Seasonal Trivalent Vaccine Research Articles

Murine Broadly Reactive Antineuraminidase Monoclonal Antibodies Protect Mice from Recent Influenza B Virus Isolates and Partially Inhibit Virus Transmission in the Guinea Pig Model.

ABSTRACTCurrent influenza virus vaccines and antivirals have limitations, some of which disproportionately affect their utilization against influenza B viruses. To inform ongoing efforts to address the considerable global burden of influenza B viruses, we previously described five murine monoclonal antibodies that broadly bind conserved epitopes on the neuraminidase of influenza B viruses and protect against lethal challenge in a mouse model when delivered via intraperitoneal injection. Here, we validate the continued relevance of these antibodies by demonstrating that their protective effects extend to lethal challenge with mouse-adapted influenza B viruses recently isolated from humans. We also found that humanization of murine antibodies 1F2 and 4F11 resulted in molecules that retain the ability to protect mice from lethal challenge when administered prophylactically. Intranasal administration as an alternative route of 1F2 delivery revealed no differences in the mouse challenge model compared to intraperitoneal injection, supporting further assessment of this more targeted and convenient administration method. Lastly, we evaluated the potential for intranasal 1F2 administration initiated 1 day after infection to prevent transmission of an influenza B virus between cocaged guinea pigs. Here, we observed a 40% rate of transmission with the 1F2 antibody administered to the infected donor compared to 100% transmission with administration of an irrelevant control antibody. These data suggest that intranasal administration could be a viable route of administration for antibody therapeutics. Collectively, these findings demonstrate the potential of broad antineuraminidase antibodies as therapeutics to prevent and treat infections caused by influenza B viruses.IMPORTANCE The global health burden of influenza B viruses, especially in children, has long been underappreciated. Although two antigenically distinct influenza B virus lineages cocirculated before the coronavirus disease 2019 (COVID-19) pandemic, the commonly used trivalent seasonal vaccines contain antigens from only one influenza B virus, providing limited cross-protection against viruses of the other lineage. Additionally, studies have called into question the clinical effectiveness of the neuraminidase inhibitors that comprise the majority of available antivirals in treating influenza B virus infections. We previously described antibodies that bind broadly to neuraminidases of influenza B viruses across decades of antigenic evolution and potently protect mice against lethal challenge. Here we appraise additional factors to develop these antineuraminidase antibodies as antivirals to prevent and treat infections caused by an extensive range of influenza B viruses. In addition this work assesses recent clinical isolates belonging to the two influenza B virus lineages, finding evidence supporting the development of these antibodies for prophylactic and therapeutic use.

The immune responses to influenza vaccine in aged and metabolic disease occurred cynomolgus macaques

Abstract The analysis of age-related immune senescent is extremely meaningful to understand the vital homeostasis in individuals among the aging society. Influenza virus (FluV) infection is a major public health concern due to its high infectivity and ability to severe respiratory illness in elderly people. The reduced immune responses after Flu vaccination in humans are recognized in aging and also in lifestyle diseases such as diabetes mellitus (DM). Understanding the hypofunction in aging and lifestyle diseases is necessary to optimize vaccination resume and the comprehensive analysis of that will provide a great impact on public health burden. However, several factors affect the biofunctional analysis in human. Cynomolgus macaques (CMs) show human-like characteristics such as higher brain functions, long life span, single pregnancy. In the present study, several groups of CMs, including DM and hyperlipidemia (HL) occurred CMs, were subcutaneously immunized with seasonal trivalent Flu vaccine and assessed immune responses. The reduced humoral and cellular immune responses to Flu vaccine were observed in the elderly CMs group compare to the young group and induced anti-HA antibody titers were negatively correlated with age. In particular, Flu-specific immune responses were considerably decreased in DM group despite their youth. However, the reduced humoral and cellular immune responses were not observed in HL group, unlike DM CMs. These results suggested that elderly or DM and HL occurred CMs should be a powerful tool to reveal the comprehensive mechanisms for hypofunction in aging and lifestyle diseases through a long-life span. This study will help to enhance the immune response to vaccine in metabolic disease and aged person.

Rationale for vaccination with trivalent or quadrivalent live attenuated influenza vaccines: Protective vaccine efficacy in the ferret model.

Background and aimThe majority of seasonal influenza vaccines are trivalent, containing two A virus strains (H1N1 and H3N2) and one B virus strain. The co-circulation of two distinct lineages of B viruses can lead to mismatch between the influenza B virus strain recommended for the trivalent seasonal vaccine and the circulating B virus. This has led some manufacturers to produce quadrivalent influenza vaccines containing one strain from each B lineage in addition to H1N1 and H3N2 strains. However, it is also important to know whether vaccines containing a single influenza B strain can provide cross-protectivity against viruses of the antigenically distinct lineage. The aim of this study was to assess in naïve ferrets the potential cross-protective activity of trivalent live attenuated influenza vaccine (T-LAIV) against challenge with a heterologous wild-type influenza B virus belonging to the genetically different lineage and to compare this activity with effectiveness of quadrivalent LAIV (Q-LAIV) in the ferret model.Methods and resultsFerrets were vaccinated with either one dose of trivalent LAIV containing B/Victoria or B/Yamagata lineage virus, or quadrivalent LAIV (containing both B lineages), or placebo. They were then challenged with B/Victoria or B/Yamagata lineage wild-type virus 28 days after vaccination. The ferrets were monitored for clinical signs and morbidity. Nasal swabs and lung tissue samples were analyzed for the presence of challenge virus. Antibody response to vaccination was assessed by routine hemagglutination inhibition assay. All LAIVs tested were found to be safe and effective against wild-type influenza B viruses based on clinical signs, and virological and histological data. The absence of interference between vaccine strains in trivalent and quadrivalent vaccine formulations was confirmed. Trivalent LAIVs were shown to have the potential to be cross-protective against infection with genetically different influenza B/Victoria and B/Yamagata lineages.ConclusionsIn this ferret model, quadrivalent vaccine provided higher protection to challenge against both B/Victoria and B/Yamagata lineage viruses. However, T-LAIV provided some cross-protection in the case of a mismatch between circulating and vaccine type B strains. Notably, B/Victoria-based T-LAIV was more protective compared to B/Yamagata-based T-LAIV.

Prevalence of antibodies and humoral response after seasonal trivalent vaccination against influenza B lineages in an elderly population of Spain

IntroductionThe aim of this study was to analyze the presence of antibodies against both Yamagata and Victoria influenza B lineages and to check the response after seasonal trivalent vaccination. Materials and methodsHaemagglutination inhibition assays were performed with pre-and post-vaccination serum samples from 174 individuals ≥65 years of age vaccinated with seasonal trivalent influenza vaccines during the 2006–2007, 2008–2009, 2009–2010 and 2010–2011 vaccine campaigns. Results33.9% of individuals showed pre-vaccine protective antibodies (≥1/40) against B/Yamagata lineage and 41.4% against B/Victoria lineage. The annual trivalent vaccine induced significant homologous seroconversion in 14–35.6% of individuals in each vaccine campaign. ConclusionsThe population ≥65 years has low-moderate seroprotection against B influenza lineages. Trivalent vaccination induced a slight increase of seroprotection. The trivalent vaccine should be administered to all individuals ≥65 years in all vaccine campaigns.

Influenza B in the general population. Retrospective analysis of French surveillance data from 2003 to 2017

Context Much attention has been paid to influenza over the past three decades with a rare focus on influenza B. Since 2000, two distinct influenza B lineages (Yamagata and Victoria) circulate alternately or simultaneously, raising the issue of potential vaccine mismatch with trivalent vaccines that contain only one of the 2 B lineages. Since 2013, WHO influenza vaccine recommendations give advice on a vaccine strain for each influenza B lineage and manufacturers have developed quadrivalent seasonal vaccines containing the two lineages of influenza B viruses. In France, between 1984 and 2017, influenza surveillance in the general population has been performed by two sentinel networks, based on general practitioners and paediatricians, the Reseau national des GROG (from 1984 to 2014) and the Sentinelles network (since 2014). Practitioners of the network are providing weekly data describing their activity and collect nasal swabs in a fraction of their patients consulting for acute respiratory infection (ARI) or influenza-like infection (ILI). These swabs are sent by surface mail to the laboratories of the National Reference Centre. Objective Our study aims to describe the circulation of the two lineages of influenza B viruses in the general population, during fourteen influenza seasons in France (2003–2017). Methods A retrospective descriptive analysis of the GROG 2003–2013 database, completed by the Sentinelles surveillance data publicly available from 2014 was performed. Every virologically confirmed influenza positive case was included in the study, except for those with an influenza A and B co-infection. Patients whose age was unknown were also excluded. Results and discussion Overall, 21,070 virologically confirmed influenza cases could be included, comprising 5478 influenza B cases (26.0%). The contribution of influenza B to the seasonal influenza burden varied from year-to-year. Influenza B represented more than 5% of influenza viruses detected in eight of the fourteen studied seasons. Influenza B was considered as dominant (> 60% of all influenza viruses of the season) in 2005–2006 (61.8%) and 2015–2016 (71.5%) and was co-dominant (41–60% of all influenza viruses of the season) in 2010–2011 (47.4%) and 2012–2013 (55.0%). The influenza B viruses impact was mainly observed in children of the 5–14 years old group (33.0%) but was also significant in the ≥ 65 years old group (22.5%). In the 8 seasons where influenza B viruses substantially circulated, both Victoria and Yamagata lineages were detected. They respectively accounted for 57.8% and 42.2% of all influenza B cases for which the lineage was available. Each lineage was predominant during four seasons: Victoria in 2005–2006, 2008–2009, 2010–2011 and 2015–2016; Yamagata in 2004–2005, 2007–2008, 2012–2013 and 2014–2015. A mismatch between the dominant circulating influenza B lineage and the lineage included in the seasonal influenza vaccine was observed during four (28.5%) of the fourteen seasons analysed, including two seasons where influenza B viruses predominated (2005–2006, 2007–2008, 2008–2009 and 2015–2016). This is consistent with the results of a similar study carried out in 26 countries that reported a type B lineage mismatch in 25% of seasons. In our study, for 58.2% of the documented type B infections, the reported lineage was not included in the seasonal trivalent vaccine. Again, this is consistent with results recently published from Finland between 1999 and 2012 where 41.7% of the documented influenza B cases belonged to the mismatched lineage. Conclusion Our results support the added value of the quadrivalent vaccine to increase vaccine effectiveness.

Assessment of Reactogenicity and Immunogenicity of the Quadrivalent Live Attenuated Influenza Vaccine

In this multicenter double blind randomized clinical study with parallel groups conducted with 612 healthy volunteers, domestic influenza quadrivalent inactivated subunit vaccine Grippol® Quadrivalent safety, tolerability and immunogenicity was evaluated in comparison with seasonal trivalent vaccines, It was demonstrated that quadrivalent influenza vaccine Grippol® Quadrivalent possesses good tolerability, low reactogenicity, and has favorable safety profile similar to that for trivalent comparators. Besides, it was proven that quadrivalent influenza vaccine Grippol® Quadrivalent has same immunogenicity for three conventional strains and significantly exceeds trivalent comparators for missed influenza B strain.

A Systematic Review and Metaanalysis of Antirheumatic Drugs and Vaccine Immunogenicity in Rheumatoid Arthritis.

Vaccination is a key strategy to reduce infection risk in patients with rheumatoid arthritis (RA) and is advocated in internationally recognized rheumatology society guidelines. The aim was to evaluate to the effect of antirheumatic drugs on influenza and pneumococcal vaccine immunogenicity. We conducted a systematic literature review and metaanalysis comparing the humoral response to influenza (pandemic and seasonal trivalent subunit vaccines) and pneumococcal (23-valent pneumococcal polysaccharide vaccine, 7- and 13-valent pneumococcal conjugated vaccines) vaccination in adult patients with RA treated with antirheumatic drugs. Vaccine immunogenicity was assessed by seroprotection rates measured 3 to 6 weeks postimmunization. Risk ratios (RR) and 95% CI were pooled. Nine studies were included in the metaanalysis (7 studies investigating antirheumatic drug exposures and influenza humoral response, 2 studies investigating pneumococcal vaccine response). Influenza vaccine responses to all subunit strains (H1N1, H3N2, B strain) were preserved with methotrexate (MTX) and tumor necrosis factor inhibitor (TNFi) drug exposure. MTX but not TNFi drug exposure was associated with reduced 6B and 23F serotype pneumococcal vaccine response (RR 0.42, 95% CI 0.28-0.63 vs RR 0.98, 95% CI 0.58-1.67); however, limited data were available to draw any firm conclusions. Combination of MTX with tocilizumab or tofacitinib was associated with reduced pneumococcal and influenza vaccine responses. Antirheumatic drugs may limit humoral responses to vaccination as evidenced by pneumococcal responses with MTX exposure; however, they are safe and should not preclude immunization against vaccine-preventable disease. Vaccination should be considered in all patients with RA and encouraged as part of routine care. (Systematic review registration number: PROSPERO 2016: CRD42016048093.).

Prevalence of antibodies and humoral response after seasonal trivalent vaccination against influenza B lineages in an elderly population of Spain

IntroductionThe aim of this study was to analyze the presence of antibodies against both Yamagata and Victoria influenza B lineages and to check the response after seasonal trivalent vaccination. Materials and methodsHaemagglutination inhibition assays were performed with pre-and post-vaccination serum samples from 174 individuals ≥65 years of age vaccinated with seasonal trivalent influenza vaccines during the 2006–2007, 2008–2009, 2009–2010 and 2010–2011 vaccine campaigns. Results33.9% of individuals showed pre-vaccine protective antibodies (≥1/40) against B/Yamagata lineage and 41.4% against B/Victoria lineage. The annual trivalent vaccine induced significant homologous seroconversion in 14–35.6% of individuals in each vaccine campaign. ConclusionsThe population ≥65 years has low-moderate seroprotection against B influenza lineages. Trivalent vaccination induced a slight increase of seroprotection. The trivalent vaccine should be administered to all individuals ≥65 years in all vaccine campaigns.

Recommendations for Prevention and Control of Influenza in Children, 2016-2017.

The purpose of this statement is to update recommendations for the routine use of seasonal influenza vaccine and antiviral medications for the prevention and treatment of influenza in children. The AAP recommends annual seasonal influenza immunization for everyone 6 months and older, including children and adolescents. Highlights for the upcoming 2016-2017 season include the following: 1. Annual universal influenza immunization is indicated with either a trivalent or quadrivalent (no preference) inactivated vaccine.2. The 2016-2017 influenza A (H3N2) vaccine strain differs from that contained in the 2015-2016 seasonal vaccines. The 2016-2017 influenza B vaccine strain (Victoria lineage) included in the trivalent vaccine differs from that contained in the 2015-2016 seasonal trivalent vaccines (Yamagata lineage). a. Trivalent vaccine contains an A/California/7/2009 (H1N1)pdm09-like virus, an A/Hong Kong/4801/2014 (H3N2)-like virus, and a B/Brisbane/60/2008-like virus (B/Victoria lineage). b. Quadrivalent vaccine contains an additional B virus (B/Phuket/3073/2013-like virus [B/Yamagata lineage]).3. Quadrivalent live attenuated influenza vaccine (LAIV4) should not be used in any setting during the 2016-2017 influenza season in light of the evidence for poor effectiveness of LAIV4 in recent seasons, particularly against influenza A (H1N1)pdm09 viruses.4. All children with egg allergy can receive influenza vaccine with no additional precautions from those of routine vaccinations.5. All HCP should receive an annual influenza vaccine, a crucial step in preventing influenza and reducing health care-associated influenza infections. Because HCP may care for or live with people at high risk of influenza-related complications, it is especially important for them to get vaccinated annually.6. Pediatricians should attempt to promptly identify children suspected of having influenza for rapid antiviral treatment, when indicated, to reduce morbidity and mortality.

An overview of the regulation of influenza vaccines in the United States.

Influenza virus vaccines are unique among currently licensed viral vaccines. The vaccines designed to protect against seasonal influenza illness must be updated periodically in an effort to match the vaccine strain with currently circulating viruses, and the vaccine manufacturing timeline includes multiple, overlapping processes with a very limited amount of flexibility. In the United States (U.S.), over 150 million doses of seasonal trivalent and quadrivalent vaccine are produced annually, a mammoth effort, particularly in the context of a vaccine with components that usually change on a yearly basis. In addition, emergence of an influenza virus containing an HA subtype that has not recently circulated in humans is an ever present possibility. Recently, pandemic influenza vaccines have been licensed, and the pathways for licensure of pandemic vaccines and subsequent strain updating have been defined. Thus, there are formidable challenges for the regulation of currently licensed influenza vaccines, as well as for the regulation of influenza vaccines under development. This review describes the process of licensing influenza vaccines in the U.S., the process and steps involved in the annual updating of seasonal influenza vaccines, and some recent experiences and regulatory challenges faced in development and evaluation of novel influenza vaccines.

Matrix-M™ adjuvation broadens protection induced by seasonal trivalent virosomal influenza vaccine.

BackgroundInfluenza virus infections are responsible for significant morbidity worldwide and therefore it remains a high priority to develop more broadly protective vaccines. Adjuvation of current seasonal influenza vaccines has the potential to achieve this goal.MethodsTo assess the immune potentiating properties of Matrix-M™, mice were immunized with virosomal trivalent seasonal vaccine adjuvated with Matrix-M™. Serum samples were isolated to determine the hemagglutination inhibiting (HAI) antibody titers against vaccine homologous and heterologous strains. Furthermore, we assess whether adjuvation with Matrix-M™ broadens the protective efficacy of the virosomal trivalent seasonal vaccine against vaccine homologous and heterologous influenza viruses.ResultsMatrix-M™ adjuvation enhanced HAI antibody titers and protection against vaccine homologous strains. Interestingly, Matrix-M™ adjuvation also resulted in HAI antibody titers against heterologous influenza B strains, but not against the tested influenza A strains. Even though the protection against heterologous influenza A was induced by the adjuvated vaccine, in the absence of HAI titers the protection was accompanied by severe clinical scores and body weight loss. In contrast, in the presence of heterologous HAI titers full protection against the heterologous influenza B strain without any disease symptoms was obtained.ConclusionThe results of this study emphasize the promising potential of a Matrix-M™-adjuvated seasonal trivalent virosomal influenza vaccine. Adjuvation of trivalent virosomal vaccine does not only enhance homologous protection, but in addition induces protection against heterologous strains and thus provides overall more potent and broad protective immunity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-015-0435-9) contains supplementary material, which is available to authorized users.

Matrix-M Adjuvated Seasonal Virosomal Influenza Vaccine Induces Partial Protection in Mice and Ferrets against Avian H5 and H7 Challenge.

There is a constant threat of zoonotic influenza viruses causing a pandemic outbreak in humans. It is virtually impossible to predict which virus strain will cause the next pandemic and it takes a considerable amount of time before a safe and effective vaccine will be available once a pandemic occurs. In addition, development of pandemic vaccines is hampered by the generally poor immunogenicity of avian influenza viruses in humans. An effective pre-pandemic vaccine is therefore required as a first line of defense. Broadening of the protective efficacy of current seasonal vaccines by adding an adjuvant may be a way to provide such first line of defense. Here we evaluate whether a seasonal trivalent virosomal vaccine (TVV) adjuvated with the saponin-based adjuvant Matrix-M (MM) can confer protection against avian influenza H5 and H7 virus strains in mice and ferrets. We demonstrate that mice were protected from death against challenges with H5N1 and H7N7, but that the protection was not complete as evidenced by severe clinical signs. In ferrets, protection against H7N9 was not observed. In contrast, reduced upper and lower respiratory tract viral loads and reduced lung pathology, was achieved in H5N1 challenged ferrets. Together these results suggest that, at least to some extent, Matrix-M adjuvated seasonal virosomal influenza vaccine can serve as an interim measure to decrease morbidity and mortality associated with a pandemic outbreak.

Immunogenicity of virosomal adjuvanted trivalent influenza vaccination in allogeneic stem cell transplant recipients.

Influenza vaccination is generally recommended to hematopoietic stem cell transplant (HSCT) recipients. However, the seasonal subunit vaccination response is frequently suboptimal, and alternate more efficient vaccination systems must be examined. We compared the immunogenicity of an adjuvanted virosomal influenza and subunit vaccine in HSCT recipients. The immunogenicity after a single dose (0.5 mL) of adjuvanted trivalent virosomal vaccination was evaluated in a study cohort of 21 HSCT recipients and compared to a control cohort of 30 HSCT recipients who received a single dose (0.5 mL) of non-adjuvanted seasonal trivalent subunit vaccination over 4 seasons from 2010 to 2014. Whole blood interferon-gamma (IFN-γ) release assays were tested, both before and 30 days after vaccination, in response to influenza pandemic (pdm) H1N1, H3N2, and B antigens. HLA-A*02 dextramers, to gauge for the absolute number of antigen-specific CD8(+) T-cells, and pdm 2009 hemagglutinin inhibition (HI) assays, to test for neutralizing antibodies, were used as immunological readouts. The pdm HI titers were poor in both cohorts with only 23% (5/21) after virosomal vaccination and 13.3% (4/30) in the seasonal vaccine cohort having protective titers (≥40). The delta change of IFN-γ production in response to influenza pdm H1N1 (P = 0.005) and influenza B antigens (P = 0.01) were significantly elevated in blood from individuals who received the virosomal as compared to the seasonal vaccine. The IFN-γ response to pdm H1N1 was stronger (P < 0.001), as compared to seasonal vaccination, in patients vaccinated >6 month post HSCT. We detected a significant increase in the frequency of matrix 1 (GILGFVTL) dextramer-specific CD8(+) T-cells after the virosomal vaccine (P = 0.01). No differences were seen in the hemagglutinin-specific CD8(+) T-cells between the 2 cohorts. Vaccination using a virosomal delivery system is beneficial in eliciting robust cellular immune responses to pdm H1N1 influenza in SCT recipients.

Field seasonal influenza vaccine effectiveness

Thanks to the screening method, we estimated among target groups the 2010/2011 field vaccine effectiveness (FVE) against laboratory confirmed influenza cases seen in general practice. We also compared the values of FVE estimations obtained by using three sources of the population vaccination coverage (VC) based on three different methodologies: (1) administrative data from the main social security scheme (Caisse Nationale d’Assurance Maladie des Travailleurs Salariés—CNAMTS) covering about 85% of the French population, (2) a cross-sectional national telephone survey in the general population, and (3) a declarative survey in the population seen in a one-day general practitioner (GP) consultations. The FVE estimates among target groups were stratified by age (<65 y old with reported chronic illness; ≥65 y old and overall). Using the VC of the CNAMTS, the FVE of the 2010/2011 seasonal trivalent vaccine against laboratory confirmed infection with any influenza virus was 59% (95% Confidence Interval, 17 to 81). It was 85% (17 to 99) and 50% (–16 to 80) for A(H1N1)pdm09 and B influenza infections, respectively. The values of FVE using the influenza VC obtained in a sample of the general population and of the population of GPs’ patients were 73% (45 to 87) and 82% (63 to 92), respectively. We estimated a moderate influenza FVE in preventing confirmed influenza viruses in target groups by using the VC of the CNAMTS. We also observed that the screening method generates FVE values dependent on the choice of the source of VC and thus should be used cautiously.

SAT0001 Antibody Response to Pneumococcal and Influenza Vaccination in Patients With RA Receiving Subcutaneous Abatacept

BackgroundPrevious small studies have suggested that responses to some immunizations may be attenuated by intravenous abatacept but remain clinically meaningful.1,2 We investigated the magnitude of response to pneumococcal and influenza...

Neuraminidase-Inhibiting Antibody Is a Correlate of Cross-Protection against Lethal H5N1 Influenza Virus in Ferrets Immunized with Seasonal Influenza Vaccine

In preparing for the threat of a pandemic of avian H5N1 influenza virus, we need to consider the significant delay (4 to 6 months) necessary to produce a strain-matched vaccine. As some degree of cross-reactivity between seasonal influenza vaccines and H5N1 virus has been reported, this was further explored in the ferret model to determine the targets of protective immunity. Ferrets were vaccinated with two intramuscular inoculations of trivalent inactivated split influenza vaccine or subcomponent vaccines, with and without adjuvant, and later challenged with a lethal dose of A/Vietnam/1203/2004 (H5N1) influenza virus. We confirmed that vaccination with seasonal influenza vaccine afforded partial protection against lethal H5N1 challenge and showed that use of either AlPO(4) or Iscomatrix adjuvant with the vaccine resulted in complete protection against disease and death. The protection was due exclusively to the H1N1 vaccine component, and although the hemagglutinin contributed to protection, the dominant protective response was targeted toward the neuraminidase (NA) and correlated with sialic acid cleavage-inhibiting antibody titers. Purified heterologous NA formulated with Iscomatrix adjuvant was also protective. These results suggest that adjuvanted seasonal trivalent vaccine could be used as an interim measure to decrease morbidity and mortality from H5N1 prior to the availability of a specific vaccine. The data also highlight that an inducer of cross-protective immunity is the NA, a protein whose levels are not normally monitored in vaccines and whose capacity to induce immunity in recipients is not normally assessed.

Cross‐reactive antibody response to the pandemic A (H1N1) 2009 influenza virus induced by vaccination with a seasonal trivalent influenza vaccine: a longitudinal study of three influenza seasons in Japan

The cross-reactivity of antibody to the swine-origin pandemic influenza A (H1N1) 2009 virus induced by vaccination with a seasonal trivalent influenza vaccine was studied. Paired sera from a cohort of adult volunteers vaccinated with a trivalent seasonal influenza vaccine every year from 2006 to 2008 were collected each year and tested by hemagglutination inhibition (HI) for antibody against the pandemic influenza A (H1N1) 2009 virus. There was little increase in the geometric mean titer overall; a slight increase was detected in the sera obtained in the 2007-2008 season but not in the other two seasons. The proportion of individuals with HI antibody titers ≥ 1:40 did not change significantly from year to year. These results indicate that cross-reactivity of the antibodies induced by a trivalent seasonal vaccine to the pandemic influenza A (H1N1) 2009 virus is marginal.

Early uptake of seasonal influenza vaccines incorporated with pH1N1 strain among regularly vaccinated healthcare workers

Objectives: This study aims to assess the vaccination uptake and attitudes of healthcare workers (HCWs) towards seasonal influenza vaccination after incorporating pandemic H1N1 (pH1N1) strain in the vaccines. Methods: A self-administered anonymous questionnaire was issued to nurses registered with any of three collaborating nursing associations in Hong Kong. Results: A total of 709 questionnaires were completed, representing a response rate of 28.4%. The coverage of 2010/11 seasonal influenza vaccines was 24.1%. It was lower than that of 2009/10 seasonal influenza vaccines, in which pH1N1 strain was not yet included (37.1%), but higher than that of monovalent pH1N1 vaccines introduced during the pandemic in 2009 (14.2%). The reduction in the number of vaccinated HCWs varied among sub-groups classified by age, duration of employment, type of contacts with patients or past seasonal influenza vaccination record. Early recipients of the vaccine were more likely to have already been vaccinated in the preceding year (odds ratio (OR)=2.95, 95% confidence interval (95% CI) =1.15–7.59) and showed an intention to be vaccinated in the following year (OR=2.78, 95% CI=1.13–6.83). However, incorporation of pH1N1 strain in trivalent seasonal vaccines did not significantly increase the desire for vaccination. Conclusion: In addition to upholding the efficacy and safety standard of influenza vaccines, compliance and acceptance strategies shall be developed as early as possible, and tailored to the needs of different sub-groups.

Safety and immunogenicity of an AS03-adjuvanted A(H1N1)pmd09 vaccine administered simultaneously or sequentially with a seasonal trivalent vaccine in adults 61 years or older: Data from two multicentre randomised trials

During the 2009–2010 Northern Hemisphere influenza season, both seasonal and pandemic influenza vaccines were expected to be administered to elderly people, which is an important target group for influenza vaccination. Two multicentre randomised clinical studies were conducted in participants aged ≥61 years to assess the immunogenicity and reactogenicity following vaccination with two doses of an AS03-adjuvanted A(H1N1)pmd09 vaccine when either sequentially administered (21 days before first dose [N=73] or 21 days after second dose [N=72]) or co-administered (first dose [N=84] or second dose [N=84]) with a licensed trivalent seasonal influenza vaccine (TIV). Overall, 313 participants from 2 centres in Sweden (ClinicalTrials.gov, NCT00968890) and 6 centres in Germany (NCT00971425) were randomised to one of the four treatment groups. The AS03-adjuvanted A(H1N1)pmd09 vaccine elicited a good immune response against A(H1N1)pmd09-like virus in all treatment groups after the first and second dose, meeting and exceeding the European licensing criteria for pandemic influenza vaccines. After one dose of the AS03-adjuvanted A(H1N1)pmd09 vaccine, haemagglutination inhibition seroconversion rates ranged from 85% (95% confidence interval: 74–93%) to 93% (85–97%), seroprotection rates from 87% (76–94%) to 96% (90–99%) and geometric mean fold rise from 15 (11–19) to 20 (16–25). The haemagglutination inhibition immune responses to the AS03-adjuvanted A(H1N1)pmd09 vaccine seemed lower when TIV was administered 3 weeks before, while immune responses to TIV seemed not affected by either vaccination schedule. Solicited symptoms were more frequently reported following administration of the AS03-adjuvanted A(H1N1)pmd09 vaccine compared to TIV, but these were mainly mild to moderate in intensity and transient in the four treatment groups. These results suggest that sequential or co-administration of the AS03-adjuvanted A(H1N1)pmd09 vaccine and TIV induced a good immune response to both vaccines and had a clinically acceptable safety profile in people aged ≥61 years.

Influenza Pandemics—Pregnancy, Pathogenesis, and Perinatal Outcomes

SINCE THE 1918 INFLUENZA PANDEMIC, IT HAS BEEN clear that pandemic influenza is associated with increased morbidity and mortality in pregnancy, and more recent studies have shown that nonpandemic seasonal influenza strains also lead to morbidity for pregnant women and their infants. In the 2009 worldwide pandemic of influenza A(H1N1)pdm09, pregnant women were at high risk for severe complications, including death and intensive care unit admission. The adverse effects of antenatal influenza infection on pregnant women and their infants suggest a biological effect of influenza infection in the mother that compromises the fetus. These effects are rarely associated with direct infection of the fetus with influenza virus, although fetal infection has been reported infrequently during epidemics, pandemics, and with the H5N1 influenza strain. Instead, it appears that the normal pregnancy-associated immunologic changes may inhibit the inflammatory response to influenza virus infection in pregnancy, leading to increased risks to mother and infant. Because of these observations, pregnant women have been listed among high-risk groups for seasonal influenza vaccine in the United States since 1997, and safety data suggest these vaccines are safe in pregnancy. Pregnant women were prioritized for immunization during the 2009 influenza A(H1N1)pdm09 pandemic, despite limited data on the safety of pandemic influenza vaccines in pregnancy. In this issue of JAMA, Pasternak and colleagues report the results of an observational cohort study on the safety in pregnancy of the monovalent inactivated ASO3adjuvanted split virion influenza A(H1N1)pdm09 vaccine. The authors linked several Danish national registries to examine outcomes in infants born during the 2009 influenza A(H1N1)pdm09 pandemic. From a cohort of 53 432 infants, 6989 received the influenza vaccine during pregnancy. The authors included 330 infants whose mothers received the influenza A(H1N1)pdm09 vaccine in the first trimester and 6642 infants whose mothers received the vaccine in the second or third trimesters in propensity score analyses matched 1:1 with infants whose mothers were unvaccinated. No statistically significant relationships were found between receipt of vaccine and several perinatal outcomes, including major birth defects, preterm birth, and fetal growth restriction. The authors had sufficient sample size to exclude these adverse outcomes after vaccination in the second or third trimesters, but could only exclude moderate to large risks after vaccination in the first trimester. In addition, these authors recently reported on the risk of fetal death (spontaneous abortion and stillbirth) in the same cohort and found no increased risk after vaccination in pregnancy. These results suggest that this monovalent adjuvanted pandemic vaccine is safe when given during pregnancy. The authors did not address the question of vaccine effectiveness and did not discuss the issue of narcolepsy, which was observed with use of this adjuvanted vaccine in Scandinavian countries. However, the researchers have the opportunity to follow up this cohort of children to determine long-term vaccine safety, ie, assessment of early infant development. Recently, Fell et al reported a similar analysis of the use of H1N1 pdm09 adjuvanted vaccine in a cohort in Ontario, Canada, of 55 570 pregnant women, of whom 23 340 received the vaccine. This study demonstrated that mothers who were immunized were less likely than mothers who were not to have an infant with small for gestational age (relative risk [RR], 0.90; 95% CI, 0.85-0.96), preterm birth at less than 32 weeks gestation (RR, 0.73; 95% CI, 0.530.91), and fetal death (RR, 0.66; 95% CI, 0.47-0.91). Reports of maternal vaccination during seasonal influenza have also shown a reduction in the proportion of small for gestational age births and an increase in mean birth weight associated with immunization of the pregnant woman, or a decrease in birth weight related to influenza infection. The pandemic vaccine used in Denmark was an adjuvanted vaccine. In the United States, a nonadjuvanted vaccine was used during the 2009 pandemic with identical H1N1 viral antigens, which were also included in the seasonal trivalent vaccines for 2009-2012. Data from the United States