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Single-dose microparticle delivery of a malaria transmission-blocking vaccine elicits a long-lasting functional antibody response.
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PMID:  23331003     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Malaria sexual stage and mosquito transmission-blocking vaccines (SSM-TBV) have recently gained prominence as a necessary tool for malaria eradication. SSM-TBVs are unique in that, with the exception of parasite gametocyte antigens, they primarily target parasite or mosquito midgut surface antigens expressed only inside the mosquito. As such, the primary perceived limitation of SSM-TBVs is that the absence of natural boosting following immunization will limit its efficacy, since the antigens are never presented to the human immune system. An ideal, safe SSM-TBV formulation must overcome this limitation. We provide a focused evaluation of relevant nano-/microparticle technologies that can be applied toward the development of leading SSM-TBV candidates, and data from a proof-of-concept study demonstrating that a single inoculation and controlled release of antigen in mice, can elicit long-lasting protective antibody titers. We conclude by identifying the remaining critical gaps in knowledge and opportunities for moving SSM-TBVs to the field.
Authors:
R R Dinglasan; J S Armistead; J F Nyland; X Jiang; H Q Mao
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Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Current molecular medicine     Volume:  13     ISSN:  1875-5666     ISO Abbreviation:  Curr. Mol. Med.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-12     Completed Date:  2013-10-22     Revised Date:  2014-06-20    
Medline Journal Info:
Nlm Unique ID:  101093076     Medline TA:  Curr Mol Med     Country:  Netherlands    
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Languages:  eng     Pagination:  479-87     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibodies, Protozoan / biosynthesis*,  immunology
Malaria / immunology,  prevention & control*
Malaria Vaccines / administration & dosage*
Mice
Microspheres*
Particle Size
Grant Support
ID/Acronym/Agency:
F32 AI068212/AI/NIAID NIH HHS; K22 AI077707/AI/NIAID NIH HHS; T32 AI007417/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Antibodies, Protozoan; 0/Malaria Vaccines
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Journal Information
Journal ID (nlm-ta): Curr Mol Med
Journal ID (iso-abbrev): Curr. Mol. Med
Journal ID (publisher-id): CMM
ISSN: 1566-5240
ISSN: 1875-5666
Publisher: Bentham Science Publishers
Article Information
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© Bentham Science Publishers
open-access:
Received Day: 13 Month: 12 Year: 2012
Revision Received Day: 8 Month: 1 Year: 2013
Accepted Day: 12 Month: 1 Year: 2013
Print publication date: Month: 5 Year: 2013
Electronic publication date: Month: 5 Year: 2013
Volume: 13 Issue: 4
First Page: 479 Last Page: 487
PubMed Id: 23331003
ID: 3706950
Publisher Id: CMM-13-479
DOI: 10.2174/1566524011313040002

Single-Dose Microparticle Delivery of a Malaria Transmission-Blocking Vaccine Elicits a Long-Lasting Functional Antibody Response
R.R Dinglasan*1
J.S Armistead1#
J.F Nyland2#
X Jiang34
H.Q Mao34
1W. Harry Feinstone Department of Molecular Microbiology & Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA
2Department of Pathology, Microbiology & Immunology, University of South Carolina School of Medicine, 6439 Garner's Ferry Road, Columbia, SC 29209, USA
3Department of Materials Science and Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA
4Translational Tissue Engineering Center, Whitaker Biomedical Engineering Institute, Johns Hopkins School of Medicine, 400 North Broadway, Baltimore, MD 21287, USA
*Address correspondence to this author at the W. Harry Feinstone Department of Molecular Microbiology & Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Rm. E5646, Baltimore, MD 21205, USA; Tel: +1-410-614-4839; Fax: +1-410-955-0105; E-mail: rdinglas@jhsph.edu
#These authors contributed equally to this manuscript.

INTRODUCTION

The malaria eradication research agenda has re-emphasized the need for effective sexual stage and mosquito transmission-blocking vaccines (SSM-TBV) [1], which prevents malaria parasite development in its mosquito vector and the subsequent cascade of secondary infections [2-5]. SSM-TBVs, in general, work through the action of inhibitory antibodies [5-7]. Thus, the minimum objective of immunization is to induce high titer antibodies sustainable for at least one transmission season (~3-6 months), but preferably for 2 years. Achieving this minimum goal would theoretically drive the case reproductive rate, (R0) <1. A summary of the target product profile (TPP) for SSM-TBVs is shown in Table 1. With the exception of Plasmodium falciparum or P. vivax gametocyte surface antigens that are expressed in the human, SSM-TBVs are considered unique in that they target parasite (gamete, zygote, or ookinete) or Anopheles mosquito midgut surface antigens that are only expressed in the mosquito. As such, one of the potential limitations of the TBV approach is that since the antigens are never naturally presented to the human immune system, the absence of natural boosting following immunization will limit their efficacy [8-13]. A complete P. knowlesi model in non-human primates (NHP) has been used to test the “natural boosting” hypothesis for Plasmodium gamete antigens [13]. It was found that following a two-dose immunization regimen using 105-107P. knowlesi microgametes and macrogametes in a Freund’s complete adjuvant (FCA), the majority of the monkeys maintained a high level of functional transmission-blocking antibody titer for more than 1 year. Furthermore, annual challenge infections over a six year period were found to be sufficient for boosting and transmission-blocking immunity persisted in the majority of splenectomized NHPs. Importantly, as expected, they observed that transmission-blocking activity waned over time in the absence of boosting and that the challenge infection resulted in an increase in gamete-specific antibody levels. Although the likely gamete antigens had not yet been fully characterized at the time of this study, it was already known that gametocytes and gametes shared surface antigens [14, 15], thus it is possible that gametocyte exposure in the NHPs following challenge was responsible for boosting. This study further supported the notion that boosting would increase the efficacy and utility of SSM-TBVs but raised the question of the need for highly potent adjuvants such as FCA, which is considered a serious obstacle in human vaccine development.

The four leading SSM-TBVs (Table 2) include two gametocyte surface antigens, Pfs230 [16-20] and Pfs48/45 [21], the ookinete surface protein Pfs25 [22] and the Anopheles gambiae alanyl aminopeptidase N (APN1), which is an abundant, midgut-specific apical microvilli surface glycoprotein that has been shown to mediate ookinete invasion and oocyst development [7, 23]. Of these, only Pfs25 and APN1 are expressed explicitly inside the mosquito midgut. Note that the goal of this report is not to evaluate the complete repertoire of proven and possible SSM-TBV candidates, and the reader is directed to several excellent reviews for additional information [3, 4, 24-29]. Among the four leading candidates, only Pfs25 has completed Phase I clinical trials, albeit with equivocal results [29]. Efforts are underway to produce the full-length Pfs/Pvs230 [30-32] and Pfs48/45 antigens [33-35], which have proven to be a difficult undertaking using different expression platforms due to their size and/or conformation, as well as the high A+T content of plasmodial genes; and these issues have a direct impact on vaccine process development. The APN1 antigen, on the other hand, does not require the full-length antigen, is highly immunogenic [7] and is entering process development, with an optimistic initiation of Phase I clinical trials within the next 3-4 years. Since Pfs25 and APN1-based vaccines are the least likely to benefit from boosting following natural infection, we focused on these two antigens in this article to examine their current state of development, as well as similarities and differences in the context of several identified target product profiles and the “natural boosting” issue (Table 1). Furthermore, we have also used APN1 as a model antigen to directly address the above issue using nano- and microparticle technologies.

An ideal SSM-TBV formulation with a highly immunogenic antigen must therefore have the following characteristics: (i) it should be safe; (ii) it should not require a cold-chain; (iii) it should easily be administered; and (iv) a single immunization should confer long-lasting protection. A biodegradable microparticle (BMP) system, which provides sustained release of antigen and adjuvant properties, is capable of meeting these challenges. Several recent studies have demonstrated the utility of this general vaccine approach in vertebrate models [36-40]. Microparticle size is an important determinant for cell uptake [41, 42] and may also influence the antigen release rate [43]. In line with this, recent studies have shown that smaller particle delivery systems are effective in eliciting a robust immune response to the target immunogen [44-47]. The bioabsorption rate of BMPs and antigen release rate can be engineered to provide boosting from weeks to several months. Particles carrying single or multiple antigens can arguably mimic viral antigen presentation thus rapidly inducing a potent and long-lasting cellular and humoral response either by direct immune stimulation of antigen presenting cells (APCs) or/and by delivering antigen to the lymph node [30, 37, 48]. In fact, virosomes follow this approach and have shown to be effective carriers for proteins and subunit vaccines against a variety of pathogens, including malaria [49], but to date, this approach has not been used to deliver SSM-TBV antigens. With these goals in mind, we conducted proof-of-concept studies to test the hypothesis that safe biodegradable microparticles can mimic natural boosting through sustained release of antigen and, in doing so, elicit significant transmission-blocking antibodies against Plasmodium.


MATERIALS AND METHODS
Preparation of Biodegradable Microparticles (BMPs) with Different Size Range and Different Antigen Loading Levels

Recombinant APN1 was produced in E. coli as previously described [23]. Polylactofate (PLE) was used to prepare BMPs. PLE is a poly(lactide-co-glycolide) derivative with good biocompatibility and better control of biodegradation rate and physical properties [50, 51] (Fig. 1A). BMPs were prepared by a modified double emulsion method [50], and characterized by scanning electron microscopy. The release kinetics of APN1 from BMPs was characterized by monitoring the concentration of APN1 using ELISA. To modulate APN1 release, we used bovine serum albumin (BSA) as a filler protein.

Immunizations

BALB/c female mice were immunized with either (A) recombinant APN1 in PBS in suspension with alum, or (B) recombinant APN1 in PBS emulsified with incomplete Freund’s adjuvant (IFA), or (C) BMP-encapsulated recombinant APN1 delivered with alum, or (D) BMP encapsulated APN1 with IFA or (E) empty BMP with alum or (F) empty BMP with IFA. For all treatment groups, mice received 2 µg antigen/mouse/ dose. At day 0, mice received a subcutaneous (s.c.) injection of the appropriate inoculum in a volume of 100 μl per mouse. At 2, 4 and 6 weeks post priming, mice in the Control cohorts (treatments A and B, above) were boosted intraperitoneally (i.p.) with the same dose of the inoculum per mouse, whereas the BMP cohorts were boosted only with PBS. At these time points, each mouse was bled to collect sera for anti-APN1 antibody titer determination via ELISA (Fig. 1C).

ELISA and Cytokine Assay

ELISAs were performed as previously described, using recombinant APN1 as coating antigen [7]. For cytokine assays, the spleen was removed and homogenized at 10% wt/vol in 2% fetal bovine serum/minimal essential medium, and supernatants stored at -80°C until used. Cytokines were measured in tissue homogenates using bead-based multiplex cytokine kits (Bio-Plex, Bio-Rad), according to manufacturer’s instructions. The limits of detection were as follows: interleukin (IL)-1α, 1.32 pg/ml, IL-1β, 1.70 pg/ml; IL-2, 1.98 pg/ml; IL-3, 1.32 pg/ml; IL-4, 2.43 pg/ml; IL-5, 1.69 pg/ml; IL-5, 1.69 pg/ml; IL-6, 1.02 pg/ml; IL-9, 1.36 pg/ml; IL-10, 1.04 pg/ml; IL-12/23 p40, 1.15 pg/ml; IL-12 p70, 1.20 pg/ml; IL-13, 1.57 pg/ml; IL-17a, 1.44 pg/ml; interferon (IFN)-γ, 1.30 pg/ml; eotaxin, 1.70 pg/ml; granulocyte-colony stimulating factor, 1.69 pg/ml; granulocyte-macrophage-colony stimulating factor, 1.58 pg/ml; monocyte chemo-attractant protein, 1.71 pg/ml; macrophage inflammatory protein (MIP)-1α, 1.57 pg/ml; MIP-1β, 1.20 pg/ml; RANTES, 0.95 pg/ml; tumor necrosis factor (TNF)-α, 1.73 pg/ml. Cytokine measurements below the limit of detection as determined by the standard curve for each individual cytokine were assigned a value of the limit of detection/√2 for statistical analysis and plotting. Statistical significance was determined by One-way ANOVA with Bonferroni Post Test, α = 0.05.

Transmission-Blocking Assays

The Direct Feeding Assays (DFA) were conducted as previously described [7] at 2 months and at 6 months post-priming immunization (Fig. 1D). Since Plasmodium oocyst numbers are generally overdispersed in our system, statistical significance was assessed using the non-parametric Mann Whitney U Test, α = 0.05.


RESULTS

We generated PLE BMPs (Fig. 1B) and optimized the protocol for controlling the protein antigen loading levels. We then used loading level as a parameter to adjust the release rate of the antigen. Using bovine serum albumin (BSA) as a model antigen, we have shown that the amount of antigen released from the BMPs can be controlled by loading level as shown in Fig. (1C). For example, BMPs with 3.53% protein loading level released protein antigen at a rate of ~ 104 ng/day per mg of BMPs, after an initial burst release of 9.3% of the total protein loaded. These release rates amounted to a release of approximately 15% of total protein within the first 22 days. For this pilot study, we used BMPs with 3.53% of protein loading level. We compared the humoral response of mice using the schedule outlined in Fig. (1D). Mice immunized with a single inoculation of APN1-containing BMPs plus IFA or Alum alone (Fig. 2A) mounted a relatively poor antibody response in comparison to a prime and 3-boost regimen of APN1 plus IFA/Alum (Fig. 2C). Surprisingly, the immunoglobulin subtypes (IgG1, IgG2a, and IgG2b) generated in the group that received a single immunization of APN1-BMPs/alum were similar to that elicited by the APN1-alum (data not shown).

To determine the short-term and long-term efficacy of transmission-blocking serum antibodies against P. berghei we performed direct feeding assays (DFAs) two weeks following the final boost in the control group at 2 months (60 days) and at 6 months (180 days) (Figs. 1D, 2B, D). We compared parasite development in mosquitoes that were fed on four groups: (i) control cohort (primed with APN1/alum followed by three boosts); (ii) treatment group receiving a single inoculation of APN1-BMPplus alum, (iii) treatment group receiving a single inoculation of APN1-BMP plus IFA, and (iv) control (naïve/unimmunized or empty BMP immunized) infected mice. At 60 days, both the APN1-alum and APN1-IFA immunized controls elicited functional transmission-blocking antibodies against P. berghei (Fig. 2B). Despite the lower antibody titer observed previously, APN1-BMP-immunized mice generated a significant level of functional antibody titers that can effectively inhibit oocyst development in An. gambiae (Fig. 2C, D). We observed that at 6 months post-priming immunization, serum from mice immunized with APN1/alum, following a standard immunization regimen, no longer contained any transmission-blocking antibodies [refer to median oocyst number/prevalence for APN1-Alum Control (M3)]. In contrast, individual mice that received either APN1-BMPs/alum or APN1-BMPs/IFA still retained functional transmission-blocking antibody (Table 3). Cytokine levels analyzed by multiplex assay also demonstrated that APN1-BMPs significantly induced splenic pro-T-cell and B-cell cytokines such as IL-2 and IL-5. These data suggest a cell-specific immune effect rather than a general inflammatory process in response to BMP dosing, thereby validating the specificity of the immune response to the vaccine formulation (Fig. 2D-F).


DISCUSSION

Although nano- and microparticle technology has been already shown to potentiate the immune response to pathogen-derived antigens [52, 53], including malaria [44, 45, 49, 54], its use in TBV delivery while previously postulated [9], remained relatively untested [44]. Our small scale study adds to the growing body of data, and moreover, successfully demonstrates that (1) APN1-BMPs with alum adjuvant elicit antigen-specific antibody titers after single dose immunization and induce the production of cell-activation rather than broad-spectrum pro-inflammatory cytokines; (2) the functional transmission-blocking activity of APN1 antisera against P. berghei from mice immunized with a single dose of APN1-BMP in An. gambiae mosquitoes; and (3) that with a potent adjuvant such as incomplete Freund’s adjuvant, immunization with BMPs elicits and maintains transmission-blocking titers in mice for 6 months. Furthermore, the protracted release kinetics of model antigen over 16 days in vitro by our PLE BMP demonstrates a more controlled profile as compared to gel core liposome or conventional liposome particles which have been shown to exhibit a 50% cumulative percentage release of antigen at 10-15 days and 5 days, respectively [44]. These data suggest that larger microparticles allow for enhanced control over the release profile. Recently, it was shown that incorporation of TLR9 agonists in 1-µm gel core liposomes can significantly enhance the immune response to the poorly immunogenic Pfs25 SSM-TBV antigen [44]. Thus, the use of molecular adjuvants as filler molecules may also be considered in future formulations. Taken together with our proof-of-concept data, we anticipate that co-encapsulation of adjuvant and administration of different BMPs with different release profiles (e.g. burst and fast release serve as priming and sustained/delayed release as boosting dose) will significantly enhance the overall immune responses.


CONCLUSION AND FUTURE PERSPECTIVES

Vaccines are traditionally developed with the prospect of eventual parenteral administration, and the TPP for SSM-TBVs suggests that this is the primary consideration for the development of the leading candidates (Table 1). Given the uniqueness of the SSM-TBV approach it is argued that non-classical concepts for vaccine delivery may be more suitable. In this section we highlight some concerns surrounding the use of NPs and BMPs when considering vaccine delivery not only through parenteral, oral or mucosal routes, but specifically via cutaneous immunization.

Does Size Matter?

It has been shown that 40 nm polystyrene nanoparticles (NP) that are surface-coated with antigen can be targeted to the lymph nodes to generate a robust immune response [46-48, 55]. NPs have also been shown to increase the breadth and avidity of the humoral response to a Plasmodium vivax blood stage antigen [37, 45] arising in part through a synergistic effect of surface displayed and encapsulated antigen in a single formulation. However, it is likely that the nature of the particle, the characteristics of the antigen, including intrinsic immunogenicity and molecular size, presence of conformational antibody epitopes, as well as the type of immune response that should be engendered will have a direct influence on the selection of biodegradable nanoparticles (BNP) vs BMP as carrier (reviewed in [56, 57]). It was found that larger particles engender a Type 2 response while smaller, virus-sized particles induced a largely cell-mediated Type 1 response [46]. An interesting approach would be to use different BNP and BMP carriers, leveraging the advantages of antigen targeting and antigen depot effect endowed by each type of particles to reach a specific immune response endpoint [36]. In the context of SSM-TBVs, it remains to be seen if different carrier modes can further potentiate the humoral response to confer long-term protection.

Does Route of Delivery Matter?

It has been shown that size also has a direct influence on the effectiveness of delivery when the route of administration is considered. Intradermal or subcutaneous inoculation of BNPs and BMPs bypasses the issue of tissue barriers and proteolytic environments, in the case of oral administration. However, the clear potential of this technology lies in the idea of needle-free vaccination. The use of BNP and BMPs as carriers for transcutaneous or cutaneous immunization has been extensively studied [57, 58] and it is well recognized that the main barrier for trans- or percutaneous delivery of antigen payload to the rich population of APCs in the epidermis and dermis is the stratum corneum lipid bilayer overlaying the epidermis [57]. Passive diffusion of antigen carried via nanocarriers through intercellular or follicular routes to access to the APCs in the epidermis and preferably the dermis has been demonstrated, strongly implying that presentation is size dependent [58].

While there are clear opportunities for the utility of BNPs and BMPs in the development of the next generation of SSM-TBVs, the current working model by many vaccine developers remains generally conservative. This is rightly so, since malaria vaccines must be low cost to allow for general distribution. The huge number of vaccine doses to cover the more than one third of the world’s population is likely to be borne by public-private partnerships and other novel funding models. However, there is hope for this approach since the prevailing strategy has been more recently revisited by the PATH Malaria Vaccine Initiative [59]. One of the biggest benefits of the BNP/BMP approach, namely the potential to mimic natural boosting, is quite attractive, especially in light of the prediction that titers of antibody (produced either naturally or following vaccination) against sexual stage and mosquito antigens will likely wane over time [60]. Furthermore, there is optimism that by leveraging the potential advantages conferred by particle-based approaches, the community will ultimately see the incorporation of vaccine antigens targeting different life stages of the parasite in a single particle formulation.


ACKNOWLEDGEMENTS

This work was supported by the Bloomberg Family Foundation and the Johns Hopkins Malaria Research Institute Pilot Grant Award Program. The authors thank Hilary Hurd and Paul Eggleston for the Anopheles gambiae KEELE strain.


ABBREVIATIONS
BMP  = Biodegradable microparticle
NP  = Nanoparticle
TBV  = Transmission-blocking vaccine
SSM-TBV  = Sexual stage and mosquito TBV
APN1  = Alanyl aminopeptidase N 1
PLGA  = Poly-lactic-co-glycolic acid
FCA  = Freund’s complete adjuvant
IFA  = Incomplete Freund’s adjuvant.
CONFLICT OF INTEREST

The authors confirm that this article content has no conflicts of interest.


REFERENCES
1. Alonso PL,Brown G,Arevalo-Herrera M,et al. A research agenda to underpin malaria eradicationPLoS MedYear: 201181e100040621311579
2. Carter R. Transmission blocking malaria vaccinesVaccineYear: 20011917-192309231411257353
3. Dinglasan RR,Jacobs-Lorena M. Flipping the paradigm on malaria transmission-blocking vaccinesTrends ParasitolYear: 200824836437018599352
4. Lavazec C,Bourgouin C. Mosquito-based transmission blocking vaccines for interrupting Plasmodium developmentMicrobes InfectYear: 200810884584918656409
5. Sinden RE. A biologist's perspective on malaria vaccine developmentHum VaccinYear: 20106131119946205
6. Ranawaka GR,Fleck SL,Blanco AR,Sinden RE. Characterization of the modes of action of anti-Pbs21 malaria transmission-blocking immunity: ookinete to oocyst differentiation in vivoParasitologyYear: 1994109Pt 44034117800408
7. Mathias DK,Plieskatt JL,Armistead JS,et al. Expression, immunogenicity, histopathology, and potency of a mosquito-based malaria transmission-blocking recombinant vaccineInfect ImmunYear: 20128041606161422311924
8. Kaslow DC. Immunogenicity of Plasmodium falciparum sexual stage antigens: implications for the design of a transmission blocking vaccineImmunol LettYear: 1990251-383861704352
9. Kaslow DC. Transmission-blocking immunity against malaria and other vector-borne diseasesCurr Opin ImmunolYear: 1993545575658216932
10. Kaslow DC. Transmission-blocking vaccines: uses and current status of developmentInt J ParasitolYear: 19972721831899088989
11. Mendis KN,David PH,Carter R. Human immune responses against sexual stages of malaria parasites: considerations for malaria vaccinesInt J ParasitolYear: 19902044975022210943
12. Halloran ME,Struchiner CJ,Spielman A. Modeling malaria vaccines. II: Population effects of stage-specific malaria vaccines dependent on natural boostingMath BiosciYear: 19899411151492520164
13. Gwadz RW,Koontz LC. Plasmodium knowlesi: persistence of transmission blocking immunity in monkeys immunized with gamete antigensInfect ImmunYear: 19844411371406706402
14. Rener J,Carter R,Rosenberg Y,Miller LH. Anti-gamete monoclonal antibodies synergistically block transmission of malaria by preventing fertilization in the mosquitoProc Natl Acad Sci USAYear: 19807711679767996935685
15. Kaushal DC,Carter R,Rener J,Grotendorst CA,Miller LH,Howard RJ. Monoclonal antibodies against surface determinants on gametes of Plasmodium gallinaceum block transmission of malaria parasites to mosquitoesJ ImmunolYear: 19831315255725626631012
16. Quakyi IA,Carter R,Rener J,Kumar N,Good MF,Miller LH. The 230-kDa gamete surface protein of Plasmodium falciparum is also a target for transmission-blocking antibodiesJ ImmunolYear: 198713912421342172447164
17. Healer J,McGuinness D,Hopcroft P,Haley S,Carter R,Riley E. Complement-mediated lysis of Plasmodium falciparum gametes by malaria-immune human sera is associated with antibodies to the gamete surface antigen Pfs230Infect ImmunYear: 1997658301730239234748
18. Williamson KC,Keister DB,Muratova O,Kaslow DC. Recombinant Pfs230, a Plasmodium falciparum gametocyte protein, induces antisera that reduce the infectivity of Plasmodium falciparum to mosquitoesMol Biochem ParasitolYear: 199575133428720173
19. Graves PM,Carter R,Burkot TR,Rener J,Kaushal DC,Williams JL. Effects of transmission-blocking monoclonal antibodies on different isolates of Plasmodium falciparumInfect ImmunYear: 19854836116162860065
20. Williamson KC. Pfs230: from malaria transmission-blocking vaccine candidate toward functionParasite ImmunolYear: 200325735135914521577
21. Kocken CH,Jansen J,Kaan AM,et al. Cloning and expression of the gene coding for the transmission blocking target antigen Pfs48/45 of Plasmodium falciparumMol Biochem ParasitolYear: 199361159688259133
22. Stowers AW,Keister DB,Muratova O,Kaslow DC. A region of Plasmodium falciparum antigen Pfs25 that is the target of highly potent transmission-blocking antibodiesInfect ImmunYear: 200068105530553810992450
23. Dinglasan RR,Kalume DE,Kanzok SM,et al. Disruption of Plasmodium falciparum development by antibodies against a conserved mosquito midgut antigenProc Natl Acad Sci USAYear: 200710433134611346617673553
24. Kaslow DC. Transmission-blocking vaccinesChem ImmunolYear: 20028028730712058646
25. Sinden RE,Carter R,Drakeley C,Leroy D. The biology of sexual development of Plasmodium: the design and implementation of transmission-blocking strategiesMalar JYear: 2012117022424474
26. Coutinho-Abreu IV,Ramalho-Ortigao M. Transmission blocking vaccines to control insect-borne diseases: a reviewMem Inst Oswaldo CruzYear: 2010105111220209323
27. Arevalo-Herrera M,Solarte Y,Marin C,et al. Malaria transmission blocking immunity and sexual stage vaccines for interrupting malaria transmission in Latin AmericaMem Inst Oswaldo CruzYear: 2011106Suppl 120221121881775
28. Bousema T,Drakeley C. Epidemiology and infectivity of Plasmodium falciparum and Plasmodium vivax gametocytes in relation to malaria control and eliminationClin Microbiol RevYear: 201124237741021482730
29. Pradel G. Proteins of the malaria parasite sexual stages: expression, function and potential for transmission blocking strategiesParasitologyYear: 2007134Pt 141911192917714601
30. Tachibana M,Sato C,Otsuki H,et al. Plasmodium vivax gametocyte protein Pvs230 is a transmission-blocking vaccine candidateVaccineYear: 201230101807181222245309
31. Tachibana M,Wu Y,Iriko H,et al. N-terminal prodomain of Pfs230 synthesized using a cell-free system is sufficient to induce complement-dependent malaria transmission-blocking activityClin Vaccine ImmunolYear: 20111881343135021715579
32. Farrance CE,Rhee A,Jones RM,et al. A plant-produced Pfs230 vaccine candidate blocks transmission of Plasmodium falciparumClin Vaccine ImmunolYear: 20111881351135721715576
33. Chowdhury DR,Angov E,Kariuki T,Kumar N. A potent malaria transmission blocking vaccine based on codon harmonized full length Pfs48/45 expressed in Escherichia coliPLoS OneYear: 200947e635219623257
34. Outchkourov NS,Roeffen W,Kaan A,et al. Correctly folded Pfs48/45 protein of Plasmodium falciparum elicits malaria transmission-blocking immunity in miceProc Natl Acad Sci USAYear: 2008105114301430518332422
35. Jones CS,Luong T,Hannon M,et al. Heterologous expression of the C-terminal antigenic domain of the malaria vaccine candidate Pfs48/45 in the green algae Chlamydomonas reinhardtiiAppl Microbiol BiotechnolYear: 2012 in press.
36. Fredriksen BN,Grip J. PLGA/PLA micro- and nanoparticle formulations serve as antigen depots and induce elevated humoral responses after immunization of Atlantic salmon (Salmo salar L.)VaccineYear: 201230365666722100638
37. Moon JJ,Suh H,Li AV,Ockenhouse CF,Yadava A,Irvine DJ. Enhancing humoral responses to a malaria antigen with nanoparticle vaccines that expand Tfh cells and promote germinal center inductionProc Natl Acad Sci USAYear: 201210941080108522247289
38. Uppada SB,Bhat AA,Sah A,Donthamshetty RN. Enhanced humoral and mucosal immune responses after intranasal immunization with chimeric multiple antigen peptide of LcrV antigen epitopes of Yersinia pestis coupled to palmitate in miceVaccineYear: 201129509352936022001881
39. Fredriksen BN,Saevareid K,McAuley L,Lane ME,Bogwald J,Dalmo RA. Early immune responses in Atlantic salmon (Salmo salar L.) after immunization with PLGA nanoparticles loaded with a model antigen and beta-glucanVaccineYear: 201129468338834921888940
40. dos Santos SA,Zarate-Blades CR,de Sa Galetti FC,et al. A subunit vaccine based on biodegradable microspheres carrying rHsp65 protein and KLK protects BALB/c mice against tuberculosis infectionHum VaccinYear: 20106121047105321157178
41. Xiang SD,Scholzen A,Minigo G,et al. Pathogen recognition and development of particulate vaccines: does size matter?MethodsYear: 20064011916997708
42. Cruz LJ,Tacken PJ,Fokkink R,et al. Targeted PLGA nano- but not microparticles specifically deliver antigen to human dendritic cells via DC-SIGN in vitroJ Control ReleaseYear: 2010144211812620156497
43. De Koker S,Lambrecht BN,Willart MA,et al. Designing polymeric particles for antigen deliveryChem Soc RevYear: 201140132033921060941
44. Tiwari S,Goyal AK,Mishra N,et al. Development and characterization of novel carrier gel core liposomes based transmission blocking malaria vaccineJ Control ReleaseYear: 2009140215716519686788
45. Moon JJ,Suh H,Polhemus ME,Ockenhouse CF,Yadava A,Irvine DJ. Antigen-displaying lipid-enveloped PLGA nanoparticles as delivery agents for a Plasmodium vivax malaria vaccinePLoS OneYear: 201272e3147222328935
46. Fifis T,Gamvrellis A,Crimeen-Irwin B,et al. Size-dependent immunogenicity: therapeutic and protective properties of nano-vaccines against tumorsJ ImmunolYear: 200417353148315415322175
47. Hardy CL,LeMasurier JS,Belz GT,et al. Inert 50-nm polystyrene nanoparticles that modify pulmonary dendritic cell function and inhibit allergic airway inflammationJ ImmunolYear: 201218831431144122190179
48. Fifis T,Mottram P,Bogdanoska V,Hanley J,Plebanski M. Short peptide sequences containing MHC class I and/or class II epitopes linked to nano-beads induce strong immunity and inhibition of growth of antigen-specific tumour challenge in miceVaccineYear: 200423225826615531045
49. Moreno R,Jiang L,Moehle K,et al. Exploiting conformationally constrained peptidomimetics and an efficient human-compatible delivery system in synthetic vaccine designChembiochemYear: 200121183884311948870
50. Mao HQ,Zhao Z,Dang W,et al. Mathiowitz EBiodegradable poly(phosphoester)sEncyclopedia of Controlled Drug DeliveryYear: 1999New York, NYJohns Wiley & Sons, Inc4560
51. McNeela EA,Lavelle EC. Recent advances in microparticle and nanoparticle delivery vehicles for mucosal vaccinationCurr Top Microbiol ImmunolYear: 2012354759921904984
52. Zhao Z,Wang J,Mao HQ,Leong KW. Polyphosphoesters in drug and gene deliveryAdv Drug Deliv RevYear: 200355448349912706047
53. Tyagi RK,Garg NK,Sahu T. Vaccination Strategies against Malaria: novel carrier(s) more than a tour de forceJ Control ReleaseYear: 2012162124225422564369
54. Kaba SA,Brando C,Guo Q,et al. A nonadjuvanted polypeptide nanoparticle vaccine confers long-lasting protection against rodent malariaJ ImmunolYear: 2009183117268727719915055
55. Jilek S,Merkle HP,Walter E. DNA-loaded biodegradable microparticles as vaccine delivery systems and their interaction with dendritic cellsAdv Drug Deliv RevYear: 200557337739015560947
56. Jennings GT,Bachmann MF. Designing recombinant vaccines with viral properties: a rational approach to more effective vaccinesCurr Mol MedYear: 20077214315517346167
57. Hansen S,Lehr CM. Nanoparticles for transcutaneous vaccinationMicrob BiotechnolYear: 20125215616721854553
58. Combadiere B,Mahe B. Particle-based vaccines for transcutaneous vaccinationComp Immunol Microbiol Infect DisYear: 2008312-329331517915323
59. PATH-Malaria Vaccine Initiativehttp://www.malariavaccine.org/rd-collaborations.phpAccess November 2012
60. Bousema JT,Drakeley CJ,Sauerwein RW. Sexual-stage antibody responses to P. falciparum in endemic populationsCurr Mol MedYear: 20066222322916515512
61. The malERA Consultative Group on VaccinesA Research Agenda for Malaria Eradication: VaccinesPLoS MedYear: 201181e100039821311586
62. Bustamante PJ,Woodruff DC,Oh J,Keister DB,Muratova O,Williamson KC. Differential ability of specific regions of Plasmodium falciparum sexual-stage antigen, Pfs230, to induce malaria transmission-blocking immunityParasite ImmunolYear: 200022837338010972844
63. Vincent AA,Fanning S,Caira FC,Williamson KC. Immunogenicity of malaria transmission-blocking vaccine candidate, y230.CA14 following crosslinking in the presence of tetanus toxoidParasite ImmunolYear: 1999211157358110583858
64. Qian F,Wu Y,Muratova O,et al. Conjugating recombinant proteins to Pseudomonas aeruginosa ExoProtein A: a strategy for enhancing immunogenicity of malaria vaccine candidatesVaccineYear: 200725203923393317428587
65. Wu Y,Ellis RD,Shaffer D,et al. Phase 1 trial of malaria transmission blocking vaccine candidates Pfs25 and Pvs25 formulated with montanide ISA 51PLoS OneYear: 200837e263618612426
66. Kubler-Kielb J,Majadly F,Wu Y,et al. Long-lasting and transmission-blocking activity of antibodies to Plasmodium falciparum elicited in mice by protein conjugates of Pfs25Proc Natl Acad Sci USAYear: 2007104129329817190797
67. Wu Y,Przysiecki C,Flanagan E,et al. Sustained high-titer antibody responses induced by conjugating a malarial vaccine candidate to outer-membrane protein complexProc Natl Acad Sci USAYear: 200610348182431824817110440
68. Farrance CE,Chichester JA,Musiychuk K,et al. Antibodies to plant-produced Plasmodium falciparum sexual stage protein Pfs25 exhibit transmission blocking activityHum VaccinYear: 20117Suppl19119821266847

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Keywords: Keywords: Antigen, controlled release, immunity, malaria, midgut, mosquito, nanotechnology, natural boosting, sexual stages, transmission-blocking vaccine..

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