Novel vaccines: Technology and development
2018; Elsevier BV; Volume: 143; Issue: 3 Linguagem: Inglês
10.1016/j.jaci.2018.05.021
ISSN1097-6825
AutoresSarita U. Patil, Wayne G. Shreffler,
Tópico(s)Monoclonal and Polyclonal Antibodies Research
ResumoThe development and widespread use of vaccines, which are defined by the World Health Organization as "biological preparations that improve immunity to a particular disease," represents one of the most significant strides in medicine. Vaccination was first applied to reduce mortality and morbidity from infectious diseases. The World Health Organization estimates that vaccines prevent 2 to 3 million human deaths annually, and these numbers would increase by at least 6 million if all children received the recommended vaccination schedule. However, the origins of allergen immunotherapy share the same intellectual paradigm, and subsequent innovations in vaccine technology have been applied beyond the prevention of infection, including in the treatment of cancer and allergic diseases. This review will focus on how new and more rational approaches to vaccine development use novel biotechnology, target new mechanisms, and shape the immune system response, with an emphasis on discoveries that have direct translational relevance to the treatment of allergic diseases. The development and widespread use of vaccines, which are defined by the World Health Organization as "biological preparations that improve immunity to a particular disease," represents one of the most significant strides in medicine. Vaccination was first applied to reduce mortality and morbidity from infectious diseases. The World Health Organization estimates that vaccines prevent 2 to 3 million human deaths annually, and these numbers would increase by at least 6 million if all children received the recommended vaccination schedule. However, the origins of allergen immunotherapy share the same intellectual paradigm, and subsequent innovations in vaccine technology have been applied beyond the prevention of infection, including in the treatment of cancer and allergic diseases. This review will focus on how new and more rational approaches to vaccine development use novel biotechnology, target new mechanisms, and shape the immune system response, with an emphasis on discoveries that have direct translational relevance to the treatment of allergic diseases. GlossaryCD47A transmembrane protein expressed in human cells involved in cell adhesion and integrin modulation.COMPLEMENTARITY-DETERMINING REGIONS (CDRs)There are 3 CDRs (CDR1, CDR2, and CDR3), also known as hypervariable regions, located in the variable chains of antibodies and T-cell receptors that are thought to be involved in antigen binding.LYSOSOMAL-ASSOCIATED MEMBRANE PROTEIN 1 (LAMP-1)A glycoprotein also known as CD107a, which provides selectins with carbohydrate ligands.RECOMBINATION-ACTIVATING GENE 2 (Rag2)A protein involved in initiation of V(D)J recombination during B- and T-cell development.The Editors wish to acknowledge Krissy Bielewicz, MS, for preparing this glossary. A transmembrane protein expressed in human cells involved in cell adhesion and integrin modulation. There are 3 CDRs (CDR1, CDR2, and CDR3), also known as hypervariable regions, located in the variable chains of antibodies and T-cell receptors that are thought to be involved in antigen binding. A glycoprotein also known as CD107a, which provides selectins with carbohydrate ligands. A protein involved in initiation of V(D)J recombination during B- and T-cell development. The Editors wish to acknowledge Krissy Bielewicz, MS, for preparing this glossary. Early advances in vaccinology led to ground-breaking discoveries, from the role of antibodies in the adaptive immune system to the development of allergen-specific immunotherapy for the treatment of allergies. In the 18th century, Edward Jenner observed that milkmaids previously infected by cowpox, a zoonotic disease transmitted from cows to human subjects, were protected from smallpox. This observation led to the first known clinical vaccine trial conducted with cowpox in 1796.1Jenner E. An inquiry into the causes and effects of the variolae vaccinae, a disease discovered in some of the western counties of England, particularly Gloucestershire, and known by the name of the cow pox. London: Sampson Low; 1798.Google Scholar This same idea, that inoculation with an offending substance can provide future protection against disease, was applied by Noon and Freeman in 1911 to hay fever,2Noon L. Prophylactic inoculation against hay fever.Lancet. 1911; 177: 1572-1573Abstract Scopus (1128) Google Scholar, 3Freeman J. Further observations on the treatment of hay fever by hypodermic inoculations of pollen vaccine.Lancet. 1911; 178: 814-817Abstract Scopus (243) Google Scholar giving rise to allergen-specific immunotherapy, which is still used widely today in the treatment of a variety of allergic diseases. Attenuated vaccination, discovered by Louis Pasteur when he vaccinated farm animals with attenuated Bacillus anthracis in 1881,4Pasteur L. Chamberland Roux Summary report of the experiments conducted at Pouilly-le-Fort, near Melun, on the anthrax vaccination, 1881.Yale J Biol Med. 2002; 75: 59-62PubMed Google Scholar used a slightly modified and less virulent form of the microbe for vaccination. This discovery was followed by a human trial of attenuated rabies virus vaccine in a young boy in 1885.5Pasteur L. Méthode pour prévenir la rage après morsure.C R Acad Sci. 1885; 101: 765-772Google Scholar The discovery that "antitoxins" in the sera of vaccinated subjects were responsible for protection led to the discovery of antibodies and their role in clinical protection.6Behring E. Kitasato S. Ueber das Zustandekommen der Diphtherie-Immunität und der Tetanus-Immunität bei Thieren.Dtsch Med Wochenschr. 1890; 16: 1113-1114Crossref Scopus (475) Google Scholar Clinical trials demonstrated that the protective power of immunoglobulins extended from bacterial to viral agents.7Hammon W.M. Coriell L.L. Wehrle P.F. Stokes Jr., J. Evaluation of Red Cross gamma globulin as a prophylactic agent for poliomyelitis. IV. Final report of results based on clinical diagnoses.JAMA. 1953; 151: 1272-1285PubMed Google Scholar The next generation of vaccines aimed to elicit protection from multiple strains of the infectious agents. Albert Sabin demonstrated protection using 3 attenuated strains of poliovirus,8Sabin A.B. Hennessen W.A. Winsser J. Studies on variants of poliomyelitis virus. I. Experimental segregation and properties of avirulent variants of three immunologic types.J Exp Med. 1954; 99: 551-576Crossref PubMed Scopus (72) Google Scholar whereas Jonas Salk found that fully inactivated poliovirus from 3 strains could also induce protection.9Salk J.E. Krech U. Youngner J.S. Bennett B.L. Lewis L.J. Bazeley P.L. Formaldehyde treatment and safety testing of experimental poliomyelitis vaccines.Am J Public Health Nations Health. 1954; 44: 563-570Crossref PubMed Google Scholar Both types of polio vaccines, the oral polio vaccine using 3 attenuated strains approved in 1961 and the trivalent inactivated polio vaccine approved in 1955, are still used today. The explosion of molecular genetics and recombinant DNA technology led to another revolutionary step in vaccines: use of specific antigens from infectious agents to administer protective benefit more safely. The previous efforts in vaccinology required the culturing of infectious agents to produce vaccine candidates, but by using recombinant DNA, subunit vaccines could be manufactured for infectious agents that were otherwise challenging to culture or highly pathogenic. Most clinical immunotherapy in use today for treating allergies is technologically where vaccines for infectious agents were decades ago: use of whole allergen extracts. The first innovations in allergen immunotherapy have been to apply the concept of subunit vaccines by using individual dominant allergens that are the known targets of the allergic (IgE) response. Several component vaccines have now been studied in clinical trials for both environmental10Curin M. Garib V. Valenta R. Single recombinant and purified major allergens and peptides: how they are made and how they change allergy diagnosis and treatment.Ann Allergy Asthma Immunol. 2017; 119: 201-209Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar and peanut11Wood R.A. Sicherer S.H. Burks A.W. Grishin A. Henning A.K. Lindblad R. et al.A phase 1 study of heat/phenol-killed, E. coli-encapsulated, recombinant modified peanut proteins Ara h 1, Ara h 2, and Ara h 3 (EMP-123) for the treatment of peanut allergy.Allergy. 2013; 68: 803-808Crossref PubMed Scopus (107) Google Scholar allergies, and these have been thoroughly reviewed by others.12Cook Q.S. Burks A.W. Peptide and recombinant allergen vaccines for food allergy.Clin Rev Allergy Immunol. 2018; 55: 162-171Crossref PubMed Scopus (13) Google Scholar, 13Valenta R. Niespodziana K. Focke-Tejkl M. Marth K. Huber H. Neubauer A. et al.Recombinant allergens: what does the future hold?.J Allergy Clin Immunol. 2011; 127: 860-864Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar Reverse vaccinology is a new approach to designing vaccines that combines our rapidly increasing feasibility to sequence whole genomes of microorganisms and apply bioinformatic analyses to those data. Predictive modeling identifies new pathogen targets that are ideally conserved and targets of protective responses. The subsequent expression of candidate targets for screening by using human serum from those with effective immunity and for evaluation in murine models can lead to the design of optimal vaccines, particularly to bacterial pathogens. For example, Neisseria meningitidis serotype B causes quickly progressive meningitis with high mortality. Unlike the other strains of meningococcus, its capsular polysaccharide is sialylated like human glycoproteins, interfering with the ability to create a typical conjugate vaccine. Genomic sequencing of meningococcus serotype B led to the identification of 90 new surface antigens, of which about 30% bound to serum antibodies from immune patients.14Pizza M. Scarlato V. Masignani V. Giuliani M.M. Arico B. Comanducci M. et al.Identification of vaccine candidates against serogroup B meningococcus by whole-genome sequencing.Science. 2000; 287: 1816-1820Crossref PubMed Scopus (1099) Google Scholar, 15Litt D.J. Savino S. Beddek A. Comanducci M. Sandiford C. Stevens J. et al.Putative vaccine antigens from Neisseria meningitidis recognized by serum antibodies of young children convalescing after meningococcal disease.J Infect Dis. 2004; 190: 1488-1497Crossref PubMed Scopus (66) Google Scholar Subsequent murine models with selected antigens demonstrated effective protection, and ultimately, these antigens contributed to development of the currently available meningococcus B subunit vaccine.16Giuliani M.M. Adu-Bobie J. Comanducci M. Arico B. Savino S. Santini L. et al.A universal vaccine for serogroup B meningococcus.Proc Natl Acad Sci U S A. 2006; 103: 10834-10839Crossref PubMed Scopus (609) Google Scholar This antigenome analysis, interrogation of the antigenic repertoire of a pathogen using libraries of recombinantly expressed antigens screened with serum antibodies of infected patients and then subsequently evaluated by using model organism vaccination experiments, has also been used to identify novel antigens from Streptococcus pneumoniae.17Giefing C. Meinke A.L. Hanner M. Henics T. Bui M.D. Gelbmann D. et al.Discovery of a novel class of highly conserved vaccine antigens using genomic scale antigenic fingerprinting of pneumococcus with human antibodies.J Exp Med. 2008; 205: 117-131Crossref PubMed Scopus (224) Google Scholar Clinical vaccine trials using 3 of these proteins, PhtD, PcpA, and Ply, are currently underway.18Pichichero M.E. Khan M.N. Xu Q. Next generation protein based Streptococcus pneumoniae vaccines.Hum Vaccin Immunother. 2016; 12: 194-205Crossref PubMed Scopus (46) Google Scholar A variation on this approach using computational analysis of the binding site of neutralizing antibodies (NAbs) to respiratory syncytial virus led to formulation of a recombinant immunogen that, when combined with an adjuvant, demonstrates protection in animal models.19Rossey I. Gilman M.S. Kabeche S.C. Sedeyn K. Wrapp D. Kanekiyo M. et al.Potent single-domain antibodies that arrest respiratory syncytial virus fusion protein in its prefusion state.Nat Commun. 2017; 8: 14158Crossref PubMed Scopus (46) Google Scholar As a parallel in patients with allergic diseases, genomic characterization of many major allergens is also underway. The use of reverse vaccinology in the context of allergic disease has already led to novel allergen identification. Der f 24, an ubiquinol-cytochrome C reductase homologue from house dust mite, was found after the Dermatophagoides farinae genome was sequenced by using high-throughput sequencing, followed by identification of predicted genes, expression of selected genes, and validation by using immunoblotting, ELISA, and skin tests in allergic donors.20Chan T.F. Ji K.M. Yim A.K. Liu X.Y. Zhou J.W. Li R.Q. et al.The draft genome, transcriptome, and microbiome of Dermatophagoides farinae reveal a broad spectrum of dust mite allergens.J Allergy Clin Immunol. 2015; 135: 539-548Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar Further engineered immunotherapy approaches based on novel allergen discoveries might provide a more effective method of inducing more complete protective responses in allergic patients. Many of the most recent innovations in vaccine immunology have been developed for the treatment and prevention of HIV-1 infection. Therefore we focus on this particular pathogen to illustrate new vaccine approaches that target adaptive immunity. As alluded to earlier, antibody-based immunity has been the backbone of most vaccine-mediated protection, and the induction of protective humoral responses has been characterized as the holy grail of HIV vaccine research.21Ferrari G. Pollara J. Tomaras G.D. Haynes B.F. Humoral and innate antiviral immunity as tools to clear persistent HIV infection.J Infect Dis. 2017; 215: S152-S159Crossref PubMed Scopus (20) Google Scholar Protective antibodies against HIV have been classified into 2 major types: NAbs and non-NAbs. NAbs can prevent infection of target cells by binding to HIV-1 virion envelope glycoproteins (Envs). Env-specific non-NAbs can recognize Envs expressed on HIV-1–infected cells and contribute antiviral activity through Fc effector functions by inducing antibody-dependent cellular cytotoxicity through Fcγ receptor–expressing cells, such as natural killer cells. By comparison, one goal of allergen immunotherapy has been to develop a long-lasting non-IgE antibody response capable of suppressing effective engagement and cross-linking of allergen-specific IgE on effector cells, and there might be distinct functional activities of clones within the polyclonal allergen-specific response.22James L.K. Shamji M.H. Walker S.M. Wilson D.R. Wachholz P.A. Francis J.N. et al.Long-term tolerance after allergen immunotherapy is accompanied by selective persistence of blocking antibodies.J Allergy Clin Immunol. 2011; 127 (e1-5): 509-516Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar By analogy to HIV-specific antibodies, NAbs that bind specific epitopes through their Fabs are similar to allergen-specific blocking antibodies,22James L.K. Shamji M.H. Walker S.M. Wilson D.R. Wachholz P.A. Francis J.N. et al.Long-term tolerance after allergen immunotherapy is accompanied by selective persistence of blocking antibodies.J Allergy Clin Immunol. 2011; 127 (e1-5): 509-516Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar whereas non-NAbs are similar to the allergen-specific antibodies that can activate inhibitory receptors, such as CD32,23Burton O.T. Logsdon S.L. Zhou J.S. Medina-Tamayo J. Abdel-Gadir A. Noval Rivas M. et al.Oral immunotherapy induces IgG antibodies that act through FcgammaRIIb to suppress IgE-mediated hypersensitivity.J Allergy Clin Immunol. 2014; 134: 1310-1317.e6Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar through their Fc region. The relative contributions of these functional antibody attributes to tolerance despite sensitization in the context of allergic diseases are still unknown and might vary between individuals or specific allergies. Although administration of allergens as vaccines does not pose an infectious risk, it does pose the risk of triggering an allergic reaction. Hypoallergenic vaccines, or those that do not have IgE-binding epitopes, have been devised to mitigate that risk. Many clinical trials using hypoallergenic recombinant protein vaccines are currently underway (Table I), including for birch pollen allergy (Bet v 1)24Meyer W. Narkus A. Salapatek A.M. Hafner D. Double-blind, placebo-controlled, dose-ranging study of new recombinant hypoallergenic Bet v 1 in an environmental exposure chamber.Allergy. 2013; 68: 724-731Crossref PubMed Scopus (62) Google Scholar and grass pollen allergy (Phl p 1, Phl p 2, Phl p 5a and b, and Phl p 6).25Niederberger V. Neubauer A. Gevaert P. Zidarn M. Worm M. Aberer W. et al.Safety and efficacy of immunotherapy with the recombinant B-cell epitope-based grass pollen vaccine BM32.J Allergy Clin Immunol. 2018; 142: 497-509.e9Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar It is worth noting that even when IgE-dependent activation is bypassed, clinical studies with these hypoallergenic vaccines have shown that although they do not trigger immediate hypersensitivity reactions, late-phase reactions do still occur, possibly related to T cell–mediated effects.26Campana R. Mothes N. Rauter I. Vrtala S. Reininger R. Focke-Tejkl M. et al.Non-IgE-mediated chronic allergic skin inflammation revealed with rBet v 1 fragments.J Allergy Clin Immunol. 2008; 121: 528-530.e1Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 27Purohit A. Niederberger V. Kronqvist M. Horak F. Gronneberg R. Suck R. et al.Clinical effects of immunotherapy with genetically modified recombinant birch pollen Bet v 1 derivatives.Clin Exp Allergy. 2008; 38: 1514-1525Crossref PubMed Scopus (131) Google ScholarTable IClinical trials with novel allergy vaccine products using recombinant and modified allergensYearMoleculeDescriptionClinical trial phase1996Allervax CATTwo Fel d 1 peptidesDBPC2000Bet v 1 trimer, fragmentsHypoallergenic Bet v 1 proteins22002Recombinant grass pollenRecombinant Phl p 1, Phl p 2, Phl p 5a+b, Phl p 632002Folding variant of Bet v 1Hypoallergenic Bet v 132002Recombinant Bet v 1Recombinant Bet v 122006Recombinant Bet v 1 (tablets)Recombinant Bet v 1 (sublingual)22009Escherichia coli–encapsulated recombinant modified Ara h 1, Ara h 2, Ara h 3Rectal delivery of vaccine12011Fcγ1–Fel d 1 fusion proteinIntradermal delivery of fusion proteinSafety2012BM32Four hypoallergenic grass allergens22012ToleroMune CatFel d 1 synthetic peptides32012AllerTBet v 1 peptides22013FAST-FishMutated parvalbumin1/22014ToleroMune GrassPeptides from grass pollen22014ToleroMune HDMPeptides from house dust mite22014ToleroMune RagweedPeptides from Amb a 122015ASP4070Japanese cedar pollen (Cry j 1, Cry j 2) LAMP-based DNA plasmid vaccine12016ASP0892Peanut (Ara h 1, Ara h 2, Ara h 3) LAMP-based DNA plasmid vaccine1DBPC, Double-blind, placebo-controlled. Open table in a new tab DBPC, Double-blind, placebo-controlled. Another strategy to avoid triggering allergic reactions while still preserving T cell–mediated immune protection is immunotherapy with selected peptides derived from allergens. A variety of techniques have been used to define peptides having specific characteristics, such as induction of blocking antibodies28Zieglmayer P. Focke-Tejkl M. Schmutz R. Lemell P. Zieglmayer R. Weber M. et al.Mechanisms, safety and efficacy of a B cell epitope-based vaccine for immunotherapy of grass pollen allergy.EBioMedicine. 2016; 11: 43-57Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar or stimulation of T cells,29Worm M. Lee H.H. Kleine-Tebbe J. Hafner R.P. Laidler P. Healey D. et al.Development and preliminary clinical evaluation of a peptide immunotherapy vaccine for cat allergy.J Allergy Clin Immunol. 2011; 127 (e1-14): 89-97Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar without the consequence of IgE cross-linking. Several products for treatment of environmental allergies, including cat, dust mite, grass, and ragweed allergy, have been studied in clinical trials (Table I). The underlying mechanism of efficacy and relative importance of T cells versus antibodies in these engineered recombinant protein and peptide vaccines is still unclear.30O'Hehir R.E. Prickett S.R. Rolland J.M. T cell epitope peptide therapy for allergic diseases.Curr Allergy Asthma Rep. 2016; 16: 14Crossref PubMed Scopus (48) Google Scholar Induction of T-cell anergy or deletion of pathogenic TH2 cells might play a dominant role in the clinical efficacy of T-cell peptide vaccines (Fig 1). Another mechanism of vaccines lacking IgE epitopes, whether protein or peptide based, might be to increase the pool of allergen-specific T cells that can provide B-cell help on subsequent complete antigenic restimulation to then produce IgE-blocking antibodies. Alternatively, in some cases hypoallergenic vaccines might be able to directly stimulate the induction of allergen-specific blocking antibodies recognizing novel epitopes with the capacity to suppress allergen effector cells through inhibitory receptors, such as CD32.23Burton O.T. Logsdon S.L. Zhou J.S. Medina-Tamayo J. Abdel-Gadir A. Noval Rivas M. et al.Oral immunotherapy induces IgG antibodies that act through FcgammaRIIb to suppress IgE-mediated hypersensitivity.J Allergy Clin Immunol. 2014; 134: 1310-1317.e6Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar Elucidation of the underlying immunologic mechanisms in engineered vaccine approaches might provide additional insights for improving clinical outcomes after therapy. Technological advancements for the study of humoral immunity now allow us to directly study these mechanisms of allergen immunotherapy, in both conventional and engineered allergen immunotherapies. One example of those advances has been affinity-based labeling of antigen-specific B cells for analysis at the single-cell level, which was pioneered in the context of infectious diseases, such as influenza,31Franz B. May Jr., K.F. Dranoff G. Wucherpfennig K. 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Single-cell immunoglobulin sequencing of paired heavy and light chains from HIV-specific B cells followed by recombinant antibody production has allowed for further characterization of antigen-specific antibody responses, including antigen-binding sites, and structural and functional characterization. These tools have also led to the development of therapeutic approaches, including infusion of NAbs for the prevention and treatment of infection, as well as the development of bispecific antibody therapeutics (see below). Finally, these advances, including characterization of individual antibodies, are significantly complemented by next-generation sequencing of the immunoglobulin heavy chain repertoire from circulating or tissue-resident B cells. The resulting deep lineage analysis of antibodies over time (eg, before/after immunization or infection) has provided a richer understanding of antibody development in disease. 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