First-in-human, randomized, double-blind clinical trial of differentially adjuvanted PAMVAC, a vaccine candidate to prevent pregnancy-associated malaria

Benjamin Mordmüller; Mihály Sulyok; Diane Egger-Adam; Mafalda Resende; Willem A de Jongh; Mette H. Jensen; Helle Holm Smedegaard; Sisse B Ditlev; Max Soegaard; Lars Poulsen; Charlotte Dyring; Carlos Lamsfus Calle; Annette Knoblich; Javier Ibáñez; Meral Esen; Philippe Deloron; Nicaise Ndam; Saadou Issifou; Sophie Houard; Randall F Howard; Steven G Reed; Odile Leroy; Adrian J F Luty; Thor G Theander; Peter G Kremsner; Ali Salanti; Morten A Nielsen

doi:10.1093/cid/ciy1140

First-in-human, randomized, double-blind clinical trial of differentially adjuvanted PAMVAC, a vaccine candidate to prevent pregnancy-associated malaria

Benjamin Mordmüller, Mihály Sulyok, Diane Egger-Adam, Mafalda Resende, Willem A de Jongh, Mette H. Jensen, Helle Holm Smedegaard, Sisse B Ditlev, Max Soegaard, Lars Poulsen, Charlotte Dyring, Carlos Lamsfus Calle, Annette Knoblich, Javier Ibáñez, Meral Esen, Philippe Deloron, Nicaise Ndam, Saadou Issifou, Sophie Houard, Randall F HowardSteven G Reed, Odile Leroy, Adrian J F Luty, Thor G Theander, Peter G Kremsner, Ali Salanti, Morten A Nielsen

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

BACKGROUND: Malaria in pregnancy has major impacts on mother and child health. To complement existing interventions, such as intermittent preventive treatment and use of impregnated bed nets, we developed a malaria vaccine candidate with the aim of reducing sequestration of asexual "blood-stage" parasites in the placenta, the major virulence mechanism.

METHODS: The vaccine candidate PAMVAC is based on a recombinant fragment of VAR2CSA, the Plasmodium falciparum protein responsible for binding to the placenta via chondroitin sulfate A (CSA). Healthy, adult malaria-naive volunteers were immunized with 3 intramuscular injections of 20 μg (n = 9) or 50 μg (n = 27) PAMVAC, adjuvanted with Alhydrogel or glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE) or in a liposomal formulation with QS21 (GLA-LSQ). Allocation was random and double blind. The vaccine was given every 4 weeks. Volunteers were observed for 6 months following last immunization.

RESULTS: All PAMVAC formulations were safe and well tolerated. A total of 262 adverse events (AEs) occurred, 94 (10 grade 2 and 2 grade 3) at least possibly related to the vaccine. No serious AEs occurred. Distribution and severity of AEs were similar in all arms. PAMVAC was immunogenic in all participants. PAMVAC-specific antibody levels were highest with PAMVAC-GLA-SE. The antibodies inhibited binding of VAR2CSA expressing P. falciparum-infected erythrocytes to CSA in a standardized functional assay.

CONCLUSIONS: PAMVAC formulated with Alhydrogel or GLA-based adjuvants was safe, well tolerated, and induced functionally active antibodies. Next, PAMVAC will be assessed in women before first pregnancies in an endemic area.

CLINICAL TRIALS REGISTRATION: EudraCT 2015-001827-21; ClinicalTrials.gov NCT02647489.

Original language	English
Journal	Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
Volume	69
Issue number	9
Pages (from-to)	1509-1516
Number of pages	8
ISSN	1058-4838
DOIs	https://doi.org/10.1093/cid/ciy1140
Publication status	Published - 2019

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First-in-human, Randomized, Double-blind Clinical Trial of Differentially Adjuvanted PAMVAC, A Vaccine Candidate to Prevent Pregnancy-associated MalariaFinal published version, 2.1 MBLicence: CC BY

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Mordmüller, B., Sulyok, M., Egger-Adam, D., Resende, M., de Jongh, W. A., Jensen, M. H., Smedegaard, H. H., Ditlev, S. B., Soegaard, M., Poulsen, L., Dyring, C., Calle, C. L., Knoblich, A., Ibáñez, J., Esen, M., Deloron, P., Ndam, N., Issifou, S., Houard, S., ... Nielsen, M. A. (2019). First-in-human, randomized, double-blind clinical trial of differentially adjuvanted PAMVAC, a vaccine candidate to prevent pregnancy-associated malaria. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 69(9), 1509-1516. https://doi.org/10.1093/cid/ciy1140

First-in-human, randomized, double-blind clinical trial of differentially adjuvanted PAMVAC, a vaccine candidate to prevent pregnancy-associated malaria. / Mordmüller, Benjamin; Sulyok, Mihály; Egger-Adam, Diane; Resende, Mafalda; de Jongh, Willem A; Jensen, Mette H.; Smedegaard, Helle Holm; Ditlev, Sisse B; Soegaard, Max; Poulsen, Lars; Dyring, Charlotte; Calle, Carlos Lamsfus; Knoblich, Annette; Ibáñez, Javier; Esen, Meral; Deloron, Philippe; Ndam, Nicaise; Issifou, Saadou; Houard, Sophie; Howard, Randall F; Reed, Steven G; Leroy, Odile; Luty, Adrian J F; Theander, Thor G; Kremsner, Peter G; Salanti, Ali ; Nielsen, Morten A.

In: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Vol. 69, No. 9, 2019, p. 1509-1516.

Research output: Contribution to journal › Journal article › Research › peer-review

Mordmüller, B, Sulyok, M, Egger-Adam, D, Resende, M, de Jongh, WA, Jensen, MH, Smedegaard, HH, Ditlev, SB, Soegaard, M, Poulsen, L, Dyring, C, Calle, CL, Knoblich, A, Ibáñez, J, Esen, M, Deloron, P, Ndam, N, Issifou, S, Houard, S, Howard, RF, Reed, SG, Leroy, O, Luty, AJF, Theander, TG, Kremsner, PG, Salanti, A & Nielsen, MA 2019, 'First-in-human, randomized, double-blind clinical trial of differentially adjuvanted PAMVAC, a vaccine candidate to prevent pregnancy-associated malaria', Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, vol. 69, no. 9, pp. 1509-1516. https://doi.org/10.1093/cid/ciy1140

Mordmüller B, Sulyok M, Egger-Adam D, Resende M, de Jongh WA, Jensen MH et al. First-in-human, randomized, double-blind clinical trial of differentially adjuvanted PAMVAC, a vaccine candidate to prevent pregnancy-associated malaria. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019;69(9):1509-1516. https://doi.org/10.1093/cid/ciy1140

Mordmüller, Benjamin ; Sulyok, Mihály ; Egger-Adam, Diane ; Resende, Mafalda ; de Jongh, Willem A ; Jensen, Mette H. ; Smedegaard, Helle Holm ; Ditlev, Sisse B ; Soegaard, Max ; Poulsen, Lars ; Dyring, Charlotte ; Calle, Carlos Lamsfus ; Knoblich, Annette ; Ibáñez, Javier ; Esen, Meral ; Deloron, Philippe ; Ndam, Nicaise ; Issifou, Saadou ; Houard, Sophie ; Howard, Randall F ; Reed, Steven G ; Leroy, Odile ; Luty, Adrian J F ; Theander, Thor G ; Kremsner, Peter G ; Salanti, Ali ; Nielsen, Morten A. / First-in-human, randomized, double-blind clinical trial of differentially adjuvanted PAMVAC, a vaccine candidate to prevent pregnancy-associated malaria. In: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019 ; Vol. 69, No. 9. pp. 1509-1516.

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title = "First-in-human, randomized, double-blind clinical trial of differentially adjuvanted PAMVAC, a vaccine candidate to prevent pregnancy-associated malaria",

abstract = "BACKGROUND: Malaria in pregnancy has major impacts on mother and child health. To complement existing interventions, such as intermittent preventive treatment and use of impregnated bed nets, we developed a malaria vaccine candidate with the aim of reducing sequestration of asexual {"}blood-stage{"} parasites in the placenta, the major virulence mechanism.METHODS: The vaccine candidate PAMVAC is based on a recombinant fragment of VAR2CSA, the Plasmodium falciparum protein responsible for binding to the placenta via chondroitin sulfate A (CSA). Healthy, adult malaria-naive volunteers were immunized with 3 intramuscular injections of 20 μg (n = 9) or 50 μg (n = 27) PAMVAC, adjuvanted with Alhydrogel or glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE) or in a liposomal formulation with QS21 (GLA-LSQ). Allocation was random and double blind. The vaccine was given every 4 weeks. Volunteers were observed for 6 months following last immunization.RESULTS: All PAMVAC formulations were safe and well tolerated. A total of 262 adverse events (AEs) occurred, 94 (10 grade 2 and 2 grade 3) at least possibly related to the vaccine. No serious AEs occurred. Distribution and severity of AEs were similar in all arms. PAMVAC was immunogenic in all participants. PAMVAC-specific antibody levels were highest with PAMVAC-GLA-SE. The antibodies inhibited binding of VAR2CSA expressing P. falciparum-infected erythrocytes to CSA in a standardized functional assay.CONCLUSIONS: PAMVAC formulated with Alhydrogel or GLA-based adjuvants was safe, well tolerated, and induced functionally active antibodies. Next, PAMVAC will be assessed in women before first pregnancies in an endemic area.CLINICAL TRIALS REGISTRATION: EudraCT 2015-001827-21; ClinicalTrials.gov NCT02647489.",

author = "Benjamin Mordm{\"u}ller and Mih{\'a}ly Sulyok and Diane Egger-Adam and Mafalda Resende and {de Jongh}, {Willem A} and Jensen, {Mette H.} and Smedegaard, {Helle Holm} and Ditlev, {Sisse B} and Max Soegaard and Lars Poulsen and Charlotte Dyring and Calle, {Carlos Lamsfus} and Annette Knoblich and Javier Ib{\'a}{\~n}ez and Meral Esen and Philippe Deloron and Nicaise Ndam and Saadou Issifou and Sophie Houard and Howard, {Randall F} and Reed, {Steven G} and Odile Leroy and Luty, {Adrian J F} and Theander, {Thor G} and Kremsner, {Peter G} and Ali Salanti and Nielsen, {Morten A}",

note = "{\textcopyright} The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.",

year = "2019",

doi = "10.1093/cid/ciy1140",

language = "English",

volume = "69",

pages = "1509--1516",

journal = "Clinical Infectious Diseases",

issn = "1058-4838",

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TY - JOUR

T1 - First-in-human, randomized, double-blind clinical trial of differentially adjuvanted PAMVAC, a vaccine candidate to prevent pregnancy-associated malaria

AU - Mordmüller, Benjamin

AU - Sulyok, Mihály

AU - Egger-Adam, Diane

AU - Resende, Mafalda

AU - de Jongh, Willem A

AU - Jensen, Mette H.

AU - Smedegaard, Helle Holm

AU - Ditlev, Sisse B

AU - Soegaard, Max

AU - Poulsen, Lars

AU - Dyring, Charlotte

AU - Calle, Carlos Lamsfus

AU - Knoblich, Annette

AU - Ibáñez, Javier

AU - Esen, Meral

AU - Deloron, Philippe

AU - Ndam, Nicaise

AU - Issifou, Saadou

AU - Houard, Sophie

AU - Howard, Randall F

AU - Reed, Steven G

AU - Leroy, Odile

AU - Luty, Adrian J F

AU - Theander, Thor G

AU - Kremsner, Peter G

AU - Salanti, Ali

AU - Nielsen, Morten A

PY - 2019

Y1 - 2019

N2 - BACKGROUND: Malaria in pregnancy has major impacts on mother and child health. To complement existing interventions, such as intermittent preventive treatment and use of impregnated bed nets, we developed a malaria vaccine candidate with the aim of reducing sequestration of asexual "blood-stage" parasites in the placenta, the major virulence mechanism.METHODS: The vaccine candidate PAMVAC is based on a recombinant fragment of VAR2CSA, the Plasmodium falciparum protein responsible for binding to the placenta via chondroitin sulfate A (CSA). Healthy, adult malaria-naive volunteers were immunized with 3 intramuscular injections of 20 μg (n = 9) or 50 μg (n = 27) PAMVAC, adjuvanted with Alhydrogel or glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE) or in a liposomal formulation with QS21 (GLA-LSQ). Allocation was random and double blind. The vaccine was given every 4 weeks. Volunteers were observed for 6 months following last immunization.RESULTS: All PAMVAC formulations were safe and well tolerated. A total of 262 adverse events (AEs) occurred, 94 (10 grade 2 and 2 grade 3) at least possibly related to the vaccine. No serious AEs occurred. Distribution and severity of AEs were similar in all arms. PAMVAC was immunogenic in all participants. PAMVAC-specific antibody levels were highest with PAMVAC-GLA-SE. The antibodies inhibited binding of VAR2CSA expressing P. falciparum-infected erythrocytes to CSA in a standardized functional assay.CONCLUSIONS: PAMVAC formulated with Alhydrogel or GLA-based adjuvants was safe, well tolerated, and induced functionally active antibodies. Next, PAMVAC will be assessed in women before first pregnancies in an endemic area.CLINICAL TRIALS REGISTRATION: EudraCT 2015-001827-21; ClinicalTrials.gov NCT02647489.

AB - BACKGROUND: Malaria in pregnancy has major impacts on mother and child health. To complement existing interventions, such as intermittent preventive treatment and use of impregnated bed nets, we developed a malaria vaccine candidate with the aim of reducing sequestration of asexual "blood-stage" parasites in the placenta, the major virulence mechanism.METHODS: The vaccine candidate PAMVAC is based on a recombinant fragment of VAR2CSA, the Plasmodium falciparum protein responsible for binding to the placenta via chondroitin sulfate A (CSA). Healthy, adult malaria-naive volunteers were immunized with 3 intramuscular injections of 20 μg (n = 9) or 50 μg (n = 27) PAMVAC, adjuvanted with Alhydrogel or glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE) or in a liposomal formulation with QS21 (GLA-LSQ). Allocation was random and double blind. The vaccine was given every 4 weeks. Volunteers were observed for 6 months following last immunization.RESULTS: All PAMVAC formulations were safe and well tolerated. A total of 262 adverse events (AEs) occurred, 94 (10 grade 2 and 2 grade 3) at least possibly related to the vaccine. No serious AEs occurred. Distribution and severity of AEs were similar in all arms. PAMVAC was immunogenic in all participants. PAMVAC-specific antibody levels were highest with PAMVAC-GLA-SE. The antibodies inhibited binding of VAR2CSA expressing P. falciparum-infected erythrocytes to CSA in a standardized functional assay.CONCLUSIONS: PAMVAC formulated with Alhydrogel or GLA-based adjuvants was safe, well tolerated, and induced functionally active antibodies. Next, PAMVAC will be assessed in women before first pregnancies in an endemic area.CLINICAL TRIALS REGISTRATION: EudraCT 2015-001827-21; ClinicalTrials.gov NCT02647489.

U2 - 10.1093/cid/ciy1140

DO - 10.1093/cid/ciy1140

M3 - Journal article

C2 - 30629148

VL - 69

SP - 1509

EP - 1516

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

SN - 1058-4838

IS - 9

ER -