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.

<h4>Background</h4>A DNA-prime/human adenovirus serotype 5 (HuAd5) boost vaccine encoding Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) and Pf apical membrane antigen-1 (PfAMA1), elicited protection in 4/15 (27%) of subjects against controlled human malaria infection (CHMI)...

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Autores principales:	Marvin J Sklar, Santina Maiolatesi, Noelle Patterson, Martha Sedegah, Keith Limbach, Nimfa Teneza-Mora, Ilin Chuang, K Monique Hollis-Perry, Jo Glenna Banania, Ivelese Guzman, Harini Ganeshan, Sharina Reyes, Michael R Hollingdale, Mimi Wong, Ashley Lindstrom, Anatalio Reyes, Yolanda Alcorta, Lindsey Garver, Kelli Bankard, Arnel Belmonte, Maria Belmonte, Jun Huang, Kalpana Gowda, Sandra Inoue, Rachel Velasco, Elke Bergmann-Leitner, Jack Hutter, Tida Lee, Nehkonti Adams, Sidhartha Chaudhury, Devin Hunt, Cindy Tamminga, Eleanor Berrie, Duncan Bellamy, Mustapha Bittaye, Katie Ewer, Carter Diggs, Lorraine A Soisson, Alison Lawrie, Adrian Hill, Thomas L Richie, Eileen Villasante, Judith E Epstein, Christopher A Duplessis
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4dc547617946467c9611eaa99d4458b4
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id	oai:doaj.org-article:4dc547617946467c9611eaa99d4458b4
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Marvin J Sklar Santina Maiolatesi Noelle Patterson Martha Sedegah Keith Limbach Nimfa Teneza-Mora Ilin Chuang K Monique Hollis-Perry Jo Glenna Banania Ivelese Guzman Harini Ganeshan Sharina Reyes Michael R Hollingdale Mimi Wong Ashley Lindstrom Anatalio Reyes Yolanda Alcorta Lindsey Garver Kelli Bankard Arnel Belmonte Maria Belmonte Jun Huang Kalpana Gowda Sandra Inoue Rachel Velasco Elke Bergmann-Leitner Jack Hutter Tida Lee Nehkonti Adams Sidhartha Chaudhury Devin Hunt Cindy Tamminga Eleanor Berrie Duncan Bellamy Mustapha Bittaye Katie Ewer Carter Diggs Lorraine A Soisson Alison Lawrie Adrian Hill Thomas L Richie Eileen Villasante Judith E Epstein Christopher A Duplessis 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.
description	<h4>Background</h4>A DNA-prime/human adenovirus serotype 5 (HuAd5) boost vaccine encoding Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) and Pf apical membrane antigen-1 (PfAMA1), elicited protection in 4/15 (27%) of subjects against controlled human malaria infection (CHMI) that was statistically associated with CD8+ T cell responses. Subjects with high level pre-existing immunity to HuAd5 were not protected, suggesting an adverse effect on vaccine efficacy (VE). We replaced HuAd5 with chimpanzee adenovirus 63 (ChAd63), and repeated the study, assessing both the two-antigen (CSP, AMA1 = CA) vaccine, and a novel three-antigen (CSP, AMA1, ME-TRAP = CAT) vaccine that included a third pre-erythrocytic stage antigen [malaria multiple epitopes (ME) fused to the Pf thrombospondin-related adhesive protein (TRAP)] to potentially enhance protection.<h4>Methodology</h4>This was an open label, randomized Phase 1 trial, assessing safety, tolerability, and VE against CHMI in healthy, malaria naïve adults. Forty subjects (20 each group) were to receive three monthly CA or CAT DNA priming immunizations, followed by corresponding ChAd63 boost four months later. Four weeks after the boost, immunized subjects and 12 infectivity controls underwent CHMI by mosquito bite using the Pf3D7 strain. VE was assessed by determining the differences in time to parasitemia as detected by thick blood smears up to 28-days post CHMI and utilizing the log rank test, and by calculating the risk ratio of each treatment group and subtracting from 1, with significance calculated by the Cochran-Mantel-Haenszel method.<h4>Results</h4>In both groups, systemic adverse events (AEs) were significantly higher after the ChAd63 boost than DNA immunizations. Eleven of 12 infectivity controls developed parasitemia (mean 11.7 days). In the CA group, 15 of 16 (93.8%) immunized subjects developed parasitemia (mean 12.0 days). In the CAT group, 11 of 16 (63.8%) immunized subjects developed parasitemia (mean 13.0 days), indicating significant protection by log rank test compared to infectivity controls (p = 0.0406) and the CA group (p = 0.0229). VE (1 minus the risk ratio) in the CAT group was 25% compared to -2% in the CA group. The CA and CAT vaccines induced robust humoral (ELISA antibodies against CSP, AMA1 and TRAP, and IFA responses against sporozoites and Pf3D7 blood stages), and cellular responses (IFN-γ FluoroSpot responses to CSP, AMA1 and TRAP) that were not associated with protection.<h4>Conclusions</h4>This study demonstrated that the ChAd63 CAT vaccine exhibited significant protective efficacy, and confirmed protection was afforded by adding a third antigen (T) to a two-antigen (CA) formulation to achieve increased VE. Although the ChAd63-CAT vaccine was associated with increased frequencies of systemic AEs compared to the CA vaccine and, historically, compared to the HuAd5 vectored malaria vaccine encoding CSP and AMA1, they were transient and associated with increased vector dosing.
format	article
author	Marvin J Sklar Santina Maiolatesi Noelle Patterson Martha Sedegah Keith Limbach Nimfa Teneza-Mora Ilin Chuang K Monique Hollis-Perry Jo Glenna Banania Ivelese Guzman Harini Ganeshan Sharina Reyes Michael R Hollingdale Mimi Wong Ashley Lindstrom Anatalio Reyes Yolanda Alcorta Lindsey Garver Kelli Bankard Arnel Belmonte Maria Belmonte Jun Huang Kalpana Gowda Sandra Inoue Rachel Velasco Elke Bergmann-Leitner Jack Hutter Tida Lee Nehkonti Adams Sidhartha Chaudhury Devin Hunt Cindy Tamminga Eleanor Berrie Duncan Bellamy Mustapha Bittaye Katie Ewer Carter Diggs Lorraine A Soisson Alison Lawrie Adrian Hill Thomas L Richie Eileen Villasante Judith E Epstein Christopher A Duplessis
author_facet	Marvin J Sklar Santina Maiolatesi Noelle Patterson Martha Sedegah Keith Limbach Nimfa Teneza-Mora Ilin Chuang K Monique Hollis-Perry Jo Glenna Banania Ivelese Guzman Harini Ganeshan Sharina Reyes Michael R Hollingdale Mimi Wong Ashley Lindstrom Anatalio Reyes Yolanda Alcorta Lindsey Garver Kelli Bankard Arnel Belmonte Maria Belmonte Jun Huang Kalpana Gowda Sandra Inoue Rachel Velasco Elke Bergmann-Leitner Jack Hutter Tida Lee Nehkonti Adams Sidhartha Chaudhury Devin Hunt Cindy Tamminga Eleanor Berrie Duncan Bellamy Mustapha Bittaye Katie Ewer Carter Diggs Lorraine A Soisson Alison Lawrie Adrian Hill Thomas L Richie Eileen Villasante Judith E Epstein Christopher A Duplessis
author_sort	Marvin J Sklar
title	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.
title_short	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.
title_full	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.
title_fullStr	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.
title_full_unstemmed	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.
title_sort	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.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/4dc547617946467c9611eaa99d4458b4
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spelling	oai:doaj.org-article:4dc547617946467c9611eaa99d4458b42021-12-02T20:14:46ZA 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.1932-620310.1371/journal.pone.0256980https://doaj.org/article/4dc547617946467c9611eaa99d4458b42021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0256980https://doaj.org/toc/1932-6203<h4>Background</h4>A DNA-prime/human adenovirus serotype 5 (HuAd5) boost vaccine encoding Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) and Pf apical membrane antigen-1 (PfAMA1), elicited protection in 4/15 (27%) of subjects against controlled human malaria infection (CHMI) that was statistically associated with CD8+ T cell responses. Subjects with high level pre-existing immunity to HuAd5 were not protected, suggesting an adverse effect on vaccine efficacy (VE). We replaced HuAd5 with chimpanzee adenovirus 63 (ChAd63), and repeated the study, assessing both the two-antigen (CSP, AMA1 = CA) vaccine, and a novel three-antigen (CSP, AMA1, ME-TRAP = CAT) vaccine that included a third pre-erythrocytic stage antigen [malaria multiple epitopes (ME) fused to the Pf thrombospondin-related adhesive protein (TRAP)] to potentially enhance protection.<h4>Methodology</h4>This was an open label, randomized Phase 1 trial, assessing safety, tolerability, and VE against CHMI in healthy, malaria naïve adults. Forty subjects (20 each group) were to receive three monthly CA or CAT DNA priming immunizations, followed by corresponding ChAd63 boost four months later. Four weeks after the boost, immunized subjects and 12 infectivity controls underwent CHMI by mosquito bite using the Pf3D7 strain. VE was assessed by determining the differences in time to parasitemia as detected by thick blood smears up to 28-days post CHMI and utilizing the log rank test, and by calculating the risk ratio of each treatment group and subtracting from 1, with significance calculated by the Cochran-Mantel-Haenszel method.<h4>Results</h4>In both groups, systemic adverse events (AEs) were significantly higher after the ChAd63 boost than DNA immunizations. Eleven of 12 infectivity controls developed parasitemia (mean 11.7 days). In the CA group, 15 of 16 (93.8%) immunized subjects developed parasitemia (mean 12.0 days). In the CAT group, 11 of 16 (63.8%) immunized subjects developed parasitemia (mean 13.0 days), indicating significant protection by log rank test compared to infectivity controls (p = 0.0406) and the CA group (p = 0.0229). VE (1 minus the risk ratio) in the CAT group was 25% compared to -2% in the CA group. The CA and CAT vaccines induced robust humoral (ELISA antibodies against CSP, AMA1 and TRAP, and IFA responses against sporozoites and Pf3D7 blood stages), and cellular responses (IFN-γ FluoroSpot responses to CSP, AMA1 and TRAP) that were not associated with protection.<h4>Conclusions</h4>This study demonstrated that the ChAd63 CAT vaccine exhibited significant protective efficacy, and confirmed protection was afforded by adding a third antigen (T) to a two-antigen (CA) formulation to achieve increased VE. Although the ChAd63-CAT vaccine was associated with increased frequencies of systemic AEs compared to the CA vaccine and, historically, compared to the HuAd5 vectored malaria vaccine encoding CSP and AMA1, they were transient and associated with increased vector dosing.Marvin J SklarSantina MaiolatesiNoelle PattersonMartha SedegahKeith LimbachNimfa Teneza-MoraIlin ChuangK Monique Hollis-PerryJo Glenna BananiaIvelese GuzmanHarini GaneshanSharina ReyesMichael R HollingdaleMimi WongAshley LindstromAnatalio ReyesYolanda AlcortaLindsey GarverKelli BankardArnel BelmonteMaria BelmonteJun HuangKalpana GowdaSandra InoueRachel VelascoElke Bergmann-LeitnerJack HutterTida LeeNehkonti AdamsSidhartha ChaudhuryDevin HuntCindy TammingaEleanor BerrieDuncan BellamyMustapha BittayeKatie EwerCarter DiggsLorraine A SoissonAlison LawrieAdrian HillThomas L RichieEileen VillasanteJudith E EpsteinChristopher A DuplessisPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 9, p e0256980 (2021)

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.

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