strain. After H1N1pdm09 infection, both vaccine groups showed higher virus-neutralizing titers against two H1N1 strains of intermediate antigenic distance between the H1N1 vaccine strains and H1N1pdm09, compared with the naive control group. Furthermore, both vaccine groups had higher HA-stem antibodies early after infection than the control group. In conclusion, immunization with VLPs displaying HA from antigenically distinct H1N1 variants increased the breadth of the immune response during subsequent H1N1pdm09 challenge, although this phenomenon was limited to intermediate antigenic variants.

Overcoming Aging-Associated Poor Influenza Vaccine Responses with CpG 1018 Adjuvant.

Aging is associated with diminished immune system function, which renders old people vulnerable to influenza infection and also less responsive to influenza vaccination. This study explored whether the CpG 1018 adjuvant was effective in enhancing influenza vaccine efficacy in aged mice equivalent to human beings in their late 50s to early 60s. Using the influenza pandemic 2009 H1N1 (pdm09) vaccine as a model, we found that the CpG 1018 adjuvant could significantly enhance the pdm09 vaccine-induced serum antibody titer, while the pdm09 vaccine alone failed to elicit significant antibody titer. In contrast, the pdm09 vaccine alone elicited significant antibody titer in young adult mice. Antibody subtype analysis found that the pdm09 vaccine alone elicited Th2-biased antibody responses in young adult mice, while incorporation of the CpG 1018 adjuvant promoted the elicitation of potent Th1-biased antibody responses in aged mice. The pdm09 vaccine alone was further found to induce significant expansion of Th2 cells in young adult mice, while incorporation of the CpG 1018 adjuvant stimulated significant expansion of Th1 cells in aged mice. The CpG 1018 adjuvant also stimulated vaccine-specific cytotoxic T lymphocytes in aged mice. The pdm09 vaccine in the presence of CpG 1018 elicited significant protection against lethal viral challenges, while the pdm09 vaccine alone failed to confer significant protection in young adult or aged mice. Our study provided strong evidence to support the high effectiveness of the CpG 1018 adjuvant to boost influenza vaccination in aged mouse models.

Taiwan's Response to Influenza: A Seroepidemiological Evaluation of Policies and Implications for Pandemic Preparedness

To evaluate class suspension and mass vaccination implemented among Taipei schoolchildren during the 2009 influenza pandemic and investigate factors affecting antibody responses. We conducted 2 cohort studies on: (1) 972 schoolchildren from November 2009-March 2010 to evaluate pandemic policies and (2) 935 schoolchildren from November 2011-March 2012 to verify factors in antibody waning. Anti-influenza H1N1pdm09 hemagglutination inhibition antibodies (HI-Ab) were measured from serum samples collected before vaccination, and at 1 and 4 months after vaccination. Factors affecting HI-Ab responses were investigated through logistic regression and generalized estimating equation. Seroprevalence of H1N1pdm09 before vaccination was significantly higher among schoolchildren who experienced class suspensions than those who did not (59.6% vs 47.5%, p<0.05). Participating in after-school activities (adjusted odds ratio [aOR]=2.47, p=0.047) and having ≥3 hours per week of exercise (aOR=2.86, p=0.019) were significantly correlated with H1N1pdm09 infection. Two doses of the H1N1pdm09 vaccine demonstrated significantly better antibody persistence than 1 dose (HI-Ab geometric mean titer: 132.5 vs 88.6, p=0.047). Vaccine effectiveness after controlling for preexisting immunity was 86% (32%-97%). Exercise ≥3 hours per week and preexisting immunity were significantly associated with antibody waning/maintenance. This study is the first to show that exercise and preexisting immunity may affect antibody waning. Further investigation is needed to identify immune correlates of protection.

Safety of Influenza A H1N1pdm09 Vaccines: An Overview of Systematic Reviews.

BackgroundIn 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.MethodsFour 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.Results16 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.ConclusionAdjuvanted 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.

Swine influenza A virus subtypes circulating in Brazilian commercial pig herds from 2012 to 2019.

The swine influenza A virus (SIAV) subtypes/lineages H1N1pdm09, H3N2, H1N2, and H1N1 of seasonal human origin are widespread in Brazilian swine herds. A monovalent inactivated H1N1pdm09 vaccine was licensed in Brazil in 2014. However, there are concerns about its efficacy due to the limited vaccine cross-protection against heterologous viruses and the potential for exacerbated reactions against vaccine strains. Thus, monitoring SIAVs subtypes/lineages that are circulating in the Brazilian swine population is important, by applying a fast and efficient diagnostic test in herd field samples. A RT-PCR assay was developed, using primers specific for HA subtyping of Brazilian SIAV, and was used to evaluate the occurrence of subtypes from samples collected between 2012 and 2019. From 167 field samples positive for influenza A, 117 were subtyped by nested RT-PCR assay. A higher occurrence of H1N1pdm was observed from 2012 to 2015, H3N2 in 2017, and H1hu in 2017 to 2019. A hemagglutination inhibition test was performed in serum samples received from 2017 to 2019, confirming these data. The molecular data highlights the importance of H1hu and H3N2 detection since there are no vaccines available for the subtypes/lineages and raises an alert of H1hu for its potential to infect humans. Serological data suggest a cyclical profile of occurrence between the H3N2 and H1N1pdm over time. Monitoring SIAVs circulating in Brazilian swine herds is necessary, which provides the relevant information for field veterinarians to apply effective control measures on the properties.Supplementary InformationThe online version contains supplementary material available at 10.1007/s42770-021-00550-y.

Persistently high antibody responses after AS03-adjuvanted H1N1pdm09 vaccine: Dissecting the HA specific antibody response

Current influenza vaccines have a suboptimal effectiveness. The introduction of a novel A/H1N1 influenza virus in 2009 (H1N1pdm09) provided a unique opportunity to study the humoral response to the AS03-adjuvanted H1N1pdm09 vaccine and repeated annual vaccination with the homologous virus in subsequent influenza seasons. Thirty-two HCWs immunized with the AS03-adjuvanted H1N1pdm09 vaccine in 2009 were divided into four groups based on the longevity of their antibody responses (persistently high or transient), and whether they were repeatedly annually vaccinated in the subsequent four influenza seasons or not. Serological assays were utilized to measure the quantity, quality and functionality of antibodies targeting the major surface glycoprotein hemagglutinin (HA). Persistent high responders (hemagglutination inhibition (HI) titre ≥ 80 at 12 months after H1N1pdm09 vaccination) had protective levels of HI antibodies throughout the study period. In addition, the quality and functionality of these antibodies were greater than the individuals who had a transient antibody response to the pandemic vaccine (HI titre < 40 at 12 months after H1N1pdm09 vaccination). All groups had similar levels of antibodies towards the conserved HA stalk domain. The level of HA head-specific antibodies gradually increased over time with annual vaccination in the transient responders. The AS03-adjuvanted H1N1pdm09 vaccine elicited a robust humoral response that persisted up to 5 years in some individuals. Seasonal annual vaccination boosted the HA-antibodies over time in individuals with a transient response to the pandemic H1N1pdm09 vaccine.

Pandemic influenza A(H1N1pdm09) vaccine induced high levels of influenza-specific IgG and IgM antibodies as analyzed by enzyme immunoassay and dual-mode multiplex microarray immunoassay methods

Influenza A viruses continue to circulate throughout the world as yearly epidemics or occasional pandemics. Influenza infections can be prevented by seasonal multivalent or monovalent pandemic vaccines. In the present study, we describe a novel multiplex microarray immunoassay (MAIA) for simultaneous measurement of virus-specific IgG and IgM antibodies using Pandemrix-vaccinated adult sera collected at day 0 and 28 and 180 days after vaccination as the study material. MAIA showed excellent correlation with a conventional enzyme immunoassay (EIA) in both IgG and IgM anti-influenza A antibodies and good correlation with hemagglutination inhibition (HI) test. Pandemrix vaccine induced 5–30 fold increases in anti-H1N1pdm09 influenza antibodies as measured by HI, EIA or MAIA. A clear increase in virus-specific IgG antibodies was found in 93–97% of vaccinees by MAIA and EIA. Virus-specific IgM antibodies were found in 90–92% of vaccinees by MAIA and EIA, respectively and IgM antibodies persisted for up to 6 months after vaccination in 55–62% of the vaccinees. Pandemic influenza vaccine induced strong anti-influenza A IgG and IgM responses that persisted several months after vaccination. MAIA was demonstrated to be an excellent method for simultaneous measurement of antiviral IgG and IgM antibodies against multiple virus antigens. Thus the method is well suitable for large scale epidemiological and vaccine immunity studies.

A Recombinant Influenza A/H1N1 Carrying A Short Immunogenic Peptide of MERS-CoV as Bivalent Vaccine in BALB/c Mice.

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) became a global human health threat since its first documentation in humans in 2012. An efficient vaccine for the prophylaxis of humans in hotspots of the infection (e.g., Saudi Arabia) is necessary but no commercial vaccines are yet approved. In this study, a chimeric DNA construct was designed to encode an influenza A/H1N1 NA protein which is flanking immunogenic amino acids (aa) 736–761 of MERS-CoV spike protein. Using the generated chimeric construct, a novel recombinant vaccine strain against pandemic influenza A virus (H1N1pdm09) and MERS-CoV was generated (chimeric bivalent 5 + 3). The chimeric bivalent 5 + 3 vaccine strain comprises a recombinant PR8-based vaccine, expressing the PB1, HA, and chimeric NA of pandemic 2009 H1N1. Interestingly, an increase in replication efficiency of the generated vaccine strain was observed when compared to the PR8-based 5 + 3 H1N1pdm09 vaccine strain that lacks the MERS-CoV spike peptide insert. In BALB/c mice, the inactivated chimeric bivalent vaccine induced potent and specific neutralizing antibodies against MERS-CoV and H1N1pdm09. This novel approach succeeded in developing a recombinant influenza virus with potential use as a bivalent vaccine against H1N1pdm09 and MERS-CoV. This approach provides a basis for the future development of chimeric influenza-based vaccines against MERS-CoV and other viruses.

No evidence of antigenic seniority in hemagglutinin specific antibody responses after adjuvanted pandemic 2009 influenza vaccination

Influenza is a contagious respiratory illness caused by the influenza virus. The pandemic outbreak of influenza A H1N1 in 2009 (H1N1pdm09) gave us a unique opportunity to study humoral immune responses to a novel influenza vaccine strain. Here, we investigate how an individual’s previous encounter with different influenza subtypes influences the humoral response after pandemic vaccination in 2009.We retrospectively chose and grouped 80 vaccinated healthcare workers (HCWs) based on their year of birth into 4 groups, reflecting which influenza subtype they were likely first exposed to during childhood. Pre- and 21 days post- vaccination sera were analyzed. We investigated antibodies to the major surface protein hemagglutinin (HA), and specifically antibodies binding to the conserved stalk domain of the HA-protein. Serological assays were used to assess the quantity and functionality of the influenza-specific antibodies, including virus neutralization and activation of natural killer (NK) cells involved in antibody-dependent cell-mediated cytotoxicity (ADCC).The AS03-adjuvanted H1N1pdm09 vaccine elicited robust antibody responses in all groups of HCWs. We found that the more antigenically experienced individuals had higher pre-vaccination antibody-levels towards the stalk domain of the HA. We also demonstrated that despite their inferior pre-vaccination antibody levels, the younger individuals reached similar antibody levels as the older birth-cohorts after pandemic vaccination. Our findings are important for understanding the effect of AS03 adjuvant on the antibody response in individuals exposed to different influenza viruses during their early childhood years, which is crucial for developing vaccine strategies against influenza.

Adjuvanted influenza vaccine dynamics

Adjuvanted influenza vaccines constitute a key element towards inducing neutralizing antibody responses in populations with reduced responsiveness, such as infants and elderly subjects, as well as in devising antigen-sparing strategies. In particular, squalene-containing adjuvants have been observed to induce enhanced antibody responses, as well as having an influence on cross-reactive immunity. To explore the effects of adjuvanted vaccine formulations on antibody response and their relation to protein-specific immunity, we propose different mathematical models of antibody production dynamics in response to influenza vaccination. Data from ferrets immunized with commercial H1N1pdm09 vaccine antigen alone or formulated with different adjuvants was instrumental to adjust model parameters. While the affinity maturation process complexity is abridged, the proposed model is able to recapitulate the essential features of the observed dynamics. Our numerical results suggest that there exists a qualitative shift in protein-specific antibody response, with enhanced production of antibodies targeting the NA protein in adjuvanted versus non-adjuvanted formulations, in conjunction with a protein-independent boost that is over one order of magnitude larger for squalene-containing adjuvants. Furthermore, simulations predict that vaccines formulated with squalene-containing adjuvants are able to induce sustained antibody titers in a robust way, with little impact of the time interval between immunizations.

Antibody Responses to Influenza A/H1N1pdm09 Virus After Pandemic and Seasonal Influenza Vaccination in Healthcare Workers: A 5-Year Follow-up Study.

BackgroundThe 2009 influenza pandemic was caused by the A/H1N1pdm09 virus, which was subsequently included in the seasonal vaccine, up to 2016/2017, as the A/H1N1 strain. This provided a unique opportunity to investigate the antibody response to H1N1pdm09 over time.MethodsHealthcare workers (HCWs) were immunized with the AS03-adjuvanted H1N1pdm09 vaccine in 2009 (N = 250), and subsequently vaccinated with seasonal vaccines containing H1N1pdm09 for 4 seasons (repeated group), <4 seasons (occasional group), or no seasons (single group). Blood samples were collected pre and at 21 days and 3, 6, and 12 months after each vaccination, or annually (pre-season) from 2010 in the single group. The H1N1pdm09-specific antibodies were measured by the hemagglutination inhibition (HI) assay.ResultsPandemic vaccination robustly induced HI antibodies that persisted above the 50% protective threshold (HI titers ≥ 40) over 12 months post-vaccination. Previous seasonal vaccination and the duration of adverse events after the pandemic vaccination influenced the decision to vaccinate in subsequent seasons. During 2010/2011–2013/2014, antibodies were boosted after each seasonal vaccination, although no significant difference was observed between the repeated and occasional groups. In the single group without seasonal vaccination, 32% of HCWs seroconverted (≥4-fold increase in HI titers) during the 4 subsequent years, most of whom had HI titers <40 prior to seroconversion. When excluding these seroconverted HCWs, HI titers gradually declined from 12 to 60 months post–pandemic vaccination.ConclusionsPandemic vaccination elicited durable antibodies, supporting the incorporation of adjuvant. Our findings support the current recommendation of annual influenza vaccination in HCWs.Clinical Trials RegistrationNCT01003288.

Distinct patterns of cellular immune response elicited by influenza non-adjuvanted and AS03-adjuvanted monovalent H1N1(pdm09) vaccine

The study aimed at identifying biomarkers of immune response elicited by non-adjuvanted-(NAV) and adjuvanted-(AV) H1N1(pdm09) vaccines. The results showed that despite both vaccines elicited similar levels of anti-H1N1 antibodies at day30 after vaccination, higher reactivity was observed in AV at day180. While AV induced early changes in cell-surface molecules on monocytes, CD4+, CD8+ T-cells and B-cells, NAV triggered minor changes, starting later on at day3. Furthermore, AV induced a late and persistent increase in TLR gene expression after day3, except for tlr4, while NAV displayed earlier but transient tlr3/4/7/9 up-regulation. Contrasting with NAV, prominent chemokine gene expression (cxcl8,cxcl9,ccl5) and a broad spectrum up-regulation of plasmatic biomarkers (CXCL8,IL-6,IL-1β,IL-12,IL-10) was evident in AV, which showed a major involvement of TNF and IL-10. Similarly, AV induced a robust IL-10-modulated proinflammatory storm, with early and persistent involvement of TNF-α/IL-12/IFN-γ axis derived from NK-cells, CD4+ and CD8+ T-cells along with promiscuous production of IL-4/IL-5/IL-13. Conversely, NAV promotes a concise and restricted intracytoplasmic chemokine/cytokine response, essentially mediated by TNF-α and IL-4, with late IL-10 production by CD8+ T-cells. Systems biology approach underscored that AV guided the formation of an imbricate network characterized by a progressive increase in the number of neighborhood connections amongst innate and adaptive immunity. In AV, the early cross-talk between innate and adaptive immunity, followed by the triad NK/CD4+/CD8+ T-cells at day3, sponsored a later/robust biomarker network. These findings indicate the relevance of adjuvanted vaccination to orchestrate broad, balanced and multifactorial cellular immune events that lead ultimately to a stronger H1N1 humoral immunity.

Long-term Maintenance of the Influenza-Specific Cross-Reactive Memory CD4+ T-Cell Responses Following Repeated Annual Influenza Vaccination.

Annual vaccination for healthcare workers and other high-risk groups is the mainstay of the public health strategy to combat influenza. Inactivated influenza vaccines confer protection by inducing neutralizing antibodies efficiently against homologous and closely matched virus strains. In the absence of neutralizing antibodies, cross-reactive T cells have been shown to limit disease severity. However, animal studies and a study in immunocompromised children suggested that repeated vaccination hampers CD8+ T cells. Yet the impact of repeated annual influenza vaccination on both cross-reactive CD4+ and CD8+ T cells has not been explored, particularly in healthy adults. We assembled a unique cohort of healthcare workers who received a single AS03-adjuvanted H1N1pdm09 vaccine in 2009 and subsequently either repeated annual vaccination or no further vaccination during 2010-2013. Blood samples were collected before the influenza season or vaccination to assess antibody and T-cell responses. Antibody titers to H1N1pdm09 persisted above the protective level in both the repeated- and single-vaccination groups. The interferon γ+ (IFN-γ+) and multifunctional CD4+ T-cell responses were maintained in the repeated group but declined significantly in the single-vaccination group. The IFN-γ+CD8+ T cells remained stable in both groups. This study provides the immunological evidence base for continuing annual influenza vaccination in adults.

Squalene-containing licensed adjuvants enhance strain-specific antibody responses against the influenza hemagglutinin and induce subtype-specific antibodies against the neuraminidase

While seasonal influenza vaccines are usually non-adjuvanted, H1N1pdm09 vaccines were formulated with different squalene-containing adjuvants, to enable the reduction of antigen content thus increasing the number of doses available. To comparatively assess the effects of these adjuvants on antibody responses against matched and mismatched strains, and to correlate antibody levels with protection from disease, ferrets were immunized with 2μg of commercial H1N1pdm09 vaccine antigen alone or formulated with different licensed adjuvants. The use of squalene-containing adjuvants increased neutralizing antibody responses around 100-fold, and resulted in a significantly reduced viral load after challenge with a matched strain. While all animals mounted strong total antibody responses against the homologous H1N1 hemagglutinin (HA) protein, which correlated with the respective neutralizing antibody titers, no reactivity with the divergent H3, H5, H7, and H9 proteins were detected. Only the adjuvanted vaccines also induced antibodies against the neuraminidase (NA) protein, which were able to also recognize NA proteins from other N1 carrying strains. These findings not only support the use of squalene-containing adjuvants in dose-sparing strategies but also support speculations that the induction of NA-specific responses associated with the use of these adjuvants may confer partial protection to heterologous strains carrying the same NA subtype.

The priming effect of previous natural pandemic H1N1 infection on the immunogenicity to subsequent 2010-2011 influenza vaccination in children: a prospective cohort study

BackgroundThe effect of previous natural pandemic H1N1 (H1N1 pdm09) influenza infection on the immunogenicity to subsequent inactivated influenza vaccination in children has not been well studied. We aimed to evaluate the effect of H1N1 pdm09 natural infection and vaccination on the immunogenicity to subsequent 2010-2011 seasonal inactivated influenza vaccination in children.MethodsFrom October 2010 to May 2011, we conducted an open-label, multi-center study in children aged 6 months -18 years in Korea. We measured antibody titers with a hemagglutination-inhibition (HI) assay at baseline, 1 month, and 6 months after vaccination with trivalent split or subunit vaccines containing H1N1 pdm, A/H3N2, and B. The subjects were classified into 4 groups depending on the presence of laboratory-confirmed H1N1 pdm09 infection and/or vaccination in the 2009-2010 season; Group I: vaccination (-)/infection(-), Group II: vaccination (-)/infection(+), Group III: vaccination (+)/infection(-), Group IV: vaccination (+)/infection(+).ResultsAmong the subjects in group I, 47 subjects who had a baseline titer >1:10 were considered to have an asymptomatic infection. They were included into the final group II (n = 80). We defined the new group II as the infection-primed (IP) group and group III as the vaccine-primed (VP) group. Seroconversion rate (57.5 % vs 35.9 %, p = 0.001), seroprotection rate at 6 months after vaccination (70.8 % vs 61.8 %, p = 0.032), and GMT at 1 month after vaccination (129.9 vs 66.5, p = 0.002) were significantly higher in the IP group than in the VP group. In the 9–18 year-old group, seroconversion rate and immunogenicity at 1 and 6 months were significantly higher in the IP group than in the VP group. However in the 1–7 year-old age group, there was no significant difference between the two groups.ConclusionsPrevious H1N1 pdm09 infection appears to have positive effects on immunogenicity of subsequent inactivated influenza vaccines against H1N1 pdm09 in older children.

How successful is influenza vaccination in HIV infected patients? Results from an influenza A(H1N1)pdm09 vaccine study

AimTo determine immune response after single vaccination with AS03-adjuvanted pandemic H1N1 vaccine in HIV-infected patients. BackgroundIndividuals living with human immunodeficiency virus (HIV) are at risk with influenza due to hyporesponsiveness to influenza vaccine and a higher probability for developing severe disease. Especially, immunogenicity and tolerability of adjuvanted influenza vaccines in a pandemic setting are not well characterized in HIV infected individuals. MethodsImmune response following vaccination with a single dose of influenza A (H1N1)pdm09 AS03-adjuvanted vaccine (H1N1pdm09 vaccine) containing 3.75μg hemagglutinin was evaluated in HIV infected individuals by hemagglutination inhibition assay. Tolerability was assessed by questionnaires. ResultsThree hundred eighty-nine patients from two German HIV clinics were evaluated. Seroprotection was found in as much as 191/389 (49%) of patients before vaccination. Following vaccination with H1N1pdm09 vaccine seroprotection rate increased to 66% (257/389). Due to high pre-vaccination seroprotection rates seroconversion was only found in a total of 27/389 (7%) of HIV patients. There was no association of seroprotection/seroconversion and current CD4+ T-cell count, HIV-RNA load in plasma, antiretroviral treatment or demographic factors such as gender, age and ethnicity. The vaccine was overall well tolerated. ConclusionsIn this large cohort of HIV infected patients with high baseline H1N1 seroprotective titers only a moderate antibody response to a single vaccination with H1N1pdm09 AS03-adjuvanted vaccine was detected. Emerging influenza pandemics warrant usage of booster vaccinations in order to achieve higher immunogenicity to protect a vulnerable patient population such as HIV positive individuals against influenza.

Pandemic influenza 2009: Impact of vaccination coverage on critical illness in children, a Canada and France observational study.

AIMTo study the impact of vaccination critical illness due to H1N1pdm09, we compared the incidence and severity of H1N1pdm09 infection in Canada and France.METHODSWe studied two national cohorts that included children with documented H1N1pdm09 infection, admitted to a pediatric intensive care unit (PICU) in Canada and in France between October 1, 2009 and January 31, 2010.RESULTSVaccination coverage prior to admission to PICUs was higher in Canada than in France (21% vs 2% of children respectively, P < 0.001), and in both countries, vaccination coverage prior to admission of these critically ill patients was substantially lower than in the general pediatric population (P < 0.001). In Canada, 160 children (incidence = 2.6/100000 children) were hospitalized in PICU compared to 125 children (incidence = 1.1/100000) in France (P < 0.001). Mortality rates were similar in Canada and France (4.4% vs 6.5%, P = 0.45, respectively), median invasive mechanical ventilation duration and mean PICU length of stay were shorter in Canada (4 d vs 6 d, P = 0.02 and 5.7 d vs 8.2 d, P = 0.03, respectively). H1N1pdm09 vaccination prior to PICU admission was associated with a decreased risk of requiring invasive mechanical ventilation (OR = 0.30, 95%CI: 0.11-0.83, P = 0.02).CONCLUSIONThe critical illness due to H1N1pdm09 had a higher incidence in Canada than in France. Critically ill children were less likely to have received vaccination prior to hospitalization in comparison to general population and children vaccinated had lower risk of ventilation.

Maternal Influenza Immunization and Birth Outcomes of Stillbirth and Spontaneous Abortion: A Systematic Review and Meta-analysis

Despite strong evidence that maternal influenza vaccination during pregnancy is safe, uptake of influenza vaccination during pregnancy remains low. We identified studies that assessed outcomes of stillbirth or spontaneous abortion after administration of influenza vaccine during pregnancy. We conducted a literature search in November 2013 that yielded 447 total citations. After removal of duplicates and studies deemed not relevant based on the title and abstract, 36 records underwent a full text review and 7 studies were included in the final review. Where possible, adjusted results were included in the meta-analysis. Women in the influenza vaccine group had a lower likelihood of stillbirth (relative risk [RR], 0.73; 95% confidence interval [CI], .55-.96); this association was similar when restricted to the H1N1pdm09 vaccine (RR, 0.69; 95% CI, .53-.90). The pooled estimate for spontaneous abortion was not significant (RR, 0.91; 95% CI, .68-1.22). These analyses add to the evidence base for the safety of influenza vaccination in pregnancy.

Analysis of the Influenza A (H1N1) 2009 Pandemic Infection in Japanese Asthmatic Patients: Using a Questionnaire-Based Survey

Influenza infection is known to be an exacerbating factor in the control of asthma, therfore its prevention is critical in managing asthma. The aim of this study was to investigate the influenza A H1N1 2009 pandemic virus (H1N1 pdm09) infection in adult asthmatic patients. Data were obtained from a questionnaire-based survey of asthmatic patients conducted from September to October 2010 in Niigata Prefecture. Patient background, H1N1 pdm09 infection, vaccination status, and asthma exacerbation due to influenza infection were analyzed. In total, 2,555 cases were analyzed. The incidence of the infection was 6.7% (95% confidence interval [CI]: 5.7-7.6), and the rate of vaccination was 63.9% (95% CI: 62.1-65.8). The odds ratio (OR) for vaccination against the infection among adult patients and younger patients (≤ the median age) were 0.61 (95% CI: 0.45-0.84) and 0.62 (95% CI: 0.42-0.90), respectively. However, OR among the older patient (> median age) were 1.38 (95%CI: 0.66-2.89). The rate of infection-induced asthma exacerbation was 23.2% (95% CI: 18.6-29.6), and the OR for vaccination against the infection-induced asthma exacerbation was 1.42 (95% CI: 0.69-2.92). The effectiveness of the vaccination against the H1N1 pdm09 virus was confirmed during the first pandemic season, but it was limited. Further investigation on H1N1 pdm09 virus infection in asthmatics will be required.

Increased risk of anaphylaxis following administration of 2009 AS03-adjuvanted monovalent pandemic A/H1N1 (H1N1pdm09) vaccine

BackgroundAnaphylaxis after trivalent influenza vaccination is typically reported at a rate of <1 per million doses. In Quebec, Canada, anaphylaxis following administration of the monovalent AS03-adjuvanted H1N1pdm09 vaccine was reported through passive surveillance at a rate of 8 per million doses administered. This was 20 times higher than the reporting rate for non-adjuvanted trivalent vaccines administered during the six previous seasons. However, adequate estimation of the incidence of anaphylaxis is hindered by wide variations in definitions and diagnosis. MethodsUsing the Brighton collaboration case definition of anaphylaxis, all cases with allergic symptoms (AS) reported to public health were reviewed to estimate the incidence of anaphylaxis following AS03-adjuvanted H1N1pdm09 vaccine. ResultsAmong 752 reports of allergic symptoms, 33 were initially reported as anaphylaxis of which 20/33 (60%) met the Brighton definition (19/20 with certainty levels 1 or 2). A total of 38 additional cases with onset within 1h of vaccination also met the Brighton definition of anaphylaxis (27 (71%) with certainty levels 1 or 2). The 58 cases meeting Brighton Level 1 or 2 criteria for anaphylaxis represent a 75% increase over the 33 passively reported and an incidence of 13 per million doses administered. ConclusionA substantial number of patients with early-onset allergic symptoms met the most specific levels of the Brighton case definition but were not reported as anaphylaxis. Based on this specific case definition, the incidence of anaphylaxis after AS03-adjuvanted H1N1pdm09 vaccine substantially exceeded that reported with seasonal influenza vaccines, a signal that warrants better understanding.