Generation Influenza Vaccines Research Articles

The potential cost-effectiveness of next generation influenza vaccines in England and Wales: A modelling analysis

Next generation influenza vaccines are in development and have the potential for widespread health and economic benefits. Determining the potential health and economic impact for these vaccines is needed to drive investment in bringing these vaccines to the market, and to inform which groups public health policies on influenza vaccination should target.We used a mathematical modelling approach to estimate the epidemiological impact and cost-effectiveness of next generation influenza vaccines in England and Wales. We used data from an existing fitted model, and evaluated new vaccines with different characteristics ranging from improved vaccines with increased efficacy duration and breadth of protection, to universal vaccines, defined in line with the World Health Organisation (WHO) Preferred Product Characteristics (PPC). We calculated the cost effectiveness of new vaccines in comparison to the current seasonal vaccination programme. We calculated and compared the Incremental Cost-Effectiveness Ratio and Incremental Net Monetary Benefit for each new vaccine type. All analysis was conducted in R.We show that next generation influenza vaccines may result in a 21% to 77% reduction in influenza infections, dependent on vaccine characteristics. Our economic modelling shows that using any of these next generation vaccines at 2019 coverage levels would be highly cost-effective at a willingness to pay threshold of £20,000 for a range of vaccine prices. The vaccine threshold price for the best next generation vaccines in £-2019 is £230 (95%CrI £192 - £269) per dose, but even minimally-improved influenza vaccines could be priced at £18 (95%CrI £16 - £21) per dose and still remain cost-effective.This evaluation demonstrates the promise of next generation influenza vaccines for impact on influenza epidemics, and likely cost-effectiveness profiles. We have provided evidence towards a full value of vaccines assessment which bolsters the investment case for development and roll-out of next-generation influenza vaccines.

A systematic review of randomized clinical trials on quadrivalent influenza vaccines for adults

Abstract Background Vaccination is the most effective intervention to prevent influenza. Adults at risk of complications are among the targets of annual vaccination campaigns and can receive different types of quadrivalent influenza vaccines (QIV). To assess the immunogenicity of different QIVs we performed a systematic review of available randomized controlled trials (RCTs) with the aim of indirectly compare them through a network meta-analysis. Methods The systematic review was conducted in accordance with PRISMA-NMA guidelines. We systematically searched RCTs conducted in adults aged 18-64 years that assessed the immunogenicity, namely seroprotection and seroconversion rate (SPR and SCR), of any QIV compared to any comparator. The literature search was performed on three databases (Medline, Cochrane Library and Scopus) until March 30th, 2021. Results Twenty-four RCTs were included in the systematic review. A network meta-analysis was not possible: the assumption of transitivity was not satisfied. Therefore, we decided to combine data on immunogenicity and efficacy of each QIV through single meta-analyses in the presence of at least two studies. Live attenuated QIV showed the worst results in terms of both SCR and SPR. Standard dose egg based, low dose adjuvanted, cell based, recombinant and intradermal QIV showed similar SCR in respect to influenza strain A, whereas low dose adjuvanted QIV showed an overall better profile in respect to B lineages. Regarding SCR, the better results were issued by standard egg based, cell based, recombinant, and low dose adjuvanted QIVs. Conclusions Albeit an indirect comparison among different QIVs was not possible, the assessment of SCR and SPR provided an overview of their respective potentiality and criticality in adulthood. In particular attention should be paid to new generation influenza vaccines that can have an antigen sparing effect and to the collection of real world data to make comparison among different QIVs possible. Key messages • Available evidence does not allow to perform indirect comparison of the quadrivalent influenza vaccines for adults. • Some QIVs, including new generation ones, elicit a better antibody response.

Universally Immune: How Infection Permissive Next Generation Influenza Vaccines May Affect Population Immunity and Viral Spread.

Next generation influenza vaccines that target conserved epitopes are becoming a clinical reality but still have challenges to overcome. Universal next generation vaccines are considered a vital tool to combat future pandemic viruses and have the potential to vastly improve long-term protection against seasonal influenza viruses. Key vaccine strategies include HA-stem and T cell activating vaccines; however, they could have unintended effects for virus adaptation as they recognise the virus after cell entry and do not directly block infection. This may lead to immune pressure on residual viruses. The potential for immune escape is already evident, for both the HA stem and T cell epitopes, and mosaic approaches for pre-emptive immune priming may be needed to circumvent key variants. Live attenuated influenza vaccines have not been immunogenic enough to boost T cells in adults with established prior immunity. Therefore, viral vectors or peptide approaches are key to harnessing T cell responses. A plethora of viral vector vaccines and routes of administration may be needed for next generation vaccine strategies that require repeated long-term administration to overcome vector immunity and increase our arsenal against diverse influenza viruses.

Seasonal influenza vaccination policies in the 194 WHO Member States: The evolution of global influenza pandemic preparedness and the challenge of sustaining equitable vaccine access

IntroductionAs of 2018, 118 of 194 WHO Member States reported the presence of an influenza vaccination policy. Although influenza vaccination policies do not guarantee equitable access or ensure vaccination coverage, they are critical to establishing a coordinated influenza vaccination program, which can reduce morbidity and mortality associated with yearly influenza, especially in high-risk groups. Established programs can also provide a good foundation for pandemic preparedness and response. MethodsWe utilized EXCEL and STATA to evaluate changes to national seasonal influenza vaccination policies reported on the WHO/UNICEF Joint Reporting Forms on Immunization (JRF) in 2014 and 2018. To characterize countries with or without policies, we incorporated external data on World Bank income groupings, WHO regions, and immunization system strength (using 3 proxy indicators). ResultsFrom 2014 to 2018 there was a small net increase in national seasonal influenza vaccination policies from 114 (59%) to 118 (61%). There was an increase in policies targeting high-risk groups from 34 in 2014 (34 /114 policies, 29%) to 56 (56/118 policies, 47%) in 2018. Policies were consistently more frequent in high-income countries, in WHO Regions of the Americas (89% of countries) and Europe (89%), and in countries satisfying all three immunization system strength indicators. Low and low-middle income countries, representing 40% of the worlds’ population, accounted for 52/61 (85%) of countries with no evidence of a policy in either year. ConclusionOur results demonstrate that national influenza vaccination policies vary significantly by region, income, and immunization system strength, and are less common in lower-income countries. Barriers to establishing and maintaining policies should be further examined as part of international efforts to expand influenza vaccination policies globally. Next generation influenza vaccine development should work to address barriers to influenza vaccination policy adoption, such as cost, logistics for adult vaccination, country priorities, need for yearly vaccination, and variations in seasonality.

Autoreactivity of Broadly Neutralizing Influenza Human Antibodies to Human Tissues and Human Proteins.

Broadly neutralizing monoclonal antibodies (bNAbs) against conserved domains in the influenza hemagglutinin are in clinical trials. Several next generation influenza vaccines designed to elicit such bNAbs are also in clinical development. One of the common features of the isolated bNAbs is the use of restricted IgVH repertoire. More than 80% of stem-targeting bNAbs express IgVH1-69, which may indicate genetic constraints on the evolution of such antibodies. In the current study, we evaluated a panel of influenza virus bNAbs in comparison with HIV-1 MAb 4E10 and anti-RSV MAb Palivizumab (approved for human use) for autoreactivity using 30 normal human tissues microarray and human protein (>9000) arrays. We found that several human bNAbs (CR6261, CR9114, and F2603) reacted with human tissues, especially with pituitary gland tissue. Importantly, protein array analysis identified high-affinity interaction of CR6261 with the autoantigen “Enhancer of mRNA decapping 3 homolog” (EDC3), which was not previously described. Moreover, EDC3 competed with hemagglutinin for binding to bNAb CR6261. These autoreactivity findings underscores the need for careful evaluation of such bNAbs for therapeutics and stem-based vaccines against influenza virus.

Tetramerizing tGCN4 domain facilitates production of Influenza A H1N1 M2e higher order soluble oligomers that show enhanced immunogenicity in vivo

One strategy for the development of a next generation influenza vaccine centers upon using conserved domains of the virus to induce broader and long-lasting immune responses. The production of artificial proteins by mimicking native-like structures has shown to be a promising approach for vaccine design against diverse enveloped viruses. The amino terminus of influenza A virus matrix 2 ectodomain (M2e) is highly conserved among influenza subtypes, and previous studies have shown M2e-based vaccines are strongly immunogenic, making it an attractive target for further exploration. We hypothesized that stabilizing M2e protein in the mammalian system might influence the immunogenicity of M2e with the added advantage to robustly produce the large scale of proteins with native-like fold and hence can act as an efficient vaccine candidate. In this study, we created an engineered construct in which the amino terminus of M2e is linked to the tetramerizing domain tGCN4, expressed the construct in a mammalian system, and tested for immunogenicity in BALB/c mice. We have also constructed a stand-alone M2e construct (without tGCN4) and compared the protein expressed in mammalian cells and in Escherichia coli using in vitro and in vivo methods. The mammalian-expressed protein was found to be more stable, more antigenic than the E. coli protein, and form higher-order oligomers. In an intramuscular protein priming and boosting regimen in mice, these proteins induced high titers of antibodies and elicited a mixed Th1/Th2 response. These results highlight the mammalian-expressed M2e soluble proteins as a promising vaccine development platform.

Measuring influenza hemagglutinin (HA) stem-specific antibody-dependent cellular cytotoxicity (ADCC) in human sera using novel stabilized stem nanoparticle probes

BackgroundGenerating vaccine that confers a complete protection is a major goal in designing a universal influenza vaccine. Currently, there is a considerable interest in the broadly neutralizing antibodies (bnAb) targeting the conserved HA stem region. These antibodies have been shown to activate cellular immune responses, such as ADCC, in addition to their neutralization activity. We had previously demonstrated that immunization with H1-based stabilized stem (SS) nanoparticles (np) protects against heterosubtypic lethal H5N1 challenge, despite the absence of detectable neutralizing activity. Utilizing these novel SS probes to develop an ADCC assay would help in understanding the mechanism of action of stem-specific antibodies, as well as evaluating future influenza vaccines. ObjectivesTo develop a new protocol to assess the ADCC activity mediated by stem-directed antibodies in human sera using novel SS np probes. Study designHuman sera samples were screened for binding and ADCC activities to different influenza group 1 SS probes (H1, H2, and H5) using trimeric SS or multivalent SS-np (n = 8 trimers) formats. ResultsInitial screening revealed 63% (57/90) seroprevalence of anti-HA (H1) stem-epitope antibodies, as determined by the differential binding to HA SS and its corresponding epitope-mutant (Ile45Arg/Thr49Arg) probe. Using equimolar amounts, the multivalent presentation of HA SS on np induced significantly higher ADCC activity compared to the monovalent (trimer) SS probes (2–6 fold increase). Further, ADCC activity was similarly reported against different group 1 influenza subtypes: H1, H2, and H5. Importantly, ADCC was mediated mainly by antibodies targeting the bnAb-epitope on the HA stem. ConclusionWe report on an assay to measure stem-specific ADCC activity using SS np probes. Our results indicate high prevalence of HA-stem antibodies with cross-reactive ADCC activity. Such assay could be utilized in the assessment of next generation influenza vaccines.

Improving influenza vaccines: challenges to effective implementation.

Influenza virus causes contagious respiratory illness and remains a major burden on healthcare systems and the economy. Seasonal influenza vaccine is the most cost-effective way to combat the disease. However, underestimation of disease severity and controversy over vaccine safety and effectiveness hampers public confidence in vaccination. Action is needed to restore public confidence and improve vaccine uptake. Tailoring seasonal influenza vaccines according to immune responsiveness and infection/vaccination history of different populations can improve vaccine efficacy and effectiveness. Steady progress has been made in next generation influenza vaccine designs aiming at broad and long-lasting protective immunity in pre-clinical and clinical studies. However, substantial research and regulatory effort is required before reaching the goal of a truly universal vaccine.

Epidemiological Studies to Support the Development of Next Generation Influenza Vaccines.

The National Institute of Allergy and Infectious Diseases recently published a strategic plan for the development of a universal influenza vaccine. This plan focuses on improving understanding of influenza infection, the development of influenza immunity, and rational design of new vaccines. Epidemiological studies such as prospective, longitudinal cohort studies are essential to the completion of these objectives. In this review, we discuss the contributions of epidemiological studies to our current knowledge of vaccines and correlates of immunity, and how they can contribute to the development and evaluation of the next generation of influenza vaccines. These studies have been critical in monitoring the effectiveness of current influenza vaccines, identifying issues such as low vaccine effectiveness, reduced effectiveness among those who receive repeated vaccination, and issues related to egg adaptation during the manufacturing process. Epidemiological studies have also identified population-level correlates of protection that can inform the design and development of next generation influenza vaccines. Going forward, there is an enduring need for epidemiological studies to continue advancing knowledge of correlates of protection and the development of immunity, to evaluate and monitor the effectiveness of next generation influenza vaccines, and to inform recommendations for their use.

Current and Next Generation Vaccines Against Influenza

Influenza is an infectious disease. In order to overcome various infectious diseases, many vaccines have been developed so far. Influenza vaccines have played an important role in prevention and control of influenza. However, current influenza vaccines are not perfect. Current influenza vaccines are produced by anticipating influenza viruses that may occur in annual epidemics or pandemics because influenza viruses have characteristic of antigen mutations. Furthermore, current subcutaneous or intramuscular inoculation of vaccine cannot sufficiently induce IgA that plays an important role in defending the entry of pathogens from the mucosa. In order to overcome the drawbacks of these current influenza vaccines, next generation vaccines are under investigation. One candidate is universal influenza vaccine using the antigens that are conserved among influenza virus strains. Another one is mucosal vaccine that can induce IgA on the mucosa of the upper respiratory tract. Here current and next generation influenza vaccines are described.

Study of Next Generation Influenza Vaccine Focused on “Cross-Protection by Mucosal Immunization” and “Seed Virus Strains”

Endemic infection by seasonal influenza virus usually occurs every winter season. Inside the host, human influenza viruses frequently undergo various point mutations at antigenic regions, in response to antibody pressure. Furthermore, the influenza virus has undergone frequent antigenic shifts for at least 100 years, some of which have caused influenza pandemics. In Japan, intramuscular immunization with influenza split-virion vaccines has been used to prevent seasonal influenza virus infections. Unfortunately, the efficacy of the current influenza vaccine immunization method is limited, even against viruses belonging to the same clade. Furthermore, the current vaccines are not expected to be protective against antigenically shifted viruses. Therefore, new approaches to vaccine development are needed to protect human populations against a potential pandemic virus. We are studying novel influenza vaccine designs to resolve the above weaknesses of the current influenza vaccines. I will describe our vaccine studies, "Cross-protection by mucosal immunization," and, "Preparation of seed virus strains to produce vaccines for possible pandemic influenza," in this symposium.

Development of new generation influenza vaccines: Recipes for success?

As infectious diseases cause approximately 25% of the annual global mortality, vaccines are found to be a time proven and promising response to infectious disease need. However, like for pharmaceutical small molecules, vaccine development is lengthy, risky and resource demanding. Faced with an attrition rate estimated around 80%, key opinion leaders were interviewed with the question: is there a recipe for success?

Vaccine protection against lethal homologous and heterologous challenge using recombinant AAV vectors expressing codon-optimized genes from pandemic swine origin influenza virus (SOIV)

The recent H1N1 influenza pandemic and the inevitable delay between identification of the virus and production of the specific vaccine have highlighted the urgent need for new generation influenza vaccines that can preemptively induce broad immunity to different strains of the virus. In this study we have produced AAV-based vectors expressing the A/Mexico/4603/2009 (H1N1) hemagglutinin (HA), nucleocapsid (NP) and the matrix protein M1 and have evaluated their ability to induce specific immune response and protect mice against homologous and heterologous challenge. Each of the vaccine vectors elicited potent cellular and humoral immune responses in mice. Although immunization with AAV-M1 did not improve survival after challenge with the homologous strain, immunization with the AAV-H1 and AAV-NP vectors resulted in survival of all mice, as did inoculation with a combination of all three vectors. Furthermore, trivalent vaccination also conferred partial protection against challenge with the highly heterologous and virulent A/PR/8/34 strain of H1N1 influenza.

FluBlok, a next generation influenza vaccine manufactured in insect cells

FluBlok, a recombinant trivalent hemagglutinin (rHA) vaccine produced in insect cell culture using the baculovirus expression system, provides an attractive alternative to the current egg-based trivalent inactivated influenza vaccine (TIV). Its manufacturing process presents the possibility for safe and expeditious vaccine production. FluBlok contains three times more HA than TIV and does not contain egg-protein or preservatives. The high purity of the antigen enables administration at higher doses without a significant increase in side-effects in human subjects. The insect cell–baculovirus production technology is particularly suitable for influenza where annual adjustment of the vaccine is required. The baculovirus–insect expression system is generally considered a safe production system, with limited growth potential for adventitious agents. Still regulators question and challenge the safety of this novel cell substrate as FluBlok continues to advance toward product approval. This review provides an overview of cell substrate characterization for expresSF cell line used for the manufacturing of FluBlok. In addition, this review includes an update on the clinical development of FluBlok. The highly purified protein vaccine, administered at three times higher antigen content than TIV, is well tolerated and results in stronger immunogenicity, a long lasting immune response and provides cross-protection against drift influenza viruses.

Combination adjuvants for the induction of potent, long-lasting antibody and T-cell responses to influenza vaccine in mice

Influenza is controlled by protective titres of neutralizing antibodies, induced with the help of CD4 T-cells, and by antiviral T-cell effector function. Adjuvants are essential for the efficient vaccination of a naïve population against avian influenza. We evaluated a range of adjuvants for their ability to enhance, in naïve mice, protective hemagglutination inhibition (HI) titres, which represent the generally accepted correlate of protection, virus-neutralizing titres and T-cell responses to a new generation influenza vaccine produced in cell culture. The selected adjuvants include alum, calcium phosphate (CAP), MF59, the delivery system poly-(lactide co-glycolide) (PLG) and the immune potentiator CpG. MF59 was clearly the most potent single adjuvant and induced significantly enhanced, long-lasting HI and neutralizing titres and T-cell responses in comparison to all alternatives. The combination of alum, MF59, CAP or PLG with CpG generally induced slightly more potent titres. The addition of CpG to MF59 also induced a more potent Th1 cellular immune response, represented by higher IgG2a titres and the induction of a strongly enhanced IFN-gamma response in splenocytes from immunized mice. These observations have significant implications for the development of new and improved flu vaccines against pandemic and inter-pandemic influenza virus strains.

Vaxfectin™-Formulated Influenza DNA Vaccines Encoding NP and M2 Viral Proteins Protect Mice against Lethal Viral Challenge

Next generation influenza vaccines containing conserved antigens may enhance immunity against seasonal or pandemic influenza virus strains. Using a plasmid DNA (pDNA)-based vaccine approach, we systematically tested combinations of NP, M1, and M2 antigens derived from consensus sequences for protection against lethal influenza challenge and compared formulations for adjuvanting low pDNA vaccine doses. The highest level of protection at the lowest pDNA doses was provided by Vaxfectin™-formulated NP + M2. Vaxfectin™ adjuvanticity was confirmed with a low dose of HA pDNA. These promising proof-of-concept data support the clinical development of Vaxfectin™-formulated pDNA encoding NP + M2 consensus proteins.