Next-generation anti–Staphylococcus aureus vaccines: A potential new therapeutic option for atopic dermatitis?
Authors: Julianne Clowry, Alan D. Irvine, Rachel M. McLoughlin
Journal: Journal of Allergy and Clinical Immunology (2018)

Disease severity in patients with atopic dermatitis (AD) is directly correlated with colonization by Staphylococcus aureus.1Kong H.H. Oh J. Deming C. Conlan S. Grice E.A. Beatson M.A. et al.Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis.Genome Res. 2012; 22: 850-859Crossref PubMed Scopus (1099) Google Scholar An increasing body of evidence now also supports a role for S aureus in the pathogenesis of AD in genetically susceptible subjects.2Geoghegan J.A. Irvine A.D. Foster T.J. Staphylococcus aureus and atopic dermatitis: a complex and evolving relationship.Trends Microbiol. 2018; 26: 484-497Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar Increased prevalence of S aureus preceding and coinciding with AD onset in an infant cohort suggests that early skin colonization can contribute to the development of clinical AD.3Meylan P. Lang C. Mermoud S. Johannsen A. Norrenberg S. Hohl D. et al.Skin colonization by Staphylococcus aureus precedes the clinical diagnosis of atopic dermatitis in infancy.J Invest Dermatol. 2017; 137: 2497-2504Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar However, these findings only partially explain the complex role of this organism given that another birth cohort4Kennedy E.A. Connolly J. Hourihane J.O. Fallon P.G. McLean W.H.I. Murray D. et al.Skin microbiome before development of atopic dermatitis: early colonization with commensal staphylococci at 2 months is associated with a lower risk of atopic dermatitis at 1 year.J Allergy Clin Immunology. 2017; 139: 166-172Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar did not demonstrate S aureus colonization before development of infantile AD but did show a protective effect of commensal staphylococci against later development of AD. A vaccine against S aureus in patients with AD could potentially reduce the incidence of and prevent or attenuate symptoms in a subpopulation of high-risk atopic subjects. Such a targeted approach could reduce or eliminate the role of broad-spectrum antibiotics to treat S aureus–mediated flares of AD in an era of increasing antimicrobial resistance.5Harkins C.P. McAleer M.A. Bennett D. McHugh M. Fleury O.M. Pettigrew K.A. et al.The widespread use of topical antimicrobials enriches for resistance in Staphylococcus aureus isolated from atopic dermatitis patients.Br J Dermatol. 2018; 179: 951-958Crossref PubMed Scopus (22) Google Scholar This would also avoid the suppression of potentially beneficial commensal strains of coagulase-negative staphylococci, such as Staphylococcus epidermidis and Staphylococcus hominis, which exert anti-inflammatory and selective antimicrobial activity against S aureus and are also under investigation as potential therapeutic agents in patients with AD.6Nakatsuji T. Chen T.H. Narala S. Chun K.A. Two A.M. Yun T. et al.Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis.Sci Transl Med. 2017; 9Crossref PubMed Scopus (552) Google Scholar Our understanding of the cause of AD, a complex heterogenous condition, has evolved considerably in the past decade. Dichotomous views of an "outside-in" versus an "inside-out" disease process have been superseded by the recognition that AD is characterized by the interplay of both a compromised skin barrier and aberrant local and systemic immune responses. Although TH2-deviated inflammation has been long recognized as central to disease expression, TH22- and TH17-mediated inflammation are now also implicated to varying degrees across specific patient age profiles and ethnicities.7Noda S. Suárez-Fariñas M. Ungar B. Kim S.J. de Guzman Strong C. Xu H. The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization.J Allergy Clin Immunol. 2015; 136: 1254-1264Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar S aureus is also now recognized as an additional key pathogenic factor in patients with AD, including its critical role in amplifying TH2-mediated responses. S aureus exploits decreased filaggrin expression resulting from inherited loss-of-function mutations and acquired through TH2 polarization and reduced antimicrobial peptide levels secondary to cutaneous dysbiosis (Fig 1).2Geoghegan J.A. Irvine A.D. Foster T.J. Staphylococcus aureus and atopic dermatitis: a complex and evolving relationship.Trends Microbiol. 2018; 26: 484-497Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar These factors contribute to high colonization rates in atopic skin. Once established, S aureus releases multiple virulence factors, including serine proteases, exotoxins, and lysins, such as phenol-soluble modulins. These exacerbate underlying barrier dysfunction and perpetuate endogenous dysregulated proinflammatory pathways.8Karauzum H. Datta S.K. Adaptive immunity against Staphylococcus aureus.Curr Top Microbiol Immunol. 2017; 409: 419-439PubMed Google Scholar S aureus cell-wall components, including peptidoglycan, amplify the TH2-driven response,8Karauzum H. Datta S.K. Adaptive immunity against Staphylococcus aureus.Curr Top Microbiol Immunol. 2017; 409: 419-439PubMed Google Scholar leading to increased expression of adhesion molecules (fibronectin and fibrinogen) and reduced expression of antimicrobial peptides (human β-defensin 2 and cathelicidin antimicrobial peptide) and barrier proteins (filaggrin and loricrin). Studies on established therapies for AD, including topical corticosteroids,9Hung S.H. Lin Y.T. Chu C.Y. Lee C.C. Liang T.C. Yang Y.H. et al.Staphylococcus colonization in atopic dermatitis treated with fluticasone or tacrolimus with or without antibiotics.Ann Allergy Asthma Immunol. 2007; 98: 51-56Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar topical calcineurin inhibitors,9Hung S.H. Lin Y.T. Chu C.Y. Lee C.C. Liang T.C. Yang Y.H. et al.Staphylococcus colonization in atopic dermatitis treated with fluticasone or tacrolimus with or without antibiotics.Ann Allergy Asthma Immunol. 2007; 98: 51-56Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar narrow-band UVB phototherapy,10Silva S.H. Guedes A.C. Gontijo B. Ramos A.M. Carmo L.S. Farias L.M. et al.Influence of narrow-band UVB phototherapy on cutaneous microbiota of children with atopic dermatitis.J Eur Acad Dermatol Venereol. 2006; 20: 1114-1120Crossref PubMed Scopus (59) Google Scholar and ciclosporin,11Bunikowski R. Mielke M. Bräutigam M. Renz H. Wahn U. Effect of oral cyclosporin A in children with Staphylococcus aureus-colonized vs S aureus-infected severe atopic dermatitis.Pediatr Allergy Immunol. 2003; 14: 55-59Crossref PubMed Scopus (11) Google Scholar have shown that symptomatic improvement corresponds to reduced S aureus colonization. To date, these effects have been attributed to recovery of skin barrier function and immunomodulation, particularly suppression of superantigen-activated T cells. Research is currently underway to investigate the effects of dupilumab, an anti–IL-4 receptor α blocker targeting the TH2 cytokines IL-4 and IL-13 in S aureus–colonized versus noncolonized patients with AD.12ClinicalTrials.gov [Internet]. Identifier NCT03389893, Effect of dupilumab (anti-IL4Rα) on the host microbe interface in atopic dermatitis.https://clinicaltrials.gov/ct2/show/NCT03389893?term=IL4RA&cond=atopic+dermatitis&cntry=US&rank=1Date accessed: July 31, 2018Google Scholar However, active infection causing flares still requires the use of antibiotics, highlighting the role of alternative approaches, including active and passive vaccination strategies (Table I).13Schmidt C.S. White C.J. Ibrahim A.S. Filler S.G. Fu Y. Yeaman M.R. et al.NDV-3, a recombinant alum-adjuvanted vaccine for Candida and Staphylococcus aureus, is safe and immunogenic in healthy adults.Vaccine. 2012; 30: 7594-7600Crossref PubMed Scopus (150) Google Scholar, 14Levy J. Licini L. Haelterman E. Moris P. Lestrate P. Damaso S. et al.Safety and immunogenicity of an investigational 4-component Staphylococcus aureus vaccine with or without AS03B adjuvant: results of a randomized phase I trial.Hum Vaccin Immunother. 2015; 11: 620-631Crossref PubMed Scopus (51) Google Scholar, 15Chen W.H. Pasetti M.F. Adhikari R.P. Baughman H. Douglas R. El-Khorazaty J. et al.Safety and immunogenicity of a parenterally administered, structure-based rationally modified recombinant staphylococcal enterotoxin B protein vaccine, STEBVax.Clin Vaccine Immunol. 2016; 23: 918-925Crossref PubMed Scopus (33) Google Scholar, 16Nissen M. Marshall H. Richmond P. Shakib S. Jiang Q. Cooper D. et al.A randomized phase I study of the safety and immunogenicity of three ascending dose levels of a 3-antigen Staphylococcus aureus vaccine (SA3Ag) in healthy adults.Vaccine. 2015; 33: 1846-1854Crossref PubMed Scopus (49) Google Scholar, 17Marshall H. Nissen M. Richmond P. Shakib S. Jiang Q. Cooper D. et al.Safety and immunogenicity of a booster dose of a 3-antigen Staphylococcus aureus vaccine (SA3Ag) in healthy adults: a randomized phase 1 study.J Infect. 2016; 73: 437-454Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 18Frenck Jr., R.W. Creech C.B. Sheldon E.A. Seiden D.J. Kankam M.K. Baber J. et al.Safety, tolerability, and immunogenicity of a 4-antigen Staphylococcus aureus vaccine (SA4Ag): results from a first-in-human randomised, placebo-controlled phase 1/2 study.Vaccine. 2017; 35: 375-384Crossref PubMed Scopus (47) Google Scholar, 19Creech C.B. Frenck Jr., R.W. Sheldon E.A. Seiden D.J. Kankam M.K. Zito E.T. et al.Safety, tolerability, and immunogenicity of a single dose 4-antigen or 3-antigen Staphylococcus aureus vaccine in healthy older adults: results of a randomised trial.Vaccine. 2017; 35: 385-394Crossref PubMed Scopus (37) Google Scholar, 20Begier E. Seiden D.J. Patton M. Zito E. Severs J. Cooper D. et al.SA4Ag, a 4-antigen Staphylococcus aureus vaccine, rapidly induces high levels of bacteria-killing antibodies.Vaccine. 2017; 35: 1132-1139Crossref PubMed Scopus (50) Google Scholar, 21Landrum M.L. Lalani T. Niknian M. Maguire J.D. Hospenthal D.R. Fattom A. et al.Safety and immunogenicity of a recombinant Staphylococcus aureus α-toxoid and a recombinant Panton-Valentine leukocidin subunit, in healthy adults.Hum Vaccin Immunother. 2017; 13: 791-801Crossref PubMed Scopus (25) Google Scholar, 22Ruzin A. Wu Y. Yu L. Yu X.Q. Tabor D.E. Mok H. et al.Characterisation of anti-alpha toxin antibody levels and colonisation status after administration of an investigational human monoclonal antibody, MEDI4893, against Staphylococcus aureus alpha toxin.Clin Transl Immunol. 2018; 7: e1009Crossref PubMed Scopus (20) Google Scholar, 23Varshney A.K. Kuzmicheva G.A. Lin J. Sunley K.M. Bowling Jr., R.A. Kwan T.Y. et al.A natural human monoclonal antibody targeting Staphylococcus protein A protects against Staphylococcus aureus bacteremia.PLoS One. 2018; 13: e0190537Crossref PubMed Scopus (48) Google Scholar Passive immunization strategies using mAbs against specific S aureus toxins are under investigation, although typically as adjuncts to standard antibiotic regimens in high-risk patient groups.Table IClinical trial status of S aureus vaccine candidatesVaccine components and pharmaceutical companiesPhaseNCT study no.ReferenceActive prophylactic vaccines1NDV-3: recombinant Candida albicans Als3p adhesion protein (homologous to S aureus surface proteins) with alum adjuvantNovaDigm Therapeutics, Brookline, Mass122NCT01273922NCT02996448NCT03455309Schmidt et al, 201213Schmidt C.S. White C.J. Ibrahim A.S. Filler S.G. Fu Y. Yeaman M.R. et al.NDV-3, a recombinant alum-adjuvanted vaccine for Candida and Staphylococcus aureus, is safe and immunogenic in healthy adults.Vaccine. 2012; 30: 7594-7600Crossref PubMed Scopus (150) Google ScholarNot publishedNot published2S aureus capsular polysaccharides CP5 and CP8 conjugated to TT, mutated detoxified AT and ClfA ± AS03B adjuvantGlaxoSmithKline, Research Triangle Park, NC1NCT01160172Levy et al, 201514Levy J. Licini L. Haelterman E. Moris P. Lestrate P. Damaso S. et al.Safety and immunogenicity of an investigational 4-component Staphylococcus aureus vaccine with or without AS03B adjuvant: results of a randomized phase I trial.Hum Vaccin Immunother. 2015; 11: 620-631Crossref PubMed Scopus (51) Google Scholar3STEBVax: recombinant SEB with alum adjuvantIntegrated BioTherapeutics, Gaithersburg, Md1NCT00974935Chen et al, 201615Chen W.H. Pasetti M.F. Adhikari R.P. Baughman H. Douglas R. El-Khorazaty J. et al.Safety and immunogenicity of a parenterally administered, structure-based rationally modified recombinant staphylococcal enterotoxin B protein vaccine, STEBVax.Clin Vaccine Immunol. 2016; 23: 918-925Crossref PubMed Scopus (33) Google Scholar4HI, SpA5, mSEB, MntC recombinant proteins and aluminum phosphate adjuvantsOlymvax, Chengdu, China11NCT02820883NCT02804711Not publishedNot published5SA3Ag/SA4AgPfizer, New York, NYSA3Ag: CP5, CP8, conjugated to CRM197 and recombinant ClfASA4g: CP5, CP8, conjugated to CRM197, recombinant ClfA and MntC11/21/211/2a2bNCT01018641NCT01364571NCT01643941NCT02364596NCT02492958NCT02388165Nissen et al, 201516Nissen M. Marshall H. Richmond P. Shakib S. Jiang Q. Cooper D. et al.A randomized phase I study of the safety and immunogenicity of three ascending dose levels of a 3-antigen Staphylococcus aureus vaccine (SA3Ag) in healthy adults.Vaccine. 2015; 33: 1846-1854Crossref PubMed Scopus (49) Google ScholarMarshall et al, 201617Marshall H. Nissen M. Richmond P. Shakib S. Jiang Q. Cooper D. et al.Safety and immunogenicity of a booster dose of a 3-antigen Staphylococcus aureus vaccine (SA3Ag) in healthy adults: a randomized phase 1 study.J Infect. 2016; 73: 437-454Abstract Full Text Full Text PDF PubMed Scopus (10) Google ScholarFrenck RW Jr, et al, 201718Frenck Jr., R.W. Creech C.B. Sheldon E.A. Seiden D.J. Kankam M.K. Baber J. et al.Safety, tolerability, and immunogenicity of a 4-antigen Staphylococcus aureus vaccine (SA4Ag): results from a first-in-human randomised, placebo-controlled phase 1/2 study.Vaccine. 2017; 35: 375-384Crossref PubMed Scopus (47) Google ScholarCreech et al, 201719Creech C.B. Frenck Jr., R.W. Sheldon E.A. Seiden D.J. Kankam M.K. Zito E.T. et al.Safety, tolerability, and immunogenicity of a single dose 4-antigen or 3-antigen Staphylococcus aureus vaccine in healthy older adults: results of a randomised trial.Vaccine. 2017; 35: 385-394Crossref PubMed Scopus (37) Google ScholarBegier et al, 201720Begier E. Seiden D.J. Patton M. Zito E. Severs J. Cooper D. et al.SA4Ag, a 4-antigen Staphylococcus aureus vaccine, rapidly induces high levels of bacteria-killing antibodies.Vaccine. 2017; 35: 1132-1139Crossref PubMed Scopus (50) Google ScholarNot publishedNot published6Recombinant α-toxoid (rAT) and subunit of Panton-Valentine leukocidin (rLukS-PV).Nabi Biopharmaceuticals, Boca Raton, Fla1/2NCT01011335Landrum et al, 201721Landrum M.L. Lalani T. Niknian M. Maguire J.D. Hospenthal D.R. Fattom A. et al.Safety and immunogenicity of a recombinant Staphylococcus aureus α-toxoid and a recombinant Panton-Valentine leukocidin subunit, in healthy adults.Hum Vaccin Immunother. 2017; 13: 791-801Crossref PubMed Scopus (25) Google ScholarPassive prophylaxis (mAbs)1MEDI4893: extended half-life human mAb against S aureus ATMedImmune, Gaithersburg, Md12NCT01769417NCT02296320Ruzin et al, 201822Ruzin A. Wu Y. Yu L. Yu X.Q. Tabor D.E. Mok H. et al.Characterisation of anti-alpha toxin antibody levels and colonisation status after administration of an investigational human monoclonal antibody, MEDI4893, against Staphylococcus aureus alpha toxin.Clin Transl Immunol. 2018; 7: e1009Crossref PubMed Scopus (20) Google ScholarNot published2KBSA301/AR 301: mAb to S aureus AT Aridis Pharmaceuticals, San Jose, Calif1/2aNCT01589185Not published3514G: mAb to S aureus/MRSA to SpAXBiotech, Austin, Tex1/2NCT02357966Varshney et al, 201823Varshney A.K. Kuzmicheva G.A. Lin J. Sunley K.M. Bowling Jr., R.A. Kwan T.Y. et al.A natural human monoclonal antibody targeting Staphylococcus protein A protects against Staphylococcus aureus bacteremia.PLoS One. 2018; 13: e0190537Crossref PubMed Scopus (48) Google ScholarAls3p, Agglutinin-like sequence 3 protein; AT, α-toxin; ClfA, staphylococcal clumping factor A; CP, capsular polysaccharide; CRM197, cross-reactive material 197, nontoxic mutant form of diphtheria toxin; HI, fusion protein consisting of hemolysin A and IsdB (iron-regulated surface determinant protein B); MntC, manganese transport protein C; MRSA, methicillin-resistant Staphylococcus aureus; mSEB, mutagenized staphylococcal enterotoxin B; PVL, Panton-Valentin leucocidin; SAE, serious adverse events; SEB, staphylococcal enterotoxin B; SpA, staphylococcal protein A; TT, tetanus toxoid. Open table in a new tab Als3p, Agglutinin-like sequence 3 protein; AT, α-toxin; ClfA, staphylococcal clumping factor A; CP, capsular polysaccharide; CRM197, cross-reactive material 197, nontoxic mutant form of diphtheria toxin; HI, fusion protein consisting of hemolysin A and IsdB (iron-regulated surface determinant protein B); MntC, manganese transport protein C; MRSA, methicillin-resistant Staphylococcus aureus; mSEB, mutagenized staphylococcal enterotoxin B; PVL, Panton-Valentin leucocidin; SAE, serious adverse events; SEB, staphylococcal enterotoxin B; SpA, staphylococcal protein A; TT, tetanus toxoid. S aureus occupies a niche as both a commensal and pathogenic organism in human hosts. It has evolved over time to manipulate host immunity to its survival advantage, as shown by the prevalence of recurrent and chronic infections and the lack of readily identifiable markers of protective long-term immunity.8Karauzum H. Datta S.K. Adaptive immunity against Staphylococcus aureus.Curr Top Microbiol Immunol. 2017; 409: 419-439PubMed Google Scholar As a result, antibody-based active vaccination strategies, which are effective against other opportunistic bacteria, such as Streptococcus pneumoniae and Haemophilus influenzae, have been unsuccessful in the context of S aureus.24Fowler Jr., V.G. Proctor R.A. Where does a Staphylococcus aureus vaccine stand?.Clin Microbiol Infect. 2014; 20: 66-75Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar These previous failed approaches have been attributed in part to S aureus virulence factors that interfere with antibody function, including immunoglobulin-binding proteins, such as staphylococcal protein A and Staphylococcus binder of IgG; vaccine testing in murine models, which do not adequately replicate human clinical phenotypes; and, more significantly, poor recognition of the importance of cellular immunity in human hosts. There is now a consensus that individual T-cell subsets play a pivotal role in controlling S aureus colonization and infection at specific sites by coordinating downstream phagocytic responses. Targeting specific effector T-cell subsets, in combination with inducing specific neutralizing anti-toxin antibodies, will be required to improve the efficacy of next-generation anti–S aureus vaccines. TH1 cells driving an IFN-γ–mediated macrophage response are critically important in both clearance and immunologic memory against S aureus bloodstream infections,25Brown A.F. Murphy A.G. Lalor S.J. Leech J.M. O'Keeffe K.M. Mac Aogáin M. et al.Memory Th1 cells are protective in invasive Staphylococcus aureus infection.PLoS Pathog. 2015; 11: e1005226Crossref PubMed Scopus (109) Google Scholar whereas IL-17–producing γδ and TH17 T cells are crucial at cutaneous sites.26Cho J.S. Pietras E.M. Garcia N.C. Ramos R.I. Farzam D.M. Monroe H.R. et al.IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice.J Clin Invest. 2010; 120: 1762-1773Crossref PubMed Scopus (478) Google Scholar, 27Minegishi Y. Saito M. Nagasawa M. Takada H. Hara T. Tsuchiya S. et al.Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome.J Exp Med. 2009; 206: 1291-1301Crossref PubMed Scopus (197) Google Scholar A recent study has also identified TNF/IFN-γ–producing γδ T cells in skin-draining lymph nodes, which protect against subsequent S aureus skin challenges28Dillen C.A. Pinsker B.L. Marusina A.I. Merleev A.A. Farber O.N. Liu H. et al.Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection.J Clin Invest. 2018; 128: 1026-1042Crossref PubMed Scopus (63) Google Scholar and which could represent novel targets for next-generation vaccines. Given the tissue-specific roles of T-cell subtypes, it is unlikely that a single vaccine will address the burden of all S aureus–mediated disease. Additionally, challenges can arise in overcoming S aureus–mediated immune dysregulation.29Goldmann O. Medina E. Staphylococcus aureus strategies to evade the host acquired immune response.Int J Med Microbiol. 2018; 308: 625-630Crossref PubMed Scopus (39) Google Scholar Adaptive tolerance refers to the generalized inhibition of T-cell responses after prolonged antigen exposure and has been reported in patients with S aureus infection. Expansion of regulatory T cells, for example, which can exert considerable immunosuppressive effects, are described in patients with chronic S aureus infection. Other cell types implicated in S aureus–mediated immunosuppression include dendritic cells, which have a reduced ability to activate T cells when exposed to phenol-soluble modulins and can inhibit TH1 differentiation, and also myeloid-derived suppressor cells, which suppress T-cell responses, facilitating S aureus survival. Identifying and overcoming these immunosuppressive strategies of S aureus in a broad spectrum of patients with AD will be critical in the development of a vaccine, aiming to promote effector γδ T and TH17 cell subsets. Although a direct causal role for S aureus in patients with AD has not been definitively established, a select cohort of patients at risk of severe S aureus–exacerbated atopic disease could derive considerable benefit from new targeted treatments, including anti–S aureus vaccines. Reduction or elimination of S aureus skin colonization offers an exciting new avenue to eliminate or reduce this major AD disease amplifier; however, negotiating the amplified TH2 activation will be key to vaccine efficacy (Fig 1). Enhanced understanding of the complexities of the host-pathogen relationship, including recognition of the importance of both cutaneous and systemic T-cell effector responses to S aureus, is essential to inform ongoing efforts to develop a new generation of anti–S aureus vaccines tailored to AD. Despite significant outstanding challenges, these novel treatment approaches, if successful, could herald a new era in AD management.