Pandemic H1N1 Influenza Vaccine Research Articles

Vaccines and Bell's palsy: A narrative review

The association between vaccines and peripheral facial palsy (PFP), an issue that has been the subject of debate for many years, has been raised again following results of clinical trials assessing mRNA based COVID-19 vaccines. To review the available literature on this topic, PubMed was searched from inception until February 25, 2022. Inclusion criteria were case reports with documented rechallenge and comparative epidemiological studies. Cases of COVID-19 vaccine-induced PFP with available data on vaccine rechallenge were also identified from Vigibase until December 31, 2021. Of the 347 articles retrieved, 32 comparative epidemiological studies, 1 meta-analysis and 4 case reports met our criteria, of which 13 involved COVID-19 vaccines. Eight studies found an association between at least one vaccine and the occurrence of PFP, whereas 24 did not. Positive studies involved seasonal or pandemic H1N1 influenza vaccines administered parenterally (4 studies) or intranasally (1 study with a toxin-adjuvanted vaccine), BNT162b2, a mRNA COVID-19 vaccine (1 disproportionality analysis and 1 observed-to-expected analysis) and an inactivated virus COVID-19 vaccine (CoronaVac®) (1 study combining a case-control and an observed-to-expected approach). Strong evidence was found only for the intranasal influenza vaccine while other positive studies detected only a marginal association between PFP and vaccination. Of the four case reports with documented rechallenge, only two were positive and involved an influenza vaccine and tozinameran in one case each. In Vigibase, rechallenge was documented in 49 reports with 29 (59.2%) cases being negative and 20 (40.8%) positive. The available data did not confirm an excess risk of PFP after vaccination in most studies. Moreover, of the eight epidemiological studies suggesting a possible excess risk of PFP after any vaccine, three were disproportionality analyses and two observed-to excepted analyses, suggesting great caution should be taken when interpreting these results.

Improvement of the aging-related reduced efficacy of the H1N1 pandemic influenza vaccine by the complex of poly-γ-glutamic acid and alum

Abstract Highly contagious respiratory diseases caused by viral infections, like influenza are a constantly emerging threat, particularly among the elderly. Vaccination is one of the most effective strategy for preventing influenza, but the aged-related reduced efficacy of the influenza vaccine remains an unresolved problem. Here, we demonstrate that the aging-related reduced efficacy of the influenza vaccine can be improved by the complex of poly-γ-glutamic acid (γ-PGA) and alum called PGA/Alum, a new adjuvant capable of inducing innate and adaptive immune responses in aged mice. PGA/Alum induced activation of dendritic cells isolated from spleen of aged mice, with increases of expression of co-stimulatory molecules and production of pro-inflammatory cytokines. Although aged mice were observed decrease of T and B cell population and weaken efficacy of pandemic H1N1 influenza vaccine than young mice, PGA/Alum recovered the vaccine efficacy in aged mice. Notably, the vaccine-PGA/Alum-immunized aged mice increased hemagglutination-inhibition titers, serum-neutralization titers, cytotoxic T lymphocyte activity, and generation of multifunctional CD4+ T lymphocytes. Taken together, these results suggest that PGA/Alum could be a potent vaccine adjuvant that improves the aging-related reduced efficacy of the influenza vaccine, thereby resulting in effective prevention against influenza virus infection in the elderly. This research was funded by a grant from KRIBB Research Initiative Program (KGM9942112).

No evidence of birth defects or spontaneous abortion from pandemic H1N1-influenza vaccine

No evidence of birth defects or spontaneous abortion from pandemic H1N1-influenza vaccine

The Complex of Poly-γ-Glutamic Acid and Alum Induces Cross-Protective Immunity of Pandemic H1N1 Influenza Vaccine

Abstract Vaccination is the most effective strategy to protect against infectious diseases, and adjuvants are key vaccine components that improve antigen-specific immune responses. Here, we developed a new adjuvant named PGA/Alum by combining poly-γ-glutamic acid (γ-PGA) with alum and investigated its ability to enhance the immunogenicity and the cross-reactive efficacy of pandemic H1N1 (pH1N1) influenza vaccine antigen. PGA/Alum highly induced in vitro activation and antigen processing of dendritic cells, and enhanced antigen delivery to draining lymph nodes and antigen-specific immunogenicity in mice using OVA as a model antigen. Also, OVA-specific antibody production, cytotoxic T lymphocyte (CTL) activity, and antibody-dependent cellular cytotoxicity (ADCC) were greatly increased by PGA/Alum. These abilities of PGA/Alum improved the protective efficacy of pH1N1 vaccine antigen by increasing hemagglutination-inhibition titers, enhancing ADCC and CTL activity, and speeding viral clearance following homologous viral challenge. Importantly, PGA/Alum significantly enhanced the cross-protective efficacy of pH1N1 vaccine against heterologous viruses [A/Puerto Rico/8/34 (H1N1) and A/Hong Kong/1/1968 (H3N2)] by inducing cross-reactive ADCC and CTL activities. Together, our results strongly suggest that PGA/Alum may be a promising vaccine adjuvant for preventing influenza and other infectious diseases.

Pharmacovigilance and drug-induced rare diseases: Strengths of the French Network of Regional Pharmacovigilance Centres

The French-style organization in the field of rare diseases allows a close contact between reference centres and regional pharmacovigilance centres thanks to their implementation within the French university hospital. This collaboration leads to highlight more and more drug-induced rare diseases. Through several historical examples (eosinophilia-myalgia syndrome due to L-tryptophan, type 1 narcolepsy with H1N1 pandemic influenza vaccine, capillary leak syndrome, acquired von Willebrand syndrome), it remains clear that pharmacovigilance is the cornerstone of the alert system. Clinicians from the rare disease reference centres can easily report adverse drug reactions (ADRs) to pharmacologists from their regional pharmacovigilance centre. Through experience, collaboration between countries, large database, and sometimes pharmacoepidemiological studies, an alert can then be raised. This collaboration underlines also similarities between the two disciplines, through the frequency of ADRs and diseases, the difficulty of the diagnosis in front of scarce data, and through the unusual worsening symptoms. Patients and associations of patients play also a proactive role as research partners at different steps, to quantify and qualify symptoms and ADRs, and also to develop orphan drugs. These several collaborations are a precious tool to improve patients' outcomes. These close contacts between the different actors are important to make earlier diagnosis of rare diseases and severe ADRs. Rare disease does not have to mean overlooked diseases.

Poly-γ-Glutamic Acid Complexed With Alum Induces Cross-Protective Immunity of Pandemic H1N1 Vaccine.

The use of a good vaccine adjuvant may induce a higher immunogenicity profile of vaccine antigens. Here, we developed a new adjuvant by combining poly-γ-glutamic acid (γ-PGA) with alum (PGA/Alum) and investigated its ability to enhance the immunogenicity and the cross-reactive efficacy of pandemic H1N1 (pH1N1) influenza vaccine antigen. PGA/Alum enhanced antigen delivery to draining lymph nodes and antigen-specific immunogenicity in mice using OVA as a model antigen. It also greatly increased OVA-specific antibody production, cytotoxic T lymphocyte (CTL) activity, and antibody-dependent cellular cytotoxicity (ADCC). These abilities of PGA/Alum improved the protective efficacy of pH1N1 vaccine antigen by increasing hemagglutination-inhibition titers, enhancing ADCC and CTL activity, and speeding viral clearance following homologous viral challenge. Importantly, the cross-protective efficacy of pH1N1 vaccine against heterologous viruses [A/Puerto Rico/8/34 (H1N1) and A/Hong Kong/1/1968 (H3N2)] was significantly enhanced by PGA/Alum, and cross-reactive ADCC and CTL activities were observed. Together, our results strongly suggest that PGA/Alum may be a promising vaccine adjuvant for preventing influenza and other infectious diseases.

Health outcomes of young children born to mothers who received 2009 pandemic H1N1 influenza vaccination during pregnancy: retrospective cohort study

ObjectiveTo determine whether any association exists between exposure to 2009 pandemic H1N1 (pH1N1) influenza vaccination during pregnancy and negative health outcomes in early childhood.DesignRetrospective cohort study.SettingPopulation based birth registry linked...

Vitamin A Supplementation during Pregnancy Enhances Pandemic H1N1 Vaccine Response in Mothers, but Enhancement of Transplacental Antibody Transfer May Depend on When Mothers Are Vaccinated during Pregnancy

In the growing embryo, the vitamin A requirement is tightly regulated. Maternal vitamin A deficiency during pregnancy may alter maternal immune function to accommodate the fetus. Our primary objective was to determine the effect of oral vitamin A supplementation (VAS) during pregnancy and until 6 mo postpartum on pandemic H1N1-vaccine responses in mothers and their infants at 6 mo of age. In this randomized controlled clinical trial, pregnant women (n=112) during the second trimester (mean ± SD:14±1wk) were assigned to receive either an oral dose of 10,000 IU vitamin A or placebo weekly until 6 mo postpartum. During the third trimester, mothers received a single dose of inactivated pandemic H1N1-influenza vaccine. Hemagglutination-inhibition (HAI) titer was measured in cord, infant, and maternal blood samples. Multivariate regressions with adjustments were used for data analysis. Seventy-six percent of women had low plasma retinol concentrations (<1.05 μmol/L) in their second trimester. VAS of mothers increased vitamin A concentrations in cord blood by 21.4% and in colostrum by 40.7%. At 6 mo postpartum, women in the vitamin A group had 38.7% higher HAI titers and a higher proportion of HAI titer of ≥1:40 of the cutoff compared with the placebo group. A total of 54.5% of infants had an HAI titer ≥1:40 at 6 mo of age, but there was no difference in HAI titer in infants between groups. Overall, HAI in cord blood did not differ between groups, but in the placebo group, cord blood HAI was negatively associated with maternal "vaccination-to-delivery intervals" (rs=-0.401; P = 0.5), and maternal VAS increased cord blood HAI 6-fold if antenatal immunization was administered ≥10 wk before delivery. In a community with low vitamin A status, weekly maternal VAS during pregnancy and postpartum increases the breast-milk vitamin A concentration and enhances prenatal H1N1-vaccine responses in mothers, but the benefits of maternal VAS in transplacental antibody transfer may depend on the time of gestation when mothers were vaccinated. This trial was registered at clinicaltrials.gov as NCT00817661.

Incidence rates of narcolepsy diagnoses in Taiwan, Canada, and Europe: The use of statistical simulation to evaluate methods for the rapid assessment of potential safety issues on a population level in the SOMNIA study.

Background & objectivesVaccine safety signals require investigation, which may be done rapidly at the population level using ecological studies, before embarking on hypothesis-testing studies. Incidence rates were used to assess a signal of narcolepsy following AS03-adjuvanted monovalent pandemic H1N1 (pH1N1) influenza vaccination among children and adolescents in Sweden and Finland in 2010. We explored the utility of ecological data to assess incidence of narcolepsy following exposure to pandemic H1N1 virus or vaccination in 10 sites that used different vaccines, adjuvants, and had varying vaccine coverage.MethodsWe calculated incidence rates of diagnosed narcolepsy for periods defined by influenza virus circulation and vaccination campaign dates, and used Poisson regression to estimate incidence rate ratios (IRRs) comparing the periods during which wild-type virus circulated and after the start of vaccination campaigns vs. the period prior to pH1N1 virus circulation. We used electronic health care data from Sweden, Denmark, the United Kingdom, Canada (3 provinces), Taiwan, Netherlands, and Spain (2 regions) from 2003 to 2013. We investigated interactions between age group and adjuvant in European sites and conducted a simulation study to investigate how vaccine coverage, age, and the interval from onset to diagnosis may impact the ability to detect safety signals.ResultsIncidence rates of narcolepsy varied by age, continent, and period. Only in Taiwan and Sweden were significant time-period-by-age-group interactions observed. Associations were found for children in Taiwan (following pH1N1 virus circulation) and Sweden (following vaccination). Simulations showed that the individual-level relative risk of narcolepsy was underestimated using ecological methods comparing post- vs. pre-vaccination periods; this effect was attenuated with higher vaccine coverage and a shorter interval from disease onset to diagnosis.ConclusionsEcological methods can be useful for vaccine safety assessment but the results are influenced by diagnostic delay and vaccine coverage. Because ecological methods assess risk at the population level, these methods should be treated as signal-generating methods and drawing conclusions regarding individual-level risk should be avoided.

Prenatal exposure to the 2009 pandemic H1N1 influenza vaccine on health outcomes in children

IntroductionDuring the 2009 H1N1 pandemic, less than half of pregnant women in Ontario received the recommended influenza vaccine. Commonly-cited reasons for low vaccine uptake include misconceptions about the possible impact of maternal influenza infection and vaccine safety. Providing data on previously understudied pediatric health outcomes may help increase vaccine uptake.&#x0D; Objectives and ApproachWe conducted a retrospective cohort study of all live births from November 2nd, 2009 to October 31st, 2010 using the BORN Ontario province-wide birth registry containing information on H1N1 vaccination. These data were deterministically/probabilistically linked with several health administrative databases held at the Institute for Clinical Evaluative Sciences to ascertain specific immune-related pediatric health outcomes and health services utilization over 5 years of follow-up. Negative binomial regression models were used to evaluate the association between prenatal H1N1 vaccination and outcomes. Stabilized inverse probability of treatment weights (sIPTW) derived from the propensity scores were used to adjust for potential confounding.&#x0D; ResultsThe study cohort included 104,310 eligible infants, 31,310 (30%) of whom were born to H1N1-vaccinated women. Median follow-up time was 5 years. Using sIPTWs we were able to achieve good balance of baseline measured covariates across exposure groups, with no absolute standardized differences larger than 7%. The sIPTW-adjusted analyses indicated no significant associations between prenatal exposure to H1N1 vaccination and upper respiratory infections (adjusted rate ratio [aRR] 1.01; 95% confidence interval [CI] 0.98-1.03), lower respiratory infections (aRR 1.00; 95%CI 0.96-1.04), otitis media (aRR 1.04; 95%CI 1.00-1.07), all infections (aRR 1.00; 95%CI 0.98-1.03), and rates of urgent and in-patient health services utilization (aRR 1.00; 95%CI 0.98-1.02).&#x0D; Conclusion/ImplicationsOur primary findings suggest there are no associations between prenatal exposure to H1N1 vaccination and (1) the development of several immune-related health outcomes in children; (2) rates of health services utilization. Furthermore, our study provides new evidence on the long-term safety of influenza vaccination during pregnancy, which is currently lacking.

Narcolepsy and adjuvanted pandemic influenza A (H1N1) 2009 vaccines – Multi-country assessment

BackgroundIn 2010, a safety signal was detected for narcolepsy following vaccination with Pandemrix, an AS03-adjuvanted monovalent pandemic H1N1 influenza (pH1N1) vaccine. To further assess a possible association and inform policy on future use of adjuvants, we conducted a multi-country study of narcolepsy and adjuvanted pH1N1 vaccines. MethodsWe used electronic health databases to conduct a dynamic retrospective cohort study to assess narcolepsy incidence rates (IR) before and during pH1N1 virus circulation, and after pH1N1 vaccination campaigns in Canada, Denmark, Spain, Sweden, Taiwan, the Netherlands, and the United Kingdom. Using a case-control study design, we evaluated the risk of narcolepsy following AS03- and MF59-adjuvanted pH1N1 vaccines in Argentina, Canada, Spain, Switzerland, Taiwan, and the Netherlands. In the Netherlands, we also conducted a case-coverage study in children born between 2004 and 2009. ResultsNo changes in narcolepsy IRs were observed in any periods in single study sites except Sweden and Taiwan; in Taiwan incidence increased after wild-type pH1N1 virus circulation and in Sweden (a previously identified signaling country), incidence increased after the start of pH1N1 vaccination. No association was observed for Arepanrix-AS03 or Focetria-MF59 adjuvanted pH1N1 vaccines and narcolepsy in children or adults in the case-control study nor for children born between 2004 and 2009 in the Netherlands case-coverage study for Pandemrix-AS03. ConclusionsOther than elevated narcolepsy IRs in the period after vaccination campaigns in Sweden, we did not find an association between AS03- or MF59-adjuvanted pH1N1 vaccines and narcolepsy in children or adults in the sites studied, although power to evaluate the AS03-adjuvanted Pandemrix brand vaccine was limited in our study.

Poly-gamma glutamic acid/alum enhances the efficacy of vaccine antigen by modulating antigen transport to lymph nodes and the adaptive immune responses

Abstract Vaccination is the most effective strategy to protect against infectious diseases and adjuvants are proven to be the key component in vaccines capable of improving antigen-specific immune responses. Conventional vaccine adjuvants, however, still have several limitations such as safety concerns and insufficient induction of vaccine efficacy. Here, we developed a novel adjuvant by combining poly-gamma glutamic acid (γ-PGA) with alum that is already approved for human use worldwide. The physiochemical properties, efficacy, and underlying mechanism of the PGA/Alum as an adjuvant were investigated using ovalbumin (OVA) as a model antigen in vivo and in vitro. PGA/Alum-OVA administered mice showed the robust increase of antigen-specific humoral and cellular immune responses compared to mice administered with γ-PGA-OVA or alum-OVA. Importantly, the PGA/Alum-OVA-induced antibodies had significantly higher antibody-dependent cellular cytotoxicity (ADCC) activity. The enhanced activation and antigen processing of dendritic cells (DCs) and the facilitated migration of antigen-loaded DCs from the injection sites to draining lymph nodes were observed in PGA/Alum-OVA administered mice. Finally, the efficacy of the PGA/Alum as a vaccine adjuvant was evaluated using pandemic H1N1 influenza vaccine antigen. The PGA/Alum drastically enhanced protective efficacy of the pandemic H1N1 vaccine against influenza virus infection. Taken together, PGA/Alum may be a promising adjuvant to improve the influenza vaccine efficacy.

Birth outcomes following immunization of pregnant women with pandemic H1N1 influenza vaccine 2009–2010

BackgroundFollowing the H1N1 influenza pandemic in 2009, pregnant women were recommended to receive both seasonal (TIV) and H1N1 influenza vaccines. This study presents incidence of adverse birth and pregnancy outcomes among a population of pregnant women immunized with TIV and H1N1 vaccines at Kaiser Permanente Northern California during 2009–2010. MethodsWe telephone surveyed pregnant Kaiser Permanente Northern California members to assess non-medically-attended reactions following H1N1, TIV or both vaccines during 2009–2010 (n=5365) in a separate study. Here we assessed preterm birth (<37weeks), very preterm birth (<32weeks), low birth weight (<2500 g, LBW), very low birth weight (<1500g), small for gestational age, spontaneous abortions, stillbirths and congenital anomalies among this cohort by comparing incidence and 95% confidence intervals between the following immunization groups: TIV only, H1N1 only, H1N1 prior to TIV immunization, TIV prior to H1N1 and both immunizations given at the same time. ResultsResults did not vary significantly between groups. Comparing H1N1 with TIV, incidence were similar for preterm births (6.37vs 6.28/100 births), very preterm births (5.30vs 8.29/1000 births), LBW (4.19vs 2.90/100 births), very LBW (4.54vs 5.52/1000 births), small for gestational age (9.99vs 9.24/1000 births), spontaneous abortion (7.10vs 6.83/1000 pregnancies), stillbirths (7.10vs 4.57/1000 pregnancies), and congenital anomalies (2.66vs 2.43/100 births). ConclusionsAlthough constrained by small sample size, complex vaccine groups, and differential vaccine availability during 2009–2010, this study found no difference in adverse birth outcomes between H1N1 vaccine and TIV.

Nontoxic outer membrane vesicles efficiently increase the efficacy of an influenza vaccine in mice and ferrets

In this study, we developed a further-modified outer membrane vesicle (fmOMV) from the ΔmsbB/ΔpagP mutant of Escherichia coli transformed with the plasmid, pLpxF, in order to use it as an adjuvant for pandemic H1N1 (pH1N1) influenza vaccine. We evaluated the efficacy of the pH1N1 influenza vaccine containing the fmOMV in animal models as compared to the commercial adjuvants, alum or AddaVaxTM. The fmOMV–adjuvanted pH1N1 influenza vaccine induced a significant increase in the humoral immunity; however, this effect was less than that of the AddaVaxTM. The fmOMV–adjuvanted vaccine displayed pronounced an enhanced protective efficacy with increased T cell immune response and reduced the viral load in the lungs of the infected mice after challenging them with a lethal dose of the homologous virus. Moreover, it resulted in a significantly higher cross-protection against heterologous virus challenge than that of the pH1N1 vaccine with alum or with no adjuvants. In ferrets, the fmOMV–adjuvanted vaccine elicited a superior antibody response based on the HI titer and efficiently protected the animals from the lethal viral challenges. Taken together, the nontoxic fmOMV could be a promising adjuvant for inducing robust T cell priming into the pH1N1 vaccine and might be broadly applicable to the development of preventive measures against influenza virus infection.

Poly-\u03b3-glutamic acid/chitosan nanogel greatly enhances the efficacy and heterosubtypic cross-reactivity of H1N1 pandemic influenza vaccine

In 2009, the global outbreak of an influenza pandemic emphasized the need for an effective vaccine adjuvant. In this study, we examined the efficacy of poly-γ-glutamic acid/chitosan (PC) nanogel as an adjuvant for the influenza vaccine. PC nanogel significantly enhanced antigen-specific cross-presentation and cytotoxic T lymphocyte (CTL) activity. Compared with alum, the protective efficacy of the pandemic H1N1 influenza (pH1N1) vaccine was substantially increased by PC nanogel, with increased hemagglutination-inhibition titers, CTL activity, and earlier virus clearance after homologous and heterosubtypic [A/Philippines/2/82 (H3N2)] virus challenges. However, CD8+ T cell-depleted mice displayed no protection against the heterosubtypic virus challenge after immunization with PC nanogel-adjuvanted pH1N1 vaccine. We also observed that using PC nanogel as a vaccine adjuvant had a dose-sparing effect and significantly enhanced the long-lasting protection of the pH1N1 vaccine. Together, these results suggest that PC nanogel is a promising vaccine adjuvant that could broadly prevent influenza virus infection.

A De-O-acylated Lipooligosaccharide-Based Adjuvant System Promotes Antibody and Th1-Type Immune Responses to H1N1 Pandemic Influenza Vaccine in Mice.

Vaccine adjuvants are agents that are used to promote immune responses to vaccine antigens and thereby to enhance the protective efficacy of the vaccines. In this study, we investigated the adjuvant activity of CIA06, an adjuvant system that is composed of a toll-like receptor 4 agonist de-O-acylated lipooligosaccharide (dLOS) and aluminum hydroxide, on the H1N1 pandemic influenza vaccine Greenflu-S® in mice. CIA06 significantly enhanced influenza-specific serum IgG, hemagglutination-inhibition, and virus-neutralizing antibody titers, which eliminated vaccine dose-dependency in the antibody response. Mice immunized with the CIA06-adjuvanted Greenflu-S showed Th1-type-predominant cytokine profiles, and both CD4+ and CD8+ T cell responses were induced. Immunization of mice with the CIA06-adjuvanted vaccine reduced the mortality and morbidity of mice upon lethal challenges with influenza virus, and no excessive inflammatory responses were observed in the lung tissues of the immunized mice after viral infection. These data suggest that the dLOS-based adjuvant system CIA06 can be used to promote the immune responses to influenza vaccine or to spare antigen dose without causing harmful inflammatory responses.

Incidence of Narcolepsy in Germany.

Following the 2009 pandemic, reports of an association between an AS03 adjuvanted H1N1 pandemic influenza vaccine and narcolepsy were published. Besides determining background incidence rates for narcolepsy in Germany this study aimed at investigating whether there was a change in incidence rates of narcolepsy between the pre-pandemic, pandemic, and the post-pandemic period on the population level. Retrospective epidemiological study on the incidence of narcolepsy with additional capture-recapture analysis. German sleep centers. Eligible were patients with an initial diagnosis of narcolepsy (ICD10 Code G47.4) within the period from January 1, 2007 to December 31, 2011. None; observational study. A total of 342 sleep centers were invited to participate in the study. Adequate and suitable data were provided by 233 sleep centers (68.1%). A total of 1,198 patients with an initial diagnosis of narcolepsy within the observed period were included, of whom 106 (8.8%) were children and adolescents under the age of 18 years and 1,092 (91.2%) were adults. In children and adolescents, the age-standardized adjusted incidence rate significantly increased from 0.14/100,000 person-years in the pre-pandemic period to 0.50/100,000 person-years in the post-pandemic period (incidence density ratio, IDR 3.57; 95% CI 1.94-7.00). In adults, no significant change was detectable. This increase started in spring 2009. For the years 2007-2011, valid estimates for the incidence of narcolepsy in Germany were provided. In individuals under 18, the incidence rates continuously increased from spring 2009.

Preliminary study about sublingual administration of bacteria-expressed pandemic H1N1 influenza vaccine in miniature pigs.

Sublingual (SL) administration of influenza vaccine would be non-invasive and effective way to give human populations protective immunity against the virus, especially when pandemic influenza outbreaks. In this study, the efficacy of pandemic influenza virus-based subunit vaccines was tested after sublingual (SL) adjuvant administration in pigs. Eight specific pathogen-free Yucatan pigs were divided into 4 groups: nonvaccinated but challenged (A) and vaccinated and challenged (B, C, and D). The vaccinated groups were subdivided by vaccine type and inoculation route: SL subunit vaccine (hemagglutinin antigen 1 [HA1] + wild-type cholera toxin [wtCT], B); IM subunit vaccine (HA1 + aluminum hydroxide, C); and IM inactivated vaccine (+ aluminum hydroxide, D). The vaccines were administered twice at a 2-week interval. All pigs were challenged with pandemic influenza virus (A/swine/GCVP-KS01/2009 [H1N1]) and monitored for clinical signs, serology, viral shedding, and histopathology. After vaccination, hemagglutination inhibition titre was higher in group D (320) than in the other vaccinated groups (40-80) at the time of challenge. The mobility and feed intake were reduced in group C. Both viral shedding and histopathological lesions were reduced in groups B and D. Although this study has limitation due to the limited number of pigs (2 pigs per a group), the preliminary data in this study provided the protective potential of SL administration of bacteria-expressed pandemic H1N1 influenza vaccine in pigs. There should be additional animal studies about effective adjuvant system and vaccine types for the use of SL influenza vaccination.

Durability of protective antibody titres is not enhanced by a two-dose schedule of an ASO3-adjuvanted pandemic H1N1 influenza vaccine in adult HIV-1-infected patients.

The immune response after influenza vaccination is impaired in HIV-infected individuals and can be enhanced by a second dose. The durability of the antibody protection and its clinical benefit is not known. We investigated clinical symptoms and antibody titres against H1N1 influenza A following no dose, 1 dose, or 2 doses of an ASO3-adjuvanted H1N1 vaccine in HIV-infected patients. Seroprotection was found in 7.9%, 52.2%, and 57.3% of patients who received no dose, 1 dose, and 2 doses of the vaccine, respectively (p-value for group comparison < 0.001), after a median of 8.2 ± 1.6 months. Clinical symptoms suggestive of an influenza-like illness were slightly more frequently reported in the unvaccinated group. Vaccinated HIV-infected patients were more likely to be seroprotected at follow-up, but there was no difference comparing those who had received 1 or 2 doses of the vaccine.

Signal detection based on time-to-onset: extending a new method from spontaneous reports to observational studies.

A proof-of-concept study has previously highlighted the added value of a method using time-to-onset (TTO) for quantitative and non-parametric signal detection on spontaneous report data. The aim of this study was to assess the added value of this new TTO signal detection method adapted to observational studies. For each adverse event collected during the conduct of an observational study of H1N1 pandemic influenza vaccine, the TTO distribution was tested against the 'follow-up distribution' from vaccination to 'lost to follow-up' by a Kolmogorov-Smirnov test. Events rejecting the null hypothesis of similar distribution were flagged as signals, and a safety physician evaluated their relevance for further medical assessment. We simulated ongoing surveillance by performing retrospective weekly signal detection based on TTO. The TTO method detected 21, 15 and 4 signals within a 30-day period post-dose 1 with confidence levels set at 90%, 95% and 99%, respectively. Of these signals, 14 (67%), 10 (67%) and 2 (50%) were considered as relevant. Among the 14, six had not been identified by previous signal detection activities. When performed weekly, the Kolmogorov-Smirnov test detected 26 events as signals (alpha = 0.05). Three weeks after first participant first dose, one of the six new signals could theoretically have been detected. This study provided evidence that the Kolmogorov-Smirnov method can screen all TTO distributions and objectively flag the unexpected, leading to earlier detection of signals, and thus potential safety issues.