Adjuvanted Subunit Vaccine Research Articles

Heterologous Boost Following Mycobacterium bovis BCG Reduces the Late Persistent, Rather Than the Early Stage of Intranasal Tuberculosis Challenge Infection

Adults are the leading population affected by tuberculosis (TB) epidemic and death. Developing an effective vaccine against adult TB is urgently needed. Mycobacterium bovis Bacillus Calmette-Guerin (BCG) prime-heterologous boost strategy has been explored extensively to protect adults against primary TB infection, but the majority of experimental regimens have not improved the protection primed by the BCG vaccine. The reason attributed to the failure remains unknown. In this study, CTT3H-based vaccines, namely DMT adjuvanted CTT3H subunit or DNA vaccine (pCTT3H-DMT), and recombinant adenovirus rAdCTT3H were constructed. Protective efficacy and immunogenicity of BCG prime-CTT3H based boosters were compared in C57BL/c mice models of primary or late persistent TB infection. Similar protective efficacy against early intranasal infection was provided by different CTT3H-based vaccines alone in vaccinated mice, and their protection was inferior to that of the BCG vaccine. In addition, CTT3H-based heterologous boosters did not enhance the protection conferred by the BCG vaccine against primary infection. However, all of these three boosters provided stronger protection against late persistent TB infection than BCG alone, regardless of vaccine types. Although BCG prime-boosters elicited Th1-biased responses to the antigen CTT3H, the number of CTT3H-sepcific IFN-γ-expressing TEM (CD62LloCD44hi) and IL-2-expressing TCM (CD62LhiCD44hi) cells in the spleen was not improved before exposure to Mycobacterium tuberculosis infection. In contrast, IFN-γ+ TEM and IL-2+ TCM cells in spleens, especially in lungs were significantly increased in BCG prime-boosters after exposure vaccination. Our results indicate that BCG prime-boost strategy might be a promising measure for the prevention against late persistent TB infection by induction of IFN-γ+ TEM and IL-2+ TCM cells in the lung, which can be used as alternative biomarkers for guiding the clinical practice and future development of TB vaccine for adults.

Efficacy, effectiveness, and safety of herpes zoster vaccines in adults aged 50 and older: systematic review and network meta-analysis

ObjectiveTo compare the efficacy, effectiveness, and safety of the herpes zoster live attenuated vaccine with the herpes zoster adjuvant recombinant subunit vaccine or placebo for adults aged 50 and older.DesignSystematic...

A novel nonlive, adjuvanted herpes zoster subunit vaccine: a report on the emerging clinical data and safety profile.

Herpes zoster (HZ) is an acute vesicular dermatitis with a typical dermatomal distribution, caused by the varicella zoster virus (VZV), often preceded and accompanied by prodromal pain or pruritus. HZ may be related to several complications such as postherpetic neuralgia (PHN). The incidence and severity of the disease increase with aging, due to immunosenescence and in particular to the decline of the specific cell-mediated immunity (CMI). The impact of HZ in terms of morbidity and short- and long-term complications, the availability of suboptimal treatment options to date, and the high costs for the diagnostic and clinical-therapeutic management of patients have motivated the search for a new preventive approach through the development of a vaccine. The vaccine currently in use with live-attenuated virus (ZVL) has been shown to be effective in reducing the incidence of HZ, its impact, and the onset of PHN, although the efficacy is lower in older subjects and tends to decrease some years after immunization. A new adjuvanted recombinant subunit vaccine (HZ/su), containing the VZV glycoprotein E (gE) and the AS01B adjuvant system, is now a very promising alternative to ZVL; in several clinical studies, it showed a good safety profile and was able to elicit high immune humoral and cell-mediated responses, both maintained up to 9 years. Furthermore, HZ/su vaccine was effective both in preventing HZ and in reducing the onset of PHN and other complications. HZ/su has been recommended and preferred over ZVL by the Advisory Committee on Immunization Practices (ACIP) for the prevention of HZ and its complications in immunocompetent adults aged ≥50 years, even if already vaccinated with ZVL, through a two-dose schedule. HZ/su has been approved in Canada, USA, Europe, and Japan and is currently being approved in Australia. The aim of this review was to describe the epidemiological data, HZ and PHN risks and their impact on the social life and common life of infected people, and ZVL and HZ/su vaccine development including various clinical trials and efficacy, safety, and tolerability profiles.

Synergistic effect of dual targeting vaccine adjuvant with aminated β-glucan and CpG-oligodeoxynucleotides for both humoral and cellular immune responses

Presently, clinically approved adjuvants (such as aluminum salts) fail to induce cellular immune responses, which is crucial to defend against intracellular pathogens (including HIV, malaria, tuberculosis and Ebola) and cancer. However, Freund’s complete adjuvant potently stimulates both humoral and cellular immune responses, accompanying by high toxicity and severe side reactions. Here in this work, a CpG-oligodeoxynucleotides (CpG-OND) crosslinked aminated β-glucan-Ovalbumin dual targeting nanoparticle (CpG-OND-AG-OVA) is prepared through a simple and mild ionic complexation method. The aminated β-glucan plays dual roles as antigen presenting cells (APCs) targeted carrier and immunopotentiator (targeting and activating dectin-1 on APCs). Meanwhile, CpG-OND also plays dual roles as ionic crosslinker and immunopotentiator (targeting and activating Toll-like receptor 9 in APCs). The adjuvant activity of the particles is evaluated through in vitro and in vivo experiments. The particles significantly enhance uptake and sustained proteolytic processing of antigens, and result in APCs maturation, inducing robust Th1 and Th2-type immune responses comparable to Freund’s adjuvant without obvious toxicity. The potent adjuvant activity of the nanoparticles may originate from dual targeting synergistic effects between aminated β-glucan and CpG-OND. Accordingly, the dual targeting nanoparticles may be a promising vaccine adjuvant for inducing robust humoral and cellular immune responses against infectious diseases and cancers. Statement of SignificanceAn ideal adjuvant for subunit vaccine should act as both a carrier to enhance the uptake, sustained processing and cytosolic delivery of antigens, and an immunopotentiator to stimulate antigen presenting cells (APCs) for activation of naive T cells. Additionally, it should be easy to obtain and safe with negligible toxicity. Unfortunately, both synthetic and natural polymers that have been developed into antigen delivery system cannot completely fulfill the requirements. In the present study, the authors design nanoparticles with aminated β-glucan and CpG-oligodeoxynucleotides (CpG-OND) through a simple and mild method. β-Glucan (a dectin-1 and TLR2 targeted PAMP) and CpG-OND (a TLR9 targeted PAMP) are readily accessible. Aminated β-glucan plays dual roles in the nanoparticle as APCs targeted carrier and immunopotentiator. Meanwhile, CpG-OND also plays dual roles as crosslinker and APCs targeted immunopotentiator. By making use of synergistic effect of the dual targeting vaccine adjuvant with aminated β-glucan and CpG-OND, the nanoparticles induce robust antigen specific immune responses comparable to Freund’s adjuvant without obvious toxicity.

Heterologous Boost Vaccination Improves BCG Priming Protection Against Latent Tuberculosis Infection Rather than Primary Infection

Adults are the leading population affected by tuberculosis (TB) epidemic and death. Developing an effective vaccine against adult TB is urgently needed. BCG prime-heterologous boost strategy has been explored extensively to protect adults against primary TB infection, but the majority of experimental regimens have not improved the protection primed by the BCG vaccine with unknown reason. In this study, CTT3H-based vaccines, namely recombinant adenovirus rAdCTT3H, DMT adjuvanted subunit or DNA vaccine were constructed. Protective efficacy and immunogenicity of BCG prime-CTT3H based boosters were compared in C57BL/c mice models of primary TB and latent TB infection. Heterologous boosters did not enhance the protection primed by the BCG vaccine against primary infection, but they conferred stronger protection against latent TB infection than BCG alone, regardless of vaccine types. BCG prime-boosters elicited Th1-biased responses and increased the number of CTT3H-sepcific IFN-γ T cells and IFN-γ TEM cells in the spleen before exposure to M. tuberculosis infection, while IFN-γ and IL-2 T cells and memory T cells, including IL-2-expressing TCM cells and IFN-γ-expressing TEM cells, in the spleen and lung were significantly increased post-exposure vaccination. Therefore, BCG prime-boost strategy might be a promising measure to protect adult against latent TB infection. Funding Statement: This work was supported by grants of the National Megaproject of Science Research for both the 13th Five-year Plan of China (No. 2018ZX10302302002-001) and the 12th Five-year Plan of China (No. 2012ZX10003008-005), and the National Natural Science Foundation of China (No.81772147). The funders had no role in study design, data collection, data analysis,interpretation, and writing of the report. Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: The study protocol involving animal experiments were performed in accordance with the guidelines of the Chinese Council on Animal Care. The Committee on the Ethics of Animal Experiments and the School Committee on Biosaftey of Tongji Medical College (Wuhan, China) approved the research protocols.

Cost-effectiveness of the Recommendations of the Advisory Committee on Immunization Practices for the Recombinant Adjuvanted Zoster Subunit Vaccine

This cost-effectiveness study evaluates use of the recombinant adjuvanted zoster subunit vaccine among patients 50 years and older.

Current vaccines for the prevention of herpes zoster.

To summarize the recent advances in the prevention of herpes zoster. The recent Food and Drug Administration (FDA) approval of an adjuvanted subunit vaccine may have a significant impact on the prevention of herpes zoster ophthalmicus. There are currently two commercially available vaccines for the prevention of herpes zoster: a live-attenuated vaccine and a new recombinant subunit vaccine. The latter has been shown to be more effective, have fewer contraindications, but requires two separate inoculations, has higher reactogenicity, and has only short-term postmarketing surveillance. The adjuvanted zoster subunit vaccine offers several advantages over the previously available vaccine. Following the current treatment recommendations, physicians should recommend vaccination to all patients older than 50 years of age with no contraindications, this should also prevent ophthalmic complications of the disease.

Comparative study of the adjuvant potential of four Th0 cytokines of flounder (Paralichthys olivaceus) on an E. tarda subunit vaccine

Cytokines have the potential as adjuvants for the application of vaccines in mammals. However, the adjuvant potential of teleost cytokines was limited. In the present work, the adjuvant effects of four recombinant cytokines including IL-1β, IL-8, TNF-α and G-CSF on E. tarda subunit vaccine rOmpV were comparatively investigated in flounder (Paralichthys olivaceus). Compared with control, the levels of specific serum antibodies and IgM + B lymphocytes were significantly enhanced by rIL-1β, rIL-8 and rG-CSF, whereas rIL-1β and rIL-8 induced significantly higher levels than rG-CSF. All four cytokines enhanced the expression of genes involved in humoral and/or cellular immunities, whereas rIL-1β and rIL-8 induced highest levels of genes involved in humoral immunities and cellular immunities, respectively. Compared to the relative percent survivals (RPS) of control group (40%) and rOmpV plus rG-CSF group (54%), rOmpV plus rIL-1β or rIL-8 produced higher RPS of 75% and 68%, respectively. Our results indicated that rIL-1β and rIL-8 are promising adjuvants for subunit vaccines against E. tarda.

Herpes zoster in frail elderly patients: prevalence, impact, management, and preventive strategies.

Population aging is a worldwide phenomenon with significant and manifold impacts on society. Advanced age correlates with the onset of frailty. In this vulnerable state, the immune response is weakened and a higher susceptibility to infectious diseases is observed. The present narrative review aims to cover the topic of herpes zoster (HZ) and its complications in frail populations. The lifetime risk of developing HZ is estimated at about 20-30%, and the risk increases with age. In older people, HZ can lead to the inability to recover the lifestyle, the interests, and the level of activity that existed before its development. Severity of the disease at presentation and depression are the major correlates of pain burden in patients with acute HZ and postherpetic neuralgia (PHN). The frail elderly need careful assessment prior to treatment initiation and could be affected to a greater extent by treatment-related adverse events. In light of the significant burden caused by HZ and its complications in the frail elderly, the adoption of a preventive strategy appears to be promising, particularly using vaccination in appropriate age- and risk-groups. Although very few vaccine studies consider explicitly the frail elderly as their study population, there is evidence that the live, attenuated vaccine induces significant immunological responses. An adjuvanted recombinant subunit vaccine has recently been approved in Canada, in the United States, in the European Union, and in Japan, and will likely provide additional opportunities for prevention.

PIN11 - The Comparative Efficacy, Safety, And Reactogenicity, of Herpes Zoster Vaccines: A Network Meta-Analysis

To estimate the relative efficacy, safety, and reactogenicity of vaccines for prevention of herpes zoster (HZ) using network meta-analysis (NMA) based on evidence from randomized controlled trials. A systematic literature review evaluated two different HZ vaccines: HZ adjuvanted subunit (HZ/su) and Zoster Vaccine Live (ZVL), with different formulations assessed. Detailed feasibility assessment indicated that a NMA was feasible for efficacy (against HZ and postherpetic neuralgia (PHN)), safety (serious adverse events), and reactogenicity (injection-site reactions, systemic reaction) outcomes. Primary analyses included frequentist NMAs with fixed effects for efficacy outcomes, due to limited data availability, and both fixed and random effects for safety and reactogenicity outcomes. As age is a known effect modifier of vaccine efficacy (VE), VE analyses were stratified by age. HZ/su demonstrated significantly higher HZ efficacy than ZVL in adults ≥60 years of age (YOA) (VEHZ/su=0.92 (95% confidence interval (95%CI): 0.88, 0.94), VEZVL=0.51 (95%CI: 0.44, 0.57)) and adults ≥70 YOA (VEHZ/su=0.91 (95%CI: 0.87, 0.94), VEZVL=0.37 (95%CI: 0.25, 0.48)). Similarly, HZ/su demonstrated significantly higher PHN efficacy than ZVL in adults ≥60 YOA (VEHZ/su=0.89 (95%CI: 0.70, 0.96), VEZVL=0.66 (95%CI: 0.48, 0.78)) and adults ≥70 YOA (VEHZ/su=0.89 (95%CI: 0.69, 0.96), VEZVL=0.67 (95%CI: 0.44, 0.80). The 95%CIs of the differences of VEHZ/su and VEZVL estimates did not contain 0, indicating that these were statistically significant. HZ/su was associated with significantly more injection-site and systemic reactions compared to most formulations of ZVL and placebo, however definitions and data collection procedures differed. There were no statistically significant differences found between HZ/su and any formulation of ZVL or placebo for serious adverse events. HZ/su is significantly more effective in reducing HZ and PHN incidence in adults ≥60 YOA when compared to ZVL. As anticipated with an adjuvanted vaccine, HZ/su results in more reactogenicity following immunization, but no safety differences were found between HZ/su and ZVL.

HCMV glycoprotein B subunit vaccine efficacy mediated by nonneutralizing antibody effector functions

Human cytomegalovirus (HCMV) is the most common congenital infection worldwide, frequently causing hearing loss and brain damage in afflicted infants. A vaccine to prevent maternal acquisition of HCMV during pregnancy is necessary to reduce the incidence of infant disease. The glycoprotein B (gB) + MF59 adjuvant subunit vaccine platform is the most successful HCMV vaccine tested to date, demonstrating ∼50% efficacy in preventing HCMV acquisition in multiple phase 2 trials. However, the mechanism of vaccine protection remains unknown. Plasma from 33 postpartum women gB/MF59 vaccinees at peak immunogenicity was tested for gB epitope specificity as well as neutralizing and nonneutralizing anti-HCMV effector functions and compared with an HCMV-seropositive cohort. gB/MF59 vaccination elicited IgG responses with gB-binding magnitude and avidity comparable to natural infection. Additionally, IgG subclass distribution was similar with predominant IgG1 and IgG3 responses induced by gB vaccination and HCMV infection. However, vaccine-elicited antibodies exhibited limited neutralization of the autologous virus, negligible neutralization of multiple heterologous strains, and limited binding responses against gB structural motifs targeted by neutralizing antibodies including AD-1, AD-2, and domain I. Vaccinees had high-magnitude IgG responses against AD-3 linear epitopes, demonstrating immunodominance against this nonneutralizing, cytosolic region. Finally, vaccine-elicited IgG robustly bound membrane-associated gB on the surface of transfected or HCMV-infected cells and mediated virion phagocytosis, although were poor mediators of NK cell activation. Altogether, these data suggest that nonneutralizing antibody functions, including virion phagocytosis, likely played a role in the observed 50% vaccine-mediated protection against HCMV acquisition.

Tuberculosis vaccines: Opportunities and challenges.

Tuberculosis (TB) is a serious disease around the world. Bacillus Calmette-Guérin (BCG) is the only TB vaccine licensed for use in human beings, and is effective in protecting infants and children against severe miliary and meningeal TB. However, BCG's protective efficacy is variable in adults. Novel TB vaccine candidates being developed include whole-cell vaccines (recombinant BCG (rBCG), attenuated Mycobacterium tuberculosis, killed M. tuberculosis or Mycobacterium vaccae), adjuvanted protein subunit vaccines, viral vector-delivered subunit vaccines, plasmid DNA vaccines, RNA-based vaccines etc. At least 12 novel TB vaccine candidates are now in clinical trials, including killed M. vaccae, rBCG ΔureC::hly, adjuvanted fusion proteins M72 and H56 and viral vectored MVA85A. Unfortunately, in TB, there are no correlates of vaccine-induced protection, although cell-mediated immune responses such as interferon-gamma (IFN-γ) production are widely used to assess vaccine's immunogenicity. Recent studies suggested that central memory T cells and local secreted IgA correlated with protection against TB disease. Clinical TB vaccine efficacy trials should invest in identifying correlates of protection, and evaluate new TB biomarkers emerging from human and animal studies. Accumulating new knowledge on M. tuberculosis antigens and immune profiles correlating with protection or disease risk will be of great help in designing next generation of TB vaccines.

A phase I, open-label trial on the safety and immunogenicity of the adjuvanted tuberculosis subunit vaccine H1/IC31\xae in people living in a TB-endemic area

BackgroundH1/IC31® is a tuberculosis (TB) subunit vaccine candidate consisting of the fusion protein of Ag85B and ESAT-6 (H1) formulated with the IC31® adjuvant. Previous trials have reported on the H1/IC31® vaccine in M. tuberculosis (Mtb)-naïve, BCG-vaccinated and previously Mtb-infected individuals. In this trial, conducted between December 2008 and April 2010, the safety and immunogenicity of H1/IC31® was assessed in participants living in Ethiopia – a highly TB-endemic area.MethodsHealthy male participants aged 18–25 years were recruited into four groups. Participants in group 1 (N = 12) and group 2 (N = 12) were Tuberculin Skin Test (TST) negative and QuantiFERON-TB Gold in-tube test (QFT) negative (Mtb-naïve groups), participants in group 3 (N = 3) were TST positive and QFT negative (BCG group), and participants in group 4 (N = 12) were both TST and QFT positive (Mtb-infected group). H1 vaccine alone (group 1) or H1 formulated with the adjuvant IC31® (groups 2, 3 and 4) was administered intramuscularly on day 0 and day 56. Safety and immunogenicity parameters were evaluated for up to 32 weeks after day 0.ResultsThe H1/IC31®vaccine was safe and generally well tolerated. There was little difference among the four groups, with a tendency towards a higher incidence of adverse events in Mtb-infected compared to Mtb-naïve participants. Two serious adverse events were reported in the Mtb-infected group where a relationship to the vaccine could not be excluded. In both cases the participants recovered without sequelae within 72 h. Immunogenicity assays, evaluated in the 29 participants who received both vaccinations, showed a stronger response to TB antigens in the Mtb-naïve group vaccinated with the adjuvant.ConclusionThe trial confirmed the need for an adjuvant for the vaccine to be immunogenic and highlighted the importance of early phase testing of a novel TB vaccine candidate in TB-endemic areas.Trial registrationClinicalTrials.gov, ID: NCT01049282. Retrospectively registered on 14 January 2010.

Fighting against a protean enemy: immunosenescence, vaccines, and healthy aging

The progressive increase of the aged population worldwide mandates new strategies to ensure sustained health and well-being with age. The development of better and/or new vaccines against pathogens that affect older adults is one pivotal intervention in approaching this goal. However, the functional decline of various physiological systems, including the immune system, requires novel approaches to counteract immunosenescence. Although important progress has been made in understanding the mechanisms underlying the age-related decline of the immune response to infections and vaccinations, knowledge gaps remain, both in the areas of basic and translational research. In particular, it will be important to better understand how environmental factors, such as diet, physical activity, co-morbidities, and pharmacological treatments, delay or contribute to the decline of the capability of the aging immune system to appropriately respond to infectious diseases and vaccination. Recent findings suggest that successful approaches specifically targeted to the older population can be developed, such as the high-dose and adjuvanted vaccines against seasonal influenza, the adjuvanted subunit vaccine against herpes zoster, as well as experimental interventions with immune-potentiators or immunostimulants. Learning from these first successes may pave the way to developing novel and improved vaccines for the older adults and immunocompromised. With an integrated, holistic vaccination strategy, society will offer the opportunity for an improved quality of life to the segment of the population that is going to increase most significantly in numbers and proportion over future decades.

A Cost-Effectiveness Analysis of an Adjuvanted Subunit Vaccine for the Prevention of Herpes Zoster and Post-Herpetic Neuralgia

BackgroundHerpes zoster (HZ) develops in up to 50% of unvaccinated individuals who live to 85 years of age, accounting for more than 1 million cases of HZ annually in the United States. A live attenuated vaccine (LAV) for HZ is U.S. FDA approved for persons 50 years or older, though CDC Advisory Committee on Immunization Practices (ACIP) recommendations are only for persons beginning at age 60 years. LAV efficacy at preventing HZ is ~70% for persons 50–59 years of age, with lower efficacy in older adults, and it is efficacious in preventing post-herpetic neuralgia (PHN) beyond the HZ prevention. The efficacy of LAV after vaccination wanes over time. A new adjuvanted HZ subunit vaccine (SUV), administered as a two-dose series, has greater than 95% efficacy against HZ in persons 50–69 years of age. SUV efficacy remains greater than 90% in persons vaccinated at age 70 years and older, including the subgroup older than 80 years of age. Overall efficacy of SUV against PHN approaches 90%. The waning rate of efficacy after SUV vaccination is unknown.MethodsTo estimate the relative cost-effectiveness of SUV, LAV and no vaccination (NV) strategies, a Markov model was developed based on published trials and data on vaccine efficacy persistence, quality of life, resource utilization, costs and disease epidemiology. The perspective was U.S. societal, and the cycle length was one year with a lifelong time horizon. SUV efficacy was estimated for the base case to wane at the same rate as LAV, all persons were assumed to receive both doses of SUV, and the cost of SUV included both doses.ResultsFor individuals vaccinated at age 50 years the incremental cost-effectiveness ratio (ICER) for LAV vs. NV was $142,811 per quality-adjusted life-year (QALY); at age 60 years the ICER dropped to $59,482 per QALY. The cost-effectiveness ratio of SUV approached that of LAV when the SUV cost approached $500 for persons vaccinated at age 50 years and when the cost was $400 for those vaccinated at age 60 years. The SUV cost that would result in achieving an ICER target of $100,000 per QALY for SUV vaccination vs. NV at age 50 years was $316; at age 60 years the cost was $638.ConclusionVaccination at age 60 years with SUV was more cost-effective than LAV when SUV cost was ~$450 or less. Vaccination with SUV at age 50 years appeared to be cost-effective if SUV cost was ~$315 or less.Disclosures All authors: No reported disclosures.

Assessment of the Potential Herpes Zoster and Post Herpetic Neuralgia Case Avoidance with Vaccination in the United States

BackgroundHerpes zoster (HZ), commonly referred to as shingles, is a reactivation of latent varicella zoster virus in patients previously infected. Clinical characteristics of HZ include painful rash with potential complications, including post herpetic neuralgia (PHN). Care for HZ and PHN incurs significant costs and vaccination is beneficial. The aim of this study was to compare the impact on HZ and PHN case avoidance of two HZ vaccines, an available live-attenuated zoster vaccine (zoster vaccine live [ZVL]) vs. a candidate non-live adjuvanted HZ subunit vaccine (HZ/su), in the US population.MethodsA Markov model called ZONA (ZOster ecoNomic Analyses) was developed following two age cohorts (≥60 years to represent the current ACIP recommendation and ≥65 years to represent the Medicare population) over their lifetimes from the year of vaccination. Demographic data were obtained from the US Census, whereas HZ incidence and the proportion of HZ individuals developing PHN were derived from published US-specific sources. Age-specific vaccine efficacy and waning rates were based on published clinical trial data. Vaccine coverage for both vaccines was assumed to be 30.6% and 34.2% in the two age cohorts, respectively, based on CDC data; compliance of the second dose of the HZ/su vaccine was 69%, based on data from clinical trials and Hepatitis B seconddose completion. Sensitivity analyses demonstrated robustness of the base analysis findings.ResultsIn the US, for cohorts of 66.83 million (M) persons aged 60+ and 47.76M aged 65+ it was estimated that the HZ/su vaccine would reduce the number of HZ cases by 2.12M and 1.55M in the two age cohorts, respectively, compared with 0.65M and 0.45M using the ZVL. Furthermore, the HZ/su vaccine would reduce the number of PHN cases by 0.23M and 0.18M in the two age cohorts, respectively, compared with 0.10M and 0.09 using the ZVL. The number needed to vaccinate to prevent one HZ case were 10 and 11, in the respective cohorts, using the HZ/su vaccine compared with 31 and 37, in the respective cohorts, using the ZVL.ConclusionDue to higher and sustained vaccine efficacy, the candidate HZ/su vaccine demonstrated superior public health impact in the US compared with the currently available ZVL.Disclosures B. J. Patterson, GSK: Employee and Shareholder, GSK stock options or restricted shares and Salary; Pennsylvania Pharmacists Association: Scientific Advisor, stipend; P. O. Buck, GSK: Employee and Shareholder, GSK stock options or restricted shares and Salary; J. Carrico, RTI Health Solutions: Employee, Salary GSK: Research Contractor, Research support; K. A. Hicks, RTI: Employee, Salary GSK: Research Contractor, Research support; D. Curran, GSK: Employee and Shareholder, GSK stock options or restricted shares and Salary; D. Van Oorschot, GSK: Employee, Salary; J. E. Pawlowski, GSK: Employee and Shareholder, GSK stock options or restricted shares and Salary; B. Y. Lee, GSK: Consultant, Consulting fee; B. P. Yawn, GSK: Consultant and Scientific Advisor, Consulting fee

Immunogenicity and Safety of the HZ/su Adjuvanted Herpes Zoster Subunit Vaccine in Adults Previously Vaccinated With a Live Attenuated Herpes Zoster Vaccine

Protection against herpes zoster (HZ) induced by the live attenuated zoster vaccine Zostavax (ZVL) wanes within 3-7 years. Revaccination may renew protection. We assessed whether (re)vaccination with the adjuvanted HZ subunit vaccine candidate (HZ/su) induced comparable immune responses in previous ZVL recipients and ZVL-naive individuals (HZ-NonVac). In an open-label, multicenter study, adults ≥65 years of age, vaccinated with ZVL ≥5 years previously (HZ-PreVac), were matched to ZVL-naive adults (HZ-NonVac). Participants received 2 doses of HZ/su 2 months apart. The primary objective of noninferiority of the humoral immune response 1 month post-dose 2 was considered demonstrated if the upper limit of the 95% confidence interval (CI) of the adjusted anti-glycoprotein E geometric mean concentration (GMC) ratio of HZ-NonVac over HZ-PreVac was <1.5. HZ/su cellular immunogenicity, reactogenicity, and safety were also assessed. In 430 participants, humoral immune response to HZ/su was noninferior in HZ-PreVac compared with HZ-NonVac (adjusted GMC ratio, 1.04 [95% CI, .92-1.17]). Cellular immunogenicity, reactogenicity, and safety appeared to be comparable between groups. HZ/su was well-tolerated, with no safety concerns raised within 1 month post-dose 2. HZ/su induces a strong immune response irrespective of prior vaccination with ZVL, and may be an attractive option to revaccinate prior ZVL recipients. NCT02581410.

Immunostimulatory Properties of Lipid Modified CpG Oligonucleotides

Innate immune responses recognizing pathogen associated molecular patterns play important roles in adaptive immunity. As such, ligands which mimic the conserved products of microbial and activate innate immunity are widely used as adjuvants for vaccines. Synthetic single strand oligodeoxynucleotides (ODNs) containing unmethylated cytosine-guanine (CpG) motifs which bind Toll-like receptor 9 (TLR9) are powerful molecular adjuvants, potentiating both humoral and cellular responses. However, CpG ODN's in vitro potency has not been translated to in vivo settings primarily due to issues associated with delivery and toxicity. A major challenge in clinical application of CpG ODN is the efficient delivery to lymph nodes, the anatomic sites where all the immune responses are initiated. Targeting CpG to the key antigen presenting cells (APC) is essential for its application as a vaccine adjuvant, as it not only enhances CpG's efficacy, but also greatly reduces the systemic toxicity. We recently discovered an "albumin-hitchhiking" approach by which CpG ODNs were conjugated to a lipophilic lipid tail and follow subcutaneous injection, accumulated in lymph nodes by binding and transporting with endogenous albumin. This molecular approach targets CpG to antigen presenting cells in the draining lymph nodes via an endogenous albumin-mediated mechanism and simultaneously improves both the efficacy and safety of CpG as a vaccine adjuvant. Since CpG ODNs can be divided into structurally distinct classes, and each class of CpG ODN activates different types of immune cells and triggers different types of immunostimulatory activities, it is important to thoroughly evaluate the efficacy of this "albumin-hitchhiking" strategy in each class of CpG. Here we compare the immunostimulatory activities of three classes of lipid conjugated CpG ODNs in vitro and in vivo. Three representative sequences of lipid modified CpG ODNs were synthesized and their stimulatory effects as a vaccine adjuvant were evaluated. Our results showed that in vitro, lipid modified class A CpG exhibited enhanced stimulatory activities toward TLR transfected reporter cells or bone-marrow derived dendritic cells, whereas lipid-modification of class B or C CpG reduces the activation of TLR9 by 2-3 fold, as compared with unmodified class B and class C CpG, respectively. However, in vivo coadministration of ovalbumin (OVA) protein antigen mixed with lipid-conjugated class B or C CpG ODNs, but not class A CpGs induced dramatically increased OVA-specific humoral and cytotoxic CD8+ T cells responses compared with OVA mixed with unmodified CpGs. Further, lipid-modification greatly reduces the toxicity associated with CpG by minimizing the systemic dissemination. Taken together, these results demonstrated that amphiphilic modification of three classes of CpG motifs differentially affected and modulated the immunostimulatory activities in vitro and in vivo. Our study highlights the importance of in vivo lymph node targeting of CpG ODNs in fulfilling their use as vaccine adjuvants, providing implications for the rational design of molecular adjuvant for subunit vaccines.

Recent mouse models and vaccine candidates for preventing chronic/latent tuberculosis infection and its reactivation

Tuberculosis (TB) remains a major challenge in public health worldwide. Until today, the only widely used and approved vaccine is the Mycobacterium bovis bacille Calmette-Guerin (BCG). This vaccine provides a highly variable level of protection against the active, pulmonary form of tuberculosis, and practically none against the latent form of TB infection. This disparity in protection has been extensively studied, and for this reason, several groups have focused their research on the quest for attenuated vaccines based on M. tuberculosis or on the identification of latency-associated antigens that can be incorporated into modified BCG, or that can be used as adjuvanted subunit vaccines. In order to seek new potential antigens relevant for infection, some researchers have performed experiments with highly sensitive techniques such as transcriptomic and proteomic analyses using sputum samples from humans or by using mouse models resembling several aspects of TB. In this review, we focus on reports of new mouse models or mycobacterial antigens recently tested for developing vaccine candidates against chronic/latent tuberculosis and its reactivation.

IMMUNOGENICITY OF ADJUVANT INFLUENZA VACCINE FOR PREGNANT WOMEN

Recent epidemiological events showed that pregnant women are the most vulnerable part of population if there is the flu in the country and they die much more often than the rest part of people. That is why influenza vaccination of population including pregnant women is one of the priorities of public health service in our state. Worldwide experience of influenza vaccination of either adults or children by new adjuvant vaccine has caused our research of its efficiency among pregnant women. The aim of the study was to investigate the level of antibodies to influenza virus strain A/H1N1/v, A/H3N2 and B in pregnant women vaccinated adjuvant trivalent subunit vaccine. Our research is randomized and comparative on parallel groups. It was carried out within the demands of Russian Federation and International ethic norms adapted to such kind of researches. Evaluation of the immunogenicity of the vaccine was conducted in 27 pregnant women in the II trimester of gestation, and in 23 pregnant women in the III trimester of gestation, 19 non-pregnant women was in the control group. The level of antibodies in the serum was determined using a reaction of hemagglutination inhibition before and 1, 3, 6, 9 and 12 months after the vaccination. Revealed that influenza vaccination of pregnant women in the II and III trimester, causes the increase in titers of antibodies to vaccine influenza strains A and B, to fully meet the required criteria CPMP, and does not differ from the nonpregnant group. In a month after vaccination the level of seroprotective against A/H1N1/v was 77.0%, A/H3N2 — 88.9%, B — 85.2% after vaccination in II trimester, and 87.0; 87.0; 91.35% in III trimester of gestation. The factor of seroconversion after vaccination in II trimester for A/H1N1/v was equal to 6.5, A/H3N2 — 7.2, B — 6.5, after vaccination in III trimester of pregnancy: 7.1, 6.5 and 5.1 correspondingly. At the same time revealed accelerated decline in antibody titer against influenza in pregnant women compared to nonpregnant women in a year after immunization The set of results of the study can be concluded that adjuvant trivalent subunit vaccine effective in vaccination of pregnant women in II and III trimester of pregnancy, and it is able to effectively provide immune protection against viruses of the flu A and B within all pregnancy long.