Systems analysis of protective immune responses to RTS,S malaria vaccination in humans
RTS,S is an advanced malaria vaccine candidate and confers significant protection against Plasmodium falciparum infection in humans. Little is known about the molecular mechanisms driving vaccine immunity. Here, we applied a systems biology approach to study immune responses in subjects receiving th...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 9; pp. 2425 - 2430 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
28.02.2017
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| Subjects | |
| Online Access | Get full text |
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| Abstract | RTS,S is an advanced malaria vaccine candidate and confers significant protection against Plasmodium falciparum infection in humans. Little is known about the molecular mechanisms driving vaccine immunity. Here, we applied a systems biology approach to study immune responses in subjects receiving three consecutive immunizations with RTS,S (RRR), or in those receiving two immunizations of RTS,S/AS01 following a primary immunization with adenovirus 35 (Ad35) (ARR) vector expressing circumsporozoite protein. Subsequent controlled human malaria challenge (CHMI) of the vaccinees with Plasmodium-infected mosquitoes, 3 wk after the final immunization, resulted in ∼50% protection in both groups of vaccinees. Circumsporozoite protein (CSP)-specific antibody titers, prechallenge, were associated with protection in the RRR group. In contrast, ARR-induced lower antibody responses, and protection was associated with polyfunctional CD4⁺ T-cell responses 2 wk after priming with Ad35. Molecular signatures of B and plasma cells detected in PBMCs were highly correlated with antibody titers prechallenge and protection in the RRR cohort. In contrast, early signatures of innate immunity and dendritic cell activation were highly associated with protection in the ARR cohort. For both vaccine regimens, natural killer (NK) cell signatures negatively correlated with and predicted protection. These results suggest that protective immunity against P. falciparum can be achieved via multiple mechanisms and highlight the utility of systems approaches in defining molecular correlates of protection to vaccination. |
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| AbstractList | RTS,S is an advanced malaria vaccine candidate and confers significant protection against Plasmodium falciparum infection in humans. Little is known about the molecular mechanisms driving vaccine immunity. Here, we applied a systems biology approach to study immune responses in subjects receiving three consecutive immunizations with RTS,S (RRR), or in those receiving two immunizations of RTS,S/AS01 following a primary immunization with adenovirus 35 (Ad35) (ARR) vector expressing circumsporozoite protein. Subsequent controlled human malaria challenge (CHMI) of the vaccinees with Plasmodium-infected mosquitoes, 3 wk after the final immunization, resulted in ∼50% protection in both groups of vaccinees. Circumsporozoite protein (CSP)-specific antibody titers, prechallenge, were associated with protection in the RRR group. In contrast, ARR-induced lower antibody responses, and protection was associated with polyfunctional CD4+ T-cell responses 2 wk after priming with Ad35. Molecular signatures of B and plasma cells detected in PBMCs were highly correlated with antibody titers prechallenge and protection in the RRR cohort. In contrast, early signatures of innate immunity and dendritic cell activation were highly associated with protection in the ARR cohort. For both vaccine regimens, natural killer (NK) cell signatures negatively correlated with and predicted protection. These results suggest that protective immunity against P. falciparum can be achieved via multiple mechanisms and highlight the utility of systems approaches in defining molecular correlates of protection to vaccination. RTS,S is an advanced malaria vaccine candidate and confers significant protection against infection in humans. Little is known about the molecular mechanisms driving vaccine immunity. Here, we applied a systems biology approach to study immune responses in subjects receiving three consecutive immunizations with RTS,S (RRR), or in those receiving two immunizations of RTS,S/AS01 following a primary immunization with adenovirus 35 (Ad35) (ARR) vector expressing circumsporozoite protein. Subsequent controlled human malaria challenge (CHMI) of the vaccinees with -infected mosquitoes, 3 wk after the final immunization, resulted in ∼50% protection in both groups of vaccinees. Circumsporozoite protein (CSP)-specific antibody titers, prechallenge, were associated with protection in the RRR group. In contrast, ARR-induced lower antibody responses, and protection was associated with polyfunctional CD4 T-cell responses 2 wk after priming with Ad35. Molecular signatures of B and plasma cells detected in PBMCs were highly correlated with antibody titers prechallenge and protection in the RRR cohort. In contrast, early signatures of innate immunity and dendritic cell activation were highly associated with protection in the ARR cohort. For both vaccine regimens, natural killer (NK) cell signatures negatively correlated with and predicted protection. These results suggest that protective immunity against can be achieved via multiple mechanisms and highlight the utility of systems approaches in defining molecular correlates of protection to vaccination. The RTS,S malaria vaccine is the most advanced malaria vaccine candidate to be tested in humans. Despite its promise, there is little understanding of its mechanism of action. In this work, we describe the use of a systems biological approach to identify “molecular signatures” that are induced rapidly after the standard RTS,S vaccination regimen, consisting of three RTS,S immunizations, or with a different regimen consisting of a primary immunization with recombinant adenovirus 35 (Ad35) expressing the circumsporozoite malaria antigen followed by two immunizations with RTS,S. These results reveal important insights about the innate and adaptive responses to vaccination and identify signatures of protective immunity against malaria. RTS,S is an advanced malaria vaccine candidate and confers significant protection against Plasmodium falciparum infection in humans. Little is known about the molecular mechanisms driving vaccine immunity. Here, we applied a systems biology approach to study immune responses in subjects receiving three consecutive immunizations with RTS,S (RRR), or in those receiving two immunizations of RTS,S/AS01 following a primary immunization with adenovirus 35 (Ad35) (ARR) vector expressing circumsporozoite protein. Subsequent controlled human malaria challenge (CHMI) of the vaccinees with Plasmodium -infected mosquitoes, 3 wk after the final immunization, resulted in ∼50% protection in both groups of vaccinees. Circumsporozoite protein (CSP)-specific antibody titers, prechallenge, were associated with protection in the RRR group. In contrast, ARR-induced lower antibody responses, and protection was associated with polyfunctional CD4 + T-cell responses 2 wk after priming with Ad35. Molecular signatures of B and plasma cells detected in PBMCs were highly correlated with antibody titers prechallenge and protection in the RRR cohort. In contrast, early signatures of innate immunity and dendritic cell activation were highly associated with protection in the ARR cohort. For both vaccine regimens, natural killer (NK) cell signatures negatively correlated with and predicted protection. These results suggest that protective immunity against P. falciparum can be achieved via multiple mechanisms and highlight the utility of systems approaches in defining molecular correlates of protection to vaccination. RTS,S is an advanced malaria vaccine candidate and confers significant protection against Plasmodium falciparum infection in humans. Little is known about the molecular mechanisms driving vaccine immunity. Here, we applied a systems biology approach to study immune responses in subjects receiving three consecutive immunizations with RTS,S (RRR), or in those receiving two immunizations of RTS,S/AS01 following a primary immunization with adenovirus 35 (Ad35) (ARR) vector expressing circumsporozoite protein. Subsequent controlled human malaria challenge (CHMI) of the vaccinees with Plasmodium-infected mosquitoes, 3 wk after the final immunization, resulted in ~50% protection in both groups of vaccinees. Circumsporozoite protein (CSP)-specific antibody titers, prechallenge, were associated with protection in the RRR group. In contrast, ARR-induced lower antibody responses, and protection was associated with polyfunctional CD4+ T-cell responses 2 wk after priming with Ad35. Molecular signatures of B and plasma cells detected in PBMCs were highly correlated with antibody titers prechallenge and protection in the RRR cohort. In contrast, early signatures of innate immunity and dendritic cell activation were highly associated with protection in the ARR cohort. For both vaccine regimens, natural killer (NK) cell signatures negatively correlated with and predicted protection. These results suggest that protective immunity against P. falciparum can be achieved via multiple mechanisms and highlight the utility of systems approaches in defining molecular correlates of protection to vaccination. RTS,S is an advanced malaria vaccine candidate and confers significant protection against Plasmodium falciparum infection in humans. Little is known about the molecular mechanisms driving vaccine immunity. Here, we applied a systems biology approach to study immune responses in subjects receiving three consecutive immunizations with RTS,S (RRR), or in those receiving two immunizations of RTS,S/AS01 following a primary immunization with adenovirus 35 (Ad35) (ARR) vector expressing circumsporozoite protein. Subsequent controlled human malaria challenge (CHMI) of the vaccinees with Plasmodium-infected mosquitoes, 3 wk after the final immunization, resulted in ∼50% protection in both groups of vaccinees. Circumsporozoite protein (CSP)-specific antibody titers, prechallenge, were associated with protection in the RRR group. In contrast, ARR-induced lower antibody responses, and protection was associated with polyfunctional CD4⁺ T-cell responses 2 wk after priming with Ad35. Molecular signatures of B and plasma cells detected in PBMCs were highly correlated with antibody titers prechallenge and protection in the RRR cohort. In contrast, early signatures of innate immunity and dendritic cell activation were highly associated with protection in the ARR cohort. For both vaccine regimens, natural killer (NK) cell signatures negatively correlated with and predicted protection. These results suggest that protective immunity against P. falciparum can be achieved via multiple mechanisms and highlight the utility of systems approaches in defining molecular correlates of protection to vaccination. |
| Author | Nakaya, Helder I. Ahmed, Rafi Jongert, Erik Sadoff, Jerald Zak, Daniel E. Kazmin, Dmitri Hendriks, Jenny Pulendran, Bali Johnson, Matthew J. Wille-Reece, Ulrike Ballou, W. Ripley Lee, Eva K. van der Most, Robbert Wrammert, Jens van den Berg, Robert A. Ockenhouse, Christian Aderem, Alan |
| Author_xml | – sequence: 1 givenname: Dmitri surname: Kazmin fullname: Kazmin, Dmitri organization: Emory Vaccine Center, Emory University, Atlanta, GA 30329 – sequence: 2 givenname: Helder I. surname: Nakaya fullname: Nakaya, Helder I. organization: School of Pharmaceutical Sciences, University of Sao Paulo, São Paulo 05508, Brazil – sequence: 3 givenname: Eva K. surname: Lee fullname: Lee, Eva K. organization: School of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA 30332 – sequence: 4 givenname: Matthew J. surname: Johnson fullname: Johnson, Matthew J. organization: Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55108 – sequence: 5 givenname: Robbert surname: van der Most fullname: van der Most, Robbert organization: GSK Vaccines, Rixensart 1330, Belgium – sequence: 6 givenname: Robert A. surname: van den Berg fullname: van den Berg, Robert A. organization: GSK Vaccines, Rockville, MD 20850 – sequence: 7 givenname: W. Ripley surname: Ballou fullname: Ballou, W. Ripley organization: GSK Vaccines, Rockville, MD 20850 – sequence: 8 givenname: Erik surname: Jongert fullname: Jongert, Erik organization: GSK Vaccines, Rixensart 1330, Belgium – sequence: 9 givenname: Ulrike surname: Wille-Reece fullname: Wille-Reece, Ulrike organization: Program for Appropriate Technology in Health-Malaria Vaccine Initiative, Washington, DC 20001 – sequence: 10 givenname: Christian surname: Ockenhouse fullname: Ockenhouse, Christian organization: Program for Appropriate Technology in Health-Malaria Vaccine Initiative, Washington, DC 20001 – sequence: 11 givenname: Alan surname: Aderem fullname: Aderem, Alan organization: Center for Infectious Disease Research, Seattle, WA 98109 – sequence: 12 givenname: Daniel E. surname: Zak fullname: Zak, Daniel E. organization: Center for Infectious Disease Research, Seattle, WA 98109 – sequence: 13 givenname: Jerald surname: Sadoff fullname: Sadoff, Jerald organization: Crucell, Leiden 2333, The Netherlands – sequence: 14 givenname: Jenny surname: Hendriks fullname: Hendriks, Jenny organization: Crucell, Leiden 2333, The Netherlands – sequence: 15 givenname: Jens surname: Wrammert fullname: Wrammert, Jens organization: Emory Vaccine Center, Emory University, Atlanta, GA 30329 – sequence: 16 givenname: Rafi surname: Ahmed fullname: Ahmed, Rafi organization: Emory Vaccine Center, Emory University, Atlanta, GA 30329 – sequence: 17 givenname: Bali surname: Pulendran fullname: Pulendran, Bali organization: Emory Vaccine Center, Emory University, Atlanta, GA 30329 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28193898$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | Volumes 1–89 and 106–114, copyright as a collective work only; author(s) retains copyright to individual articles Copyright National Academy of Sciences Feb 28, 2017 |
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| DOI | 10.1073/pnas.1621489114 |
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| Keywords | systems biology systems vaccinology vaccine immune malaria |
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| Notes | SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-2 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 Reviewers: E.H., Drexel University; and R.S., National Institutes of Health. 1D.K. and H.I.N. contributed equally to this work. Contributed by Rafi Ahmed, January 4, 2017 (sent for review December 19, 2016; reviewed by Elias Haddad and Robert Seder) Author contributions: D.K., R.v.d.M., R.A.v.d.B., W.R.B., E.J., U.W.-R., C.O., A.A., J.S., J.H., R.A., and B.P. designed research; D.K., H.I.N., E.K.L., M.J.J., and J.W. performed research; J.S. and J.H. contributed new reagents/analytic tools; D.K., H.I.N., A.A., D.E.Z., R.A., and B.P. analyzed data; R.v.d.M. and R.A.v.d.B. contributed to the development of the clinical study; R.A.v.d.B. contributed to the analysis plan; and D.K., H.I.N., and B.P. wrote the paper. |
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| Snippet | RTS,S is an advanced malaria vaccine candidate and confers significant protection against Plasmodium falciparum infection in humans. Little is known about the... The RTS,S malaria vaccine is the most advanced malaria vaccine candidate to be tested in humans. Despite its promise, there is little understanding of its... RTS,S is an advanced malaria vaccine candidate and confers significant protection against infection in humans. Little is known about the molecular mechanisms... |
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| SubjectTerms | Adaptive Immunity - drug effects Adenoviridae Adenoviridae - genetics Adenoviridae - immunology Antibodies, Protozoan - biosynthesis B-Lymphocytes - drug effects B-Lymphocytes - immunology B-Lymphocytes - metabolism Biological Sciences CD4-Positive T-Lymphocytes - drug effects CD4-Positive T-Lymphocytes - immunology CD4-Positive T-Lymphocytes - metabolism Dendritic Cells - drug effects Dendritic Cells - immunology Dendritic Cells - metabolism Gene Expression Profiling Gene Expression Regulation Genetic Vectors - chemistry Genetic Vectors - immunology Humans Immunity (Disease) Immunity, Innate - drug effects Immunization Immunization, Secondary - methods Immunogenicity, Vaccine Killer Cells, Natural - drug effects Killer Cells, Natural - immunology Killer Cells, Natural - metabolism Malaria Malaria Vaccines - administration & dosage Malaria, Falciparum - immunology Malaria, Falciparum - parasitology Malaria, Falciparum - prevention & control Parasitic protozoa Plasmodium falciparum Plasmodium falciparum - immunology Plasmodium falciparum - pathogenicity Proteins Protozoan Proteins - administration & dosage Protozoan Proteins - genetics Protozoan Proteins - immunology Systematic biology Systems analysis Vaccination - methods Vaccines Vaccines, Synthetic - administration & dosage Vector-borne diseases |
| Title | Systems analysis of protective immune responses to RTS,S malaria vaccination in humans |
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