Synthetic peptides as vaccines Ruth Arnon and Robert J. Horwitz W e i z m a n n Institute of Science, Rehovot, Israel

The use of synthetic peptides as an alternative approach to vaccination is currently being pursued. This is particularly true for viral and parasitic diseases in which no vaccines are yet available, most notably the acquired immune deficiency syndrome.

Current Opinion in Immunology 1992, 4:449-453

Introduction The development of vaccines has been one of medicine's greatest achievements. Traditional vaccines consist of either live attenuated, or killed organisms. However, considerable problems are often encountered with these vaccines, including the following: high restriction to strain and type specificity due to continuous antigenic variations in viruses and parasites; MHC restriction; difficulties in production, storage and delivery systems; contaminating materials; and undesirable side effects [ 1]. Mso, there are still many viral and parasitic diseases for which no effective vaccine exists, such as acquired immune deficiency syndrome (AIDS), Malaria and others. Therefore, altemative approaches to vaccine preparation are being sought.

The use of synthetic peptides for vaccination is one alternative which is vigorously being explored. Its attractiveness is the simplicity of the approach, the information it brings to the molecular understanding of the immune response required for protection and the considerable practical advantage that such products could offer. These vaccines contain a relatively small peptide or peptides shown to constitute epitopes of the organism which elicit a protective immune response [2]. In principle, by selection of only those epitopes which confer an effective immune response, it should be possible to exclude all those epitopes responsible for deleterious immune responses. Furthermore, an important advantage of synthetic peptide vaccines is that they are chemically defined and don't contain infectious material, and hence are devoid of any risk as biohazard factors. They can be readily synthesized in unlimited quantities and thus, if found sufficiently efficacious, they might prove to be the vaccines of choice.

Carriers and adjuvants for synthetic peptide vaccines Carriers and adjuvants are believed to be essential for endowing synthetic peptides vaccines with adequate efficacy, and, although as will be shown later this may not always be the case, efforts are being devoted to their development. Often the carrier itself acts as an adjuvant, as in the case of liposomes, membranous vesicles formed by the dispersion of phospholipids in aqueous solution. Frisch et al. [3] examined the immunogenicity of a hexapeptide, from the carboxyl terminal of the histone H3, when associated with liposomes. This peptide was not immunogenic when administered without carrier and adjuvant. When encapsulated in large vesicles it was again ineffective, but covalent coupling of this peptide to the surface of large vesicles yielded both an IgM and IgG response, though of short duration. Furthermore, when covalently linked to the surface of small unilamellar vesicles containing monophosphoryl lipid A as adjuvant, a relatively long-lasting response with memory cell induction was observed. The conclusion from these studies is that for short synthetic peptides liposomes can provide a substitute for a carrier protein, but the vesicle must contain an adjuvant to obtain an efficient immune response

[4]. Schild et al. [5 ~176have developed a synthetic lipopeptide vaccine, tripalmitoyl-S-glycerylcysteinyl-seryl-serine (P3CSS) coupled to various peptides of influenza virus. They found that immunization with synthetic influenza peptide alone failed to induce virus-specific cytotoxic T lymphocytes (CTLs) in vivo. However, priming with a synthetic lipopeptide vaccine was usually successful and was comparable with the priming efficiency seen with the infectious virus. Goodman-Snitkoff et al.

Abbreviations AIDS~acquired immune deficiency syndrome; CTL--cytotoxic T lymphocyte; FMDV--foot and mouth disease virus; imp~integral membrane protein; LCMV--lymphocytic choriomeningitis virus; LT--heat labile; MAP--multiple antigen peptide; MSA--merozoite surface antigen; NP-nucleoprotein; PE--phosphatidylethanolamine; PN~principal neutralizing determinant; P3CSS~tripalmitoyI-S-glyceryl cysteinyl-seryl-serine; SFV--Semliki Forest virus.

(~ Current Biology Ltd ISSN 0952-7915

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Immunity to infection [6] have described a technique to stimulate an immune response to small non-immunogenic peptides. They covalently linked a peptide to phosphatidylethanolamine (PE), then complexed the peptide--PE conjugate with additional phospholipid and cholesterol. This complex was highly immunogenic in mice without additional adjuvants. Lussow et al. [7] found that heat-shock proteins can act as cartier molecules when conjugated to synthetic peptides without requiring additional adjuvants. A number of integral membrane proteins (imps) isolated from E. coli, when covalently conjugated to antigenic peptides, significantly enhanced the immune response to the peptide, compared with injection of the peptide alone. The antibody response could not be significantly increased by the addition of incomplete Freund's adjuvant [8]. Redmond et al. [9] found that the inner capsid protein of bovine rotavirus can be made to self-assemble in vitro and form spherical particles which have an inherent capacity to target to cells of the immune system. These spheres can, therefore, act as novel immunological carriers when coupled to peptides. Every epitope they tested gave an excellent immune response without the use of adjuvants. One method for the preparation of a completely synthetic product containing both antigen and carrier is the multiple antigen peptide (MAP) system developed by Tam [10]. The surface of these macromolecules consists of multiple clusters of the antigenic epitope with a small oligolysine core at the center. The MAP system has the advantage of being completely chemically defined, containing either multiple copies of a single peptide epitope or different antigenic peptides which can be attached to the same macromolecule. Several recent examples of the use of the MAP system will be described later.

Parasites and bacteria In the case of parasites, where it is difficult to grow the organisms in culture and to prepare sufficient material for production of conventional vaccines, synthetic vaccines are particularly relevant. Studies on synthetic peptide vaccines against parasitic diseases have focused mostly on malaria. The circumsporozoite protein, the major surface antigen of malaria sporozoites, contains a region of multiple tandem amino acid repeats. In Plasmodium falciparum this region is a tetrapeptide, AsnAla-Asn-Pro, which is repeated up to about 40 times [11]. This sequence has been considered, therefore, as the basis for the development of a subunit vaccine against P. falciparum malaria. However, both synthetic and recombinant Asn-Ala-Asn-Pro peptides have been shown to be immunogenic only in H-2 b mice. Pessi et al. [12"] showed recently that when the Asn-Ala-AsnPro sequence was incorporated into a MAP, all except one of the mouse strains tested mounted an anti-peptide antibody response.

Saul et al. [13] were interested in an antigen of the merozoite stage of malaria. They selected three octapeptides from two invariable domains in the amino and carboxyl terminals of the merozoite surface antigen 2 (MSA 2) of P. falciparum. When conjugated with diphtheria toxoid, these peptides elicited anti-MSA 2 antibodies, which also bound the MSA 2 homologue from P. chabaudi. T h e mice vaccinated with these conjugates and then challenged with a lethal inoculum of P. chabaudi showed a high level of protection and most of them survived. These results suggest that the conserved regions of MSA 2, when presented in a suitable immunogenic form, could form the basis for a malaria vaccine that circumvents some of the problems of antigenic diversity. In the system of Schistosomiasis, the 28 kD protein of Schistosoma m a n s o n i has received considerable attention as a vaccine candidate. A synthetic peptide derived from the sequence comprising amino acids 115-131 has been shown to contain both T- and B-cell recognition sites. Wolowczuk et al. [14.o] synthesized an octameric peptide from this region which was immunogenic in rats, mice and baboons. Immunized Fischer rats were able to mediate platelet-, macrophage-, and eosinophil-dependent cytotoxicity toward Schistosomula. Furthermore, rats immunized with this peptide were partially protected against a challenge infection with S. m a n s o n i cercariae with a concomitant increase in the levels of IgG and IgE antibody to the 28 kD peptide. As for bacterial infections, despite the tremendous success of antibiotics and traditional vaccines against these diseases, in certain instances these measures are not sufficient and an alternative approach for vaccination, such as the use of synthetic peptides, is being explored. A case in point is Listeria monocytogenes a Gram-positive bacterium, which grows in the cytoplasm of eukaryotic cells and in an immunocompromised person it can lead to severe disease. Pamer et aL [15] identified a dominant class I MHC restricted L. monocytogenes epitope, by the synthesis of 11 nonapeptides based on a peptide-binding motif described recently [16]. This peptide was recognized very efficiently by the CTL clone B9 and represents the first MHC restricted class I epitope identified in bacteria. The identification of bacterial CTL epitopes has been hampered by the large number and diversity of bacterially expressed proteins, but identification may now be possible by using this or other peptide-binding motifs. Synthetic peptides of bacterial toxins were also tested for immunization and found to induce toxin neutralizing antibodies. Thus, a peptide from the region comprising amino acids 5 0 4 4 of cholera toxin B-subunit induced protective immunity against the toxic manifestations of cholera toxin as well as those of the homologous heatlabile (LT) toxin of Escherichia coli [17]. The same approach was employed with the Shiga toxin. Peptides stemming from the amino- and carboxyl-termini of the B-chain of this toxin induced neutralizing antibodies as well as a local response against the toxin, and conferred protective immunity in both mice and rats [18]. Furthermore, recombinant vectors containing synthetic oligonucleotides coding for these peptides, and thus expressing

Synthetic peptides as vaccines Arnon and Horwitz these epitopes in either E. coli or Salmonella, were also capable of eliciting protective immunity [19].

Viruses The last few years have seen considerable progress in the investigation and development of peptides leading to anti-viral immune response, which could serve as adequate candidates for the production of synthetic vaccines. This is demonstrated by several examples. Kast et aL [20~ identified a single peptide from Sendai virus nucleoprotein (NP) that is recognized by the CTLs of B6 mice. Subcutaneous immunization of mice with the free peptide led to a NP peptide-specific CTL memory re sponse, as well as an in vivo response against the Sendai virus. Consequently, mice immunized with this peptide were protected against lethal virus challenge. This work demonstrates that even free peptide can be effective as an anti-viral T cell vaccine.

Snijders et al. [21] identified linear epitopes on the E2 membrane protein of Semliki Forest virus (SFV) with vaccine potential. Mice immunized with the peptide comprising amino acids 240-255 of this protein were protected against viral challenge. This protection correlated well with SFV-specific antibody titre, suggesting antibodymediated protection.

from protected and unprotected animals. They found that the affinities of serum antibodies for both the peptide and the virus in protected cattle were significantly higher than those in unprotected animals. In view of this correlation, they recommend that antibody affinity should be one of the parameters considered in the assessment of the efficacy of synthetic immunogens in general. Influenza virus was also subjected to the synthetic vaccination approach [26]. Early studies indicated that the region 91-108 in the sequence of the haemagglutinin comprises a protective epitope [27]. Another region of the haemagglutinin, namely the membrane anchoring region (residues 1-11 of haemagglutinin 2) induced antibodies that bound to the peptide and the intact virus, but failed to exhibit viral neutralization [26]. Recently, Deres et al. [28] obtained in vivo priming of virus-specific CTLs using a synthetic oligopeptide vaccine. CTLs are of particular significance and constitute an essential part of the immune response in influenza infection. The peptide, corresponding to the sequence comprising amino acids 147-158 of the influenza NP covalently linked to the P3CSS,induced high affinity CTLs as does the infectious virus. These data are relevant not only to vaccine development but also to antigen presentation by MHC class I molecules.

Schulz et al. [23 "~ injected subcutaneously a T-cell epitope from the NP of lymphocytic choriomeningitis virus (LCMV) as a free synthetic peptide. This immunization led to the induction of a specific anti-LCMV CTL response in viva Protection was demonstrated by inhibition of LCMV replication in mice spleens, which correlated with CD8 + LCMV-specific CTL.

Human immunodeficiency virus In view of the immense impact of AIDS on society, a major effort is being devoted to the development of a vaccine against this disease. This system will be dealt herewith separately from other viruses since most of the current work on synthetic peptide viral vaccines has focused on human immunodeficiency virus (HW), the putative cause of the AIDS disease. At present there is no vaccine available for this disease, and live attenuated vaccines are probably not appropriate in this case, both because of the high risk in reverting to virulence and because HW infection leads to a deleterious immune response. Hence, the synthetic approach seems especially attractive for this system. An ideal peptide vaccine would consist of only those epitopes known to be protective, while avoiding the risk of inducing HW infection. It is of interest that the significant applicability of this research prompted not only research institutes, but also many companies, to develop synthetic peptide vaccines to MDS [29].

Foot and mouth disease virus (FMDV) was one of the earliest viruses in which a synthetic peptide approach was attempted. In recent studies [24~176 the MAP approach was employed, using the peptide comprising amino acids 141-160 of the VP1 protein, which had been previously shown to induce virus neutralizing antibodies [2]. Monomer, tetramer and octamer structures of this peptide were examined, with the tetrameric structure giving an optimal response. The levels of neutralizing antibody obtained compared favorably with those obtained when the FMDV peptide was attached to various carrier proteins. Steward et aL [25] have immunized cattle with this synthetic 'vaccine' and compared the affinity of the antibodies for the peptide and for the whole virus in sera

The V3 loop of the envelope protein, gp 120, is the principal neutralizing determinant (PND) of HW and an immunodominant CTL epitope has also been identified in this region [30]. Synthetic peptides based on sequences within this region were indeed found to induce isolate-restricted neutralizing antibody. Hence, immunization with the PND was thought to induce only subtype specifc immunity [31]. However, Javaherian et al. [32] immunized animals with a peptide of 13 amino acids from this region and observed that sera from these animals were cross-neutralizing for several HW isolates. A smaller hexapeptide (Gty-Pro-Gly-Arg-Ma-Phe) from this region, when used to immunize rabbits, was also capable of neutralizing divergent isolates.

Dion etal. [22] synthesized four peptides predicted to be surface-accessible regions of the major viral envelope glycoprotein gp52 of murine mammary tumor virus. These peptides were coupled to a carrier and their ability to protect Balb/c mice against live viral challenge tested. One of these peptides (EP-3) significantly reduced the frequency of early onset tumors and 67% of the test animals were tumor-free for the entire observation period. This is in contrast to immunization with the intact gp52 which provided only marginal protection.

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Immunityto infection Holley et al. [33] analyzed the PND sequences of gp120 from 245 isolates of HW-1. Their results suggest that peptide cocktails of limited size may be feasible vaccine candidates. Nardelli et al. [31] used also the MAP system to present multiple copies of the PND of the divergent HIV isolates IIIB, RF and MN, and tested its e~cacy in three species of animals. The MAP used was either synthesized in a monoepitope configuration, containing four repeats of each individual peptide, or synthesized with a diepitope configuration, adding a conserved sequence, known to be a T helper cell epitope of gpl20, to the carboxyl terminus of the PND peptides. The monoepitope construct yielded a species-dependent antibody response whereas the diepitope MAPs were immunogenic in all three animal species. Also the antibody titers elicited by the diepitopes were significantly higher than those raised by immunization with the monoepitope MAPs. These results show that a synthetic peptide MAP antigen with a chemically defined structure and without the use of a protein carrier, may be potentially useful for the design of a HIV vaccine. It is generally thought that antiviral CTLs constitute an essential component of a successful immune response to viral infection. Hart et al. [34 ~ used various hybrid synthetic peptides to construct a carrier-free synthetic immunogen containing only those HIV epitopes necessary to induce a protective immune response. The complete hybrid consisted of (from amino to carboxyl terminus) the first 12 amino acid residues of the gp41 fusion domain (F), a T-cell epitope of gp120 (T1), a gp120 B-cell epitope from the V3 loop region, and extending from this region, an additional five- or six-residue segment which comprises a CTL epitope. They found that a carrier-free hybrid peptide, containing either the T1 or F HIV region amino terminus attached to a HIV CTL epitope, had the ability to induce CD8 + MHC class I restricted CTLs in vivo in mice. Takahashi et al. [35] examined in detail the specificity of CTL recognition of an immunodominant determinant in the hypervariable portion of H1V gp160. Three mouse CTL lines were examined but only one elicited CTLs that showed extensive cross-reactivity between isolates. Residue 325 of gp160 played a critical role in the specificity of the CTL response. Hence, CTLs with different specificities were generated by restimulating gpl60primed cells with peptides containing substitutions at position 325. This indicates the potential of synthetic peptide-based vaccines to induce broad specificity CTLs towards HIV.

quences and MHC restriction. These vaccines will probably contain both B- and T-cell epitopes, and possibly a CTL-inducing region. Carrier molecules and adjuvants may be required but these too will probably be synthetic, probably in a combined structure with the peptides, that will include built-in adjuvanticity. It is obvious, however, from the rapid progress in this field in recent years, that the prospect of constructing successful synthetic peptide vaccines grows as our knowledge in all areas of immunology increases, and might become a reality in the not too distant future.

References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: 9 of special interest 9. of outstanding interest 1.

STEWARDMW, HOWARDCR: Synthetic Peptides: a Next Generation of Vaccines? Immunol Today 1987, 8:51 58.

2.

BROWNFJ: The Potential of Peptides as Vaccines. Semin Virol 1990, 1:67-74.

3.

FRISCH B, MULLER S, BRIAND JP, VAN REGENMORTEL MHV, SCHUBER F: Parameters Affecting t h e lmmunogenicity of a Liposome-associated Synthetic Hexapeptide Antigen. Eur J lmmunol 1991, 21:185-193.

4.

GARCONNMJ, SIX HR: Universal Vaccine Carrier: Liposomes that Provide T - d e p e n d e n t Help to Weak Antigens. J lmmunol 1991, 146:3697-3702.

5. 99

SCHILDH, DERES K, WIESMULLERK-H, JUNG G, RAMMENSEEH-G: Efficiency of Peptides and Lipopeptides for In-vivo Priming of Virus-specific Cytotoxic T Cells. Eur J Immunol 1991, 21:2649-2654. The authors compare the in vivo e~ciency of synthetic peptides and lipopeptides, which contain CTL epitopes, to prime CTLs. They find that priming with a synthetic lipopeptide vaccine, but not synthetic peptide alone, matches the priming e~ciency seen with infectious virus. They suggest that the attachment of the lipopeptide to the cell membrane may be responsible for its efficiency. 6.

GOODMAN-SNrrKOFFG, GOOD MF, BEP,ZOFSKY JA, MANNINO RJ: Role of Intrastructural/Intermolecular Help in Immunization with Peptide-phospholipid Complexes. J Immunol 1991, 147:410-415.

7.

Lussow AR, BARmOSC, EMBDEN VAN J, ZEE VAN DER R, VERDINI AS, PESS1 A, LOUIS JA, LAMBERT P-H, GIUDICE DEL G: i y c o b a c terial Heat-shock Proteins as Carrier Molecules. Eur J Immunol 1991, 21:2297-2302.

8.

CROFTS, WALSHJ, LLOYDW, RUSSEL-JONES GJ: TraT: a Pow-

erful Carrier Molecule for the Stimulation of I m m u n e Responses to Protein and Peptide Antigens. J lmmunol 1991, 146:793-798. 9.

PJ, POKU SK, IJAZ ML, PARKER MD, LAARVELDB, BABIUK LA: Rotavirus Particles Function as Immunological Carriers for the Delivery of Peptides from Infectious Agents and Endogenous Proteins. Mol Immunol 1991, 28:269-278.

Conclusions As clearly demonstrated above, there has been considerable effort in the past few years towards developing synthetic peptide vaccines for diverse groups of organisms. Some general conclusions are that a successful synthetic vaccine will probably consist of a cocktail of peptides to overcome the problem of hypervariable se-

REDMONDMJ, OHMANN HB, HUGHES HP, SABARAM, FRENCHICK

10.

TAM JP: Synthetic Peptide Vaccine Design: Synthesis and Properties of a High-density Multiple Antigenic Peptide System. Proc Natl Acad Sci USA 1988, 85:5409-5413.

11.

ZAVALA F,

COCHRANE All, NARDJN EH, NUSSENZWEIG RN, NUSSENZWEIGV: Circumsporozoite Proteins of Malaria Parasites Contain a Single I m m u n o d o m i n a n t Region with Two or More Identical Epitopes. J Exp Med 1983, 157:1947-1957.

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PESSI A, VALMORI D, MIGLIORNI P, TOUGNE C, BIANCHI E, lAMBERT P-H, CORRADIN G, GIUDICE DEL G: Lack of H2 Restriction of the Plasmodium falciparum (NANP) Sequence as Multiple Antigen Peptide. Eur J I m m u n o l 1991, 21:2273~2276. In this paper the authors incorporate the repetitive P. falciparum AsnMa-Asn-Pro sequence into a MAP. M1 mouse strains tested, except one, mount an anti-peptide antibody response. This paper demonstrates that the immunogenicity of the Asn-Ma-Asn-Pro can be significantly changed when prepared as a MAP. ee

13.

SAUL A, LORD R, JONES GL, SPENCER L: Protective Immunization with Invariant Peptides of the Plasmodium falciparum Antigen MSA2. J I m m u n o l 1992, 148:208-211.

14. ee

WOLOWCZUK1, AURIAULT C, BOSSUS M, BOULANGER D, GRASMASSEH, MAZINGUEC, PIERCE RJ, GREZEL D, REID GD, TARTER A, ET A L . : Antigenicity and Immunogenicity of a Multiple Peptidic Construction of the Schistosoma mansoni SM-28 GST Antigen in Rat, Mouse, and Monkey. 1. Partial Protection of Fischer Rat after Active Immunization. J lrnmunol 1991, 146:1987-1995. The peptide comprising amino acids 115-131 of the schistosome 28 kD protein contains both T- and B-cell recognition sites. The authors ex amine the immunogenicity of an octameric construct of this peptide. Rats immunized with this construct were partialb~ protected against a challenge infection with S. mansoni cercafiae. 15.

16.

PAMEREG, HARTYJT, BEVANMJ: Precise Prediction of a Dominant Class I MHC-restricted Epitope of Listeria Monocytogenes. Nature 1991, 353:852~55. FALK K, ROTZSCHKE O, STEVANOVIC S, JUNG G, RAMMENSEE H-G: Allele-specific Motifs Revealed by Sequencing fo Self-peptides Eluted from MHC Molecules. Nature 1991, 351:290-296.

This is an example of the use of an unmodified flee synthetic peptide for immunization, in this case against LCMV vires. Once again, protection could be demonstrated, which correlated with the production of CD8 + LCMV-specific CTLs. 24. ,,.

FRANCISMJ, HASTINGS GZ, BROWN F, MCDERMED J, LU Y A, TAM JP: Immunological Evaluation of the Multiple Antigen Peptide (MAP) System Using the Major Immunogenic Site of Foot-and-Mouth Disease Virus. Immunology 1991, 73:24~254. This is another example of the successful use of the MAP s/stem. Here the authors used the foot and mouth disease VP1 peptide comprising amino acids 141 160. Neutralizing antibodies known to protect guineapigs against challenge infection were obtained. This demonstrates that the MAP .system can circumvent the need for a carrier protein. 25.

STEWARDM'W, STANLEY SM, DIMARCH1 R, MULCAHY G, DOEL TR: High-alt~nity Antibody Induced by Immunization with a Synthetic Peptide is Associated with Protection of Cattle against Foot-and-Mouth Disease. Immunology 1991, 72:99-103.

26.

HORX~ITZRJ, ARNON R: Influenza. In Synthetic Vaccines. Edited by Nicholson BH. Oxford: Blackwell Scientific Publishing; 1992; in press.

27.

MUIZERGM, SHAFIRA M, A~NON R: Anti-influenza Response Achieved by Immunization with a Synthetic Antigen. Proc Natl Ac ad Sci USA 1982, 79:569-573.

28.

DERES K, SCHILD H, WIESMUUs K H, JUNG G, RAMMENSEE H H: In Vivo Priming of Virus-specific Cytotoxic T Lymphocytes with Synthetic Lipopeptide Vaccine. Nature 1989, 342:561-564.

29.

SeAmINGBJ: In Hot Pursuit of an HW Vaccine. Biotechnology 1992, 10:24-29.

30.

TAKAHASHIH, COHEN J, HOSMALINA, CEASE KB, HOUGHTEN R, CORNETFE JL, DELISHI C, MOSS B, GERMAIN RN, BERZOFSKY JA: An Immunodominant Epitope of the Human Immunodeficiency Virus Envelope Glycoprotein g p l 6 0 Recognized by Class I Major Histocompatibility Complex Molecule-restricted Murine Cytotoxic T Lymphocytes. Proc Natl Sci USA 1988, 85:3105-3109.

17.

JACOBCO, PINES M, ARNON R: Neutralization of Heat-labile Toxin of E. cull by Antibodies to Synthetic Peptides Derived from the B Subunit of Cholera Toxin. EMBO J 1984, 3:2889-2893.

18.

ARNON R, HARAm I, KEUSCH G: Synthetic Peptide Toxoid Vaccines against Shiga Dysentery. In N e w Generation Vaccines Edited by Woodrow GC, Levine MM. New York: Marcel Dekker, 1990:688~97.

31.

19.

MCEWENJ, LEITNERM, HARARI1, ARNONR: Expression of Shiga Toxin Epitopes in E. coil Immunological Characterization. lmmu nol Lett 1989, 21:157-164.

NARDELLIB, LU Y-A, SHIU DR, DELPIERRE-DEFOORTC, PROFYAT, TAM JP: A Chemically Defined Synthetic Vaccine Model for HW-1. J l m m u n o l 1992, 148:914-920.

32.

JAVAHERIANK, LANGLOISAJ, LAROSE GJ, PROFY AT, BOLOGNESI DP, HERLIHYWC, PUTNEY SD, MATFHEWSTJ: Broadly Neutralizing Antibodies Elicited by the Hypervariable Neutralizing Determinant of HIV-O1. Science 1990, 250:1590-1593.

33.

HOLLEYEll, GOUDSMITJ, KARPLUS M: Prediction of Optimal Peptide Mixtures to Induce Broadly Neutralizing Antibodies to Human Immunodeficiency Virus Type 1. Proc Natl Acad Sci USA 1991, 88:6800~5804.

20.

KASTWM, ROUX L, CURREN J, BLOM HJJ, VOORDOUW AC, MELOENRH, KOLAKOFSKYD, MELIEF CJM: Protection against Lethal Sendal Virus Infection by in Vivo Priming of Virusspecific Cytotoxic T Lymphocytes with a Free Synthetic Peptide. Proc Natl Acad Sci USA 1991, 88:2283-2287. An immunodominant Sendai vires NP peptide recognized by Sendai vires specific CTLs was used to immunize mice. This peptide induced Sendai virus and NP peptide specific CTL memory and protected mice against a lethal viral challenge. This paper demonstrates that in certain cases even free peptide alone can result in successful protection. ee

34. .o

HARTMK, WEINHOLD KJ, SCEARCE RM, WASHBURN EM, CLARK CA, PALKER TJ, HAYNESBF: Priming of Anti-human Immunodeficiency Virus (HW) CD8 + Cytotoxic T Cells in Vivo by Carrier-free HIV Synthetic Peptides. Proc Natl Acad Sci USA 1991, 88:9448-9452. Here the successful use of hybrid synthetic peptides containing various HW epitopes is demonstrated. The authors show that carrier free synthetic peptides can be used in l,ivo to induce an anti-HW CTL response.

21.

SNIJDEKqA, BENMSSA-TROUWBJ, OOSTERLAKENTAM, PU1JKWC, POSTtIUMUS WPA, MELOEN RH, I3OERE WAM, OOSTING JD, KRAA~JEVEm CA, SNWPE H: Identification of Linear Epitopes on Semliki Forest Virus E2 Membrane and Their Effectiveness as a Synthetic Peptide Vaccine. J Gen Virol 1991, 72:557 565.

22.

DIONAS, KNITTELJJ, MORNEWECK ST: Virus Envelope-based Peptide Vaccines against Virus-induced Mammary Tumors. Virology 1990, 179:474~77.

TAKAHASHIIt, NAKAGAWAY, PENDLETON CD, HOUGHTEN RA, YOKOMtJRO K, GEKMAIN PuN, BERZOFSKY JA: Induction of Broadly Cross-reactive Cytotoxic T Cells Recognizing an HIV-1 Envelope Determinant. Science 1992, 255:333-336.

23. 9.

SCHUIZM, ZINKERNAGELRM, HENGARTNERH: Peptide-induced Antiviral Protection by Cytotoxic T Cells. Proc Natl Acad Sci USA 1991, 88:991-993.

R Arnon and RJ Horwitz, Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, 76100, Israel.

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Synthetic peptides as vaccines.

The use of synthetic peptides as an alternative approach to vaccination is currently being pursued. This is particularly true for viral and parasitic ...
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