PMID- 34495988
OWN - NLM
STAT- MEDLINE
DCOM- 20211122
LR  - 20211122
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 16
IP  - 9
DP  - 2021
TI  - 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-naive adults.
PG  - e0256980
LID - 10.1371/journal.pone.0256980 [doi]
LID - e0256980
AB  - BACKGROUND: 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. METHODOLOGY: This was an open label, randomized Phase 1 trial, 
      assessing safety, tolerability, and VE against CHMI in healthy, malaria naive 
      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. RESULTS: 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-gamma 
      FluoroSpot responses to CSP, AMA1 and TRAP) that were not associated with 
      protection. CONCLUSIONS: 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.
FAU - Sklar, Marvin J
AU  - Sklar MJ
AUID- ORCID: 0000-0003-4109-8924
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
FAU - Maiolatesi, Santina
AU  - Maiolatesi S
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
AD  - Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.
FAU - Patterson, Noelle
AU  - Patterson N
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
AD  - Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.
FAU - Sedegah, Martha
AU  - Sedegah M
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
FAU - Limbach, Keith
AU  - Limbach K
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
AD  - Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.
FAU - Teneza-Mora, Nimfa
AU  - Teneza-Mora N
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
FAU - Chuang, Ilin
AU  - Chuang I
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
FAU - Hollis-Perry, K Monique
AU  - Hollis-Perry KM
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
FAU - Banania, Jo Glenna
AU  - Banania JG
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
AD  - Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.
FAU - Guzman, Ivelese
AU  - Guzman I
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
AD  - Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.
FAU - Ganeshan, Harini
AU  - Ganeshan H
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
AD  - Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.
FAU - Reyes, Sharina
AU  - Reyes S
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
AD  - Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.
FAU - Hollingdale, Michael R
AU  - Hollingdale MR
AUID- ORCID: 0000-0002-2343-3824
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
AD  - Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.
FAU - Wong, Mimi
AU  - Wong M
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
AD  - Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.
FAU - Lindstrom, Ashley
AU  - Lindstrom A
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
FAU - Reyes, Anatalio
AU  - Reyes A
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
AD  - Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.
FAU - Alcorta, Yolanda
AU  - Alcorta Y
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
AD  - Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.
FAU - Garver, Lindsey
AU  - Garver L
AD  - Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of 
      America.
FAU - Bankard, Kelli
AU  - Bankard K
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
AD  - Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.
FAU - Belmonte, Arnel
AU  - Belmonte A
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
AD  - Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.
FAU - Belmonte, Maria
AU  - Belmonte M
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
AD  - Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.
FAU - Huang, Jun
AU  - Huang J
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
AD  - Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.
FAU - Gowda, Kalpana
AU  - Gowda K
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
FAU - Inoue, Sandra
AU  - Inoue S
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
AD  - Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.
FAU - Velasco, Rachel
AU  - Velasco R
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
AD  - Henry M. Jackson Foundation, Bethesda, Maryland, United States of America.
FAU - Bergmann-Leitner, Elke
AU  - Bergmann-Leitner E
AD  - Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of 
      America.
FAU - Hutter, Jack
AU  - Hutter J
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
FAU - Lee, Tida
AU  - Lee T
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
FAU - Adams, Nehkonti
AU  - Adams N
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
FAU - Chaudhury, Sidhartha
AU  - Chaudhury S
AD  - Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of 
      America.
FAU - Hunt, Devin
AU  - Hunt D
AD  - Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of 
      America.
FAU - Tamminga, Cindy
AU  - Tamminga C
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
FAU - Berrie, Eleanor
AU  - Berrie E
AD  - University of Oxford, Oxford, United Kingdom.
FAU - Bellamy, Duncan
AU  - Bellamy D
AD  - University of Oxford, Oxford, United Kingdom.
FAU - Bittaye, Mustapha
AU  - Bittaye M
AD  - University of Oxford, Oxford, United Kingdom.
FAU - Ewer, Katie
AU  - Ewer K
AUID- ORCID: 0000-0001-9827-9836
AD  - University of Oxford, Oxford, United Kingdom.
FAU - Diggs, Carter
AU  - Diggs C
AD  - United States Agency for International Development (USAID), Washington, DC, 
      United States of America.
FAU - Soisson, Lorraine A
AU  - Soisson LA
AD  - United States Agency for International Development (USAID), Washington, DC, 
      United States of America.
FAU - Lawrie, Alison
AU  - Lawrie A
AD  - University of Oxford, Oxford, United Kingdom.
FAU - Hill, Adrian
AU  - Hill A
AD  - University of Oxford, Oxford, United Kingdom.
FAU - Richie, Thomas L
AU  - Richie TL
AD  - Naval Medical Research Center, Malaria Department, Silver Spring, Maryland, 
      United States of America.
FAU - Villasante, Eileen
AU  - Villasante E
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
FAU - Epstein, Judith E
AU  - Epstein JE
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
FAU - Duplessis, Christopher A
AU  - Duplessis CA
AD  - Naval Medical Research Center, Silver Spring, Maryland, United States of America.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20210908
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Adenovirus Vaccines)
RN  - 0 (Antigens, Protozoan)
RN  - 0 (DNA, Protozoan)
RN  - 0 (DNA, Recombinant)
RN  - 0 (Epitopes)
RN  - 0 (Malaria Vaccines)
RN  - 0 (Membrane Proteins)
RN  - 0 (Protozoan Proteins)
RN  - 0 (Vaccines, DNA)
RN  - 0 (apical membrane antigen I, Plasmodium)
RN  - 0 (circumsporozoite protein, Protozoan)
RN  - 120300-02-9 (thrombospondin-related adhesive protein, protozoan)
SB  - IM
MH  - Adenovirus Vaccines/administration & dosage/adverse effects/*immunology
MH  - Adenoviruses, Simian/genetics/*immunology
MH  - Adult
MH  - Antigens, Protozoan/genetics/*immunology
MH  - CD8-Positive T-Lymphocytes/immunology
MH  - DNA, Protozoan/genetics/*immunology
MH  - DNA, Recombinant/*immunology
MH  - Epitopes/genetics/immunology
MH  - Female
MH  - Genetic Vectors/administration & dosage/immunology
MH  - Healthy Volunteers
MH  - Humans
MH  - Immunization, Secondary/*methods
MH  - Immunogenicity, Vaccine/immunology
MH  - Malaria Vaccines/administration & dosage/adverse effects/*immunology
MH  - Malaria, Falciparum/immunology/parasitology/*prevention & control
MH  - Male
MH  - Membrane Proteins/genetics/*immunology
MH  - Plasmodium falciparum/*immunology
MH  - Protozoan Proteins/genetics/*immunology
MH  - Treatment Outcome
MH  - Vaccines, DNA/administration & dosage/adverse effects/*immunology
MH  - Young Adult
PMC - PMC8425539
COIS- The authors have declared that no competing interests exist. This does not alter 
      our adherence to PLOS ONE policies on sharing data and materials.
EDAT- 2021/09/09 06:00
MHDA- 2021/11/23 06:00
PMCR- 2021/09/08
CRDT- 2021/09/08 17:26
PHST- 2021/03/17 00:00 [received]
PHST- 2021/08/15 00:00 [accepted]
PHST- 2021/09/08 17:26 [entrez]
PHST- 2021/09/09 06:00 [pubmed]
PHST- 2021/11/23 06:00 [medline]
PHST- 2021/09/08 00:00 [pmc-release]
AID - PONE-D-21-08843 [pii]
AID - 10.1371/journal.pone.0256980 [doi]
PST - epublish
SO  - PLoS One. 2021 Sep 8;16(9):e0256980. doi: 10.1371/journal.pone.0256980. 
      eCollection 2021.