DNA prime/Adenovirus boost malaria vaccine encoding P. falciparum CSP and AMA1 induces sterile protection associated with cell-mediated immunity
Ilin Chuang, Martha Sedegah, Susan Cicatelli, Michele Spring, Mark Polhemus, Cindy Tamminga, Noelle Patterson, Melanie Guerrero, Jason W Bennett, Shannon McGrath, Harini Ganeshan, Maria Belmonte, Fouzia Farooq, Esteban Abot, Jo Glenna Banania, Jun Huang, Rhonda Newcomer, Lisa Rein, Dianne Litilit, Nancy O Richie, Chloe Wood, Jittawadee Murphy, Robert Sauerwein, Cornelus C Hermsen, Andrea J McCoy, Edwin Kamau, James Cummings, Jack Komisar, Awalludin Sutamihardja, Meng Shi, Judith E Epstein, Santina Maiolatesi, Donna Tosh, Keith Limbach, Evelina Angov, Elke Bergmann-Leitner, Joseph T Bruder, Denise L Doolan, C Richter King, Daniel Carucci, Sheetij Dutta, Lorraine Soisson, Carter Diggs, Michael R Hollingdale, Christian F Ockenhouse, Thomas L Richie, Ilin Chuang, Martha Sedegah, Susan Cicatelli, Michele Spring, Mark Polhemus, Cindy Tamminga, Noelle Patterson, Melanie Guerrero, Jason W Bennett, Shannon McGrath, Harini Ganeshan, Maria Belmonte, Fouzia Farooq, Esteban Abot, Jo Glenna Banania, Jun Huang, Rhonda Newcomer, Lisa Rein, Dianne Litilit, Nancy O Richie, Chloe Wood, Jittawadee Murphy, Robert Sauerwein, Cornelus C Hermsen, Andrea J McCoy, Edwin Kamau, James Cummings, Jack Komisar, Awalludin Sutamihardja, Meng Shi, Judith E Epstein, Santina Maiolatesi, Donna Tosh, Keith Limbach, Evelina Angov, Elke Bergmann-Leitner, Joseph T Bruder, Denise L Doolan, C Richter King, Daniel Carucci, Sheetij Dutta, Lorraine Soisson, Carter Diggs, Michael R Hollingdale, Christian F Ockenhouse, Thomas L Richie
Abstract
Background: Gene-based vaccination using prime/boost regimens protects animals and humans against malaria, inducing cell-mediated responses that in animal models target liver stage malaria parasites. We tested a DNA prime/adenovirus boost malaria vaccine in a Phase 1 clinical trial with controlled human malaria infection.
Methodology/principal findings: The vaccine regimen was three monthly doses of two DNA plasmids (DNA) followed four months later by a single boost with two non-replicating human serotype 5 adenovirus vectors (Ad). The constructs encoded genes expressing P. falciparum circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). The regimen was safe and well-tolerated, with mostly mild adverse events that occurred at the site of injection. Only one AE (diarrhea), possibly related to immunization, was severe (Grade 3), preventing daily activities. Four weeks after the Ad boost, 15 study subjects were challenged with P. falciparum sporozoites by mosquito bite, and four (27%) were sterilely protected. Antibody responses by ELISA rose after Ad boost but were low (CSP geometric mean titer 210, range 44-817; AMA1 geometric mean micrograms/milliliter 11.9, range 1.5-102) and were not associated with protection. Ex vivo IFN-γ ELISpot responses after Ad boost were modest (CSP geometric mean spot forming cells/million peripheral blood mononuclear cells 86, range 13-408; AMA1 348, range 88-1270) and were highest in three protected subjects. ELISpot responses to AMA1 were significantly associated with protection (p = 0.019). Flow cytometry identified predominant IFN-γ mono-secreting CD8+ T cell responses in three protected subjects. No subjects with high pre-existing anti-Ad5 neutralizing antibodies were protected but the association was not statistically significant.
Significance: The DNA/Ad regimen provided the highest sterile immunity achieved against malaria following immunization with a gene-based subunit vaccine (27%). Protection was associated with cell-mediated immunity to AMA1, with CSP probably contributing. Substituting a low seroprevalence vector for Ad5 and supplementing CSP/AMA1 with additional antigens may improve protection.
Trial registration: ClinicalTrials.govNCT00870987.
Conflict of interest statement
Competing Interests: CD and LS from USAID (funders) played a role in study design. JTB and CRK worked for Gen Vec, Inc. (financial interest in the vaccine) and helped design the vaccine constructs. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.
Figures
![Figure 1. Trial design.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3573028/bin/pone.0055571.g001.jpg)
![Figure 2. Schematic of DNA and Adenovirus…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3573028/bin/pone.0055571.g002.jpg)
![Figure 3. Flow diagram of immunized and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3573028/bin/pone.0055571.g003.jpg)
![Figure 4. Development of parasitemia in the…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3573028/bin/pone.0055571.g004.jpg)
![Figure 5. Pre-existing NAb to Ad5 may…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3573028/bin/pone.0055571.g005.jpg)
Figure 6. Antibody responses by ELISA to…
Figure 6. Antibody responses by ELISA to CSP and AMA1.
The box plots (see Statistical…
Figure 7. Ex vivo T cell IFN-γ…
Figure 7. Ex vivo T cell IFN-γ activities by ELISpot Assay for CSP and AMA1.
Figure 8. IFN-γ activities by flow cytometry…
Figure 8. IFN-γ activities by flow cytometry for CSP and AMA1.
The box plots (see…
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- A three-antigen Plasmodium falciparum DNA prime-Adenovirus boost malaria vaccine regimen is superior to a two-antigen regimen and protects against controlled human malaria infection in healthy malaria-naïve adults.Sklar MJ, Maiolatesi S, Patterson N, Sedegah M, Limbach K, Teneza-Mora N, Chuang I, Hollis-Perry KM, Banania JG, Guzman I, Ganeshan H, Reyes S, Hollingdale MR, Wong M, Lindstrom A, Reyes A, Alcorta Y, Garver L, Bankard K, Belmonte A, Belmonte M, Huang J, Gowda K, Inoue S, Velasco R, Bergmann-Leitner E, Hutter J, Lee T, Adams N, Chaudhury S, Hunt D, Tamminga C, Berrie E, Bellamy D, Bittaye M, Ewer K, Diggs C, Soisson LA, Lawrie A, Hill A, Richie TL, Villasante E, Epstein JE, Duplessis CA. Sklar MJ, et al. PLoS One. 2021 Sep 8;16(9):e0256980. doi: 10.1371/journal.pone.0256980. eCollection 2021. PLoS One. 2021. PMID: 34495988 Free PMC article. Clinical Trial.
- Sterile immunity to malaria after DNA prime/adenovirus boost immunization is associated with effector memory CD8+T cells targeting AMA1 class I epitopes.Sedegah M, Hollingdale MR, Farooq F, Ganeshan H, Belmonte M, Kim Y, Peters B, Sette A, Huang J, McGrath S, Abot E, Limbach K, Shi M, Soisson L, Diggs C, Chuang I, Tamminga C, Epstein JE, Villasante E, Richie TL. Sedegah M, et al. PLoS One. 2014 Sep 11;9(9):e106241. doi: 10.1371/journal.pone.0106241. eCollection 2014. PLoS One. 2014. PMID: 25211344 Free PMC article. Clinical Trial.
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- PMI (2011) Fifth Annual Report to Congress.
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- Clyde DF (1975) Immunization of man against falciparum and vivax malaria by use of attenuated sporozoites. Am J Trop Med Hyg 24: 397–401. - PubMed
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- Roestenberg M, McCall M, Hopman J, Wiersma J, Luty AJ, et al. (2009) Protection against a malaria challenge by sporozoite inoculation. N Engl J Med 361: 468–477. - PubMed
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- Roestenberg M, Teirlinck AC, McCall MB, Teelen K, Makamdop KN, et al. (2011) Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study. Lancet 377: 1770–1776. - PubMed
- Clinical Trial, Phase I
- Research Support, Non-U.S. Gov't
- Adenoviruses, Human / genetics*
- Adenoviruses, Human / immunology
- Adolescent
- Adult
- Antigens, Protozoan / genetics*
- Antigens, Protozoan / immunology
- CD8-Positive T-Lymphocytes / immunology
- Female
- Humans
- Immunity, Cellular
- Interferon-gamma / immunology
- Malaria Vaccines / adverse effects
- Malaria Vaccines / genetics
- Malaria Vaccines / immunology
- Malaria Vaccines / therapeutic use*
- Malaria, Falciparum / immunology
- Malaria, Falciparum / parasitology
- Malaria, Falciparum / prevention & control*
- Male
- Membrane Proteins / genetics*
- Membrane Proteins / immunology
- Middle Aged
- Plasmodium falciparum / genetics*
- Plasmodium falciparum / immunology
- Protozoan Proteins / genetics*
- Protozoan Proteins / immunology
- Vaccines, DNA / adverse effects
- Vaccines, DNA / genetics
- Vaccines, DNA / immunology
- Vaccines, DNA / therapeutic use*
- Young Adult
- Antigens, Protozoan
- Malaria Vaccines
- Membrane Proteins
- Protozoan Proteins
- Vaccines, DNA
- apical membrane antigen I, Plasmodium
- circumsporozoite protein, Protozoan
- Interferon-gamma
- ClinicalTrials.gov/NCT00870987
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
![Figure 6. Antibody responses by ELISA to…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3573028/bin/pone.0055571.g006.jpg)
Figure 7. Ex vivo T cell IFN-γ…
Figure 7. Ex vivo T cell IFN-γ activities by ELISpot Assay for CSP and AMA1.
Figure 8. IFN-γ activities by flow cytometry…
Figure 8. IFN-γ activities by flow cytometry for CSP and AMA1.
The box plots (see…
![Figure 7. Ex vivo T cell IFN-γ…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3573028/bin/pone.0055571.g007.jpg)
![Figure 8. IFN-γ activities by flow cytometry…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3573028/bin/pone.0055571.g008.jpg)
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Source: PubMed