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New advances in mucosal vaccination Charani Ranasinghe ∗ Molecular Mucosal Vaccine Immunology Group, Department of Immunology, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia

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Article history: Received 13 December 2013 Accepted 12 January 2014 Available online xxx Keywords: Mucosal vaccines oral delivery intranasal delivery Intra-cheek delivery Mucosal adjuvants IgA T cell avidity Autophagy M cells Plant-based vaccines

a b s t r a c t The ICI 2013 Mucosal Vaccine Workshop presentations covered a wide range of topics, these mainly fell into three categories: (i) Understanding the interactions of host and microbes, specifically commensal pathogens and improving the antigen uptake via the (microfold cells) M cells to induce effective IgA antibody immunity at the gut mucosa; (ii) effective plant-based vaccines and (iii) development of prophylactic and therapeutic mucosal-based vaccine strategies for virus infections such as human immunodeficiency virus (HIV), influenza and human papillomavirus (HPV) associated head and neck cancers. How to improve the efficacy of oral vaccines, novel intranasal mucosal adjuvants and a unique intra-cheek delivery method were also discussed. Presenters emphasized the differences associated with systemic and mucosal vaccination, specifically, how mucosal vaccines unlike systemic delivery can induce effective immunity at the first line of defence. Collectively, the workshop provided insights into recent developments in the mucosal vaccine research field, highlighting the complexities associated with designing safe and effective mucosal vaccines. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Over the years, designing safe and effective mucosal vaccines and adjuvants have been a challenge task. Unlike vaccines delivered to the blood compartment, how and why mucosal vaccines can induce sustained immunity at the mucosae has been greatly debated. Deciphering the molecular mechanisms involved in the antigen uptake/presentation at the mucosae and how mucosal vaccines modulate innate and adaptive immunity compared to systemic vaccines are now been widely studied. During the last decade there has been significant progresses made in the design of effective mucosal vaccines against many mucosal pathogens. At the ICI 2013 Mucosal Vaccine Workshop seven scientists shared their recent findings in this field of research. 2. Induction of effective immunity at the gut mucosa Understanding the interactions of host and microbes specifically commensal pathogens is becoming an important topic in mucosal immunology [1,2]. The workshop co-chair Mi-Na Kowen from International Vaccine Institute, Seoul, Korea elegantly addressed this question. She described mechanisms of autophagy associated

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with oral infection of Shigella in adult mice, in their quest to understand, why some pathogens such as Shigella causes disease in human and nonhuman primates but not in other animals. Pathogenic Shigella species and Escherichia coli can cause acute diarrheal diseases by invading colon epithelium and promoting a strong inflammatory response in humans and nonhuman primates, but adult mice can be naturally resistant to intra-gastric infection by these enteric pathogens. Their data indicated that even though entero-pathogenic Shigellae can invade the terminal ileum of the small intestine of adult mice within 1 h of infection, the infection can be cleared within 24 h post infection. They found that even though the infection results in epithelial shedding, degranulation of Paneth cells and cell death in the lamina propria and crypt, interestingly these did not lead to any inflammation [3]. They showed that blocking of the autophagy protein (Atg)-5- or Atg7mediated autophagy process in the epithelial cells could enhance host cell death causing tissue destruction and eventual intestinal inflammation. These findings clearly indicated that autophagic flow could relieve the cellular stress associated with inflammation and death caused by oral Shigella infection [3]. From these findings they hypothesize that in mice there is a general intrinsic mechanism that repels the entero-pathogenic bacteria and that process is regulated via autophagy. Their findings offered new insight into mechanisms of interrelations between bacterial infection, intestinal inflammation and canonical autophagy stipulating more effective treatment options against entero-pathogenic bacteria in the future.

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It is well established that IgA antibody is mainly detected in the intestinal lumen, where it plays an important role in protecting the host against pathogenic infections and commensal bacteria [4–6]. In an interesting presentation by Kunisawa and co-workers from The University of Tokyo and National Institute of Biomedical Innovation, Japan, new class of IgA(+) plasma cells in the murine intestine was discussed. They described their recent studies on identifying a unique microbe-dependent murine intestinal IgA plasma cell (PCs) population on the basis of CD11b expression. They demonstrated that induction of CD11b+ IgA+ PCs require the lymphoid structure of Peyer’s patches, microbial stimulation and presence of cytokine IL-10 [7]. Following induction, these PCs produce elevated IgA and higher proliferation compared to CD11b− IgA+ PCs. Although no human intestinal IgA+ cells that express CD11b have been identified, proliferative (Ki67+) IgA+ PC subsets have been identified in humans [7]. Their studies also showed that oral protein immunization can induce CD11b+ IgA+ PC mediated early-phase antigen-specific intestinal IgA production. Specifically, preferential depletion of CD11b+ IgA+ PCs was shown to result in the significant impairment of intestinal IgA production against orally immunized antigens. The data highlighted the functional diversity of IgA+ PCs in the murine intestine and possible targets for the development of oral vaccines [7]. Similar to what has been echoed by many researches in the mucosal vaccine field Shima and co-workers from RIKEN Yokohama institute, Japan highlighted that purely systemic vaccines are incapable of inducing sustained mucosal immunity, whereas, mucosal vaccines can induce both systemic and mucosal immunity including antigen-specific SIgA, on mucosal surface at the first line of defense [8–11]. They elegantly described the difficulties associated with designing effective orally deliverable vaccines, mainly due to problems associated with gastric acid and digestive enzymes in the gut mucosa, preventing the antigen uptake via the M cells. They presented their work on a novel anti-glycoprotein 2-steptoavidinbased (GP2-SA) mucosal vaccine strategy, targeting the uptake of vaccines via the glycoprotein 2 (GP2) of FimH+ bacteria receptor (mannose-specific fimbrial adhesion receptor) [12] on Peyer’s patch M cells [13]. The anti-GP2-SA vaccine consisted of a fusion protein of the Fab fragment from anti-GP2 monoclonal antibody bound to streptavidin which was able to bind to GP2 on Peyer’s patch M cells and get taken up effectively into the gut mucosa. These results highlighted the potential use of anti-GP2-SA/biotinylated antigen protein delivery system (the use of GP2-dependent transcytotic pathway) as a safe and effective M-cell-targeted mucosal vaccine strategy.

3. Designing safe plant-based vaccines Plant-based vaccines have been tested for a number of years [14–16] with limited success. Yuki and co-workers from The University of Tokyo, Japan discussed how a cold-chain free rice-based oral cholera toxin B subunit vaccine could help induce toxinspecific neutralizing immune responses in mice and macaques. It is known that, the expression of vaccines in plants can result in unexpected modification of the vaccines by N-terminal blocking and sugar-chain attachment and can cause undesirable immune outcomes. Although MucoRice cholera toxin B (CTB) is one of the first cold-chain-free and unpurified oral vaccines, the molecular heterogeneity of MucoRice-CTB, together with plant-based sugar modifications of the CTB protein, has made it difficult to assess the vaccine dose in a rice seed and relative dose-dependent immunological activity induced. By using a T-DNA vector driven by a prolamin promoter and a signal peptide added to an overexpression vaccine cassette, they have now designed a MucoRice-CTB/Q, a new generation of oral cholera vaccine for human use [17]. They showed

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that the new MucoRice-CTB/Q produces a single CTB monomer with an Asn to Gln substitution at the 4th glycosylation position, making it possible to quantify the average amount of vaccine produced which was in the order of 2.35 mg of CTB/g of rice seed. When they orally immunized mice and macaques with the MucoRiceCTB/Q, which had no plant-based glycosylation modifications, it was shown to induce quantifiable CTB-specific systemic IgG and mucosal IgA antibodies with toxin-neutralizing activity eliciting that the substitutions had no impact on the efficacy of the vaccine [17]. These results demonstrated that MucoRice-CTB/Q vaccine with no plant N-glycan has potential to be uses as a safe and efficacious oral vaccine candidate in humans.

4. Development of mucosal prophylactic and therapeutic vaccines against viral infections Co-chair Charani Ranasinghe from The Australian National University shared some of the recent advances in her laboratory regarding the design of more effective mucosal pox viral-based HIV vaccines that induced higher quality T cell immunity. She presented data showing that compared to a purely systemic (intramuscular – i.m.) HIV-1 prime-boost immunization, mucosal (intranasal – i.n.) immunization can induce cytotoxic CD8 T cells (CTL) of higher quality or avidity with lower IL-4/IL-13 activity and better protective immunity [18]. Recent finding in her laboratory have shown that co-expression of IL-13R␣2 (soluble or membrane bound forms) together with HIV-1 vaccine antigens in an i.n./i.m. pox viral prime-boost vaccination modality can (i) transiently block IL-13 activity at the vaccination site, (ii) dramatically enhance HIVspecific systemic and mucosal cytotoxic T cell (CTL) avidity, (iii) induce mucosal and systemic CTLs that are multi-functional with boarder cytokine/chemokine profiles and (iv) induce excellent protective immunity in immunized animals similar to an IL-13 gene knockout animals following a surrogate mucosal HIV-1 challenge [19]. Their findings indicated that CD8 T cell avidity is defined at the vaccination site (i.e. the lung mucosae) at very early stages of priming and according to the antigen presenting cell subsets recruited or induced to the vaccination site [19] (Trivedi et al., submitted for publication). Moreover at the T cell level, following infection/vaccination the down-regulation of IL-4R␣ densities on effector CD8 T cells and up-regulation of CD8␣/␤ co-receptors also play a important role in modulating CD8 T cell avidity [20,21]. They believe that these findings not only offer exciting prospects for a future HIV-1 vaccine development but also many other chronic mucosal infections where high avidity CD8 T cells are required for protection. Macedo and co-workers from Groupe hospitalier PitiéSalpêtrière, Paris, France presented their work on the advantages of a new intra-cheek therapeutic vaccine for human papillomavirus (HPV)-associated head and neck cancers (NHCs). HPV-16 infection has recently been associated with oropharyngeal NHCs that express the viral E6 and E7 oncoproteins. Although the licensed vaccines can efficiently prevent HPV infection, these have not been proven to control established tumors. Thus other DNA-based therapeutic vaccines strategies have been tested as treatments [22]. Macedo and colleagues demonstrated the design and use of a novel therapeutic intra-dermic DNA vaccination strategy using plasmo-virus like particles carrying the E7 oncoprotein (pVLPs-E7 – a plasmid DNA that is able to form recombinant retrovirus-based virus-like particles) for HNCs. The anti-tumoral efficacy of pVLPs-E7 was compared according to the route of vaccine delivery. Specifically, following intra-cheek (i.c.) and intra-dermal (i.d.) pVLP-E7 vaccinations. The data demonstrated that while i.d. route of delivery elicited better systemic anti-E7 cellular immune response compared to i.c. route in mice, but the i.c. delivery route was also capable of inducing

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robust anti-E7-specific humoral immunity [23]. More interestingly, they found that in mice bearing well-established tumors, i.c. immunization induced a better therapeutic effect compared to i.d. immunization. Collectively, their data also showed that i.c. mucosal vaccination with pVLP-E7 specifically together with TLR agonists (Imiquimod and CpG) have good potential as a therapeutic strategy for HPV-induced NHCs [23]. In the final presentation Zeng and co-workers from Texas Tech University Health Sciences Center, El Paso, United States discussed the design of a universal influenza prime-boost immunization vaccine approach. The trivalent live attenuated (LAIV, nasal spray FluMist) and inactivated (TIV, intramuscular injection FluZone) influenza vaccines have shown to induce varying immune outcomes, often LAIV vaccine performing better in young children [24,25]. Zeng and co-workers showed that LAIV and TIV influenza vaccines given to mice in a 1–3 dose prime-boost vaccination regimen induce differential protective efficacy. Specifically, whilst both LAIV and TIV induced strong humoral responses, only the LAIV vaccine was found to induce significantly elevated IL-2 and IFN-␥ cytokine expression in lung mucosae and good protective efficacy against H1N1 PR8 heterosubtype influenza virus challenge. Also they showed that depletion of T cell from LAIV-immunized mice compromised protection against H1N1 PR8 influenza virus challenge, indicating the importance of T cell-mediated immunity. Finally, they also showed that three doses of LAIV provided protection against challenge with two additional heterologous viruses; FM/47 (H1N1) and HK/68 (H3N2). These results supported the notion that unlike TIV, LAIV could be considered as a universal influenza vaccine in a prime-boost vaccination setting. In conclusion, the Mucosal Vaccine Workshop showcased the latest advances in the mucosal vaccine field and highlighted the ever-increasing complexities associate with designing safe and effective mucosal vaccination strategies against chronic mucosal pathogens. Acknowledgements Author would like to thank Danushka Wijesundara and Shubhanshi Trivedi for proof reading the article. CR gratefully acknowledges the funding support from Australian Centre for Hepatitis and HIV Virology Research and National Health and Medical Research Council Project and Development grants # 525431 and APP1000703 respectively. References [1] Jarchum I, Pamer EG. Regulation of innate and adaptive immunity by the commensal microbiota. Curr Opin Immunol 2011;23:353–60. [2] Tanoue T, Umesaki Y, Honda K. Immune responses to gut microbiotacommensals and pathogens. Gut Microbes 2010;1:224–33. [3] Chang SY, Lee SN, Yang JY, Kim DW, Yoon JH, Ko HJ, et al. Autophagy controls an intrinsic host defense to bacteria by promoting epithelial cell survival: a murine model. PLoS ONE 2013;8:e81095.

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[4] Macpherson AJ, McCoy KD, Johansen FE, Brandtzaeg P. The immune geography of IgA induction and function. Mucosal Immunol 2008;1:11–22. [5] Macpherson AJ, Slack E. The functional interactions of commensal bacteria with intestinal secretory IgA. Curr Opin Gastroenterol 2007;23:673–8. [6] Spencer J, Klavinskis LS, Fraser LD. The human intestinal IgA response; burning questions. Front Immunol 2012;3:108. [7] Kunisawa J, Gohda M, Hashimoto E, Ishikawa I, Higuchi M, Suzuki Y, et al. Microbe-dependent CD11b(+) IgA(+) plasma cells mediate robust early-phase intestinal IgA responses in mice. Nat Commun 2013;4:1772. [8] Belyakov IM, Ahlers JD. Comment on “trafficking of antigen-specific CD8+ T lymphocytes to mucosal surfaces following intramuscular vaccination”. J Immunol 2009;182:1779, author reply 1779–1780. [9] Ranasinghe C, Eyers F, Stambas J, Boyle DB, Ramshaw IA, Ramsay AJ. A comparative analysis of HIV-specific mucosal/systemic T cell immunity and avidity following rDNA/rFPV and poxvirus-poxvirus prime boost immunisations. Vaccine 2011;29:3008–20. [10] Neutra MR, Kozlowski PA. Mucosal vaccines: the promise and the challenge. Nat Rev Immunol 2006;6:148–58. [11] Kiyono H, Fukuyama S. NALT-versus peyer’s-patch mediated mucosal immunity. Nat Immunol 2004;4:699–710. [12] Krogfelt KA, Bergmans H, Klemm P. Direct evidence that the FimH protein is the mannose-specific adhesin of Escherichia coli type 1 fimbriae. Infect Immun 1990;58:1995–8. [13] Hase K, Kawano K, Nochi T, Pontes GS, Fukuda S, Ebisawa M, et al. Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response. Nature 2009;462:226–30. [14] Nochi T, Takagi H, Yuki Y, Yang L, Masumura T, Mejima M, et al. Rice-based mucosal vaccine as a global strategy for cold-chain- and needle-free vaccination. Proc Natl Acad Sci USA 2007;104:10986–91. [15] Rosales-Mendoza S, Govea-Alonso DO, Monreal-Escalante E, Fragoso G, Sciutto E. Developing plant-based vaccines against neglected tropical diseases: where are we? Vaccine 2012;31:40–8. [16] Lugade AA, Kalathil S, Heald JL, Thanavala Y. Transgenic plant-based oral vaccines. Immunol Invest 2010;39:468–82. [17] Yuki Y, Mejima M, Kurokawa S, Hiroiwa T, Takahashi Y, Tokuhara D, et al. Induction of toxin-specific neutralizing immunity by molecularly uniform rice-based oral cholera toxin B subunit vaccine without plant-associated sugar modification. Plant Biotechnol J 2013;11:799–808. [18] Ranasinghe C, Turner SJ, McArthur C, Sutherland DB, Kim JH, Doherty PC, et al. Mucosal HIV-1 pox virus prime-boost immunization induces high-avidity CD8+ T cells with regime-dependent cytokine/granzyme B profiles. J Immunol 2007;178:2370–9. [19] Ranasinghe C, Trivedi S, Stambas J, Jackson RJ. Unique IL-13Ralpha2-based HIV1 vaccine strategy to enhance mucosal immunity, CD8(+) T-cell avidity and protective immunity. Mucosal Immunol 2013;6:1068–80. [20] Wijesundara DK, Tscharke DC, Jackson RJ, Ranasinghe C. Reduced interleukin-4 receptor alpha expression on CD8+ T cells correlates with higher quality antiviral immunity. PLoS ONE 2013;8:e55788. [21] Wijesundara DK, Jackson RJ, Tscharke DC, Ranasinghe C. IL-4 and IL-13 mediated down-regulation of CD8 expression levels can dampen anti-viral CD8 T cell avidity following HIV-1 recombinant pox viral vaccination. Vaccine 2013:4548–55. [22] Wu A, Zeng Q, Kang TH, Peng S, Roosinovich E, Pai SI, et al. Innovative DNA vaccine for human papillomavirus (HPV)-associated head and neck cancer. Gene Ther 2011;18:304–12. [23] Lescaille G, Pitoiset F, Macedo R, Baillou C, Huret C, Klatzmann D, et al. Efficacy of DNA vaccines forming e7 recombinant retroviral virus-like particles for the treatment of human papillomavirus-induced cancers. Hum Gene Ther 2013;24:533–44. [24] Hoft DF, Babusis E, Worku S, Spencer CT, Lottenbach K, Truscott SM, et al. Live and inactivated influenza vaccines induce similar humoral responses, but only live vaccines induce diverse T-cell responses in young children. J Infect Dis 2011;204:845–53. [25] Osterholm MT, Kelley NS, Sommer A, Belongia EA. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect Dis 2012;12:36–44.

advances

in

mucosal

vaccination.

Immunol

Lett

(2014),

New advances in mucosal vaccination.

The ICI 2013 Mucosal Vaccine Workshop presentations covered a wide range of topics, these mainly fell into three categories: (i) Understanding the int...
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