A biomimetic VLP influenza vaccine with interior NP/exterior M2e antigens constructed through a temperature shift-based encapsulation strategy

Here we present a biomimetic strategy towards an influenza vaccine design based on hepatitis B virus core virus-like particles (HBc VLP). To this end, a temperature-shift based encapsulation process based on analysis of the unique thermal-associated structural flexibility of HBc VLP nanocages was proposed and proved efficient for encapsulation of antigen inside the VLP. By displaying a matrix protein 2 ectodomain (M2e) antigen on the exterior of HBc VLP through genetic fusion, and encapsulate a conserved internal nucleoprotein (NP) antigen peptide inside the VLP, a biomimetic dual-antigen influenza vaccine with interior NP/exterior M2e was constructed. For comparison, another non-biomimetic dual-antigen vaccine with interior M2e/exterior NP, and other four VLP-based single-antigen vaccines with NP or M2e either being encapsulated inside or genetically displayed outside the VLP were also constructed. Upon intraperitoneal immunization in mice, the dual-antigen VLP influenza vaccine elicited both NP and M2e-specific antibodies, which were stronger than those elicited by the single-antigen vaccines. Most importantly, after a lethal challenge of H1N1 virus, the biomimetic dual-antigen vaccine conferred the mice 100% protection without noticeable body weight loss in the absence of any adjuvant. While the protective efficacy conferred by the non-biomimetic one was only 62.5%, accompanying 12.5% body weight loss in the immunized mice. Besides the high level of antigen-specific antibodies, more efficient formation of total germinal center (GC) B cells and a higher level of effector memory CD8⁺ T cell population were observed in the biomimetic vaccine group, as compared with the non-biomimetic one. All these results demonstrate that VLP assembly and display of antigens in a biomimetic manner making this a promising strategy for the production of efficient universal vaccines to influenza and other rapidly emerging pathogens.     

Vaccination with viral vectors expressing NP,M1 and chimeric hemagglutinin induces broad protection against influenza virus challenge in mice

Seasonal influenza virus infections cause significant morbidity and mortality every year. Annual influenza virus vaccines are effective but only when well matched with circulating strains. Therefore, there is an urgent need for better vaccines that induce broad protection against drifted seasonal and emerging pandemic influenza viruses. One approach to design such vaccines is based on targeting conserved regions of the influenza virus hemagglutinin. Sequential vaccination with chimeric hemagglutinin constructs can refocus antibody responses towards the conserved immunosubdominant stalk domain of the hemagglutinin, rather than the variable immunodominant head. A complementary approach for a universal influenza A virus vaccine is to induce T-cell responses to conserved internal influenza virus antigens. For this purpose, replication deficient recombinant viral vectors based on Chimpanzee Adenovirus Oxford 1 and Modified Vaccinia Ankara virus are used to express the viral nucleoprotein and the matrix protein 1. In this study, we combined these two strategies and evaluated the efficacy of viral vectors expressing both chimeric hemagglutinin and nucleoprotein plus matrix protein 1 in a mouse model against challenge with group 2 influenza viruses including H3N2, H7N9 and H10N8. We found that vectored vaccines expressing both sets of antigens provided enhanced protection against H3N2 virus challenge when compared to vaccination with viral vectors expressing only one set of antigens. Vaccine induced antibody responses against divergent group 2 hemagglutinins, nucleoprotein and matrix protein 1 as well as robust T-cell responses to the nucleoprotein and matrix protein 1 were detected. Of note, it was observed that while antibodies to the H3 stalk were already boosted to high levels after two vaccinations with chimeric hemagglutinins (cHAs), three exposures were required to induce strong reactivity across subtypes. Overall, these results show that a combinations of different universal influenza virus vaccine strategies can induce broad antibody and T-cell responses and can provide increased protection against influenza.     

Influenza H7N9 LAH-HBc virus-like particle vaccine with adjuvant protects mice against homologous and heterologous influenza viruses

The long alpha-helix (LAH) region located in influenza virus hemagglutinin (HA) shows conservation among different influenza A strains, which could be used as a candidate target of influenza vaccines. Moreover, the hepatitis B virus core protein (HBc) is a carrier for heterologous epitopes in eliciting effective immune responses. We inserted the LAH region of H7N9 influenza virus into the HBc and prepared the LAH-HBc protein, which were capable of self-assembly into virus-like particles (VLP), by using E. coli expression system. Intranasal immunization of the LAH-HBc VLP in combination with chitosan adjuvant or CTB¹ adjuvant in mice could induce both humoral and cellular immune responses effectively and provide complete protection against lethal challenge of homologous H7N9 virus or heterologous H3N2 virus, as well as partial protection against lethal challenge of heterologous H1N1 virus. These results provide a proof of concept for LAH-HBc VLP vaccine that would be fast and easy to be produced and might be an ideal candidate as a rapid-response tool against a future influenza pandemic.     

Activation of cross-reactive mucosal T and B cell responses in human nasopharynx-associated lymphoid tissue in vitro by Modified Vaccinia Ankara-vectored influenza vaccines

Recent efforts have been focused on the development of vaccines that could induce broad immunity against influenza virus, either through T cell responses to conserved internal antigens or B cell response to cross-reactive haemagglutinin (HA). We studied the capacity of Modified Vaccinia Ankara (MVA)-vectored influenza vaccines to induce cross-reactive immunity to influenza virus in human nasopharynx-associated lymphoid tissue (NALT) in vitro. Adenotonsillar cells were isolated and stimulated with MVA vaccines expressing either conserved nucleoprotein (NP) and matrix protein 1 (M1) (MVA-NP-M1) or pandemic H1N1 HA (MVA-pdmH1HA). The MVA vaccine uptake and expression, and T and B cell responses were analyzed. MVA-vectored vaccines were highly efficient infecting NALT and vaccine antigens were highly expressed by B cells. MVA-NP-M1 elicited T cell response with greater numbers of IFNγ-producing CD4+ T cells and tissue-resident memory T cells than controls. MVA-pdmH1HA induced cross-reactive anti-HA antibodies to a number of influenza subtypes, in an age-dependent manner. The cross-reactive antibodies include anti-avian H5N1 and mainly target HA2 domain. Conclusion: MVA vaccines are efficient in infecting NALT and the vaccine antigen is highly expressed by B cells. MVA vaccines expressing conserved influenza antigens induce cross-reactive T and B cell responses in human NALT in vitro, suggesting the potential as mucosal vaccines for broader immunity against influenza.     

Universal influenza vaccine based on conserved antigens provides long-term durability of immune responses and durable broad protection against diverse challenge virus strains in mice

Current influenza vaccines rely on inducing antibody responses to the rapidly evolving hemagglutinin (HA) and neuraminidase (NA) proteins, and thus need to be strain-matched. However, predictions of strains that will circulate are imperfect, and manufacturing of new vaccines based on them takes months. As an alternative, universal influenza vaccines target highly conserved antigens. In proof of concept studies of universal vaccine candidates in animal models challenge is generally conducted only a short time after vaccination, but protective immunity lasting far longer is important for the intended public health impact. We address the challenge of providing long-term protection. We demonstrate here broad, powerful, and long-lasting immune protection for a promising universal vaccine candidate. A single intranasal dose of recombinant adenoviruses (rAd) expressing influenza A nucleoprotein (A/NP) and matrix 2 (M2) was used. Extending our previous studies of this type of vaccine, we show that antibody and T-cell responses persist for over a year without boosting, and that protection against challenge persists a year after vaccination and remains broad, covering both group 1 and 2 influenza A viruses. In addition, we extend the work to influenza B. Immunization with influenza B nucleoprotein (B/NP)-rAd also gives immune responses that last a year without boosting and protect against challenge with influenza B viruses of mismatched HA lineages. Despite host immunity to adenoviral antigens, effective readministration is possible a year after primary vaccination, as shown by successful immunization to a transgene product the animals had not seen before. Protection against challenge with divergent and highly pathogenic A/H7N9 virus was weaker but was enhanced by a second dose of vaccine. Thus, this mucosal vaccination to conserved influenza antigens confers very long-lasting immune protection in animals against a broad range of influenza A and B viruses.     

A multi-valent vaccine approach that elicits broad immunity within an influenza subtype

Vaccines directed toward individual strains of highly variable viruses like influenza lose efficacy when the circulating viruses no longer resemble the vaccine isolate. Historically, inclusion of more than one isolate per subtype of influenza has been limited by the need to include large doses of antigen with typical protein-based vaccine approaches and by concerns that an immunodominant response to one antigen will limit the response to closely related antigens. Here we provide proof of principle demonstrating that a multi-valent vaccine directed against multiple influenza A virus hemagglutinins (HAs) can elicit broad, neutralizing immunity against multiple strains within a single influenza subtype (H3). We employed a DNA vaccine to direct immunity toward the HA component alone, and a live attenuated influenza virus (LAIV) to assess immunity against the whole virus. Delivery of either HA-DNA or LAIV yielded broad protective immunity across multiple antigenic clusters, including heterologous strains, that was similar to the combined immunity of each antigen assessed separately. Priming with HA-DNA followed by an LAIV boost strengthened and broadened the antibody response toward all three H3 HAs. This prime:boost multi-valent approach was thus able to elicit immunity against multiple strains within the H3 subtype without evidence of immune interference between closely related antigens. Although the trivalent vaccine described here is not a universal vaccine, since protection was limited to circulating viruses from about a two-decade period, these data suggest that full protection within a subtype is possible using this approach with multiple antigens from current and predicted future influenza strains.     

A polyvalent influenza A DNA vaccine induces heterologous immunity and protects pigs against pandemic A(H1N1)pdm09 virus infection

The composition of current influenza protein vaccines has to be reconsidered every season to match the circulating influenza viruses, continuously changing antigenicity. Thus, influenza vaccines inducing a broad cross-reactive immune response would be a great advantage for protection against both seasonal and emerging influenza viruses. We have developed an alternative influenza vaccine based on DNA expressing selected influenza proteins of pandemic and seasonal origin. In the current study, we investigated the protection of a polyvalent influenza DNA vaccine approach in pigs. We immunised pigs intradermally with a combination of influenza DNA vaccine components based on the pandemic 1918 H1N1 (M and NP genes), pandemic 2009 H1N1pdm09 (HA and NA genes) and seasonal 2005 H3N2 genes (HA and NA genes) and investigated the protection against infection with virus both homologous and heterologous to the DNA vaccine components.     

Recombinant M2e outer membrane vesicle vaccines protect against lethal influenza A challenge in BALB/c mice

Currently approved influenza vaccines predominantly protect through antibodies directed against the highly variable glycoprotein hemagglutinin (HA), necessitating annual redesign and formulation based on epidemiological prediction of predominant circulating strains. More conserved influenza protein sequences, such as the ectodomain of the influenza M2 protein, or M2e, show promise as a component of a universal influenza A vaccine, but require a Th1-biased immune response for activity. Recently, recombinant, bacterially derived outer membrane vesicles (OMVs) demonstrated potential as a platform to promote a Th1-biased immune response to subunit antigens. Here, we engineer three M2e-OMV vaccines and show that all elicit strong IgG titers, with high IgG2a:IgG1 ratios, in BALB/c mice. Additionally, the administration of one M2e-OMV construct containing tandem heterologous M2e peptides (M2e4xHet-OMV) resulted in 100% survival against lethal doses of the mouse-adapted H1N1 influenza strain PR8. Passive transfer of antibodies from M2e4xHet-OMV vaccinated mice to unvaccinated mice also resulted in 100% survival to challenge, indicating that protection is driven largely via antibody-mediated immunity. The potential mechanism through which M2e-OMVs initiated the immune response was explored and it was found that the constructs triggered TLR1/2, TLR4, and TLR5. Our data indicate that OMVs have potential as a platform for influenza A vaccine development due to their unique adjuvant profile and intrinsic pathogen-mimetic nature.     

Report of the fourth meeting on ‘Influenza vaccines that induce broad spectrum and long-lasting immune responses’, World Health Organization and Wellcome Trust,London, United Kingdom, 9–10 November 2009

Current influenza vaccines are limited by the need for annual immunisation, frequent antigenic updating to match the evolution of circulating influenza virus strains, and reduced efficacy in elderly persons. On 9–10 November 2009, the Initiative for Vaccine Research of the World Health Organization convened jointly with the Wellcome Trust in London, United Kingdom, the fourth meeting on ‘Influenza vaccines that induce broad spectrum and long-lasting immune responses’. Presentations were made by representatives from industry, academia, governmental and non-governmental organisations. The objectives of the meeting were to update the progress of research in the field of influenza vaccine strategies able to generate cross protection against divergent influenza virus strains. Improvements in existing strategies including live attenuated influenza vaccines and adjuvantation of inactivated vaccines were summarised. Developments in novel antigen production methods, new routes of vaccine delivery and administration, and vaccine approaches based on conserved virus antigens were explored. In addition, correlates of immune protection and regulatory issues for the evaluation and approval of future novel vaccine strategies were discussed.     

Influenza virus-like particle can accommodate multiple subtypes of hemagglutinin and protect from multiple influenza types and subtypes

Despite existing vaccines and specific therapies, epidemics of seasonal influenza annually claim 200,000-500,000 lives worldwide. Pandemic influenza represents an even greater threat, with numerous potentially pandemic viruses circulating in nature. Development of multi-specific vaccines against multiple pandemic or seasonal strains is important for human health and the global economy. Here we report a novel virus-like particle (VLP) platform that contains three hemagglutinin (HA) subtypes. This recombinant vaccine design resulted in the expression of three HA subtypes co-localized within a VLP. Experimental triple-HA VLPs containing HA proteins derived from H5N1, H7N2, and H2N3 viruses were immunogenic and protected ferrets from challenge from all three potentially pandemic viruses. Similarly, VLPs containing HA subtypes derived from seasonal H1N1, H3N2, and type B influenza viruses protected ferrets from three seasonal influenza viruses. We conclude that this technology may represent a novel strategy for rapid development of trivalent seasonal and pandemic vaccines.     

A computationally designed H5 antigen shows immunological breadth of coverage and protects against drifting avian strains

Since the first identification of the H5N1 Goose/Guangdong lineage in 1996, this highly pathogenic avian influenza virus has spread worldwide, becoming endemic in domestic poultry. Sporadic transmission to humans has raised concerns of a potential pandemic and underscores the need for a broad cross-protective influenza vaccine. Here, we tested our previously described methodology, termed Computationally Optimized Broadly Reactive Antigen (COBRA), to generate a novel hemagglutinin (HA) gene, termed COBRA-2, that was based on H5 HA sequences from 2005 to 2006. The COBRA-2 HA virus-like particle (VLP) vaccines were used to vaccinate chickens and the immune responses were compared to responses elicited by VLP’s expressing HA from A/whooper swan/Mongolia/244/2005 (WS/05), a representative 2005 vaccine virus from clade 2.2. To support this evaluation a hemagglutination inhibition (HAI) breadth panel was developed consisting of phylogenetically and antigenically diverse H5 strains in circulation from 2005 to 2006, as well as recent drift variants (2008 – 2014). We found that the COBRA-2 VLP vaccines elicited robust HAI titers against this entire breadth panel, whereas the VLP vaccine based upon the recommended WS/05 HA only elicited HAI responses against a subset of strains. Furthermore, while all vaccines protected chickens against challenge with the WS/05 virus, only the human COBRA-2 VLP vaccinated birds were protected (80%) against a recent drifted clade 2.3.2.1B, A/duck/Vietnam/NCVD-672/2011 (VN/11) virus. This is the first report to demonstrate seroprotective antibody responses against genetically diverse clades and sub-clades of H5 viruses and protective efficacy against a recent drifted variant using a globular head based design strategy.     

Influenza B vaccine lineage selection—An optimized trivalent vaccine

Epidemics of seasonal influenza viruses cause considerable morbidity and mortality each year. Various types and subtypes of influenza circulate in humans and evolve continuously such that individuals at risk of serious complications need to be vaccinated annually to keep protection up to date with circulating viruses. The influenza vaccine in most parts of the world is a trivalent vaccine, including an antigenically representative virus of recently circulating influenza A/H3N2, A/H1N1, and influenza B viruses. However, since the 1970s influenza B has split into two antigenically distinct lineages, only one of which is represented in the annual trivalent vaccine at any time. We describe a lineage selection strategy that optimizes protection against influenza B using the standard trivalent vaccine as a potentially cost effective alternative to quadrivalent vaccines.     

Supplementation of H1N1pdm09 split vaccine with heterologous tandem repeat M2e5x virus-like particles confers improved cross-protection in ferrets

Current influenza vaccines induce strain-specific immunity to the highly variable hemagglutinin (HA) protein. It is therefore a high priority to develop vaccines that induce broadly cross-protective immunity to different strains of influenza. Since influenza A M2 proteins are highly conserved among different strains, five tandem repeats of the extracellular peptide of M2 in a membrane-anchored form on virus-like particles (VLPs) have been suggested to be a promising candidate for universal influenza vaccine. In this study, ferrets were intramuscularly immunized with 2009 H1N1 split HA vaccine (“Split”) alone, influenza split vaccine supplemented with M2e5x VLP (“Split+M2e5x”), M2e5x VLP alone (“M2e5x”), or mock immunized. Vaccine efficacy was measured serologically and by protection against a serologically distinct viral challenge. Ferrets immunized with Split+M2e5x induced HA strain specific and conserved M2e immunity. Supplementation of M2e5x VLP to split vaccination significantly increased the immunogenicity of split vaccine compared to split alone. The Split+M2e5x ferret group showed evidence of cross-reactive protection, including faster recovery from weight loss, and reduced inflammation, as inferred from changes in peripheral leukocyte subsets, compared to mock-immunized animals. In addition, ferrets immunized with Split+M2e5x shed lower viral nasal-wash titers than the other groups. Ferrets immunized with M2e5x alone also show some protective effects, while those immunized with split vaccine alone induced no protective effects compared to mock-immunized ferrets. These studies suggest that supplementation of split vaccine with M2e5x-VLP may provide broader and improved cross-protection than split vaccine alone.     

Effective mosaic-based nanovaccines against avian influenza in poultry

Avian influenza virus (AIV) is an extraordinarily diverse pathogen that causes significant morbidity in domesticated poultry populations and threatens human life with looming pandemic potential. Controlling avian influenza in susceptible populations requires highly effective, economical and broadly reactive vaccines. Several AIV vaccines have proven insufficient despite their wide use, and better technologies are needed to improve their immunogenicity and broaden effectiveness. Previously, we developed a “mosaic” H5 subtype hemagglutinin (HA) AIV vaccine and demonstrated its broad protection against diverse highly pathogenic H5N1 and seasonal H1N1 virus strains in mouse and non-human primate models. There is a significant interest in developing effective and safe vaccines against AIV that cannot contribute to the emergence of new strains of the virus once circulating in poultry. Here, we report on the development of an H5 mosaic (H5M) vaccine antigen formulated with polyanhydride nanoparticles (PAN) that provide sustained release of encapsulated antigens. H5M vaccine constructs were immunogenic whether delivered by the modified virus Ankara (MVA) strain or encapsulated within PAN. Both humoral and cellular immune responses were generated in both specific-pathogen free (SPF) and commercial chicks. Importantly, chicks vaccinated by H5M constructs were protected in terms of viral shedding from divergent challenge with a low pathogenicity avian influenza (LPAI) strain at 8 weeks post-vaccination. In addition, protective levels of humoral immunity were generated against highly pathogenic avian influenza (HPAI) of the similar H5N1 and genetically dissimilar H5N2 viruses. Overall, the developed platform technologies (MVA vector and PAN encapsulation) were safe and provided high levels of sustained protection against AIV in chickens. Such approaches could be used to design more efficacious vaccines against other important poultry infections.     

Protective efficacy in mice of monovalent and trivalent live attenuated influenza vaccines in the background of cold-adapted A/X-31 and B/Lee/40 donor strains

Influenza virus continues to take a heavy toll on human health and vaccination remains the mainstay of efforts to reduce the clinical impact imposed by viral infections. Proven successful for establishing live attenuated vaccine donor strains, cold-adapted live attenuated influenza vaccines (CAIVs) have become an attractive modality for controlling the virus infection. Previously, we developed the cold-adapted strains A/X-31 and B/Lee/40 as novel donor strains of CAIVs against influenza A and B viruses. In this study, we investigated the protective immune responses of both mono- and trivalent vaccine formulations in the mouse model. Two type A vaccines and one type B vaccine against A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), and B/Shangdong/7/97 in the background of the A/X-31 ca or B/Lee/40 ca were generated by a reassortment procedure and evaluated for their immunogenicity and protective efficacy. Each monovalent vaccine elicited high levels of serum antibodies and conferred complete protection against homologous wild type virus infection. As compared to the monovalent vaccines, trivalent formulation induced higher levels of type A-specific serum antibodies and slightly lower levels of type B-specific antibodies, suggesting an immunological synergism within type A viruses and an interference in the replication of type B virus. Relatively lower type B-specific immunogenicity in trivalent vaccine formulation could be effectively implemented by increasing the vaccine dose of influenza B virus. These results of immunogenicity, protection efficacy, and immunological synergism between type A vaccines provide an experimental basis for optimal composition of trivalent vaccines for subsequent developments of multivalent CAIVs against seasonal and pandemic influenza viruses.     

Identification of potent epitopes on hexon capsid protein and their evaluation as vaccine candidates against infections caused by members of Adenoviridae family

Adenoviruses cause economically important diseases in vertebrates. Effective vaccines against adenoviral diseases are currently lacking. Here, we report a highly conserved epitopic region on hexon proteins of adenoviruses that generate a strong immune response when used as a virus-like-particle (VLP) vaccine, produced by inserting the epitopic region into the core protein of hepatitis B virus. For evaluation of its protective efficacy, the epitopic region from a representative adenovirus, fowl adenovirus serotype 4 (FAdV-4), was tested as a VLP vaccine which conferred 90% protection against challenge with a virulent FAdV-4 isolate in chickens. Importantly, such a high level of protection is not achieved when the epitopic region is employed as a part of a subunit vaccine. As the sequence and the structure of the epitopic region are highly conserved in hexon proteins of adenoviruses, the epitopic region could be employed as a promising VLP vaccine candidate against adenoviral diseases, in general.     

A bivalent influenza VLP vaccine confers complete inhibition of virus replication in lungs

The conventional egg-grown influenza vaccines are trivalent. To test the feasibility of using multivalent influenza virus-like particles (VLPs) as an alternative influenza vaccine, we developed cell-derived influenza VLPs containing the hemagglutinin (HA) of the H1 subtype virus A/PR/8/34 or the H3 subtype virus A/Aichi/2/68 (X31). Mice immunized intramuscularly with bivalent influenza VLPs containing H1 and H3 HAs induced neutralizing activities against the homologous and closely related H1N1 strains A/PR/8/34 and A/WSN/33 as well as the H3N2 strains A/Aichi/2/68 (X31) and A/Hong Kong/68, but not the A/Philippines/2/82 strain isolated 14 years later. HA sequence and structure analysis indicated that antigenic distance could be a major factor in predicting cross-protection by VLP vaccines. The bivalent influenza VLP vaccine demonstrated advantages in broadening the protective immunity after lethal challenge infections when compared to a monovalent influenza VLP vaccine. High levels of the inflammatory cytokine IL-6 were observed in na?ve or unprotected immunized mice but not in protected mice upon lethal challenge. These results indicate that multivalent influenza VLP vaccines can be an effective antigen for developing safe and alternative vaccine to control the spread of influenza viruses.     

Broad cross-protective anti-hemagglutination responses elicited by influenza microconsensus DNA vaccine

Despite the routine development and distribution of seasonal influenza vaccines, influenza remains an important pathogen contributing to significant human morbidity as well as mortality each year. The seasonal variability of influenza creates a significant issue for vaccine development of seasonal strains that can afford protection from infection or disease based on serotype matching. It is appreciated that the globular head of the HA antigen contained in the vaccines generates antibodies that result in HAI activity that are a major correlates of the protection against a particular strain. Due to seasonal genetic changes in the HA protein, however, new vaccine strains are needed to be developed continually to match the new HA antigen of that seasons virus. A distinct advantage in seasonal vaccine development would be if a small group of antigens could be developed that could span many seasons without needed to be replaced due to this genetic drift. Here we report on a synthetic microconsensus approach that relies on a small collection of 4 synthetic H1HA DNA antigens which together induce broad protective HAI immunity spanning decades of H1 influenza viruses in mice, guinea pigs and non-human primates. The protective HAI titers induced by microconsensus immunogens are fully functional in vivo as immunized ferrets were completely protected from A/Mexico/InDRE4487/2009 virus infection and morbidity associated with lethal challenge. These results are encouraging that a limited easy-to-formulate collection of invariant antigens can be developed which can span seasonal vaccine changes allowing for continued immune protection.     

Efficacy of live attenuated influenza vaccine in children against influenza B viruses by lineage and antigenic similarity

Seasonal influenza vaccines, including live attenuated influenza vaccine (LAIV), contain three vaccine strains (two type A and one type B). Ideally, the hemagglutinin antigens of the recommended vaccine strains are antigenically similar to epidemic wild-type strains; in actuality, the antigenic match between circulating and vaccine strains each year can vary significantly owing to intermittent genetic reassortment and continuous antigenic drift. For influenza B, antigenic relatedness is further complicated by the existence of two distinct lineages. Consequently, the influenza B vaccine component can be of a completely different antigenic lineage from the circulating epidemic strains. Using data from nine randomized clinical trials in young children (6 months to 6 years of age), vaccine efficacy of LAIV against influenza B strains was assessed across this spectrum of antigenic relatedness. In an integrated analysis, vaccine efficacy of two doses of LAIV in vaccine-naive children was 86% against B strains of the same lineage and closely matched to the vaccine strain, 55% against strains of the same lineage but antigenically drifted from the vaccine strain, and 31% against strains of the opposite B lineage and antigenically unrelated to the vaccine strain. These data provide a more accurate assessment of the protection provided by the current trivalent vaccine and highlight the need for vaccination strategies that provide enhanced protection against both lineages of influenza B such as a quadrivalent influenza vaccine.     

Influenza bivalent vaccine comprising recombinant H3 hemagglutinin (HA) and H1 HA containing replaced H3 hemagglutinin transmembrane domain exhibited improved heterosubtypic protection immunity in mice

Influenza caused by infection of influenza viruses is still a leading cause of morbidity and mortality in human. Vaccination is the main defense against influenza virus, but current influenza trivalent or quatrivalent vaccines (TIV/QIV) would lose their effectiveness when vaccine strains are mismatched with circulating strains. Our early study showed that recombinant influenza Hx-TM HA proteins containing H3 HA transmembrane domain(TM) had improved immunogenicity and heterosubtypic protection over corresponding wild-type Hx-WT HA proteins. In present study, bivalent vaccines containing H3-WT + Hx-TM were investigated for their immune responses and heterosubtypic protection immunities. The data showed that the bivalent vaccines containing H3-WT and H5-TM or H1-TM had improved immune responses and heterosubtypic protection over the bivalent vaccines containing H3-WT and H5-WT or H1-WT respectively. These results demonstrated that the improved immune responses and heterosubtypic protection of Hx-TM HA proteins could be translated into bivalent vaccines, suggesting a feasible strategy of improving the immune responses and heterosubtypic protection of influenza multivalent vaccines such as TIV and QIV.