Non-adjuvanted Vaccine Research Articles

Safety and Immunogenicity of a Nonadjuvant Human Papillomavirus Type 6 Virus-like Particle Vaccine in Recurrent Respiratory Papillomatosis

To assess the safety and immunogenicity of a nonadjuvant human papillomavirus (HPV) type 6 L1 virus-like particle (VLP) vaccine in recurrent respiratory papillomatosis (RRP) in local Chinese patients. Patients with RRP who had undergone surgical treatment before intramuscular administration of an escalating dose of HPV type 6 L1 VLPs (1, 5, and 25 µg at 4 weekly intervals) as part of their treatment were followed up for more than 10 years. Efficacy was assessed by detecting the vaccine-induced type-specific antibody titer, calculating the intersurgical interval, and observing recurrence or remission of papillomas after receiving the vaccine. Nonadjuvant HPV vaccine was generally well tolerated, with no serious vaccine-related adverse episodes. It induced seroconversion for each vaccine-related HPV type. At week 12 (4 weeks after injecting 25 µg), the vaccine-induced type-specific antibody titer was significantly high. Analysis of all patients found a significant increase in the intersurgical interval and decrease in the scores. One patient (16.7%; female) experienced complete remission. Five patients (83.3%) (two males and three females) experienced partial remission. In total, complete or partial remission was achieved in six (100%) patients. Administration of nonadjuvant HPV type 6 L1 VLPs vaccine to RRP was generally well tolerated and highly immunogenic.

Efficacy of an adenovirus-vectored foot-and-mouth disease virus serotype A subunit vaccine in cattle using a direct contact transmission model

BackgroundA direct contact transmission challenge model was used to simulate natural foot-and-mouth disease virus (FMDV) spread from FMDV A24/Cruzeiro/BRA/55 infected ‘seeder’ steers to naïve or vaccinated steers previously immunized with a replication-deficient human adenovirus-vectored FMDV A24/Cruzeiro/BRA/55 capsid-based subunit vaccine (AdtA24). In two independent vaccine efficacy trials, AdtA24 was administered once intramuscularly in the neck 7 days prior to contact with FMDV A24/Cruzeiro/BRA/55-infected seeder steers.ResultsIn Efficacy Study 1, we evaluated three doses of AdtA24 to estimate the 50%/90% bovine protective dose (BPD50/90) for prevention of clinical FMD. In vaccinated, contact-challenged steers, the BPD50/90 was 3.1 × 1010 / 5.5 × 1010 AdtA24 particles formulated without adjuvant. In Efficacy Study 2, steers vaccinated with 5 × 1010 AdtA24 particles, exposed to FMDV A24/Cruzeiro/BRA/55-infected seeder steers, did not develop clinical FMD or transmit FMDV to other vaccinated or naïve, non-vaccinated steers. In contrast, naïve, non-vaccinated steers that were subsequently exposed to FMDV A24/Cruzeiro/BRA/55-infected seeder steers developed clinical FMD and transmitted FMDV by contact to additional naïve, non-vaccinated steers. The AdtA24 vaccine differentiated infected from vaccinated animals (DIVA) because no antibodies to FMDV nonstructural proteins were detected prior to FMDV exposure.ConclusionsA single dose of the AdtA24 non-adjuvanted vaccine conferred protection against clinical FMD at 7 days post-vaccination following direct contact transmission from FMDV-infected, naïve, non-vaccinated steers. The AdtA24 vaccine was effective in preventing FMDV transmission from homologous challenged, contact-exposed, AdtA24-vaccinated, protected steers to co-mingled, susceptible steers, suggesting that the vaccine may be beneficial in reducing both the magnitude and duration of a FMDV outbreak in a commercial cattle production setting.

Safety and immunogenicity of a pentavalent meningococcal conjugate vaccine containing serogroups A, C, Y, W, and X in healthy adults: a phase 1, single-centre, double-blind, randomised, controlled study

Invasive meningococcal disease is an important public health problem, especially in sub-Saharan Africa. After introduction of MenAfriVac in 2010, Neisseria meningitidis serogroup A disease has been almost eliminated from the region. However, serogroups C, W, Y, and X continue to cause disease outbreaks. We assessed the NmCV-5 pentavalent meningococcal conjugate vaccine targeting A, C, Y, W, and X serogroups in a first-in-man, phase 1 study. We did a single-centre, double-blind, randomised controlled trial at a research clinic in Baltimore (MD, USA). Participants were healthy adults aged 18-45 years with no history of meningococcal vaccination or previous meningococcal infection. We randomly assigned participants (1:1:1) by an SAS-generated random schedule to a single, 0·5 mL, intramuscular injection of aluminium-phosphate adjuvanted NmCV-5, non-adjuvanted NmCV-5, or control (the quadrivalent meningococcal conjugate vaccine Menactra). The randomisation sequence used a permuted block design with randomly chosen block sizes of three and six. The vaccines were prepared, labelled, and administered with procedures to ensure participants and study personnel remained masked to treatment. After vaccination, participants were observed in the clinic for 60 min for adverse reactions. Participants recorded daily temperature and injection site or systemic reactions at home and returned to the clinic for follow-up visits on days 7, 28, and 84 for safety assessments; blood samples were also collected on day 7 for safety laboratory assessment. A phone call contact was made 6 months after vaccination. Serum was collected before vaccination and 28 days after vaccination for immunological assessment with a rabbit complement-dependent serum bactericidal antibody (rSBA) assay. The primary objective was an intention-to-treat assessment of safety, measuring local and systemic reactogenicity over 7 days, unsolicited adverse events through 28 days, and serious adverse events over 6 months. The secondary objective for the assessment of immunogenicity, was a per-protocol analysis of rSBA before and 28 days after vaccination. This trial is registered with ClinicalTrials.gov, number NCT02810340. Between Aug 17, 2016, and Feb 16, 2017, we assigned 20 participants to each vaccine. All vaccines were well-tolerated. Pain was the most common local reaction, occurring in 12 (60%), ten (50%), and seven (35%) participants in the adjuvanted NmCV-5, non-adjuvanted NmCV-5, and control groups, respectively. Headache was the most common systemic reaction, occurring in five (25%), three (15%), and three (15%), respectively. Most solicited reactogenicity adverse reactions were mild (60 [74%] of 81) and all were self-limiting. None of the differences in proportions of individuals with each solicited reaction was significant (p>0·300 for all comparisons) between the three vaccination groups. There were no serious adverse events and 19 unsolicited non-serious adverse events in 14 (23%) participants. Both adjuvanted and non-adjuvanted NmCV-5 elicited high rSBA titres against all five meningococcal serogroups. The pre-vaccination geometric mean titres (GMTs) ranged from 3·36 to 53·80 for the control, from 6·28 to 187·00 for the adjuvanted vaccine, and from 4·29 to 350·00 for the non-adjuvanted vaccine, and the post-vaccination GMT ranged from 3·14 to 3214 for the control, from 1351 to 8192 for the adjuvanted vaccine, and from 1607 to 11 191 for the non-adjuvanted vaccine. Predicted seroprotective responses (ie, an increase in rSBA titres of eight times or more) for the adjuvanted and non-adjuvanted NmCV-5 were similar to control responses for all five serogroups. The adjuvanted and non-adjuvanted NmCV-5 vaccines were well tolerated and did not produce concerning adverse effects and resulted in immune responses that are predicted to confer protection against all five targeted serogroups of invasive meningococcal disease. Further clinical testing of NmCV-5 is ongoing, and additional clinical trials are necessary to confirm the safety and immunogenicity of NmCV-5 in target populations. UK Department for International Development.

Influenza virus-like particles composed of conserved influenza proteins and GPI-anchored CCL28/GM-CSF fusion proteins enhance protective immunity against homologous and heterologous viruses

Influenza viruses cause significant morbidity and mortality and pose a substantial threat to public health. Vaccination represents the principle means of preventing influenza virus infection. Current vaccine approaches are hindered by the need to routinely reformulate vaccine compositions in an effort to account for the progressive antigenic changes that occur as influenza viruses circulate in the human population. In this study, we evaluated chimeric virus-like particle (cVLP) vaccines containing conserved elements of influenza proteins (HL5M2e (HA stem gene with 5M2e gene inserted) and NP), with or without glycosylphosphatidylinositol-anchored CCL28 (GPI-CCL28) and/or GM-CSF (GPI-GM-CSF) fusion proteins as molecular adjuvants. cVLPs elicited strong humoral and cellular immune responses against homologous and heterologous viruses, and improved survival following lethal challenge with both homologous and heterologous viruses. Inclusion of GPI-anchored adjuvants in cVLP vaccines augmented the generation of influenza-specific humoral and cellular immune responses in mice in comparison to the non-adjuvanted cVLP vaccines. VLPs containing GPI-anchored adjuvants reduced morbidity and improved survival to lethal challenge with homologous and heterologous influenza viruses. This work suggests that VLP vaccines incorporating conserved influenza virus proteins and GPI-anchored molecular adjuvants may serve as a platform for a broadly protective “universal” influenza vaccine.

Feline Injection Site Sarcomas: Data from Switzerland 2009–2014

Feline injection site sarcomas (FISS) were first described in the early 1990s. Despite extensive research, the pathogenesis of these tumours has not been elucidated conclusively. Their appearance and the marked increase in their incidence has been mainly connected to the injection of vaccines,and it is assumed that a chronic inflammatory reaction at the injection site triggers subsequent malignant transformation. The role of alum-based adjuvants has been discussed, but is controversial. The present study of the Swiss Feline Cancer Registry (SFCR) with data from 2009 to 2014 revealed a marked decrease of the incidence of fibrosarcomas compared with the previous observation period. Notably, this drop occurred after a non-adjuvanted feline leukaemia virus vaccine was introduced in Switzerland in 2007. This observation, together with the previous findings of the SFCR, further supports the notion that alum-adjuvanted vaccines are involved in the genesis of FISS and that non-adjuvanted vaccines might be safer for cats.

Rational Zika vaccine design via the modulation of antigen membrane anchors in chimpanzee adenoviral vectors

Zika virus (ZIKV) emerged on a global scale and no licensed vaccine ensures long-lasting anti-ZIKV immunity. Here we report the design and comparative evaluation of four replication-deficient chimpanzee adenoviral (ChAdOx1) ZIKV vaccine candidates comprising the addition or deletion of precursor membrane (prM) and envelope, with or without its transmembrane domain (TM). A single, non-adjuvanted vaccination of ChAdOx1 ZIKV vaccines elicits suitable levels of protective responses in mice challenged with ZIKV. ChAdOx1 prME ∆TM encoding prM and envelope without TM provides 100% protection, as well as long-lasting anti-envelope immune responses and no evidence of in vitro antibody-dependent enhancement to dengue virus. Deletion of prM and addition of TM reduces protective efficacy and yields lower anti-envelope responses. Our finding that immunity against ZIKV can be enhanced by modulating antigen membrane anchoring highlights important parameters in the design of viral vectored ZIKV vaccines to support further clinical assessments.

A novel adjuvant G3 induces both Th1 and Th2 related immune responses in mice after immunization with a trivalent inactivated split-virion influenza vaccine

A preferred adjuvant should promote both Th1 and Th2 responses. However, most adjuvants in common use are biased towards a Th2-driven response. Therefore, the ability of a novel saponin-based adjuvant G3 to inducing balanced Th1 and Th2 responses in BALB/c mice immunized with a split trivalent seasonal influenza vaccine was evaluated in comparison to that of the adjuvant Al(OH)3. Clear differences in the IgG profiles induced by G3, Al(OH)3 or non-adjuvanted vaccine were recorded. Both adjuvants enhanced high and similar levels of the Th2 associated IgG1 subtype compared to mice given vaccine alone. Only G3 enhanced the IgG2a subclass reflecting a Th1 response, whereas Al(OH)3 even abrogated the IgG2a production. Accordingly, G3 enhanced the production of IL-2 and IFN-γ and also of IL-2/IFN-γ double secreting cells, emphasizing the strong Th1 driving effect of G3. Only Al(OH)3 increased splenocyte production of IL-17. Taken together, the results indicate a strong propensity for G3 to induce both Th1 and Th2 driven immune responses.

Vaccination with killed whole-cells of Escherichia coli O157:H7 hha mutant emulsified with an adjuvant induced vaccine strain-specific serum antibodies and reduced E. coli O157:H7 fecal shedding in cattle

Escherichia coli O157:H7 (O157) can cause from a mild diarrheal illness to hemorrhagic colitis and hemolytic uremic syndrome in humans. Cattle are the primary reservoir for O157 and fecal shedding of O157 by these animals is a major risk factor in contamination of cattle hides and carcasses at slaughter. Vaccination is an important strategy to reduce fecal shedding of O157 in cattle. In this study, we evaluated the immunogenicity and efficacy of an inactivated vaccine strain of O157 formulated with an adjuvant. This vaccine strain was deleted of the hha gene enabling high level expression of the locus of enterocyte effacement (LEE) encoded proteins required for O157 colonization in cattle. The inactivated vaccine strain emulsified with the adjuvant or suspended in the phosphate-buffered saline (PBS) was injected in the neck muscles of two groups of weaned calves followed by a booster three weeks later with the corresponding formulation. Animals in groups 3 and 4 were injected similarly with the adjuvant and PBS, respectively. All animals were orally inoculated three weeks post-booster vaccination with a live culture of O157. The animals vaccinated with the adjuvanted vaccine showed higher serum antibody titers to the vaccine strain and shed O157 for a shorter duration and at lower numbers compared to the animals vaccinated with the non-adjuvanted vaccine, adjuvant-only, or PBS. Western blotting of the vaccine strain lysates showed higher immunoreactivity of serum IgG in vaccinated animals to several O157-specific proteins and lipopolysaccharides (LPS). The vaccination induced IgG showed specificity to LEE-encoded proteins and outer membrane LPS as LEE and waaL deletion mutants, unable to produce LEE proteins and synthesize high molecular weight LPS, respectively, yielded significantly lower antibody titers compared to the parent vaccine strain. The positive reactivity of the immune serum was also observed for purified LEE-encoded proteins EspA and EspB. In conclusion, the results of this animal study showed that a two-dose regimen of an adjuvanted vaccine is capable of inducing O157-specific immune response that directly or indirectly reduced fecal shedding of O157 in cattle.

Efficacy, immunogenicity, and safety evaluation of an MF59-adjuvanted quadrivalent influenza virus vaccine compared with non-adjuvanted influenza vaccine in children: a multicentre, randomised controlled, observer-blinded, phase 3 trial

Young children have immature immune systems and respond poorly to standard influenza vaccines. The oil-in-water emulsion adjuvant MF59 can increase antigen uptake, macrophage recruitment, lymph node migration, and avidity to influenza virus. Therefore, we aimed to assess the relative efficacy, immunogenicity, and safety of an MF59-adjuvanted, quadrivalent, inactivated (subunit) influenza vaccine (aIIV4) compared with a US-licensed non-adjuvanted influenza vaccine in children. We did a multicentre, randomised controlled, observer-blinded, phase 3 trial of 146 sites including hospitals, clinics, and clinician offices in nine countries over two influenza seasons. We included children of either sex aged 6 months through 5 years. We stratified eligible participants and randomly assigned them (1:1), using a block size of four, to receive either aIIV4 or non-adjuvanted inactivated influenza vaccine (ie, trivalent inactivated influenza vaccine [IIV3] or quadrivalent inactivated influenza vaccine [IIV4]). We masked participants, parents or guardians, and outcome assessors to the administered vaccine. Designated personnel who were not masked administered aIIV4 in both seasons, or IIV3 in season one and IIV4 in season two. All vaccinations were administered intramuscularly. Children aged 6 through 35 months received one or two 0·25 mL doses, whereas those aged 3 through 5 years received one or two doses of 0·5 mL. The number of doses was dependent on previous vaccination status: vaccine-naive participants received a total of two doses of study vaccine, the first on day 1 and the second on day 29, whereas non-naive participants received only one dose on day 1. The primary outcome was relative vaccine efficacy assessed by RT-PCR-confirmed influenza due to any influenza strain in the overall study population and in prespecified age and dose subgroups. Immunogenicity against homologous and heterologous strains of influenza and safety were also measured. This study is registered with ClinicalTrials.gov, number NCT01964989. Between Nov 3, 2013, and March 5, 2014 (season one), and between Sept 30, 2014, and March 29, 2015 (season two), 10 644 participants were enrolled in this study. Of these participants, 10 612 were vaccinated (n=5338 with aIIV4 and n=5274 with comparator). Relative vaccine efficacy was not different between aIIV4 and the comparator vaccines in the overall study population (relative vaccine efficacy -0·67, 95% CI -19·81 to 15·41). The relative vaccine efficacy in the 6 through 23-month subgroup was significantly greater for aIIV4 than for the comparator vaccine (relative vaccine efficacy 31·37, 95% CI 3·14-51·38). aIIV4 elicited superior immunogenic response compared with the comparator for all four vaccine strains (geometric mean titre ratios 1·91 [95% CI 1·8-2·0] for A/H1N1, 1·71 [1·6-1·8] for A/H3N2, 2·19 [2·0-2·4] for B/Yamagata, and 2·27 [2·0-2·6] for B/Victoria) and three heterologous strains (1·94 [1·6-2·3] for A/H3N2, 2·17 [1·8-2·6] for B/Yamagata, and 2·12 [1·6-2·7] for B/Victoria) in participants aged 6 months through 5 years. The highest geometric mean titre ratios were observed in participants aged 6 through 23 months. Safety profiles were similar but more frequent solicited adverse events were reported with aIIV4 than with the comparator (3748 [73%] of 5138 vs 3242 [64%] of 5056). Although there was no additional benefit of aIIV4 compared with the US-licensed non-adjuvanted influenza vaccines in the overall study population, in the youngest and most vulnerable population of children in this trial, aIIV4 provided greater protection against influenza than a non-adjuvanted vaccine when assessed in this prespecified age group of 6 through 23 months. Additional clinical benefit was also apparent early after first vaccination in vaccine-naive participants aged 6 months through 5 years. Finally, aIIV4 and comparator had similar efficacy and vaccine safety profiles in children aged 6 months through 5 years. Seqirus UK Ltd.

Nasal route favors the induction of CD4+ T cell responses in the liver of HBV-carrier mice immunized with a recombinant hepatitis B surface- and core-based therapeutic vaccine

Immunization routes and number of doses remain largely unexplored in therapeutic vaccination. The aim of the present work is to evaluate their impact on immune responses in naïve and hepatitis B virus (HBV)-carrier mouse models following immunization with a non-adjuvanted recombinant vaccine comprising the hepatitis B surface (HBsAg) and core (HBcAg) antigens. Mice were immunized either by intranasal (i.n.), subcutaneous (s.c.) or simultaneous (i.n. + s.c.) routes. Humoral immunity was detected in all the animal models with the induction of a potent antibody (Ab) response against HBcAg, which was stronger than the anti-HBs response. In the HBV-carrier mouse model, the anti-HBs response was predominantly subtype-specific and preferentially induced by the i.n. route. However, the Ab titers were not sufficient to clear the high concentration of HBsAg present in the sera of these mice. The i.n. route was the most efficacious at inducing cellular immune responses, in particular CD4+ T cells. In naïve mice, cellular responses in spleen were strong and mainly due to CD4+ T cells whereas the CD8+ T-cell response was low. In HBV-carrier mice, high frequencies of HBs-specific CD4+ T cells secreting interferon (IFN)-γ, interleukin (IL)-2 and tumor necrosis factor (TNF)-α were found in liver only after i.n. immunization. Increased frequencies of CD4+ T cells expressing the integrin CD49a in liver suggest a role of nasal route in the cellular homing process. Multiple dose schedules appear to be a prerequisite for protein-based immunization in order to overcome immunotolerance in HBV-carrier mice. These findings provide new avenues for further preclinical and clinical development.

Modeling for influenza vaccines and adjuvants profile for safety prediction system using gene expression profiling and statistical tools.

Historically, vaccine safety assessments have been conducted by animal testing (e.g., quality control tests and adjuvant development). However, classical evaluation methods do not provide sufficient information to make treatment decisions. We previously identified biomarker genes as novel safety markers. Here, we developed a practical safety assessment system used to evaluate the intramuscular, intraperitoneal, and nasal inoculation routes to provide robust and comprehensive safety data. Influenza vaccines were used as model vaccines. A toxicity reference vaccine (RE) and poly I:C-adjuvanted hemagglutinin split vaccine were used as toxicity controls, while a non-adjuvanted hemagglutinin split vaccine and AddaVax (squalene-based oil-in-water nano-emulsion with a formulation similar to MF59)-adjuvanted hemagglutinin split vaccine were used as safety controls. Body weight changes, number of white blood cells, and lung biomarker gene expression profiles were determined in mice. In addition, vaccines were inoculated into mice by three different administration routes. Logistic regression analyses were carried out to determine the expression changes of each biomarker. The results showed that the regression equations clearly classified each vaccine according to its toxic potential and inoculation amount by biomarker expression levels. Interestingly, lung biomarker expression was nearly equivalent for the various inoculation routes. The results of the present safety evaluation were confirmed by the approximation rate for the toxicity control. This method may contribute to toxicity evaluation such as quality control tests and adjuvant development.

Influenza vaccines in immunosuppressed adults with cancer.

This is an update of the Cochrane review published in 2013, Issue 10.Immunosuppressed cancer patients are at increased risk of serious influenza-related complications. Guidelines, therefore, recommend influenza vaccination for these patients. However, data on vaccine effectiveness in this population are lacking, and the value of vaccination in this population remains unclear. To assess the effectiveness of influenza vaccine in immunosuppressed adults with malignancies. The primary review outcome is all-cause mortality, preferably at the end of the influenza season. Influenza-like illness (ILI, a clinical definition), confirmed influenza, pneumonia, any hospitalisations, influenza-related mortality and immunogenicity were defined as secondary outcomes. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and LILACS databases up to May 2017. We searched the following conference proceedings: ICAAC, ECCMID, IDSA (infectious disease conferences), ASH, ASBMT, EBMT (haematological), and ASCO (oncological) between the years 2006 to 2017. In addition, we scanned the references of all identified studies and pertinent reviews. We searched the websites of the manufacturers of influenza vaccine. Finally, we searched for ongoing or unpublished trials in clinical trial registry databases. Randomised controlled trials (RCTs), prospective and retrospective cohort studies and case-control studies were considered, comparing inactivated influenza vaccines versus placebo, no vaccination or a different vaccine, in adults (16 years and over) with cancer. We considered solid malignancies treated with chemotherapy, haematological cancer patients treated or not treated with chemotherapy, cancer patients post-autologous (up to six months after transplantation) or allogeneic (at any time) haematopoietic stem cell transplantation (HSCT). Two review authors independently assessed the risk of bias and extracted data from included studies adhering to Cochrane methodology. Meta-analysis could not be performed because of different outcome and denominator definitions in the included studies. We identified six studies with a total of 2275 participants: five studies comparing vaccination with no vaccination, and one comparing adjuvanted vaccine with non-adjuvanted vaccine. Three studies were RCTs, one was a prospective observational cohort study and two were retrospective cohort studies.For the comparison of vaccination with no vaccination we included two RCTs and three observational studies, including 2202 participants. One study reported results in person-years while the others reported results per person. The five studies were performed between 1993 and 2015 and included adults with haematological diseases (three studies), patients following bone marrow transplantation (BMT) (two studies) and solid malignancies (three studies).One RCT and two observational studies reported all-cause mortality; the RCT showed similar mortality rates in both arms (odds ratio (OR) 1.25 (95% CI 0.43 to 3.62; 1 study, 78 participants, low-certainty evidence)); and the observational studies demonstrated a significant association between vaccine receipt and lower risk of death, adjusted hazard ratio 0.88 (95% CI 0.78 to 1; 1 study, 1577 participants, very low-certainty evidence) in one study and OR 0.42 (95% CI 0.24 to 0.75; 1 study, 806 participants, very low-certainty evidence) in the other. One RCT reported a reduction in ILI with vaccination, while no difference was observed in one observational study. Confirmed influenza rates were lower with vaccination in one RCT and the three observational studies, the difference reaching statistical significance in one. Pneumonia was observed significantly less frequently with vaccination in one observational study, but no difference was detected in another or in the RCT. One RCT showed a reduction in hospitalisations following vaccination, while an observational study found no difference. No life-threatening or persistent adverse effects from vaccination were reported. The strength of evidence was limited by the low number of included studies and by their low methodological quality and the certainty of the evidence for the mortality outcome according to GRADE was low to very low.For the comparison of adjuvanted vaccine with non-adjuvanted vaccine, we identified one RCT, including 73 patients. No differences were found for the primary and all secondary outcomes assessed. Mortality risk ratio was 0.54 (95% CI 0.05 to 5.73; low-certainty evidence) in the adjuvanted vaccine group. The quality of evidence was low due to the small sample size and the large confidence intervals for all outcomes. Observational data suggest lower mortality and infection-related outcomes with influenza vaccination. The strength of evidence is limited by the small number of studies and low grade of evidence. It seems that the evidence, although weak, shows that the benefits overweigh the potential risks when vaccinating adults with cancer against influenza. However, additional placebo or no-treatment controlled RCTs of influenza vaccination among adults with cancer is ethically questionable.There is no conclusive evidence regarding the use of adjuvanted versus non-adjuvanted influenza vaccine in this population.

MF59-adjuvanted influenza vaccine (FLUAD®) elicits higher immune responses than a non-adjuvanted influenza vaccine (Fluzone®): A randomized, multicenter, Phase III pediatric trial in Mexico

ABSTRACTThe poor immune response elicited by trivalent influenza vaccines (TIVs) in children can be enhanced by the addition of adjuvants. This observer-blind, randomized Phase III trial assessed the immunogenicity and safety of the MF59-adjuvanted trivalent influenza vaccine FLUAD® (aTIV) and a non-adjuvanted TIV, in healthy children (aged 6 to <72 months) from 3 centers in Mexico, during the 2014–2015 season. The primary objectives were to assess the non-inferiority of aTIV to TIV, measured by geometric mean titers (GMTs), and the safety of aTIV and TIV. Seroconversion was one of several secondary objectives. In total, 287 children were enrolled. The non-inferiority criteria for GMTs and seroconversion were met for aTIV for all 3 vaccine strains. Lower bounds of the 95% confidence intervals for all 3 aTIV:TIV vaccine ratios were >2, showing that the immunogenicity of aTIV was superior to that of TIV for all 3 strains. Solicited adverse events (AEs) were experienced more frequently with aTIV than TIV by younger children (aged 6 to <36 months), but were more frequent with TIV than aTIV in older children (aged 36 to <72 months) who had been vaccinated previously. More unsolicited AEs were associated with aTIV than the TIV. All AEs were of mild or moderate severity. No deaths, serious AEs, or AEs leading to premature withdrawal were reported. Overall, aTIV was highly immunogenic and was well tolerated in healthy children 6 to <72 months of age. These results indicate that aTIV may be a beneficial addition to national pediatric vaccination programs.

AS03- and MF59-Adjuvanted Influenza Vaccines in Children.

Influenza is a major cause of respiratory disease leading to hospitalization in young children. However, seasonal trivalent influenza vaccines (TIVs) have been shown to be ineffective and poorly immunogenic in this population. The development of live-attenuated influenza vaccines and adjuvanted vaccines are important advances in the prevention of influenza in young children. The oil-in-water emulsions MF59 and adjuvant systems 03 (AS03) have been used as adjuvants in both seasonal adjuvanted trivalent influenza vaccines (ATIVs) and pandemic monovalent influenza vaccines. Compared with non-adjuvanted vaccine responses, these vaccines induce a more robust and persistent antibody response for both homologous and heterologous influenza strains in infants and young children. Evidence of a significant improvement in vaccine efficacy with these adjuvanted vaccines resulted in the use of the monovalent (A/H1N1) AS03-adjuvanted vaccine in children in the 2009 influenza pandemic and the licensure of the seasonal MF59 ATIV for children aged 6 months to 2 years in Canada. The mechanism of action of MF59 and AS03 remains unclear. Adjuvants such as MF59 induce proinflammatory cytokines and chemokines, including CXCL10, but independently of type-1 interferon. This proinflammatory response is associated with improved recruitment, activation and maturation of antigen presenting cells at the injection site. In young children MF59 ATIV produced more homogenous and robust transcriptional responses, more similar to adult-like patterns, than did TIV. Early gene signatures characteristic of the innate immune response, which correlated with antibody titers were also identified. Differences were detected when comparing child and adult responses including opposite trends in gene set enrichment at day 3 postvaccination and, unlike adult data, a lack of correlation between magnitude of plasmablast response at day 7 and antibody titers at day 28 in children. These insights show the utility of novel approaches in understanding new adjuvants and their importance for developing improved influenza vaccines for children.

Research progress in human infection with avian influenza H7N9 virus.

Since the identification of the novel reassortant avian influenza A (H7N9) virus in China in 2013, until Jun 30, 2017, the virus has caused five epidemic waves leading to a total of 1,552 human infections, with a fatality rate of about 40%. In the spring of 2017, highly pathogenic avian influenza (HPAI) H7N9 virus emerged and has caused 25 human infections. The HPAI H7N9 virus has some biological differences from the LPAI one, such as its multiple basic amino acid residues on HA leading to its independence on trypsin for replication. The pathogenicity of the HPAI H7N9 virus to experimental animals or humans is still unclear. A(H7N9) vaccine development for pandemic preparedness is ongoing, including the reassortment (H7N9/PR8) reverse genetic based vaccine, the virus like particle (VLP) vaccine, the intranasal live attenuated influenza vaccine (LAIV), the non-adjuvant Vero cell culture-derived inactivated whole-virus vaccine, the MDCK culture-derived vaccine, the H7 DNA vaccine and the recombinant replicative H7N9 virus (H7N9-53TM) vaccine. Five neuramidinase resistant sites of A(H7N9) virus isolated from patients have been reported. Some alternative drugs have been studied, such as DAS181 (Fludase), ribavirin, troglitazone and minocycline. Persistent surveillance and enhanced global control are essential to fight against human infections with A(H7N9) virus.

Efficacy and safety of a non-mineral oil adjuvanted injectable vaccine for the protection of Atlantic salmon (Salmo salar L.) against Flavobacterium psychrophilum

Flavobacterium psychrophilum is the causative agent of Rainbow Trout Fry Syndrome which has had a major impact on global salmonid aquaculture. Recent outbreaks in Atlantic salmon in Scotland and Chile have added to the need for a vaccine to protect both salmon and trout. At present no licensed vaccines are available in Europe, leaving antibiotics as the only course of action to contain disease outbreaks. Outbreaks generally occur in fry at temperatures between 10 and 15 °C. Recently outbreaks in larger fish have given added impetus to the development of a vaccine which can provide long term protection from this highly heterogeneous pathogen. Most fish injectable vaccines are formulated with oil emulsion adjuvants to induce strong and long lasting immunity, but which are known to cause side effects. Alternative adjuvants are currently sought to minimise these adverse effects.The current study was performed to assess the efficacy of a polyvalent, whole cell vaccine containing formalin-inactivated F. psychrophilum to induce protective immunity in Atlantic salmon. The vaccine was formulated with an adjuvant containing squalene and aluminium hydroxide, and was compared to a vaccine formulated with a traditional oil adjuvant, Montanide ISA 760VG, and a non-adjuvanted vaccine. Duplicate groups of salmon (23.5 ± 6.8 g) were vaccinated with each of the vaccine formulations or phosphate buffered saline by intraperitoneal injection. Fish were challenged by intramuscular injection with F. psychrophilum six weeks post-vaccination to test the efficacy of the vaccines. Cumulative mortality reached 70% in the control salmon, while the groups of salmon that received vaccine had significantly lower mortality than the controls (p = 0.0001), with no significant difference in survival between vaccinated groups. The squalene/alum adjuvant was safe, more readily metabolised by the fish and induced less histopathological changes than the traditional oil adjuvant.

Adjuvanting an inactivated influenza vaccine with conjugated R848 improves the level of antibody present at 6months in a nonhuman primate neonate model.

Generation of a potent antibody response that can be sustained over time is highly challenging in young infants. Our previous studies using a nursery-reared nonhuman primate model identified R848 conjugated to inactivated influenza virus as a highly immunogenic vaccine for neonates. Here we determined the effectiveness of this vaccine in mother-reared infants as well as its ability to promote improved responses at 6months compared to vaccination in the absence of R848. In agreement with our nursery study, R848 conjugated to influenza virus induced a higher antibody response in neonates compared to the non-adjuvanted vaccine. Further, the increase in the response relative to that induced by the non-adjuvanted vaccine was maintained at 6months suggesting the increased antibody secreting cells that resulted from inclusion of conjugated R848 production were capable of surviving long term. There was no significant difference in quality of antibody (i.e. neutralization or affinity), suggesting the beneficial effect of conjugated R848 during vaccination of neonates with inactivated influenza virus is likely manifest during the early generation of antibody secreting cells.

New Guidance Clarifies Use of Pneumococcal, Influenza Vaccines in Older Adults

New Guidance Clarifies Use of Pneumococcal, Influenza Vaccines in Older Adults

Adjuvantation of Pulmonary-Administered Influenza Vaccine with GPI-0100 Primarily Stimulates Antibody Production and Memory B Cell Proliferation.

Adjuvants are key components in vaccines, they help in reducing the required antigen dose but also modulate the phenotype of the induced immune response. We previously showed that GPI-0100, a saponin-derived adjuvant, enhances antigen-specific mucosal and systemic antibody responses to influenza subunit and whole inactivated influenza virus (WIV) vaccine administered via the pulmonary route. However, the impact of the GPI-0100 dose on immune stimulation and the immune mechanisms stimulated by GPI-0100 along with antigen are poorly understood. Therefore, in this study we immunized C57BL/6 mice via the pulmonary route with vaccine consisting of WIV combined with increasing amounts of GPI-0100, formulated as a dry powder. Adjuvantation of WIV enhanced influenza-specific mucosal and systemic immune responses, with intermediate doses of 5 and 7.5 μg GPI-0100 being most effective. The predominant antibody subtype induced by GPI-0100-adjuvanted vaccine was IgG1. Compared to non-adjuvanted vaccine, GPI-0100-adjuvanted WIV vaccine gave rise to higher numbers of antigen-specific IgA- but not IgG-producing B cells in the lungs along with better mucosal and systemic memory B cell responses. The GPI-0100 dose was negatively correlated with the number of influenza-specific IFNγ- and IL17-producing T cells and positively correlated with the number of IL4-producing T cells observed after immunization and challenge. Overall, our results show that adjuvantation of pulmonary-delivered WIV with GPI-0100 mostly affects B cell responses and effectively induces B cell memory.

Efficacy of a nonadjuvanted recombinant FeLV vaccine and two inactivated FeLV vaccines when subject to consistent virulent FeLV challenge conditions

The purpose of this study was to compare the efficacy of three FeLV vaccines, under identical conditions in a laboratory challenge model that closely mimics natural infection. Four groups of cats (n = 20 per group) were administered two doses of vaccine, 21 days apart, starting at 9–10 weeks of age (Purevax® FeLV, Versifel® FeLV, Nobivac® feline 2-FeLV, and a placebo). Cats were challenged 3 weeks later with a virulent, heterologous FeLV isolate. FeLV antigenemia was determined at weekly intervals from 3 to 15 weeks postchallenge. Circulating proviral DNA was determined on terminal PBMC samples. Following challenge, persistent antigenemia developed in 15 (75%) placebo-vaccinated cats, 3 (15%) cats in the Versifel FeLV vaccinated group, and 1 cat (5%) each in the Purevax FeLV and the Nobivac FeLV vaccinated groups. The prevented fractions for three vaccine groups were 93%, 93%, and 80% respectively. The adjusted p-values for all vaccine group comparisons fail to approach statistical significance. There was excellent agreement between proviral FeLV DNA in circulating PBMCs and persistent antigenemia. It is shown that when cats are managed under the same conditions during a virulent challenge, via the normal route of infection, the tested vaccines all show a comparable degree of protection.